EP0000656B1 - 4"-ureido-oleandomycin derivatives, process for their preparation and their use in pharmaceutical compositions - Google Patents
4"-ureido-oleandomycin derivatives, process for their preparation and their use in pharmaceutical compositions Download PDFInfo
- Publication number
- EP0000656B1 EP0000656B1 EP78300186A EP78300186A EP0000656B1 EP 0000656 B1 EP0000656 B1 EP 0000656B1 EP 78300186 A EP78300186 A EP 78300186A EP 78300186 A EP78300186 A EP 78300186A EP 0000656 B1 EP0000656 B1 EP 0000656B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- deoxy
- acetyl
- oleandomycyl
- urea
- formula
- 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
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 3
- 238000000034 method Methods 0.000 title description 26
- 238000002360 preparation method Methods 0.000 title description 4
- 239000004202 carbamide Substances 0.000 claims description 51
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 42
- 229960002351 oleandomycin Drugs 0.000 claims description 41
- 239000004104 Oleandomycin Substances 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 12
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- -1 hydroxypyridyl Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- 239000000243 solution Substances 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 239000000047 product Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000002904 solvent Substances 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 239000006260 foam Substances 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 239000010410 layer Substances 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 239000012948 isocyanate Substances 0.000 description 5
- 150000002513 isocyanates Chemical class 0.000 description 5
- 239000002516 radical scavenger Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- RZPAKFUAFGMUPI-UHFFFAOYSA-N Oleandomycin Natural products O1C(C)C(O)C(OC)CC1OC1C(C)C(=O)OC(C)C(C)C(O)C(C)C(=O)C2(OC2)CC(C)C(OC2C(C(CC(C)O2)N(C)C)O)C1C RZPAKFUAFGMUPI-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- RZPAKFUAFGMUPI-KGIGTXTPSA-N oleandomycin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C RZPAKFUAFGMUPI-KGIGTXTPSA-N 0.000 description 4
- 235000019367 oleandomycin Nutrition 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000013505 freshwater Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- LURYMYITPCOQAU-UHFFFAOYSA-N benzoyl isocyanate Chemical compound O=C=NC(=O)C1=CC=CC=C1 LURYMYITPCOQAU-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 239000000039 congener Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- DDRPCXLAQZKBJP-UHFFFAOYSA-N furfurylamine Chemical compound NCC1=CC=CO1 DDRPCXLAQZKBJP-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical compound NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- ADAKRBAJFHTIEW-UHFFFAOYSA-N 1-chloro-4-isocyanatobenzene Chemical compound ClC1=CC=C(N=C=O)C=C1 ADAKRBAJFHTIEW-UHFFFAOYSA-N 0.000 description 1
- GDBZDLPGORORCQ-UHFFFAOYSA-N 2-(aminomethyl)aniline;dihydrochloride Chemical compound Cl.Cl.NCC1=CC=CC=C1N GDBZDLPGORORCQ-UHFFFAOYSA-N 0.000 description 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 1
- BMTSZVZQNMNPCT-UHFFFAOYSA-N 2-aminopyridin-3-ol Chemical compound NC1=NC=CC=C1O BMTSZVZQNMNPCT-UHFFFAOYSA-N 0.000 description 1
- WBFOBYQRRHXCMI-UHFFFAOYSA-N 4-methoxybenzoyl isocyanate Chemical compound COC1=CC=C(C(=O)N=C=O)C=C1 WBFOBYQRRHXCMI-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Substances ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 1
- 229910017974 NH40H Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 238000010936 aqueous wash Methods 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 150000001510 aspartic acids Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 235000010633 broth Nutrition 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- YUVJRAGXZDXKHH-UHFFFAOYSA-N carbonyl dichloride;chloroform Chemical compound ClC(Cl)Cl.ClC(Cl)=O YUVJRAGXZDXKHH-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- XNABHFLZYMCJHE-UHFFFAOYSA-N furan-3-ylmethanamine Chemical compound NCC=1C=COC=1 XNABHFLZYMCJHE-UHFFFAOYSA-N 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000012809 post-inoculation Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- 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
Definitions
- This invention relates to novel antibacterial agents and, in particular, to a series of 11-0-alkanoyl-4"-deoxy-4"-ureido-oleandomycins and their pharmaceutically acceptable acid addition salts.
- the invention also relates to key intermediates leading to the 4"-ureido compounds and to other 4"-amino derived antibacterial agents.
- Oleandomycin its production in fermentation broths and its use as an antibacterial agent were first described in U.S. Patent 2,757,123.
- the naturally occurring compound is known to have the following structure: The conventionally accepted numbering scheme and stereochemical representation for oleandomycin and similar compounds is shown at a variety of positions.
- Preferred antibacterials related to the compounds of formula 1 are those wherein R is acetyl.
- Especially preferred species within this group are N-(11-O-acetyl-4"-deoxy-4"-oleandomycyl)-N'-(p-methoxybenzyl)urea, N-(11-0-acetyl-4"-deoxy-4"-oleandomycyl)-N'-(p-chlorobenzyl)urea; N-(11-0- acetyl-4"-deoxy-4"-oleandomycyl)-N'-(o-chlorobenzyl)urea, N-(11-0-acetyl-4"-deoxy-4"-oleandomycyl)-N' -(m-methylbenzyl)urea, N-(11-0-acetyl-4"-deoxy-4"-oleandomycyl)-N'-(m-tolyl)urea and N-
- Preferred antibacterials related to the compounds of formula 2 are those wherein R is acetyl.
- Especially preferred species within this group are N-(11-0-acetyl-4"-deoxy-4"-oleandomycyl)-N'-(m-methylbenzoyl)urea and N-(11-0-acetyl-4"-deoxy-4"-oleandomycyl)-N'-(p-methoxybenzoyl)urea.
- Preferred within the compounds of formula 3 are those wherein R is acetyl. Especially preferred as an intermediate is 11-0-acetyl-4"-deoxy-4"-isocyanato-oleandomycin.
- reaction-inert solvent a reaction-inert solvent
- solvents should appreciably solubilize the reactants while not reacting to any significant extent with either the starting reagents or the products formed.
- aprotic, polar solvents which are immiscible with water.
- methylene chloride and chloroform are especially preferred.
- one mole of the isocyanate is contacted with up to four moles of the requisite amine.
- one to two moles of the amine can be employed in conjunction with the balance of the four moles being a tertiary amine, such as triethylamine or pyridine.
- Reaction time is not critical and is dependent on reaction temperature, concentration and inherent reactivity of the starting reagents.
- concentration concentration of the starting reagents.
- the reaction on completion, is worked-up by the addition of additional solvent and water.
- the water layer is made strongly basic with an aqueous sodium hydroxide solution and the water immiscible organic phase separated, dried and evaporated to dryness.
- the crude product can, if desired, be further purified by chromatographing on silica gel, a procedure well known in the art.
- An alternative method according to the invention for synthesising compounds related to 1 comprises the reaction of the appropriate 11-0-alkanoyl-4"-deoxy-4"-amino-oleandomycin with the requisite isocyanate as illustrated:
- This alternative method for preparing compounds related to 1 is conducted in a similar manner to the initial route.
- the reactants are contacted in the same type of reaction-inert solvents at ice-bath temperature. It is convenient, in employing this alternative method, to allow the reaction temperature to warm to room temperature after the reactants have initially been brought into contact with one another. The reaction at ambient temperatures is complete in 30-60 minutes.
- the ratio of 4"-amino-oleandomycin to isocyanate is about one to one with as much as a 10-20% excess of the isocyanate.
- the antibacterial agents of formula 2 are prepared according to the invention through the reaction of the appropriate 11-0-alkanoyl-4" -deoxy-4" -amino-oleandomycin and benzoyl isocyanate as illustrated: wherein R and X are as previously defined.
- reaction is conducted in a reaction-inert solvent similar to that employed in the routes leading to compounds of formula 1.
- one mole of the 4"-amino compound is contacted with one mole of phosgene plus as much as a 10-20% excess in the presence of three to four moles of a hydrogen chloride scavenger such as pyridine or triethylamine.
- a hydrogen chloride scavenger such as pyridine or triethylamine.
- the reaction is best carried out under anhydrous conditions in a chlorinated hydrocarbon solvent such as methylene chloride or chloroform.
- the product is isolated by removal of the solvent and excess acid scavenger, followed by redissolution in fresh solvent, washing with water to remove scavenger amine hydrochloride and removing the solvent in vacuo. No further purification of the intermediate is necessary.
- reaction is substantially complete in 10-20 minutes.
- the starting 4"-amino compounds used in the synthesis of antibacterial agents of the present invention are synthesized by oxidation of the natural oleandomycin followed by a reductive amination of the resultant ketone as hereinafter described.
- the isocyanates employed in the processes for preparing compounds of formulae 1 and 2 are either commercially available or are synthesized according to the procedures as taught by Speziale et al., J. Org. Chem., 30, 4306 (1965) and Wagner and Zook, "Synthetic Organic Chemistry", John Wiley and Sons, New York, N.Y., 1956, p. 640.
- the chemotherapeutic activity of those compounds of the present invention which form salts it is preferred, of course, to use pharmaceutically acceptable salts.
- pharmaceutically acceptable salts water- insolubility, high toxicity, or lack of crystalline nature may make some particular salt species unsuitable or less desirable for use as such in a given pharmaceutical application, the water insoluble or toxic salts can be converted to the corresponding pharmaceutically acceptable bases by decomposition of the salt as described above, or alternatively they can be converted to any desired pharmaceutically acceptable acid addition salt.
- acids which provide pharmaceutically acceptable anions are hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, sulphurous, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, gluconic and aspartic acids.
- novel 4"-deoxy-4"-amino-oleandomycin derivatives described herein exhibit in vitro activity against a variety of Grampositive microorganisms such as Staphylococcus aureus and Streptococcus pyogenes and against certain Gram-negative microorganisms such as those of spherical or ellipsoidal shape (cocci).
- Grampositive microorganisms such as Staphylococcus aureus and Streptococcus pyogenes
- certain Gram-negative microorganisms such as those of spherical or ellipsoidal shape (cocci).
- Their activity is readily demonstrated by in vitro tests against various microorganisms in a brain-heart infusion medium by the usual two-fold serial dilution technique.
- Their in vitro activity renders them useful for topical application in the form of ointments, creams and the like; for sterilisation purposes, e.g. sick-room utensils; and
- a pharmaceutically-acceptable carrier such as vegetable or mineral oil or an emollient cream.
- a pharmaceutically-acceptable carrier such as vegetable or mineral oil or an emollient cream.
- they may be dissolved or dispersed in liquid carriers or solvent, such as water, alcohol, glycols or mixtures thereof or other pharmaceutically-acceptable inert media; that is, media which have no harmful effect on the active ingredient.
- concentrations of active ingredients of from 0.01 percent to 10 percent by weight based on total composition.
- mice are active versus Gram-positive microorganisms via the oral and/or parenteral routes of administration in animals, including man.
- Their in vivo activity is more limited as regards susceptible organisms and is determined by the usual procedure which comprises infecting mice of substantially uniform weight with the test organism and subsequently treating them orally or subcutaneously with the test compound.
- the mice e.g. 10 are given an intraperitoneal inoculation of suitably diluted cultures containing approximately 1 to 10 times the LD 100 (the lowest concentration of organisms required to produce 100% deaths).
- Control tests are simultaneously run in which mice receive inoculum of lower dilutions as a check on possible variation in virulence of the test organism.
- the test compound is administered 0.5 hour post-inoculation, and is repeated 4, 24 and 48 hours later. Surviving mice are held for four days after the last treatment and the number of survivors is noted.
- these novel compounds When used in vivo, these novel compounds can be administered orally or parenterally, e.g., by subcutaneous or intramuscular injection at a dosage of from 5 mg./kg. to 200 mg./kg. of body weight per day.
- the favoured dosage range is from 25 mg./kg. to 100 mg./kg. of body weight per day and the preferred range from 50 mg./kg. to 75 mg./kg. of body weight per day.
- Vehicles suitable for parenteral injection may be either aqueous such as water, isotonic saline, isotonic dextrose, Ringers' solution, or non-aqueous such as fatty oils of vegetable origin (cotton seed, peanut oil, corn, sesame), dimethylsulfoxide and other non-aqueous vehicles which will not interfere with therapeutic efficiency of the preparation and are non-toxic in the volume of proportion used (glycol, propylene glycol, sorbitol). Additionally, compositions suitable for extemporaneous preparation of solutions prior to administration may advantageously be made.
- aqueous such as water, isotonic saline, isotonic dextrose, Ringers' solution
- non-aqueous such as fatty oils of vegetable origin (cotton seed, peanut oil, corn, sesame), dimethylsulfoxide and other non-aqueous vehicles which will not interfere with therapeutic efficiency of the preparation and are non-toxic in the volume of proportion used (glycol, propylene glycol, sorb
- compositions may include liquid diluents, for example, propylene glycol, diethyl carbonate, glycerol, sorbitol, etc.; buffering agents, hyaluronidase, local anaesthetics and inorganic salts to afford desirable pharmacological properties.
- liquid diluents for example, propylene glycol, diethyl carbonate, glycerol, sorbitol, etc.
- buffering agents hyaluronidase, local anaesthetics and inorganic salts to afford desirable pharmacological properties.
- hyaluronidase hyaluronidase
- local anaesthetics and inorganic salts to afford desirable pharmacological properties.
- inert carriers including solid diluents, aqueous vehicles, non-toxic organic solvents in the form of capsules, tablets, lozenges, troches, dry mixes, suspensions, solutions elixirs and parenter
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the formula 1 or 2 or 3 wherein R 2 is -NHCN; or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier.
- a cold (0°C) solution of 3.0g. (4.11 mmoles) of 11-0-acetyl-4" -deoxy-4" -amino-oleandomycin and .99 ml. of pyridine in 60 ml. of dry methylene chloride is rapidly stirred while 10.98 mi. of a .41M solution of phosgene in chloroform is added rapidly. After 5 min. 1.8 ml. of benzylamine is added and the stirring continued in the cold for an additional 15 min.
- the reaction is diluted with 150 ml. of methylene chloride, layered with 150 ml. of water and the pH of the aqueous layer adjusted to 9.5 with aqueous 6N sodium hydroxide solution.
- a .3M solution of phosgene in chloroform (10 mi.) is added rapidly with stirring to a solution of 2.0 g. (2.7 mmoles) of 11-0-acetyl-4"-deoxy-4"-amino-oleandomycin and .65 mi. of pyridine in 50 ml. of dry methylene chloride cooled to 0°C in an ice bath. The solvent is removed under reduced pressure, and the residual yellow foam dissolved in 50 mi. of dry methylene chloride. The solution is cooled with an ice bath and treated with 1.08 ml. of o-chlorobenzylamine.
- reaction solution is washed with water (2 x 100 ml.), the pH being adjusted to 9.5 with 6N aqueous sodium hydroxide solution during the final washing.
- the methylene chloride layer is separated, dried over sodium sulphate and concentrated in vacuo to give 3.3 g. of the desired product as a yellow foam.
- the product is further purified by chromatographing on a 3.25 x 38 cm., silica gel-acetone packed column, using acetone as the eluate. Fractions 201-300, comprising 5 ml. each, are combined and concentrated to dryness to give 1.9 g. of the pure product.
- the product is further purified by chromatographing on silica gel using acetone as the elutent. Fractions, which are comprised of 5 ml. each, 221-395 are combined and concentrated in vacuo to dryness to give 1.4 g. of the product.
- Example 9 The procedure of Example 9 is repeated, starting with the requisite reagents, to give the following compounds:
- reaction mixture is concentrated under reduced pressure, and the residual yellow foam dissolved in 50 ml. of dry methylene chloride.
- the solution is cooled in an ice bath and is then treated with 2.5 mi. of triethylamine followed immediately by 1.8 g. of o-aminobenzylamine dihydrochloride.
- the reaction is quenched with water (75 ml.) and the pH of the aqueous wash adjusted to 9.5 with 1N aqueous sodium hydroxide solution.
- the organic phase is separated, dried over sodium sulphate and concentrated in vacuo to dryness to give 3.0 g. of the product as a yellow foam.
- Example 11 The procedure of Example 11 is employed, starting with the appropriate reagents, to give the following compounds:
- the reaction mixture is concentrated in vacuo to a foam, which is dissolved in 50 ml. of methylene chloride.
- the solution is subsequently cooled to ice bath temperatures and treated with .93 ml. of 4-aminomethylpryidine.
- After one hour of stirring in the cold the reaction mixture is treated with 100 ml. of methylene chloride and 75 ml. of water.
- the water is separated and fresh water mixed with the methylene chloride.
- the pH of the aqueous layer is adjusted to 9.5 with 6N aqueous sodium hydroxide solution.
- the organic phase is separated, dried over sodium sulphate and concentrated to dryness to give 2.3 g. of the product as a yellow foam.
- N-(11-O-propionyl-4"-deoxy-4"-oleandomycyl)-N'-(2-furylmethyl)-urea and N-(11-0-acetyl-4"-deoxy-4"-oleandomycyl)-N'-(3-furylmethyl)urea starting from, respectively, 11-0-propionyl-4"-deoxy-4"-amino-oleandomycin and 2-furylmethylamine, and 11-0- acetyl-4"-deoxy-4'iamino-oleandomycin and 3-furylmethylamine.
- Example 13 The procedure of Example 13 is repeated, starting with the requisite reagents to give the following compounds:
- the sample is further purified by chromatographing over silica gel using acetone eluate. Combined fractions (5 ml. each) 115-770 are concentrated in vacuo to give 800 mg. of pure product.
- a reaction mixture comprising 25 g. (3.4 mmoles) of 11-0-acetyl-4"-deoxy-4"-amino-oleandomycin and .41 ml. (3.8 mmoles) of phenylisocyanate in 25 ml. of dry methylene chloride at 0°C . is stirred for one hour and warmed to room temperature.
- the reaction mixture is treated with 100 ml. of methylene chloride and 100 ml. of water.
- the pH of the water layer is adjusted to 9.9 with 1N aqueous sodium hydroxide and the methylene chloride layer separated, dried over sodium sulphate and concentrated in vacuo to dryness.
- the residual product is further purified by chromatographing on silica gel, the fraction 5 ml. each, being monitored by thin layer chromatography (CHCI 3 /CH 3 0H/NH 4 0H 9:1:0.1 by volume). Fractions 115-155 are combined and stripped under reduced pressure to give 716 mg. of the product as a white foam.
- Example 19 The procedure of Example 19 is again repeated, starting with the requisite reagents, to provide the following compounds:
- the residual yellow foam is chromatographed over silica gel using acetone as the eluate.
- the fractions which are comprised of 5 ml. each, are monitored with thin layer chromatography. Those fractions containing the pure product are combined and concentrated to give 440 mg. of the product as a colourless amorphous solid.
- reaction mixture is stirred at 0°C for 15 min., and is subsequently poured into 500 ml. of water.
- the pH is adjusted to 9.5 with 1N aqueous sodium hydroxide and the organic layer separated, washed with water and a brine solution and dried over sodium sulphate. Removal of the solvent in vacuo gives 4.9 g. of the desired product as a foam.
- the aqueous layer after a further extraction with 500 ml. of chloroform, is treated with 500 mi. of ethyl acetate and the pH adjusted to 9.5 with 1N sodium hydroxide.
- the ethyl acetate layer is separated and the aqueous layer extracted again with ethyl acetate.
- the ethyl acetate extracts are combined, dried over sodium sulphate and concentrated to a yellow foam (18.6 g.), which on crystallisation from diisopropyl ether, provides 6.85 g. of the purified product, m.p. 157.5-160 0 C.
- the other epimer which exists in the crude foam to the extent of 20-25% is obtained by gradual concentration and filtration of the mother liquors.
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US05/818,907 US4098993A (en) | 1977-07-25 | 1977-07-25 | Semi-synthetic 4-ureido-oleandomycin derivatives |
US818907 | 1977-07-25 |
Publications (2)
Publication Number | Publication Date |
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EP0000656A1 EP0000656A1 (en) | 1979-02-07 |
EP0000656B1 true EP0000656B1 (en) | 1981-02-11 |
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ID=25226721
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Application Number | Title | Priority Date | Filing Date |
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EP78300186A Expired EP0000656B1 (en) | 1977-07-25 | 1978-07-24 | 4"-ureido-oleandomycin derivatives, process for their preparation and their use in pharmaceutical compositions |
Country Status (7)
Country | Link |
---|---|
US (1) | US4098993A (enrdf_load_stackoverflow) |
EP (1) | EP0000656B1 (enrdf_load_stackoverflow) |
JP (3) | JPS5463094A (enrdf_load_stackoverflow) |
DE (1) | DE2860469D1 (enrdf_load_stackoverflow) |
DK (1) | DK329078A (enrdf_load_stackoverflow) |
IE (1) | IE47714B1 (enrdf_load_stackoverflow) |
IT (1) | IT1097329B (enrdf_load_stackoverflow) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4133950A (en) * | 1978-01-03 | 1979-01-09 | Pfizer Inc. | 4"-Deoxy-4"-carbamate and dithiocarbamate derivatives of oleandomycin and its esters |
US4124755A (en) * | 1978-01-03 | 1978-11-07 | Pfizer Inc. | 11-Alkanoyl-4"-deoxy-4"-isonitrilo-oleandomycin derivatives |
US4166901A (en) * | 1978-01-03 | 1979-09-04 | Pfizer Inc. | 4"-Deoxy-4"-arylglyoxamido- and aroylthioformamido derivatives of oleandomycin and its esters |
US4427663A (en) | 1982-03-16 | 1984-01-24 | Merck & Co., Inc. | 4"-Keto-and 4"-amino-4"-deoxy avermectin compounds and substituted amino derivatives thereof |
JPH0384727U (enrdf_load_stackoverflow) * | 1989-12-15 | 1991-08-28 | ||
JPH07115113B2 (ja) * | 1991-03-04 | 1995-12-13 | 三菱製鋼株式会社 | 有機質粘結材系鋳物砂に含有される酸化鉄の再利用方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US3022219A (en) * | 1958-03-07 | 1962-02-20 | Pfizer & Co C | Acyl esters of oleandomycin |
US4069379A (en) * | 1976-07-08 | 1978-01-17 | Pfizer Inc. | Semi-synthetic oleandomycins |
US4036853A (en) * | 1976-08-06 | 1977-07-19 | Pfizer Inc. | Semi-synthetic oleandomycin derivatives-C8 modifications |
-
1977
- 1977-07-25 US US05/818,907 patent/US4098993A/en not_active Expired - Lifetime
-
1978
- 1978-07-21 IE IE1467/78A patent/IE47714B1/en not_active IP Right Cessation
- 1978-07-24 JP JP9031778A patent/JPS5463094A/ja active Granted
- 1978-07-24 EP EP78300186A patent/EP0000656B1/en not_active Expired
- 1978-07-24 IT IT26036/78A patent/IT1097329B/it active
- 1978-07-24 JP JP9031878A patent/JPS5463095A/ja active Granted
- 1978-07-24 DK DK329078A patent/DK329078A/da unknown
- 1978-07-24 DE DE7878300186T patent/DE2860469D1/de not_active Expired
- 1978-07-24 JP JP9031678A patent/JPS5424887A/ja active Granted
Also Published As
Publication number | Publication date |
---|---|
DE2860469D1 (en) | 1981-03-26 |
IT7826036A0 (it) | 1978-07-24 |
JPS564560B2 (enrdf_load_stackoverflow) | 1981-01-30 |
IE781467L (en) | 1979-01-25 |
US4098993A (en) | 1978-07-04 |
JPS5463095A (en) | 1979-05-21 |
JPS5463094A (en) | 1979-05-21 |
EP0000656A1 (en) | 1979-02-07 |
JPS5715120B2 (enrdf_load_stackoverflow) | 1982-03-29 |
IE47714B1 (en) | 1984-05-30 |
IT1097329B (it) | 1985-08-31 |
DK329078A (da) | 1979-01-26 |
JPS5424887A (en) | 1979-02-24 |
JPS5628919B2 (enrdf_load_stackoverflow) | 1981-07-04 |
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