DE69632074T2 - Oxazolidinone mit tricyclische substituente als antibacterielle mittel - Google Patents
Oxazolidinone mit tricyclische substituente als antibacterielle mittel Download PDFInfo
- Publication number
- DE69632074T2 DE69632074T2 DE69632074T DE69632074T DE69632074T2 DE 69632074 T2 DE69632074 T2 DE 69632074T2 DE 69632074 T DE69632074 T DE 69632074T DE 69632074 T DE69632074 T DE 69632074T DE 69632074 T2 DE69632074 T2 DE 69632074T2
- Authority
- DE
- Germany
- Prior art keywords
- methyl
- oxo
- oxazolidinyl
- acetamide
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 239000003242 anti bacterial agent Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 13
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- -1 2-quinolyl Chemical group 0.000 claims description 93
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- LDECUSDQMXVUMP-UHFFFAOYSA-N benzyl 3-[6-[[2-(butylamino)-1-[3-methoxycarbonyl-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]-hexylamino]-6-oxohexyl]-4-methyl-2-oxo-6-(4-phenylphenyl)-1,6-dihydropyrimidine-5-carboxylate Chemical compound O=C1NC(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C(=O)OCC=2C=CC=CC=2)=C(C)N1CCCCCC(=O)N(CCCCCC)C(C(=O)NCCCC)C1=CC=C(OCC(=O)OC)C(C(=O)OC)=C1 LDECUSDQMXVUMP-UHFFFAOYSA-N 0.000 claims description 6
- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- NBQPXPSQEPGQQG-QRFGZVGRSA-N n-[[(5s)-3-[(4as)-1,2,3,4,4a,11a-hexahydropyrido[2,1-c][1,4]benzoxazin-8-yl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=CN12)=CC1=CO[C@@H]1C2CCCC1 NBQPXPSQEPGQQG-QRFGZVGRSA-N 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- FELVISBKRDWTCM-LYKKTTPLSA-N n-[[(5s)-3-[3-(1,2-oxazole-5-carbonyl)-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazin-8-yl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2C(CN(CC2)C(=O)C=2ON=CC=2)CO2)C2=C1 FELVISBKRDWTCM-LYKKTTPLSA-N 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 claims description 3
- KPIULKQIINEKKR-RTWAWAEBSA-N O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2[C@H](CN(CC2)C(=O)OCC=2C=CC=CC=2)CO2)C2=C1 Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2[C@H](CN(CC2)C(=O)OCC=2C=CC=CC=2)CO2)C2=C1 KPIULKQIINEKKR-RTWAWAEBSA-N 0.000 claims description 3
- WEJLKOVMFOAKDD-DJNXLDHESA-N [2-[8-[(5s)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazin-3-yl]-2-oxoethyl] acetate Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2C(CN(CC2)C(=O)COC(C)=O)CO2)C2=C1 WEJLKOVMFOAKDD-DJNXLDHESA-N 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- KPIULKQIINEKKR-LBAQZLPGSA-N benzyl 8-[(5s)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazine-3-carboxylate Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2C(CN(CC2)C(=O)OCC=2C=CC=CC=2)CO2)C2=C1 KPIULKQIINEKKR-LBAQZLPGSA-N 0.000 claims description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- XLAWHTQCSAQICK-KEKNWZKVSA-N n-[[(5s)-2-oxo-3-[3-(2-phenylmethoxyacetyl)-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazin-8-yl]-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2C(CN(CC2)C(=O)COCC=2C=CC=CC=2)CO2)C2=C1 XLAWHTQCSAQICK-KEKNWZKVSA-N 0.000 claims description 3
- 238000007911 parenteral administration Methods 0.000 claims description 3
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 3
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- JMDBEQOAQDPKJV-DJNXLDHESA-N O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2C(CN(CC2)C(=O)OC(C)(C)C)CO2)C2=C1 Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2C(CN(CC2)C(=O)OC(C)(C)C)CO2)C2=C1 JMDBEQOAQDPKJV-DJNXLDHESA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 230000037396 body weight Effects 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- WVEGETGQVKOFCU-LOACHALJSA-N methyl 8-[(5s)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazine-3-carboxylate Chemical compound C1N(C(=O)OC)CCN(C2=CC=3)C1COC2=CC=3N1C[C@H](CNC(C)=O)OC1=O WVEGETGQVKOFCU-LOACHALJSA-N 0.000 claims description 2
- 230000000813 microbial effect Effects 0.000 claims description 2
- FJKBTKWLARTTRU-LYKKTTPLSA-N n-[[(5s)-3-(3-acetyl-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazin-8-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2C(CN(CC2)C(C)=O)CO2)C2=C1 FJKBTKWLARTTRU-LYKKTTPLSA-N 0.000 claims description 2
- WSEFYXJQSMSBGY-LOACHALJSA-N n-[[(5s)-3-(3-methylsulfonyl-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazin-8-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2C(CN(CC2)S(C)(=O)=O)CO2)C2=C1 WSEFYXJQSMSBGY-LOACHALJSA-N 0.000 claims description 2
- JVKIMZOZFAIBMZ-ANYOKISRSA-N n-[[(5s)-3-[3-(1h-indole-2-carbonyl)-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazin-8-yl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2C(CN(CC2)C(=O)C=2NC3=CC=CC=C3C=2)CO2)C2=C1 JVKIMZOZFAIBMZ-ANYOKISRSA-N 0.000 claims description 2
- JAEOHARRNNNQFO-LYKKTTPLSA-N n-[[(5s)-3-[3-(2-fluoroethyl)-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazin-8-yl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2C(CN(CCF)CC2)CO2)C2=C1 JAEOHARRNNNQFO-LYKKTTPLSA-N 0.000 claims description 2
- ZXRUPEPLOJQJLN-LYKKTTPLSA-N n-[[(5s)-3-[3-(3-hydroxypropanoyl)-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazin-8-yl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2C(CN(CC2)C(=O)CCO)CO2)C2=C1 ZXRUPEPLOJQJLN-LYKKTTPLSA-N 0.000 claims description 2
- VAIZIMNKRCYSTB-LYKKTTPLSA-N n-[[(5s)-3-[3-(cyanomethyl)-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazin-8-yl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2C(CN(CC#N)CC2)CO2)C2=C1 VAIZIMNKRCYSTB-LYKKTTPLSA-N 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 238000011200 topical administration Methods 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- RIFXCWJMPYMDEZ-SJORKVTESA-N COCCC(=O)N1C[C@@H]2COC3=C(N2CC1)C=CC(=C3)N3C(O[C@H](C3)CNC(C)=O)=O Chemical compound COCCC(=O)N1C[C@@H]2COC3=C(N2CC1)C=CC(=C3)N3C(O[C@H](C3)CNC(C)=O)=O RIFXCWJMPYMDEZ-SJORKVTESA-N 0.000 claims 1
- IOVIWJAOWCYNJG-ROUUACIJSA-N N-[[(5S)-3-[(4aS)-3-(4-oxopentanoyl)-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazin-8-yl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C(CCC(=O)N1C[C@H]2COC3=C(N2CC1)C=CC(=C3)N3C(O[C@H](C3)CNC(C)=O)=O)C IOVIWJAOWCYNJG-ROUUACIJSA-N 0.000 claims 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims 1
- WVEGETGQVKOFCU-GJZGRUSLSA-N methyl (4as)-8-[(5s)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazine-3-carboxylate Chemical compound C([C@H]1N(C2=CC=3)CCN(C1)C(=O)OC)OC2=CC=3N1C[C@H](CNC(C)=O)OC1=O WVEGETGQVKOFCU-GJZGRUSLSA-N 0.000 claims 1
- QYUQIFGSVMLQCP-UHFFFAOYSA-N methyl 4H-1,4-benzoxazine-3-carboxylate Chemical compound C1=CC=C2NC(C(=O)OC)=COC2=C1 QYUQIFGSVMLQCP-UHFFFAOYSA-N 0.000 claims 1
- BNTSHFZYGMFSCK-UHFFFAOYSA-N pyrazino[2,1-c][1,4]benzoxazine Chemical compound C1=CN=CC2=COC3=C(N21)C=CC=C3 BNTSHFZYGMFSCK-UHFFFAOYSA-N 0.000 claims 1
- 241000186367 Mycobacterium avium Species 0.000 abstract description 8
- 239000004599 antimicrobial Substances 0.000 abstract description 7
- 244000052769 pathogen Species 0.000 abstract description 5
- 241000606125 Bacteroides Species 0.000 abstract description 4
- 241001112696 Clostridia Species 0.000 abstract description 4
- 241000295644 Staphylococcaceae Species 0.000 abstract description 4
- 241001148470 aerobic bacillus Species 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 38
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 239000011734 sodium Substances 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 7
- 239000011593 sulfur Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 150000001540 azides Chemical class 0.000 description 5
- 238000007429 general method Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000010933 acylation Effects 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 235000010419 agar Nutrition 0.000 description 4
- 230000000845 anti-microbial effect Effects 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 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 4
- WXQFHIXVEGWTFS-UHFFFAOYSA-N 1,4-bis(phenylmethoxycarbonyl)piperazine-2-carboxylic acid Chemical compound OC(=O)C1CN(C(=O)OCC=2C=CC=CC=2)CCN1C(=O)OCC1=CC=CC=C1 WXQFHIXVEGWTFS-UHFFFAOYSA-N 0.000 description 3
- QISAUDWTBBNJIR-UHFFFAOYSA-N 2-phenylmethoxyacetyl chloride Chemical compound ClC(=O)COCC1=CC=CC=C1 QISAUDWTBBNJIR-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
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- YMZGPDDOOSSQMY-LYKKTTPLSA-N n-[[(5s)-3-[3-(2-methoxyacetyl)-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazin-8-yl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound C1N(C(=O)COC)CCN(C2=CC=3)C1COC2=CC=3N1C[C@H](CNC(C)=O)OC1=O YMZGPDDOOSSQMY-LYKKTTPLSA-N 0.000 description 1
- RIFXCWJMPYMDEZ-DJNXLDHESA-N n-[[(5s)-3-[3-(3-methoxypropanoyl)-2,4,4a,5-tetrahydro-1h-pyrazino[2,1-c][1,4]benzoxazin-8-yl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound C1N(C(=O)CCOC)CCN(C2=CC=3)C1COC2=CC=3N1C[C@H](CNC(C)=O)OC1=O RIFXCWJMPYMDEZ-DJNXLDHESA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical group C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 description 1
- 125000003544 oxime group Chemical group 0.000 description 1
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- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PRAYXGYYVXRDDW-UHFFFAOYSA-N piperidin-2-ylmethanol Chemical compound OCC1CCCCN1 PRAYXGYYVXRDDW-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 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
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 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
- 238000010998 test method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
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- 229930192474 thiophene Chemical group 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US737195P | 1995-11-17 | 1995-11-17 | |
| US7371P | 1995-11-17 | ||
| PCT/US1996/017120 WO1997019089A1 (en) | 1995-11-17 | 1996-11-05 | Oxazolidinone antibacterial agent with tricyclic substituents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69632074D1 DE69632074D1 (de) | 2004-05-06 |
| DE69632074T2 true DE69632074T2 (de) | 2005-01-20 |
Family
ID=21725778
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69632074T Expired - Fee Related DE69632074T2 (de) | 1995-11-17 | 1996-11-05 | Oxazolidinone mit tricyclische substituente als antibacterielle mittel |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US5922707A (enExample) |
| EP (1) | EP0874852B1 (enExample) |
| JP (1) | JP2000500489A (enExample) |
| AT (1) | ATE263172T1 (enExample) |
| AU (1) | AU7665196A (enExample) |
| DE (1) | DE69632074T2 (enExample) |
| DK (1) | DK0874852T3 (enExample) |
| ES (1) | ES2217329T3 (enExample) |
| PT (1) | PT874852E (enExample) |
| TW (1) | TW426683B (enExample) |
| WO (1) | WO1997019089A1 (enExample) |
| ZA (1) | ZA968661B (enExample) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA968661B (en) * | 1995-11-17 | 1998-04-14 | Upjohn Co | Oxazolidinone antibacterial agent with tricyclic substituents. |
| GB9601666D0 (en) * | 1996-01-27 | 1996-03-27 | Zeneca Ltd | Chemical compounds |
| GB9702213D0 (en) | 1996-02-24 | 1997-03-26 | Zeneca Ltd | Chemical compounds |
| GB9609919D0 (en) * | 1996-05-11 | 1996-07-17 | Zeneca Ltd | Chemical compounds |
| ID23803A (id) * | 1997-08-15 | 2000-05-11 | Pfizer Prod Inc | Turunan-turunan 2-(4-aril atau heteroaril-piperazin-1-ilmetil)-1h-indola |
| GB9717804D0 (en) | 1997-08-22 | 1997-10-29 | Zeneca Ltd | Chemical compounds |
| GB9717807D0 (en) | 1997-08-22 | 1997-10-29 | Zeneca Ltd | Chemical compounds |
| GB9725244D0 (en) | 1997-11-29 | 1998-01-28 | Zeneca Ltd | Chemical compounds |
| DE19802239A1 (de) * | 1998-01-22 | 1999-07-29 | Bayer Ag | Neue mit Bicyclen substituierte Oxazolidinone |
| DE19802235A1 (de) * | 1998-01-22 | 1999-07-29 | Bayer Ag | Mit tricyclischen Indolen substituierte Oxazolidinone |
| CA2318969A1 (en) | 1998-01-23 | 1999-07-29 | Mikhail F. Gordeev | Oxazolidinone combinatorial libraries, compositions and methods of preparation |
| US7002020B1 (en) | 1998-01-23 | 2006-02-21 | Pharmacia & Upjohn Company | Oxazolidinone combinatorial libraries, compositions and methods of preparation |
| US6562844B2 (en) | 1998-01-23 | 2003-05-13 | Pharmacia & Upjohn Company | Oxazolidinone combinatorial libraries, compositions and methods of preparation |
| DE19805117A1 (de) * | 1998-02-09 | 1999-08-12 | Bayer Ag | Neue Oxazolidinone mit azolhaltigen Tricyclen |
| EP1082323A2 (en) * | 1998-06-05 | 2001-03-14 | AstraZeneca UK Limited | Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them |
| MY122454A (en) * | 1998-06-05 | 2006-04-29 | Upjohn Co | Use of oxazolidinones for the preparation of a medicament for transdermal delivery |
| WO2000017163A1 (en) | 1998-09-22 | 2000-03-30 | Yamanouchi Pharmaceutical Co., Ltd. | Cyanophenyl derivatives |
| AU4224699A (en) | 1999-01-27 | 2000-08-18 | Pharmacia & Upjohn Company | Assays for modulators of elongation factor p activity |
| EP1181288B1 (en) * | 1999-05-27 | 2003-07-30 | PHARMACIA & UPJOHN COMPANY | Bicyclic oxazolidinones as antibacterial agent |
| GB9928568D0 (en) | 1999-12-03 | 2000-02-02 | Zeneca Ltd | Chemical compounds |
| GB0009803D0 (en) * | 2000-04-25 | 2000-06-07 | Astrazeneca Ab | Chemical compounds |
| MXPA05001558A (es) | 2002-08-12 | 2005-09-08 | Pharmacia & Upjohn Co Llc | N-aril-2-oxazolidinonas y sus derivados. |
| ATE344036T1 (de) | 2002-11-21 | 2006-11-15 | Pharmacia & Upjohn Co Llc | N-(4-(piperazin-1-yl)-phenyl-2-oxazolidinon-5- carbonsäureamid-derivate und verwandte verbindungen als antibakterielle mittel |
| CA2515311A1 (en) * | 2003-02-07 | 2004-08-19 | Warner-Lambert Company Llc | Antibacterial agents |
| WO2005021555A1 (ja) * | 2003-08-29 | 2005-03-10 | Takeda Pharmaceutical Company Limited | 二環性ピペラジン化合物およびその用途 |
| AR057828A1 (es) * | 2005-09-29 | 2007-12-19 | Astrazeneca Ab | Compuestos derivados de azetidina, su preparacion y composicion farmaceuutica |
| CA2636043A1 (en) | 2006-01-23 | 2007-08-02 | Amira Pharmaceuticals, Inc. | Tricyclic inhibitors of 5-lipoxygenase |
| CN110746443B (zh) * | 2016-12-12 | 2021-04-27 | 杭州英创医药科技有限公司 | 一类含有三环杂芳基的化合物 |
| CN114644634B (zh) * | 2020-12-21 | 2023-06-20 | 深圳市祥根生物医药有限公司 | 一种吡咯衍生物及其制备方法和用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3883522A (en) * | 1974-02-11 | 1975-05-13 | Riker Laboratories Inc | Substituted pyrido(1,2,3-de)-1,4-benzoxazines |
| US4080499A (en) * | 1976-12-20 | 1978-03-21 | 1 | Substituted 7,8-dihydro-6H-(1,2,5)thiadiazolo(3',4'-5,6)pyrazino(2,3-b)(1,4)oxazines |
| US5039690A (en) * | 1987-10-09 | 1991-08-13 | Du Pont Merck Pharmaceutical Company | Aminomethyl oxooxazolidinyl oxa or thia cycloalkylbenzene derivatives useful as antibacterial agents |
| ES2157934T3 (es) * | 1988-09-15 | 2001-09-01 | Upjohn Co | Fenil-5-beta-amidometiloxazolidin-2-onas sustituidas con nitrogeno en la posicion 3. |
| US5225565A (en) * | 1988-09-15 | 1993-07-06 | The Upjohn Company | Antibacterial 3-(fused-ring substituted)phenyl-5β-amidomethyloxazolidin-2-ones |
| EP0625982B1 (en) * | 1992-02-13 | 2002-06-12 | PHARMACIA & UPJOHN COMPANY | 4-oxo- and 4h-imidazo(5,1-c)(1,4)benzoxazines useful as benzodiazepine receptor-binding agents |
| SK283420B6 (sk) * | 1992-05-08 | 2003-07-01 | Pharmacia & Upjohn Company | Antimikrobiálne oxazolidinóny obsahujúce substituované diazínové skupiny |
| US5668286A (en) * | 1994-03-15 | 1997-09-16 | Pharmacia & Upjohn Company | Oxazolidinone derivatives and pharmaceutical compositions containing them |
| BR9509673A (pt) * | 1994-11-15 | 1997-09-30 | Upjohn Co | Compostos e uso dos mesmos |
| ZA968661B (en) * | 1995-11-17 | 1998-04-14 | Upjohn Co | Oxazolidinone antibacterial agent with tricyclic substituents. |
-
1996
- 1996-10-14 ZA ZA9608661A patent/ZA968661B/xx unknown
- 1996-11-05 EP EP96939496A patent/EP0874852B1/en not_active Expired - Lifetime
- 1996-11-05 PT PT96939496T patent/PT874852E/pt unknown
- 1996-11-05 ES ES96939496T patent/ES2217329T3/es not_active Expired - Lifetime
- 1996-11-05 JP JP9519726A patent/JP2000500489A/ja not_active Withdrawn
- 1996-11-05 DK DK96939496T patent/DK0874852T3/da active
- 1996-11-05 AT AT96939496T patent/ATE263172T1/de not_active IP Right Cessation
- 1996-11-05 WO PCT/US1996/017120 patent/WO1997019089A1/en not_active Ceased
- 1996-11-05 AU AU76651/96A patent/AU7665196A/en not_active Abandoned
- 1996-11-05 DE DE69632074T patent/DE69632074T2/de not_active Expired - Fee Related
- 1996-11-15 TW TW085114048A patent/TW426683B/zh not_active IP Right Cessation
-
1997
- 1997-05-02 US US08/850,424 patent/US5922707A/en not_active Expired - Fee Related
-
1999
- 1999-02-15 US US09/250,382 patent/US5955460A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP0874852A1 (en) | 1998-11-04 |
| ES2217329T3 (es) | 2004-11-01 |
| EP0874852B1 (en) | 2004-03-31 |
| WO1997019089A1 (en) | 1997-05-29 |
| TW426683B (en) | 2001-03-21 |
| PT874852E (pt) | 2004-08-31 |
| ZA968661B (en) | 1998-04-14 |
| DE69632074D1 (de) | 2004-05-06 |
| AU7665196A (en) | 1997-06-11 |
| DK0874852T3 (da) | 2004-06-07 |
| JP2000500489A (ja) | 2000-01-18 |
| US5955460A (en) | 1999-09-21 |
| ATE263172T1 (de) | 2004-04-15 |
| US5922707A (en) | 1999-07-13 |
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