NO850314L - Fremgangsmaate for fremstilling av forbindelser med farmasoeytisk aktivitet - Google Patents
Fremgangsmaate for fremstilling av forbindelser med farmasoeytisk aktivitetInfo
- Publication number
- NO850314L NO850314L NO850314A NO850314A NO850314L NO 850314 L NO850314 L NO 850314L NO 850314 A NO850314 A NO 850314A NO 850314 A NO850314 A NO 850314A NO 850314 L NO850314 L NO 850314L
- Authority
- NO
- Norway
- Prior art keywords
- penem
- preparation
- methyl
- compound
- vmax
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 44
- 230000000694 effects Effects 0.000 title description 4
- 238000002360 preparation method Methods 0.000 claims description 304
- -1 penem compound Chemical class 0.000 claims description 261
- 150000001875 compounds Chemical class 0.000 claims description 132
- 150000002148 esters Chemical class 0.000 claims description 47
- 125000003118 aryl group Chemical group 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 238000001727 in vivo Methods 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 13
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 230000036961 partial effect Effects 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000000962 organic group Chemical group 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 150000002430 hydrocarbons Chemical class 0.000 claims description 6
- 229910052717 sulfur Chemical group 0.000 claims description 6
- 239000004215 Carbon black (E152) Substances 0.000 claims description 5
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Chemical group 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 239000011593 sulfur Chemical group 0.000 claims description 4
- 150000003573 thiols Chemical class 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- DFFVJNWUKHDODC-MEHWWPQUSA-N (5r,6z)-6-[(1-methyltriazol-4-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound N1=NN(C)C=C1\C=C/1C(=O)N2C(C(O)=O)=CS[C@@H]2\1 DFFVJNWUKHDODC-MEHWWPQUSA-N 0.000 claims description 2
- IKFWMQQQXPBSJU-GORDUTHDSA-N (6E)-6-[(4-methylthiadiazol-5-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CC=1N=NSC=1\C=C/1\C2N(C(=CS2)C(=O)O)C\1=O IKFWMQQQXPBSJU-GORDUTHDSA-N 0.000 claims description 2
- DFRYDALVPCAVIC-YWEYNIOJSA-N (6Z)-3-(2-hydroxyethylsulfanyl)-6-[(1-methylpyrazol-4-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound OCCSC=1SC\2N(C=1C(=O)O)C(/C/2=C/C=1C=NN(C=1)C)=O DFRYDALVPCAVIC-YWEYNIOJSA-N 0.000 claims description 2
- BFXMBSUUIMSNJC-UQCOIBPSSA-N (6Z)-3-(hydroxymethyl)-6-[(1-methylpyrazol-4-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound OCC=1SC\2N(C=1C(=O)O)C(/C/2=C/C=1C=NN(C=1)C)=O BFXMBSUUIMSNJC-UQCOIBPSSA-N 0.000 claims description 2
- GGORNUHISVDDKS-UTCJRWHESA-N (6Z)-6-(1,2-oxazol-3-ylmethylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound O1N=C(C=C1)\C=C\1/C2N(C(=CS2)C(=O)O)C/1=O GGORNUHISVDDKS-UTCJRWHESA-N 0.000 claims description 2
- JHZLXOXPFAPZSK-UQCOIBPSSA-N (6Z)-6-[(1-methylimidazol-4-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CN1C=NC(=C1)\C=C\1/C2N(C(=CS2)C(=O)O)C/1=O JHZLXOXPFAPZSK-UQCOIBPSSA-N 0.000 claims description 2
- GEFFMQPWXXHOQY-DAXSKMNVSA-N (6Z)-6-[(1-methylpyrazol-3-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CN1N=C(C=C1)\C=C\1/C2N(C(=CS2)C(=O)O)C/1=O GEFFMQPWXXHOQY-DAXSKMNVSA-N 0.000 claims description 2
- HPRSMSACANRVIM-UQCOIBPSSA-N (6Z)-6-[(1-methylpyrazol-4-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CN1N=CC(=C1)\C=C\1/C2N(C(=CS2)C(=O)O)C/1=O HPRSMSACANRVIM-UQCOIBPSSA-N 0.000 claims description 2
- DCSWSGWINNQWKK-RQOWECAXSA-N (6Z)-6-[(1-methyltetrazol-5-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CN1N=NN=C1\C=C\1/C2N(C(=CS2)C(=O)O)C/1=O DCSWSGWINNQWKK-RQOWECAXSA-N 0.000 claims description 2
- DFFVJNWUKHDODC-KXFIGUGUSA-N (6Z)-6-[(1-methyltriazol-4-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CN1N=NC(=C1)\C=C\1/C2N(C(=CS2)C(=O)O)C/1=O DFFVJNWUKHDODC-KXFIGUGUSA-N 0.000 claims description 2
- HHGNXSYLWBARNA-UQCOIBPSSA-N (6Z)-6-[(2-methyl-1,3-oxazol-4-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CC=1OC=C(N=1)\C=C\1/C2N(C(=CS2)C(=O)O)C/1=O HHGNXSYLWBARNA-UQCOIBPSSA-N 0.000 claims description 2
- RZVJDSBXJQOLGX-UQCOIBPSSA-N (6Z)-6-[(2-methyl-1,3-thiazol-4-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CC=1SC=C(N=1)\C=C\1/C2N(C(=CS2)C(=O)O)C/1=O RZVJDSBXJQOLGX-UQCOIBPSSA-N 0.000 claims description 2
- IKFWMQQQXPBSJU-DJWKRKHSSA-N (6Z)-6-[(4-methylthiadiazol-5-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CC=1N=NSC=1\C=C\1/C2N(C(=CS2)C(=O)O)C/1=O IKFWMQQQXPBSJU-DJWKRKHSSA-N 0.000 claims description 2
- PKHYXDQYFONFBN-DJWKRKHSSA-N (6Z)-6-[(5-methyl-1,2,4-oxadiazol-3-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CC1=NC(=NO1)\C=C\1/C2N(C(=CS2)C(=O)O)C/1=O PKHYXDQYFONFBN-DJWKRKHSSA-N 0.000 claims description 2
- HPRSMSACANRVIM-FARCUNLSSA-N (6e)-6-[(1-methylpyrazol-4-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1=NN(C)C=C1\C=C\1C(=O)N2C(C(O)=O)=CSC2/1 HPRSMSACANRVIM-FARCUNLSSA-N 0.000 claims description 2
- DFFVJNWUKHDODC-QHHAFSJGSA-N (6e)-6-[(1-methyltriazol-4-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound N1=NN(C)C=C1\C=C\1C(=O)N2C(C(O)=O)=CSC2/1 DFFVJNWUKHDODC-QHHAFSJGSA-N 0.000 claims description 2
- BFWJUQQSESKLQR-YWEYNIOJSA-N (6Z)-3-ethylsulfanyl-6-[(1-methylpyrazol-4-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C(C)SC=1SC\2N(C=1C(=O)O)C(/C/2=C/C=1C=NN(C=1)C)=O BFWJUQQSESKLQR-YWEYNIOJSA-N 0.000 claims 1
- PDWSBCUIOVJFJC-UTCJRWHESA-N (6Z)-7-oxo-6-(1,2-thiazol-5-ylmethylidene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound S1N=CC=C1\C=C\1/C2N(C(=CS2)C(=O)O)C/1=O PDWSBCUIOVJFJC-UTCJRWHESA-N 0.000 claims 1
- HLSXROWQGCOQCK-DJWKRKHSSA-N (6z)-6-[(1-methyl-1,2,4-triazol-3-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CN1C=NC(\C=C/2C(N3C(=CSC3\2)C(O)=O)=O)=N1 HLSXROWQGCOQCK-DJWKRKHSSA-N 0.000 claims 1
- 125000002971 oxazolyl group Chemical group 0.000 claims 1
- 125000003226 pyrazolyl group Chemical group 0.000 claims 1
- 125000001425 triazolyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 270
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 237
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 117
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 106
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 98
- 239000000243 solution Substances 0.000 description 98
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 93
- 239000007787 solid Substances 0.000 description 79
- 101150041968 CDC13 gene Proteins 0.000 description 75
- 239000000203 mixture Substances 0.000 description 68
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 238000004519 manufacturing process Methods 0.000 description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
- 159000000000 sodium salts Chemical class 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 125000000217 alkyl group Chemical group 0.000 description 31
- 150000002576 ketones Chemical class 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 28
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 27
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
- 239000012267 brine Substances 0.000 description 26
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 26
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 23
- 239000000047 product Substances 0.000 description 22
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- 229930182555 Penicillin Natural products 0.000 description 18
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 18
- 229910001868 water Inorganic materials 0.000 description 18
- 239000000460 chlorine Substances 0.000 description 17
- 238000001704 evaporation Methods 0.000 description 16
- 230000008020 evaporation Effects 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- 239000012258 stirred mixture Substances 0.000 description 15
- 229930186147 Cephalosporin Natural products 0.000 description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 229940124587 cephalosporin Drugs 0.000 description 14
- 150000001780 cephalosporins Chemical class 0.000 description 14
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 14
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 13
- 229910052786 argon Inorganic materials 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229960003022 amoxicillin Drugs 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 12
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 11
- 238000003379 elimination reaction Methods 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- ZISQMZNAYGXRTB-UHFFFAOYSA-N 1-[tert-butyl(dimethyl)silyl]-4-tritylsulfanylazetidin-2-one Chemical compound C1C(=O)N([Si](C)(C)C(C)(C)C)C1SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 ZISQMZNAYGXRTB-UHFFFAOYSA-N 0.000 description 10
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 10
- 150000002960 penicillins Chemical class 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 description 10
- 239000012279 sodium borohydride Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 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 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 238000010828 elution Methods 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 229910052709 silver Inorganic materials 0.000 description 9
- 239000004332 silver Substances 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 125000004414 alkyl thio group Chemical group 0.000 description 8
- 230000003115 biocidal effect Effects 0.000 description 8
- 230000007717 exclusion Effects 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 229940049954 penicillin Drugs 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 229960000723 ampicillin Drugs 0.000 description 7
- 125000005110 aryl thio group Chemical group 0.000 description 7
- 230000008030 elimination Effects 0.000 description 7
- 229910001961 silver nitrate Inorganic materials 0.000 description 7
- 238000001665 trituration Methods 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000005909 Kieselgur Substances 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 6
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- FSYCJDVCYJBFCB-DFJJNBFHSA-M sodium (5R,6Z)-6-[(1-methyl-1,2,4-triazol-3-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound CN1N=C(N=C1)\C=C\1/[C@@H]2N(C(=CS2)C(=O)[O-])C/1=O.[Na+] FSYCJDVCYJBFCB-DFJJNBFHSA-M 0.000 description 1
- KTIUOCWZVXRSTF-NKXSAXQTSA-M sodium (5R,6Z)-6-[(1-methylpyrazol-4-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound CN1N=CC(=C1)\C=C\1/[C@@H]2N(C(=CS2)C(=O)[O-])C/1=O.[Na+] KTIUOCWZVXRSTF-NKXSAXQTSA-M 0.000 description 1
- VHSCMIMUZFHKEV-ZYFYRQFPSA-M sodium (6Z)-3-ethylsulfanyl-6-[(1-methylpyrazol-4-yl)methylidene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound C(C)SC=1SC\2N(C=1C(=O)[O-])C(/C/2=C/C=1C=NN(C=1)C)=O.[Na+] VHSCMIMUZFHKEV-ZYFYRQFPSA-M 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 229960004932 sulbenicillin Drugs 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 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
- 229960002780 talampicillin Drugs 0.000 description 1
- SOROUYSPFADXSN-SUWVAFIASA-N talampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(=O)OC2C3=CC=CC=C3C(=O)O2)(C)C)=CC=CC=C1 SOROUYSPFADXSN-SUWVAFIASA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB848402085A GB8402085D0 (en) | 1984-01-26 | 1984-01-26 | Compounds |
GB848417659A GB8417659D0 (en) | 1984-07-11 | 1984-07-11 | Compounds |
GB848425889A GB8425889D0 (en) | 1984-10-12 | 1984-10-12 | Compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
NO850314L true NO850314L (no) | 1985-07-29 |
Family
ID=27262267
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO850314A NO850314L (no) | 1984-01-26 | 1985-01-25 | Fremgangsmaate for fremstilling av forbindelser med farmasoeytisk aktivitet |
Country Status (19)
Country | Link |
---|---|
US (1) | US4798828A (sv) |
EP (1) | EP0154132B1 (sv) |
JP (1) | JPH0696579B2 (sv) |
KR (1) | KR850005444A (sv) |
AU (1) | AU569366B2 (sv) |
CA (1) | CA1272479A (sv) |
DE (1) | DE3585095D1 (sv) |
DK (1) | DK32485A (sv) |
ES (3) | ES8707244A1 (sv) |
FI (1) | FI82471C (sv) |
GR (1) | GR850208B (sv) |
HU (1) | HU197013B (sv) |
IL (1) | IL74153A (sv) |
NO (1) | NO850314L (sv) |
NZ (1) | NZ210929A (sv) |
PH (1) | PH23447A (sv) |
PL (1) | PL149297B1 (sv) |
PT (1) | PT79873B (sv) |
YU (1) | YU45695B (sv) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8518422D0 (en) * | 1985-07-22 | 1985-08-29 | Beecham Group Plc | Compounds |
GB8711391D0 (en) * | 1987-05-14 | 1987-06-17 | Beecham Group Plc | Process |
GB8729613D0 (en) * | 1987-12-18 | 1988-02-03 | Beecham Group Plc | Novel compounds |
GB8729614D0 (en) * | 1987-12-18 | 1988-02-03 | Beecham Group Plc | Novel compounds |
ATE118215T1 (de) * | 1989-09-04 | 1995-02-15 | Beecham Group Plc | Cephalosporinderivate, verfahren zu ihrer herstellung, pharmazeutische präparate und zwischenverbindungen. |
GB9222700D0 (en) * | 1992-10-29 | 1992-12-09 | Smithkline Beecham Plc | Chemical compounds |
GB9305837D0 (en) * | 1993-03-20 | 1993-05-05 | Smithkline Beecham Plc | Novel compounds |
GB9326248D0 (en) * | 1993-12-23 | 1994-02-23 | Smithkline Beecham Plc | Pharmaceutical formulations |
US5464616A (en) * | 1994-08-04 | 1995-11-07 | Synphar Laboratories, Ind. | 6β-substituted penicillanic acids as beta-lactamase inhibitors |
AR039475A1 (es) | 2002-05-01 | 2005-02-23 | Wyeth Corp | 6-alquiliden-penems triciclicos como inhibidores de beta-lactamasa |
AR039774A1 (es) | 2002-05-01 | 2005-03-02 | Wyeth Corp | 6-alquiliden-penems biciclicos como inhibidores de beta-lactamasas |
US20060105941A1 (en) * | 2004-11-12 | 2006-05-18 | Allergan, Inc. | Mixed antibiotic codrugs |
AU2012233003B2 (en) * | 2005-12-07 | 2014-12-18 | Basilea Pharmaceutica Ag | Useful combinations of monobactam antibiotics with beta-lactamase inhibitors |
CN103724330B (zh) * | 2005-12-07 | 2015-08-19 | 巴斯利尔药物股份公司 | 单环-内酰胺类抗生素与β-内酰胺酶抑制剂的有效的联合应用 |
US10399041B2 (en) * | 2014-11-17 | 2019-09-03 | Qatar Foundation For Education, Science And Community Development | Two-dimensional metal carbide antimicrobial membrane and antimicrobial agent |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3176517D1 (en) * | 1980-04-24 | 1987-12-17 | Beecham Group Plc | Beta-lactam compounds, their preparation and use |
EP0046363B1 (en) * | 1980-08-16 | 1984-11-14 | Beecham Group Plc | Process for the preparation of 2-thio penem derivatives and intermediates therefor |
EP0120613A1 (en) * | 1983-03-02 | 1984-10-03 | Beecham Group Plc | Penem derivatives and precursors |
-
1985
- 1985-01-15 FI FI850174A patent/FI82471C/sv not_active IP Right Cessation
- 1985-01-18 DE DE8585100521T patent/DE3585095D1/de not_active Expired - Fee Related
- 1985-01-18 EP EP85100521A patent/EP0154132B1/en not_active Expired - Lifetime
- 1985-01-24 IL IL74153A patent/IL74153A/xx unknown
- 1985-01-24 PT PT79873A patent/PT79873B/pt unknown
- 1985-01-24 DK DK32485A patent/DK32485A/da not_active Application Discontinuation
- 1985-01-24 AU AU38058/85A patent/AU569366B2/en not_active Ceased
- 1985-01-24 KR KR1019850000435A patent/KR850005444A/ko not_active Application Discontinuation
- 1985-01-24 US US06/694,607 patent/US4798828A/en not_active Expired - Fee Related
- 1985-01-24 NZ NZ210929A patent/NZ210929A/en unknown
- 1985-01-24 GR GR850208A patent/GR850208B/el unknown
- 1985-01-24 PH PH31766A patent/PH23447A/en unknown
- 1985-01-24 CA CA000472745A patent/CA1272479A/en not_active Expired - Fee Related
- 1985-01-25 JP JP60013393A patent/JPH0696579B2/ja not_active Expired - Lifetime
- 1985-01-25 NO NO850314A patent/NO850314L/no unknown
- 1985-01-25 ES ES539853A patent/ES8707244A1/es not_active Expired
- 1985-01-25 YU YU11685A patent/YU45695B/sh unknown
- 1985-01-25 HU HU85300A patent/HU197013B/hu not_active IP Right Cessation
- 1985-01-25 PL PL1985251703A patent/PL149297B1/pl unknown
- 1985-10-18 ES ES548033A patent/ES8609338A1/es not_active Expired
-
1986
- 1986-04-01 ES ES553604A patent/ES8800683A1/es not_active Expired
Also Published As
Publication number | Publication date |
---|---|
ES548033A0 (es) | 1986-09-01 |
YU45695B (sh) | 1992-07-20 |
ES8800683A1 (es) | 1987-11-16 |
DK32485D0 (da) | 1985-01-24 |
HUT38352A (en) | 1986-05-28 |
FI850174L (fi) | 1985-07-27 |
CA1272479A (en) | 1990-08-07 |
AU3805885A (en) | 1985-08-01 |
PL251703A1 (en) | 1985-12-03 |
JPS60185786A (ja) | 1985-09-21 |
IL74153A (en) | 1990-04-29 |
ES8707244A1 (es) | 1987-07-16 |
AU569366B2 (en) | 1988-01-28 |
DK32485A (da) | 1985-07-27 |
ES539853A0 (es) | 1987-07-16 |
PT79873A (en) | 1985-02-01 |
ES8609338A1 (es) | 1986-09-01 |
HU197013B (en) | 1989-02-28 |
FI82471C (sv) | 1991-03-11 |
US4798828A (en) | 1989-01-17 |
PL149297B1 (en) | 1990-01-31 |
GR850208B (sv) | 1985-05-24 |
KR850005444A (ko) | 1985-08-26 |
FI82471B (fi) | 1990-11-30 |
EP0154132A1 (en) | 1985-09-11 |
YU11685A (en) | 1988-02-29 |
NZ210929A (en) | 1987-08-31 |
DE3585095D1 (de) | 1992-02-20 |
ES553604A0 (es) | 1987-11-16 |
EP0154132B1 (en) | 1992-01-08 |
FI850174A0 (fi) | 1985-01-15 |
PT79873B (pt) | 1986-06-02 |
JPH0696579B2 (ja) | 1994-11-30 |
PH23447A (en) | 1989-08-07 |
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