CA2250002C - Cephem compounds and drugs containing the compounds - Google Patents
Cephem compounds and drugs containing the compounds Download PDFInfo
- Publication number
- CA2250002C CA2250002C CA002250002A CA2250002A CA2250002C CA 2250002 C CA2250002 C CA 2250002C CA 002250002 A CA002250002 A CA 002250002A CA 2250002 A CA2250002 A CA 2250002A CA 2250002 C CA2250002 C CA 2250002C
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- -1 Cephem compounds Chemical class 0.000 title claims abstract description 151
- 150000001875 compounds Chemical class 0.000 title claims description 166
- 229940079593 drug Drugs 0.000 title description 5
- 239000003814 drug Substances 0.000 title description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract description 20
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 125000001841 imino group Chemical group [H]N=* 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims description 39
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 125000002252 acyl group Chemical group 0.000 claims description 18
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 3
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 3
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000005974 C6-C14 arylcarbonyl group Chemical group 0.000 claims description 2
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 2
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 2
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 2
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 4
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 2
- 125000004758 (C1-C4) alkoxyimino group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims 1
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 150000001782 cephems Chemical group 0.000 abstract description 7
- 125000002947 alkylene group Chemical group 0.000 abstract description 5
- 125000002950 monocyclic group Chemical group 0.000 abstract description 5
- 125000003367 polycyclic group Chemical group 0.000 abstract description 5
- 125000004450 alkenylene group Chemical group 0.000 abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 285
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 224
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 186
- 239000000203 mixture Substances 0.000 description 186
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 174
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 156
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 143
- 238000006243 chemical reaction Methods 0.000 description 101
- 238000001816 cooling Methods 0.000 description 89
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 88
- 238000001914 filtration Methods 0.000 description 86
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 81
- 235000019439 ethyl acetate Nutrition 0.000 description 75
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 69
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
- 239000000843 powder Substances 0.000 description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 62
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 62
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 60
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 50
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 48
- 239000000725 suspension Substances 0.000 description 47
- 239000013078 crystal Substances 0.000 description 45
- 239000002198 insoluble material Substances 0.000 description 43
- 235000002639 sodium chloride Nutrition 0.000 description 41
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
- 229910000104 sodium hydride Inorganic materials 0.000 description 38
- 239000007787 solid Substances 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 35
- 238000002360 preparation method Methods 0.000 description 34
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 31
- 239000010410 layer Substances 0.000 description 29
- 238000003756 stirring Methods 0.000 description 29
- 239000007789 gas Substances 0.000 description 26
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 23
- 235000019341 magnesium sulphate Nutrition 0.000 description 23
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 20
- 150000002148 esters Chemical class 0.000 description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- 235000017557 sodium bicarbonate Nutrition 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 13
- 239000012452 mother liquor Substances 0.000 description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
- 239000011259 mixed solution Substances 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- 241000894006 Bacteria Species 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 125000000753 cycloalkyl group Chemical group 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 150000002430 hydrocarbons Chemical group 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
- 229910001873 dinitrogen Inorganic materials 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 101150041968 CDC13 gene Proteins 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 229940052303 ethers for general anesthesia Drugs 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 150000007529 inorganic bases Chemical class 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 241000589516 Pseudomonas Species 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 125000003302 alkenyloxy group Chemical group 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000003115 biocidal effect Effects 0.000 description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 4
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 4
- 150000008282 halocarbons Chemical class 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 244000110797 Polygonum persicaria Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 235000008504 concentrate Nutrition 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 239000012024 dehydrating agents Substances 0.000 description 3
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- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
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- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
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- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
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- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
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- 125000001544 thienyl group Chemical group 0.000 description 1
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- 125000001166 thiolanyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Chemical group 0.000 description 1
- 125000001239 threonyl group Chemical group 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000006150 trypticase soy agar Substances 0.000 description 1
- 125000002233 tyrosyl group Chemical group 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8/82531 | 1996-04-04 | ||
| JP8253196 | 1996-04-04 | ||
| PCT/JP1997/001161 WO1997037996A1 (en) | 1996-04-04 | 1997-04-04 | Cephem compounds and drugs containing the compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2250002A1 CA2250002A1 (en) | 1997-10-16 |
| CA2250002C true CA2250002C (en) | 2008-03-25 |
Family
ID=13777098
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002250002A Expired - Fee Related CA2250002C (en) | 1996-04-04 | 1997-04-04 | Cephem compounds and drugs containing the compounds |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US6214818B1 (enExample) |
| EP (3) | EP1671966A1 (enExample) |
| JP (1) | JP4064462B2 (enExample) |
| KR (1) | KR20000005238A (enExample) |
| CN (2) | CN1088711C (enExample) |
| AT (1) | ATE341554T1 (enExample) |
| AU (1) | AU2178497A (enExample) |
| CA (1) | CA2250002C (enExample) |
| DE (1) | DE69736775T2 (enExample) |
| ES (1) | ES2273364T3 (enExample) |
| WO (1) | WO1997037996A1 (enExample) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998022469A1 (en) * | 1996-11-22 | 1998-05-28 | Meiji Seika Kaisha, Ltd. | Cephem intermediates and process for producing the same |
| EP1394159A1 (fr) * | 2002-08-13 | 2004-03-03 | Warner-Lambert Company LLC | Nouveaux dérivés de thiophène, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent |
| JP3928086B2 (ja) * | 2005-03-29 | 2007-06-13 | 塩野義製薬株式会社 | ３−プロペニルセフェム誘導体 |
| CA2658764A1 (en) * | 2006-07-20 | 2008-01-24 | Mehmet Kahraman | Benzothiophene inhibitors of rho kinase |
| CN101153028B (zh) * | 2006-09-30 | 2010-12-15 | 山东轩竹医药科技有限公司 | 具有抗菌抗病毒活性的化合物 |
| TWI574957B (zh) | 2011-07-29 | 2017-03-21 | 佳佑製藥治療公司 | 含有醯肼的核運輸調控子及其用途 |
| WO2013019561A1 (en) * | 2011-07-29 | 2013-02-07 | Karyopharm Therapeutics, Inc. | Nuclear transport modulators and uses thereof |
| EP3616695B1 (en) | 2011-09-09 | 2024-10-23 | Merck Sharp & Dohme LLC | Ceftolozane/tazobactam for treating intrapulmonary infections |
| RS58058B1 (sr) | 2012-05-09 | 2019-02-28 | Biogen Ma Inc | Modulatori nukleusnog transporta i njihove upotrebe |
| US8809314B1 (en) | 2012-09-07 | 2014-08-19 | Cubist Pharmacueticals, Inc. | Cephalosporin compound |
| US8476425B1 (en) | 2012-09-27 | 2013-07-02 | Cubist Pharmaceuticals, Inc. | Tazobactam arginine compositions |
| US10202366B2 (en) | 2013-03-15 | 2019-02-12 | Karyopharm Therapeutics Inc. | Methods of promoting wound healing using CRM1 inhibitors |
| EP2893929B1 (en) | 2013-03-15 | 2025-04-16 | Merck Sharp & Dohme LLC | Ceftolozane antibiotic compositions |
| US9320740B2 (en) | 2013-03-15 | 2016-04-26 | Merck Sharp & Dohme Corp. | Ceftolozane-tazobactam pharmaceutical compositions |
| US9872906B2 (en) | 2013-03-15 | 2018-01-23 | Merck Sharp & Dohme Corp. | Ceftolozane antibiotic compositions |
| DK3010892T3 (en) | 2013-06-21 | 2019-04-15 | Karyopharm Therapeutics Inc | 1,2,4-TRIAZOLES AS NUCLEAR TRANSPORT MODULATORS AND APPLICATIONS THEREOF |
| US10376496B2 (en) | 2013-09-09 | 2019-08-13 | Merck, Sharp & Dohme Corp. | Treating infections with ceftolozane/tazobactam in subjects having impaired renal function |
| US8906898B1 (en) | 2013-09-27 | 2014-12-09 | Calixa Therapeutics, Inc. | Solid forms of ceftolozane |
| KR102608259B1 (ko) | 2014-08-15 | 2023-11-29 | 카리오팜 쎄라퓨틱스, 인코포레이티드 | 셀리넥소의 다형태 |
| EP3397633A1 (en) | 2015-12-31 | 2018-11-07 | Karyopharm Therapeutics, Inc. | Nuclear transport modulators and uses thereof |
| WO2017117535A1 (en) | 2015-12-31 | 2017-07-06 | Karyopharm Therapeutics Inc. | Nuclear transport modulators and uses thereof |
| US11602530B2 (en) | 2016-11-28 | 2023-03-14 | Biogen Ma Inc. | CRM1 inhibitors for treating epilepsy |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5271239A (en) * | 1975-12-10 | 1977-06-14 | Matsushita Electric Ind Co Ltd | Electron beam sensitive material |
| DE3118732A1 (de) * | 1981-05-12 | 1982-12-02 | Hoechst Ag, 6000 Frankfurt | Cephalosporinderivate und verfahren zu ihrer herstellung |
| DE3207840A1 (de) * | 1982-03-04 | 1983-09-15 | Hoechst Ag, 6230 Frankfurt | "cephalosporinderivate und verfahren zu ihrer herstellung" |
| JPS6064988A (ja) * | 1983-09-21 | 1985-04-13 | Sankyo Co Ltd | セフアロスポリン誘導体 |
| JPS60237090A (ja) * | 1984-02-21 | 1985-11-25 | Takeda Chem Ind Ltd | セフエム化合物 |
| GB8520155D0 (en) * | 1985-08-10 | 1985-09-18 | Beecham Group Plc | Compounds |
| JPS62158290A (ja) * | 1985-12-28 | 1987-07-14 | Banyu Pharmaceut Co Ltd | 新規セフアロスポリン誘導体 |
| JPS62158291A (ja) * | 1986-01-07 | 1987-07-14 | Sagami Chem Res Center | セフアロスポリン誘導体 |
| JPH0459730A (ja) * | 1990-06-26 | 1992-02-26 | Dai Ichi Seiyaku Co Ltd | セフェム系抗生物質含有凍結乾燥製剤 |
| US5202321A (en) * | 1991-06-13 | 1993-04-13 | Merck Frosst Canada, Inc. | Thiopyrano[2,3,4-c,d]indoles as inhibitors of leukotriene biosynthesis |
| JPH05217239A (ja) * | 1991-10-31 | 1993-08-27 | Sony Corp | 光磁気ディスク記録再生装置 |
| EP0554004A3 (en) * | 1992-01-27 | 1993-11-24 | Katayama Seisakusho | Cephem compounds and antibacterial agents |
| JPH0741485A (ja) * | 1993-07-30 | 1995-02-10 | Katayama Seiyakushiyo:Kk | セフェム誘導体およびそれを含有する抗菌剤 |
-
1997
- 1997-04-04 EP EP06005931A patent/EP1671966A1/en not_active Withdrawn
- 1997-04-04 EP EP05006670A patent/EP1544197A1/en not_active Withdrawn
- 1997-04-04 DE DE69736775T patent/DE69736775T2/de not_active Expired - Fee Related
- 1997-04-04 WO PCT/JP1997/001161 patent/WO1997037996A1/ja not_active Ceased
- 1997-04-04 JP JP53604897A patent/JP4064462B2/ja not_active Expired - Fee Related
- 1997-04-04 AU AU21784/97A patent/AU2178497A/en not_active Abandoned
- 1997-04-04 KR KR1019980707925A patent/KR20000005238A/ko not_active Ceased
- 1997-04-04 CA CA002250002A patent/CA2250002C/en not_active Expired - Fee Related
- 1997-04-04 ES ES97914600T patent/ES2273364T3/es not_active Expired - Lifetime
- 1997-04-04 EP EP97914600A patent/EP0893446B1/en not_active Expired - Lifetime
- 1997-04-04 CN CN97193623A patent/CN1088711C/zh not_active Expired - Fee Related
- 1997-04-04 AT AT97914600T patent/ATE341554T1/de not_active IP Right Cessation
- 1997-04-04 US US09/147,074 patent/US6214818B1/en not_active Expired - Fee Related
-
2000
- 2000-08-03 US US09/631,947 patent/US6458950B1/en not_active Expired - Fee Related
- 2000-08-15 CN CN00124231A patent/CN1129596C/zh not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP0893446A1 (en) | 1999-01-27 |
| EP0893446A4 (enExample) | 1999-01-27 |
| AU2178497A (en) | 1997-10-29 |
| DE69736775D1 (de) | 2006-11-16 |
| ATE341554T1 (de) | 2006-10-15 |
| ES2273364T3 (es) | 2007-05-01 |
| EP1671966A1 (en) | 2006-06-21 |
| EP0893446B1 (en) | 2006-10-04 |
| KR20000005238A (ko) | 2000-01-25 |
| CA2250002A1 (en) | 1997-10-16 |
| JP4064462B2 (ja) | 2008-03-19 |
| CN1215403A (zh) | 1999-04-28 |
| DE69736775T2 (de) | 2007-08-23 |
| CN1088711C (zh) | 2002-08-07 |
| CN1129596C (zh) | 2003-12-03 |
| CN1290702A (zh) | 2001-04-11 |
| EP1544197A1 (en) | 2005-06-22 |
| US6214818B1 (en) | 2001-04-10 |
| US6458950B1 (en) | 2002-10-01 |
| WO1997037996A1 (en) | 1997-10-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |