JPH03188080A - Pyridonecarboxylic acid derivative - Google Patents
Pyridonecarboxylic acid derivativeInfo
- Publication number
- JPH03188080A JPH03188080A JP1325183A JP32518389A JPH03188080A JP H03188080 A JPH03188080 A JP H03188080A JP 1325183 A JP1325183 A JP 1325183A JP 32518389 A JP32518389 A JP 32518389A JP H03188080 A JPH03188080 A JP H03188080A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- diazabicyclo
- oxa
- compound
- 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.)
- Pending
Links
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 81
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 15
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 13
- 125000006239 protecting group Chemical group 0.000 claims abstract description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 6
- -1 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(tran s-2-oxa-5,8-diazabicyclo[4.3.0 ]nonan-8-yl)-4-oxo-3-quinolinecarboxylic acid Chemical compound 0.000 claims description 61
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 125000004122 cyclic group Chemical group 0.000 claims description 17
- 150000002148 esters Chemical class 0.000 claims description 11
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- KJMDWKUAJVIUFV-UONOGXRCSA-N 7-[(4as,7ar)-3,4,4a,5,7,7a-hexahydro-2h-pyrrolo[3,4-b][1,4]oxazin-6-yl]-1-cyclopropyl-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(F)C(N3C[C@H]4OCCN[C@H]4C3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 KJMDWKUAJVIUFV-UONOGXRCSA-N 0.000 claims 1
- GVTGCNMIJGKIAY-WMLDXEAASA-N 7-[(4as,7ar)-3,4,4a,5,7,7a-hexahydro-2h-pyrrolo[3,4-b][1,4]oxazin-6-yl]-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(N3C[C@H]4OCCN[C@H]4C3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 GVTGCNMIJGKIAY-WMLDXEAASA-N 0.000 claims 1
- KJMDWKUAJVIUFV-ZIAGYGMSSA-N C12=C(F)C(N3C[C@H]4OCCN[C@@H]4C3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 Chemical compound C12=C(F)C(N3C[C@H]4OCCN[C@@H]4C3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 KJMDWKUAJVIUFV-ZIAGYGMSSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 17
- 241000894006 Bacteria Species 0.000 abstract description 15
- 238000002360 preparation method Methods 0.000 abstract description 5
- 239000012442 inert solvent Substances 0.000 abstract description 4
- 241000192125 Firmicutes Species 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 24
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- 230000000844 anti-bacterial effect Effects 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- ULJQCMWYUDGYLB-HUUCEWRRSA-N C(C1=CC=CC=C1)N1[C@H]2[C@H](OCC1=O)CN(C2)C(=O)OC(C)(C)C Chemical compound C(C1=CC=CC=C1)N1[C@H]2[C@H](OCC1=O)CN(C2)C(=O)OC(C)(C)C ULJQCMWYUDGYLB-HUUCEWRRSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229960001866 silicon dioxide Drugs 0.000 description 4
- NXZIGGBPLGAPTI-UHFFFAOYSA-N tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC2OC21 NXZIGGBPLGAPTI-UHFFFAOYSA-N 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical group N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229960003085 meticillin Drugs 0.000 description 3
- 125000005633 phthalidyl group Chemical group 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- APCBTRDHCDOPNY-UHFFFAOYSA-N tert-butyl 3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)C1 APCBTRDHCDOPNY-UHFFFAOYSA-N 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 3
- UMIZTIYZNFUATK-PHDIDXHHSA-N (4ar,7ar)-2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazine Chemical compound O1CCN[C@@H]2CNC[C@H]21 UMIZTIYZNFUATK-PHDIDXHHSA-N 0.000 description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000005205 alkoxycarbonyloxyalkyl group Chemical group 0.000 description 2
- 125000005103 alkyl silyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid 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
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 229960001180 norfloxacin Drugs 0.000 description 2
- 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 2
- 229960001699 ofloxacin Drugs 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 229940072132 quinolone antibacterials Drugs 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 2
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 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
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 229960004016 sucrose syrup Drugs 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- CEDVAXOUBFPERN-HZPDHXFCSA-N tert-butyl (4aR,7aR)-4-benzyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxylate Chemical group CC(C)(C)OC(=O)N1C[C@H]2OCCN(Cc3ccccc3)[C@@H]2C1 CEDVAXOUBFPERN-HZPDHXFCSA-N 0.000 description 1
- AUXXIKSVHUSTOA-RKDXNWHRSA-N tert-butyl (4ar,7ar)-3,4,4a,5,7,7a-hexahydro-2h-pyrrolo[3,4-b][1,4]oxazine-6-carboxylate Chemical compound N1CCO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]21 AUXXIKSVHUSTOA-RKDXNWHRSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
り策上立且里豆!
本発明は、新規なピリドンカルボン酸誘導体、その製法
および該誘導体を有効成分とする抗菌剤に関する。[Detailed Description of the Invention] Risaku Tadashi Bean! The present invention relates to a novel pyridonecarboxylic acid derivative, a method for producing the same, and an antibacterial agent containing the derivative as an active ingredient.
従来技亘
近年開発されたキノロン系合成抗菌剤、例えばノルフロ
キサシン、オフロキサシン、シプロフロキサシン等の1
.4−ジヒドロ−4−オキソ−3−キノリンカルボン酸
誘導体は、ダラム陰性菌およびダラム陽性菌に対して幅
広いスペクトルと優れた抗菌力を有し、感染症の治療薬
として臨床に汎用されていキノロン系合成抗菌剤は、キ
ノロンカルボン酸骨格の7位にピペラジニル基またはピ
ロリジニル基を有するものが多く、ピロリジニル基にモ
ルホリン環が縮合した一般式
[式中、R2は水素原子または直鎖状、分岐状もしくは
環状の低級アルキル基を示す]で表される2−オキサ−
5,8−ジアザビシクロ[4,3,0]ノナン−8−イ
ル基を有するピリドンカルボン酸は、文献未記載の新規
化合物であり、文献および特許出願明細書にも全く開示
されず、また示唆すらされていない。Prior art quinolone synthetic antibacterial agents developed in recent years, such as norfloxacin, ofloxacin, ciprofloxacin, etc.
.. 4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives have a broad spectrum and excellent antibacterial activity against Durum-negative and Durum-positive bacteria, and are widely used clinically as therapeutic agents for infectious diseases. Synthetic antibacterial agents often have a piperazinyl group or pyrrolidinyl group at the 7-position of the quinolone carboxylic acid skeleton, and have a general formula in which a morpholine ring is fused to a pyrrolidinyl group [wherein R2 is a hydrogen atom or a linear, branched or 2-oxa-, which represents a cyclic lower alkyl group]
Pyridonecarboxylic acid having a 5,8-diazabicyclo[4,3,0]nonan-8-yl group is a new compound that has not been described in any literature, and is not disclosed at all in literature or patent application specifications, nor has it even been suggested. It has not been.
・ しよ−と る
ノルフロキサシン、オフロキサシン、シプロフロキサシ
ン等の市販のキノロン系抗菌剤は、グラム陰性菌および
緑膿菌を含むグラム陰性菌に対して著しい抗菌活性を有
し、細菌感染症の治療に広く使用され、有用性の高い薬
剤である。- Commercially available quinolone antibacterial agents such as norfloxacin, ofloxacin, and ciprofloxacin have significant antibacterial activity against Gram-negative bacteria and Gram-negative bacteria including Pseudomonas aeruginosa, and are effective against bacterial infections. It is a highly useful drug that is widely used for treatment.
しかしながら、近年、第三世代セフェム系およびキノロ
ン系抗菌剤等が感染症の治療に頻繁に使用されるに伴い
、これらの抗菌剤に耐性なメチシリン耐性黄色ブドウ球
菌、表皮ブドウ球菌、溶連菌、腸球菌等のグラム陰性菌
および耐性緑膿菌等のグラム陰性菌による難治性の感染
菌が臨床の場で増加しつつある。これらの耐性菌に対し
て、既存のキノロン系薬剤は充分な治療効果を示してい
ない。However, in recent years, with the frequent use of third-generation cephems and quinolone antibacterial agents to treat infectious diseases, methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, streptococci, and enterococci are resistant to these antibacterial agents. The number of refractory infections caused by Gram-negative bacteria such as Pseudomonas aeruginosa and resistant Pseudomonas aeruginosa is increasing in clinical practice. Existing quinolone drugs have not shown sufficient therapeutic effects against these resistant bacteria.
また、これらの薬剤はグラム陰性菌に対してはグラム陰
性菌に対する抗菌力はど強くないという問題点があり、
ヒトあるいは動物に投与した場合、その経口吸収性の点
についても改善が望まれている。Additionally, these drugs have the problem that their antibacterial activity against Gram-negative bacteria is not very strong.
Improvements are also desired in terms of oral absorption when administered to humans or animals.
本発明の目的は、グラム陰性菌に対する抗菌力の増強、
耐性菌に対する抗菌力の改善、生体内における優れた体
内動態を有し、更には、特に中枢神経系に対する副作用
の少ないピリドンカルボン酸系抗菌剤を提供することに
ある。The purpose of the present invention is to enhance antibacterial activity against Gram-negative bacteria,
The object of the present invention is to provide a pyridonecarboxylic acid-based antibacterial agent that has improved antibacterial activity against resistant bacteria, has excellent pharmacokinetics in vivo, and has fewer side effects, particularly on the central nervous system.
量 を ・ るための
本発明者らは、優れた抗菌力と体内動態を有するピリド
ンカルボン酸系化合物を医薬として提供することを目的
とし、鋭意研究を行った。その結果、キノリン骨格また
は1.8−ナフチリジン骨格の7位に前記一般式[V]
で表される2−オキサ−5,8−ジアザビシクロ[4,
3,0]ノナン−8−イル基を有する新規なピリドンカ
ルボン酸化合物がメチシリン耐性黄色ブドウ球菌を含む
グラム陰性菌およびグラム陰性菌に対して、強い抗菌力
を有することを見出し、本発明を完成した。The present inventors conducted intensive research with the aim of providing a pyridonecarboxylic acid compound having excellent antibacterial activity and pharmacokinetics as a medicine. As a result, at the 7th position of the quinoline skeleton or 1,8-naphthyridine skeleton, the general formula [V]
2-oxa-5,8-diazabicyclo[4,
The present invention was completed based on the discovery that a new pyridonecarboxylic acid compound having a nonan-8-yl group has strong antibacterial activity against Gram-negative bacteria and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus. did.
本発明は、一般式
[式中、R1は直鎖状、分岐状または環状の低級アルキ
ル基、またはふっ素原子により置換されていてもよいフ
ェニル基、R2は水素原子または直鎖状、分岐状もしく
は環状の低級アルキル基、Xは窒素原子またはC−Y
(ここにおいて、Yは水素原子、ハロゲン原子、メチル
基またはメトキシ基を示す)を示す]で表される化合物
またはその医薬として許容される塩またはエステル、そ
の製造法およびその用途に関する。The present invention is based on the general formula [wherein R1 is a linear, branched or cyclic lower alkyl group, or a phenyl group optionally substituted with a fluorine atom, and R2 is a hydrogen atom or a linear, branched or cyclic lower alkyl group, X is a nitrogen atom or C-Y
(wherein Y represents a hydrogen atom, a halogen atom, a methyl group, or a methoxy group)] or a pharmaceutically acceptable salt or ester thereof, a method for producing the same, and uses thereof.
本明細書に記載された記号および用語について説明する
。The symbols and terms described in this specification will be explained.
直鎖状の低級アルキル基としては、例えばメチル基、エ
チル基、プロピル基、ブチル基を意味し、エチル基が好
適である。Examples of the linear lower alkyl group include methyl, ethyl, propyl, and butyl, with ethyl being preferred.
分岐状の低級アルキル基としては、例えばイソプロピル
基、イソブチル基、tert−ブチル基を意味し、te
rt−ブチル基が好適である。Examples of the branched lower alkyl group include isopropyl group, isobutyl group, and tert-butyl group;
An rt-butyl group is preferred.
環状の低級アルキル基としては、例えばシクロプロピル
基、シクロブチル基、シクロペンチル基を意味し、シク
ロプロピル基、シクロブチル基が好適であり、中でも、
シクロプロピル基が好ましい。Examples of the cyclic lower alkyl group include a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group, with a cyclopropyl group and a cyclobutyl group being preferred, and among them,
Cyclopropyl group is preferred.
ふっ素原子により置換されていてもよいフェニル基とし
ては、例えばフェニル基、2−フルオロフェニル基、3
−フルオロフェニル基、4−フルオロフェニル基、2.
3−ジフルオロフェニル基、2.4−ジフルオキサリル
基、3.4−ジフルオロフェニル基を意味し、2−フル
オロフェニル基、2.4−ジフルオロフェニル基、4−
フルオロフェニル基が好適である。Examples of the phenyl group which may be substituted with a fluorine atom include phenyl group, 2-fluorophenyl group, 3-fluorophenyl group,
-fluorophenyl group, 4-fluorophenyl group, 2.
3-difluorophenyl group, 2.4-difluoroxalyl group, 3.4-difluorophenyl group, 2-fluorophenyl group, 2.4-difluorophenyl group, 4-
Fluorophenyl groups are preferred.
ハロゲン原子としては、例えばふっ素原子、塩素原子、
臭素原子を意味し、ふっ素原子が好適である。Examples of halogen atoms include fluorine atoms, chlorine atoms,
It means a bromine atom, with a fluorine atom being preferred.
脱離基としては、例えばふっ素原子、塩素原子、臭素原
子等のハロゲン原子を意味し、ふっ素原子が好適である
。The leaving group means, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and a fluorine atom is preferred.
カルボキシル基の保護基としては、例えばメチル基、エ
チル基、プロピル基、イソプロピル基、tert−ブチ
ル基等の低級アルキル基;例えばアセトキシメチル基、
プロピオニルオキシメチル基、ピバロイルオキシメチル
基、l−アセトキシエチル基、1−プロピオニルオキシ
エチル基等の低級アルカノイルオキシアルキル基;例え
ば1−(メトキシカルボニルオキシ)エチル基、l−(
エトキシカルボニルオキシ)エチル基、l−(イソプロ
ポキシカルボニルオキシ)エチル基等の低級アルコキシ
カルボニルオキシアルキル基;例えば(5−メチル−2
−オキソ−1,3−ジオキソ−ルー4−イル)メチル基
等の(5−置換−2−オキソ−1,3−ジオキソ−ルー
4−イル)メチル基; 例えばトリメチルシリル基、t
art−ブチルジメチルシリル基等の低級アルキルシリ
ル基;例えばインダニル基、フタリジル基、メトキシメ
チル基等が挙げられ、特にメチル基、エチル基等が好適
である。Examples of protective groups for carboxyl groups include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, and tert-butyl; for example, acetoxymethyl,
Lower alkanoyloxyalkyl groups such as propionyloxymethyl group, pivaloyloxymethyl group, l-acetoxyethyl group, 1-propionyloxyethyl group; for example, 1-(methoxycarbonyloxy)ethyl group, l-(
Lower alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxy)ethyl group and l-(isopropoxycarbonyloxy)ethyl group; for example, (5-methyl-2
(5-substituted-2-oxo-1,3-dioxo-4-yl)methyl groups such as -oxo-1,3-dioxo-4-yl)methyl groups; e.g. trimethylsilyl group, t
Lower alkylsilyl groups such as art-butyldimethylsilyl; examples include indanyl, phthalidyl, and methoxymethyl groups, with methyl and ethyl groups being particularly preferred.
アミノ保護基としては、例えばベンジル基、p−メトキ
シベンジル基、3.4−ジメトキシベンジル基、0−二
トロベンジル基、p−ニトロベンジル基、ベンズヒドリ
ル基、ビス(p−メトキシフェニル)メチル基等のアラ
ルキル基;例えばホルミル基、アセチル基、プロピオニ
ル基、ブチリル基、オキサリル基、スクシニル基、ピバ
ロイル基等の低級アルカノイル基;例えばクロロアセチ
ル基、ジクロロアセチル基、トリクロロアセチル基、ト
リフルオロアセチル基等のハロ置換低級アルカノイル基
;例えばフェニルアセチル基、フェノキシアセチル基等
のアリールアルカノイル基;例えばメトキシカルボニル
基、エトキシカルボニル基、プロポキシカルボニル基、
1eri−ブトキシカルボニル基等の低級アルコキシカ
ルボニル基;例えば2−ヨウ化エチルオキシカルボニル
基、2,2.2−1−リクロロエトキシ力ルポニル基等
のハロ置換低級アルコキシカルボニル基;例えば2−プ
ロペニルオキシカルボニル基、2−クロロ−2−プロペ
ニルオキシカルボニル基、3−メトキシカルボニル−2
−プロペニルオキシカルボニル基、2−メチル−2−プ
ロペニルオキシカルボニル基、2−ブテニルオキシカル
ボニル基、シンナミルオキシカルボニル基等のアルケニ
ルオキシカルボニル基:例えばベンジルオキシカルボニ
ル基、〇−ニトロベンジルオキシカルボニル基、p−ニ
トロベンジルオキシカルボニル基、フェネチルオキシカ
ルボニル基等のアラルキルオキシカルボニル基:例えば
トリメチルシリル基、tert−ブチルジメチルシリル
基等の低級アルキルシリル基が挙げられ、特に、2−プ
ロペニルオキシカルボニル基、tert−ブトキシカル
ボニル基、p−ニトロベンジルオキシカルボニル基等が
好ましい。Examples of amino protecting groups include benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, 0-nitrobenzyl group, p-nitrobenzyl group, benzhydryl group, bis(p-methoxyphenyl)methyl group, etc. Aralkyl groups; for example, lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, oxalyl, succinyl, pivaloyl; haloacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc. Substituted lower alkanoyl group; For example, arylalkanoyl group such as phenylacetyl group, phenoxyacetyl group; For example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,
Lower alkoxycarbonyl groups such as 1eri-butoxycarbonyl group; For example, halo-substituted lower alkoxycarbonyl groups such as 2-iodide ethyloxycarbonyl group and 2,2,2-1-lichloroethoxyluponyl group; For example, 2-propenyloxy Carbonyl group, 2-chloro-2-propenyloxycarbonyl group, 3-methoxycarbonyl-2
- Alkenyloxycarbonyl groups such as propenyloxycarbonyl group, 2-methyl-2-propenyloxycarbonyl group, 2-butenyloxycarbonyl group, cinnamyloxycarbonyl group: For example, benzyloxycarbonyl group, 〇-nitrobenzyloxycarbonyl group , p-nitrobenzyloxycarbonyl group, phenethyloxycarbonyl group, and other aralkyloxycarbonyl groups; examples include lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; in particular, 2-propenyloxycarbonyl group, tert-butyloxycarbonyl group, etc. -butoxycarbonyl group, p-nitrobenzyloxycarbonyl group, etc. are preferred.
一般式[I]の化合物は、常法により医薬として許容さ
れる無毒性塩またはそのエステルとすることができる。The compound of general formula [I] can be converted into a pharmaceutically acceptable non-toxic salt or ester thereof by a conventional method.
一般式[1]の化合物の無毒性塩としては、医薬として
許容される慣用的なものを意味し、キノリン骨格または
1,8−ナフチリジン骨格の3位のカルボキシル基また
は7位側鎖の遊離アミノ基の塩基における塩を挙げるこ
とができる。The non-toxic salt of the compound of general formula [1] refers to a conventional pharmaceutically acceptable salt, and the carboxyl group at the 3-position of the quinoline skeleton or 1,8-naphthyridine skeleton or the free amino acid at the side chain at the 7-position Mention may be made of the base salts of the groups.
カルボキシル基における塩基性付加塩としては、例えば
ナトリウム塩、カリウム塩等のアルカリ金属塩;例えば
カルシウム塩、マグネシウム塩等のアルカリ土類金属塩
:例えばアンモニウム塩;例えばトリメチルアミン塩、
トリエチルアミン塩;ジシクロヘキシルアミン塩、エタ
ノールアミン塩、ジェタノールアミン塩、トリエタノー
ルアミン塩、プロカイン塩等の脂肪族アミン塩;例えば
N、N’−ジベンジルエチレンジアミン等のアラルキル
アミン塩;例えばピリジン塩、ピコリン塩、キノリン塩
、イソキノリン塩等の複素環芳香族アミン塩;例えばテ
トラメチルアンモニウム塩、テトラエチルアンモニウム
塩、ベンジルトリメチルアンモニウム塩、ベンジルトリ
エチルアンモニウム塩、ペンジルトリブチルアンモニウ
ム塩、メチルトリオクチルアンモニウム塩、テトラブチ
ルアンモニウム塩等の第4級アンモニウム塩;アルギニ
ン塩、リジン塩等の塩基性アミノ酸塩等が挙げられる。Examples of basic addition salts at carboxyl groups include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; e.g. ammonium salts; e.g. trimethylamine salts;
Triethylamine salt; aliphatic amine salt such as dicyclohexylamine salt, ethanolamine salt, jetanolamine salt, triethanolamine salt, procaine salt; aralkylamine salt such as N,N'-dibenzylethylenediamine; e.g. pyridine salt, picoline Heterocyclic aromatic amine salts such as salts, quinoline salts, isoquinoline salts; for example, tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, penzyltributylammonium salts, methyltrioctylammonium salts, tetrabutyl Examples include quaternary ammonium salts such as ammonium salts; basic amino acid salts such as arginine salts and lysine salts.
7位側鎖の遊離アミノ基の塩基における酸付加塩として
は、例えば塩酸塩、硫酸塩、硝酸塩、燐酸塩、炭酸塩、
炭酸水素塩、過塩素酸塩等の無機酸塩;例えば酢酸塩、
プロピオン酸塩、乳酸塩、マレイン酸塩、フマール酸塩
、酒石酸塩、りんご酸塩、くえん酸塩、アスコルビン酸
塩等の有機酸塩;例えばメタンスルホン酸塩、イセチオ
ン酸塩、ベンゼンスルホン酸塩、p−トルエンスルホン
酸塩等のスルホン酸塩;例えばアスパラギン酸塩、グル
タミン酸塩等の酸性アミノ酸塩等が挙げられる。Examples of acid addition salts of the free amino group in the 7-position side chain include hydrochloride, sulfate, nitrate, phosphate, carbonate,
Inorganic acid salts such as bicarbonates, perchlorates; e.g. acetates,
Organic acid salts such as propionate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbate; e.g. methanesulfonate, isethionate, benzenesulfonate, Sulfonic acid salts such as p-toluenesulfonate; examples include acidic amino acid salts such as aspartate and glutamate.
上記の無毒性塩の中で、最も好適なものは、p−トルエ
ンスルホン酸塩である。Among the above non-toxic salts, p-toluenesulfonate is the most preferred.
一般式[I]の化合物の無毒性エステルとしては、キノ
リン骨格または1.8−ナフチリジン骨格の3位のカル
ボキシル基における医薬として許容される慣用的なもの
を意味する。例えばアセトキシメチル基、ピバロイルオ
キシメチル基等のアルカノイルオキシメチル基とのエス
テル、■−(エトキシカルボニルオキシ)エチル基等の
アルコキシカルボニルオキシアルキル基とのエステル、
フタリジル基とのエステル、(5−メチル−2−オキソ
−1,3−ジオキソ−ルー4−イル)メチル基等の(5
−置換−2−オキソ−1,3−ジオキソ−ルー4−イル
)メチル基とのエステル等が挙げられる。The non-toxic ester of the compound of general formula [I] means a conventional pharmaceutically acceptable ester at the carboxyl group at the 3-position of the quinoline skeleton or 1,8-naphthyridine skeleton. For example, esters with alkanoyloxymethyl groups such as acetoxymethyl group and pivaloyloxymethyl group, ■ esters with alkoxycarbonyloxyalkyl groups such as -(ethoxycarbonyloxy)ethyl group,
Esters with phthalidyl groups, (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl groups, etc.
-substituted-2-oxo-1,3-dioxo-4-yl) methyl group, and the like.
本発明は、7位側鎖の2−オキサ−5,8−ジアザビシ
クロ[4,3,0]ノナン−8−イル基の1位および6
位の不斉炭素に基づく光学異性体および立体異性体が存
在し、これらの異性体のいずれも包含する。The present invention relates to the 1-position and 6-position of the 2-oxa-5,8-diazabicyclo[4,3,0]nonan-8-yl group in the 7-position side chain.
Optical isomers and stereoisomers based on the asymmetric carbon position exist, and both of these isomers are included.
一般式[I]の化合物の好適な化合物について説明する
。Suitable compounds of general formula [I] will be explained.
一般式[I]の化合物中、一般式
[式中、R1+は直鎖状、分岐状または環状の低級アル
キル基、R2は水素原子または直鎮状、分岐状または環
状の低級アルキル基、Y’は水素原子またはハロゲン原
子を示す]で表される化合物は好適な化合物群である。In the compound of the general formula [I], R1+ is a linear, branched or cyclic lower alkyl group, R2 is a hydrogen atom or a straight chain, branched or cyclic lower alkyl group, Y' represents a hydrogen atom or a halogen atom] is a preferred group of compounds.
一般式[I]の化合物の具体例を例示する。Specific examples of the compound of general formula [I] will be illustrated.
本発明によって得られる一般式[I]の化合物の具体例
を以下の表に示す。尚、表における略号の意味を以下に
示す。Specific examples of the compound of general formula [I] obtained by the present invention are shown in the table below. The meanings of the abbreviations in the table are shown below.
Me : メチル基
Et: エチル基
Pr: プロピル基
iPr : イソプロピル基
tBu : tert−ブチル基
(以下余白)
上記の化合物中、好適な化合物は、
1−エチル−6,8−ジフルオロ−1,4−ジヒドロ−
7−(2−オキサ−5,8−ジアザビシクロ[4,3,
0]ノナン−8−イル)−4−オキソ−3−キノリンカ
ルボン酸(化合物1)、]−]tert−ブチル〜6,
8−ジフルオロ1.4−ジヒドロ−7−(2−オキサ−
5,8−ジアザビシクロ[4,3,0]ノナン−8−イ
ル)−4−オキソ−3−キノリンカルボン酸(化合物1
5)、
l−シクロプロピル−6,8−ジフルオロ−1,4−ジ
ヒドロ−7−(2−オキサ−5,8−ジアザビシクロ[
4,3,0]ノナン−8−イル)−4−オキソ−3−゛
キノリンカルボン酸(化合物22)、
6.8−ジフルオロ−1−(4−フルオロ)フェニル−
1,4−ジヒドロ−7−(2−オキサ−5,8−ジアザ
ビシクロ[4,3,0]ノナン−8−イル)−4−オキ
ソ−3−キノリンカルボン酸(化合物35)、
6.8−ジフルオロ−1−(3,4−ジフルオロ)フェ
ニル1.4−ジヒドロ−7−(2−オキサ−5,8−ジ
アザビシクロ[4,3,0]ノナン−8−イル)−4−
オキソ−3−キノリンカルボン酸(化合物42)、
l−エチル−6−フルオロ−1,4−ジヒドロ−7−(
2−オキサ−5,8−ジアザビシクロ[4,3,01ノ
ナン−8−イル)−4−オキソ−3−キノリンカルボン
酸(化合物48)、1−tert−ブチル−6−フルオ
ロ−1,4−ジヒドロ−7−(2−オキサ−5,8−ジ
アザビシクロ[4,3,0]ノナン−8−イル)−4−
オキソ−3−キノリンカルボン酸(化合物62)、l−
シクロプロピル−6−フルオロ−1,4−ジヒドロ−7
−(2−オキサ−5,8−ジアザビシクロ[4,3,0
] ノナン−8−イル)−4−オキソ−3−キノリンカ
ルボン酸(化合物69)、
6−フルオロ−1−(4−フルオロ)フェニル−1,4
−ジヒドロ−7−(2−オキサ−5,8−ジアザビシク
ロ[4,3,0]ノナン−8−イル)−4−オキ゛へ3
−キノリンカルボン酸(化合物82)、
6−フルオロ−1−(3,4−ジフルオロ)フェニル−
1,4−ジヒドロ−7−(2−オキサ−5,8−ジアザ
ビシクロ[4,3,0]ノナン−8−イル)−4−オキ
ソ−3−キノリンカルボン酸(化合物89)、
l−エチル−6−フルオロ−1,4−ジヒドロ−7−(
2−オキサ−5,8−ジアザビシクロ[4,3,0]ノ
ナン−8−イル)−8−メチル−4−オキソ−3−キノ
リンカルボン酸(化合物96)、1−tert−ブチル
−6−フルオo−1,4−ジヒドo−7−(2−オキサ
−5,8−ジアザビシクロ[4,3,0]ノナン−8−
イル)−8−メチル−4−オキソ−3−キノリンカルボ
ン酸(化合物110)、
1−シクロプロピル−6−フルオロ−1,4−ジヒドロ
−7=(2−オキサ−5,8−ジアザビシクロ[4,3
,0] ノナン−8−イル)−8−メチル−4−オキソ
−3−キノリンカルボン酸(化合物117)、
6−フルオロ−1−(4−フルオロ)フェニル−1,4
−ジヒドロ−7−(2−オキサ−5,8−ジアザビシク
ロ[4,3,0]ノナン−8−イル)−8−メチル−4
−オキソ−3−キノリンカルボン酸(化合物130)、
6−フルオロ−1−(3,4−ジフルオロ)フェニル−
1,4−ジヒドロ−7−(2−オキサ−5,8−ジアザ
ビシクロ[4,3,0]ノナン−8−イル)−8−メチ
ル−4−オキソ−3−キノリンカルボン酸(化合物13
7)、
l−エチル−6−フルオロ−1,4−ジヒドロ−7−(
2−オキサ−5,8−ジアザビシクロ[4,3,O]ノ
ナン−8−イル)−8−メトキシ−4・オキソ−3−キ
ノリンカルボン酸(化合物145)、
1−tert−ブチル−6−フルオロ−1,4−ジヒド
o−7−(2オキサ−5,8−ジアザビシクロ[4,3
,0]ノナン−8−イル)−8−メトキシ−4−オキソ
−3−キノリンカルボン酸(化合物159)、
l−シクロプロピル−6−フルオロ−1,4−ジヒドロ
−7−(2−オキサ−5,8−ジアザビシクロ[4,3
,0]ノナン−8−イル)−8−メトキシ−4−オキソ
−3−キノリンカルボン酸(化合物166)、
6−フルオロ−1−(4−フルオロ)フェニル−1,4
−ジヒドロ−7−(2−オキサ−5,8−ジアザビシク
ロ[4,3,0]ノナン−8−イル)−8−メトキシ−
4−オキソ−3−キノリンカルボン酸(化合物179)
、
6−フルオロ−1−(3,4−ジフルオロ)フェニル−
1,4−ジヒドロ−7−(2−オキサ−5,8−ジアザ
ビシクロ[4,3,0]ノナン−8−イル)−8−メト
キシ−4−オキソ−3−キノリンカルボン酸(化合物1
86)、
1−エチル−6−フルオロ−1,4−ジヒドロ−7−(
2−オキサ−5,8−ジアザビシクロ[4,3,0]
ノナン−8−イル)−4−オキソ−1,8−ナフチリジ
ン−3−カルボン酸(化合物!93)、1−tert−
ブチル−6−フルオo−1,4−ジヒドo−7−(2オ
キサ−5,8−ジアザビシクロ[4,3,O]ノナン−
8−イル)−4−オキソ−1,8−ナフチリジン−3−
カルボン酸(化合物206)、
l−シクロプロピル−6−フルオロ−1,4−ジヒドロ
−7=(2−オキサ−5,8−ジアザビシクロ[4,3
,0]ノナン−8−イル)−4−オキソ−1,8−ナフ
チリジン−3−カルボン酸(化合物213)、
6−フルオロ−1−(4−フルオロ)フェニル−1,4
−ジヒドロ−7〜(2−オキサ−5,8−ジアザビシク
ロ[4,3:O]ノナン−8−イル)−4−オキソ−1
,8−ナフチリジン−3−カルボン酸(化合物225)
および
6、フルオロ−1−(3,4−ジフルオロ)フェニル−
1,4−ジヒドロ−7−(2−オキサ−5,8−ジアザ
ビシクロ[4,3,0]ノナン−8−イル)−4−オキ
ソ−1,8−ナフチリジン−3−カルボン酸(化合物2
32)の化合物が好適である。Me: Methyl group Et: Ethyl group Pr: Propyl group iPr: Isopropyl group tBu: tert-butyl group (blank below) Among the above compounds, preferred compounds are: 1-ethyl-6,8-difluoro-1,4- dihydro-
7-(2-oxa-5,8-diazabicyclo[4,3,
0]nonan-8-yl)-4-oxo-3-quinolinecarboxylic acid (compound 1),]-]tert-butyl~6,
8-difluoro1,4-dihydro-7-(2-oxa-
5,8-diazabicyclo[4,3,0]nonan-8-yl)-4-oxo-3-quinolinecarboxylic acid (compound 1
5), l-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[
4,3,0]nonan-8-yl)-4-oxo-3-'quinolinecarboxylic acid (compound 22), 6,8-difluoro-1-(4-fluoro)phenyl-
1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4,3,0]nonan-8-yl)-4-oxo-3-quinolinecarboxylic acid (compound 35), 6.8- Difluoro-1-(3,4-difluoro)phenyl 1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4,3,0]nonan-8-yl)-4-
Oxo-3-quinolinecarboxylic acid (compound 42), l-ethyl-6-fluoro-1,4-dihydro-7-(
2-Oxa-5,8-diazabicyclo[4,3,01nonan-8-yl)-4-oxo-3-quinolinecarboxylic acid (compound 48), 1-tert-butyl-6-fluoro-1,4- Dihydro-7-(2-oxa-5,8-diazabicyclo[4,3,0]nonan-8-yl)-4-
Oxo-3-quinolinecarboxylic acid (compound 62), l-
cyclopropyl-6-fluoro-1,4-dihydro-7
-(2-oxa-5,8-diazabicyclo[4,3,0
] nonan-8-yl)-4-oxo-3-quinolinecarboxylic acid (compound 69), 6-fluoro-1-(4-fluoro)phenyl-1,4
-dihydro-7-(2-oxa-5,8-diazabicyclo[4,3,0]nonan-8-yl)-4-oxa-3
-quinolinecarboxylic acid (compound 82), 6-fluoro-1-(3,4-difluoro)phenyl-
1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4,3,0]nonan-8-yl)-4-oxo-3-quinolinecarboxylic acid (compound 89), l-ethyl- 6-fluoro-1,4-dihydro-7-(
2-oxa-5,8-diazabicyclo[4,3,0]nonan-8-yl)-8-methyl-4-oxo-3-quinolinecarboxylic acid (compound 96), 1-tert-butyl-6-fluoro o-1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4,3,0]nonane-8-
)-8-methyl-4-oxo-3-quinolinecarboxylic acid (compound 110), 1-cyclopropyl-6-fluoro-1,4-dihydro-7=(2-oxa-5,8-diazabicyclo[4 ,3
,0] nonan-8-yl)-8-methyl-4-oxo-3-quinolinecarboxylic acid (compound 117), 6-fluoro-1-(4-fluoro)phenyl-1,4
-dihydro-7-(2-oxa-5,8-diazabicyclo[4,3,0]nonan-8-yl)-8-methyl-4
-oxo-3-quinolinecarboxylic acid (compound 130), 6-fluoro-1-(3,4-difluoro)phenyl-
1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4,3,0]nonan-8-yl)-8-methyl-4-oxo-3-quinolinecarboxylic acid (compound 13
7), l-ethyl-6-fluoro-1,4-dihydro-7-(
2-Oxa-5,8-diazabicyclo[4,3,O]nonan-8-yl)-8-methoxy-4-oxo-3-quinolinecarboxylic acid (compound 145), 1-tert-butyl-6-fluoro -1,4-dihydro-7-(2oxa-5,8-diazabicyclo[4,3
,0]nonan-8-yl)-8-methoxy-4-oxo-3-quinolinecarboxylic acid (compound 159), l-cyclopropyl-6-fluoro-1,4-dihydro-7-(2-oxa- 5,8-diazabicyclo[4,3
,0]nonan-8-yl)-8-methoxy-4-oxo-3-quinolinecarboxylic acid (compound 166), 6-fluoro-1-(4-fluoro)phenyl-1,4
-dihydro-7-(2-oxa-5,8-diazabicyclo[4,3,0]nonan-8-yl)-8-methoxy-
4-oxo-3-quinolinecarboxylic acid (compound 179)
, 6-fluoro-1-(3,4-difluoro)phenyl-
1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4,3,0]nonan-8-yl)-8-methoxy-4-oxo-3-quinolinecarboxylic acid (compound 1
86), 1-ethyl-6-fluoro-1,4-dihydro-7-(
2-Oxa-5,8-diazabicyclo[4,3,0]
nonan-8-yl)-4-oxo-1,8-naphthyridine-3-carboxylic acid (compound!93), 1-tert-
Butyl-6-fluoro-1,4-dihydro-7-(2oxa-5,8-diazabicyclo[4,3,O]nonane-
8-yl)-4-oxo-1,8-naphthyridine-3-
Carboxylic acid (compound 206), l-cyclopropyl-6-fluoro-1,4-dihydro-7=(2-oxa-5,8-diazabicyclo[4,3
,0]nonan-8-yl)-4-oxo-1,8-naphthyridine-3-carboxylic acid (compound 213), 6-fluoro-1-(4-fluoro)phenyl-1,4
-dihydro-7-(2-oxa-5,8-diazabicyclo[4,3:O]nonan-8-yl)-4-oxo-1
, 8-naphthyridine-3-carboxylic acid (compound 225)
and 6, fluoro-1-(3,4-difluoro)phenyl-
1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4,3,0]nonan-8-yl)-4-oxo-1,8-naphthyridine-3-carboxylic acid (compound 2
Compounds 32) are preferred.
前記一般式[I]の化合物および一般式[I]の化合物
の具体例中、より好適な化合物群は、一般式
表される化合物またはその塩と
一般式
[式中、R11は直鎖状または環状の低級アルキル基、
R”は水素原子または直鎖状の低級アルキル基を示す]
で表される化合物である。Among the compounds of the general formula [I] and specific examples of the compounds of the general formula [I], a more preferable group of compounds is the compound represented by the general formula or a salt thereof and the compound represented by the general formula [wherein R11 is linear or cyclic lower alkyl group,
R'' represents a hydrogen atom or a linear lower alkyl group]
It is a compound represented by
本発明化合物の製造法について説明する。The method for producing the compound of the present invention will be explained.
本発明の一般式[I]の化合物は、一般式[式中、RX
Iは水素原子、アミノ基の保護基または直鎖状、分岐状
もしくは環状の低級アルキル基を示す]で表される化合
物またはその塩とを脱酸剤の存在下に反応させて、
一般式
[式中、R’は直鎖状、分岐状または環状の低級アルキ
ル基、またはふっ素原子により置換されていてもよいフ
ェニル基、R3は水素原子またはカルボキシル基の保護
基、Xは窒素原子またはC−Y (ここにおいて、Yは
水素原子、ハロゲン原子、メチル基またはメトキシ基を
示す)、Zは脱離基を示す]で日s
[式中、R1、R”、 R″およびXは前記の意味を有
する〕で表される化合物とし、必要に応じて該化合物の
保護基を除去することにより製造することができる。The compound of the general formula [I] of the present invention is a compound of the general formula [wherein RX
I represents a hydrogen atom, a protecting group for an amino group, or a linear, branched, or cyclic lower alkyl group] or a salt thereof is reacted with the compound represented by the formula [ In the formula, R' is a linear, branched or cyclic lower alkyl group, or a phenyl group optionally substituted with a fluorine atom, R3 is a hydrogen atom or a carboxyl group protecting group, and X is a nitrogen atom or C- Y (wherein, Y represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group), Z represents a leaving group] [wherein, R1, R'', R'' and X have the above meanings It can be produced by removing the protecting group of the compound as required.
一般式[1[I]の化合物と一般式[I’/]の化合物
との反応は、通常例えばエタノール、メタノール等のア
ルコール類、例えばジオキサン、テトラヒドロフラン等
のエーテル類、例えばベンゼン、トルエン等の芳香族炭
化水素類、例えばアセトニトリル、N、N−ジメチルホ
ルムアミド、ジメチルスルホキシド等の不活性溶媒中で
行われる。反応温度は室温〜200℃、好ましくは80
〜150℃にて、反応時間は0.5〜24時間、通常は
1〜6時間で行う。The reaction between the compound of general formula [1[I] and the compound of general formula [I'/] is usually carried out using alcohols such as ethanol and methanol, ethers such as dioxane and tetrahydrofuran, and aromatic substances such as benzene and toluene. The reaction is carried out in an inert solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide and the like. The reaction temperature is room temperature to 200°C, preferably 80°C.
The reaction time is 0.5 to 24 hours, usually 1 to 6 hours.
本反応は通常脱酸剤の存在下に、一般式[IV]の化合
物1モルに対して一般式[1[1]の化合物は1.0〜
1.2モル使用する。脱酸剤は、一般式[IV]の化合
物1モルに対して1.0〜1.2モル使用する。脱酸剤
としては、例えば水酸化ナトリウム、水酸化カリウム等
のアルカリ金属水酸化物、例えば炭酸ナトリウム、炭酸
カリウム等のアルカリ金属炭酸塩、例えば炭酸水素ナト
リウム等のアルカリ金属炭酸水素塩、例えばトリエチル
アミン、ピリジン、1.8ジアザビシクロ[5,4,0
]ウンデカ−7−エン(DBU)、1.5−ジアザビシ
クロ[4,3,O]ノナン−5−エン(DBN)等の有
機塩基等が挙げられる。反応は、例えばトリエチルアミ
ン、ピリジン等の塩基化合物を過剰に用いて脱酸剤と溶
媒を兼ねて使用することもできる。This reaction is usually carried out in the presence of a deoxidizing agent, and the amount of the compound of general formula [1[1] is 1.0 to 1 mole of the compound of general formula [IV].
Use 1.2 mol. The deoxidizing agent is used in an amount of 1.0 to 1.2 mol per 1 mol of the compound of general formula [IV]. Examples of deoxidizers include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, triethylamine, etc. Pyridine, 1.8 diazabicyclo[5,4,0
] Undec-7-ene (DBU), 1,5-diazabicyclo[4,3,O]nonan-5-ene (DBN), and other organic bases. In the reaction, for example, an excess of a basic compound such as triethylamine or pyridine may be used to serve as both a deoxidizing agent and a solvent.
反応終了後、通常の処理を行い一般式[11]で表され
る粗生成物が得られる。一般式[■]の化合物のR8が
カルボキシル基の保護基である場合、精製することなく
カルボキシル基の保護基を除去することにより、一般式
[1]の化合物を製造することができる。After the reaction is completed, a crude product represented by the general formula [11] is obtained by performing usual treatments. When R8 in the compound of general formula [■] is a carboxyl group-protecting group, the compound of general formula [1] can be produced by removing the carboxyl group-protecting group without purification.
保護基の除去は、常法に従って不活性溶媒中、酸または
アルカリ存在下に加水分解または加溶媒分解により行わ
れる。Removal of the protecting group is carried out by hydrolysis or solvolysis in an inert solvent in the presence of an acid or alkali according to a conventional method.
不活性溶媒としては、例えば水、メタノール、エタノー
ル、プロパツール、テトラヒドロフランまたはこれらの
混合溶媒が挙げられる。Examples of the inert solvent include water, methanol, ethanol, propatool, tetrahydrofuran, and a mixed solvent thereof.
反応に使用する酸としては、例えば塩酸、硫酸等が挙げ
られ、一般式[1]の化合物1モルに対して酸は2〜2
0モルを用いる。反応温度は0〜80℃で0.5〜3時
間で反応は完結する。Examples of the acid used in the reaction include hydrochloric acid, sulfuric acid, etc., and the amount of acid used is 2 to 2 per mol of the compound of general formula [1].
Use 0 mol. The reaction temperature is 0 to 80°C and the reaction is completed in 0.5 to 3 hours.
反応に使用する塩基としては、例えば水酸化ナトリウム
、水酸化カリウム等のアルカリ金属水酸化物、例えば炭
酸ナトリウム、炭酸カリウム等のアルカリ金属炭酸塩、
例えば炭酸水素ナトリウム、炭酸水素カリウム等のアル
カリ金属炭酸水素塩等が挙げられる。反応は一般式[I
[]の化合物1モルに対して塩基1〜3モルを用い、反
応温度は0〜so’cで5〜30分間で反応は完結する
。Examples of the base used in the reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate;
Examples include alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. The reaction is expressed by the general formula [I
The reaction is completed in 5 to 30 minutes at a reaction temperature of 0 to SO'C using 1 to 3 moles of base per 1 mole of the compound [ ].
保護基の除去反応の終了後、通常の処理法により、例え
ば溶媒抽出、結晶化またはシリカゲルもしくは吸着樹脂
等を用いるカラムクロマトグラフィー等により、一般式
[1]の化合物を単離することができる。単離、精製条
件によって、一般式[I]の化合物は、分子内塩、無毒
性付加塩、水和物の形で得られるが、これらは目的に応
じて常法により相互に変換することができる。After the protective group removal reaction is completed, the compound of general formula [1] can be isolated by conventional processing methods, such as solvent extraction, crystallization, or column chromatography using silica gel or adsorption resin. Depending on the isolation and purification conditions, the compound of general formula [I] can be obtained in the form of an inner salt, a nontoxic addition salt, or a hydrate, but these can be converted into each other by conventional methods depending on the purpose. can.
尚、一般式[II]の化合物の3位のカルボキシル基の
保護基が、例えばアセトキシメチル基、ピバロイルオキ
シメチル基等の低級アルカノイルオキシアルキル基;例
えばメトキシメチル基、インダニル基、フタリジル基等
である場合、このようなエステルは生体内で生理的に加
水分解されるので、保護基を除去することな(、直接、
ヒトまたは動物に投与することができる。The protecting group for the carboxyl group at position 3 of the compound of general formula [II] is, for example, a lower alkanoyloxyalkyl group such as an acetoxymethyl group or a pivaloyloxymethyl group; for example, a methoxymethyl group, an indanyl group, a phthalidyl group, etc. , such esters are physiologically hydrolyzed in vivo, so it is not necessary to remove the protecting group (directly,
It can be administered to humans or animals.
一般式[1[I]で表される化合物は新規化合物であり
、これらのcisおよびtrans異性体は3−ビロー
ルから製造される。The compounds represented by the general formula [1[I] are new compounds, and their cis and trans isomers are produced from 3-virol.
(1) (リ ■ (l!1)(
■ (Ω) (Z)
(影一般式[1[I]で表されるtrans異性
体(釦の合成法を説明する(参考例1)。(1) (li ■ (l!1)(
■ (Ω) (Z)
(Trans isomer represented by the general formula [1[I]) A method for synthesizing the button will be explained (Reference Example 1).
3−ビロール(1)から特開昭64−3181号公報に
記載の方法により製造した1−tert−ブトキシカル
ボニル−3,4−エポキシピロリジン(旦)をエタノー
ル溶媒中、2倍モルのベンジルアミンと3時間還流して
、trans−3−ベンジルアミノ−1−tert−ブ
トキシカルボニル−4化ドロキシピロリジン(りとした
。化合物(4)を塩化メチレン溶媒中、1.3倍モルの
トリエチルアミンの存在下に1,2倍モルのクロロアセ
チルクロリドを反応させて、trans−3−[N−ベ
ンジル−N−(クロロアセチル)アミノ]−1−ter
t−ブトキシカルボニル−4−ヒドロキシピロリジン(
巨)を得た。化合物(4)をテトラヒドロフラン溶媒中
、室温下でカリウムtert−ブトキシドで処理して、
trans−5−ベンジル−8−tert−ブトキシカ
ルボニル−2−オキサ−4−オキソ−5,8−ジアザビ
シクロ[4,3,0]ノナン(6)とし、次いで化合物
(りをテトラヒドロフラン溶媒中、ジボラン還元してt
rans−5−ベンジル−8−tert−ブトキシカル
ボニル−2−オキサ−5,8−ジアザビシクロ[4,3
,0]ノナン(′L)とした。化合物(Z)をメタノー
ル溶媒中、パラジウム炭素触媒の存在下に接触還元して
、trams−8−tert−ブトキシカルボニル2−
オキサ−5,8−ジアザビシクロ[4,3,0]ノナン
(旦)を得、化合物印)を塩化メチレン溶媒中、水冷下
にトリフルオロ酢酸で処理して、一般式[n[]のR′
が水素であるtrans−2−オキサ−5,8,ジアザ
ビシクロ[4,3,O]ノナン(13)を得た。1-tert-butoxycarbonyl-3,4-epoxypyrrolidine (Dan) produced from 3-virol (1) by the method described in JP-A-64-3181 was mixed with 2 times the mole of benzylamine in an ethanol solvent. After refluxing for 3 hours, trans-3-benzylamino-1-tert-butoxycarbonyl-4-droxypyrrolidine was prepared. Compound (4) was dissolved in a methylene chloride solvent in the presence of 1.3 times the mole of triethylamine. was reacted with 1 to 2 times the mole of chloroacetyl chloride to form trans-3-[N-benzyl-N-(chloroacetyl)amino]-1-ter.
t-Butoxycarbonyl-4-hydroxypyrrolidine (
(huge). Compound (4) was treated with potassium tert-butoxide in tetrahydrofuran solvent at room temperature,
trans-5-benzyl-8-tert-butoxycarbonyl-2-oxa-4-oxo-5,8-diazabicyclo[4,3,0]nonane (6) and then diborane reduction in tetrahydrofuran solvent. then t
rans-5-benzyl-8-tert-butoxycarbonyl-2-oxa-5,8-diazabicyclo[4,3
, 0] nonane ('L). Compound (Z) was catalytically reduced in methanol solvent in the presence of a palladium on carbon catalyst to give trams-8-tert-butoxycarbonyl 2-
Oxa-5,8-diazabicyclo[4,3,0]nonane (dan) was obtained by treating R' of the general formula [n[] with trifluoroacetic acid in a methylene chloride solvent under water cooling.
trans-2-oxa-5,8,diazabicyclo[4,3,O]nonane (13) in which is hydrogen was obtained.
(す
(IQ)
■
(拶
(即
一般式[I[[]で表されるcis異性体(12)の合
成法を説明する(参考例2)。(IQ) ■ (Greetings) A method for synthesizing the cis isomer (12) represented by the general formula [I[[] will now be described (Reference Example 2).
1−tert−ブトキシカルボニル−3−ビロール(2
)をシャープレス(Sharpless)等の方法[J
、 Org。1-tert-butoxycarbonyl-3-virol (2
) by the method of Sharpless et al. [J
, Org.
Chem、、 41.177 (1976))を用いて
、cis−1−tert−ブトキシカルボニル−3−ヒ
ドロキシ−4−(p−トルエンスルホニルアミノ)ピロ
リジン(10)とし、化合物(旦)を液体アンモニア中
、金属ナトリウムを作用させて、cis−3−アミノ−
1−tert−ブトキシカルボニル−4−ヒドロキシピ
ロリジン(11)とした。Chem., 41.177 (1976)) to prepare cis-1-tert-butoxycarbonyl-3-hydroxy-4-(p-toluenesulfonylamino)pyrrolidine (10), and the compound (tan) was dissolved in liquid ammonia. , cis-3-amino-
This was designated as 1-tert-butoxycarbonyl-4-hydroxypyrrolidine (11).
化合物(月すをアセトニトリル溶媒中、1.5倍モルの
ベンズアルデヒドの存在下にシアノ水素化はう素ナトリ
ウムを作用させて、cis−3−ベンジルアミノ−1−
tert−ブトキシカルボニル−4−ヒドロキシピロリ
ジン(11)とした後、化合物(挫)を参考例1−2)
〜l−6)と同様の反応を行い、一般式[211]のR
2が水素原子であるcis体(13)を得た。The compound (cis-3-benzylamino-1-
After preparing tert-butoxycarbonyl-4-hydroxypyrrolidine (11), the compound (frustration) was converted into Reference Example 1-2)
〜l-6), and R of general formula [211]
A cis form (13) in which 2 is a hydrogen atom was obtained.
さらに化合物(旦)および化合物(民)を用いて常法に
より、4位の窒素原子を選択的にN−アルキル化するこ
とにより、一般式[In]の化合物を容易に製造するこ
とができる。Further, by selectively N-alkylating the nitrogen atom at the 4-position using Compound (Dan) and Compound (Min) by a conventional method, a compound of the general formula [In] can be easily produced.
一般式[rV]の化合物は、例えば特開昭59−212
,475号、同60−172,981号、同61−26
7.573号、同62−215.572号、同63−2
97,366号公報等に記載の方法に準じて製造される
。The compound of the general formula [rV] is, for example, JP-A-59-212
, No. 475, No. 60-172,981, No. 61-26
No. 7.573, No. 62-215.572, No. 63-2
It is manufactured according to the method described in Japanese Patent No. 97,366 and the like.
本発明化合物の種々の細菌に対する試験管内抗菌活性を
下記の寒天平板希釈法により測定した。[日本化学療法
学会標準法:ケモテラピ−(Chemotherapい
、第29巻、76〜79頁(1981年)]ミュラー
ヒントン ブロス(Mueller Hinton b
roth)中で一夜培養した各試験菌株の一白金耳(接
種菌量:10’cFU/m/)をミュラー ヒントン
アガー(MHagar)に接種した。この培地には抗菌
剤が各濃度で含まれており、37℃で16時間培養した
後、最小発育阻止濃度(MIC:μg/mりを測定した
。その結果を下記表に示す。The in vitro antibacterial activity of the compounds of the present invention against various bacteria was measured by the agar plate dilution method described below. [Japanese Society of Chemotherapy Standard Method: Chemotherapy (Chemotherapy, Vol. 29, pp. 76-79 (1981))] Muller
Hinton Bros (Mueller Hinton b)
A loopful of each test strain (inoculum amount: 10'cFU/m/) cultured overnight in Mueller Hinton
Agar (MHagar) was inoculated. This medium contained antibacterial agents at various concentrations, and after culturing at 37° C. for 16 hours, the minimum inhibitory concentration (MIC: μg/m2) was measured. The results are shown in the table below.
本発明の化合物は、種々のダラム陽性菌およびダラム陰
性菌に対して優れた抗菌活性を有し、これら病原菌を起
炎菌とするヒトの細菌感染症の治療および予防に、抗菌
剤として有用な化合物である。The compounds of the present invention have excellent antibacterial activity against various Durum-positive and Durum-negative bacteria, and are useful as antibacterial agents for the treatment and prevention of human bacterial infections caused by these pathogenic bacteria. It is a compound.
本発明の抗菌剤に感受性のある代表的な病原体としては
、例えばスタフィロコッカス(Sta h Iococ
cus)属、エンテロコツカス(Enterococc
us)属、エシェリキア(Escherichia)属
、エンテロバクター(Enterobacter)属、
クレブシェラ(Klebsiella)属、セレビシエ
(Serratia)属、プロテウス(Proteus
)属、シュードモナス(P s e u d o m
o n a s )属等の菌種を挙げることができ、特
にメチシリン耐性スタフィロコッカス アウレウス(M
ethicillin resistantSta h
Iococcus aureus)およびチェナ
マイシン耐性シュードモナス アエルギノーサ(Thi
enamycinres i s t a n t P
s e u d o m o n a s 巨■加1
)に対して優れた抗菌活性を示した。Typical pathogens susceptible to the antibacterial agent of the present invention include, for example, Staphylococcus
cus), Enterococcus
us) genus, Escherichia genus, Enterobacter genus,
Klebsiella spp., Serratia spp., Proteus spp.
), Pseudomonas (Pseudomonas)
Bacterial species such as the genus M. on a s can be mentioned, and in particular, methicillin-resistant Staphylococcus aureus (M.
ethicillin resistant Sta h
Iococcus aureus) and chenamycin-resistant Pseudomonas aeruginosa (Th
Enemycinres ist a n t P
s e u d o m o n a s big ■ addition 1
) showed excellent antibacterial activity.
本発明化合物は、当分野で公知の固体または液体の賦形
剤の担体と混合し、非経口投与、経口投与、外部投与に
適した医薬製剤の形で使用することができる。主なもの
は、局所的または注射による非経口的(静注又は筋注)
な投与である。医薬製剤としては、例えば注射剤、シロ
ップ剤、乳剤等の液剤;錠剤、カプセル剤、粒剤等の固
形剤;軟膏、坐剤等の外用剤等が挙げられる。これらの
製剤には、必要に応じて塩基、助剤、安定化剤、湿潤剤
、乳化剤、吸収促進剤、界面活性剤等の通常使用される
添加剤が含まれていてもよい。The compounds of the present invention can be mixed with solid or liquid excipient carriers known in the art and used in the form of pharmaceutical formulations suitable for parenteral, oral, or external administration. The main ones are topical or parenteral (intravenous or intramuscular) by injection.
This is a very effective administration. Examples of pharmaceutical preparations include liquid preparations such as injections, syrups, and emulsions; solid preparations such as tablets, capsules, and granules; and external preparations such as ointments and suppositories. These preparations may contain commonly used additives such as bases, auxiliaries, stabilizers, wetting agents, emulsifiers, absorption enhancers, surfactants, etc., as required.
添加剤としては、例えば注射用蒸留水、リンゲル液、グ
ルコース、しょ糖シロップ、ゼラチン、食用油、カカオ
脂、エチレングリコール、しょ糖、とうもろこし澱粉、
ステアリン酸マグネシウム、タルク等があげられる。Examples of additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch,
Examples include magnesium stearate and talc.
投与量は、患者の症状、体重、年齢、性別、投与形態、
投与回数等によって異なるが、通常、成人に対しての好
ましい日用量は有効成分約5〜50mg/kg、子供に
対しての好ましい日用量は約5〜25 m g/kgの
範囲にあり、1日当り1回または数回に分けて投与する
のが好ましい。The dosage depends on the patient's symptoms, weight, age, gender, dosage form,
Although it varies depending on the number of administrations, etc., the preferred daily dose for adults is usually about 5 to 50 mg/kg of the active ingredient, and the preferred daily dose for children is about 5 to 25 mg/kg. It is preferable to administer once or in divided doses per day.
お び
実施例および参考例を挙げて本発明を更に具体的に説明
するが、本発明はこれらによって何ら限定されるもので
はない。The present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is not limited by these in any way.
実施例および参考例の薄層クロマトグラフは、プレート
としてSilicagel 60F、、、 (Merc
k)を、検出法としてUV検出器またはニンヒドリン発
色法を用いた。カラム用シリカゲルとしては、W a
k o g e l@C−300(和光純薬)を用いた
。NMRスペクトルは、重ジメチルスルホキシドまたは
重クロロホルム溶液で測定する場合には、内部基準とし
てテトラメチルシラン(TMS)を用い、XL−200
(200MHz ;Varian)型スペクトロメータ
を用いて測定し、全δ値をppmで示した。The thin layer chromatographs of Examples and Reference Examples were plated using Silicagel 60F (Merc
k), a UV detector or ninhydrin coloring method was used as the detection method. As the silica gel for columns, W a
Kogel@C-300 (Wako Pure Chemical Industries, Ltd.) was used. When measuring NMR spectra in deuterated dimethyl sulfoxide or deuterated chloroform solutions, tetramethylsilane (TMS) is used as an internal standard and XL-200
(200 MHz; Varian) type spectrometer, and all δ values are expressed in ppm.
NMR測定における略号の意味を以下に示す。The meanings of the abbreviations in NMR measurement are shown below.
S : シングレット
d : ダブレット
br: ブロード
m : マルチプレット
J : カップリング定数
H2: ヘル′ン
CDC1,: 重クロロホルム
CD、OD : 重メタノール
DMSO−da : 重ジメチルスルホキシドTFA
−d、 : 重トリフルオロ酢酸り、0: 重水
反応式における略号の意味を以下に示す。S: singlet d: doublet br: broad m: multiplet J: coupling constant H2: Hern CDC1,: heavy chloroform CD, OD: heavy methanol DMSO-da: heavy dimethyl sulfoxide TFA
-d, : heavy trifluoroacetic acid, 0: meanings of the abbreviations in the heavy water reaction formula are shown below.
Boc : tert−ブトキシカルボニル基
Bn : ベンジル基
Et: エチル基
Me : メチル基
Ts : p−)ルエンスルホニル基実施例
1
ソー8− ルー4−オ ソー3− ノ1ンカル ンl−
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−3−キノリンカルボン酸(17
0mg。Boc: tert-butoxycarbonyl group Bn: benzyl group Et: ethyl group Me: methyl group Ts: p-) luenesulfonyl group Example 1
cyclopropyl-6,7,8-trifluoro-1,4-
Dihydro-4-oxo-3-quinolinecarboxylic acid (17
0mg.
0 、6 m m o l ; 特開昭59−212
474号公報により製造)、trans−2−オキサ−
5,8−ジアザビシクロ[4,3,0]ノナン(76m
g 、 0 、6 m m o l )および1.8
−ジアザビシクロ[5,4,0]ウンデカ−7−エン(
0,09m/、 0.6m m o ! )のアセトニ
トリル(lom/)溶液を窒素気流中で4時間還流した
。室温で15時間撹拌した後、析出物を濾取し、アセト
ニトリルで洗浄して淡黄色粉末(114mg)を得た。0,6 mmol; JP-A-59-212
474), trans-2-oxa-
5,8-Diazabicyclo[4,3,0]nonane (76m
g, 0, 6 mmol) and 1.8
-diazabicyclo[5,4,0]undec-7-ene (
0.09m/, 0.6m m o! ) in acetonitrile (lom/) was refluxed for 4 hours in a nitrogen stream. After stirring at room temperature for 15 hours, the precipitate was collected by filtration and washed with acetonitrile to obtain a pale yellow powder (114 mg).
この粉末98.5mgをエタノール−塩化メチレンより
再結晶し、淡黄色結晶として標記化合物(73mg、収
率: 74.1%)を得た。98.5 mg of this powder was recrystallized from ethanol-methylene chloride to obtain the title compound (73 mg, yield: 74.1%) as pale yellow crystals.
TLC(Rf) + 0.48 (CH2C1,: M
eOH= 9 + 1)MP: 255℃(dec)
IR(KBr) cm−’ :3430.3050.2
900.1720゜1665、1625.1515.1
450.1410゜1330.131O
NMR(TFA−d、 : CDC1,= I : I
)δ:1.2〜1.6(4H,m)、3.5〜4.0
(3H,m)、 4.0〜4.5 (8H,m)、 8
.03 (IH,d、J = 12Hz)9.18 (
IH,s)
MS (m/e) : 392 CM” + H)U
V 2=’ n rn : 290 、9実施例2
ルー4−オ ソー3−キノ1ンカル゛ン1−シクロプロ
ピル−6,7−ジフルオロ−1,4−ジヒドロ−4−オ
キソ−3−キノリンカルボン酸(146mg、 0.5
5mmo7; 特開昭60−126,271号公報によ
り製造)、trans−2−オキサ−5,8−ジアザビ
シクロ[4,3,0]ノナン(70,4mg、 0.5
5mmof)および1.8−ジアザビシフo [5,4
,0]ウンデカ−7−エン(0,1m40.67mmo
r)を用いて、実施例1と同様の方法により標記化合物
(118mg、収率: 72.4%)を得た。TLC(Rf) + 0.48 (CH2C1,: M
eOH = 9 + 1) MP: 255°C (dec) IR (KBr) cm-': 3430.3050.2
900.1720°1665, 1625.1515.1
450.1410°1330.131O NMR (TFA-d, : CDC1, = I : I
) δ: 1.2 to 1.6 (4H, m), 3.5 to 4.0
(3H, m), 4.0-4.5 (8H, m), 8
.. 03 (IH, d, J = 12Hz) 9.18 (
IH, s) MS (m/e): 392 CM” + H)U
V2='nrn: 290, 9Example 2-4-oxo-3-quinolinecarbon 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarbon Acid (146 mg, 0.5
5mmo7; manufactured according to JP-A-60-126,271), trans-2-oxa-5,8-diazabicyclo[4,3,0]nonane (70.4mg, 0.5
5 mmof) and 1,8-diazabisifu o [5,4
,0]undec-7-ene (0.1m40.67mmo
r), the title compound (118 mg, yield: 72.4%) was obtained in the same manner as in Example 1.
TLC(Rf) : 0.52 (CH2Cl、 :
MeOH= 9 : 1)MP : 260°C(de
c)
IR(KBr) cm−’ :3420.2950.1
715.1630゜1550、1510.1480.1
450.1410゜1380、1360.1340.1
140.80ONMR(TFA−d、 : CDCL、
= 1 : 1)δ:1.2〜1.4(2H,m)、
1.5〜1.8 (2H,m)、3.5〜4.1(7H
,m)、4.1〜4.5 (4H,m)、7.30 (
IH。TLC (Rf): 0.52 (CH2Cl, :
MeOH=9:1) MP: 260°C (de
c) IR (KBr) cm-': 3420.2950.1
715.1630°1550, 1510.1480.1
450.1410°1380, 1360.1340.1
140.80ONMR (TFA-d, : CDCL,
= 1: 1) δ: 1.2 to 1.4 (2H, m),
1.5-1.8 (2H, m), 3.5-4.1 (7H
, m), 4.1-4.5 (4H, m), 7.30 (
IH.
d、J = 8Hz)、8.10 (IH,d、J =
14Hz)。d, J = 8Hz), 8.10 (IH, d, J =
14Hz).
9.11 (IH,s)
MS (m/e): 374 (M”+ H)UV 2
’::nm : 2B5.3
実施例3
ルー4−オキソ−3−ノリンカルボン
1−エチル−6,7−ジフルオロ−1,4−ジヒドロ−
4−オキソ−3−キノリンカルボン酸(139mg、
0.55mmol ;特開昭56−30,964号公報
により製造)、trans−2−オキソ−5,8−ジア
ザビシクロ[4,3,0]ノナン(70,4mg、 0
.55mmor)および1.8−ジアザビシフo [5
,4,0]ウンデカ−7−エン(0,1ml、 0.6
7mmo!>を用いて、実施例1と同様の方法により、
標記化合物(105mg収率ニア0%)を得た。9.11 (IH,s) MS (m/e): 374 (M”+H)UV 2
'::nm: 2B5.3 Example 3 -4-oxo-3-nolinecarbon 1-ethyl-6,7-difluoro-1,4-dihydro-
4-oxo-3-quinolinecarboxylic acid (139 mg,
0.55 mmol; manufactured according to JP-A-56-30,964), trans-2-oxo-5,8-diazabicyclo[4,3,0]nonane (70.4 mg, 0
.. 55 mmor) and 1,8-diazabisifu o [5
,4,0] undec-7-ene (0.1 ml, 0.6
7 mmo! > by the same method as in Example 1,
The title compound (105 mg yield near 0%) was obtained.
TLC(Rf) : 0.53 (CH*C1−: M
eOH= 9 : 1 )MP : 260℃(dec
)
IR(KBr) cm” :3420.2950.17
10.1630゜1550、1510.1480.14
50.1410゜13B0.1360.1340.11
40.80ONMR(TFA−d、 : CDCl5
= l : 1)δ: 1.71 (3H。TLC (Rf): 0.53 (CH*C1-: M
eOH = 9:1) MP: 260°C (dec
) IR (KBr) cm”: 3420.2950.17
10.1630°1550, 1510.1480.14
50.1410゜13B0.1360.1340.11
40.80ONMR (TFA-d, : CDCl5
= l: 1) δ: 1.71 (3H.
t、J = 6Hz)、3.5〜4.1 (6H,m)
、4.1〜4.5 (4H,m)、4.72 (2H,
q、J = 6Hz)。t, J = 6Hz), 3.5-4.1 (6H, m)
, 4.1-4.5 (4H, m), 4.72 (2H,
q, J = 6Hz).
6.85 (IH,d、J = 8Hz)、8゜17
(LH,d。6.85 (IH, d, J = 8Hz), 8°17
(LH, d.
J = 13Hz)、9.10 (IH,s)MS (
m/e) + 362 (M’ + H)UVλ=nm
: 285.3
実施例4
4−オキ八3− ノIンカルボン
l−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−3−キノリンカルボン酸(
170mg。J = 13Hz), 9.10 (IH,s)MS (
m/e) + 362 (M' + H)UVλ=nm
: 285.3 Example 4 4-Oxy3-Icarvone l-cyclopropyl-6,7,8-trifluoro-1,
4-dihydro-4-oxo-3-quinolinecarboxylic acid (
170mg.
0 、6 m m o ! )、cis−2−オキサ−
5,8−ジアザビシクロ[4,3,0]ノナン(77m
g、0.6mmoりおよび1.8ジアザビシクロ[5,
4,0]ウンデカ−7−エン(0,09m l 、 0
、6 m m o / )を用いて、実施例1と同様
の方法により、標記化合物(107mg、収率: 45
.7%)を得た。0,6 m m o! ), cis-2-oxa-
5,8-diazabicyclo[4,3,0]nonane (77m
g, 0.6 mmol and 1.8 diazabicyclo[5,
4,0] undec-7-ene (0,09 ml, 0
, 6 m m o / ), the title compound (107 mg, yield: 45
.. 7%).
TLC(Rf) : 0.57 (CH,C1,: M
eOH= 9 : 1)MP : 210’C(dec
)
IR(KBr) am” :3430.3330.29
50.1735゜1620、1600.1515.14
50.1405゜1335、1315.80O
NMR(CDC1,)δ: 1.0〜1.4 (4H,
m)、 2.7〜2.84 (IH,m)、 3.2〜
3.4 (IH,m)。TLC (Rf): 0.57 (CH, C1,: M
eOH = 9: 1) MP: 210'C (dec
) IR(KBr) am” :3430.3330.29
50.1735°1620, 1600.1515.14
50.1405°1335, 1315.80O NMR (CDC1,) δ: 1.0-1.4 (4H,
m), 2.7~2.84 (IH, m), 3.2~
3.4 (IH, m).
3.4〜3.8 (4H,m)、 3.8〜4.4 (
5H。3.4~3.8 (4H, m), 3.8~4.4 (
5H.
m)、7.97 (IH,dd、J=2& 14Hz)
。m), 7.97 (IH, dd, J=2&14Hz)
.
8.78 (IH,s)
MS (m/e): 392 (M”+ H)UVλ=
rnm : 292.7
実施例5
イル−4−オ ソー3− ノ1ンカルポン1−シクロプ
ロピル−6,7−ジフルオロ−1,4−ジヒドロ4−オ
キソ−3−キノリンカルボン酸(82,2mg、 0.
31mmor)、cis−2−オキサ−5,8−ジアザ
ビシフo [4,3,O]ノナ7 (40mg、 0.
31mmor)および1.8−ジアザビシクロ[5,4
,0]ウンデカ−7−エン(47111,0,31m
m o ! )を用いて、実施例1と同様の方法により
標記化合物(s3mg、収率・70,6%)を得た。8.78 (IH,s) MS (m/e): 392 (M”+H)UVλ=
rnm: 292.7 Example 5 yl-4-o-3-no-1-carpone-1-cyclopropyl-6,7-difluoro-1,4-dihydro 4-oxo-3-quinolinecarboxylic acid (82.2 mg, 0 ..
31 mmor), cis-2-oxa-5,8-diazabisifu o[4,3,O]nona7 (40 mg, 0.
31 mmor) and 1,8-diazabicyclo[5,4
,0] undec-7-ene (47111,0,31m
Mo! ), the title compound (s3 mg, yield: 70.6%) was obtained in the same manner as in Example 1.
TLC(Rf) : 0.54 (CH=Cb : M
eOH= 9 : I )MP : 224℃(dec
)
IR(KBr)cm−’ : 3430,3050.2
950.28B0゜2850、1720.1630.1
510.1470゜1400、 1340. 1330
.1080’、 81ONMR(CDC1,: CD、
OD = 6 : 1) 6 : 1.2〜1.6(4
H,m)、 2.7〜2.9 (IH,m)、 3.
2〜3.4 (IH,m)、 3.5〜4.6 (9H
,m)。TLC (Rf): 0.54 (CH=Cb: M
eOH = 9: I) MP: 224°C (dec
) IR (KBr) cm-': 3430, 3050.2
950.28B0゜2850, 1720.1630.1
510.1470°1400, 1340. 1330
.. 1080', 81ONMR (CDC1,: CD,
OD = 6:1) 6:1.2~1.6(4
H, m), 2.7-2.9 (IH, m), 3.
2-3.4 (IH, m), 3.5-4.6 (9H
, m).
7.06 (IH,d、J==8Hz)、 8.01
(IH。7.06 (IH, d, J==8Hz), 8.01
(IH.
d、J= 14Hz)、 8.82 (IH,s)MS
(m/e) : 374 (M’+ H)UVλ’:
rnm : 2B5.9
実施例6
4−オキ゛へ3−キノリンカルボン
ソー3−キノリンカルボン酸(102mg、0.4mm
o!>、cis−2−オキサ−5,8−ジアザビシクロ
[4,3,0コノナン(51mg、0.4mmor)お
よび1.8−ジアザビシクロ[5,4,0]ウンデカ−
7−エン(60ti 、 0 、4 m m o !
)を用いて、実施例1と同様の方法により標記化合物(
60mg、収率: 41.6%)を得た。d, J = 14Hz), 8.82 (IH, s) MS
(m/e): 374 (M'+H)UVλ':
rnm: 2B5.9 Example 6 4-oxy-3-quinolinecarboxylic acid (102 mg, 0.4 mm
o! >, cis-2-oxa-5,8-diazabicyclo[4,3,0 cononane (51 mg, 0.4 mmor) and 1,8-diazabicyclo[5,4,0]undec-
7-ene (60ti, 0, 4 mmo!
), the title compound (
60 mg, yield: 41.6%) was obtained.
TLC(Rf) : 0.56 (CH2C12: M
eOH= 9 : l )MP : 232℃(dec
)
IR(KBr) cm−’ : 3440.3050.
2940.2880゜1700、1830.1515.
1465.1410゜1375、1350.81O
NMR(CDC1,: CD、OD = 6 : 1)
δ: 1.77 (3H。TLC (Rf): 0.56 (CH2C12: M
eOH = 9: l) MP: 232°C (dec
) IR (KBr) cm-': 3440.3050.
2940.2880°1700, 1830.1515.
1465.1410° 1375, 1350.81O NMR (CDC1,: CD, OD = 6: 1)
δ: 1.77 (3H.
t、J=6Hz)、 2.8〜3.0 (IH,m)、
3.2〜3.4 (IH,m)、 3.7〜4.4
(9H,m)。t, J=6Hz), 2.8-3.0 (IH, m),
3.2-3.4 (IH, m), 3.7-4.4
(9H, m).
4.52 (2H,q、J =6Hz)、 6.62
(IH。4.52 (2H, q, J = 6Hz), 6.62
(IH.
d、J = 8Hz)、 8.10 (IH,d、J
= 14Hz)。d, J = 8Hz), 8.10 (IH, d, J
= 14Hz).
8.79 (IH,s)
MS (m/e): 362 (M”+ H)UVλ=
−nm:286.7
I−エチル−6,7−ジフルオロ−1,4−ジヒドロ−
4−オキ実施例7
左tltM乙敢
l−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−3−キノリンカルボン酸(
160mg。8.79 (IH,s) MS (m/e): 362 (M”+H)UVλ=
-nm: 286.7 I-ethyl-6,7-difluoro-1,4-dihydro-
4-Oki Example 7 Left tltM Otsugan l-cyclopropyl-6,7,8-trifluoro-1,
4-dihydro-4-oxo-3-quinolinecarboxylic acid (
160mg.
0 、56 m m o l )、trans−5−メ
チル−2−オキサ−5,8−ジアザビシクロ[4,3,
0]ノナン(80mg、 0.56mmoりおよび1.
8−ジアザビシクロ[5,4,0]ウンデカ−7エ:/
(84,#、 0.56mmor)を用いて、実施例
1と同様の方法により標記化合物(51mg、収率:
22.5%)を得た。0,56 mmol), trans-5-methyl-2-oxa-5,8-diazabicyclo[4,3,
0] Nonane (80 mg, 0.56 mmol and 1.
8-diazabicyclo[5,4,0]undec-7e:/
The title compound (51 mg, yield:
22.5%).
TLC(Rf) + 0.50 (CH−CL : M
eOH= 9 : l )MP : 216℃(dec
)
IR(KBr) cm−’ : 3420.1730.
1625.1520゜455
NMR(CDCIs) δ: 1.0〜1.35 (
4H,m)、 2.1〜2.45 (lH,m)、
2.32 (3H,s)、 2.75〜2.9 (IH
,m)、 3.6〜4.5 (9H,m)。TLC (Rf) + 0.50 (CH-CL: M
eOH = 9: l) MP: 216°C (dec
) IR (KBr) cm-': 3420.1730.
1625.1520°455 NMR (CDCIs) δ: 1.0-1.35 (
4H, m), 2.1 to 2.45 (lH, m),
2.32 (3H, s), 2.75-2.9 (IH
, m), 3.6-4.5 (9H, m).
7.88 (IH,dd、J=2& 14Hz)、8.
76(LH,s)
MS (m/e) : 406 (M−十H)UVλ:
’nm : 291.1
参考例1
trans−2−オ −58−シア ビシ 口 4.
3.Oナン1)
1−tert−ブトキシカルボニル−3,4−エポキシ
ピロリジン(3,72g、 20mmo/ ;特開昭6
4−3181により製造)およびベンジルアミン(4,
36m/、 40m m o I )のエタノール(4
0mり溶液を3日間還流した。反応溶液を水冷した後、
析出した結晶を濾取し、エタノールで洗浄し、tran
s−3−ベンジルアミン−1−tert−ブトキシカル
ボニル−4−ヒドロキシピロリジン(5,44g、収率
: 92.8%)を淡黄色結晶として得た。7.88 (IH, dd, J=2&14Hz), 8.
76 (LH, s) MS (m/e): 406 (M-10H) UVλ:
'nm: 291.1 Reference Example 1 trans-2-o-58-cyabisi 4.
3. O Nan 1) 1-tert-butoxycarbonyl-3,4-epoxypyrrolidine (3,72g, 20mmo/; JP-A-1983
4-3181) and benzylamine (4,
36 m/, 40 m m o I) of ethanol (4
The 0ml solution was refluxed for 3 days. After cooling the reaction solution with water,
The precipitated crystals were collected by filtration, washed with ethanol, and tran
s-3-Benzylamine-1-tert-butoxycarbonyl-4-hydroxypyrrolidine (5.44 g, yield: 92.8%) was obtained as pale yellow crystals.
TLC(Rf) : 0.62 (CH,C1,: M
eOH= 9 : 1)IR(KBr) cm−’ :
3250.2975.2925.1670゜1475
、1450.1420.1360.1170゜11O
NMR(DMSO−d、) : 1.35 (9H,s
)、 2.9〜3.0(2H,br)、 3.0〜3.
1 (3H,m)、 3.2〜3.3 (3H,m)、
3.95〜4.0 (2H,br)。TLC (Rf): 0.62 (CH, C1,: M
eOH = 9: 1) IR (KBr) cm-':
3250.2975.2925.1670°1475
, 1450.1420.1360.1170°11O NMR (DMSO-d,): 1.35 (9H,s
), 2.9-3.0 (2H, br), 3.0-3.
1 (3H, m), 3.2-3.3 (3H, m),
3.95-4.0 (2H, br).
7.1〜7.4 (5H,m)
MS (m/e) : 294 (M”+ H)2)
trans−3−ベンジルアミノ−1−tert−ブト
キシカルボニル−4化ドロキシピロリジン(5,44g
、 18.6mmof)塩化メチレン(20mi’)溶
液に一20℃で撹拌下に、クロロアセチルクロリド(1
,78m/、 22.3mmor)の塩化メチレン(6
m/)溶液を滴下した。反応溶液を室温で1時間撹拌し
た後、反応液に水50m4を加えた。有機層をIN塩酸
、5%炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナ
トリウムで乾燥し、溶媒を減圧下で留去した。残渣をシ
リカゲルカラムクロマトグラフィー (Wakogel
@C−300゜100m4 CHsC1* : MeO
H= 100 : 1−10 : 1)にて精製し、t
rans−3−[N−ベンジル−N−(クロロアセチル
)アミノ]−1−tert−ブトキシカルボニル−4−
ヒドロキシピロリジン(6,23g、収率: 90.6
%)を得た。7.1-7.4 (5H, m) MS (m/e): 294 (M''+H)2) trans-3-benzylamino-1-tert-butoxycarbonyl-4-droxypyrrolidine (5, 44g
, 18.6 mmof) methylene chloride (20 mi') was added with chloroacetyl chloride (18.6 mmof) under stirring at -20°C.
,78 m/, 22.3 mmor) of methylene chloride (6
m/) solution was added dropwise. After stirring the reaction solution at room temperature for 1 hour, 50 m4 of water was added to the reaction solution. The organic layer was washed with IN hydrochloric acid and 5% aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel
@C-300゜100m4 CHsC1*: MeO
Purified at H = 100: 1-10: 1), t
rans-3-[N-benzyl-N-(chloroacetyl)amino]-1-tert-butoxycarbonyl-4-
Hydroxypyrrolidine (6.23g, yield: 90.6
%) was obtained.
TLC(Rf) : 0.59 (CH,CI、 :
MeOH= 9 : 1)IR(KBr) cm−’
: 3400.2970.1690.1860゜141
0.1360.116O
NMR(CDCIs)δ: 1.42 (9H,s)、
3.0〜3.2(2H,m)、 3.2〜3.35
(2H,m)、 4.04(2H,s)、 4.1〜4
.8 (4H,m)、 7.1〜およびトリエチルアミ
ン(3,36m4.24mmor)の7.5 (5h、
m)
MS (m/e): 370 (M”+ H)3)
trans−3−[N−ベンジル−N−(クロロアセチ
ル)アミノ]−1−tert−ブトキシカルボニル−4
−ヒドロキシピロリジン(11,38g、 30.8m
mor)のテトラヒドロフラン(50m4)溶液にカリ
ウムtert−ブトキシド(3,47g、 31mmo
りを室温で撹拌下に加えた。反応液を10分間撹拌した
後、溶媒を減圧下で留去した。残渣をシリカゲルカラム
クロマトグラフィ(W a k o g e l@C−
300、200m l 、 n −ヘキサン:酢酸エチ
ル=10:1−41:1)で精製し、trans−5−
ベンジル−8−tert−ブトキシカルボニル−2−オ
キサ−4−オキソ−5,8−ジアザビシクロ(4,s、
O]ノナン(5,01g、収率: 48.9%)を得た
。TLC (Rf): 0.59 (CH, CI, :
MeOH=9:1)IR(KBr) cm-'
: 3400.2970.1690.1860°141
0.1360.116O NMR (CDCIs) δ: 1.42 (9H, s),
3.0-3.2 (2H, m), 3.2-3.35
(2H, m), 4.04 (2H, s), 4.1~4
.. 8 (4H, m), 7.1 to 7.5 (5h,
m) MS (m/e): 370 (M”+H)3) trans-3-[N-benzyl-N-(chloroacetyl)amino]-1-tert-butoxycarbonyl-4
-Hydroxypyrrolidine (11.38g, 30.8m
potassium tert-butoxide (3.47 g, 31 mmol) in tetrahydrofuran (50 m4)
was added under stirring at room temperature. After stirring the reaction solution for 10 minutes, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (WAKOGEL@C-
Trans-5-
Benzyl-8-tert-butoxycarbonyl-2-oxa-4-oxo-5,8-diazabicyclo(4,s,
O]nonane (5.01 g, yield: 48.9%) was obtained.
TLC(Rf) : 0.6 (n−hexanq :
EtOAc = 1 : 1)IR(KBr) cm
−’ :3500.2970.2890.1700゜1
670.1480,1410,1365,1180゜1
110、 1010
95N (CDCIs) δ: 1.42 (9H,
s)、 3.0〜3.3(2H,m)、 3.5〜
3.9 (3H,m)、3.9〜4.10 (2H,m
)、4.48 (2H,s)、5.10(IH,d、J
=15Hz)、7.2〜7.6 (5H,m)MS (
m/e): 333 (M”+ H)4)
trans−5−ベンジル−8−tert−ブトキシカ
ルボニル−2−オキサ−4−オキソ−5,8−ジアザビ
シクロ[4,3,0]ノナン(510m g 、 1
、53 m m o / )のテトラヒドロフラン(l
om/)溶液に水冷撹拌下でIM ジボラン−テトラヒ
ドロフラン溶液(1,6m/、1.6mmof)を滴下
した。反応溶液を室温下で、15時間撹拌した後、水冷
下で水1rr+4、さらに室温下で炭酸カリウム飽和水
溶液(2m4)を加え、この溶液を2時間撹拌した。こ
の溶液に酢酸エチル(20rr+4)を加え、有機層を
飽和食塩水で洗浄し、溶媒を減圧下で留去した。残渣を
シリカゲルカラムクロマトグラフィー (Wakoge
l・C−300,20m/、 ヘキサン:酢酸エチル=
lO:1−+1:1)で精製し、trans5−ベンジ
ル−8−tert−ブトキシカルボニル−2−オキサ−
5,8−ジアザビシクロ[4,3,0]ノナン(436
mg。TLC (Rf): 0.6 (n-hexanq:
EtOAc = 1 : 1) IR(KBr) cm
-': 3500.2970.2890.1700゜1
670.1480, 1410, 1365, 1180゜1
110, 1010 95N (CDCIs) δ: 1.42 (9H,
s), 3.0~3.3 (2H, m), 3.5~
3.9 (3H, m), 3.9-4.10 (2H, m
), 4.48 (2H, s), 5.10 (IH, d, J
= 15Hz), 7.2-7.6 (5H, m) MS (
m/e): 333 (M”+H)4) trans-5-benzyl-8-tert-butoxycarbonyl-2-oxa-4-oxo-5,8-diazabicyclo[4,3,0]nonane (510 m g, 1
, 53 m m o / ) of tetrahydrofuran (l
IM diborane-tetrahydrofuran solution (1.6 m/, 1.6 mmof) was added dropwise to the IM diborane-tetrahydrofuran solution (1.6 m/, 1.6 mmof) under water-cooling and stirring. After stirring the reaction solution at room temperature for 15 hours, 1rr+4 of water was added under water cooling, and a saturated aqueous potassium carbonate solution (2 m4) was added at room temperature, and this solution was stirred for 2 hours. Ethyl acetate (20rr+4) was added to this solution, the organic layer was washed with saturated brine, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakoge
l・C-300,20m/, hexane:ethyl acetate=
trans5-benzyl-8-tert-butoxycarbonyl-2-oxa-
5,8-diazabicyclo[4,3,0]nonane (436
mg.
収率: 89.6%)を得た。Yield: 89.6%) was obtained.
TLC(Rf) : 0.55 (n−hexane
: EtOAc = 2 : 1)IR(KBr) c
m−’ : 3420.2980.2870.1690
゜1415、1395.1365.1140.1010
9ON (CDCl2)δ: 1.44 (9H,s)
、 2.05〜2.5(2H,m)、 2.6〜2.7
(IH,m)、 2.9〜3.3 (3H,m)、
3.5〜4.0 (6H,m)、 7.2〜7.5 (
5H,brs)
MS (m/e) : 319 (M= + H)5)
2−オキサ−5,8−ジアザビシクロ[4,3,0]ノ
ナン(500mg1 、57 m m o Z )のメ
タノール(5m/)溶液に、20%パラジウム炭素(3
00mg)を加え、室温、水素ガス常圧下で、16時間
水素添加した。触媒を濾別した後、濾液の溶媒を減圧下
で留去した。残渣をシリカゲルカラムクロマトグラフィ
ー(Wakogel・C−300,20m/、 CH,
C1* : MeOH= 100 : 1−10 :
1)で精製し、trans−8−tert−ブトキシカ
ルボニル−2オキサ−5,8−ジアザビシクロ[4,3
,0]ノナン(275mg。TLC (Rf): 0.55 (n-hexane
: EtOAc = 2 : 1) IR(KBr) c
m-': 3420.2980.2870.1690
゜1415, 1395.1365.1140.1010
9ON (CDCl2)δ: 1.44 (9H, s)
, 2.05-2.5 (2H, m), 2.6-2.7
(IH, m), 2.9-3.3 (3H, m),
3.5~4.0 (6H, m), 7.2~7.5 (
5H, brs) MS (m/e): 319 (M = + H) 5) 2-oxa-5,8-diazabicyclo[4,3,0]nonane (500 mg1, 57 m m o Z ) in methanol (5 m /) solution, add 20% palladium on carbon (3
00 mg) was added thereto, and hydrogenation was carried out at room temperature and under hydrogen gas normal pressure for 16 hours. After filtering off the catalyst, the solvent of the filtrate was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel C-300, 20m/, CH,
C1*: MeOH=100: 1-10:
1), trans-8-tert-butoxycarbonyl-2oxa-5,8-diazabicyclo[4,3
, 0] nonane (275 mg.
収率: 76.8%)を得た。Yield: 76.8%) was obtained.
TLC(Rf) : 0.44 (CH,C1,: M
eOH= 9 : 1)IR(KBr) cm−’ :
3420.2980.2880.1690゜1415、
1395.1360.1140.1090゜03O
NMR(CDC1,: CD、OD = 4 : 1
)δ: 1.46 (9H,s)。TLC (Rf): 0.44 (CH, C1,: M
eOH = 9: 1) IR (KBr) cm-':
3420.2980.2880.1690°1415,
1395.1360.1140.1090°03O NMR (CDC1,: CD, OD = 4: 1
) δ: 1.46 (9H, s).
2.8〜3.2 (4H,m)、 3.4〜3.95
(5H。2.8~3.2 (4H, m), 3.4~3.95
(5H.
m)、 3.95〜4.05 (IH,m)MS (m
/e) : 229 (M” + H)trans−5
−ベンジル−8−tert−ブトキシカルボニルtra
ns−8−tert−ブトキシカルボニル−2−オキサ
−5,8−ジアザビシクo [4,3,0]ノナン(2
74mg、 1.2m m o l )の塩化メチレン
(4m7)溶液に水冷撹拌下でトリフルオロ酢酸(3m
/)を滴下した。0℃で2時間撹拌した後、溶媒を留去
した。残渣にジイソプロピルエーテルを加え、固化物を
ジイソプロピルエーテルで洗浄し、乾燥してtrans
−2−オキサ−5,8−ジアザビシクロ[4,3,0]
ノナンのトリフルオロ酢酸塩(405mg、収率: 9
2.7%)を得た。m), 3.95-4.05 (IH, m) MS (m
/e): 229 (M" + H) trans-5
-benzyl-8-tert-butoxycarbonyltra
ns-8-tert-butoxycarbonyl-2-oxa-5,8-diazabicyclo[4,3,0]nonane (2
To a solution of 74 mg, 1.2 mmol) in methylene chloride (4 m7) was added trifluoroacetic acid (3 m
/) was added dropwise. After stirring at 0°C for 2 hours, the solvent was distilled off. Diisopropyl ether is added to the residue, the solidified product is washed with diisopropyl ether, dried and trans
-2-oxa-5,8-diazabicyclo[4,3,0]
Nonane trifluoroacetate (405 mg, yield: 9
2.7%).
TLC(Rf) + 0.04 (CH,C1,: M
eOH= 9 : 1)IR(KBr) cm−’ :
3420.2970.1675.1430゜1205
、1180.114O
NMR(DMSO−da)δ: 2.95〜3.30
(3H,m)。TLC (Rf) + 0.04 (CH, C1,: M
eOH = 9: 1) IR (KBr) cm-':
3420.2970.1675.1430°1205
, 1180.114O NMR (DMSO-da) δ: 2.95-3.30
(3H, m).
3.3〜3.7 (4)1.m)、 3.7〜4.0
(2)(。3.3-3.7 (4)1. m), 3.7-4.0
(2)(.
m)、 4.0〜4.1 (IH,m)、 9.64
(4H。m), 4.0-4.1 (IH, m), 9.64
(4H.
br)
MS (m/s): 129 (M’+ H)このトリ
フルオロ酢酸塩のメタノール(20mj)溶液にアンバ
ーライト(Amberlite’) IRA401(5
g)を加え、2時間撹拌した。樹脂を濾別し、濾液の溶
媒を減圧下で留去して、油状のtrans−2−オキサ
−5,8−ジアザビシフo [4,3,0]ノナン(1
65mg)を得た。br) MS (m/s): 129 (M'+H) Amberlite' IRA401 (5
g) was added and stirred for 2 hours. The resin was filtered off, and the solvent of the filtrate was distilled off under reduced pressure to obtain oily trans-2-oxa-5,8-diazabisipho[4,3,0]nonane (1
65 mg) was obtained.
参考例2
cis−2−オ −58−ジ ビシ ロ 4.3.
Oす1)
1−tert−ブトキシカルボニル−3−ピロール(8
,05g。Reference Example 2 cis-2-o-58-di-bicylo 4.3.
Osu1) 1-tert-butoxycarbonyl-3-pyrrole (8
,05g.
47.4mmo/)、クロラミンT (22,6g、
59.3mmo7)、0.079M四酸化オスミウム−
ヘキサン溶液(6,0m40.47mmof)および硝
酸銀(10,07g、 59.3mmo/)のtert
−ブタノール(400m4)溶液を60℃で18時間撹
拌した。析出物を濾別した後、濾液の溶媒を減圧留去し
た。残渣にジエチルエーテルを加え、析出物を濾取して
cis−1−tert−ブトキシカルボニル−3化ドロ
キシ−4−(p−トルエンスルホニルアミノ)ピロリジ
ン(11,70g、収率: 65.3%)を得た。47.4 mmo/), Chloramine T (22.6 g,
59.3mmo7), 0.079M osmium tetroxide
tert of hexane solution (6.0 m 40.47 mmof) and silver nitrate (10.07 g, 59.3 mmo/)
-Butanol (400m4) solution was stirred at 60°C for 18 hours. After filtering off the precipitate, the solvent of the filtrate was distilled off under reduced pressure. Diethyl ether was added to the residue, and the precipitate was collected by filtration to give cis-1-tert-butoxycarbonyl-droxy-4-(p-toluenesulfonylamino)pyrrolidine (11.70 g, yield: 65.3%) I got it.
TLC(Rf) : 0.33 (n−hexane
: EtOAc = l : 1)IR(KBr) c
m” : 3400.3275.1690.1660゜
1420、1325.1165.1150.10109
ON (DMSO−da) :’ 1.33 (9H,
s)、、 2.39 (3H。TLC (Rf): 0.33 (n-hexane
: EtOAc = l : 1) IR(KBr) c
m”: 3400.3275.1690.1660°1420, 1325.1165.1150.10109
ON (DMSO-da):' 1.33 (9H,
s),, 2.39 (3H.
s)、 2.7〜4.0 (6H,m)、 5.30
(IH。s), 2.7-4.0 (6H, m), 5.30
(IH.
brs)、 7.40 (2H,d、J=8Hz)MS
(m/e) : 379 (M” + Na)2)
滴下で過剰の液体アンモニアを留去した。残渣に水(1
00m4)、酢酸エチル(100m/)を加え、有機層
を無水硫酸ナトリウムで乾燥した。溶媒を減圧下で留去
し、cis−3−アミノ−1−tert−ブトキシカル
ボニル−4−ヒドロキシピロリジン(4,04g、収率
:56.1%)を得た。brs), 7.40 (2H, d, J=8Hz) MS
(m/e): 379 (M" + Na)2) Excess liquid ammonia was distilled off by dropwise addition. Water (1
00 m4) and ethyl acetate (100 m/4) were added, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain cis-3-amino-1-tert-butoxycarbonyl-4-hydroxypyrrolidine (4.04 g, yield: 56.1%).
TLC(Rf) : 0.20 (CHzCIt :
MeOH= 9 : I )IR(KBr) am”
: 3400.2960.1680.1560゜141
0、 116O
NMR(DMSO−d、)δ: 1.38 (9H,s
)、 2.4〜3.6 (6H,m)、3.98 (I
H,brs)MS (m/e): 203 (M”+
H)3)
cis−1−tert−ブトキシカルボニル−3−ヒド
ロキシ−4−(p−)ルエンスルホニルアミノ)ピロリ
ジン(12,7g 、 35 、6 m m o l
)の液体アンモニア(100m4)溶液にナトリウム(
4,14g、 O,18mof)を加えた。TLC (Rf): 0.20 (CHzCIt:
MeOH=9:I)IR(KBr)am”
: 3400.2960.1680.1560°141
0, 116O NMR (DMSO-d,) δ: 1.38 (9H,s
), 2.4-3.6 (6H, m), 3.98 (I
H, brs) MS (m/e): 203 (M”+
H) 3) cis-1-tert-butoxycarbonyl-3-hydroxy-4-(p-)luenesulfonylamino)pyrrolidine (12,7 g, 35,6 mmol
) in liquid ammonia (100 m4) solution of sodium (
4,14 g, O, 18 mof) were added.
反応溶液を−50〜−78℃で1時間撹拌した後、室c
is−3−アミノ−1−tert−ブトキシカルボニル
−4−ヒドロキシピロリジン(4,04g、 20mm
or)、ベンズアルデヒド(3、2g 、 30 m
m o ! )のアセトニトリル(40m/)溶液に、
水冷撹拌下でシアノ水素化はう素ナトリウム(1,21
g、 32mmof)を加え、15分間撹拌した。反応
溶液に酢酸を加えて中和し、水(70m/)を加え、酢
酸エチル(loomりで抽出した。有機層を無水硫酸ナ
トリウムで乾燥し、溶媒を常圧下で留去した。残渣をシ
リカゲルカラムクロマトグラフィ (Wakogel
@C−300,100m/。The reaction solution was stirred at -50 to -78°C for 1 hour, then transferred to room c.
is-3-amino-1-tert-butoxycarbonyl-4-hydroxypyrrolidine (4,04g, 20mm
or), benzaldehyde (3,2g, 30m
Mo! ) in acetonitrile (40 m/) solution,
Sodium cyanohydride (1,21
g, 32 mmof) was added and stirred for 15 minutes. The reaction solution was neutralized by adding acetic acid, water (70 m/) was added, and extracted with ethyl acetate (rooming). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under normal pressure. The residue was purified using silica gel. Column chromatography (Wakogel
@C-300,100m/.
CHzCIt : MeOH= l 00 : l →
10 : 1 )で精製し、cis−3−ベンジルアミ
/−1−tert−ブトキシカルボニル−4−ヒドロキ
シピロリジン(2,17g、収率二2462%)を得た
。CHzCIt : MeOH= l 00 : l →
10:1) to obtain cis-3-benzylamine/-1-tert-butoxycarbonyl-4-hydroxypyrrolidine (2.17 g, yield: 22462%).
TLC(Rf) : 0.63 (CH*CI−: M
eOH= 9 : 1)IR(KBr) cm” :
3400.2970.2920.2870゜1690、
1670.1410.1360.1160゜12O
NMR(DMSO−d−) : 1.39 (9H,s
)、 2.8〜3.8(7H,m)、 4.12 (I
H,brs)、 5.04 (IH。TLC (Rf): 0.63 (CH*CI-: M
eOH = 9: 1) IR (KBr) cm”:
3400.2970.2920.2870°1690,
1670.1410.1360.1160°12O NMR (DMSO-d-): 1.39 (9H, s
), 2.8-3.8 (7H, m), 4.12 (I
H, brs), 5.04 (IH.
br)、 7.2〜7.6 (5H,m)MS (m/
e) : 293 (M” + H)cis−3−ベン
ジルアミノ−1−tert−ブトキシカルボニル−4−
ヒドロキシピロリジン(440mg、 1.5mmof
)、トリエチルアミン(0、28m l 、 2 m
m o / )、りo。br), 7.2-7.6 (5H, m) MS (m/
e): 293 (M” + H)cis-3-benzylamino-1-tert-butoxycarbonyl-4-
Hydroxypyrrolidine (440mg, 1.5mmof
), triethylamine (0, 28 ml, 2 m
m o / ), rio.
アセチルクロリド(0,144m4.1.8mmor)
を用いて、参考例1−2と同様の方法でcis−3−[
N−ベンジル−N−(クロロアセチル)アミノ]−1−
tert−ブトキシカルボニル−4−ヒドロキシピロリ
ジン(555mg。Acetyl chloride (0,144m4.1.8mmol)
cis-3-[
N-benzyl-N-(chloroacetyl)amino]-1-
tert-butoxycarbonyl-4-hydroxypyrrolidine (555 mg).
収率: 100%)を得た。Yield: 100%) was obtained.
TLC(Rf) + 0.24 (n−hexane
: EtOAc = 1 : 1)IR(KBr) c
m−’ : 3410.2975.1695.1660
゜1410、1165.1135
NMR(CDCl2)δ: 1.41 (9H,s)、
3.3〜3.7(4)T、m)、 3.95〜4.3
(2H,m)、4.2〜4.7 (2H,m)、4.
85 (2H,brs)、 7.0〜7.5 (5H,
m)
MS (m/e): 370 (M゛+ H)5)
(IH,d、J = 16Hz)、 4.40 (IH
,d、J =16Hz)、 5.1〜5.22 (IH
,m)、 7.2〜7.5 (5H,m)
MS (m/e): 333 (M”+H)6)
cis−3−[N−ベンジル−N−(クロロアセチル)
アミノ]−1−tert−ブトキシカルボニル−3−ヒ
ドロキシピロリジン(535mg、 1.45mmo7
)、カリウムtert−ブトキシド(165mg、 1
.47mmor)を用いて参考例1−3と同様の方法に
より、cis−5−ベンジル−8−tert−ブトキシ
カルボニル−2−オキソ−5,8−ジアザビシフo [
4,3,0]ノナン(352mg、収率: 73.1%
)を得た。TLC (Rf) + 0.24 (n-hexane
: EtOAc = 1 : 1) IR(KBr) c
m-': 3410.2975.1695.1660
゜1410, 1165.1135 NMR (CDCl2) δ: 1.41 (9H, s),
3.3-3.7(4)T, m), 3.95-4.3
(2H, m), 4.2-4.7 (2H, m), 4.
85 (2H, brs), 7.0~7.5 (5H,
m) MS (m/e): 370 (M゛+H)5) (IH, d, J = 16Hz), 4.40 (IH
, d, J = 16Hz), 5.1~5.22 (IH
, m), 7.2-7.5 (5H, m) MS (m/e): 333 (M"+H)6) cis-3-[N-benzyl-N-(chloroacetyl)
amino]-1-tert-butoxycarbonyl-3-hydroxypyrrolidine (535 mg, 1.45 mmo7
), potassium tert-butoxide (165 mg, 1
.. cis-5-benzyl-8-tert-butoxycarbonyl-2-oxo-5,8-diazabisifu o [
4,3,0]nonane (352 mg, yield: 73.1%
) was obtained.
TLC(Rf) : 0.43 (n−hexane
: EtOAc = 1 : 1)IR(KBr) c
m−’ : 3480.2970.2930.2880
゜1700、1680.1650.1470.1400
゜1360、1340.1260.1160.11l1
00N (CDCIs) 6 : 1.44 (9H,
s)、 2.14〜2.30(IH,m)、 2.4〜
4.2 (6H,m)、 4.22cis−5−ベンジ
ル−8−tert−ブトキシカルボニル−2−オキサ−
4−オキソ、5,8−ジアザビシクロ[4,3,0]ノ
ナン(1,313g、 3.95mmo/)、IM ジ
ポラン−テトラヒドロフラン溶液(3,95m43.9
5mmoりを用いて、参考例1−4と同様の方法により
、cis−5−ベンジル−8−tert−ブトキシカル
ボニル−2−オキサ−5,8−ジアザビシクロ[4,3
,0]ノナン(1,12g、収率: 89.4%)を得
た。TLC (Rf): 0.43 (n-hexane
: EtOAc = 1 : 1) IR(KBr) c
m-': 3480.2970.2930.2880
゜1700, 1680.1650.1470.1400
゜1360, 1340.1260.1160.11l1
00N (CDCIs) 6: 1.44 (9H,
s), 2.14~2.30 (IH, m), 2.4~
4.2 (6H, m), 4.22cis-5-benzyl-8-tert-butoxycarbonyl-2-oxa-
4-oxo,5,8-diazabicyclo[4,3,0]nonane (1,313g, 3.95mmo/), IM diporane-tetrahydrofuran solution (3,95m43.9
Cis-5-benzyl-8-tert-butoxycarbonyl-2-oxa-5,8-diazabicyclo[4,3
,0]nonane (1.12 g, yield: 89.4%) was obtained.
TLC(Rf) : 0.60 (n−hexane
: EtOAc = 1 : 1)IR(KBr) c
m−’ : 3500.2975.2900.1700
゜1690、1480.1455.1400.1360
゜1255、1180.1140.1090NMR(C
DC1,) δ: 1.44 (9H,s)、 2
.3〜2.8(2H,m)、3.2〜4.1 (IO
H,m)、7.2〜7.6 (5H,m)
MS (m/e): 319 (M”+ H)7)
cis−5−ベンジル−8−tert−ブトキシカルボ
ニル−2オキサ−5,8−ジアザビシクロ[4,3,0
]ノナン(1,12g、 3.5mmor)、 20%
パラジウム炭素(390m g )を用いて参考例1−
5と同様の方法により、cis−8−tert−ブトキ
シカルボニル−2−オキサ−5,8−ジアザビシクロ[
4,3,0]ノナン(565mg、収率: 70.2%
)を得た。TLC (Rf): 0.60 (n-hexane
: EtOAc = 1 : 1) IR(KBr) c
m-': 3500.2975.2900.1700
゜1690, 1480.1455.1400.1360
゜1255, 1180.1140.1090NMR (C
DC1,) δ: 1.44 (9H,s), 2
.. 3-2.8 (2H, m), 3.2-4.1 (IO
H,m), 7.2-7.6 (5H,m) MS (m/e): 319 (M"+H)7) cis-5-benzyl-8-tert-butoxycarbonyl-2oxa-5 ,8-diazabicyclo[4,3,0
] Nonane (1.12g, 3.5mmol), 20%
Reference example 1- using palladium on carbon (390 mg)
5, cis-8-tert-butoxycarbonyl-2-oxa-5,8-diazabicyclo[
4,3,0]nonane (565 mg, yield: 70.2%
) was obtained.
TLC(Rf) + 0.44 (CH2C12: M
eOH=9 : 1)IR(KBr) Cm” : 3
450.3330.2975.2B90゜1695、1
410.1170.1130.10109ON (CD
C1,)δ: 2.47 (9H,s)、 2.6〜2
゜8(IH,m)、3.0〜4.1 (9H,m)MS
(m/s): 229 (M”+ H)8)
cis−8−tert−ブトキシカルボニル−2−オキ
サ−5,8ジアザビシクo [4,3,0]ノナン(2
50mg、 1.1mmo/)、トリフルオロ酢酸(2
m4)を用いて、参考例1−6と同様の方法により、c
is−2−オキサ−5,8ジアザビシクロ[4,3,0
]ノナンのトリフルオロ酢酸塩(403m g、収率:
100%)を得た。TLC (Rf) + 0.44 (CH2C12: M
eOH=9: 1) IR (KBr) Cm”: 3
450.3330.2975.2B90°1695, 1
410.1170.1130.10109ON (CD
C1,) δ: 2.47 (9H, s), 2.6~2
゜8 (IH, m), 3.0-4.1 (9H, m) MS
(m/s): 229 (M”+H)8) cis-8-tert-butoxycarbonyl-2-oxa-5,8diazabicyclo[4,3,0]nonane (2
50mg, 1.1mmo/), trifluoroacetic acid (2
m4) in the same manner as in Reference Example 1-6, c
is-2-oxa-5,8 diazabicyclo[4,3,0
] Nonane trifluoroacetate (403 mg, yield:
100%) was obtained.
TLC(Rf) : 0.02 (CH2C1,: M
eOH= 9 : 1)IR(KBr) cm−’ :
3440.2970.2725.1680゜1635
、 1200. 1180.1140. 1120゜0
95
NMR(DMSO−d6)δ: 3.0〜3.8 (7
H,m)、3.9〜4.1 (2H,m)、 4.34
(IH,brs)、 9.7(4H,br)
MS (m/e): 129 (M’+ H)上記トリ
フルオロ酢酸塩より油状の遊離アミン(140mg)を
得た。TLC (Rf): 0.02 (CH2C1,: M
eOH = 9: 1) IR (KBr) cm-':
3440.2970.2725.1680°1635
, 1200. 1180.1140. 1120゜0
95 NMR (DMSO-d6) δ: 3.0-3.8 (7
H, m), 3.9-4.1 (2H, m), 4.34
(IH, brs), 9.7 (4H, br) MS (m/e): 129 (M'+H) An oily free amine (140 mg) was obtained from the above trifluoroacetate.
参考例3
trans−5−メチル−2−オキ −58−シア ビ
シ 口 4.3.0ム土2
trans−1−tert−ブトキシカルボニル−2−
オキサ−5,8−ジアザビシクロ[4,3,0]ノナン
(228mg、1mmof)のアセトニトリル(10m
/)溶液に水冷撹拌下でシアノ水素化はう素ナトリウム
(94mg、1.5mmo/)を加え、この反応溶液を
30分間撹拌した。反応液を酢酸で中和した後、溶媒を
減圧留去した。残渣をシリカゲルカラムクロマトグラフ
ィー(Wakogel’C−300,20m/、 CH
zCb : MeOH= 100 : 1−10 :
l )で精製し、trans−1−tert−ブトキシ
カルボニル−5メチル−2−オキサ−5,8−ジアザビ
シクロ[4,3,0]ノナン(170mg、収率ニア0
%)を得た。Reference example 3 trans-5-methyl-2-oxy-58-cyanoxycarbonyl-2-
Oxa-5,8-diazabicyclo[4,3,0]nonane (228 mg, 1 mmof) in acetonitrile (10 m
/) Sodium cyanoborohydride (94 mg, 1.5 mmo/) was added to the solution under water-cooling and stirring, and the reaction solution was stirred for 30 minutes. After neutralizing the reaction solution with acetic acid, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel'C-300, 20m/, CH
zCb: MeOH=100: 1-10:
trans-1-tert-butoxycarbonyl-5methyl-2-oxa-5,8-diazabicyclo[4,3,0]nonane (170 mg, yield near 0).
%) was obtained.
TLC(Rf) : 0.68 (CH,C1,: M
eOH= 9 : 1)IR(KBr) cm”’ :
3450.2960.2880.2800゜1685
.1410,1360,1165,1135゜1100
.108O
N M R(CD CIs ) δ: 1.45 (9
H,s)、 1.95〜2.40(2H,m)、 2
.25 (3H,s)、 2.7〜3.25(3H,m
)、3.45〜4.05 (5H,m)MS (m/e
): 243 (M”+ H)2)
trans−1−tert−ブトキシカルボニル−5−
メチル−2−オキサ−5,8−ジアザビシクロ[4,3
,0]ノナン(160mg。TLC (Rf): 0.68 (CH, C1,: M
eOH = 9: 1) IR (KBr) cm"':
3450.2960.2880.2800°1685
.. 1410, 1360, 1165, 1135° 1100
.. 108O NMR (CD CIs) δ: 1.45 (9
H, s), 1.95-2.40 (2H, m), 2
.. 25 (3H, s), 2.7-3.25 (3H, m
), 3.45-4.05 (5H, m) MS (m/e
): 243 (M”+H)2) trans-1-tert-butoxycarbonyl-5-
Methyl-2-oxa-5,8-diazabicyclo[4,3
,0] Nonane (160 mg.
0 、66 m m o ! )、トリフルオロ酢酸(
1,3m7)を用いて参考例1−6と同様の方法により
、trans−5−メチル−2−オキサ−5,8−ジア
ザビシクロ[4,3,0]ノナンのトリフルオロ酢酸塩
(220mg、収率:90%)を得た。0,66 m m o! ), trifluoroacetic acid (
Trans-5-methyl-2-oxa-5,8-diazabicyclo[4,3,0]nonane trifluoroacetate (220 mg, yield rate: 90%).
TLC(Rf) : 0.04 (CH2C12: M
eOH= 9 + 1 )IR(KBr) cm−I:
3030.2400.1690.1685゜1410
、1380.1200.1180.1165゜1135
NMR(DMSO−da) δ: 2.52〜3.4
4 (6H,m)。TLC (Rf): 0.04 (CH2C12: M
eOH=9+1)IR(KBr)cm-I:
3030.2400.1690.1685°1410
, 1380.1200.1180.1165°1135 NMR (DMSO-da) δ: 2.52-3.4
4 (6H, m).
3.52〜3.95 (3H,m)、 4.0〜4.2
(IH。3.52-3.95 (3H, m), 4.0-4.2
(IH.
m)
MS (m/e) : 143 (M” 十H)上記の
トリフルオロ酢酸塩より油状の遊離アミン(82m g
)を得た。m) MS (m/e): 143 (M” 10H) Oily free amine (82 mg
) was obtained.
見肌Ω盈玉
本発明の化合物は、文献未記載の新規化合物であり、感
受性・耐性のダラム陽性菌およびダラム陰性菌に対する
強い抗菌力を有するので、抗菌剤として有用である。The compound of the present invention is a novel compound that has not been described in any literature, and is useful as an antibacterial agent because it has strong antibacterial activity against sensitive and resistant Durum-positive bacteria and Durum-negative bacteria.
Claims (1)
キル基、またはふっ素原子により置換されていてもよい
フェニル基、R^2は水素原子または直鎖状、分岐状も
しくは環状の低級アルキル基、Xは窒素原子またはC−
Y(ここにおいて、Yは水素原子、ハロゲン原子、メチ
ル基またはメトキシ基を示す)を示す]で表される化合
物またはその医薬として許容される塩またはエステル。 2)一般式 ▲数式、化学式、表等があります▼[ I −a] [式中、R^1^1は直鎖状、分岐状または環状の低級
アルキル基、R^2は水素原子または直鎖状、分岐状ま
たは環状の低級アルキル基、Y^1は水素原子またはハ
ロゲン原子を示す]で表される第1請求項記載の化合物
。 3)R^1がシクロプロピル基である第1請求項記載の
化合物。 4)1−シクロプロピル−6,8−ジフルオロ−1,4
−ジヒドロ−7−(trans−2−オキサ−5,8−
ジアザビシクロ[4.3.0]ノナン−8−イル)−4
−オキソ−3−キノリンカルボン酸、1−シクロプロピ
ル−6−フルオロ−1,4−ジヒドロ−7−(tran
s−2−オキサ−5,8−ジアザビシクロ[4.3.0
]ノナン−8−イル)−4−オキソ−3−キノリンカル
ボン酸、1−エチル−6−フルオロ−1,4−ジヒドロ
−7−(trans−2−オキサ−5,8−ジアザビシ
クロ[4.3.0]ノナン−8−イル)−4−オキソ−
3−キノリンカルボン酸、1−シクロプロピル−6,8
−ジフルオロ−7−(cis−2−オキサ−5,8−ジ
アザビシクロ[4.3.0]ノナン−8−イル)−4−
オキソ−3−キノリンカルボン酸、 1−シクロプロピル−6−フルオロ−1,4−ジヒドロ
−7−(cis−2−オキサ−5,8−ジアザビシクロ
[4.3.0]ノナン−8−イル)−4−オキソ−3−
キノリンカルボン酸、1−エチル−6−フルオロ−1,
4−ジヒドロ−7−(cis−2−オキサ−5,8−ジ
アザビシクロ[4.3.0]ノナン−8−イル)−4−
オキソ−3−キノリンカルボン酸および1−シクロプロ
ピル−6,8−ジフルオロ−1,4−ジヒドロ−7−(
trans−5−メチル−2−オキサ−5,8−ジアザ
ビシクロ[4.3.0]ノナン−8−イル)−4−オキ
ソ−3−キノリンカルボン酸である第1請求項記載の化
合物。 5)一般式 ▲数式、化学式、表等があります▼[IV] [式中,R^1は直鎖状、分岐状または環状の低級アル
キル基、またはふっ素原子により置換されていてもよい
フェニル基、R^3は水素原子またはカルボキシル基の
保護基、Xは窒素原子またはC−Y(ここにおいて、Y
は水素原子、ハロゲン原子、メチル基またはメトキシ基
を示す)、Zは脱離基を示す]で表される化合物または
その塩と 一般式 ▲数式、化学式、表等があります▼[III] [式中、R^2^0は水素原子、アミノ基の保護基また
は直鎖状、分岐状もしくは環状の低級アルキル基を示す
]で表される化合物またはその塩とを反応させて、 一般式 ▲数式、化学式、表等があります▼[II] [式中、R^1、R^3、R^2^0およびXは前記の
意味を有する]で表される化合物とし、必要に応じて該
化合物の保護基を除去することを特徴とする、 一般式 ▲数式、化学式、表等があります▼[ I ] [式中、R^2は水素原子または直鎖状、分岐状もしく
は環状の低級アルキル基、R^1およびXは前記の意味
を有する]で表される化合物またはその医薬として許容
される塩またはエステルの製造法。 6)一般式 ▲数式、化学式、表等があります▼[ I ] [式中、R^1は直鎖状、分岐状または環状の低級アル
キル基、またはふっ素原子により置換されていてもよい
フェニル基、R^2は水素原子または直鎖状、分岐状も
しくは環状の低級アルキル基、Xは窒素原子またはC−
Y(ここにおいて、Yは水素原子、ハロゲン原子、メチ
ル基またはメトキシ基を示す)を示す]で表される化合
物またはその医薬として許容される塩またはエステルを
有効成分とする抗菌剤。[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [I] [In the formula, R^1 is substituted with a linear, branched or cyclic lower alkyl group, or a fluorine atom. R^2 is a hydrogen atom or a linear, branched or cyclic lower alkyl group, X is a nitrogen atom or a C-
Y (herein, Y represents a hydrogen atom, a halogen atom, a methyl group, or a methoxy group)] or a pharmaceutically acceptable salt or ester thereof. 2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [ I -a] [In the formula, R^1^1 is a linear, branched or cyclic lower alkyl group, and R^2 is a hydrogen atom or a straight The compound according to claim 1, which is a chain, branched or cyclic lower alkyl group, Y^1 represents a hydrogen atom or a halogen atom. 3) The compound according to claim 1, wherein R^1 is a cyclopropyl group. 4) 1-cyclopropyl-6,8-difluoro-1,4
-dihydro-7-(trans-2-oxa-5,8-
diazabicyclo[4.3.0]nonan-8-yl)-4
-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(tran
s-2-oxa-5,8-diazabicyclo[4.3.0
]nonan-8-yl)-4-oxo-3-quinolinecarboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-7-(trans-2-oxa-5,8-diazabicyclo[4.3 .0]nonan-8-yl)-4-oxo-
3-quinolinecarboxylic acid, 1-cyclopropyl-6,8
-difluoro-7-(cis-2-oxa-5,8-diazabicyclo[4.3.0]nonan-8-yl)-4-
Oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(cis-2-oxa-5,8-diazabicyclo[4.3.0]nonan-8-yl) -4-oxo-3-
Quinolinecarboxylic acid, 1-ethyl-6-fluoro-1,
4-dihydro-7-(cis-2-oxa-5,8-diazabicyclo[4.3.0]nonan-8-yl)-4-
Oxo-3-quinolinecarboxylic acid and 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(
A compound according to claim 1 which is trans-5-methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonan-8-yl)-4-oxo-3-quinolinecarboxylic acid. 5) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [IV] [In the formula, R^1 is a linear, branched or cyclic lower alkyl group, or a phenyl group which may be substituted with a fluorine atom , R^3 is a hydrogen atom or a carboxyl group protecting group, X is a nitrogen atom or C-Y (here, Y
represents a hydrogen atom, a halogen atom, a methyl group, or a methoxy group), and Z represents a leaving group] or its salt and the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [III] [Formula (wherein, R^2^0 represents a hydrogen atom, a protecting group for an amino group, or a linear, branched, or cyclic lower alkyl group) or a salt thereof] to form the general formula ▲ Formula , chemical formulas, tables, etc. ▼ [II] A compound represented by [In the formula, R^1, R^3, R^2^0 and X have the above meanings], and if necessary, the compound There are general formulas, mathematical formulas, chemical formulas, tables, etc., which are characterized by removing the protective group of , R^1 and X have the above-mentioned meanings] or a pharmaceutically acceptable salt or ester thereof. 6) General formula▲ Numerical formula, chemical formula, table, etc.▼ [I] [In the formula, R^1 is a linear, branched or cyclic lower alkyl group, or a phenyl group which may be substituted with a fluorine atom. , R^2 is a hydrogen atom or a linear, branched or cyclic lower alkyl group, X is a nitrogen atom or C-
An antibacterial agent containing a compound represented by Y (here, Y represents a hydrogen atom, a halogen atom, a methyl group, or a methoxy group) or a pharmaceutically acceptable salt or ester thereof as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1325183A JPH03188080A (en) | 1989-12-15 | 1989-12-15 | Pyridonecarboxylic acid derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1325183A JPH03188080A (en) | 1989-12-15 | 1989-12-15 | Pyridonecarboxylic acid derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH03188080A true JPH03188080A (en) | 1991-08-16 |
Family
ID=18173935
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1325183A Pending JPH03188080A (en) | 1989-12-15 | 1989-12-15 | Pyridonecarboxylic acid derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH03188080A (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0589318A2 (en) * | 1992-09-25 | 1994-03-30 | Bayer Ag | Antibacterial 7-(aminomethyl-oxa-7-azabicyclo(3.3.0)oct-7-yl)quinolone- and -naphthyridonecarboxylic acid derivatives |
EP0591808A1 (en) * | 1992-10-09 | 1994-04-13 | Bayer Ag | Quinolonecarboxylic acids |
EP0592868A1 (en) * | 1992-10-12 | 1994-04-20 | Bayer Ag | Quinolonecarboxylic acids |
EP0603887A2 (en) * | 1992-12-25 | 1994-06-29 | Daiichi Pharmaceutical Co., Ltd. | Bicyclic amine derivatives |
US6004956A (en) * | 1992-01-10 | 1999-12-21 | Bayer Aktiengesellschaft | Enantiomerically pure 2-oxa-5,8-dizaabicyclo[4.3.0] nonanes and process for their preparation |
KR100270898B1 (en) * | 1992-01-10 | 2000-10-16 | 빌프리더 하이더 | Quinolone- and Naphthyridone-Carboxylic Acid Derivatives |
CN1061351C (en) * | 1992-01-10 | 2001-01-31 | 拜尔公司 | The intermediates diaza or oxadiazabicyclic compounds |
-
1989
- 1989-12-15 JP JP1325183A patent/JPH03188080A/en active Pending
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6004956A (en) * | 1992-01-10 | 1999-12-21 | Bayer Aktiengesellschaft | Enantiomerically pure 2-oxa-5,8-dizaabicyclo[4.3.0] nonanes and process for their preparation |
KR100270898B1 (en) * | 1992-01-10 | 2000-10-16 | 빌프리더 하이더 | Quinolone- and Naphthyridone-Carboxylic Acid Derivatives |
CN1061351C (en) * | 1992-01-10 | 2001-01-31 | 拜尔公司 | The intermediates diaza or oxadiazabicyclic compounds |
EP0589318A2 (en) * | 1992-09-25 | 1994-03-30 | Bayer Ag | Antibacterial 7-(aminomethyl-oxa-7-azabicyclo(3.3.0)oct-7-yl)quinolone- and -naphthyridonecarboxylic acid derivatives |
EP0589318A3 (en) * | 1992-09-25 | 1994-04-27 | Bayer Ag | |
EP0591808A1 (en) * | 1992-10-09 | 1994-04-13 | Bayer Ag | Quinolonecarboxylic acids |
EP0592868A1 (en) * | 1992-10-12 | 1994-04-20 | Bayer Ag | Quinolonecarboxylic acids |
EP0603887A2 (en) * | 1992-12-25 | 1994-06-29 | Daiichi Pharmaceutical Co., Ltd. | Bicyclic amine derivatives |
EP0603887A3 (en) * | 1992-12-25 | 1995-04-26 | Daiichi Seiyaku Co | Bicyclic amine derivatives. |
US5654318A (en) * | 1992-12-25 | 1997-08-05 | Daiichi Pharmaceutical Co., Ltd. | Bicyclic amine derivatives |
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