NO145384B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE OLEANDOMYCIN DERIVATIVES - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE OLEANDOMYCIN DERIVATIVES Download PDFInfo
- Publication number
- NO145384B NO145384B NO781656A NO781656A NO145384B NO 145384 B NO145384 B NO 145384B NO 781656 A NO781656 A NO 781656A NO 781656 A NO781656 A NO 781656A NO 145384 B NO145384 B NO 145384B
- Authority
- NO
- Norway
- Prior art keywords
- oleandomycin
- deoxy
- acetyl
- thienyl
- amino
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 30
- 238000002360 preparation method Methods 0.000 title claims description 10
- RZPAKFUAFGMUPI-KGIGTXTPSA-N oleandomycin Chemical class 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 title description 46
- 230000001225 therapeutic effect Effects 0.000 title description 2
- -1 monosubstituted phenyl Chemical group 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 28
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000001544 thienyl group Chemical group 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 239000007858 starting material Substances 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000002516 radical scavenger Substances 0.000 claims description 4
- 150000003461 sulfonyl halides Chemical class 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 125000005518 carboxamido 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
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000012442 inert solvent Substances 0.000 claims 1
- 229960002351 oleandomycin Drugs 0.000 description 97
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 93
- 239000004104 Oleandomycin Substances 0.000 description 93
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- 235000019367 oleandomycin Nutrition 0.000 description 51
- 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 49
- 239000000047 product Substances 0.000 description 48
- 239000002904 solvent Substances 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000003480 eluent Substances 0.000 description 17
- 239000006260 foam Substances 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000010410 layer Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000012043 crude product Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000012266 salt solution Substances 0.000 description 7
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 4
- ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 4-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1 ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000002024 ethyl acetate extract Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 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
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 239000008365 aqueous carrier Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- CXCHEKCRJQRVNG-UHFFFAOYSA-N 2,2,2-trifluoroethanesulfonyl chloride Chemical compound FC(F)(F)CS(Cl)(=O)=O CXCHEKCRJQRVNG-UHFFFAOYSA-N 0.000 description 1
- JDAJYNHGBUXIKS-UHFFFAOYSA-N 2,3,4-trichlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C(Cl)=C1Cl JDAJYNHGBUXIKS-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- WPHUUIODWRNJLO-UHFFFAOYSA-N 2-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1S(Cl)(=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 description 1
- NYIBPWGZGSXURD-UHFFFAOYSA-N 3,4-dichlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1Cl NYIBPWGZGSXURD-UHFFFAOYSA-N 0.000 description 1
- KXFQRJNVGBIDHA-UHFFFAOYSA-N 3,5-dichloro-2-hydroxybenzenesulfonyl chloride Chemical compound OC1=C(Cl)C=C(Cl)C=C1S(Cl)(=O)=O KXFQRJNVGBIDHA-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- RXFIISJOFYQYKK-UHFFFAOYSA-N 3-methylthiophene-2-sulfonyl chloride Chemical compound CC=1C=CSC=1S(Cl)(=O)=O RXFIISJOFYQYKK-UHFFFAOYSA-N 0.000 description 1
- OZDCZHDOIBUGAJ-UHFFFAOYSA-N 4-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC=C(S(Cl)(=O)=O)C=C1 OZDCZHDOIBUGAJ-UHFFFAOYSA-N 0.000 description 1
- GRDXCFKBQWDAJH-UHFFFAOYSA-N 4-acetamidobenzenesulfonyl chloride Chemical compound CC(=O)NC1=CC=C(S(Cl)(=O)=O)C=C1 GRDXCFKBQWDAJH-UHFFFAOYSA-N 0.000 description 1
- DBMFYTQPPBBKHI-UHFFFAOYSA-N 4-cyanobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(C#N)C=C1 DBMFYTQPPBBKHI-UHFFFAOYSA-N 0.000 description 1
- XKQZGGLHJYTXJA-UHFFFAOYSA-N 4-hydroxybenzenesulfonyl chloride Chemical compound OC1=CC=C(S(Cl)(=O)=O)C=C1 XKQZGGLHJYTXJA-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- 244000252363 Amydrium medium Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-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
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 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
- RXELPOGHCHDCFH-HTPNXTHCSA-N [(3R,5S,6S,7R,8S,9R,12R,13S,14S,15R)-6-[(2S,3R,4S,6R)-3-acetyloxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-8-[(2R,4S,5S,6S)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy-5,7,9,12,13,15-hexamethyl-10,16-dioxo-1,11-dioxaspiro[2.13]hexadecan-14-yl] acetate Chemical compound CO[C@H]1C[C@H](O[C@H]2[C@H](C)[C@@H](O[C@@H]3O[C@H](C)C[C@@H]([C@H]3OC(C)=O)N(C)C)[C@@H](C)C[C@@]3(CO3)C(=O)[C@H](C)[C@@H](OC(C)=O)[C@@H](C)[C@@H](C)OC(=O)[C@@H]2C)O[C@@H](C)[C@@H]1O RXELPOGHCHDCFH-HTPNXTHCSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- SNHZVLCTLMSLKW-UHFFFAOYSA-N benzyl 4-chlorosulfonylbenzoate Chemical compound C1=CC(S(=O)(=O)Cl)=CC=C1C(=O)OCC1=CC=CC=C1 SNHZVLCTLMSLKW-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method 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
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 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
- 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
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- YPPVMLHOORADOQ-UHFFFAOYSA-N methyl 5-chlorosulfonyl-1h-pyrrole-2-carboxylate Chemical compound COC(=O)C1=CC=C(S(Cl)(=O)=O)N1 YPPVMLHOORADOQ-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere 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
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- OAHKWDDSKCRNFE-UHFFFAOYSA-N phenylmethanesulfonyl chloride Chemical compound ClS(=O)(=O)CC1=CC=CC=C1 OAHKWDDSKCRNFE-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification 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
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000001954 sterilising effect Effects 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
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- VNNLHYZDXIBHKZ-UHFFFAOYSA-N thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CS1 VNNLHYZDXIBHKZ-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover 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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Enzymes And Modification Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
Denne oppfinnelse angår en analogifremgangsmåte for fremstilling av nye antibakterielle forbindelser og spesielt en serie av 4"-deoksy-4"-sulfonylamino-oleandomyciner og deres farmasøytisk godtagbare syreaddisjonssalter. This invention relates to an analogous process for the preparation of new antibacterial compounds and in particular to a series of 4"-deoxy-4"-sulfonylamino-oleandomycins and their pharmaceutically acceptable acid addition salts.
Oleandomycin, fremstilling derav i fermenteringsvæske og anvendelse som et antibakterielt middel ble først beskrevet i US-patent 2.757.123. Det er kjent at den naturlig forekommende forbindelse har den følgende struktur: Oleandomycin, its preparation in fermentation broth and its use as an antibacterial agent was first described in US Patent 2,757,123. It is known that the naturally occurring compound has the following structure:
Det konvensjonelt godtatte nummereringssystem og den stereokjemiske angivelse for oleandomycin og lignende forbindelser er vist i en rekke stillinger. The conventionally accepted numbering system and the stereochemical notation for oleandomycin and similar compounds are shown in a number of positions.
US-patenter 3.884.902 og 3.983.103 angår henholdsvis 4"-erytromycin-sulfonatestere og N-sulfonylerytromycylaminer som har biologiske profiler forskjellig fra forbindelsene som fremstilles ifølge foreliggende oppfinnelse. US Patents 3,884,902 and 3,983,103 relate respectively to 4"-erythromycin sulfonate esters and N-sulfonylerythromycin amines which have biological profiles different from the compounds produced according to the present invention.
Flere syntetiske modifikasjoner av oleandomycin er kjent, særlig de hvor fra én til tre av de frie hydroksylgrupper i 2'-, Several synthetic modifications of oleandomycin are known, especially those where from one to three of the free hydroxyl groups in the 2'-,
4"- og 11-stillingene er forestret som acetylestere. I tillegg er det i US-patent 3.022.219 beskrevet lignende modifikasjoner hvor acetylgruppene i de ovennevnte estere er erstattet med en annen, fortrinnsvis uforgrenet lavere alkanoylgruppe med 3 til 6 karbonatomer. The 4" and 11-positions are esterified as acetyl esters. In addition, US patent 3,022,219 describes similar modifications where the acetyl groups in the above-mentioned esters are replaced with another, preferably unbranched, lower alkanoyl group with 3 to 6 carbon atoms.
De halvsyntetiske oleandomycin-antibakterielle midler The semi-synthetic oleandomycin antibacterial agents
som fremstilles ifølge oppfinnelsen, omfattes av formelen: which is produced according to the invention, is covered by the formula:
og and
de farmasøytisk godtagbare syreaddisjonssalter derav, hvor R er alkyl med fra 1 til 3 karbonatomer; pyridyl; 1,1,1-trifluor-etyl; fenyl; monosubstituert fenyl hvor substituenten er valgt fra fluor, klor, brom, jod, hydroksy, metoksy, cyano, karboksamido, nitro, amino, karbometoksy, karbobenzyloksy, karboksy, trifluormetyl, alkyl med fra 1 til 4 karbonatomer og acetamido; disubstituert fenyl hvor substituentene hver er valgt fra klor, nitro, amino, metoksy og metyl; triklorfenyl; hydroksydiklorfenyl; benzyl'; naftyl; tienyl; klortienyl; 2-acetamido-5-tiazolyl; 2-acetamido-4-metyl-5-tiazolyl; 2-benzimidazolyl; dimetyl-2-pyrimidinyl; pyrryl; furyl; monosubstituert tienyl, pyrryl og furyl hvor substituenten er valgt fra karbometoksy og alkyl med 1 til 2 karbonatomer; eller l-metyl-5-karbometoksy-3-pyrryl; og the pharmaceutically acceptable acid addition salts thereof, wherein R is alkyl having from 1 to 3 carbon atoms; pyridyl; 1,1,1-trifluoroethyl; phenyl; monosubstituted phenyl wherein the substituent is selected from fluorine, chlorine, bromine, iodo, hydroxy, methoxy, cyano, carboxamido, nitro, amino, carbomethoxy, carbobenzyloxy, carboxy, trifluoromethyl, alkyl having from 1 to 4 carbon atoms and acetamido; disubstituted phenyl wherein the substituents are each selected from chloro, nitro, amino, methoxy and methyl; trichlorophenyl; hydroxydichlorophenyl; benzyl'; naphthyl; thienyl; chlorothienyl; 2-acetamido-5-thiazolyl; 2-acetamido-4-methyl-5-thiazolyl; 2-benzimidazolyl; dimethyl-2-pyrimidinyl; pyrryl; furyl; monosubstituted thienyl, pyrryl and furyl wherein the substituent is selected from carbomethoxy and alkyl of 1 to 2 carbon atoms; or 1-methyl-5-carbomethoxy-3-pyrryl; and
er hydrogen eller alkanoyl med 2 til 3 karbonatomer; is hydrogen or alkanoyl of 2 to 3 carbon atoms;
forutsatt at når. R-^ er hydrogen, er R fenyl; tienyl; mono-substituert fenyl hvor substituenten er valgt fra klor, fluor, metyl, metoksy og trifluormetyl; eller alkylsubstituert tienyl hvor alkylgruppen har fra 1 til 2 karbonatomer. provided that when. R-1 is hydrogen, R is phenyl; thienyl; mono-substituted phenyl wherein the substituent is selected from chloro, fluoro, methyl, methoxy and trifluoromethyl; or alkyl substituted thienyl where the alkyl group has from 1 to 2 carbon atoms.
Amin-utgangsmaterialene som anvendes ved fremstilling av de nye forbindelser, omfattes, på grunn av den syntesemetode som anvendes for fremstilling derav, av 4"-epimere aminer. De nye sulfonamido-forbindelser som fremstilles fra nevnte aminer, omfatter således også en epimer blanding. Eksperimentelt er det funnet at begge epimere sulfonamider er tilstede i sluttproduktet i varierende forhold avhengig av valg av syntesemetode som er anvendt for fremstilling av amin-mellomproduktet. Hvis det isolerte produkt består overveiende av én av epimerene, kan nevnte epimer renses ved gjentatt omkrystallisering fra et egnet opp-løsningsmiddel til konstant smeltepunkt. Den annen epimer, den som er til stede i mindre mengder i det opprinnelig isolerte, faste materiale, er det overveiende produkt i moderluten. Den kan gjenvinnes fra denne ved i og for seg kjente metoder, som f.eks. ved inndampning av moderluten og gjentatt omkrystallisering av residuet til et produkt med konstant smeltepunkt eller ved kromatografi. The amine starting materials used in the production of the new compounds comprise, due to the synthesis method used for their production, 4"-epimeric amines. The new sulfonamido compounds produced from said amines thus also comprise an epimeric mixture. Experimentally, it has been found that both epimeric sulfonamides are present in the final product in varying proportions depending on the choice of synthesis method used to prepare the amine intermediate. If the isolated product consists predominantly of one of the epimers, said epimer can be purified by repeated recrystallization from a suitable solvent of constant melting point. The other epimer, which is present in smaller amounts in the initially isolated solid material, is the predominant product in the mother liquor. It can be recovered from this by methods known per se, such as f .eg by evaporation of the mother liquor and repeated recrystallization of the residue into a product with a constant melting point or d chromatography.
Selv om blandingen av epimerer kan separeres ved i og for seg kjente metoder, er det av praktiske grunner hensiktsmessig å anvende blandingen slik som den isoleres fra reaksjonsblandingen. Det er imidlertid ofte hensiktsmessig å rense blandingen av epimerer ved minst én omkrystallisering fra et passende oppløsningsmiddel, ved å underkaste den kolonnekromatografi, oppløsningsmiddelfordeling eller ved utgnidning i et passende oppløsningsmiddel. Denne rensning som ikke nødvendigvis adskiller epimerene, fører til fjernelse av slike fremmede materialer som utgangsmaterialer og uønskede biprodukter. Although the mixture of epimers can be separated by methods known per se, for practical reasons it is appropriate to use the mixture as it is isolated from the reaction mixture. However, it is often convenient to purify the mixture of epimers by at least one recrystallization from a suitable solvent, by subjecting it to column chromatography, solvent partitioning or by trituration in a suitable solvent. This purification, which does not necessarily separate the epimers, leads to the removal of such foreign materials as starting materials and unwanted by-products.
: .Den,absolutte .stereokjemiske fastleggelse av epimerene er ikke fullført. Begge epimerer av en gitt forbindelse oppviser 'imidlertid' den samme type-' aktivitet, f.eks. som antibakterielle : The absolute stereochemical determination of the epimers has not been completed. However, both epimers of a given compound exhibit the same type of activity, e.g. as antibacterial
Foretrukne forbindelser med formel 1 ef de hvor R er substituert fenyl, tienyl og substituert tienyl hvor substituenten er alkyl med,fra 1 til 2 karbonatomer eller karbometoksy.- Preferred compounds of formula 1 if those where R is substituted phenyl, thienyl and substituted thienyl where the substituent is alkyl with from 1 to 2 carbon atoms or carbomethoxy.
Foretrukne blant disse forbindelser på grunn av deres antibakterielle egenskaper er ll-acetyl-4"-deoksy-4"-(2-tienylsulfonylamino)oleandomycin, ll-acetyl-4"-deoksy-4"- (3-tienylsulfonylamino)oleandomycin, ll-acetyl-4"-deoksy-4"-(3-metyl-2-tienylsulfonylamino)oleandomycin, 4"-deoksy-4"-(p-klorfenylsulfonylamino)-oleandomycin, 4"-deoksy-4"- (2-tienylsulfonylamino)-oleandomycin, 4"-deoksy-4"-(3-tienylsulfonylamino)oleandomycin, og 4"-deoksy-4"-(3-metyl-2-tienylsulfonylamino)oleandomycin. Preferred among these compounds because of their antibacterial properties are 11-acetyl-4"-deoxy-4"-(2-thienylsulfonylamino)oleandomycin, 11-acetyl-4"-deoxy-4"-(3-thienylsulfonylamino)oleandomycin, 11 -acetyl-4"-deoxy-4"-(3-methyl-2-thienylsulfonylamino)oleandomycin, 4"-deoxy-4"-(p-chlorophenylsulfonylamino)-oleandomycin, 4"-deoxy-4"-(2-thienylsulfonylamino )-oleandomycin, 4"-deoxy-4"-(3-thienylsulfonylamino)oleandomycin, and 4"-deoxy-4"-(3-methyl-2-thienylsulfonylamino)oleandomycin.
Fremgangsmåten i henhold til oppfinnelsen for fremstilling av 4"-deoksy-4"-sulfonylamino-oleandomycin-avledede antibakterielle midler med formel _1 ved å starte med 4"-deoksy-4"-amino-oleandomycin eller et 11-alkanoyl-derivat derav, kan illustreres ved hjelp av The method according to the invention for the production of 4"-deoxy-4"-sulfonylamino-oleandomycin-derived antibacterial agents of formula _1 by starting with 4"-deoxy-4"-amino-oleandomycin or an 11-alkanoyl derivative thereof, can be illustrated by means of
det følgende skjema: the following form:
hvor R og R^ er som tidligere angitt, og W er et halogenatom. where R and R 1 are as previously indicated, and W is a halogen atom.
De ovenfor angitte omsetninger utføres mellom et 4"-deoksy-4"-amino-oleandomycin og et passende sulfonylhalogenid i nærvær av et syreoppfangende middel i et reaksjonsinert oppløsningsmiddel. The above reactions are carried out between a 4"-deoxy-4"-amino-oleandomycin and an appropriate sulfonyl halide in the presence of an acid scavenger in a reaction-initiated solvent.
I praksis bringes ett mol 4"-amino-oleandomycin i kontakt med ett mol av sulfonylhalogenidet pluss så mye som et 2-3% overskudd In practice, one mole of 4"-amino-oleandomycin is contacted with one mole of the sulfonyl halide plus as much as a 2-3% excess
av nevnte halogenid. Det syreoppfangende middel, som kan være av uorganisk eller organisk natur, anvendes i en mengde på ett mol pluss så mye som 4-6% overskudd. of said halide. The acid scavenger, which may be inorganic or organic in nature, is used in an amount of one mole plus as much as 4-6% excess.
Det syreoppfangende middel kan være alkalimetall- eller jordalkalimetallhydroksyder, -hydrider eller -karbonater så vel som et tertiært organisk amin. Dessuten kan man også anvende sekundære aminer, så som diisopropylamin, som er tilstrekkelig hindret til at de ikke reagerer med sulfonylhalogenid-utgangsmaterialet.. The acid scavenger may be alkali metal or alkaline earth metal hydroxides, hydrides or carbonates as well as a tertiary organic amine. In addition, one can also use secondary amines, such as diisopropylamine, which are sufficiently hindered so that they do not react with the sulfonyl halide starting material.
Den foretrukne klasse syreoppfangende midler er tertiære aminer.. Særlig foretrukket innen denne klasse er trietylamin. The preferred class of acid scavengers are tertiary amines. Particularly preferred within this class is triethylamine.
Det reaksjonsinerte oppløsningsmiddel som anvendes ved den ovenfor angitte fremgangsmåte, bør være et som i vesentlig grad solubiliserer reaksjonskomponentene og ikke. reagerer i noen vesentlig utstrekning med hverken reaksjonskomponentene eller de dannede produkter. Særlig foretrekkes polare oppløsningsmidler som er blandbare eller ikke-blandbare med vann. Spesielt foretrekkes metylenklorid og aceton-vann. The reaction-initiated solvent used in the above-mentioned method should be one that substantially solubilizes the reaction components and does not. reacts to any significant extent with either the reaction components or the products formed. Particularly preferred are polar solvents which are miscible or immiscible with water. Methylene chloride and acetone-water are particularly preferred.
Eftersom pppvarmning av amino-oleandomyciner -fører til Since ppp heating of amino-oleandomycins -leads to
en viss spaltning, foretrekkes at fremgangsmåten for fremstilling av forbindelsene med formell foretas ved 0-25°C. Spesielt foretrekkes at omsetningen foretas ved omgivelses- eller romtemperatur. a certain cleavage, it is preferred that the method for preparing the compounds with formal is carried out at 0-25°C. It is particularly preferred that the turnover is carried out at ambient or room temperature.
Reaksjonstiden er ikke kritisk og er avhengig av reaksjonstemperatur, konsentrasjon og iboende reaktivitet hos utgangsmaterialene. Når omsetningen utføres ved romtemperatur under anvendelse av de nedenfor angitte konsentrasjoner, er omsetningen i alt vesentlig fullstendig efter 2 til 48 timer. The reaction time is not critical and depends on the reaction temperature, concentration and inherent reactivity of the starting materials. When the reaction is carried out at room temperature using the concentrations indicated below, the reaction is essentially complete after 2 to 48 hours.
Efter fullførelse av omsetningen kan reaksjonsblandingen opparbeides ved en av to metoder, som begge er kjent for fagfolk. Den første opparbeidelsesmetode omfatter at reaksjonsblandingen settes til vann, fulgt av fraskillelse av det ikke-vannblandbare. oppløsningsmiddel som inneholder det ønskede produkt, og fjernelse av dette gir så råproduktet. Når et vannblandbart oppløsnings-middel anvendes som reaksjonsinert oppløsningsmiddel, ekstraheres produktet fra den vanntilsatte reaksjonsblanding under anvendelse av et ikke-vannblandbart oppløsningsmiddel så som metylenklorid. After completion of the reaction, the reaction mixture can be worked up by one of two methods, both of which are known to those skilled in the art. The first work-up method involves adding the reaction mixture to water, followed by separation of the non-water-miscible. solvent containing the desired product, and removal of this then yields the crude product. When a water-miscible solvent is used as the reaction-initiated solvent, the product is extracted from the aqueous reaction mixture using a water-immiscible solvent such as methylene chloride.
Den annen opparbeidelsesmetode omfatter konséntrering The other processing method includes concentration
av reaksjonsblandingen til tørrhet fulgt av ekstraksjon av produktet fra det salt som er resultatet av den syreoppfangende base og hydrogenhalogenid-biprodukt, under anvendelse av aceton. Aceton-ekstrakten kan konsentreres for å gi et råprodukt. of the reaction mixture to dryness followed by extraction of the product from the salt resulting from the acid-trapping base and hydrogen halide by-product, using acetone. The acetone extract can be concentrated to give a crude product.
Råproduktet eller en acetonoppløsning derav renses ved kromatografering på silikagel, hvilket er en velkjent metode, eller omkrystallisering. The crude product or an acetone solution thereof is purified by chromatography on silica gel, which is a well-known method, or recrystallization.
'.'r- 4"-amino-utgangsforbindelsene som anvendes ved syntese av de antibakterielle midler,- fremstilles ved oksydasjon av det naturlige oleandomycin, fulgt av en reduktiv aminering av det resulterende keton som beskrevet nedenfor. The '.'r-4"-amino starting compounds used in the synthesis of the antibacterial agents are prepared by oxidation of the natural oleandomycin, followed by a reductive amination of the resulting ketone as described below.
Ved utnyttelse av den kjemoterapeutiske virkning av de forbindelser som fremstilles ifølge oppfinnelsen, som danner salter, By utilizing the chemotherapeutic effect of the compounds produced according to the invention, which form salts,
foretrekkes selvsagt å anvende farmasøytisk godtagbare salter. it is of course preferred to use pharmaceutically acceptable salts.
Selv om vannuoppløselighet, høy giftighet eller mangel på Although water insolubility, high toxicity or lack of
• krystallinsk natur .kan gjøre noen spesielle salttyper uegnet eller mindre ønsket for anvendelse som sådanne i et farmasøytisk preparat, kan vannuoppløselige eller giftige salter omdannes til de tilsvarende farmasøytisk godtagbare baser ved spaltning av saltet med en egnet base, eller alternativt kan de omdannes til et hvilket som helst ønsket farmasøytisk godtagbart syreaddisjonssalt. Eksempler på syrer som tilveiebringer farmasøytisk godtagbare anioner, er saltsyre, bromhydrogensyre, jodhydrogensyre, salpetersyre, svovelsyre, svovelsyrling, fos forsyre,. -eddiksy re, melkesyre, sitronsyré, vinsyre, ravsyre, maleinsyre, glukonsyre, asparaginsyre, glutaminsyre, pyroglutaminsyre og laurylsvovelsyre*. De nye 4"^deoksy-4"-amino-oleandomycin-derivater som fremstilles ifølge-oppfinnelsen, oppviser in vitro aktivitet mot forskjellige Gram-.positive mikroorganismer så som Staphylococcus aureus og Streptocpccus pyogenes, og mot visse Gram-negative mikroorganismer.slik som de som har sfærisk eller eliipsoid form (cocci). Deres aktivitet påvises lett ved in vitro forsøk mot .forskjellige.mikroorganismer i et hjerne-hjerte-infusjonsmedium ved.den vanlige dobbelte seriefortynningstékriikk. Deres in vitro ■'"aktivitet gjør dem nyttige for lokal anvendelse i form av salver, . .kremer o.l., for steriliserings formål, f.eks*., sykeromsutstyr, og ."som industrielle antimikrobielle midler, f.eks. for vannbehandling, "slimkontroll, maling- og tre-konservering. • crystalline nature can make some particular types of salt unsuitable or less desirable for use as such in a pharmaceutical preparation, water-insoluble or toxic salts can be converted into the corresponding pharmaceutically acceptable bases by cleavage of the salt with a suitable base, or alternatively they can be converted into a any desired pharmaceutically acceptable acid addition salt. Examples of acids which provide pharmaceutically acceptable anions are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulfuric acid, phosphoric acid. -acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, gluconic acid, aspartic acid, glutamic acid, pyroglutamic acid and laurylsulphuric acid*. The new 4"^deoxy-4"-amino-oleandomycin derivatives prepared according to the invention exhibit in vitro activity against various Gram-positive microorganisms such as Staphylococcus aureus and Streptococcus pyogenes, and against certain Gram-negative microorganisms such as those that have a spherical or ellipsoid shape (cocci). Their activity is easily demonstrated by in vitro tests against various micro-organisms in a brain-heart infusion medium by the usual two-fold serial dilution technique. Their in vitro ■'"activity makes them useful for local application in the form of ointments, . .creams, etc., for sterilization purposes, e.g.*., hospital equipment, and "as industrial antimicrobial agents, e.g. for water treatment, slime control, paint and wood preservation.
For in vitro bruk, f.eks. for lokal administrering, vil <!> de t ofte være hensiktsmessig å blande det utvalgte produkt med et farmasøytisk godtagbart 'bæremiddel-.: så som.,en vegetabilsk olje eller en mineralolje eller en bløtgjørende krem. Likeledes karr produktene oppløses eller dispergeres i flytende bæremidler eller oppløsningsmidler så som vann, alkohol, glykoler eller blandinger derav, eller andre farmasøytisk godtagbare inerte medier, dvs. medier som ikke har noen skadelig virkning på den aktive bestanddel. For slike formål vil det vanligvis være godtagbart å anvende konsentrasjoner av de aktive bestanddeler på fra ca. 0,01 til ca. 10 vekt%, basert på det totale preparat. For in vitro use, e.g. for local administration, it will often be convenient to mix the selected product with a pharmaceutically acceptable carrier such as a vegetable oil or a mineral oil or an emollient cream. Likewise, the products can be dissolved or dispersed in liquid carriers or solvents such as water, alcohol, glycols or mixtures thereof, or other pharmaceutically acceptable inert media, i.e. media that have no harmful effect on the active ingredient. For such purposes, it will usually be acceptable to use concentrations of the active ingredients of from approx. 0.01 to approx. 10% by weight, based on the total preparation.
Dessuten er mange av forbindelsene fremstilt ifølge oppfinnelsen aktive mot Gram-positive mikroorganismer ved oral og/eller parenteral administrering på dyr, innbefattet mennesker. Deres Moreover, many of the compounds produced according to the invention are active against Gram-positive microorganisms when administered orally and/or parenterally to animals, including humans. Their
in vivo aktivitet er mer begrenset med hensyn til organismer som påvirkes, og bestemmes ved den vanlige metode som omfatter at mus med tilnærmet jevn vekt infiseres med prøveorganismen og derefter behandles oralt eller subkutant med prøveforbindelsen. I praksis gis musene, f.eks. 10, en intraperitoneal innpodning av egnede fortynnede kulturer inneholdende omtrentlig 1 til 10 ganger LD^q0 (den laveste konsentrasjon av organismer som er nødvendig for å frembringe 100% dødsfall). Kontrollforsøk foretas samtidig med mus som mottar podestoff i lavere fortynninger som en kontroll på mulige variasjoner i styrken av prøveorganismen. Prøve-forbindelsen administreres 0,5 time efter innpodning og gjentas 4, 24 og 48 timer senere. Overlevende mus holdes i 4 dager efter den siste behandling, og antall overlevende nedtegnes. in vivo activity is more limited with respect to organisms affected, and is determined by the usual method which involves infecting mice of approximately equal weight with the test organism and then treating them orally or subcutaneously with the test compound. In practice, the mice are given, e.g. 10, an intraperitoneal inoculation of suitable diluted cultures containing approximately 1 to 10 times the LD^q0 (the lowest concentration of organisms necessary to produce 100% mortality). Control experiments are carried out simultaneously with mice receiving inoculum in lower dilutions as a check for possible variations in the strength of the test organism. The test compound is administered 0.5 hour after inoculation and repeated 4, 24 and 48 hours later. Surviving mice are kept for 4 days after the last treatment, and the number of survivors is recorded.
Når de anvendes in vivo, kan disse nye forbindelser administreres oralt eller parenteralt, f.eks. ved subkutan eller intramuskulær injeksjon, i en dose fra ca. 1 til ca. 200 mg/kg kroppsvekt pr. dag. Det foretrukne doseområde er fra ca. 2 til ca. 100 mg/kg kroppsvekt pr. dag, og det særlig foretrukne område er fra ca. 2 til ca. 50 mg/kg kroppsvekt pr. dag. Bæremidler som er egnet for parenteral injeksjon, kan enten, være vandig, så som vann, isotonisk saltvann, isotonisk dekstrose eller Ringers opp-løsning, eller ikke-vandig, så som fete oljer av vegetabilsk opprinnelse (bomullsfrø, jordnøttolje, mais, sesam), dimetyl-sulfoksyd og andre ikke-vandige bæremidler som ikke vil påvirke preparatets terapeutiske virkning og er ugiftige i den anvendte mengde (glycerol, propylenglykol, sorbitol). Preparater som er egnet for fremstilling av oppløsninger på stedet før administrering, kan dessuten hensiktsmessig fremstilles. Slike preparater kan inneholde flytende fortynningsmidler, f.eks. propylenglykol, dietylkarbonat, glycerol, sorbitol osv.; buffer-midler, hyaluronidase, lokalbedøvelsesmidler og uorganiske salter for å oppnå ønskede farmakologiske egenskaper. Disse forbindelser kan også blandes med forskjellige farmasøytisk godtagbare inerte bæremidler innbefattet faste fortynningsmidler, vandige bæremidler, og ugiftige organiske oppløsningsmidler i form av kapsler, tabletter, piller, pastiller, tørrblandinger, suspensjoner, opp-løsninger, eliksirer og parenterale oppløsninger eller suspensjoner. Generelt anvendes forbindelsene i forskjellige doseformer i konsentrasjoner varierende fra ca. 0,5 til ca. 90 vekt% av det totale preparat. When used in vivo, these new compounds can be administered orally or parenterally, e.g. by subcutaneous or intramuscular injection, in a dose from approx. 1 to approx. 200 mg/kg body weight per day. The preferred dose range is from approx. 2 to approx. 100 mg/kg body weight per day, and the particularly preferred area is from approx. 2 to approx. 50 mg/kg body weight per day. Carriers suitable for parenteral injection can either be aqueous, such as water, isotonic saline, isotonic dextrose or Ringer's solution, or non-aqueous, such as fatty oils of vegetable origin (cottonseed, peanut oil, corn, sesame). , dimethyl sulphoxide and other non-aqueous carriers which will not affect the therapeutic effect of the preparation and are non-toxic in the amount used (glycerol, propylene glycol, sorbitol). Preparations which are suitable for the preparation of solutions on the spot before administration can also be appropriately prepared. Such preparations may contain liquid diluents, e.g. propylene glycol, diethyl carbonate, glycerol, sorbitol, etc.; buffer agents, hyaluronidase, local anesthetics and inorganic salts to achieve desired pharmacological properties. These compounds can also be mixed with various pharmaceutically acceptable inert carriers including solid diluents, aqueous carriers, and non-toxic organic solvents in the form of capsules, tablets, pills, lozenges, dry mixes, suspensions, solutions, elixirs and parenteral solutions or suspensions. In general, the compounds are used in different dosage forms in concentrations varying from approx. 0.5 to approx. 90% by weight of the total preparation.
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere. The following examples shall serve to further illustrate the invention.
Eksempel 1 Example 1
ll- acetyl- 4"- deoksy- 4"-( 2- tienylsulfonylamino) oleandomycin ll- acetyl- 4"- deoxy- 4"-( 2- thienylsulfonylamino) oleandomycin
Til 30 ml tørr metylenklorid settes 2,9 g (4,0 mmol) ll-acetyl-4"-deoksy-4"-amino-oleandomycin, 740 mg (4,1 mmol) 2-tienylsulfonylklorid og 0,58 ml (4,2 mmol) trietylamin, og den resulterende blanding omrøres ved romtemperatur i 18 timer. Reaksjonsblandingen helles i 50 ml vann og vaskes derefter med en mettet saltoppløsning og tørres over natriumsulfat. Oppløsnings-midlet fjernes under redusert trykk, og det gjenværende skum renses ved kromatografi over en silikagelgelkolonne under anvendelse av aceton som oppløsningsmiddel og elueringsmiddel. Fraksjonene inneholdende produktet samles og konsentreres i vakuum til tørrhet, 1,3 g.. To 30 ml of dry methylene chloride are added 2.9 g (4.0 mmol) of 11-acetyl-4"-deoxy-4"-amino-oleandomycin, 740 mg (4.1 mmol) of 2-thienylsulfonyl chloride and 0.58 ml (4 .2 mmol) of triethylamine, and the resulting mixture is stirred at room temperature for 18 hours. The reaction mixture is poured into 50 ml of water and then washed with a saturated salt solution and dried over sodium sulfate. The solvent is removed under reduced pressure, and the remaining foam is purified by chromatography over a silica gel column using acetone as solvent and eluent. The fractions containing the product are collected and concentrated in vacuo to dryness, 1.3 g..
NMR (6, CDC13): 2,03 (3H) s, 2,30 (6H) s, 2,63 (2H) d, 3,16 (3H) s og 6,8-7,8 (3H) m. NMR (6, CDCl 3 ): 2.03 (3H) s, 2.30 (6H) s, 2.63 (2H) d, 3.16 (3H) s and 6.8-7.8 (3H) m .
Eksempel 2 Example 2
Ved å starte med ll-acetyl-4"-deoksy-4"-amino-oleandomycin det passende sulfonylklorid og å anvende fremgangsmåten ifølge eksempel 1, fremstilles de følgende forbindelser: By starting with 11-acetyl-4"-deoxy-4"-amino-oleandomycin the appropriate sulfonyl chloride and using the procedure of Example 1, the following compounds are prepared:
Eksempel 3 Example 3
ll- acetyl- 4 "-deoksy-4"-( p- klor fenylsulfonylamino) oleandomycin 11-acetyl-4"-deoxy-4"-(p-chlorophenylsulfonylamino)oleandomycin
Til en oppløsning av 2,91 g (4,0 mmol) ll-acetyl-4"-deoksy-4'-amino-oleandomycin og 528 \ il (4,2 mmol)- trietylamin i 20 ml metylenklorid settes porsjonsvis 865 mg (4,1 mmol) p-klorfenylsulfonylklorid, og den resulterende reaksjonsblariding omrøres ved romtemperatur natten over. Reaksjonsblandingen konsentreres til tørrhet i vakuum, og residuet behandles med 10 ml aceton. Suspensjonen filtreres, og filtratet kromatograferes på 160 g silikagel under anvendelse av aceton som elueringsmiddel. Fraksjonene 51 til 6 3 som hver omfatter 10 ml, oppsamles og konsentreres under redusert trykk for å gi 857 mg rent produkt. Fraksjonene 42-52 og 64-92 gir 1,21 g mindre rent produkt. 865 mg ( 4.1 mmol) of p-chlorophenylsulfonyl chloride, and the resulting reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated to dryness in vacuo, and the residue is treated with 10 mL of acetone. The suspension is filtered, and the filtrate is chromatographed on 160 g of silica gel using acetone as eluent. Fractions 51 to 6 3 each comprising 10 ml are collected and concentrated under reduced pressure to give 857 mg of pure product.Fractions 42-52 and 64-92 give 1.21 g of less pure product.
NMR (6, CDC13):;2,13 (3H) s, 2,36 (6H) s, 2,73 (2H) d, 3,13 (3H) s og 7,3-8,2 (4H)Wq. 20 g ll-acetyl-4"-deoksy-4"-amino-oleandomycin, 7,24 g p-klorfenylsulfonylklorid og 5,36 g trietylamin i et oppløsnings-middelsystem omfattende 350 ml aceton og 350 ml vann, gir tilsvarende 17,1 g av det ønskede produkt som krystalliseres fra reaksjonsblandingen, sm.p. 202-203,5°C. Den analytiske prøve om-krystalliseres fra etanol/vann. NMR (6, CDCl 3 ):;2.13 (3H) s, 2.36 (6H) s, 2.73 (2H) d, 3.13 (3H) s and 7.3-8.2 (4H) Wq. 20 g of 11-acetyl-4"-deoxy-4"-amino-oleandomycin, 7.24 g of p-chlorophenylsulfonyl chloride and 5.36 g of triethylamine in a solvent system comprising 350 ml of acetone and 350 ml of water gives correspondingly 17.1 g of the desired product which crystallizes from the reaction mixture, m.p. 202-203.5°C. The analytical sample is recrystallized from ethanol/water.
E ksempel 4 Example 4
Under.:'airvendelse av fremgangsmåten ifølge eksempel 3 og ved å starte med det passende sulfonylklorid og ll-acetyl-4"-deoksy-4"-amino-oleand@myjGin, fremstilles de følgende forbindelser: Reversing the procedure according to Example 3 and starting with the appropriate sulfonyl chloride and 11-acetyl-4"-deoxy-4"-amino-oleand@myjGin, the following compounds are prepared:
Eksempel 5 V. Example 5 V.
ll- acetyl- 4 "■^ Heoksy- 4 "- ( o- tolylsulfonylamino) oleandomycin ll- acetyl- 4 "■^ Heoxy- 4 "-( o- tolylsulfonylamino) oleandomycin
En oppløsning av 2,9 g (4,0 mmol) ll-acetyl-4"-deoksy-4"-amino-oleandomycin, 780 mg (4,1 mmol) o-tolylsulfonylklorid og A solution of 2.9 g (4.0 mmol) of 11-acetyl-4"-deoxy-4"-amino-oleandomycin, 780 mg (4.1 mmol) of o-tolylsulfonyl chloride and
0,58 ml (4,2 mmol) trietylamin i 30 ml metylenklorid omrøres ved romtemperatur i 48 timer. Reaksjonsblandingen bråkjøles i 50 ml vann, og det fraskilte organiske lag vaskes, med.en mettet salt-oppløsning og tørres over natriumsulf at. Oppiøsningsmidletv fjernes. i vakuum, og det .gjenværende gule skum kromatograferes på 200 g silikagel i en kolonne med en diamter på 3 cm. Produktet elueres 0.58 ml (4.2 mmol) of triethylamine in 30 ml of methylene chloride is stirred at room temperature for 48 hours. The reaction mixture is quenched in 50 ml of water, and the separated organic layer is washed with a saturated salt solution and dried over sodium sulphate. The solvent is removed. in vacuum, and the remaining yellow foam is chromatographed on 200 g of silica gel in a column with a diameter of 3 cm. The product is eluted
fra kolonnen med aceton og oppsamles i 10 ml fraksjoner.: De : v fraksjoner som inneholder det rene produkt, som påvist ved tynnskiktkromatografi, samles og konsentreres til tørrhet under redusert trykk for å gi 1,3 g. from the column with acetone and collected in 10 ml fractions.: The : v fractions containing the pure product, as detected by thin layer chromatography, are collected and concentrated to dryness under reduced pressure to give 1.3 g.
NMR (6, CDC13): 2,06 (3H) s, 2,33 (6H) s, 2,46 (2H) d, 2,73 (3H) s NMR (6, CDCl 3 ): 2.06 (3H) s, 2.33 (6H) s, 2.46 (2H) d, 2.73 (3H) s
og 7,1-8,2 (4H) m. and 7.1-8.2 (4H) m.
Eksempel 6 Example 6
Fremgangsmåten ifølge eksempel 5 gjentas, idet man starter med det passende sulfonylklorid og ll-acetyl-4"-deoksy-4"-amino-oleandomycin, for fremstilling av de følgende forbindelser: The procedure according to Example 5 is repeated, starting with the appropriate sulfonyl chloride and 11-acetyl-4"-deoxy-4"-amino-oleandomycin, to prepare the following compounds:
Eksempel 7Example 7
ll- acetyl- 4"- deoksy- 4"- fenylsulfonylamino- oleandomycin ll- acetyl- 4"- deoxy- 4"- phenylsulfonylamino- oleandomycin
Til en oppløsning av 2,91 g (4,0 mmol) ll-acetyl-4 "-. deoksy-4"-amino-oleandomycin og 4 24 mg (4,2 mmol) trietylamin i 30 ml metylenklorid som holdes avkjølt i et isbad, settes 722 mg (4,1 mmol) benzylsulfonylklorid. Efter 10 minutter fjernes badet, og reaksjonsblandingen omrøres ved romtemperatur natten over. Reaksjonsblandingen bråkjøles med 50 ml vann, pg det organiske lag vaskes med en mettet saltoppløsning og tørres over natriumsulfat. Fjernelse av oppløsningsmidlet gir råproduktet som renses ytterligere ved kromatografi over 160 g silikagel under anvendelse av aceton som elueringsmiddel. Fraksjonene (10 ml hver) 61-93 som inneholder det rene produkt som påvist ved tynnskiktkromatografi, samles og konsentreres og tørres under redusert trykk for å gi 1,5 g av det ønskede produkt. To a solution of 2.91 g (4.0 mmol) of 11-acetyl-4"-.deoxy-4"-amino-oleandomycin and 424 mg (4.2 mmol) of triethylamine in 30 ml of methylene chloride which is kept cooled in a ice bath, add 722 mg (4.1 mmol) of benzylsulfonyl chloride. After 10 minutes, the bath is removed, and the reaction mixture is stirred at room temperature overnight. The reaction mixture is quenched with 50 ml of water, then the organic layer is washed with a saturated salt solution and dried over sodium sulphate. Removal of the solvent gives the crude product which is further purified by chromatography over 160 g of silica gel using acetone as eluent. Fractions (10 ml each) 61-93 containing the pure product as detected by thin layer chromatography are pooled and concentrated and dried under reduced pressure to give 1.5 g of the desired product.
NMR (6, CDC1'3) : 2,06 (3H) s, 2,30 (6H) s, 2,63 (2H) d, 3,06 (3H) s, og 7,3-8,2 (5H) m. NMR (6, CDCl'3) : 2.06 (3H) s, 2.30 (6H) s, 2.63 (2H) d, 3.06 (3H) s, and 7.3-8.2 ( 5H) m.
o o
Ved fremgangsmåten ifølge eksempel 7 fremstilles også under anvendelse av de passende utgangsmaterialer de følgende forbindelser: In the method according to example 7, the following compounds are also produced using the appropriate starting materials:
ll- acetyl- 4"- deoksy- 4"-(2- naftylsulfonylamino) oleandomycin 11-acetyl-4"-deoxy-4"-(2-naphthylsulfonylamino)oleandomycin
NMR (6, CDC13): 2,03 (3H) s, 2,26 (6H) s, 2,65 (2H) d, 2,96 (3H) NMR (6, CDCl 3 ): 2.03 (3H) s, 2.26 (6H) s, 2.65 (2H) d, 2.96 (3H)
og 7,4-8,6 (7H) m; og ll- acetyl- 4"- deoksy- 4"- benzylsulfonylamino- oleandomycin NMR (6, CDC13): 2,00 (3H) s, 2,30 (6H) s, 2,63 (2H) d, 3,46 (3H) s, 4,33 (2H) s, og 7,36 (5H) s. and 7.4-8.6 (7H) m; and 11- acetyl- 4"- deoxy- 4"- benzylsulfonylamino- oleandomycin NMR (6, CDCl 3 ): 2.00 (3H) s, 2.30 (6H) s, 2.63 (2H) d, 3.46 (3H) s, 4.33 (2H) s, and 7.36 (5H) s.
Eksempel 8 Example 8
ll- acetyl- 4"- deoksy- 4"-( p- benzyloksykarbonylfenylsulfonylamino)-oleandomycin ll- acetyl- 4"- deoxy- 4"-( p- benzyloxycarbonylphenylsulfonylamino)-oleandomycin
En oppløsning av 2,55 g (3,5 mmol) ll-acetyl-4"-deoksy-4"-amino-oleandomycin, 1,12 g (3;6 mmol) p-benzyloksykarbonyl-fenylsulfonylklorid og 379 mg (3,75 mmol) trietylamin i 25 ml metylenklorid omrøres ved romtemperatur natten over. Oppløsnings-midlet fjernes i vakuum, og residuet utgnies i 10 ml aceton.. A solution of 2.55 g (3.5 mmol) of 11-acetyl-4"-deoxy-4"-amino-oleandomycin, 1.12 g (3.6 mmol) of p-benzyloxycarbonyl-phenylsulfonyl chloride and 379 mg (3, 75 mmol) of triethylamine in 25 ml of methylene chloride is stirred at room temperature overnight. The solvent is removed in vacuo, and the residue is triturated in 10 ml of acetone.
De faste stoffer filtreres, og filtratet kromatograferes på The solids are filtered, and the filtrate is chromatographed on
280 g silikagel under anvendelse av aceton som elueringsmiddel og med fraksjonsmengder på 10 ml. Fraksjonene 90-203, som ved tynn- 280 g of silica gel using acetone as eluent and with fractional quantities of 10 ml. Fractions 90-203, as in thin-
skiktkromatografi er vist å inneholde mesteparten av det rene produkt, samles og konsentreres under redusert trykk for å gi 1,25 g av det ønskede produkt. layer chromatography is shown to contain most of the pure product, is collected and concentrated under reduced pressure to give 1.25 g of the desired product.
NMR (6, CDC13): 2,04 (3H) s, 2,30 (6H) s, 2,66 (2H) d, 3,01 (3H) s, 5,48 (2H) s, 7,50 (5H) s og 8,03-8,53 (4H) m. NMR (6, CDCl 3 ): 2.04 (3H) s, 2.30 (6H) s, 2.66 (2H) d, 3.01 (3H) s, 5.48 (2H) s, 7.50 (5H) s and 8.03-8.53 (4H) m.
Eksempel 9 Example 9
Ved å starte med det passende sulfonylklorid og 11-acetyl-4"-deoksy-4"-amino-oleandomycin og å anvende fremgangsmåten ifølge eksempel <8> r fremstilles de følgende forbindelser: By starting with the appropriate sulfonyl chloride and 11-acetyl-4"-deoxy-4"-amino-oleandomycin and using the method according to example <8> r, the following compounds are prepared:
Eksempel 10 Example 10
ll- acetyl- 4"- deoksy- 4"-( p- karboksyfenylsulfonylamino) oleandomycin ll- acetyl- 4"- deoxy- 4"-( p- carboxyphenylsulfonylamino) oleandomycin
En suspensjon av 400 mg 10% palladium-på-trekull i 40 ml etylacetat inneholdende 800 mg ll-acetyl-4"-deoksy-4"-(p-benzyloksykarbonylfenylsulfonylamino)oleandomycin ristes i en hydrogenatmosfære ved et opprinnelig trykk på 3,5 kg/cm 2 ved romtemperatur i 2 timer. En ytterligere mengde på 250 mg katalysator tilsettes, og omsetningen fortsettes i 2 timer. A suspension of 400 mg of 10% palladium-on-charcoal in 40 ml of ethyl acetate containing 800 mg of 11-acetyl-4"-deoxy-4"-(p-benzyloxycarbonylphenylsulfonylamino)oleandomycin is shaken in a hydrogen atmosphere at an initial pressure of 3.5 kg /cm 2 at room temperature for 2 hours. A further amount of 250 mg of catalyst is added and the reaction is continued for 2 hours.
Den brukte katalysator frafiltreres, og oppløsningsmidlet fjernes The spent catalyst is filtered off, and the solvent is removed
i vakuum for å gi 450 mg av det ønskede produkt. in vacuo to give 450 mg of the desired product.
NMR (6, CDC13): 2,06 (3H).s, 2,86 (6H) s, 2,68 (2H) d, 3,30 (3H) s, og 7,5-8,4 (4H) m. NMR (6, CDCl 3 ): 2.06 (3H) s, 2.86 (6H) s, 2.68 (2H) d, 3.30 (3H) s, and 7.5-8.4 (4H ) m.
Eksempel 11 Example 11
ll- acetyl- 4"- deoksy- 4"-( o- nitrofenylsulfonylamino) oleandomycin 11-acetyl-4"-deoxy-4"-(o-nitrophenylsulfonylamino) oleandomycin
5 g (6,8 mmol) ll-acetyl-4"-deoksy-4"-amino-oleandomycin, 1,5 g (7,0 mmol) o-nitrobenzensulfonylklorid og 0,98 ml trietylamin blandes i 50 ml metylenklorid og omrøres ved romtemperatur i 48 timer. Reaksjonsblandingen bråkjøles med et likt volum vann, og den organiske fase vaskes med en mettet saltoppløsning og tørres over natriumsulfat. Fjernelse av oppløsningsmidlet under redusert trykk gir råproduktet som et skum. Produktet renses ved kromatografi på 140 g silikagel i en kolonne med en diameter på 3 cm, under anvendelse av aceton som elueringsmiddel. Fraksjonene 20-30, som hver omfatter 50 ml, oppsamles, blandes og konsentreres til tørrhet for å gi 3,4 g av den ønskede forbindelse. 5 g (6.8 mmol) 11-acetyl-4"-deoxy-4"-amino-oleandomycin, 1.5 g (7.0 mmol) o-nitrobenzenesulfonyl chloride and 0.98 ml triethylamine are mixed in 50 ml methylene chloride and stirred at room temperature for 48 hours. The reaction mixture is quenched with an equal volume of water, and the organic phase is washed with a saturated salt solution and dried over sodium sulfate. Removal of the solvent under reduced pressure gives the crude product as a foam. The product is purified by chromatography on 140 g of silica gel in a column with a diameter of 3 cm, using acetone as eluent. Fractions 20-30, each comprising 50 ml, are collected, mixed and concentrated to dryness to give 3.4 g of the desired compound.
NMR (6, CDC13): 2,10 (3H) s, 2,33 (6H) s, 4,36 (2H) d, 2;90 (3H) s og 7,4-8,4 (4H) m. NMR (6, CDCl 3 ): 2.10 (3H) s, 2.33 (6H) s, 4.36 (2H) d, 2.90 (3H) s and 7.4-8.4 (4H) m .
Under anvendelse av de passende utgangsmaterialer og Using the appropriate starting materials and
den ovenfor angitte fremgangsmåte fremstilles tilsvarende de følgende forbindelser: the above-mentioned method is prepared correspondingly to the following compounds:
ll- acetyl- 4"- deoksy- 4"-( m- nitrofenylsulfonylamino) oleandomycin NMR (6, CDC13): 2,06 (3H) s, 2,30 (6H) s, 2,66 (2H) d, 3,06 (3H) s, og 7,4-9,0 (4H) m; og ll- acetyl- 4"- deoksy- 4"-( p- nitrofenylsulfonylamino) oleandomycin NMR (6, CDC13): 2,10 (3H) s, 2,35 (6H) s, 2,68 (2H) d, 3,06 (3H) s, og 8,0-8,6 (4H) m. 11- acetyl- 4"- deoxy- 4"-( m- nitrophenylsulfonylamino) oleandomycin NMR (6, CDCl 3 ): 2.06 (3H) s, 2.30 (6H) s, 2.66 (2H) d, 3 .06 (3H) s, and 7.4-9.0 (4H) m; and 11-acetyl-4"-deoxy-4"-(p-nitrophenylsulfonylamino)oleandomycin NMR (6, CDCl 3 ): 2.10 (3H) s, 2.35 (6H) s, 2.68 (2H) d, 3.06 (3H) s, and 8.0-8.6 (4H) m.
Eksempel 12 Example 12
ll- acetyl- 4"- deoksy- 4" ( p- hydroksyfenylsulfonylamino) oleandomycin ll- acetyl- 4"- deoxy- 4" (p- hydroxyphenylsulfonylamino) oleandomycin
En oppløsning av 2,55 g (3,5 mmol) ll-acetyl-4"-deoksy-4"-amino-oleandomycin, 701 mg (3,65 mmol) p-hydroksyfenyl-sulfonylklorid og 51,8 yl trietylamin i 25 ml metylenklorid om-røres ved romtemperatur i 48 timer. Oppløsningsmidlet fjernes i vakuum, og residuet behandles med 10 ml aceton. De uoppløselige bestanddeler f raf iltreres, og filtratet kromatograf eres over T.. 200 g silikagel under anvendelse av aceton som elueringsmiddel. Fraksjonene 116-175, som ved tynnskiktkromatografi vises å inneholde det rene produkt, samles og konsentreres til tørrhet under redusert trykk for å gi 550 mg av det ønskede produkt.. A solution of 2.55 g (3.5 mmol) of 11-acetyl-4"-deoxy-4"-amino-oleandomycin, 701 mg (3.65 mmol) of p-hydroxyphenyl-sulfonyl chloride and 51.8 yl of triethylamine in 25 ml of methylene chloride is stirred at room temperature for 48 hours. The solvent is removed in vacuo, and the residue is treated with 10 ml of acetone. The insoluble components are filtered off, and the filtrate is chromatographed over T.. 200 g of silica gel using acetone as eluent. Fractions 116-175, which by thin-layer chromatography are shown to contain the pure product, are collected and concentrated to dryness under reduced pressure to give 550 mg of the desired product.
NMR (6, CDC13): 2,0 (3H) s, 2,33 (6H) s, 2,68 (2H) d, 3,06 (3H) s NMR (6, CDCl 3 ): 2.0 (3H) s, 2.33 (6H) s, 2.68 (2H) d, 3.06 (3H) s
og 6,6-8,0 (4H) m. and 6.6-8.0 (4H) m.
Eksempel 13 Example 13
ll- acetyl- 4"- deoksy- 4"-( m- karboksamidofenyjsulfonylamino) oleandomycin ll- acetyl- 4"- deoxy- 4"-( m-carboxamidophenysulfonylamino) oleandomycin
Til 20 ml metylenklorid inneholdende 2,91 g (4,0 mmol) ll-acetyl-4"-deoksy-4"-amino-olandomycin og 434 mg (4,2 mmol) trietylamin settes 898 mg (4,1 mmol) m-karboksamidofenylsulfonyl-klorid, og den resulterende reaksjonsblanding omrøres i 48 timer. Oppløsningsmidlet fjernes i vakuum, og residuet behandles med 25 ml aceton. Trietylamin-hydrokloridet frafiltreres, og filtratet kromatograferes på 160 g silikagel. Fraksjoner som hver inneholder 50 ml, oppsamles og undersøkes ved tynnskikt-kromatograf i for å bestemme produktets renhet. Fraksjonene 66-93 samles og konsentreres under redusert trykk for å gi 800 mg av det ønskede produkt. 898 mg (4.1 mmol) m -carboxamidophenylsulfonyl chloride, and the resulting reaction mixture is stirred for 48 hours. The solvent is removed in vacuo, and the residue is treated with 25 ml of acetone. The triethylamine hydrochloride is filtered off, and the filtrate is chromatographed on 160 g of silica gel. Fractions, each containing 50 ml, are collected and examined by thin-layer chromatography to determine the purity of the product. Fractions 66-93 are combined and concentrated under reduced pressure to give 800 mg of the desired product.
NMR (6, CDC13): 2,06 (3H) s, 2,33 (6H) s, 2,70 (2H) s, 3,10 (3H) s og 7,4-9,0 (4H) m. NMR (6, CDCl 3 ): 2.06 (3H) s, 2.33 (6H) s, 2.70 (2H) s, 3.10 (3H) s and 7.4-9.0 (4H) m .
Eksempe l 14 Example l 14
ll- acetyl- 4"- deoksy- 4"-( p- acetamidofenylsulfonylamino) oleandomycin ll- acetyl- 4"- deoxy- 4"-( p- acetamidophenylsulfonylamino) oleandomycin
En oppløsning av 2,91 g (4,0 mmol) ll-acetyl-4"-deoksy-4"-amino-oleandomycin, 955 mg (4,1 mmol) p-acetamidofenylsulfonyl-klorid og 4 24 mg (4,2 mmol) trietylamin i 20 ml metylenklorid omrøres i 48 timer ved romtemperatur. Reaksjonsblandingen konsentreres under redusert trykk til et skum som derefter behandles med 10 ml aceton. Det uoppløselige trietylamin-hydroklorid frafiltreres, og filtratet kromatograferes på 160 g silikagel under anvendelse av aceton som elueringsmiddel. Fraksjonene 42-86, som ved tynnskiktkromatografi er vist å inneholde mesteparten av det rene produkt, samles og konsentreres i vakuum for å gi 1,2 g av det ønskede produkt. A solution of 2.91 g (4.0 mmol) of 11-acetyl-4"-deoxy-4"-amino-oleandomycin, 955 mg (4.1 mmol) of p-acetamidophenylsulfonyl chloride and 4 24 mg (4.2 mmol) of triethylamine in 20 ml of methylene chloride is stirred for 48 hours at room temperature. The reaction mixture is concentrated under reduced pressure to a foam which is then treated with 10 ml of acetone. The insoluble triethylamine hydrochloride is filtered off, and the filtrate is chromatographed on 160 g of silica gel using acetone as eluent. Fractions 42-86, which by thin layer chromatography have been shown to contain most of the pure product, are collected and concentrated in vacuo to give 1.2 g of the desired product.
NMR (6, CDC13): 2,06 (3H) s, 2,23 (3H) s, 2,35 (6H) S,.2,70 (2H) S, 3,13 (3H) s, og 7,6-8,2 (4H) m. NMR (6, CDCl 3 ): 2.06 (3H) s, 2.23 (3H) s, 2.35 (6H) S, 2.70 (2H) S, 3.13 (3H) s, and 7 .6-8.2 (4H) m.
Eksempel 15 Example 15
ll- acetyl- 4"- deoksy- 4"-( p- cyanofenylsulfonylamino) oleandomycin ll- acetyl- 4"- deoxy- 4"-( p- cyanophenylsulfonylamino) oleandomycin
En oppløsning av 2,55 g (3,5 mmol) ll-acetyl-4"-deoksy-4"-amino-oleandomycin, 734 mg (3,65; mmol) p-cyanofenylsulfonyl-klorid og 518 yl (3,75 mmol) trietylamin i 25 ml metylenklorid omrøres ved romtemperatur natten.over. Oppløsningsmidlet fjernes, A solution of 2.55 g (3.5 mmol) of 11-acetyl-4"-deoxy-4"-amino-oleandomycin, 734 mg (3.65; mmol) of p-cyanophenylsulfonyl chloride and 518 µl (3.75 mmol) of triethylamine in 25 ml of methylene chloride is stirred at room temperature overnight. The solvent is removed,
i vakuum, og residuet behandles med 10 ml aceton. De uoppløselige bestanddeler frafiltreres, og filtratet kromatograferes på 120 g silikagel under anvendelse av aceton som elueringsmiddel, og fraksjoner på hyer 10 ml oppsamles.. Fraksjonene 47-83 samles og konsentreres under redusert trykk :;;for å gi 281 mg av det ønskede produkt. - in vacuo, and the residue is treated with 10 ml of acetone. The insoluble components are filtered off, and the filtrate is chromatographed on 120 g of silica gel using acetone as eluent, and fractions of greater than 10 ml are collected. Fractions 47-83 are combined and concentrated under reduced pressure to give 281 mg of the desired product . -
NMR (6, CDC13): 2,10 (3H) s, 2,36 (6H) s, 2,71 (2H) d, 3,06 (3H) s, og 7,7-8,4 (4H) m. NMR (6, CDCl 3 ): 2.10 (3H) s, 2.36 (6H) s, 2.71 (2H) d, 3.06 (3H) s, and 7.7-8.4 (4H) m.
Eksempel 16 Example 16
ll- acetyl- 4 ". rdeoksy- 4 "- ( p- trifluormetylfenylsulfonylamino) oleandomycin ll-acetyl-4".rdeoxy-4"-(p-trifluoromethylphenylsulfonylamino)oleandomycin
Til en oppløsning av 2,55 g (3,5 mmol) ll-acetyl-4"-deoksy-4"-amino-oleandomycin og 518 yl (3,75 mmol) trietylamin i 25 ml metylenklorid settes 891 mg (3,65 mmol) p-trifluormetylfenylsulfonyl-klorid, og den resulterende reaksjonsblanding omrøres i 18 timer. Oppløsningsmidlet fjernes under redusert trykk, og residuet utgnies med 15 ml aceton.' De faste stoffer frafiltreres, og filtratet kromatograferes over silikagel for å gi 287 mg av det ønskede produkt. 891 mg (3.65 mmol) of p-trifluoromethylphenylsulfonyl chloride, and the resulting reaction mixture is stirred for 18 hours. The solvent is removed under reduced pressure, and the residue is triturated with 15 ml of acetone. The solids are filtered off, and the filtrate is chromatographed over silica gel to give 287 mg of the desired product.
NMR (6, CDC13): 2,03 (3H) s, 2,31 (6H) s, 2,63 (2H) d, 3,40 (3H) s, NMR (6, CDCl 3 ): 2.03 (3H) s, 2.31 (6H) s, 2.63 (2H) d, 3.40 (3H) s,
og 7,15-8,3 (4H) m. and 7.15-8.3 (4H) m.
Eksempel 17 Example 17
ll- ac ety l- 4"- deoksy- 4"-( 2, 2, 2- trifluoretylsulfonylamino) oleandomycin ll- ac ety l- 4"- deoxy- 4"-( 2, 2, 2- trifluoroethylsulfonylamino) oleandomycin
En oppløsning av 2,55 g (3,5 mmol) ll-acetyl-4"-deoksy-4"-amino-oleandomycin, 666 mg (3,65 mmol) 2,2,2-trifluoretyl-sulfonylklorid og 379 mg (3,75 mmol) trietylamin i 25 ml metylenklorid omrøres i 30 timer ved romtemperatur. Ytterligere 333 mg sulfonylklorid og 270 yl trietylamin tilsettes, og omrøring fortsettes i 4 timer. Oppløsningsmidlet fjernes derefter i vakuum, A solution of 2.55 g (3.5 mmol) of 11-acetyl-4"-deoxy-4"-amino-oleandomycin, 666 mg (3.65 mmol) of 2,2,2-trifluoroethyl-sulfonyl chloride and 379 mg ( 3.75 mmol) of triethylamine in 25 ml of methylene chloride is stirred for 30 hours at room temperature. An additional 333 mg of sulfonyl chloride and 270 µl of triethylamine are added, and stirring is continued for 4 hours. The solvent is then removed in vacuo,
og residuet behandles med 20 ml aceton. De faste stoffer fra-fil treres, .og filtratet kromatograferes på 110 mg silikagel under anvendelse av aceton som elueringsmiddel og under oppsamling av fraksjoner på 10 ml. Fraksjonene 50-80 blandes og konsentreres for å gi 385 mg av det ønskede produkt. and the residue is treated with 20 ml of acetone. The solids are filtered off, and the filtrate is chromatographed on 110 mg of silica gel using acetone as eluent and collecting fractions of 10 ml. Fractions 50-80 are mixed and concentrated to give 385 mg of the desired product.
NMR (6, CDC13): 2,06 (3H) s, 2,26 (6H) s, 2,60 (2H) d, og 3,36 (3H) s. NMR (δ, CDCl 3 ): 2.06 (3H) s, 2.26 (6H) s, 2.60 (2H) d, and 3.36 (3H) s.
Ved å starte med ll-propionyl-4"-deoksy-4"-amino-oleandomycin istedenfor 11-acetylesteren og å anvende den ovenfor angitte fremgangsmåte, fremstilles tilsvarende 11-propionyl-4"-deoksy-4"-(2,2,2-trifluoretylsulfonylamino)oleandomycin. By starting with 11-propionyl-4"-deoxy-4"-amino-oleandomycin instead of the 11-acetyl ester and using the method indicated above, the corresponding 11-propionyl-4"-deoxy-4"-(2,2, 2-trifluoroethylsulfonylamino)oleandomycin.
Eksempel 18 Example 18
ll- acetyl- 4"- deoksy- 4"-( metylsulfonylamino) oleandomycin 11-acetyl-4"-deoxy-4"-(methylsulfonylamino) oleandomycin
En oppløsning av 2,91 g'(4,0 mmol) ll-acetyl-4"-deoksy-4"-amino-oleandomycin, 467 mg (4,1 mmol) metylsulfonylklorid og 424 mg (4,2 mmol) trietylamin i 25 ml metylenklorid omrøres ved romtemperatur natten over. Oppløsningsmidlet fjernes under redusert trykk, og residuet behandles med 20 ml aceton. Trietylamin-hydrokloridet filtreres, og filtratet inneholdende produktet kromatograferes på 180 g silikagel under anvendelse av aceton A solution of 2.91 g' (4.0 mmol) of 11-acetyl-4"-deoxy-4"-amino-oleandomycin, 467 mg (4.1 mmol) of methylsulfonyl chloride and 424 mg (4.2 mmol) of triethylamine in 25 ml methylene chloride is stirred at room temperature overnight. The solvent is removed under reduced pressure, and the residue is treated with 20 ml of acetone. The triethylamine hydrochloride is filtered, and the filtrate containing the product is chromatographed on 180 g of silica gel using acetone
som elueringsmiddel, idet man oppsamler fraksjoner på 6 ml. as eluent, collecting fractions of 6 ml.
Fraksjonene 67-133 blandes og konsentreres i vakuum for å gi Fractions 67-133 are mixed and concentrated in vacuo to give
1,2 g av det ønskede produkt. 1.2 g of the desired product.
NMR (6, CDC13) : 2,06 (3H) s, 2,28 (6H) s, 3,06 (3H) s, 2,61 (2H) d, NMR (6, CDCl 3 ) : 2.06 (3H) s, 2.28 (6H) s, 3.06 (3H) s, 2.61 (2H) d,
og 8,40 (3H) s. and 8.40 (3H) p.
Eksempel 19 ll- acetyl- 4"- deoksy- 4"-( 3, 4- diklorfenylsulfonylamino) oleandomycin Example 19 11-acetyl-4"-deoxy-4"-(3,4-dichlorophenylsulfonylamino)oleandomycin
ll-acetyl-4"-deoksy-4"-amino-oleandomycin (2,9 g, 4,0 mmol), 11-acetyl-4"-deoxy-4"-amino-oleandomycin (2.9 g, 4.0 mmol),
1,0 g (4,1 mmol) 3,4-diklorfenylsulfonylklorid og 0,57 ml (4,2 mmol) trietylamin blandes i 30 ml metylenklorid, og den resulterende oppløsning omrøres ved romtemperatur i 18 timer. Reaksjonsblandingen bråkjøles med 50 ml vann, og den organiske fase vaskes med en mettet saltoppløsning og tørres over natriumsulfat. Oppløsningsmidlet fjernes i vakuum, og residuet kromatograferes på 150 g silikagel under anvendelse av aceton som elueringsmiddel. De fraksjoner som inneholder produktet, som påvist ved tynnskiktkromatografi, 1.0 g (4.1 mmol) of 3,4-dichlorophenylsulfonyl chloride and 0.57 ml (4.2 mmol) of triethylamine are mixed in 30 ml of methylene chloride, and the resulting solution is stirred at room temperature for 18 hours. The reaction mixture is quenched with 50 ml of water, and the organic phase is washed with a saturated salt solution and dried over sodium sulphate. The solvent is removed in vacuo, and the residue is chromatographed on 150 g of silica gel using acetone as eluent. The fractions containing the product, as detected by thin-layer chromatography,
samles og konsentreres til tørrhet for å gi 1,3 g av det ønskede produkt. are collected and concentrated to dryness to give 1.3 g of the desired product.
NMR (6, CDC13): 2,0 (3H) s, 2,30 (6H) s, 2,60 (2H) d, 3,06 (3H) s NMR (6, CDCl 3 ): 2.0 (3H) s, 2.30 (6H) s, 2.60 (2H) d, 3.06 (3H) s
og 7,2-8,1 (3H) m. and 7.2-8.1 (3H) m.
Eksempel 20 Example 20
Ved å følge fremgangsmåten ifølge eksempel 19 og å By following the procedure according to example 19 and ø
starte med de passende utgangsmaterialer, fremstilles de følgende forbindelser: starting with the appropriate starting materials, the following compounds are prepared:
Eksempel 21 Example 21
ll- acetyl- 4"- deoksy- 4"-( 2, 3, 4- triklorfenylsulfonylamino) oleandomycin ll- acetyl- 4"- deoxy- 4"-( 2, 3, 4- trichlorophenylsulfonylamino) oleandomycin
En oppløsning av 2,9 g (4,0 mmol) ll-acetyl-4"-deoksy-4"-amino-oleandomycin, 1,15 g (4,1 mmol) 2,3,4-triklorfenylsulfonyl-klorid og 0,5 7 ml (4,2 mmol) trietylamin i 30 ml metylenklorid omrøres ved romtemperatur i 18 timer. Det .organiske lag'vaskes med vann (1 x 50 ml) og en mettet saltoppløsning (l x 50 ml)'' og tørres derefter over natriumsulfat. Oppløsningsmidlet fjernes i vakuum, og residuet kromatograferes på 150 g silikagel under anvendelse av aceton som oppløsningsmiddel, idet man oppsamler fraksjoner på hver 7 ml. Fraksjonene 60-100 samles og konsentreres for å gi 800 mg av det ønskede produkt. A solution of 2.9 g (4.0 mmol) of 11-acetyl-4"-deoxy-4"-amino-oleandomycin, 1.15 g (4.1 mmol) of 2,3,4-trichlorophenylsulfonyl chloride and 0 .5 7 ml (4.2 mmol) of triethylamine in 30 ml of methylene chloride is stirred at room temperature for 18 hours. The organic layer is washed with water (1 x 50 ml) and a saturated saline solution (1 x 50 ml) and then dried over sodium sulfate. The solvent is removed in vacuo, and the residue is chromatographed on 150 g of silica gel using acetone as solvent, collecting fractions of 7 ml each. Fractions 60-100 are pooled and concentrated to give 800 mg of the desired product.
NMR (6, CDC13): 2,06 (3H) s, 2,33 (6H) s, 2,63 (2H) d, 3,2 (3H) s NMR (6, CDCl 3 ): 2.06 (3H) s, 2.33 (6H) s, 2.63 (2H) d, 3.2 (3H) s
og 7,2-8,2 (2H) m. and 7.2-8.2 (2H) m.
Ved å starte med de passende utgangsmaterialer og å følge den ovenfor beskrevne fremgangsmåte, fremstilles tilsvarende de følgende forbindelser: ll-acetyl-4"-deoksy-4"-(3,4,5-triklorfenylsulfonylamino)oleandomycin; ll-propionyl-4"-deoksy-4"-(2,4,6-triklorfenylsulfonylamino)-oleandomycin; og ll-acetyl-4"-deoksy-4"-(2,3,5-triklorfenyl-sulf onylamino) oleandomycin . By starting with the appropriate starting materials and following the procedure described above, the following compounds are correspondingly prepared: 11-acetyl-4"-deoxy-4"-(3,4,5-trichlorophenylsulfonylamino)oleandomycin; 11-propionyl-4"-deoxy-4"-(2,4,6-trichlorophenylsulfonylamino)-oleandomycin; and 11-acetyl-4"-deoxy-4"-(2,3,5-trichlorophenyl-sulfonylamino)oleandomycin.
Eksempel 22 Example 22
ll- acetyl- 4"- deoksy- 4"- ( 2- hydroksy- 3, 5- diklorfenylsulfonylamino)-oleandomycin ll- acetyl- 4"- deoxy- 4"-( 2- hydroxy- 3, 5- dichlorophenylsulfonylamino)-oleandomycin
Fremgangsmåten ifølge eksempel 33 gjentas, idet man The procedure according to example 33 is repeated, while
starter med 2,55 g (3,5 mmol) ll-acetyl-4"-deoksy-4"-amino-. oleandomycin, 954 mg (3,65 mmol) 2-hydroksy-3,5-diklorfenylsulfonylklorid og 518 yl (3,75 mmol) trietylamin i 25 ml metylenklorid for å gi, efter kromatografering på 220 g silikagel, starting with 2.55 g (3.5 mmol) of 11-acetyl-4"-deoxy-4"-amino-. oleandomycin, 954 mg (3.65 mmol) of 2-hydroxy-3,5-dichlorophenylsulfonyl chloride and 518 yl (3.75 mmol) of triethylamine in 25 ml of methylene chloride to give, after chromatography on 220 g of silica gel,
48 3 mg av det ønskede produkt. 48 3 mg of the desired product.
NMR (6, CDC13/DMS0): 2,03 (3H) s, 2,50 (6H) s, 3,05 (3H) s, og 7,2-7,8 (3H) m. NMR (6, CDCl 3 /DMS0): 2.03 (3H) s, 2.50 (6H) s, 3.05 (3H) s, and 7.2-7.8 (3H) m.
Eksempel 23 Example 23
ll- acetyl- 4"- deoksy- 4"- ( 3- aminc— 4- klorfenylsulfonylamino) oleandomycin ll- acetyl- 4"- deoxy- 4"-( 3- aminc— 4- chlorophenylsulfonylamino) oleandomycin
En suspensjon av 500 mg 10% palladium-på-trekull i 50 ml etylacetat inneholdende 1,0 g ll-acetyl-4"-deoksy-4"-(3-nitro-4-klorfenylsulfonylamino)oleandomycin ristes i en hydrogenatmosfære ved et begynnelsestrykk på 3,5 kg/cm 2 ved romtemperatur natten over. Den brukte katalysator frafiltreres, og oppløsningsmidlet fjernes A suspension of 500 mg of 10% palladium-on-charcoal in 50 ml of ethyl acetate containing 1.0 g of 11-acetyl-4"-deoxy-4"-(3-nitro-4-chlorophenylsulfonylamino)oleandomycin is shaken in a hydrogen atmosphere at an initial pressure of 3.5 kg/cm 2 at room temperature overnight. The spent catalyst is filtered off, and the solvent is removed
i vakuum. Det gjenværende hvite skum kromatograferes på 160 g silikagel under anvendelse av aceton som elueringsmiddel, idet man oppsamler fraksjoner på hver 50 ml. Fraksjonene inneholdende produktet samles og konsentreres under redusert trykk for å gi 450 mg av det ønskede materiale. in vacuum. The remaining white foam is chromatographed on 160 g of silica gel using acetone as eluent, collecting fractions of 50 ml each. The fractions containing the product are pooled and concentrated under reduced pressure to give 450 mg of the desired material.
NMR (6, CDC13): 2,03 (3H) s, 2,33 (6H) s, 2,66 (2H) d, 3,16 (3H) s, og 7,2-8,0 (3H) m. NMR (6, CDCl 3 ): 2.03 (3H) s, 2.33 (6H) s, 2.66 (2H) d, 3.16 (3H) s, and 7.2-8.0 (3H) m.
Under anvendelse av den passende; nitroforbindelse ifølge eksempel il fremstilles på tilsvarende måte: ll- acetyl- 4"- deoksy-4"-(m- aminofenylsulfonylamino) oleandomycin NMR (6, CDC13): 2,03 (3H) s, 2,30 (6H) s, 2,63 (2H) d, 3,10 (3H) s og 7,0-7,8 (4H) m; og ll- acetyl- 4"- deok sy- 4"-( p- aminofenylsulfonylamino) oleandomycin NMR (6, CDC13): 2,06 (3H) s, 2,31 (6H) s, 3,02 (3H) s og 6,4-7,8 (4H) dd. Under the application of the appropriate; nitro compound according to example 11 is prepared in a similar way: 11-acetyl-4"-deoxy-4"-(m-aminophenylsulfonylamino)oleandomycin NMR (6, CDCl 3 ): 2.03 (3H) s, 2.30 (6H) s, 2.63 (2H) d, 3.10 (3H) s and 7.0-7.8 (4H) m; and 11- acetyl- 4"- deoxy- 4"-( p- aminophenylsulfonylamino) oleandomycin NMR (6, CDCl 3 ): 2.06 (3H) s, 2.31 (6H) s, 3.02 (3H) s and 6.4-7.8 (4H) dd.
Eksempel 24 Example 24
ll- acetyl- 4"- deoksy- 4"-( 3- mety1- 2- tienylsulfonylamino) oleandomycin ll- acetyl- 4"- deoxy- 4"-( 3- methyl 1- 2- thienylsulfonylamino) oleandomycin
Til 100 g (0,13 mol) ll-acetyl-4"-deoksy-4"-amino-oleandomycin i 900 ml metylenklorid settes 59 3 ml trietylamin, To 100 g (0.13 mol) of 11-acetyl-4"-deoxy-4"-amino-oleandomycin in 900 ml of methylene chloride is added 59 3 ml of triethylamine,
og oppløsningen omrøres i 10 minutter. 3-metyl-2-tienylsulfonylklorid (41,9 g, 0,213 mol) i 300 ml metylenklorid tilsettes derefter dråpevis i løpet av en periode på 1 time, og reaksjonsblandingen omrøres ved romtemperatur i 48 timer. Reaksjonsblandingen settes til 2 liter vann, og det organiske lag fraskilles, vaskes suksessivt med vann (2 x 250 ml) og en saltoppløsning (1 x 250 ml) og tørres over natriumsulfat. Oppløsningsmidlet fjernes i vakuum, og residuet kromatograferes på en 105 cm x 6,5 cm kolonne inneholdende 1,5 kg silikagel. Produktet, som elueres med aceton, oppsamles fra 2,3 liter til 6 liter eluatfraksjonene. Fraksjonene samles, og oppløsningsmidlet fjernes under redusert trykk for å gi et skum. Behandling av det gjenværende skum med dietyleter gir 66,4 g av det ønskede produkt, sm.p. 184-185,5°C. and the solution is stirred for 10 minutes. 3-Methyl-2-thienylsulfonyl chloride (41.9 g, 0.213 mol) in 300 mL of methylene chloride is then added dropwise over a period of 1 hour, and the reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is added to 2 liters of water, and the organic layer is separated, washed successively with water (2 x 250 ml) and a salt solution (1 x 250 ml) and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is chromatographed on a 105 cm x 6.5 cm column containing 1.5 kg of silica gel. The product, which is eluted with acetone, is collected from the 2.3 liter to 6 liter eluate fractions. The fractions are pooled and the solvent is removed under reduced pressure to give a foam. Treatment of the remaining foam with diethyl ether yields 66.4 g of the desired product, m.p. 184-185.5°C.
NMR (<5, CDC13) : 2,04 (3H) s, 2,41 (6H) s, 2,46 (3H) s, 2,62 (2H) m, 3,02 (3H) s, 6,84 og 7,32 (2H). NMR (<5, CDCl 3 ) : 2.04 (3H) s, 2.41 (6H) s, 2.46 (3H) s, 2.62 (2H) m, 3.02 (3H) s, 6, 84 and 7.32 (2H).
Til 2 g av den ovenfor angitte frie base i 15 ml etylacetat settes 0,12 ml fosforsyre, og den resulterende oppløsning får omrøres ved romtemperatur. Efter 20 minutter begynner krystaller å dannes, og disse blir efter 2 timer filtrert, vasket med etylacetat og tørret for å gi 1,3 g ll-acetyl-4"-deoksy-4"-(3-metyl-2-tienylsulfonylamino)oleandomycin-fosfat. To 2 g of the above-mentioned free base in 15 ml of ethyl acetate is added 0.12 ml of phosphoric acid, and the resulting solution is allowed to stir at room temperature. After 20 minutes crystals begin to form, and after 2 hours these are filtered, washed with ethyl acetate and dried to give 1.3 g of 11-acetyl-4"-deoxy-4"-(3-methyl-2-thienylsulfonylamino)oleandomycin -phosphate.
NMR (<S, CD30D) : 2,01 (3H) s, 2,45 (3H) s, 2,56 (2H) m, 2,83 (6H) s, 3,0 (3H) s, 6,88 og 7,42 (2H) . NMR (<S, CD30D) : 2.01 (3H) s, 2.45 (3H) s, 2.56 (2H) m, 2.83 (6H) s, 3.0 (3H) s, 6, 88 and 7.42 (2H).
Eksempel 25 Example 25
Fremgangsmåten ifølge eksempel 24 gjentas, idet man The procedure according to example 24 is repeated, while
starter med det passende sulfonylklorid og ll-acetyl-4"-deoksy-4"-amino-oleandomycin for fremstilling av de følgende beslektede forbindelser: starting with the appropriate sulfonyl chloride and 11-acetyl-4"-deoxy-4"-amino-oleandomycin to prepare the following related compounds:
Eksempel 26 Example 26
ll- acetyl- 4"- deoksy- 4"-( 5- karbometoksy- 2- pyrrylsulfonylamino)-oleandomycin ll- acetyl- 4"- deoxy- 4"-( 5- carbomethoxy- 2- pyrrylsulfonylamino)- oleandomycin
En oppløsning av 2,96 g (0,0041 mol) ll-acetyl-4"-deoksy-4"-amino-oleandomycin og 0,62 ml trietylamin i 50 ml tørr metylenklorid avkjølt til isbad-temperatur behandles porsjonsvis med 1,0 g (0,0044 mol) 2-karbometoksy-5-pyrrylsulfonylklorid. Reaksjonsblandingen oppvarmes til romtemperatur og omrøres i 3,5 timer, og helles derefter i 200 ml vann. Det vandige lags pH reguleres til 9,5 med IN vandig natriumhydroksyd, og metylenklorid-laget fraskilles, vaskes suksessivt med vann og mettet salt-oppløsning og tørres over natriumsulfat. Fjernelse av oppløsnings-midlet under redusert trykk gir 3,8 g av råproduktet som et hvitt skum. A solution of 2.96 g (0.0041 mol) 11-acetyl-4"-deoxy-4"-amino-oleandomycin and 0.62 ml of triethylamine in 50 ml of dry methylene chloride cooled to ice-bath temperature is treated in portions with 1.0 g (0.0044 mol) 2-carbomethoxy-5-pyrrylsulfonyl chloride. The reaction mixture is heated to room temperature and stirred for 3.5 hours, and then poured into 200 ml of water. The pH of the aqueous layer is adjusted to 9.5 with 1N aqueous sodium hydroxide, and the methylene chloride layer is separated, washed successively with water and saturated salt solution and dried over sodium sulfate. Removal of the solvent under reduced pressure gives 3.8 g of the crude product as a white foam.
Nevnte skum kromatograferes derefter på en silikagel-kolonne 3,25 cm x 38 cm under anvendelse av aceton som elueringsmiddel. Fraksjonene 40-220, som utgjør .ca. 10-12 ml hver, oppsamles og blandes. Fjernelse av oppløsningsmidlet i vakuum gir 3,4 g av det ønskede produkt som et hvitt skum. Said foam is then chromatographed on a silica gel column 3.25 cm x 38 cm using acetone as eluent. Fractions 40-220, which make up approx. 10-12 ml each, collect and mix. Removal of the solvent in vacuo gives 3.4 g of the desired product as a white foam.
NMR (6, CDC13): 2,05 (3H) s, 2,58 (6H) s, 2,67 (2H) m, 3,25 (3H) s, 3,90 (3H) s, 7,20 (IB) m og 7,52 '(1H) m. NMR (6, CDCl 3 ): 2.05 (3H) s, 2.58 (6H) s, 2.67 (2H) m, 3.25 (3H) s, 3.90 (3H) s, 7.20 (IB) m and 7.52' (1H) m.
Eksempel 27 Example 27
Fremgangsmåten ifølge eksempel 26 gjentas, idet man starter med det passende sulfonylklorid og ll-acetyl-4"-deoksy-4"-amino-oleandomycin, for fremstilling av de følgende analoger: The procedure of Example 26 is repeated, starting with the appropriate sulfonyl chloride and 11-acetyl-4"-deoxy-4"-amino-oleandomycin, to prepare the following analogues:
Eksempel 27 Example 27
4"- deoksy- 4"-( p- klorfenylsulfonylamino) oleandomycin 4"-deoxy-4"-(p-chlorophenylsulfonylamino)oleandomycin
En oppløsning av 3,0 g 4"-deoksy-4"-amino-oleandomycin, 8,65 mg p-klorfenylsulfonylklorid og 424 mg trietylamin i 25 ml metylenklorid omrøres ved romtemperatur natten over. Oppløsnings-midlet fjernes i vakuum, og residuet behandles med 20 ml aceton. Det uoppløselige trietylamin-hydroklorid filtreres, og filtratet kromatograferes på 180 g silikagel under anvendelse av aceton som elueringsmiddel, idet fraksjoner på 50 ml oppsamles. Fraksjonene 18-27 samles og konsentreres under redusert trykk for å gi 1,10 g av det ønskede produkt. A solution of 3.0 g of 4"-deoxy-4"-amino-oleandomycin, 8.65 mg of p-chlorophenylsulfonyl chloride and 424 mg of triethylamine in 25 ml of methylene chloride is stirred at room temperature overnight. The solvent is removed in vacuo, and the residue is treated with 20 ml of acetone. The insoluble triethylamine hydrochloride is filtered, and the filtrate is chromatographed on 180 g of silica gel using acetone as eluent, fractions of 50 ml being collected. Fractions 18-27 are combined and concentrated under reduced pressure to give 1.10 g of the desired product.
NMR (6, CDC13): 2,33 (6H), 2,83 (2H) d, 3,06 (3H) s, og 7,2-8,4 (4H) m. NMR (6, CDCl 3 ): 2.33 (6H), 2.83 (2H) d, 3.06 (3H) s, and 7.2-8.4 (4H) m.
Eksempel 28 Example 28
4"- deoksy- 4"-( p- toluensulfonylamino) oleandomycin 4"-deoxy-4"-(p-toluenesulfonylamino)oleandomycin
Ved en fremgangsmåte lik den som er beskrevet i By a procedure similar to that described in
eksempel 27, omrøres 30 g (4,0 mmol) 4"-deoksy-4"-amino-oleandomycin, 782 mg (4,1 mmol) p-toluensulfonylklorid og 424 mg (4,2 mmol) trietylamin i 25 ml metylenklorid ved omgivelsestemperatur natten example 27, 30 g (4.0 mmol) of 4"-deoxy-4"-amino-oleandomycin, 782 mg (4.1 mmol) of p-toluenesulfonyl chloride and 424 mg (4.2 mmol) of triethylamine are stirred in 25 ml of methylene chloride at ambient temperature at night
over. Ved opparbeidelse kromatograferes råproduktet på 180 g • .-silikagel, idet man oppsamler fraksjoner på 10 ml. Fraksjonene 90-148 samlés "og konsentreres til tørrhet for å gi 1, 4 .g av det ønskede produkt. above. During work-up, the crude product is chromatographed on 180 g • .-silica gel, collecting fractions of 10 ml. Fractions 90-148 were pooled and concentrated to dryness to give 1.4 g of the desired product.
NMR (6, CDCI3): 2,33 (6H) s, 2,46 (3H) s, 2,83 (2H) d, 3,10 (3H) s, og 7,10-8,0 (4H) m. NMR (6, CDCl 3 ): 2.33 (6H) s, 2.46 (3H) s, 2.83 (2H) d, 3.10 (3H) s, and 7.10-8.0 (4H) m.
Ved en tilsvarende fremgangsmåte fremstilles også 4"-deoksy-4"-(2-tienylsulfonylamino)oleandomycin. By a similar method, 4"-deoxy-4"-(2-thienylsulfonylamino)oleandomycin is also produced.
NMR (6, CDC13) : 2,29 (6H) s, 2,88 (2H) m, 3,2 (3H) s, 5,6 (1H) m NMR (6, CDCl 3 ) : 2.29 (6H) s, 2.88 (2H) m, 3.2 (3H) s, 5.6 (1H) m
og 7.33 (3H) m. and 7.33 (3H) m.
Eksempel 29 Example 29
ll- acetyl- 4"- deoksy- 4"-( 2- tienylsulfonylamino) oleandomycin- fosfat ll- acetyl- 4"- deoxy- 4"-( 2- thienylsulfonylamino) oleandomycin- phosphate
Til en oppløsning av 15,0 g ll-acetyl-4"-deoksy-4"-(2-tienylsulfonylamino)oleandomycin i 100 ml etylacetat settes To a solution of 15.0 g of 11-acetyl-4"-deoxy-4"-(2-thienylsulfonylamino)oleandomycin in 100 ml of ethyl acetate is added
1,0 ml fosforsyre.. Den resulterende suspensjon omrøres i 4 timer ved romtemperatur. De faste stoffer frafiltreres, vaskes med etylacetat og tørres for å gi 12,5 g av det ønskede salt, 1.0 ml phosphoric acid. The resulting suspension is stirred for 4 hours at room temperature. The solids are filtered off, washed with ethyl acetate and dried to give 12.5 g of the desired salt,
sm.p. 168°C (spaltn.). sm.p. 168°C (dec.).
På tilsvarende måte fremstilles ll-acetyl-4"-deoksy-4 " - (3-mety lr-2- tienyl sulf onylamino) oleandomycin-f osf at, 11-Acetyl-4"-deoxy-4"-(3-methyl-2-thienyl sulfonylamino)oleandomycin phosphate is prepared in a similar manner,
sm.p. 184-188°C og ll-acetyl-4"-deoksy-4"-(p-klorfenylsulfonylamino)oleandomycin-fosfat, sm.p. 204-205°C. sm.p. 184-188°C and 11-acetyl-4"-deoxy-4"-(p-chlorophenylsulfonylamino)oleandomycin phosphate, m.p. 204-205°C.
FREMSTILLING A MANUFACTURE A
4"- deoksy- 4"- okso- oleandomyciner 4"- deoxy- 4"- oxo- oleandomycins
I. ll- acetyl- 4"- deoksy- 4"- okso- oleandomycin I. 11-acetyl-4"-deoxy-4"-oxo-oleandomycin
a. 11, 2'- diacetyl- 4"- deoksy- 4"- okso- oleandomycin a. 11, 2'- diacetyl- 4"- deoxy- 4"- oxo- oleandomycin
Til 4,5 g N-klorsuccinimid, 50 ml benzen og 150 ml toluen i en tørr kolbe utstyrt med en magnetrører og nitrogeninnløp og avkjølt til -5°C, settes 3,36 ml dimetylsulfid. Efter omrøring ved 0°C i 20 minutter avkjøles innholdet til -25°C og behandles med ,50 g 11,2'-diacetyl-oleandomycin i 100 ml toluen. Avkjøling og omrøring fortsettes i 2 timer fulgt av tilsetning av 4,73 ml trietylamin. Reaksjonsblandingen omrøres ved 0°C i 15 minutter og.helles derefter i 500 ml vann. pH reguleres til-9,5 med IN vandig natriumhydroksyd, og det organiske lag fraskilles, To 4.5 g of N-chlorosuccinimide, 50 ml of benzene and 150 ml of toluene in a dry flask equipped with a magnetic stirrer and nitrogen inlet and cooled to -5°C, add 3.36 ml of dimethyl sulphide. After stirring at 0°C for 20 minutes, the contents are cooled to -25°C and treated with .50 g of 11,2'-diacetyl-oleandomycin in 100 ml of toluene. Cooling and stirring are continued for 2 hours followed by the addition of 4.73 ml of triethylamine. The reaction mixture is stirred at 0°C for 15 minutes and then poured into 500 ml of water. The pH is adjusted to -9.5 with IN aqueous sodium hydroxide, and the organic layer is separated,
vaskes med vann og eh saltdppløsning og tørres over natriumsulfat. Fjernelse av oppløsningsmidlet i vakuum gir 4,9 g av det ønskede produkt som et skum. washed with water and saline solution and dried over sodium sulfate. Removal of the solvent in vacuo gives 4.9 g of the desired product as a foam.
NMR (6, CDC13): 3,48 (3H) s, 2,61 (2H) m, 2,23 (6H) s og 2,03 (6H) s. NMR (6, CDCl 3 ): 3.48 (3H) s, 2.61 (2H) m, 2.23 (6H) s and 2.03 (6H) s.
b. ll- acetyl- 4"- deoksy- 4"- okso- oleandomycin b. 11-acetyl-4"-deoxy-4"-oxo-oleandomycin
En oppløsning av 4,0 g 11,2'-diacetyl-4"-deoksy-4"-okso-oleandomycin i 75 ml metanol omrøres ved romtemperatur natten over. Reaksjonsblandingen konsentreres under redusert trykk for å gi A solution of 4.0 g of 11,2'-diacetyl-4"-deoxy-4"-oxo-oleandomycin in 75 ml of methanol is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to give
produktet som et skum. En dietyleteroppløsning av residuet gir ved behandling med heksan, 2,6 g av produktet som et hvitt, fast stoff, sm.p. 112-117°C. the product as a foam. A diethyl ether solution of the residue gives, on treatment with hexane, 2.6 g of the product as a white solid, m.p. 112-117°C.
NMR (6, CDC13): 3,43 (3H) s, 2,60 (2H) m, 2,23 (6H) s og 2,01 (3H) s. NMR (6, CDCl 3 ): 3.43 (3H) s, 2.60 (2H) m, 2.23 (6H) s and 2.01 (3H) s.
Ved å anvende 11,2<1->dipropionyl-4"-deoksy-4"-okso-oleandomycin eller ll-propionyl-2"-acetyl-4"-deoksy-4"-okso-oleandomycin ved den ovenfor beskrevne fremgangsmåte, får man tilsvarende ll-propionyl-4"-deoksy-4"-okso-oleandomycin. By using 11,2<1->dipropionyl-4"-deoxy-4"-oxo-oleandomycin or 11-propionyl-2"-acetyl-4"-deoxy-4"-oxo-oleandomycin by the method described above, the corresponding 11-propionyl-4"-deoxy-4"-oxo-oleandomycin is obtained.
II. 4"- deoksy- 4"- okso- oleandomycin II. 4"- deoxy- 4"- oxo- oleandomycin
a. 2'- acetyl- 4"- deoksy- 4"- okso- oleandomycin a. 2'- acetyl- 4"- deoxy- 4"- oxo- oleandomycin
Dimetylsulfid (0,337 ml) settes til en uklar oppløsning av 467 mg N-klorsuccinimid i 20 ml toluen og 6 ml benzen avkjølt til -5°C og holdt under en nitrogenatmosfære. Efter omrøring ved 0°C i 20 minutter avkjøles blandingen til -25°C, og 1,46 g 2'-acetyloleandomycin og 15 ml toluen tilsettes. Omrøring fortsettes i 2 timer ved -20°C fulgt av tilsetning av 0,46 ml trietylamin. Reaksjonsblandingen holdes ved -20°C i ytterligere 5 minutter og oppvarmes derefter til 0°C. Blandingen helles under omrøring i 50 ml vann og 50 ml etylacetat. Den vandige blandings pH Dimethyl sulfide (0.337 mL) is added to a cloudy solution of 467 mg of N-chlorosuccinimide in 20 mL of toluene and 6 mL of benzene cooled to -5°C and maintained under a nitrogen atmosphere. After stirring at 0°C for 20 minutes, the mixture is cooled to -25°C, and 1.46 g of 2'-acetyloleandomycin and 15 ml of toluene are added. Stirring is continued for 2 hours at -20°C followed by the addition of 0.46 ml of triethylamine. The reaction mixture is kept at -20°C for an additional 5 minutes and then warmed to 0°C. The mixture is poured with stirring into 50 ml of water and 50 ml of ethyl acetate. The pH of the aqueous mixture
reguleres til 9,5 ved tilsetning av vandig natriumhydroksyd-. oppløsning. Det organiske lag fraskilles derefter, tørres over natriumsulfat og konsentreres i vakuum til et hvitt skum (1,5 g). adjusted to 9.5 by adding aqueous sodium hydroxide. resolution. The organic layer is then separated, dried over sodium sulfate and concentrated in vacuo to a white foam (1.5 g).
Utgnidning med dietyleter gir 864 mg råprodukt, som ved to Trituration with diethyl ether gives 864 mg of crude product, as at two
gangers omkrystallisering fra metylenklorid-dietyleter gir 212 mg av det rene produkt, sm.p. 183-185,5°C. recrystallization from methylene chloride-diethyl ether yields 212 mg of the pure product, m.p. 183-185.5°C.
Analyse: Beregnet for c37H6i°13N: c 61,1, H 8,5, N 1,9. Analysis: Calculated for c37H6i°13N: c 61.1, H 8.5, N 1.9.
Funnet: C 60,9, H 8,4, N 1,9. Found: C 60.9, H 8.4, N 1.9.
NMR (6, CDC13): 5,60 (1H) m, 3,50 (3H) s, 2,73 (2H) m, 2,23 (6H) s og 2,03 (3H) s. NMR (6, CDCl 3 ): 5.60 (1H) m, 3.50 (3H) s, 2.73 (2H) m, 2.23 (6H) s and 2.03 (3H) s.
b. 4"- deoksy- 4"- okso- oleandomycin b. 4"- deoxy- 4"- oxo- oleandomycin
Én oppløsning av 1,0 g 2'-acetyl-4"-deoksy-4"-okso-oleandomycin i 20 ml metanol omrøres ved romtemperatur natten over.. Oppløsningen konsentreres i vakuum for å gi det ønskede produkt som et hvitt skum, 9 37 mg. One solution of 1.0 g of 2'-acetyl-4"-deoxy-4"-oxo-oleandomycin in 20 ml of methanol is stirred at room temperature overnight. The solution is concentrated in vacuo to give the desired product as a white foam, 9 37 mg.
NMR (6, CDC13): 5,60 (1H) m, 3,50 (3H) s, 2,85 (2H) m og 2,26 (6H) s. NMR (6, CDCl 3 ): 5.60 (1H) m, 3.50 (3H) s, 2.85 (2H) m and 2.26 (6H) s.
FREMSTILLING B MANUFACTURE B
4"- deoksy- 4"- amino- oleandomyciner 4"- deoxy- 4"- amino- oleandomycins
I. ll- acetyl- 4"- deoksy- 4"- amino- oleandomycin I. 11-Acetyl-4"-deoxy-4"-amino-oleandomycin
Til en suspensjon av 10 g 10% palladium-på-trekull i To a suspension of 10 g of 10% palladium-on-charcoal i
100 ml metanol settes 21,2 g ammoniumacetat, og den resulterende oppslemning behandles med en oppløsning av 20 g ll-acetyl-4 "-deoksy-4"-okso-oleandomycin i 100 ml av det samme oppløsningsmiddel. Suspensjonen ristes ved romtemperatur i en hydrogenatmosfære ved 21.2 g of ammonium acetate are added to 100 ml of methanol, and the resulting slurry is treated with a solution of 20 g of 11-acetyl-4"-deoxy-4"-oxo-oleandomycin in 100 ml of the same solvent. The suspension is shaken at room temperature in a hydrogen atmosphere at
et begynnelsestrykk på 3,5 kg/cm 2. Efter 1,5 timer frafiltreres katalysatoren, og filtratet settes under omrøring til en blanding av 1200 ml vann og 500 ml kloroform. pH reguleres fra 6,4 til 4,5, og det organiske lag fraskilles. Efter en ytterligere ekstraksjon med 500 ml kloroform behandles det vandige lag med 500 ml etylacetat, og pH reguleres til 9,5 med IN natriumhydroksyd. Etyl-acetatlaget fraskilles, og det vandige lag ekstraheres igjen med etylacetat. Etylacetatekstraktene samles, tørres over natriumsulfat og konsentreres til et gult skum (18,6 g), som ved krysta-lisering fra diisopropyleter gir 6,85 g renset produkt, an initial pressure of 3.5 kg/cm 2 . After 1.5 hours, the catalyst is filtered off, and the filtrate is added to a mixture of 1200 ml of water and 500 ml of chloroform with stirring. The pH is regulated from 6.4 to 4.5, and the organic layer is separated. After a further extraction with 500 ml of chloroform, the aqueous layer is treated with 500 ml of ethyl acetate, and the pH is adjusted to 9.5 with IN sodium hydroxide. The ethyl acetate layer is separated, and the aqueous layer is extracted again with ethyl acetate. The ethyl acetate extracts are collected, dried over sodium sulfate and concentrated to a yellow foam (18.6 g), which upon crystallization from diisopropyl ether gives 6.85 g of purified product,
sm.p. 157,5-160°C. sm.p. 157.5-160°C.
NMR (6, CDC13): 3,41 (3H) s, 2,70 (2H) m, 2,36 (6H) s og 2,10 (3H) s. NMR (6, CDCl 3 ): 3.41 (3H) s, 2.70 (2H) m, 2.36 (6H) s and 2.10 (3H) s.
Den annen epimer, som eksisterer i det rå skum i en mengde på 20-25%, erholdes ved gradvis konsentrering og filtrering av moderlutene. The other epimer, which exists in the raw foam in an amount of 20-25%, is obtained by gradual concentration and filtration of the mother liquors.
På tilsvarende måte, ved å starte med ll-propionyl-4"-deoksy-4"-okso-oleandomycin ved den ovenfor beskrevne fremgangsmåte, får man ll-propionyl-4"-deoksy-4"-amino-oleandomycin. Similarly, by starting with 11-propionyl-4"-deoxy-4"-oxo-oleandomycin by the method described above, 11-propionyl-4"-deoxy-4"-amino-oleandomycin is obtained.
II. 4"- deoksy- 4"- amino- oleandomycin II. 4"- deoxy- 4"- amino- oleandomycin
En oppløsning av 20 g 2'-acetyl-4"-deoksy-4"-okso-oleandomycin i 125 ml metanol, efter omrøring ved romtemperatur natten over, behandles med 21,2 g ammoniumacetat. Den resulterende oppløsning avkjøles i et isbad og behandles med 1,26 g natriumcyanoborhydrid. Kjølebadet fjernes derefter, og reaksjonsblandingen omrøres ved romtemperatur i 2 timer. Reaksjonsblandingen helles i 600 ml vann og 600 ml dietyleter, og pH reguleres fra 8,3 til 7,5. Eterlaget fraskilles, <q>g det vandige lag ekstraheres med etylacetat. Ekstraktene settes til side, og pH i det vandige lag reguleres A solution of 20 g of 2'-acetyl-4"-deoxy-4"-oxo-oleandomycin in 125 ml of methanol, after stirring at room temperature overnight, is treated with 21.2 g of ammonium acetate. The resulting solution is cooled in an ice bath and treated with 1.26 g of sodium cyanoborohydride. The cooling bath is then removed, and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into 600 ml of water and 600 ml of diethyl ether, and the pH is adjusted from 8.3 to 7.5. The ether layer is separated, and the aqueous layer is extracted with ethyl acetate. The extracts are set aside, and the pH in the aqueous layer is regulated
til 8,25. Dietyleter- og etylacetatekstraktene som er oppnådd ved denne pH, settes også til side, og pH heves til 9,9. Dietyleter- to 8.25. The diethyl ether and ethyl acetate extracts obtained at this pH are also set aside and the pH is raised to 9.9. diethyl ether-
og etylacetat-ekstraktene fra denne pH samles, vaskes suksessivt med vann (lx) og en mettet saltoppløsning og tørres over natriumsulfat. De siste ekstrakter, tatt ved pH 9,9, konsentreres til et skum og kromatograferes på 160 g silikagel under anvendelse av kloroform som utviklingsmiddel og det første elueringsmiddel. and the ethyl acetate extracts from this pH are combined, washed successively with water (1x) and a saturated saline solution and dried over sodium sulfate. The final extracts, taken at pH 9.9, are concentrated to a foam and chromatographed on 160 g of silica gel using chloroform as the developing agent and the first eluent.
Efter 11 fraksjoner på 12 ml pr. fraksjon, forandres elueringsmidlet til 5% metanol - 9 5% kloroform. Ved fraksjon 370 forandres elueringsmidlet til 10% metanol - 90% kloroform, og ved fraksjon 440 anvendes 15% metanol - 85% kloroform. Fraksjonene 85-260 samles og konsentreres i vakuum til tørrhet for å gi 2,44 g av det ønskede produkt. After 11 fractions of 12 ml per fraction, the eluent is changed to 5% methanol - 95% chloroform. For fraction 370, the eluent is changed to 10% methanol - 90% chloroform, and for fraction 440, 15% methanol - 85% chloroform is used. Fractions 85-260 are combined and concentrated in vacuo to dryness to give 2.44 g of the desired product.
NMR (6, CDC13) : 5,56 (1H) m, 2,26 (3H) s, 2,9 (2H) m og 2,26 (6H) s.'- NMR (6, CDCl 3 ) : 5.56 (1H) m, 2.26 (3H) s, 2.9 (2H) m and 2.26 (6H) s.'-
Claims (2)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US79585077A | 1977-05-11 | 1977-05-11 | |
US05/883,608 US4136253A (en) | 1977-05-11 | 1978-03-06 | Semi-synthetic 4"-sulfonylamino-oleandomycin derivatives |
Publications (3)
Publication Number | Publication Date |
---|---|
NO781656L NO781656L (en) | 1978-11-14 |
NO145384B true NO145384B (en) | 1981-11-30 |
NO145384C NO145384C (en) | 1982-03-10 |
Family
ID=27121658
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO781656A NO145384C (en) | 1977-05-11 | 1978-05-10 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE OLEANDOMYCIN DERIVATIVES. |
Country Status (31)
Country | Link |
---|---|
JP (1) | JPS53149990A (en) |
AR (1) | AR219529A1 (en) |
AT (1) | AT357263B (en) |
AU (1) | AU500587B1 (en) |
CA (1) | CA1098123A (en) |
CH (1) | CH631461A5 (en) |
CS (1) | CS199728B2 (en) |
DD (1) | DD135907A5 (en) |
DE (1) | DE2820411C2 (en) |
DK (1) | DK148845C (en) |
EG (1) | EG13371A (en) |
ES (1) | ES469648A1 (en) |
FI (1) | FI67709C (en) |
FR (1) | FR2390453A1 (en) |
GB (1) | GB1590162A (en) |
GR (1) | GR70056B (en) |
HU (1) | HU180279B (en) |
IE (1) | IE46839B1 (en) |
IL (1) | IL54688A (en) |
IT (1) | IT1094816B (en) |
LU (1) | LU79638A1 (en) |
NL (1) | NL174254C (en) |
NO (1) | NO145384C (en) |
NZ (1) | NZ187229A (en) |
PH (1) | PH15382A (en) |
PL (1) | PL111988B1 (en) |
PT (1) | PT68019B (en) |
RO (1) | RO75819A (en) |
SE (1) | SE446340B (en) |
SU (1) | SU860707A1 (en) |
YU (1) | YU40963B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4124755A (en) * | 1978-01-03 | 1978-11-07 | Pfizer Inc. | 11-Alkanoyl-4"-deoxy-4"-isonitrilo-oleandomycin derivatives |
US4133950A (en) * | 1978-01-03 | 1979-01-09 | Pfizer Inc. | 4"-Deoxy-4"-carbamate and dithiocarbamate derivatives of oleandomycin and its esters |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3836519A (en) * | 1973-05-04 | 1974-09-17 | Abbott Lab | Sulfonyl derivatives of erythromycin |
-
1978
- 1978-04-11 SE SE7804080A patent/SE446340B/en not_active IP Right Cessation
- 1978-04-24 AU AU35379/78A patent/AU500587B1/en not_active Expired
- 1978-04-25 PH PH21053A patent/PH15382A/en unknown
- 1978-05-05 YU YU1082/78A patent/YU40963B/en unknown
- 1978-05-05 CS CS782903A patent/CS199728B2/en unknown
- 1978-05-09 CA CA302,902A patent/CA1098123A/en not_active Expired
- 1978-05-09 PT PT68019A patent/PT68019B/en unknown
- 1978-05-09 GB GB18353/78A patent/GB1590162A/en not_active Expired
- 1978-05-10 DK DK205878A patent/DK148845C/en not_active IP Right Cessation
- 1978-05-10 NL NLAANVRAGE7805007,A patent/NL174254C/en not_active IP Right Cessation
- 1978-05-10 JP JP5540578A patent/JPS53149990A/en active Granted
- 1978-05-10 SU SU782616147A patent/SU860707A1/en active
- 1978-05-10 EG EG301/78A patent/EG13371A/en active
- 1978-05-10 LU LU79638A patent/LU79638A1/en unknown
- 1978-05-10 ES ES469648A patent/ES469648A1/en not_active Expired
- 1978-05-10 HU HU78PI623A patent/HU180279B/en unknown
- 1978-05-10 RO RO7894029A patent/RO75819A/en unknown
- 1978-05-10 NO NO781656A patent/NO145384C/en unknown
- 1978-05-10 IT IT23229/78A patent/IT1094816B/en active
- 1978-05-10 FI FI781478A patent/FI67709C/en not_active IP Right Cessation
- 1978-05-10 DE DE2820411A patent/DE2820411C2/en not_active Expired
- 1978-05-10 FR FR7813918A patent/FR2390453A1/en active Granted
- 1978-05-10 NZ NZ187229A patent/NZ187229A/en unknown
- 1978-05-10 AT AT338978A patent/AT357263B/en not_active IP Right Cessation
- 1978-05-10 CH CH508978A patent/CH631461A5/en not_active IP Right Cessation
- 1978-05-10 IL IL54688A patent/IL54688A/en unknown
- 1978-05-10 PL PL1978206687A patent/PL111988B1/en unknown
- 1978-05-10 IE IE953/78A patent/IE46839B1/en unknown
- 1978-05-10 GR GR56192A patent/GR70056B/el unknown
- 1978-05-11 AR AR272125A patent/AR219529A1/en active
- 1978-05-11 DD DD78205329A patent/DD135907A5/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4150220A (en) | Semi-synthetic 4"-erythromycin A derivatives | |
DK157495B (en) | ANALOGY PROCEDURE FOR PREPARING 4AE-EPI-ERYTHROMYCINE A OR DERIVATIVES THEREOF | |
NO146711B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF OLEANDOMYCIN AND ERYTHROMYCIN DERIVATIVES | |
GB1584325A (en) | Oleandomycin derivatives | |
DK159853B (en) | METHOD OF ANALOGUE FOR PREPARING 9-DIHYDRO-11,12-O-ISOPROPYLIDENE ERYTHROMYCIN A OR -4AE-EPI-ERYTHROMYCIN A OR 2'-O-ACYLATES THEREOF OR PHARMACEUTICAL ACCEPTABLE ACCEPTABLE ACCEPTABLE | |
NO143026B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF NEW, THERAPEUTICALLY EFFECTIVE HALOGEN DERIVATIVES | |
NO145384B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE OLEANDOMYCIN DERIVATIVES | |
FR2502155A1 (en) | NOVEL SEMI-SYNTHETIC MACROLIDE ANTIBIOTICS, MICROBIOLOGICAL PROCESS FOR THE PREPARATION THEREOF AND MICROORGANISM THEREFOR, NOVEL INTERMEDIATE PRODUCTS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME | |
US4098993A (en) | Semi-synthetic 4-ureido-oleandomycin derivatives | |
SU869558A3 (en) | Method of producing azetidinone derivatives | |
NO146472B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF ERYTHROMYCIN DERIVATIVES | |
KR910009271B1 (en) | 1,1-dioxopenicillanoyl oxymethyl d-6-(alpha-cmethyleneamino phenylacetamide)-penicillanate and p-tolluenesulfonic acid salts | |
US4136253A (en) | Semi-synthetic 4"-sulfonylamino-oleandomycin derivatives | |
KR820000693B1 (en) | Process for preparing semi-synthetic 4''-sulfonyl amino-oleandomycin derivatives | |
US3947453A (en) | 24-Oxo-14a-aza-D-homo-cholestadiene derivatives | |
DK148421B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF 4 '' - DEOXY-4 '' - (SUBSTITUTED) AMINO-OLEANDOMYCIN DERIVATIVES OR SALTS THEREOF | |
CA1185968A (en) | Method of preparing 23-monoesters of omt and dmt | |
US4098994A (en) | Sulfamide derivatives of 4 -deoxy-oleandomycin | |
IE47968B1 (en) | Oleandomycin-derived carbamates and thiocarbamates | |
NO120371B (en) | ||
EP1100806B1 (en) | Erythromycin derivative with antibiotic activity | |
KR790001501B1 (en) | Process for preparing midecamycine derivatives | |
PL80959B1 (en) | ||
GB2127818A (en) | Aminoglycoside derivatives processes for their production and their use | |
HU211493A9 (en) | Derivatives 10, 11, 12, 13-tetrahydrodesmycosin, processes for preparation and use thereof in pharmaceuticals |