WO1999021867A1 - Erythromycin a derivatives - Google Patents
Erythromycin a derivatives Download PDFInfo
- Publication number
- WO1999021867A1 WO1999021867A1 PCT/JP1998/004779 JP9804779W WO9921867A1 WO 1999021867 A1 WO1999021867 A1 WO 1999021867A1 JP 9804779 W JP9804779 W JP 9804779W WO 9921867 A1 WO9921867 A1 WO 9921867A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- formula
- carbon atoms
- acid
- erythromycin
- Prior art date
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- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 title claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 10
- 229960003276 erythromycin Drugs 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229930006677 Erythromycin A Natural products 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 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
- -1 etc. Chemical group 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- ZLCOWUKVVFVVKA-WDSKDSINSA-N (2r)-3-[[(2r)-2-acetamido-2-carboxyethyl]disulfanyl]-2-aminopropanoic acid Chemical compound CC(=O)N[C@H](C(O)=O)CSSC[C@H](N)C(O)=O ZLCOWUKVVFVVKA-WDSKDSINSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- RVHOBHMAPRVOLO-UHFFFAOYSA-N 2-ethylbutanedioic acid Chemical compound CCC(C(O)=O)CC(O)=O RVHOBHMAPRVOLO-UHFFFAOYSA-N 0.000 description 1
- XVCCOEWNFXXUEV-UHFFFAOYSA-N 2-pyridin-3-ylacetic acid;hydrochloride Chemical compound Cl.OC(=O)CC1=CC=CN=C1 XVCCOEWNFXXUEV-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
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 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
- 241000192125 Firmicutes Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N Glutamine Chemical class OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 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
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241001430197 Mollicutes Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000021355 Stearic acid Nutrition 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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 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
- 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 150000005676 cyclic carbonates Chemical class 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 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
- 150000002148 esters Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 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
Definitions
- the present invention relates to a novel derivative of the antibiotic erythromycin A.
- Erythromycin A is an antibiotic that is widely used as a treatment for infectious diseases caused by gram-positive bacteria, mycoplasmas, and the like. Erythromycin A, however, has the disadvantage that it is degraded by acid in the stomach because it is unstable to acids, and its pharmacokinetics is not constant. Many erythromycin A derivatives have been produced to date to improve such biological or pharmacological properties. For example, a 6-0-methylerythromycin A derivative (U.S. Pat. No. 4,331,803) has improved stability to acids, and has better in vivo antibacterial activity upon oral administration than erythromycin A. It has been reported.
- An object of the present invention is to provide a next-generation macrolide antibiotic having a strong antibacterial activity against not only conventional erythromycin-sensitive bacteria but also erythromycin-resistant bacteria, which have been increasing in recent years. To do that. Disclosure of the invention
- the present inventors have found a compound having antibacterial activity not only against susceptible bacteria but also against resistant bacteria by converting the carboxy group at the 9-position of erythromycin A to a certain substituent.
- the present invention has been completed.
- the present invention provides a compound represented by the formula (I):
- R 1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- R 2 represents a cladino siloxy group, and a formula — OCO-CH 2 -R 4
- R 4 is a phenyl group, a pyridyl group, a quinolyl group, or an alkyl group having 1 to 3 carbon atoms, a cyano group, an amino group, a dimethylamino group, a nitro group, a carbon atom.
- X is an oxygen atom
- n represents an integer of 1 to 5
- R 5 and R 6 are the same or different.
- R 7 is of the formula N—R 9
- R 8 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkanol group having 2 to 7 carbon atoms
- R 9 represents a phenyl group, a benzyl group, a pyridyl group, a pyridylmethyl group.
- R s and R 9 above are the same as) a group represented by or wherein one S0 2 - N-R 9
- Erythromycin A derivative represented by the formula or a pharmaceutically acceptable salt thereof.
- an alkyl group having 1 to 6 carbon atoms means a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isopropyl group, a tert-butyl group.
- An isopentyl group, a cyclohexyl group, etc., and an alkanoyl group having 2 to 7 carbon atoms refers to an acetyl group, a propionyl group, an isopropionyl group, a butylyl group, etc., and a halogen atom and Is fluorine, chlorine, bromine Indicates an atom or iodine atom.
- Pharmaceutically acceptable salts refer to salts used in the chemotherapy and prevention of bacterial infections. They include, for example, acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethyl succinic acid, lactobionic acid, dalconic acid, Darcoheptonic acid, benzoic acid, methansulphonic acid, benzoic sulphonic acid, 2-hydroxyethanesulphonic acid, benzenesulphonic acid, para-toluenesulphonic acid, lauryl sulphate, lingoic acid, aspartic acid, glutamin Acids, adipic acid, cystine, N-acetyl cystine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, dicotinic acid, oxalic acid, picric acid, thiocyanic acid, pende
- the compound of the present invention can be produced according to Examples described later.
- the compounds of the present invention can be administered orally or parenterally.
- the dosage forms are tablets, capsules, powders, lozenges, ointments, suspensions, suppositories, injections, etc., which can be manufactured by common formulation techniques.
- the dosage is 100-1. OOOmg daily for treatment of adults, which can be administered in 2-3 divided doses a day. This dosage may be adjusted as appropriate according to the age, weight and condition of the patient.
- Example 3 9—Doxo 9—Aminoerythromycin A 9, 11—Cyclic power—Bamate 3 g (4.0 mmol) of 9-deoxo-19-aminoinothromycin A synthesized by the method described in the literature (Tetrahedoron Le 11., p. 29, 1972) was prepared in the same manner as in Example 1 by using a method similar to that of Example 1. To give 0.6 g (yield 193 ⁇ 4) of the title compound.
- the compounds of the present invention have antibacterial activity not only against erythromycin-sensitive bacteria but also against resistant bacteria. Therefore, the compounds of the present invention are useful as antibacterial agents for treating bacterial infections in humans and animals (including farm animals).
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Abstract
Erythromycin A derivatives represented by general formula (I) or pharmaceutically acceptable salts thereof.
Description
明細書 エリ ス ロマイ シン A誘導体 技術分野 Description Erythromycin A derivative Technical field
本発明は、 抗生物質エ リ ス ロマイ シン Aの新規誘導体に関する。 背景技術 The present invention relates to a novel derivative of the antibiotic erythromycin A. Background art
エリ スロマイ シン Aはグラム陽性菌、 マイ コ プラズマなどに起因 する感染症の治療薬と して広く 使用されている抗生物質である。 し かし、 エリ スロマイ シン Aは酸に対し不安定であるため胃酸で分解 され、 体内動態が一定しないとい う欠点があっ た。 これまで多く の エ リ ス ロマイ シン A誘導体が、 このよ うな生物学的または薬効学的 特性の改良を目的に製造されてきた。 例えば 6-0-メチルエリ ス ロマ イ シン A誘導体 （米国特許第 4331803号） は酸に対する安定性が改善 され、 経口投与時の生体内抗菌活性がエ リ ス ロマイ シン Aに比較し 優れている こ とが報告されている。 この他にも酸安定性に加え抗菌 スぺク トルの拡大を狙っ た 9， 11 -アルキリ デン誘導体に関する報告も なされている （特開平 1 — 2 3 0 5 8 2 号、 J. Ant imi cro. Chemoth. 31, 65 ( 1993). ) 。 また、 本発明者らは、 3位エステル誘導体の抗菌活 性について報告している （ヨーロ ッパ特許 619320号） 。 Erythromycin A is an antibiotic that is widely used as a treatment for infectious diseases caused by gram-positive bacteria, mycoplasmas, and the like. Erythromycin A, however, has the disadvantage that it is degraded by acid in the stomach because it is unstable to acids, and its pharmacokinetics is not constant. Many erythromycin A derivatives have been produced to date to improve such biological or pharmacological properties. For example, a 6-0-methylerythromycin A derivative (U.S. Pat. No. 4,331,803) has improved stability to acids, and has better in vivo antibacterial activity upon oral administration than erythromycin A. It has been reported. In addition to this, there have been reports of 9,11-alkylidene derivatives aimed at expanding the antibacterial spectrum in addition to acid stability (Japanese Patent Application Laid-Open No. Hei 1-2352882, J. Antimicro Chemoth. 31, 65 (1993). The present inventors have also reported the antibacterial activity of the 3-position ester derivative (European Patent No. 619320).
本発明の目的は、 従来のエリ ス ロマイ シン感受性菌のみならず、 近年増加傾向を示しているエリ ス ロマイ シン耐性菌に対しても強い 抗菌力を有する次世代マク ロ ライ ド抗生物質を提供する こ とにある。
発明の開示 An object of the present invention is to provide a next-generation macrolide antibiotic having a strong antibacterial activity against not only conventional erythromycin-sensitive bacteria but also erythromycin-resistant bacteria, which have been increasing in recent years. To do that. Disclosure of the invention
本発明者らは、 エリ スロマイ シン Aの 9位カルボ二ル基をある種 の置換基に変換する こ とによ り、 感受性菌だけでなく 耐性菌に対し ても抗菌力を有する化合物を見出し本発明を完成した。 The present inventors have found a compound having antibacterial activity not only against susceptible bacteria but also against resistant bacteria by converting the carboxy group at the 9-position of erythromycin A to a certain substituent. The present invention has been completed.
すなわち本発明は、 式 （ I ) That is, the present invention provides a compound represented by the formula (I):
{式中、 R 1は水素原子または炭素原子数 1 〜 6 のアルキル基を示し. R 2はク ラジノ シルォキシ基、 式 — OCO-CH2-R4 {Wherein, R 1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R 2 represents a cladino siloxy group, and a formula — OCO-CH 2 -R 4
(式中、 R 4はフエニル基、 ピリ ジル基、 キノ リ ル基または 「炭素原 子数 1 〜 3 のアルキル基、 シァ ノ基、 アミ ノ基、 ジメチルァミ ノ基、 ニ ト ロ基、 炭素原子数 1 〜 3 のアルコキシ基も し く はハロゲン原子」 から選ばれる基の 1 〜 3個で置換されたフエニル基もしく はピ リ ジ ル基を示す。 ） で示される基または 式 — OCO-NH-R4 (In the formula, R 4 is a phenyl group, a pyridyl group, a quinolyl group, or an alkyl group having 1 to 3 carbon atoms, a cyano group, an amino group, a dimethylamino group, a nitro group, a carbon atom. A phenyl group or a pyridyl group substituted by 1 to 3 groups selected from the group consisting of an alkoxy group or a halogen atom represented by the formulas 1 to 3) or a group represented by the formula: —OCO— NH-R 4
(式中、 R 4は前記と同じである。 ) で表される基を示し、 (Wherein, R 4 is the same as defined above.)
Xは 酸素原子、 X is an oxygen atom,
式 一 H— Formula I H—
または式
Or expression
[式中、 n は 1 〜 5 の整数を示し、 R 5および R 6は同一または異なつ
て水素原子または炭素原子数 1 〜 6 のアルキル基を示し、 [Wherein, n represents an integer of 1 to 5, and R 5 and R 6 are the same or different. Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
R 7は式 一 N— R9 R 7 is of the formula N—R 9
R8 R 8
(式中、 R 8は水素原子、 炭素原子数 1 〜 6 のアルキル基または炭素 原子数 2 〜 7 のアルカ ノィ ル基を示し、 R 9はフエニル基、 ベンジル 基、 ピリ ジル基、 ピリ ジルメチル基、 キノ リ ル基、 キノ リ ルメチル 基または 「炭素原子数 1 〜 3 のアルキル基、 シァノ基、 アミ ノ基、 ジメチルァミ ノ基、 ニ ト ロ基、 炭素原子数 1 〜 3 のアルコキシ基ま たはハロゲン原子」 から選ばれる基の 1 〜 3個で置換されたフ エ二 ル基、 ベンジル基、 ピリ ジル基、 ピリ ジルメチル基、 キノ リル基ま たはキノ リルメチル基を示す。 ） で示される基、 式 — N-S02-R9 (In the formula, R 8 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkanol group having 2 to 7 carbon atoms, and R 9 represents a phenyl group, a benzyl group, a pyridyl group, a pyridylmethyl group. , A quinolyl group, a quinolylmethyl group or a `` C 1-3 alkyl group, a cyano group, an amino group, a dimethylamino group, a nitro group, a C 1-3 alkoxy group, Represents a phenyl, benzyl, pyridyl, pyridylmethyl, quinolyl or quinolylmethyl group substituted with 1 to 3 halogen atoms.) , Formula — N-S0 2 -R 9
(式中、 R sと R 9は前記と同じである。 ） で示される基または 式 一 S02 - N— R9 (. Wherein, R s and R 9 above are the same as) a group represented by or wherein one S0 2 - N-R 9
R8 R 8
(式中、 R sと R 9は前記と同じである。 ） で表される基を示す。 ]を 示す。 } で表されるエリ ス ロマイ シン A誘導体またはその医薬上許 容される塩である。 (Wherein, R s and R 9 are the same as described above.). ]. Erythromycin A derivative represented by the formula or a pharmaceutically acceptable salt thereof.
本発明において、 炭素原子数 1 〜 6 のアルキル基とは、 メチル基、 ェチル基、 プロ ピル基、 ブチル基、 ペンチル基、 へキシル基、 イ ソ プロ ピル基、 イ ソブチル基、 t e r t—ブチル基、 イ ソペンチル基、 シ ク ロへキシル基などを示し、 炭素原子数 2 〜 7 のアルカ ノィル基と は、 ァセチル基、 プロ ピオニル基、 イ ソプロ ピオニル基、 プチロイ ル基などを示し、 ハロゲン原子とは、 フ ッ素原子、 塩素原子、 臭素
原子またはヨ ウ素原子を示す。 In the present invention, an alkyl group having 1 to 6 carbon atoms means a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isopropyl group, a tert-butyl group. , An isopentyl group, a cyclohexyl group, etc., and an alkanoyl group having 2 to 7 carbon atoms refers to an acetyl group, a propionyl group, an isopropionyl group, a butylyl group, etc., and a halogen atom and Is fluorine, chlorine, bromine Indicates an atom or iodine atom.
医薬上許容される塩とは、 細菌感染症の化学療法および予防にお いて使用される塩を意味する。 それらは、 たとえば酢酸、 プロ ピオ ン酸、 酪酸、 ギ酸、 ト リ フルォロ酢酸、 マレイ ン酸、 酒石酸、 クェ ン酸、 ステア リ ン酸、 コハク酸、 ェチルコハク酸、 ラク ト ビオン酸、 ダルコ ン酸、 ダルコヘプ ト ン酸、 安息香酸、 メタ ンスルホン酸、 ェ 夕 ンスルホン酸、 2 -ヒ ドロキシエタ ンスルホン酸、 ベンゼンスルホ ン酸、 パラ トルエンスルホン酸、 ラウ リ ル硫酸、 リ ンゴ酸、 ァスパ ラギン酸、 グルタ ミ ン酸、 アジピン酸、 システィ ン、 N —ァセチル システィ ン、 塩酸、 臭化水素酸、 リ ン酸、 硫酸、 ヨ ウ化水素酸、 二 コチン酸、 シユウ酸、 ピク リ ン酸、 チォシアン酸、 ゥンデカ ン酸、 ァク リ ル酸ポリ マー、 カルボキシビ二ルポリ マーなどの酸との塩を あげる こ とができる。 本発明の化合物は後述の実施例にしたがって製造する こ とができ る。 本発明の化合物は経口または非経口的に投与する こ とができる。 その投与剤型は錠剤、 カプセル剤、 粉剤、 ト ローチ剤、 軟膏、 懸濁 液、 坐剤、 注射剤などであ り、 それらは一般的な製剤技術によって 製造する こ とができる。 その投与量は、 成人を治療する場合で 1日量 1 0 0〜 1 . O O O mgであ り、 これを 1日 2〜 3回に分けて投与する こ とができ る。 この投与量は、 患者の年齢、 体重および症状によって適宜増減 する こ とができる。
発明を実施するための最良の形態 Pharmaceutically acceptable salts refer to salts used in the chemotherapy and prevention of bacterial infections. They include, for example, acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethyl succinic acid, lactobionic acid, dalconic acid, Darcoheptonic acid, benzoic acid, methansulphonic acid, benzoic sulphonic acid, 2-hydroxyethanesulphonic acid, benzenesulphonic acid, para-toluenesulphonic acid, lauryl sulphate, lingoic acid, aspartic acid, glutamin Acids, adipic acid, cystine, N-acetyl cystine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, dicotinic acid, oxalic acid, picric acid, thiocyanic acid, pendecane Examples thereof include salts with acids such as acids, acrylic acid polymers and carboxyvinyl polymers. The compound of the present invention can be produced according to Examples described later. The compounds of the present invention can be administered orally or parenterally. The dosage forms are tablets, capsules, powders, lozenges, ointments, suspensions, suppositories, injections, etc., which can be manufactured by common formulation techniques. The dosage is 100-1. OOOmg daily for treatment of adults, which can be administered in 2-3 divided doses a day. This dosage may be adjusted as appropriate according to the age, weight and condition of the patient. BEST MODE FOR CARRYING OUT THE INVENTION
実施例にて本発明をさ らに詳細に説明する。 The present invention will be described in more detail with reference to examples.
実施例 1 9 —デォキソ — 9 —ハイ ド ロキシエ リ ス ロマイ シン A 9 , 1 1 一サイ ク リ ッ クカーボネー ト Example 1 9—Doxo — 9—Hydroxie erythromycin A 9, 1 1 Cyclic carbonate
文献記載の方法 U. Org. chem. II, 5019 ( 1982) )で合成した 2 ' — O —ァセチル— 9 —デォキソ ー 9 一ハイ ドロキシエ リ ス ロマイ シ ン A 10g( 12. 9ミ リ モル）を溶解したピリ ジン 200mlの溶液に、 ト リ ホス ゲン 7. 64g(25. 7ミ リ モル）を溶解したジク ロルメタ ン 75mlを氷冷下 で滴下し、 室温で一晩攪拌を続けた。 反応液に水を加え、 減圧下濃 縮後、 残渣を酢酸ェチルで抽出した。 酢酸ェチル層を水、 続いて飽 和食塩水で洗浄後、 無水硫酸マグネシウムで乾燥した。 齚酸ェチル を減圧下留去し、 残渣をメタ ノール 50mlに溶解し、 室温で 2 日間攪 拌を続けた。 減圧下、 メタ ノールを留去し、 残渣をジク ロルメタ ン 一 n-へキサンか ら結晶化し、 1. 96 g (収率 20%)の標記化合物を得た。 FABMS m/z： 76 (M+H) 実施例 2 9 —デォキソ — 5 — O —デソサミ ニルー 3 — O — （ 3 — ピ リ ジル） ァセチルー 9 —ハイ ド ロキシエリ ス ロ ノ ライ ド A 9 , 1 1 —サイ ク リ ッ クカーボネー 卜 2'-O-Acetyl-9-doxo-9 synthesized by U. Org. Chem. II, 5019 (1982)) 10 g (12.9 mimol) of A-hydroxyl erythromycin A 75 ml of dichloromethane dissolved with 7.64 g (25.7 mmol) of triphosgene was added dropwise to a solution of 200 ml of pyridine in which ice was dissolved, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with a saturated saline solution, and then dried over anhydrous magnesium sulfate. Ethyl diacid was distilled off under reduced pressure, the residue was dissolved in 50 ml of methanol, and stirring was continued at room temperature for 2 days. Methanol was distilled off under reduced pressure, and the residue was crystallized from dichloromethane-n-hexane to obtain 1.96 g (yield: 20%) of the title compound. FABMS m / z: 76 (M + H) Example 2 9 — Deoxo — 5 — O — Desosaminol 3 — O — (3 — pyridyl) acetyl 9 — Hydroxyelis ronolide A 9, 1 1—Cyclic carbonate
( 1 ) 実施例 1 で得た化合物 1. 9g(2. 5ミ リ モル）を 1 規定塩酸 20m 1に溶解し、 室温で一晩撹拌した。 反応液を水酸化ナ ト リ ウム水溶液 で中和後、 酢酸ェチルで抽出した。 有機層を水、 続いて飽和食塩水 で洗浄し、 無水硫酸マグネシウムで乾燥した。 溶媒を減圧留去し、 得られた残渣をシリ カゲルカ ラムク ロマ トグラフィ ー （ク ロ口ホル ム ： メタ ノール ： アンモニア水 = 20： 1： 0. 1 ) で精製し、 デク ラジ ノ シ
ル体 1.02g (収率 68%) を得た。 (1) 1.9 g (2.5 mmol) of the compound obtained in Example 1 was dissolved in 20 ml of 1N hydrochloric acid and stirred at room temperature overnight. The reaction solution was neutralized with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform form: methanol: ammonia water = 20: 1: 0.1), and degraded 1.02 g (yield: 68%) of the compound was obtained.
SIMS m/z :604 ( IH) + SIMS m / z: 604 (IH) +
( 2 ) 上記 （ 1 ) で得た化合物 0.95g(l. 58ミ リ モル）をアセ ト ン 1 0mlに溶解し、 無水酢酸 0. 22ml (2.33ミ リ モル）を加え、 室温で 6時間 撹拌を行った。 溶媒を減圧留去後、 酢酸ェチルに溶解して飽和重曹 水、 飽和食塩水で順次洗浄し、 有機層を無水硫酸マグネシウムで乾 燥した。 溶媒を減圧留去し、 得られた残渣をシリ カゲルカ ラムク ロ マ 卜グラフィ ー （アセ ト ン ： へキサン ： ト リ ェチルァミ ン =10: 10:0. 2) にて精製し、 2 ' — 0 -ァセチル体 1.0g (収率 98%)を得た。 (2) Dissolve 0.95 g (l. 58 mimol) of the compound obtained in (1) above in 10 ml of acetate, add 0.22 ml (2.33 mimol) of acetic anhydride, and stir at room temperature for 6 hours Was done. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (aceton: hexane: triethylamine = 10: 10: 0: 2), and 2'-0 1.0 g (98% yield) of the -acetyl compound was obtained.
( 3 ) 3 -ピリ ジル酢酸塩酸塩 404mg(2. 33ミ リ モル）、 ビバリ ン酸ク ロ リ ド 0. 29ml (2. 35ミ リ モル）および ト リ ェチルァミ ン 0.43ml (3.0 (3) 3-pyridylacetic acid hydrochloride 404 mg (2.33 mmol), Bivalic acid chloride 0.29 ml (2.35 mmol) and triethylamine 0.43 ml (3.0
9ミ リ モル）をジク ロルメタ ン 3mlに溶解し、 - 15°Cで 20分間攪拌した, この溶液に上記 （ 2 ) で得た化合物 0. 5 g (0. 78ミ リ モル）を溶解した ジク ロルメタ ン 2mlを室温で滴下し、 10分間攪拌を続けた。 その後、 4 —ジメチルァミ ノ ピ リ ジン 95mg(0. 78ミ リ モル）を加え、 室温で一 晚攪拌を続けた。 反応液をク ロ 口ホルムで希釈して水酸化ナ ト リ ウ ム水溶液を加えて分液した。 有機層を飽和塩化アンモニゥム水溶液、 続いて飽和食塩水で洗浄し、 無水硫酸ナ ト リ ウムで乾燥した。 溶媒 を減圧留去して得られた残渣をメタ ノール 5ιιΠに溶解し、 室温で一晩 攪拌した。 溶媒を減圧留去後、 得られた残渣をシリ カゲルカラムク 口マ トグラフィ ー （アセ ト ン ： へキサン ： 卜 リ エチルァミ ン = 10: 10 :0. 2) で精製し、 標記化合物 0. 20g (収率 36%)を得た。 Was dissolved in 3 ml of dichloromethane and stirred at -15 ° C for 20 minutes. In this solution, 0.5 g (0.78 mmol) of the compound obtained in the above (2) was dissolved. 2 ml of dichloromethane was added dropwise at room temperature, and stirring was continued for 10 minutes. Thereafter, 95 mg (0.78 mmol) of 4-dimethylaminopyridine was added, and stirring was continued at room temperature for one hour. The reaction solution was diluted with a black hole form, and an aqueous solution of sodium hydroxide was added to separate the solution. The organic layer was washed with a saturated aqueous solution of ammonium chloride and subsequently with a saturated saline solution, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in methanol and stirred at room temperature overnight. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 10: 0.2) to obtain 0.20 g of the title compound (yield Rate 36%).
FABMS m/z： 723 (M+H) + FABMS m / z: 723 (M + H) +
実施例 3 9 —デォキソ ー 9 一アミ ノエリ ス ロマイ シン A 9 , 1 1 —サイ ク リ ッ ク力—バメー ト
文献記載の方法 （Tetrahedoron Le 11. , 1972年， 29頁） で合成した 9 ーデォキソ 一 9 —ア ミ ノエリ ス ロマイ シン A 3g (4.0ミリモル） を 実施例 1と同様の方法によ り ト リ ホスゲンと反応させ、 0. 6g (収率 1 9¾) の標記化合物を得た。 Example 3 9—Doxo 9—Aminoerythromycin A 9, 11—Cyclic power—Bamate 3 g (4.0 mmol) of 9-deoxo-19-aminoinothromycin A synthesized by the method described in the literature (Tetrahedoron Le 11., p. 29, 1972) was prepared in the same manner as in Example 1 by using a method similar to that of Example 1. To give 0.6 g (yield 19¾) of the title compound.
FABMS m/z ： 761 ( +H) + 産業上の利用可能性 FABMS m / z: 761 (+ H) + industrial applicability
本発明の化合物は、 エリ ス ロマイ シン感受性菌のみならず耐性菌 に対しても抗菌力を有する。 従って本発明の化合物はヒ 卜および動 物 （農園動物を含む） における細菌感染症の治療のための抗菌剤と して有用である。
The compounds of the present invention have antibacterial activity not only against erythromycin-sensitive bacteria but also against resistant bacteria. Therefore, the compounds of the present invention are useful as antibacterial agents for treating bacterial infections in humans and animals (including farm animals).
Claims
1. 式 （ I ) 1. Formula (I)
{式中、 R 1は水素原子または炭素原子数 1 〜 6 のアルキル基を示し, R 2はク ラジノ シルォキシ基、 式 — OCO-CH2-R4 {Wherein, R 1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R 2 represents a cladino siloxy group, and the formula — OCO-CH 2 -R 4
(式中、 R 4はフエニル基、 ピリ ジル基、 キノ リル基または 「炭素原 子数 1 〜 3 のアルキル基、 シァ ノ基、 アミ ノ基、 ジメチルァミ ノ基、 ニ ト ロ基、 炭素原子数 1 〜 3 のアルコキシ基も しく はハロゲン原子」 から選ばれる基の 1 〜 3個で置換されたフエニル基も し く はピ リ ジ ル基を示す。 ） で示される基または (In the formula, R 4 is a phenyl group, a pyridyl group, a quinolyl group or an `` alkyl group having 1 to 3 carbon atoms, a cyano group, an amino group, a dimethylamino group, a nitro group, a carbon atom number. A phenyl group or a pyridyl group substituted with 1 to 3 groups selected from the group consisting of 1 to 3 alkoxy groups and a halogen atom.)
式 — OCONH-R Expression — OCONH-R
(式中、 R 4は前記と同じである。 ） で表される基を示し、 (Wherein, R 4 is the same as defined above.)
Xは 酸素原子、 X is an oxygen atom,
式 一 NH— Formula I NH—
または式
Or expression
[式中、 n は 1 〜 5 の整数を示し、 R 5および R 6は同一または異なつ て水素原子または炭素原子数 1 〜 6 のアルキル基を示し、 [Wherein, n represents an integer of 1 to 5, R 5 and R 6 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
R 7は式 一 N— R9 R 7 is of the formula N—R 9
R8
(式中、 R 8は水素原子、 炭素原子数 1 〜 6 のアルキル基または炭素 原子数 2 〜 7 のアルカ ノィル基を示し、 R 9はフエニル基、 ベンジル 基、 ピリ ジル基、 ピリ ジルメチル基、 キノ リ ル基、 キノ リルメチル 基または 「炭素原子数 1 〜 3 のアルキル基、 シァ ノ基、 アミ ノ基、 ジメチルァミ ノ基、 ニ ト ロ基、 炭素原子数 1 〜 3 のアルコキシ基ま たはハロゲン原子」 から選ばれる基の 1 〜 3個で置換されたフエ二 ル基、 ベンジル基、 ピリ ジル基、 ピリ ジルメチル基、 キノ リル基ま たはキノ リルメチル基を示す。 ） で示される基、 R 8 (In the formula, R 8 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkanol group having 2 to 7 carbon atoms, and R 9 represents a phenyl group, a benzyl group, a pyridyl group, a pyridylmethyl group, A quinolyl group, a quinolylmethyl group, or an alkyl group having 1 to 3 carbon atoms, a cyano group, an amino group, a dimethylamino group, a nitro group, an alkoxy group having 1 to 3 carbon atoms or halogen. A phenyl group, a benzyl group, a pyridyl group, a pyridylmethyl group, a quinolyl group or a quinolylmethyl group substituted with 1 to 3 of the groups selected from "atoms".
式 一 N— SOー R9 Formula 1 N—SO-R 9
(式中、 R 8と R 9は前記と同 じである。 ） で示される基または 式 一 S02— N— R9 (. Wherein, R 8 and R 9 are the a is the same) groups represented by or wherein one S0 2 - N-R 9
R8 R 8
(式中、 R 8と R 9は同じである。 ） で表される基を示す。 ]を示す。 } で表されるエリ スロマイ シン A誘導体またはその医薬上許容される 塩
(In the formula, R 8 and R 9 are the same.) ]. Erythromycin A derivative represented by the formula or a pharmaceutically acceptable salt thereof
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU96459/98A AU9645998A (en) | 1997-10-29 | 1998-10-22 | Erythromycin a derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9/296824 | 1997-10-29 | ||
| JP29682497 | 1997-10-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999021867A1 true WO1999021867A1 (en) | 1999-05-06 |
Family
ID=17838639
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1998/004779 WO1999021867A1 (en) | 1997-10-29 | 1998-10-22 | Erythromycin a derivatives |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU9645998A (en) |
| WO (1) | WO1999021867A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6946482B2 (en) | 2002-08-29 | 2005-09-20 | Kosan Biosciences, Inc. | Motilide compounds |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62158B2 (en) * | 1975-04-07 | 1987-01-06 | Thomae Gmbh Dr K | |
| WO1993013115A1 (en) * | 1991-12-27 | 1993-07-08 | Taisho Pharmaceutical Co., Ltd. | 5-0-desosaminylerythronolide derivative |
-
1998
- 1998-10-22 WO PCT/JP1998/004779 patent/WO1999021867A1/en active Application Filing
- 1998-10-22 AU AU96459/98A patent/AU9645998A/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62158B2 (en) * | 1975-04-07 | 1987-01-06 | Thomae Gmbh Dr K | |
| WO1993013115A1 (en) * | 1991-12-27 | 1993-07-08 | Taisho Pharmaceutical Co., Ltd. | 5-0-desosaminylerythronolide derivative |
| WO1993013116A1 (en) * | 1991-12-27 | 1993-07-08 | Taisho Pharmaceutical Co., Ltd. | 5-o-desosaminylerythronolide derivative |
Non-Patent Citations (1)
| Title |
|---|
| HUNT E., ET AL.: "9,11-CYCLIC ACETAL DERIVATIVES OF (9S)-9-DIHYDROERYTHROMYCIN A.", THE JOURNAL OF ANTIBIOTICS, NATURE PUBLISHING GROUP, GB, vol. 42., no. 02., 1 January 1989 (1989-01-01), GB, pages 293 - 298., XP002915959, ISSN: 0021-8820 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6946482B2 (en) | 2002-08-29 | 2005-09-20 | Kosan Biosciences, Inc. | Motilide compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| AU9645998A (en) | 1999-05-17 |
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