CN1159756A - 抑制白细胞介素5的产生的抑制剂 - Google Patents
抑制白细胞介素5的产生的抑制剂 Download PDFInfo
- Publication number
- CN1159756A CN1159756A CN95195373A CN95195373A CN1159756A CN 1159756 A CN1159756 A CN 1159756A CN 95195373 A CN95195373 A CN 95195373A CN 95195373 A CN95195373 A CN 95195373A CN 1159756 A CN1159756 A CN 1159756A
- Authority
- CN
- China
- Prior art keywords
- erythromycin
- oxime
- deoxidation
- generation
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 12
- 230000022023 interleukin-5 production Effects 0.000 title abstract 3
- 150000002923 oximes Chemical class 0.000 claims abstract description 17
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims abstract description 12
- 229960003276 erythromycin Drugs 0.000 claims description 32
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 102000000588 Interleukin-2 Human genes 0.000 claims description 8
- 108010002350 Interleukin-2 Proteins 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 230000002052 anaphylactic effect Effects 0.000 claims description 3
- 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 abstract description 18
- 150000003839 salts Chemical class 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 229960002626 clarithromycin Drugs 0.000 abstract 3
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound 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 abstract 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- 230000003389 potentiating effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 24
- 102000000743 Interleukin-5 Human genes 0.000 description 14
- 108010002616 Interleukin-5 Proteins 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 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 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000003104 tissue culture media Substances 0.000 description 4
- BASMANVIUSSIIM-UHFFFAOYSA-N 1-chloro-2-(chloromethyl)benzene Chemical compound ClCC1=CC=CC=C1Cl BASMANVIUSSIIM-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 210000003979 eosinophil Anatomy 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 238000009834 vaporization Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- -1 2-ethyl Chemical group 0.000 description 2
- 206010012438 Dermatitis atopic Diseases 0.000 description 2
- 206010013700 Drug hypersensitivity Diseases 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical class ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 206010039085 Rhinitis allergic Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 201000010105 allergic rhinitis Diseases 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000006196 deacetylation Effects 0.000 description 2
- 238000003381 deacetylation reaction Methods 0.000 description 2
- 201000005311 drug allergy Diseases 0.000 description 2
- 229950007655 esilate Drugs 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000003862 health status Effects 0.000 description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108010026206 Conalbumin Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 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
- DKMROQRQHGEIOW-UHFFFAOYSA-N Diethyl succinate Chemical compound CCOC(=O)CCC(=O)OCC DKMROQRQHGEIOW-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 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
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000053227 Themus Species 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 230000009285 allergic inflammation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000151 cysteine group Chemical class N[C@@H](CS)C(=O)* 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-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
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000011177 media preparation Methods 0.000 description 1
- 238000005497 microtitration Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 238000012549 training Methods 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
- 239000013638 trimer Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
本发明提供一种对白细胞介素5的产生有强有力的抑制活性的红霉素衍生物，它是一种对白细胞介素5的产生的抑制剂，含有作为活性成分的6-O-甲基红霉素A9-[O-(2-氯苯甲基)肟]、6-O-甲基红霉素A-9-[O-(3-甲氧基-4-叔丁基苄基)肟]11，12-环碳酸酯、11-氨基-9-N，11-N-环1，2-亚乙基-9-去氧代-11-脱氧-6-O-甲基红霉素A9-苄胺11-N，12-O-环甲氨酸酯，或其药学上可接受的酸加成盐。
Description
本发明涉及一种对白细胞介素5的产生的抑制剂，该抑制剂含有作为活性成分的红霉素衍生物。
已知白细胞介素5(下文中简写为IL-5)为刺激嗜伊红性粒细胞分化和生长的重要因子，并且后者会加剧过敏性炎症。因此作用于产生白细胞介素5的抑制剂对治疗如支气管哮喘、过敏性鼻炎、特应性皮炎、药物过敏和嗜伊红性粒细胞肺炎等各种过敏性疾病是有利的。
红霉素是一种抗生素，临床上广泛将它用作由革兰氏阳性菌、一些革兰氏阴性菌和支原体等引起的感染的治疗剂。最近报导了红霉素和罗希红霉素对产生IL-5产生有抑制活性[“日本变态反应学杂志”(Japanese Joumal ofAllergology)，44(3-2)，第424页(1993)]，但红霉素和罗希红霉素对产生IL-5的抑制活性是不足的。
本发明的目的就是提供一种有强有力的抑制IL-5产生的活性的红霉素衍生物。
本发明的发明者已广泛研究了红霉素衍生物对IL-5产生的抑制活性，结果发现了以下红霉素衍生物显示出对产生IL-5有强有力的抑制活性，从而完成了本发明。
本发明提供了一种作用于产生IL-5的抑制剂，该抑制剂含有作为活性成分的6-O-甲基红霉素A9-[O-(2-氯苯甲基)肟]，6-O-甲基红霉素A9-[O-(3-甲氧基-4-叔丁基苄基)肟]11，12-环碳酸酯，11-氨基-9-N，11-N-环1，2-亚乙基-9-去氧代-11-脱氧-6-O-甲基红霉素A9-苄胺11-N，12-O-环甲氨酸酯，或其药学上可接受的酸加成盐。
用于本发明的药学上可接受的酸加成盐包括乙酸盐、丙酸盐、丁酸盐、甲酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、柠檬酸盐、硬脂酸盐、琥珀酸盐、乙基琥珀酸盐、乳糖酸盐、葡糖酸盐、葡庚糖酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、2-乙基乙磺酸盐、苯磺酸盐、P-甲苯磺酸盐、十二烷基硫酸盐、苹果酸盐、天冬氨酸盐、谷氨酸盐、己二酸盐、半胱氨酸盐、盐酸化物、氢溴化物、磷酸盐、硫酸盐、氢碘酸盐、烟酸盐、草酸盐、苦味酸盐、硫代氰酸盐、十一烷酸盐、丙烯酸聚合物的盐和羧基乙烯聚合物的盐。
本发明中所应用的6-O-甲基红霉素A9-[O-(2-氯苯甲基)肟]和6-O-甲基红霉素A9-[O-(3-甲氧基-4-叔丁基苄基)肟]11，12-环碳酸酯可以例如下法制备。步骤(1)：在碱存在时，将溶于惰性溶剂的6-O-甲基红霉素A9-肟(美国专利4,680,386中所描述的)与2-氯苯甲基氯化物反应制备6-O-甲基红霉素A9-[O-(2-氯苯甲基)肟]。适宜的惰性溶剂为丙酮、四氢呋喃、N，N-二甲基甲酰胺、二甲基亚砜、二氧杂环己烷和其混合物。适宜的碱包括氢化物、氢氧化钠和氢氧化钾。反应温度在-20℃到50范围内变化，优选在0℃到25℃范围内变化。
步骤(2)：除用3-甲氧基-4-叔丁基苄基溴化物替代2-氯苯甲基氯化物外，重复上述步骤(1)。将得到的化合物与乙酸酐或乙酰氯反应，使在2′-位置乙酰化。在用冰冷却的条件下，在碱如吡啶存在下，于惰性溶剂中将所得的化合物和反应剂如碳酰氯二聚物或碳酰氯三聚物反应，然后在2′-位置上去乙酰化得到6-O-甲基红霉素A9-[O-(3-甲氧基-4-叔丁基苄基)肟]11，12-环碳酸酯。适宜的惰性溶剂丙酮、乙酸乙酯、二氯甲烷、四氢呋喃、乙腈和N，N-二甲基甲酰胺。反应温度在-20℃-50℃的范围内变化，优选在0℃-25℃范围内变化。
本发明中所应用的11-氨基-9-N，11-N-环1，2-亚乙基-9-去氧代-11-脱氧-6-O-甲基红霉素A9-苄胺11-N，12-O-环甲氨酸酯可以例如用下法来制备。
在适宜的酸存在下，将WO92/09014中所描述的11-氨基-9-N，11-N-环1，2-亚乙基-9-去氧代-11-脱氧-6-O-甲基红霉素A9-亚胺11-N，12-O-环甲氨酸酯和还原剂反应，得到11-氨基-9-N，11-N-环1，2-亚乙基-9-去氧代-11-脱氧-6-O-甲基红霉素A9-胺11-N、12-O-环甲氨酸酯，然后在适家的溶剂中将它和甲酸与苯甲醛反应制备11-氨基-9-N，11-N-环1，2-亚乙基-9-去氧代-11-脱氧-6-O-甲基红霉素A9-苄胺-11-N，12-O-环甲氨酸酯。适宜的溶剂包括甲醇、乙醇、N，N-二甲基甲酰胺和它们的混合物。适宜的酸包括有乙酸和甲酸。有用的还原剂有硼氢化钠和硼氰化钠。
根据本发明，这些化合物可以以片剂、胶囊、颗粒剂、粉剂、药粉、锭剂、药膏、油膏、乳剂、悬浮剂、栓剂和可注射溶液的形式口服或非口服方式给药。这些剂型可以通过常规方法，如“日本药典”(第12次修订本)所规定的方法制备。根据患者的健康状况和年龄以及治疗目的来选择适宜的剂型。在制备各种剂型中，可以应用普遍使用的载体(如，晶状体蛋白纤维素、淀粉、乳糖和甘露醇)、结合剂(如，羟丙基纤维素和聚乙烯吡咯烷酮)、润滑剂(如，硬脂酸镁和滑石)、崩解剂(如，羧甲基纤维素钙)及其类似物等等。
本发明的化合物的剂量为，例如，成人口服给药每天2-3分剂时在50-2000mg的范围内，同时根据患者的年龄、体重和健康状况可以作适度变化。
根据本发明，这些化合物显示出对IL-5的产生有强有力的抑制活性，并且可用作为人和动物(包括家畜)体内的IL-5产生的抑制剂。因此，本发明的这些化合物对于由IL-5产生所导致的各种疾病是有效的，即对例如支气管哮喘、过敏性鼻炎、特应性皮炎、药物过敏和嗜伊红性粒细胞肺炎等各种过敏性疾病是有效的。
现在参考实施例对本发明进行更为详细的说明。
实施例1
制备6-O-甲基红霉素A9-[O-(2-氯苯甲基)肟]
将5.33g(7mmol)6-O-甲基红霉素A9-肟溶于80ml二氧杂环己烷，在用冰冷却下，向溶液中加入1.69g(10.5mmol)2-氯苯甲基氯化物和536mg(9.1mmol)的95％的氢氧化钾，再于室温下搅拌2小时。用乙酸乙酯抽提反应混合物，并用饱合氯化钠不溶液洗涤抽提物，再将抽提物于无水硫酸镁上干燥，然后于减压下蒸发来除去溶剂。用硅胶柱色谱法(洗脱液：氯仿/甲醇/氨水＝19∶1∶0.1)纯化残余物，得到3.92g标题化合物，为黄色泡沫状物。熔点：145-147℃
1H核磁共振(NMR)[300兆赫(MHz)，CDCl3]，化学位移(δ)ppm：
1.43(3H，S)，2.33(6H，S)，3.01(3H，S)，3.32(3H，S)，5.10，5.17(2H，ABq，J＝13.8Hz)，7.19-7.44(4H，m)。13C-NMR(75MHz，CDCl3)δppm：
40.3，49.5，50.8，171.1，175.6，
红外光谱(KBr)，cm-1：3431，1734。
实施例2
制备6-O-甲基红霉素A9-[O-(3-甲氧基-4-叔丁基苄基)肟]11，12-环碳酸酯
(1)除用95％氢氧化钾和3-甲氧基-4-叔丁基苄基溴化物以外，重复同实施例1中的反应，从4.96g起始物质(6-O-甲基红霉A9-肟)得到4.25g的6-O-甲基红霉素A9-[O-(3-甲氧基-4-叔丁基苄基)肟]。荷质比(FAB)m/z：939[MH]+
(2)将1.6g(1.70mmol)的以上(1)中得到的化合物溶解于15ml丙酮，向溶液中加入0.32ml(3.41mmol)乙酸酐，然后于室温下搅拌2小时。在减压下蒸发除去溶剂，得到1.8g的2＇-乙酰化的化合物，为泡沫状物。将得到的化合物溶解于20ml二氯甲烷，在用冰冷却的同时加入2.06ml(25.6mmol)吡啶和0.51ml(4.26mmol)三氯甲基氯甲酸酯，然后搅拌2.5小时。向反应混合物加入冰以及碳酸氢钠，再以常规方法对混合物进行后处理。在减压下蒸发以除去溶剂。将残余物于甲醇中加热使在2＇-位置去乙酰化，得到881mg标题化合物。荷质比(FAB)m/z：965[MH]+ 1H-NMR(200MHz，CDCl3)δppm：
2.44(6H，S)，2.85(3H，S)，3.32(3H，S)，3.85(3，S)IR(KBr)cm-1：3457，2972，1815，1741，1461
实施例3
制备11-氨基-9-N，11-N-环1，2-亚乙基-9-去氧代-11-脱氧-6-O-甲基红霉素A9-苄胺11-N，12-O-环甲氨酸酯
(l)将12g(15.1mmol)的11-氨基-9-N，11-N-环1，2-亚乙基-9-去氧代-11-脱氧-6-O-甲基红霉素A9-亚胺11-N，12-O-环甲氨酸酯溶于20ml的乙醇/N，N-二甲基甲酰胺(1/l)的混合溶剂中，向溶液中加入1.72ml(30.0mmol)乙酸和3.78g(60.2mmol)的NaBH3CN，再回流加热4小时。向混合物中加入1.42g(22.6mmol)的NaBH3CN，继续回流加热1.5小时。蒸发除去溶剂，并向残余物中加入2N氢氧化钠水溶液。用乙酸乙酯抽提反应混合物，并依次用水和饱和氯化钠水溶液洗涤有机层。然后将有机层于无水硫酸钠上干燥。在减压下蒸发掉溶剂，从乙酸乙酯/二氯甲烷中再结晶残余物，得到10.9g的11-氨基-9-N，11-N-环1，2-亚乙基-9-去氧代-11-脱氧-6-O-甲基红霉素A9-胺11-N，12-O-环甲氨酸酯。
(2)将1g(1.25 mmol)上述(1)中得到的化合物溶解于5ml乙醇，向溶液中加入0.5ml(4.92mmol)苯甲醛和0.1ml(2.35mmol)的90％甲酸，再回流加热1小时，然后向溶液中分4份加入0.8ml(18.8mmol)的90％的甲酸，并继续加热21小时。反应后，以与实施例(1)中相同的方式对反应混合物进行后处理。以硅胶柱色谱法(氯仿/甲醇/氨水＝20∶1∶0.1)纯化粗产物，并从二氯甲烷/正乙烷中再结晶，得到329mg标题化合物。熔点：141-143℃和210-225℃荷质比(FAB)m/z：890[MH]+ 1H-NMR(300MHz，CDCl3)δppm：
2.29[6H，3′-N(CH3)2]，3.31(3H，6-OCH3)，3.32(3H，3″-OCH3)，4.04(2H，NCH2)，7.18-7.35(5H，苯基)
13C-NMR(75 MHz，CDCl3)δppm：
40.3[3＇-N(CH3)2]，42.1(NCH2)，42.8(NCH2)
49.4[3″-N(CH3)2]，50.9(6-OCH3)，62.1(9-NCH2)，
127.0，128.3，129.0，140.2(苯基)
实施例4
将10g实施例1中制备的化合物，550g乳糖，300g玉米淀粉、100g羧甲基纤维素钙和30g聚乙烯吡咯烷酮充分混合，以常规方法用乙醇将混合物粒化，干燥并分粒。将颗粒和10g硬脂酸镁混合，以常规方法将混合物压片，得到每片重100mg的药片。
实施例5
根据以下的M.Hikida等人，“免疫学通讯”(Immunology Letters)，第34卷，297-302页(1992)中披露的方法检测对鼠体内IL-5产生的作用。
由ATCC购得鼠Th2克隆(D10.G4.1细胞)。通过将1×10-7个8周龄雌C3H/HeN鼠的脾脏细胞悬浮于5ml RPMI-1640培养基制备产生抗原的细胞，并将它和50μg/ml丝裂霉素C(MMC)一起37摄氏度培养30分钟，然后用3份各50ml的RPMI-640洗涤。向含有10％牛血清的RPMI-1640中加入0.5单位白细胞介素2(IL-2)(由Genzyme生产)和5×10-5M的2-巯基乙醇来制备用于组织培养的培养基。将试验化合物溶于二甲基亚砜(DMSO)，并用组织培养基稀释至DMSO终浓度为0.1％和具有不同的试验化合物浓度。
在一个96-孔微量滴定板(由Coming Glass Works制造)的每一孔中加入每孔50μl的浓度为4×10-5个细胞/每毫升D10.G4.1细胞，2×106个细胞/每毫升MMC处理过的产生抗原的细胞、400μg/每毫升作为抗原的伴清蛋白，以及溶于组织培养基的试验化合物。再于5％CO2和37℃的条件下培温48小时。培温结束后，收集培养物的上层液体，离心分离细胞。用ENDOGEN生产的的IL-5酶联免疫吸附实验(ELISA)试剂盒测定上层液体中的IL-5。用50％抑制的浓度(IC50)来表示试验化合物产生IL-5的抑制作用，见于以下表1。
表1试验化合物 IC50(M)实施例1的化合物 2.7×10-7实施例2的化合物 1.2×10-7实施例3的化合物 1.2×10-7罗希红霉素 9.3×10-7红霉素 4.5×10-6
实施例6
向分成5组的ICR雄鼠经口给药实施例1、2和3的化合物。在100mg/kg的剂量水平时未观察到死亡，证明这些化合物有高度的安全性。
Claims (3)
1、一种对白细胞介素5产生的抑制剂，该抑制剂含有作为活性成分的6-O-甲基红霉素A9-[O-(2-氯苯甲基)肟]、6-O-甲基红霉素A-9-[O-(3-甲氧基-4-叔丁基苄基)肟]11，12-环碳酸酯、11-氨基-9-N，11-N-环1，2-亚乙基-9-去氧代-11-脱氧-6-O-甲基红霉素A9-苄胺11-N，12-O-环甲氨酸酯，或其药学上可接受的酸加成盐。
2、6-O-甲基红霉素A9-[O-(2-氯苯甲基)肟]、6-O-甲基红霉素A-9-[O-(3-甲氧基-4-叔丁基苄基)肟]11，12-环碳酸酯、11-氨基-9-N，11-N-环1，2-亚乙基-9-去氧代-11-脱氧-6-O-甲基红霉素A9-苄胺11-N，12-O-环甲氨酸酯，或其药学上可接受的酸加成盐在制备对白细胞介素5的产生的抑制剂中的应用。
3、一种治疗过敏性疾病的方法，该方法包括给药6-O-甲基红霉素A9-[O-(2-氯苯甲基)肟]、6-O-甲基红霉素A-9-[O-(3-甲氧基-4-叔丁基苄基)肟]11，12-环碳酸酯、11-氨基-9-N，11-N-环1，2-亚乙基-9-去氧代-11-脱氧-6-O-甲基红霉素A9-苄胺11-N，12-O-环甲氨酸酯，或其药学上可接受的酸加成盐。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19029294 | 1994-08-12 | ||
| JP190289/94 | 1994-08-12 | ||
| JP19028994 | 1994-08-12 | ||
| JP190292/94 | 1994-08-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1159756A true CN1159756A (zh) | 1997-09-17 |
Family
ID=26505990
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95195373A Pending CN1159756A (zh) | 1994-08-12 | 1995-08-10 | 抑制白细胞介素5的产生的抑制剂 |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0775489A4 (zh) |
| KR (1) | KR970704456A (zh) |
| CN (1) | CN1159756A (zh) |
| AU (1) | AU3192695A (zh) |
| CA (1) | CA2196878A1 (zh) |
| WO (1) | WO1996004920A1 (zh) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HRP20010018A2 (en) | 2001-01-09 | 2002-12-31 | Pliva D D | Novel anti-inflammatory compounds |
| US7157433B2 (en) | 2002-07-08 | 2007-01-02 | Glaxosmithkline Istrazivacki Centar Zagreb | Compounds, compositions as carriers for steroid/nonsteroid anti-inflammatory; antienoplastic and antiviral active molecules |
| WO2004005310A2 (en) | 2002-07-08 | 2004-01-15 | Pliva-Istrazivacki Institut D.O.O. | New compounds, compositions and methods for treatment of inflammatory diseases and conditions |
| ITMI20021726A1 (it) | 2002-08-01 | 2004-02-02 | Zambon Spa | Macrolidi ad attivita' antiinfiammatoria. |
| ITMI20022292A1 (it) | 2002-10-29 | 2004-04-30 | Zambon Spa | 9a-azalidi ad attivita' antiinfiammatoria. |
| HRP20030324A2 (en) | 2003-04-24 | 2005-02-28 | Pliva-Istra�iva�ki institut d.o.o. | Compounds of antiinflammatory effect |
| EP1805202B1 (en) | 2004-10-27 | 2009-12-30 | GlaxoSmithKline istrazivacki centar Zagreb d.o.o. | Conjugates with anti-inflammatory activity |
| ES2317527T3 (es) * | 2005-01-13 | 2009-04-16 | Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. | Decladinosil-macrolidos que presentan actividad anti-inflamatoria. |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5302705A (en) * | 1989-10-07 | 1994-04-12 | Taisho Pharmaceutical Co., Ltd. | 6-O-methylerythromycin a oxime derivatives |
-
1995
- 1995-08-10 CN CN95195373A patent/CN1159756A/zh active Pending
- 1995-08-10 AU AU31926/95A patent/AU3192695A/en not_active Abandoned
- 1995-08-10 EP EP95928005A patent/EP0775489A4/en not_active Withdrawn
- 1995-08-10 CA CA002196878A patent/CA2196878A1/en not_active Abandoned
- 1995-08-10 KR KR1019970700895A patent/KR970704456A/ko not_active Application Discontinuation
- 1995-08-10 WO PCT/JP1995/001592 patent/WO1996004920A1/ja not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0775489A4 (en) | 1998-05-06 |
| AU3192695A (en) | 1996-03-07 |
| KR970704456A (ko) | 1997-09-06 |
| WO1996004920A1 (fr) | 1996-02-22 |
| CA2196878A1 (en) | 1996-02-22 |
| EP0775489A1 (en) | 1997-05-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0719551A2 (en) | Isolating aminoarginine and use to block nitric oxide formation in body | |
| US5158883A (en) | Method of using aminoarginine to block nitric oxide formation in vitro | |
| US20120058963A1 (en) | Macrolides with Anti-Inflammatory Activity | |
| JPS60158197A (ja) | 抗生物質およびその製法 | |
| CN1159756A (zh) | 抑制白细胞介素5的产生的抑制剂 | |
| JPS61251696A (ja) | 新規化合物，その製法及びそれを含む医薬組成物 | |
| EP0136830A2 (en) | Azahomoerythromycin D derivative and intermediates therefor | |
| CN1159757A (zh) | 抑制白细胞介素5产生的抑制剂 | |
| EP1841776B1 (en) | Decladinosyl-macrolides with anti-inflammatory activity | |
| DK173952B1 (da) | Anvendelse af spergualinderivater til fremstilling af lægemidler med immunosuppressiv virkning | |
| EP1651628B1 (en) | Antibiotic compound | |
| MXPA04009009A (es) | Pseudopolimorfos isoestructurales de 9-desoxo-9a-aza-9a-metil-9a-homoeritromicina a. | |
| AU597194B2 (en) | Antibacterial 9-deoxo-9a-allyl and propargyl-9a-aza-9a-homoerythromycin a derivatives | |
| IE57632B1 (en) | Azahomoerythromycin b derivatives and intermediates therefor | |
| FR2502155A1 (fr) | Nouveaux antibiotiques macrolides semi-synthetiques, procede microbiologique pour leur preparation et micro-organisme s'y rapportant, nouveaux produits intermediaires pour leur preparation et compositions pharmaceutiques les contenant | |
| Kupchan | Veratrum alkaloids. XXX. 1 The structure and configuration of zygadenine2 | |
| JPH0853355A (ja) | Ｉｌ−５産生抑制剤 | |
| JP2001081088A (ja) | 新規生理活性物質ｎｋ３０４２４類縁体とそれらの製造法および用途 | |
| KR100333185B1 (ko) | 정제형스트렙토그라민및그의제법 | |
| WO2006097849A1 (en) | 9a-carbamoyl and thiocarbamoyl azalides with anti-inflammatory activity | |
| WO1998018807A1 (fr) | Derives de l'erythromycine a | |
| SK18494A3 (en) | Purificated form of streptogamides, method of its preparing and pharmaceutical compositions containing this form | |
| JPH06507407A (ja) | エリスロマイシン誘導体 | |
| JPH08104638A (ja) | Ｉｌ−５産生抑制剤 | |
| JPH01110694A (ja) | 新規化合物、その製法及びそれを含む医薬組成物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |