DE3317742C2 - - Google Patents
Info
- Publication number
- DE3317742C2 DE3317742C2 DE3317742A DE3317742A DE3317742C2 DE 3317742 C2 DE3317742 C2 DE 3317742C2 DE 3317742 A DE3317742 A DE 3317742A DE 3317742 A DE3317742 A DE 3317742A DE 3317742 C2 DE3317742 C2 DE 3317742C2
- Authority
- DE
- Germany
- Prior art keywords
- group
- penem
- carboxylic acid
- hydroxyethyl
- groups
- 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
Links
- 150000001875 compounds Chemical class 0.000 claims description 51
- 125000006239 protecting group Chemical group 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- QMNCBSOHIWPYRE-ROXVQFJHSA-N (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2-methyl-1,4,5,6-tetrahydropyrimidin-5-yl)sulfanyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound O[C@H](C)[C@@H]1[C@@H]2N(C(=C(S2)SC2CNC(=NC2)C)C(=O)O)C1=O QMNCBSOHIWPYRE-ROXVQFJHSA-N 0.000 claims description 4
- BDGBZXFEYVNOFK-NJUACVTBSA-N (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-(1,4,5,6-tetrahydropyrimidin-5-ylsulfanyl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound O[C@H](C)[C@@H]1[C@@H]2N(C(=C(S2)SC2CNC=NC2)C(=O)O)C1=O BDGBZXFEYVNOFK-NJUACVTBSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 230000032050 esterification Effects 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 claims 1
- 238000005755 formation reaction Methods 0.000 claims 1
- 238000005809 transesterification reaction Methods 0.000 claims 1
- -1 Isopropoxymethyl Chemical group 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 30
- 239000000243 solution Substances 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 8
- 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 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 238000003379 elimination reaction Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 150000002960 penicillins Chemical group 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 125000004149 thio group Chemical group *S* 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 239000002585 base Substances 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
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 230000008030 elimination Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- WKDDRNSBRWANNC-ATRFCDNQSA-N Thienamycin Chemical compound C1C(SCCN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 WKDDRNSBRWANNC-ATRFCDNQSA-N 0.000 description 3
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 3
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 150000002961 penems Chemical class 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- GSHQFGKCDGMNHE-GLDDHUGJSA-N (5r,6s)-3-(2-aminoethylsulfanyl)-6-[(1r)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound S1C(SCCN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 GSHQFGKCDGMNHE-GLDDHUGJSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000005042 acyloxymethyl group Chemical group 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 2
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000039 preparative column chromatography Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 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 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- OIHLWKOVIJPVHC-UHFFFAOYSA-N (4-nitrophenyl)methyl 2-oxoacetate;hydrate Chemical compound O.[O-][N+](=O)C1=CC=C(COC(=O)C=O)C=C1 OIHLWKOVIJPVHC-UHFFFAOYSA-N 0.000 description 1
- QLSICEGKJKUQQN-UHFFFAOYSA-N (4-nitrophenyl)methyl n-[2-hydroxy-3-[(4-nitrophenyl)methoxycarbonylamino]propyl]carbamate Chemical compound C=1C=C([N+]([O-])=O)C=CC=1COC(=O)NCC(O)CNC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 QLSICEGKJKUQQN-UHFFFAOYSA-N 0.000 description 1
- UXJPVUIDWDKGOJ-PUQNFTFYSA-N (5R,6S)-3-[[2-(cyanomethyl)-1,4,5,6-tetrahydropyrimidin-5-yl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C(#N)CC1=NCC(CN1)SC=1S[C@H]2N(C=1C(=O)O)C([C@@H]2[C@@H](C)O)=O UXJPVUIDWDKGOJ-PUQNFTFYSA-N 0.000 description 1
- GTYNDPUVQJWJAX-JJCBXJPRSA-N (5S,6S)-6-[(1R)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-[(4-nitrophenyl)methyl]-7-oxo-3-sulfanylidene-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound C[C@H]([C@@H]1[C@H]2N(C1=O)C(C(=S)S2)(CC3=CC=C(C=C3)[N+](=O)[O-])C(=O)O)O[Si](C)(C)C(C)(C)C GTYNDPUVQJWJAX-JJCBXJPRSA-N 0.000 description 1
- DUNKKIRUWZSMPT-RXMQYKEDSA-N (5r)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical class OC(=O)C1=CS[C@@H]2CC(=O)N12 DUNKKIRUWZSMPT-RXMQYKEDSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- WGMHMVLZFAJNOT-UHFFFAOYSA-N 1-ethoxyethylideneazanium;chloride Chemical compound [Cl-].CCOC(C)=[NH2+] WGMHMVLZFAJNOT-UHFFFAOYSA-N 0.000 description 1
- JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000588767 Proteus vulgaris Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 241000607762 Shigella flexneri Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical group 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910052977 alkali metal sulfide Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 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 1
- PAFZNILMFXTMIY-UHFFFAOYSA-O cyclohexylammonium Chemical compound [NH3+]C1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-O 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- NLPAKSHMMNFZGT-UHFFFAOYSA-N methyl 2-cyanoethanimidate Chemical compound COC(=N)CC#N NLPAKSHMMNFZGT-UHFFFAOYSA-N 0.000 description 1
- APJZJAXVHQZSOU-UHFFFAOYSA-N methyl methanimidate;hydrochloride Chemical compound Cl.COC=N APJZJAXVHQZSOU-UHFFFAOYSA-N 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000989 no adverse effect Toxicity 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- WSHJJCPTKWSMRR-RXMQYKEDSA-N penam Chemical compound S1CCN2C(=O)C[C@H]21 WSHJJCPTKWSMRR-RXMQYKEDSA-N 0.000 description 1
- 125000002217 penem group Chemical group 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- DPLVEEXVKBWGHE-UHFFFAOYSA-N potassium sulfide Chemical compound [S-2].[K+].[K+] DPLVEEXVKBWGHE-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 229940007042 proteus vulgaris Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- XMPBSAVUVBWQTK-UHFFFAOYSA-N s-[1,3-bis[(4-nitrophenyl)methoxycarbonylamino]propan-2-yl] ethanethioate Chemical compound C=1C=C([N+]([O-])=O)C=CC=1COC(=O)NCC(SC(=O)C)CNC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 XMPBSAVUVBWQTK-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 241000894007 species Species 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 150000003952 β-lactams Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with 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
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with 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 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with 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 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms 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 3
- C07D477/20—Sulfur 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
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D207/12—Oxygen or sulfur atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- 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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57081067A JPS58198486A (ja) | 1982-05-14 | 1982-05-14 | ペネムまたはカルバペネム−３−カルボン酸誘導体およびその製法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE3317742A1 DE3317742A1 (de) | 1983-11-17 |
| DE3317742C2 true DE3317742C2 (en, 2012) | 1991-08-29 |
Family
ID=13736043
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19833317742 Granted DE3317742A1 (de) | 1982-05-14 | 1983-05-16 | Penem-derivate, deren herstellung und die sie enthaltenden zusammensetzungen |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US4613595A (en, 2012) |
| JP (1) | JPS58198486A (en, 2012) |
| CH (1) | CH659072A5 (en, 2012) |
| DE (1) | DE3317742A1 (en, 2012) |
| ES (2) | ES522389A0 (en, 2012) |
| FR (1) | FR2526798B1 (en, 2012) |
| GB (1) | GB2121792B (en, 2012) |
| IT (1) | IT1164226B (en, 2012) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5916892A (ja) * | 1982-07-19 | 1984-01-28 | Sankyo Co Ltd | カルバペネム−３−カルボン酸誘導体およびその製法 |
| US4772597A (en) * | 1983-10-14 | 1988-09-20 | Pfizer Inc. | 2-azacycloalkylthiopenem derivatives |
| CA1339860C (en) * | 1985-06-17 | 1998-05-12 | Tsunehiko Soga | Derivatives of penem |
| US4751297A (en) * | 1987-03-20 | 1988-06-14 | Pfizer Inc. | Method for preparation of azetidinone-1-oxoacetate by oxidation of the corresponding 2-hydroxyacetate |
| ES2067534T3 (es) * | 1988-04-01 | 1995-04-01 | Sankyo Co | Derivados de 2-(heterocicliltio)carbapenemo, su preparacion y su aplicacion como antibioticos. |
| US5242914A (en) * | 1988-04-01 | 1993-09-07 | Sankyo Company, Limited | 2-(heterocyclylthio) carbapenem derivatives, their preparation and their use as antibiotics |
| JP2783683B2 (ja) * | 1992-12-21 | 1998-08-06 | ジョン グン ダン コーポレーション | ２−（２−置換されたピロリジン−４−イル）チオ−カバペネム誘導体 |
| WO2023235456A1 (en) * | 2022-06-01 | 2023-12-07 | The Johns Hopkins University | Penem antibacterials against mycobacterial pathogens and d,d- and l,d transpeptidases |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4168314A (en) * | 1977-11-17 | 1979-09-18 | Merck & Co., Inc. | 6-(1'-Hydroxyethyl)-2-aminoethylthio-pen-2-em-3-carboxylic acid |
| EP0042026B1 (de) * | 1978-02-02 | 1986-01-08 | Ciba-Geigy Ag | 3,4-Disubstituierte Azetidin-2-onverbindungen und Verfahren zu ihrer Herstellung |
| EP0008514B1 (en) * | 1978-08-25 | 1982-01-20 | Beecham Group Plc | Beta-lactam anti-bacterials, compositions containing them and a process for their preparation |
| JPS55153789A (en) * | 1979-04-11 | 1980-11-29 | Sankyo Co Ltd | Penem-3-carboxylic acid derivative and its preparation |
| EP0082133A3 (en) * | 1979-04-19 | 1983-07-20 | Merck & Co. Inc. | A process for preparing intermediates useful for preparing 2-substituted-6-substituted-1-carbadethiapen-2-em-3-carboxylic acids |
| US4386030A (en) * | 1979-12-31 | 1983-05-31 | Merck & Co., Inc. | Process for preparing 6-(1'-hydroxyethyl)-2-substituted-pen-2-em-3-carboxylic acid |
| EP0041768B1 (en) * | 1980-04-24 | 1987-11-11 | Beecham Group Plc | Beta-lactam compounds, their preparation and use |
| GB2083462B (en) * | 1980-08-16 | 1984-05-02 | Beecham Group Ltd | 2-thiopenem derivatives |
| JPS57176988A (en) * | 1981-04-09 | 1982-10-30 | Sankyo Co Ltd | Penam-3-carboxylic acid derivative and its preparation |
| EP0070204B1 (en) * | 1981-07-15 | 1987-11-19 | Sumitomo Pharmaceuticals Company, Limited | Carboxylic beta-lactam compounds and the preparation thereof |
| US4435412A (en) * | 1982-11-29 | 1984-03-06 | Schering Corporation | 5R,6S,8R-2-(1-Methyl-2-imidazolylmethylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid |
-
1982
- 1982-05-14 JP JP57081067A patent/JPS58198486A/ja active Granted
-
1983
- 1983-05-13 IT IT21084/83A patent/IT1164226B/it active
- 1983-05-13 US US06/494,570 patent/US4613595A/en not_active Expired - Fee Related
- 1983-05-13 ES ES522389A patent/ES522389A0/es active Granted
- 1983-05-13 CH CH2629/83A patent/CH659072A5/de not_active IP Right Cessation
- 1983-05-16 DE DE19833317742 patent/DE3317742A1/de active Granted
- 1983-05-16 GB GB08313399A patent/GB2121792B/en not_active Expired
- 1983-05-16 FR FR8308085A patent/FR2526798B1/fr not_active Expired
- 1983-12-28 ES ES528491A patent/ES528491A0/es active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| GB2121792B (en) | 1986-01-08 |
| US4613595A (en) | 1986-09-23 |
| JPS58198486A (ja) | 1983-11-18 |
| CH659072A5 (de) | 1986-12-31 |
| JPH0318638B2 (en, 2012) | 1991-03-13 |
| FR2526798B1 (fr) | 1985-10-04 |
| ES8407053A1 (es) | 1984-08-16 |
| DE3317742A1 (de) | 1983-11-17 |
| ES522389A0 (es) | 1984-08-16 |
| IT8321084A0 (it) | 1983-05-13 |
| IT1164226B (it) | 1987-04-08 |
| ES8504815A1 (es) | 1985-05-01 |
| FR2526798A1 (fr) | 1983-11-18 |
| ES528491A0 (es) | 1985-05-01 |
| GB2121792A (en) | 1984-01-04 |
| GB8313399D0 (en) | 1983-06-22 |
| IT8321084A1 (it) | 1984-11-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8110 | Request for examination paragraph 44 | ||
| D2 | Grant after examination | ||
| 8364 | No opposition during term of opposition | ||
| 8339 | Ceased/non-payment of the annual fee |