NO314040B1 - New derivatives of erythromycin, process for their preparation and their use as medicaments - Google Patents
New derivatives of erythromycin, process for their preparation and their use as medicaments Download PDFInfo
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- NO314040B1 NO314040B1 NO19992859A NO992859A NO314040B1 NO 314040 B1 NO314040 B1 NO 314040B1 NO 19992859 A NO19992859 A NO 19992859A NO 992859 A NO992859 A NO 992859A NO 314040 B1 NO314040 B1 NO 314040B1
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- 239000003814 drug Substances 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 8
- 238000000034 method Methods 0.000 title claims description 7
- 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 description 6
- 150000001875 compounds Chemical class 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 10
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 10
- 229960003276 erythromycin Drugs 0.000 claims description 9
- -1 2-[4-(3-pyridinyl)-1H-imidazol-1-yl]ethoxy Chemical group 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 5
- 150000002084 enol ethers Chemical class 0.000 claims description 5
- 150000002576 ketones Chemical group 0.000 claims description 5
- 125000005975 2-phenylethyloxy group Chemical group 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000000047 product Substances 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 239000012429 reaction media Substances 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000605 extraction Methods 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
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- BIAAQBNMRITRDV-UHFFFAOYSA-N 1-(chloromethoxy)-2-methoxyethane Chemical compound COCCOCCl BIAAQBNMRITRDV-UHFFFAOYSA-N 0.000 description 3
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010041925 Staphylococcal infections Diseases 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 239000002981 blocking agent Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000606768 Haemophilus influenzae Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 229940047650 haemophilus influenzae Drugs 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- TYZYRCHEVXXLSJ-UHFFFAOYSA-N phenylmethoxymethoxymethoxymethylbenzene Chemical compound C=1C=CC=CC=1COCOCOCC1=CC=CC=C1 TYZYRCHEVXXLSJ-UHFFFAOYSA-N 0.000 description 2
- 229910052814 silicon oxide Inorganic materials 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-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
- YFOKBFRTGLSZLU-UHFFFAOYSA-N 3-(1h-imidazol-5-yl)pyridine Chemical compound N1C=NC=C1C1=CC=CN=C1 YFOKBFRTGLSZLU-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 201000004813 Bronchopneumonia Diseases 0.000 description 1
- 206010006500 Brucellosis Diseases 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- 241000606161 Chlamydia Species 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
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 201000000297 Erysipelas Diseases 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 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 1
- 241000589248 Legionella Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- 208000032376 Lung infection Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 241000202934 Mycoplasma pneumoniae Species 0.000 description 1
- 208000005141 Otitis Diseases 0.000 description 1
- 208000035109 Pneumococcal Infections Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000606701 Rickettsia Species 0.000 description 1
- 206010039587 Scarlet Fever Diseases 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 206010056430 Staphylococcal sepsis Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010061372 Streptococcal infection Diseases 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
- 241000223996 Toxoplasma Species 0.000 description 1
- 241000202898 Ureaplasma Species 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- ZJMVWASAULHGOZ-UHFFFAOYSA-N azanium;dichloromethane;propan-2-ol;hydroxide Chemical compound [NH4+].[OH-].ClCCl.CC(C)O ZJMVWASAULHGOZ-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 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
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- XBYOCRCRHQJSIG-UHFFFAOYSA-N chloromethoxybenzene Chemical compound ClCOC1=CC=CC=C1 XBYOCRCRHQJSIG-UHFFFAOYSA-N 0.000 description 1
- FCYRSDMGOLYDHL-UHFFFAOYSA-N chloromethoxyethane Chemical compound CCOCCl FCYRSDMGOLYDHL-UHFFFAOYSA-N 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 208000019258 ear infection Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000006140 methanolysis reaction Methods 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 235000015097 nutrients Nutrition 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001698 pyrogenic effect Effects 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
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent 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
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (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)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicinal Preparation (AREA)
Description
Foreliggende oppfinnelse angår nye derivater av erytromycin, fremgangsmåte for fremstilling av disse og deres anvendelse som medikamenter. The present invention relates to new derivatives of erythromycin, methods for their production and their use as medicines.
I et aspekt angår oppfinnelsen forbindelser med formel (I): som er kjennetegnet ved at R betegner et lineært alkylradikal, inneholdende opptil 18 karbonatomer og eventuelt substituert med én eller flere substituenter utvalgt fra lineær O-alkyl, eventuelt med pyridyl substituert imidazolyl, eller med In one aspect, the invention relates to compounds of formula (I): which are characterized in that R denotes a linear alkyl radical, containing up to 18 carbon atoms and optionally substituted with one or more substituents selected from linear O-alkyl, optionally with pyridyl substituted imidazolyl, or with
hvori Rc, Rd og Rf, identiske eller forskjellige, betegner et lineært, forgrenet alkylradikal inneholdende opptil 4 karbon-at omer,- wherein Rc, Rd and Rf, identical or different, denote a linear, branched alkyl radical containing up to 4 carbon atoms,
eller et (CH2) nAr-radikal hvori n betegner et helt tall fra 0 til 6 og Ar betegner fenyl, or a (CH2) nAr radical in which n denotes an integer from 0 to 6 and Ar denotes phenyl,
så vel som deres addisjonssalter med syrer. as well as their addition salts with acids.
Blant addisjonssaltene med syrer kan det nevnes saltene dannet med de følgende syrer: eddiksyre, propionsyre, trifluoreddiksyré, eplesyre, vinsyre, metansulfonsyre, benzen-sulfonsyre, p-toluensulfonsyre, og spesielt stearinsyre, etylravsyre eller 1aurylsulfonsyre. Among the addition salts with acids, mention may be made of the salts formed with the following acids: acetic acid, propionic acid, trifluoroacetic acid, malic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and especially stearic acid, ethyl succinic acid or 1-aurylsulfonic acid.
Helt spesielt angår foreliggende oppfinnelse forbindelser for hvilke fremstillingen er beskrevet i det etterfølg-ende i den eksperimentelle del, og spesielt produktene fra eksempler 2 og 3. In particular, the present invention concerns compounds for which the preparation is described below in the experimental part, and in particular the products from examples 2 and 3.
Produktene med generell formel (I) har en meget god antibiotisk aktivitet på gram+ - bakterier, slik som stafylo-kokker, streptokokker, pneumokokker. The products with general formula (I) have a very good antibiotic activity on Gram+ bacteria, such as staphylococci, streptococci, pneumococci.
Forbindelsene ifølge oppfinnelsen kan derfor anvendes som medikamenter ved behandling av infeksjoner forårsaket av mikrober, og spesielt av stafylokokkinfeksjoner, slik som stafylokokksepsis, malign stafylokokkinfeksjon i ansikt eller hud, pyodermatitt, septiske eller suppurerende sår, byller, antrax, flegmoner, erysipela og akne, stafylokokkinfeksjoner, slik som akutt primær eller post-influensa-angina, bronko-pneumoni, pulmonell suppurasjon, streptokokkinfeksjoner, slik som akutt angina, otitt, sinusitt, skarlagensfeber, pneumo-kokkinfeksjoner som pneumoni, bronkitt; brucellose, difteri, gonokokkinfeksjon. The compounds according to the invention can therefore be used as drugs in the treatment of infections caused by microbes, and in particular by staphylococcal infections, such as staphylococcal sepsis, malignant staphylococcal infection of the face or skin, pyodermatitis, septic or suppurating wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcal infections , such as acute primary or post-influenza angina, broncho-pneumonia, pulmonary suppuration, streptococcal infections such as acute angina, otitis, sinusitis, scarlet fever, pneumococcal infections such as pneumonia, bronchitis; brucellosis, diphtheria, gonococcal infection.
Produktene ifølge oppfinnelsen er også aktive mot infeksjoner forårsaket av mikrober som Haemophilus influenzae, Rickettsia, Mycoplasma pneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma, eller av mikrober fra slekten Mycobac-terium. The products according to the invention are also active against infections caused by microbes such as Haemophilus influenzae, Rickettsia, Mycoplasma pneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma, or by microbes from the genus Mycobacterium.
Foreliggende oppfinnelse angår derfor .også, i form av medikamenter, og spesielt antibiotikamedikamenter, forbindelser med formel (I) som definert ovenfor, så vel som deres addisjonssalter med farmasøytisk akseptable mineralsyrer eller organiske syrer. The present invention therefore also relates, in the form of drugs, and in particular antibiotic drugs, to compounds of formula (I) as defined above, as well as their addition salts with pharmaceutically acceptable mineral acids or organic acids.
Mer spesielt angår oppfinnelsen, i form av medikamenter, og spesielt antibiotikamedikamenter, forbindelser ifølge eksempler 2 eller 3 og deres farmasøytisk akseptable salter. More particularly, the invention relates, in the form of drugs, and especially antibiotic drugs, to compounds according to examples 2 or 3 and their pharmaceutically acceptable salts.
Oppfinnelsen angår også farmasøytiske preparater inneholdende minst ett av medikamentene definert ovenfor som aktiv ingrediens. The invention also relates to pharmaceutical preparations containing at least one of the drugs defined above as active ingredient.
Disse preparater kan administreres buckalt, rektalt, parenteralt eller lokalt som en topisk applisering på huden og slimhinnemembraner, men den foretrukne administreringsmåte er buckalt. These preparations can be administered buccally, rectally, parenterally or locally as a topical application to the skin and mucous membranes, but the preferred route of administration is buccally.
Preparatene kan være faste eller flytende og foreligge i de farmasøytiske former som i dag anvendes i human medisin, slik som for eksempel enkle eller sukkerbelagte tab-letter, kapsler, granuler, suppositorier, injiserbare preparater, salver, kremer og geler; de fremstilles i overensstemmelse med vanlige metoder. Den aktive ingrediens, eller ingredienser, kan inkorporeres sammen med eksipienser som vanligvis anvendes i disse farmasøytiske preparater, slik som talkum, gummi arabicum, laktose, stivelse, magnesiumstearat, kakaosmør, vandige- eller ikke-vandige vehikler, fettstoffer av animalsk eller vegetabilsk opprinnelse, parafinderivater, glykoler, forskjellige fuktemidler, dispergeringsmidler eller emulgeringsmidler, konserveringsmidler. The preparations can be solid or liquid and present in the pharmaceutical forms that are currently used in human medicine, such as, for example, simple or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams and gels; they are produced in accordance with common methods. The active ingredient, or ingredients, can be incorporated together with excipients commonly used in these pharmaceutical preparations, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersing agents or emulsifying agents, preservatives.
Preparatene kan også foreligge i form av pulver ment å bli oppløst direkte i en egnet vehikkel, for eksempel pyro-gent, sterilt vann. The preparations can also be in the form of powder intended to be dissolved directly in a suitable vehicle, for example pyrogenic, sterile water.
Den administrerte dose er variabel i overensstemmelse med sykdommen som behandles, den aktuelle pasient, admini-streringsmåten og den anvendte forbindelse. Dosen kan for eksempel være mellom 50 mg og 300 mg pr. dag oralt av produktet ifølge eksempel 2, for en voksen person. The dose administered is variable in accordance with the disease being treated, the patient in question, the method of administration and the compound used. The dose can, for example, be between 50 mg and 300 mg per day orally of the product according to example 2, for an adult.
Foreliggende oppfinnelse angår også en fremgangsmåte for fremstilling av forbindelser med formel (I), kjennetegnet ved at en forbindelse med formel (II): The present invention also relates to a method for producing compounds of formula (I), characterized in that a compound of formula (II):
hvori Z' betegner resten av en karboksylsyre inneholdende opptil 12 karbonatomer, omsettes med et blokkeringsmiddel for ketonfunksjonene i posisjon 3 i form av en enoleter eller enolester, for å oppnå en forbindelse med formel (III): hvori E betegner resten av en enoleter eller en enolester og Z<1> har betydningen angitt ovenfor, som omsettes med en forbindelse med formel (IV): hvori Hal betegner et halogenatom, for å oppnå en tilsvarende forbindelse med formel (V): som omsettes, hvis ønskelig, med et middel som frigjør ketonfunksjonen i posisjon 3, og/eller omsettes med et middel som frigjør hydroksylfunksjonen i posisjon 2', for å oppnå en tilsvarende forbindelse med formel (I): in which Z' denotes the residue of a carboxylic acid containing up to 12 carbon atoms, is reacted with a blocking agent for the ketone functions in position 3 in the form of an enol ether or enol ester, to obtain a compound of formula (III): in which E denotes the residue of an enol ether or a enol ester and Z<1> has the meaning given above, which is reacted with a compound of formula (IV): wherein Hal represents a halogen atom, to obtain a corresponding compound of formula (V): which is reacted, if desired, with an agent which releases the ketone function in position 3, and/or is reacted with an agent that releases the hydroxyl function in position 2', to obtain a corresponding compound of formula (I):
hvori R og Z har betydningene angitt ovenfor. wherein R and Z have the meanings given above.
Forbindelsene med formel (II), anvendt som startfor-bindelser, er kjente forbindelser som fremstilles i overensstemmelse med prosessen beskrevet i EP 4 87411 eller i WO 9321199. The compounds of formula (II), used as starting compounds, are known compounds which are prepared in accordance with the process described in EP 4 87411 or in WO 9321199.
Som et blokkeringsmiddel for ketonfunksjonen i posisjon 3, i form av en enoleter, kan det anvendes en halogen-metyleter og spesielt en klormetyletyleter, slik som for eksempel MEM-klorid eller 2-metoksyetoksymetylklorid eller også SEM-klorid eller 2-(trimetylsilyl) etoksymetylklorid; som et blokkeringsmiddel av ketofunksjonen i form av en enolester kan det også anvendes benzyloksymetyleter (BOM), As a blocking agent for the ketone function in position 3, in the form of an enol ether, a halogen methyl ether and especially a chloromethyl ethyl ether can be used, such as, for example, MEM chloride or 2-methoxyethoxymethyl chloride or also SEM chloride or 2-(trimethylsilyl) ethoxymethyl chloride ; as a blocking agent of the keto function in the form of an enol ester, benzyloxymethyl ether (BOM) can also be used,
- Hal betegner fortrinnsvis et kloratom, - Hal preferably denotes a chlorine atom,
- Z' betegner fortrinnsvis et acetylradikal, - Z' preferably denotes an acetyl radical,
- middelet for frigjøring av ketofunksjonen i posisjon 3 eller - frigjøringen av hydroksylfunksjonen i posisjon 2', utføres ved metanolyse. - the agent for releasing the keto function in position 3 or - the release of the hydroxyl function in position 2', is carried out by methanolysis.
Forbindelsene med formel (III) og (V) , anvendt under fremstillingsprosessen, er nye og er i seg selv et mål for foreliggende oppfinnelse. The compounds of formula (III) and (V), used during the manufacturing process, are new and are in themselves a goal of the present invention.
De følgende eksempler illustrerer oppfinnelsen, imidlertid uten å begrense den. The following examples illustrate the invention, however, without limiting it.
Eksempel 1: 11,12-dideoksy-3-de[(2,6-dideoksy-3-C-metyl-3-0-metyl-alfa-L-riboheksopyranosyl)oksy]-6-0-metyl-3-okso-12,11-[oksykarbonyl[[(2-metoksyetoksy)metyl]imino]]-erytromycin. Example 1: 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyl)oxy]-6-0-methyl-3-oxo -12,11-[oxycarbonyl[[(2-methoxyethoxy)methyl]imino]]-erythromycin.
Trinn A: 2,3-didehydro-11,12-dideoksy-3-0-de(2,6-dideoksy-3-C-metyl-3-0-metyl-alfa-L-riboheksopyranosyl)-6-0-llmetyl-11,12-(iminokarbonyloksy)-3-0-[[(2-trimetylsilyl)-etoksy]metyl]-erytromycin 2'-acetat. Step A: 2,3-didehydro-11,12-dideoxy-3-0-de(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyl)-6-0- 11-methyl-11,12-(iminocarbonyloxy)-3-0-[[(2-trimethylsilyl)-ethoxy]methyl]-erythromycin 2'-acetate.
En oppløsning inneholdende 50%; 6 ml DMF, 0,654 g 11,12-dideoksy-3-de[(2,6-dideoksy-3-C-metyl-alfa-L-ribohek-sopyranosyl) oksy]-6-0-metyl-3-okso-11,12-(iminokarbonyloksy)-erytromycin 2'-acetat og 0,57 g natriumhydrid i olje, omrøres i 10 minutter. Reaksjonsblandingen oppvarmes til 40°C. Etter avkjøling til -5 °C tilsettes dråpevis 0,177 ul ClSEM i 5 ml DMF. Omrøringen utføres ved 0 °C i 30 minutter (pH 9) . Mediet helles over på is, etterfulgt av ekstraksjon med etylacetat, vask med vann, tørking, filtrering og konsentrering. Det oppnås 0,785 g produkt som oppløses i isopropyleter. Produktet krystalliseres, etterfulgt av separasjon, vask og tørking ved 70 °C. Det oppnås det søkte produkt med et smeltepunkt på A solution containing 50%; 6 ml DMF, 0.654 g 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-alpha-L-ribohex-sopyranosyl)oxy]-6-0-methyl-3-oxo- 11,12-(iminocarbonyloxy)-erythromycin 2'-acetate and 0.57 g of sodium hydride in oil are stirred for 10 minutes. The reaction mixture is heated to 40°C. After cooling to -5 °C, 0.177 ul ClSEM in 5 ml DMF is added dropwise. The stirring is carried out at 0 °C for 30 minutes (pH 9). The medium is poured onto ice, followed by extraction with ethyl acetate, washing with water, drying, filtration and concentration. 0.785 g of product is obtained, which is dissolved in isopropyl ether. The product is crystallized, followed by separation, washing and drying at 70 °C. The desired product with a melting point is obtained
100 °C. 100 °C.
NMR CDC13 ppm. NMR CDCl 3 ppm.
Mulig struktur: Possible structure:
0.07 (s) : Si (Me) 3; 0.87 (t) : CH3-CH2; -1.03: CH2-Si; I. 10 (d)-1.12 (d)-1.14 (d)-1.24 (d) CH3; 1.24 (s)-1.43 (s): 6 og 12 CH3; 1.95 (s): 2-Me; 2.08 (s): OAC; 2.27 (s): N(Me)2; 2.47 (m) : H8; 2.68. (m) : H'3; 2.82 (s) : 6-OMe; 3.04 (q) : H10; 3.31 (dq): H4; 3.48 (m): H'5; 3.73 (d, J = 2.5): H5; 3.80-3.92: OCH2; 3.89 (s) : Hli; 4.69 (d) : Hi; 4.78 (dd): H2; 4.99 (d)-5.04 (d) : OCH20; 5.29 (dd): Hi3. 0.07 (s) : Si (Me) 3; 0.87 (t) : CH3-CH2; -1.03: CH2-Si; I. 10 (d)-1.12 (d)-1.14 (d)-1.24 (d) CH3; 1.24 (s)-1.43 (s): 6 and 12 CH3; 1.95 (s): 2-Me; 2.08 (s): OAC; 2.27 (s): N(Me)2; 2.47 (m) : H8; 2.68. (m) : H'3; 2.82 (s) : 6-OMe; 3.04 (q) : H10; 3.31 (dq): H4; 3.48 (m): H'5; 3.73 (d, J = 2.5): H5; 3.80-3.92: OCH 2 ; 3.89 (s) : Hli; 4.69 (d) : Hi; 4.78 (dd): H2; 4.99 (d)-5.04 (d) : OCH 2 O; 5.29 (dd): Hi3.
Trinn B: 12,ll-dideoksy-3-de[(2,6-dideoksy-3-C-metyl-3-O-metyl-alfa-L-riboheksopyranosyl)oksy]-6-O-metyl-3-okso-II, 12-(oksykarbonyl[[(metoksymetyl)]imino]erytromycin). Step B: 12,11-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl)oxy]-6-O-methyl-3-oxo -II, 12-(oxycarbonyl[[(methoxymethyl)]imino]erythromycin).
0,150 g av en blanding inneholdende 0,150 g av produktet fra trinn A oppløses i 1,5 ml DMF. 0.150 g of a mixture containing 0.150 g of the product from step A is dissolved in 1.5 ml of DMF.
Reaksjonsblåndingen avkjøles til +10 °C og 50%; 14 mg natriumhydrid i olje tilsettes. Reaksjonsblåndingen avkjøles til 0 °C og tilsettes 26 ul MEM klorid oppløst i 0,5 ml DMF. Omrøringen utføres i 25 minutter ved 0 °C, etterfulgt av at blandingen helles over på is, konsentreres, oppløses i etylacetat, vaskes med vann, ekstraheres med etylacetat, tørkes, filtreres og konsentreres. Det oppnås et produkt som fortynnes i 4 ml metanol. Løsningen tilbakeløpskokes i 2 timer og av-kjøles deretter til omgivelsestemperatur. 1 ml av en 6,5 M oppløsning av saltsyre i metanol tilsettes. Metanolen avdampes, etterfulgt av at produktet oppløses i etylacetat, vaskes med ammoniumhydroksid, fortynnes, ekstraheres med etylacetat, tørkes, filtreres og konsentreres. Det oppnås 0,11 g produkt som krystalliserer. Etter rensing oppnås det søkte råprodukt. Smeltepunkt = 238-240 °C. The reaction mixture is cooled to +10 °C and 50%; 14 mg of sodium hydride in oil is added. The reaction mixture is cooled to 0 °C and 26 ul of MEM chloride dissolved in 0.5 ml of DMF is added. The stirring is carried out for 25 minutes at 0 °C, followed by the mixture being poured onto ice, concentrated, dissolved in ethyl acetate, washed with water, extracted with ethyl acetate, dried, filtered and concentrated. A product is obtained which is diluted in 4 ml of methanol. The solution is refluxed for 2 hours and then cooled to ambient temperature. 1 ml of a 6.5 M solution of hydrochloric acid in methanol is added. The methanol is evaporated, followed by the product being dissolved in ethyl acetate, washed with ammonium hydroxide, diluted, extracted with ethyl acetate, dried, filtered and concentrated. 0.11 g of product is obtained which crystallizes. After purification, the desired crude product is obtained. Melting point = 238-240 °C.
NMR CDC13 ppm NMR CDCl 3 ppm
0.88 (t): CH3-CH2; 1.03 (d): 10-Me; 1.16 (d): 8Me; 1.25 (d): 5'Me; 1.32 (d): 4Me; 1.38 (d): 2Me; 1.34 og 1.51: 0 og 12 Me; -1.57 og 1.38 CH2 i posisjon 14; -1.60 og 1.84: CH2 i posisjon 7; -1.67 og 1.25: CH2 i posisjon 4'; 2.27 (s): N(Me)2; 0.88 (t): CH3-CH2; 1.03 (d): 10-Me; 1.16 (d): 8Me; 1.25 (d): 5'Me; 1.32 (d): 4Me; 1.38 (d): 2Me; 1.34 and 1.51: 0 and 12 Me; -1.57 and 1.38 CH2 in position 14; -1.60 and 1.84: CH2 in position 7; -1.67 and 1.25: CH2 in position 4'; 2.27 (s): N(Me)2;
2.44 (m) : H'3; 2.62 (ra): HB; 2.67 (s) : 6-OMe; 3.09 (ql) : Hi0; 3.12 (m) : H4; 3.18 (dd): H'2; 3.36 (s) : OMe; -3.47: OH; 3.86 (q) : H2; 3.87 (s) : Hu; 4.24 (d) : H<»>x; 4.93 (d)-5.27 (d) : NCH20; 5.05 (dd) : H13. 2.44 (m) : H'3; 2.62 (ra): HB; 2.67 (s) : 6-OMe; 3.09 (ql) : Hi0; 3.12 (m) : H4; 3.18 (dd): H'2; 3.36 (s) : OMe; -3.47: OH; 3.86 (q) : H2; 3.87 (s) : Hu; 4.24 (d) : H<»>x; 4.93 (d)-5.27 (d) : NCH20; 5.05 (dd) : H13.
Eksempel 2: Example 2:
11,12-dideoksy-3-de[(2,6-dideoksy-3-C-metyl-3-O-metyl-alfa-L-riboheksopyranosyl)oksy]-6-0-metyl-3-okso-12,11-[oksykarbonyl[[[2-[4-(3-pyridinyl)-lH-imidiazol-l-yl]etoksy]-metyl]imino]]erytromycin. 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl)oxy]-6-0-methyl-3-oxo-12, 11-[oxycarbonyl[[[2-[4-(3-pyridinyl)-1H-imidiazol-1-yl]ethoxy]-methyl]imino]]erythromycin.
Trinn A: 2,3-didehydro-ll,12-dideoksy-3-0-de(2,6-dideoksy-3-C-metyl-3-O-metyl-alfa-L-riboheksopyranosyl)-6-0-metyl-12,11-[oksykarbonyl[[(2-brometoksy)metyl]imino]]-3-0-[[2-(trimetylsilyl)etoksy]metyl]-erytromycin-2'-acetat. Step A: 2,3-didehydro-11,12-dideoxy-3-0-de(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl)-6-0- methyl 12,11-[oxycarbonyl[[(2-bromomethoxy)methyl]imino]]-3-0-[[2-(trimethylsilyl)ethoxy]methyl]-erythromycin-2'-acetate.
50%; 0,278 g natriumhydrid i olje omrøres i 2 ml THF. Blandingen avkjøles til 0 °C og tilsettes 510 mg av produktet fra trinn A, eksempel 1, oppløst i 8 ml THF. Reaksjonsmediet avkjøles til romtemperatur og tilsettes 100 ul ClCH2OCH2CH2Br oppløst i 4 ml THF. Reaksjonsmediet avkjøles til 0 °C, helles over på is, ekstraheres med etylacetat, vaskes med saltvann, tørkes, filtreres og konsentreres. Det oppnås 0,709 g av det søkte produkt. 50%; 0.278 g of sodium hydride in oil is stirred in 2 ml of THF. The mixture is cooled to 0 °C and 510 mg of the product from step A, example 1, dissolved in 8 ml of THF, is added. The reaction medium is cooled to room temperature and 100 ul of ClCH2OCH2CH2Br dissolved in 4 ml of THF is added. The reaction medium is cooled to 0 °C, poured onto ice, extracted with ethyl acetate, washed with salt water, dried, filtered and concentrated. 0.709 g of the desired product is obtained.
Trinn B: 2,3-didehydro-11,12-dideoksy-3-0-de(2,6-dideoksy-3-C-metyl-3-O-metyl-alfa-L-riboheksopyranosyl)-6-0-metyl-12,11-[oksykarbonyl[[[2-[4-(3-pyridinyl)-lH-imidazol-1-yl]etoksy]metyl]imino]]-3-0-[[2-(trimetylsilyl)etoksy]metyl]-erytromycin-2<1->acetat. Step B: 2,3-didehydro-11,12-dideoxy-3-0-de(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl)-6-0- methyl-12,11-[oxycarbonyl[[[2-[4-(3-pyridinyl)-1H-imidazol-1-yl]ethoxy]methyl]imino]]-3-0-[[2-(trimethylsilyl)ethoxy ]methyl]-erythromycin-2<1->acetate.
En oppløsning av 3 ml DMF og 0,377 g 4-(3-pyridinyl)-lH-imidazol tilsettes til en 50 % oppløsning av' 2 ml DMF og 0,162 g natriumhydrid i olje. Omrøring utføres i 15 minutter og oppløsningen tilsettes 0,709 g av produktet fra trinn A, eksempel 2, oppløst i 8 ml DMF. A solution of 3 ml of DMF and 0.377 g of 4-(3-pyridinyl)-1H-imidazole is added to a 50% solution of 2 ml of DMF and 0.162 g of sodium hydride in oil. Stirring is carried out for 15 minutes and to the solution is added 0.709 g of the product from step A, example 2, dissolved in 8 ml of DMF.
Omrøring utføres i 3 timer ved omgivelsestempeatur og i 15 minutter ved 60 °C. Reaksjonsmediet helles over på is, ekstraheres med etylacetat, vaskes med saltvann og deretter vann, tørkes, filtreres og konsentreres. Det oppnås 0,644 g av produktet. Stirring is carried out for 3 hours at ambient temperature and for 15 minutes at 60 °C. The reaction medium is poured onto ice, extracted with ethyl acetate, washed with brine and then water, dried, filtered and concentrated. 0.644 g of the product is obtained.
Trinn C: 11,12-dideoksy-3-de[(2,6-dideoksy-3-C-metyl-3-O-raetyl-alfa-L-riboheksopyranosyl)oksy]-6-0-metyl-3-okso-12,11-[oksykarbonyl[[[2-[4-(3-pyridinyl) lH-imidazol-l-yl]-etoksy]metyl]imino]]-erytromycin. Step C: 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-O-raethyl-alpha-L-ribohexopyranosyl)oxy]-6-0-methyl-3-oxo -12,11-[oxycarbonyl[[[2-[4-(3-pyridinyl)1H-imidazol-1-yl]-ethoxy]methyl]imino]]-erythromycin.
En oppløsning inneholdende 0, 644 g av produktet fra trinn B og 8 ml metanol omrøres i 48 timer ved omgivelsestemperatur, og deretter fortynnes 0,565 g av det oppnådde produkt i 5 ml etylacetat. Reaksjonsmediet avkjøles til 0 °C og tilsettes 2,5 ml av en 2,IN oppløsning av saltsyre i metanol, og blandingen hensettes for oppvarming til omgivelsestemperatur. Blandingen omrøres ved omgivelsestemperatur i 1 time. Løsningsmidlene avdampes, resten fortynnes med vann, helles over i en mettet, vandig oppløsning av natriumkarbonat, ekstraheres med etylacetat, vaskes med vann, tørkes, filtreres og konsentreres. Det oppnås 0,508 g av en olje som kromatogra-feres på siliciumoksid, CH2Cl2/MeOH (93-7) og deretter CH2Cl2/MeOH/NH4OH (93-7-0,5). De homogene fraksjoner konsentreres ved hjelp av TLC, etterfulgt av oppløsning i etylacetat, vask med ammoniumhydroksid, fortynning, ekstraksjon med etylacetat, ekstraksjon med vann, tørking, filtrering og konsentrering. Det oppnås 66 mg av det søkte produkt. A solution containing 0.644 g of the product from step B and 8 ml of methanol is stirred for 48 hours at ambient temperature, and then 0.565 g of the product obtained is diluted in 5 ml of ethyl acetate. The reaction medium is cooled to 0 °C and 2.5 ml of a 2.1N solution of hydrochloric acid in methanol is added, and the mixture is allowed to warm to ambient temperature. The mixture is stirred at ambient temperature for 1 hour. The solvents are evaporated, the residue is diluted with water, poured into a saturated aqueous solution of sodium carbonate, extracted with ethyl acetate, washed with water, dried, filtered and concentrated. 0.508 g of an oil is obtained which is chromatographed on silicon oxide, CH2Cl2/MeOH (93-7) and then CH2Cl2/MeOH/NH4OH (93-7-0.5). The homogeneous fractions are concentrated by TLC, followed by dissolution in ethyl acetate, washing with ammonium hydroxide, dilution, extraction with ethyl acetate, extraction with water, drying, filtration and concentration. 66 mg of the desired product is obtained.
NMR CDCI3<p>pm NMR CDCl 3<p>pm
0.85 (t): CH3-CH2; 1.00 (d) - 1.15 (d) - 1.25 (d) 1.31 (d) - 1.40 (d): CH3-CH; 1.34 .og 1.51; 6 og . 12 Me; 2.26 (s): N(Me)2; 2.44 (m): H'4; 2.60 (m): Hg; 2.68 (s): 6-OMe; 3.03 (m) : H4<!>og H1Q; 3.18 (dd): H'2; 3.55 (m): H'5; 3.76 (s) - 3.92 (m) -4.38 (m): 0CH2CH2N; 3.87 (s) : H1]L; 3.83 (q) : H2; 4.24 (d) : <H>5; 4.31 (d) : H^; 4.96 (dd): H13; 4.99 (d) - 5.37 (d) : NCH20. 7.36 (d) - 7.54 (d) : H imidazol; 7^30 (ddd) : H5; 8.08 (dt) : H4 - 8.45 (dd): Hg - 8.95 (ddd): pyridin<1>. 0.85 (t): CH3-CH2; 1.00 (d) - 1.15 (d) - 1.25 (d) 1.31 (d) - 1.40 (d): CH3-CH; 1.34 .and 1.51; 6 and . 12 Me; 2.26 (s): N(Me)2; 2.44 (m): H'4; 2.60 (m): Hg; 2.68 (s): 6-OMe; 3.03 (m) : H4<!>and H1Q; 3.18 (dd): H'2; 3.55 (m): H'5; 3.76 (s) - 3.92 (m) -4.38 (m): 0CH2CH2N; 3.87 (s) : H1]L; 3.83 (q) : H2; 4.24 (d) : <H>5; 4.31 (d) : H^; 4.96 (dd): H13; 4.99 (d) - 5.37 (d) : NCH20. 7.36 (d) - 7.54 (d) : H imidazole; 7^30 (ddd) : H5; 8.08 (dt) : H4 - 8.45 (dd): Hg - 8.95 (ddd): pyridine<1>.
Eksempel 3: Example 3:
11,12-dideoksy-3-de[(2,6-dideoksy-3-C-metyl-3-0-metyl-alfa-L-riboheksopyranosyl)oksy]-6-0-metyl-3-okso-12,11-[oksykarbonyl[[(2-fenyletoksy)metyl]imino]]-erytromycin. 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyl)oxy]-6-0-methyl-3-oxo-12, 11-[oxycarbonyl[[(2-phenylethoxy)methyl]imino]]-erythromycin.
Trinn A: 2,3-didehydro-ll,12-dideoksy-3-0-de(2,6-dideoksy-3-C-metyl-3-O-metyl-alfa-L-riboheksopyranosyl)-6-O-metyl-12,11- [oksykarbonyl [ [ (2 - f enyl etoksy) metyl] imino] ] -3-0-[[2-(trimetylsilyl)etoksy]metyl]-erytromycin-2<1->acetat. Step A: 2,3-didehydro-11,12-dideoxy-3-0-de(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl)-6-O- methyl-12,11- [oxycarbonyl [ [ (2-phenylethoxy) methyl] imino] ] -3-0-[[2-(trimethylsilyl)ethoxy]methyl]-erythromycin-2<1->acetate.
En 50 % oppløsning av 18 mg natriumhydrid i olje tilsettes ved 10 °C til en oppløsning inneholdende 2 ml DMF og 203 mg av det oppnådde produkt i trinn 3, eksempel 1. A 50% solution of 18 mg of sodium hydride in oil is added at 10 °C to a solution containing 2 ml of DMF and 203 mg of the product obtained in step 3, example 1.
Blandingen omrøres i 15 minutter, avkjøles til -5 °C og tilsettes 46 ul klormetylfenyleter oppløst i 0,5 ml DMF. The mixture is stirred for 15 minutes, cooled to -5 °C and 46 µl of chloromethylphenyl ether dissolved in 0.5 ml of DMF is added.
DMF avdampes, resten oppløses i etylacetat, vaskes med vann, tørkes, filtreres og konsentreres. Det oppnås 0.277 g av det søkte produkt. DMF is evaporated, the residue is dissolved in ethyl acetate, washed with water, dried, filtered and concentrated. 0.277 g of the desired product is obtained.
Trinn B: 11,12-dideoksy-3-de[(2,6-dideoksy-3-C-metyl-3-0-metyl-alfa-L-ri bohe ksopyrano sy1)oksy]-6-0-mety1-3 -okso-12,11-[oksykarbonyl[[(2-fenyletoksy)metyl]imino]]-erytromycin. Step B: 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosy1)oxy]-6-0-methyl- 3-oxo-12,11-[oxycarbonyl[[(2-phenylethoxy)methyl]imino]]-erythromycin.
0,227 g av produktet fra trinn A tilsettes til 0.227 g of the product from step A is added
0,33 ml av en 0,19N oppløsning av saltsyre i etylacetat av-kjølt til + 5 °C. Reaksjonsmediet hensettes for oppvarming til omgivelsestemperatur og omrøres i 2 timer. Etter avkjøling til 0 °C tilsettes vann, pH justeres til 9-10 med en konsen-trert oppløsning av ammoniumhydroksid, etterfulgt av ekstraksjon med etylacetat, vask med vann, tørking, filtrering og konsentre- ring. Det oppnås 0,201 g produkt som fortynnes i 2,5 ml metanol. Blandingen tilbakeløpskokes i 2,5 timer. Metanolen avdampes og det oppnås 0,188 mg produkt som kromato-graferes på silisiumoksid under eluering med metylenklorid-isopropanol-ammoniumhydroksid (95-5-0,5) . Etter konsentrering oppløses resten i metylenklorid, tilsettes en dråpe konsen-trert ammoniumhydroksid, omrøres, tørkes, filtreres og konsentreres. Det oppnås 55 mg produkt som separeres og tørkes ved 80 °C. Det oppnås 35 mg av det søkte produkt. Smeltepunkt 210-212 °C. 0.33 ml of a 0.19N solution of hydrochloric acid in ethyl acetate cooled to + 5 °C. The reaction medium is allowed to warm to ambient temperature and stirred for 2 hours. After cooling to 0 °C, water is added, the pH is adjusted to 9-10 with a concentrated solution of ammonium hydroxide, followed by extraction with ethyl acetate, washing with water, drying, filtration and concentration. 0.201 g of product is obtained, which is diluted in 2.5 ml of methanol. The mixture is refluxed for 2.5 hours. The methanol is evaporated and 0.188 mg of product is obtained which is chromatographed on silicon oxide eluting with methylene chloride-isopropanol-ammonium hydroxide (95-5-0.5). After concentration, the residue is dissolved in methylene chloride, a drop of concentrated ammonium hydroxide is added, stirred, dried, filtered and concentrated. 55 mg of product is obtained, which is separated and dried at 80 °C. 35 mg of the desired product is obtained. Melting point 210-212 °C.
NMR CDC13 p<p>m NMR CDCl 3 p<p>m
0.88 (t): CH3-CH2; 1.02 (d) - 1.15 (d) - 1.25 (d) - 1.31 (d) 0.88 (t): CH3-CH2; 1.02 (d) - 1.15 (d) - 1.25 (d) - 1.31 (d)
- 1.39 (d): CH3-CH; 1.33-1.51: 6 og 12 Me; 2.27 (s): N(Me)2; 2.45 (m): H'3; 2.62 (m): Hg; 2.70 (s): 6-0Me; 2.91 (m): CH2*; 3.08 (ql): HlQ; _3.15 (rn) : H4; 3.18 (dd): H'2; „3.58 (m) : H'5; „3.58 og. 3.77: 0<CH>2<;> 3.87 (q) : H2; 3.91 (s) : H11(- 4.25 (d) : H5; 4.32 (d) : H^; 5.00 (d) - 5.33 (d) : NCH20; 5.05 - 1.39 (d): CH3-CH; 1.33-1.51: 6 and 12 Me; 2.27 (s): N(Me)2; 2.45 (m): H'3; 2.62 (m): Hg; 2.70 (s): 6-0Me; 2.91 (m): CH2*; 3.08 (ql): HlQ; _3.15 (rn) : H4; 3.18 (dd): H'2; „3.58 (m) : H'5; „3.58 and. 3.77: 0<CH>2<;> 3.87 (q) : H2; 3.91 (s) : H11(- 4.25 (d) : H5; 4.32 (d) : H^; 5.00 (d) - 5.33 (d) : NCH20; 5.05
(dd): <H>13; 7.13 to 7.30: fenyl, eter (_0.3 mol ). (dd): <H>13; 7.13 to 7.30: phenyl, ether (_0.3 mol ).
Ved å gå frem som angitt ovenfor ble det følgende produkt fremstilt: By proceeding as indicated above, the following product was produced:
Eksempel 4: Example 4:
11,12-dideoksy-3-de((2,6-dideoksy-3-C-metyl-3-0-metyl-alfa-L-riboheksopyranosyl)oksy)6-0-metyl-3-okso-12,11-(oksykarbonyl(((2-(trimetylsilyl)etoksy)metyl)imino))-erytromycin. 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyl)oxy)6-0-methyl-3-oxo-12,11 -(oxycarbonyl(((2-(trimethylsilyl)ethoxy)methyl)imino))-erythromycin.
Sm.pkt. = 414-143 °C; Rf = 0,38 (AcOEt-TEA 95-5). Sm.pt. = 414-143 °C; Rf = 0.38 (AcOEt-TEA 95-5).
Eksempel på farmasøytisk preparat Example of a pharmaceutical preparation
Det ble fremstilt et preparat inneholdende: A preparation containing:
Produkt fra eksempel 2: 150 mg Eksipiens s.q.f.: lg Beskrivelse av eksipiens: stivelse, talkum, magnesiumstearat. Farmakologisk undersøkelse av produktene ifølge oppfinnelsen Metode for fortynninger i flytende medium. Product from example 2: 150 mg Excipients s.q.f.: lg Description of excipients: starch, talc, magnesium stearate. Pharmacological examination of the products according to the invention Method for dilutions in liquid medium.
Det prepareres en serie rør som inneholder den samme mengde sterilt næringsmedium. Økende mengder av produktet som skal undersøkes fordeles i hvert rør, og hvert rør tilsåes med en bakteriestamme. Etter inkubasjon i 24 timer i et varmekam-mer ved 37 °C evalueres vekstinhiberingen ved hjelp av trans-illuminasjon som tillater bestemmelse av de minimale inhi-bitoriske konsentrasjoner (M.I.C.) uttrykt i mg/cm<3>. A series of tubes containing the same amount of sterile nutrient medium is prepared. Increasing amounts of the product to be examined are distributed in each tube, and each tube is inoculated with a strain of bacteria. After incubation for 24 hours in a heating chamber at 37 °C, the growth inhibition is evaluated by means of trans-illumination which allows the determination of the minimal inhibitory concentrations (M.I.C.) expressed in mg/cm<3>.
De følgende resultater ble oppnådd: The following results were obtained:
Produktet fra eksempel 1 har dessuten vist nyttig aktivitet på følgende gram-negative bakteriestammer: Haemophilus influensa 351HT3, 351CB12, 351CA1 og 351GR6. The product from example 1 has also shown useful activity on the following gram-negative bacterial strains: Haemophilus influenzae 351HT3, 351CB12, 351CA1 and 351GR6.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9615271A FR2757168B1 (en) | 1996-12-12 | 1996-12-12 | NOVEL ERYTHROMYCIN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS |
| PCT/FR1997/002254 WO1998025942A1 (en) | 1996-12-12 | 1997-12-10 | Novel erythromycin derivatives, method for preparing them and their use as medicine |
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| TR200102129T2 (en) * | 1998-12-10 | 2002-01-21 | Pfizer Products Inc. | Carbamate and carbazate ketolid antibiotics. |
| CZ20012675A3 (en) | 1999-01-27 | 2002-04-17 | Pfizer Products Inc. | Ketolide antibiotics |
| US6395710B1 (en) * | 1999-04-16 | 2002-05-28 | Kosan Biosciences, Inc. | Macrolide antiinfective agents |
| WO2000071557A1 (en) | 1999-05-24 | 2000-11-30 | Pfizer Products Inc. | 13-methyl-erythromycin derivatives |
| US6472372B1 (en) * | 2000-12-06 | 2002-10-29 | Ortho-Mcneil Pharmaceuticals, Inc. | 6-O-Carbamoyl ketolide antibacterials |
| DK200201957A (en) | 2002-12-20 | 2003-01-20 | Alpharma Aps | 10-substituted erythromycin ketolides and methods of making |
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| IL99995A (en) * | 1990-11-21 | 1997-11-20 | Roussel Uclaf | Erythromycin derivatives, their preparation and pharmaceutical compositions containing them |
| DK0638585T3 (en) * | 1992-04-22 | 1996-12-02 | Taisho Pharmaceutical Co Ltd | 5-O-desosaminylerythronolide A derivatives |
| US5527780A (en) * | 1992-11-05 | 1996-06-18 | Roussel Uclaf | Erythromycin derivatives |
| JP3709997B2 (en) * | 1994-03-29 | 2005-10-26 | 日東電工株式会社 | Heat resistant negative photoresist composition, photosensitive substrate, and negative pattern forming method |
| FR2718450B1 (en) * | 1994-04-08 | 1997-01-10 | Roussel Uclaf | New erythromycin derivatives, their preparation process and their use as drugs. |
| FR2719587B1 (en) * | 1994-05-03 | 1996-07-12 | Roussel Uclaf | New erythromycin derivatives, their preparation process and their use as drugs. |
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