HRP970551A2 - Novel o-methyl azythromycin derivatives - Google Patents
Novel o-methyl azythromycin derivatives Download PDFInfo
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- HRP970551A2 HRP970551A2 HR970551A HRP970551A HRP970551A2 HR P970551 A2 HRP970551 A2 HR P970551A2 HR 970551 A HR970551 A HR 970551A HR P970551 A HRP970551 A HR P970551A HR P970551 A2 HRP970551 A2 HR P970551A2
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- hydrogen
- methyl
- same
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 110
- 229910052739 hydrogen Inorganic materials 0.000 claims description 53
- 239000001257 hydrogen Substances 0.000 claims description 53
- 229960004099 azithromycin Drugs 0.000 claims description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 50
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 42
- 150000002431 hydrogen Chemical class 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 26
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 23
- -1 L-cladinosyl group Chemical group 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 150000002576 ketones Chemical class 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[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 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims description 12
- 239000012442 inert solvent Substances 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 150000007522 mineralic acids Chemical class 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 125000001033 ether group Chemical group 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 150000007524 organic acids Chemical class 0.000 claims description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- 238000007069 methylation reaction Methods 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 7
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 235000005985 organic acids Nutrition 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 5
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- 229910004373 HOAc Inorganic materials 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 238000006884 silylation reaction Methods 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 3
- YKFRUJSEPGHZFJ-UHFFFAOYSA-N N-trimethylsilylimidazole Chemical compound C[Si](C)(C)N1C=CN=C1 YKFRUJSEPGHZFJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 239000000872 buffer Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000012022 methylating agents Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- NRTYMEPCRDJMPZ-UHFFFAOYSA-N pyridine;2,2,2-trifluoroacetic acid Chemical compound C1=CC=NC=C1.OC(=O)C(F)(F)F NRTYMEPCRDJMPZ-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 238000003797 solvolysis reaction Methods 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims 3
- 208000035143 Bacterial infection Diseases 0.000 claims 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 239000003810 Jones reagent Substances 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 238000005947 deacylation reaction Methods 0.000 claims 1
- 238000010511 deprotection reaction Methods 0.000 claims 1
- 150000004678 hydrides Chemical class 0.000 claims 1
- 238000005984 hydrogenation reaction Methods 0.000 claims 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 29
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 229910001868 water Inorganic materials 0.000 description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 229910021529 ammonia Inorganic materials 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 238000007792 addition Methods 0.000 description 8
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 8
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 8
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- GWZLAOIJICWIRB-UHFFFAOYSA-N ethyl acetate;n-ethylethanamine;hexane Chemical compound CCNCC.CCCCCC.CCOC(C)=O GWZLAOIJICWIRB-UHFFFAOYSA-N 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin 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)(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 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 235000015320 potassium carbonate Nutrition 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229960003276 erythromycin Drugs 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 229930006677 Erythromycin A Natural products 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000003120 macrolide antibiotic agent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 2
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000606161 Chlamydia Species 0.000 description 2
- 241000589989 Helicobacter Species 0.000 description 2
- 241000589248 Legionella Species 0.000 description 2
- 208000007764 Legionnaires' Disease Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000006286 aqueous extract Substances 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000006485 reductive methylation reaction Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000006265 spirocyclization reaction Methods 0.000 description 2
- HRKNNHYKWGYTEN-HOQMJRDDSA-N (2r,3s,4r,5r,8r,10r,11r,12s,13s,14r)-11-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)NC[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 HRKNNHYKWGYTEN-HOQMJRDDSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- UTPYTEWRMXITIN-YDWXAUTNSA-N 1-methyl-3-[(e)-[(3e)-3-(methylcarbamothioylhydrazinylidene)butan-2-ylidene]amino]thiourea Chemical compound CNC(=S)N\N=C(/C)\C(\C)=N\NC(=S)NC UTPYTEWRMXITIN-YDWXAUTNSA-N 0.000 description 1
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 1
- YKAVHPRGGAUFDN-JTQLBUQXSA-N 24464-30-0 Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]2(C)O[C@]3([C@@H]([C@H]2O)C)[C@H](C)C[C@](O3)(C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 YKAVHPRGGAUFDN-JTQLBUQXSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 206010048461 Genital infection Diseases 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- 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 description 1
- 239000003245 coal Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000010235 enterohepatic circulation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000003835 ketolide antibiotic agent Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- CSYNQJPENMOLHR-UHFFFAOYSA-N n,n-diethylethanamine;ethyl acetate Chemical compound CCOC(C)=O.CCN(CC)CC CSYNQJPENMOLHR-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000021962 pH elevation Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000011935 selective methylation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Description
Oblast tehnike u koju izum spada The technical field to which the invention belongs
A 61 K 31/70, C 07 H 17/08 A 61 K 31/70, C 07 H 17/08
Tehnički problem Technical problem
Izum se odnosi na nove spojeve iz reda makrolidnog antibiotika azitromicina. Naročito, izum se odnosi na nove O-metil derivate azitromicina, na njihove farmaceutski prihvatljive adicione soli s anorganskim ili organskim kiselinama, na postupak za njihovu pripravu, na njihovu upotrebu kao antibiotika ili kao intermedijera za sintezu drugih makrolidnih antibiotika. The invention relates to new compounds from the class of macrolide antibiotic azithromycin. In particular, the invention relates to new O-methyl derivatives of azithromycin, to their pharmaceutically acceptable addition salts with inorganic or organic acids, to the process for their preparation, to their use as antibiotics or as intermediates for the synthesis of other macrolide antibiotics.
Stanje tehnike State of the art
Makrolidni antibiotik eritromicin A smatra se već više od 40 godina sigurnim i djelotvornim sredstvom u liječenju respiratornih i genitalnih infekcija uzrokovanih Gram-pozitivnim i nekim Gram-negativnim bakterijama, određenim vrstama Legionella, Mycoplasma, Chlamidia i Helicobacter-a. Zapažene promjene u bioraspoloživosti nakon oralne primjene, gastrička intolerancija kod mnogih pacijenata, te gubitak aktiviteta u kiseloj sredini uz nastajanje inaktivnog metabolita, anhidroeritromicina, osnovni su nedostatak u terapeutskoj primjeni eritromicina. Međutim, spirociklizacija aglikonskog prstena uspješno se inhibira kemijskom transformacijom C-9 ketona ili hidroksilnih grupa u C-6 i/ili C-12 položaju. Tako se npr. oksimiranjem C-9 keto grupe, a zatim Beckmannovim pregrađivanjem i redukcijom dobiva 9-deokso-9a-aza-9a-homoeritromicin A, prvi polusintetski makrolidni antibiotik s 15-članim azalaktonskim prstenom (Kobrehel G. i sur., U.S. 4,328,334 5/1982). Reduktivnim metiliranjem novo uvedene sekundarne 9a-amino grupe po Eschvveiler-Clarkovom postupku sintetiziran je 9-deokso-9a-metil-9a-aza-9a-homoeritromicin A (AZITROMICIN), prototip nove klase azalidnih antibiotika (Kobrehel G. i sur.; BE 892357 7/1982). Uz širok antimikrobni spektar, uključujući i Gram-negativne bakterije, azitromicin karakterizira dug biološki poluživot, specifičan mehanizam transporta do mjesta primjene, te kratko vrijeme terapije. Azitromicin lako prodire i akumulira se unutar humanih fagocitnih ćelija što rezultira poboljšanim aktivitetom na intracelularne patogene mikroorganizme iz reda Legionella, Chlamydia, i Helicobacter-a. For more than 40 years, the macrolide antibiotic erythromycin A has been considered a safe and effective agent in the treatment of respiratory and genital infections caused by Gram-positive and some Gram-negative bacteria, certain types of Legionella, Mycoplasma, Chlamydia and Helicobacter. Noticeable changes in bioavailability after oral administration, gastric intolerance in many patients, and loss of activity in an acidic environment with the formation of an inactive metabolite, anhydroerythromycin, are the main drawback in the therapeutic use of erythromycin. However, spirocyclization of the aglycone ring is successfully inhibited by chemical transformation of the C-9 ketone or hydroxyl groups at the C-6 and/or C-12 position. Thus, for example, by oxidizing the C-9 keto group, followed by Beckmann partitioning and reduction, 9-deoxo-9a-aza-9a-homoerythromycin A is obtained, the first semi-synthetic macrolide antibiotic with a 15-membered azalactone ring (Kobrehel G. et al., U.S. 4,328,334 5/1982). 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (AZITHROMYCIN), the prototype of a new class of azalide antibiotics, was synthesized by reductive methylation of the newly introduced secondary 9a-amino group according to the Eschvveiler-Clark procedure (Kobrehel G. et al.; BE 892357 7/1982). With a broad antimicrobial spectrum, including Gram-negative bacteria, azithromycin is characterized by a long biological half-life, a specific mechanism of transport to the site of application, and a short duration of therapy. Azithromycin easily penetrates and accumulates inside human phagocytic cells, which results in improved activity against intracellular pathogenic microorganisms from the order of Legionella, Chlamydia, and Helicobacter.
Nadalje je poznato, da se C-6/C-12 spirociklizacija eritromicina A uspješno inhibira O-metiliranjem C-6 hidroksilne grupe aglikonskog prstena (Watanabe Y. i sur., U. S. 4,331,803 5/1982). Reakcijom eritromicina A s benziloksikarbonil kloridom, a zatim metiliranjem dobivenog 2'-0,3'-N-bis(benziloksikarbonil)-derivata, eliminacijom zaštitnih grupa te N-metiliranjem, uz 6-0-metileritromicin (KLARITROMICIN) nastaju značajne količine 11-O-metileritromicina i višestruko supstituiranih analoga (Morimo S. i sur., J. Antibiotics 1984, 37, 187). U odnosu na eritromicin A, klaritromicin je znatno stabilniji u kiseloj sredini te pokazuje povećanu in vitro aktivnost prema Gram-pozitivnim bakterijskim sojevima (Kirst H. A. i sur., Antimicrobial Agents and Chemother., 1989, 1419). Na sličan način sintetizirana je također serija O-metil-derivata azitromicina (Kobrehel G. i sur., U. S. 5,250,518 5/1993). Premda glavni produkti, 6- i 11-O-metil-azitromicin derivati pokazuju značajnu aktivnost prema standardnim bakterijskim sojevima i kliničkim izolatima, te farmakokinetička svojstva slična azitromicinu, zbog neselektivnosti supstitucije separacija produkata u većem mjerilu predstavlja dodatni tehnički problem. Naknadnom HPLC analizom smjese 2'-O,3'-N-bis(benziloksikarbonil)-0-metil derivata, intermedijera u drugom stupnju sinteze O-metil-azitromicina, utvrđeno ja da uz već opisane biološki aktivne derivate nastaje također i 12-O-metil-azitromicin sa sličnim fizikalno-kemijskim karakteristikama kao što ih posjeduje 6-O-metil-derivat. Sada je nađeno, da primjena odgovarajućih zaštitnih skupina i reakcijskih uvjeta rezultira selektivnim O-metiliranjem C-12 hidroksilne grupe azitromicina. Furthermore, it is known that the C-6/C-12 spirocyclization of erythromycin A is successfully inhibited by O-methylation of the C-6 hydroxyl group of the aglycone ring (Watanabe Y. et al., U.S. 4,331,803 5/1982). By reacting erythromycin A with benzyloxycarbonyl chloride, followed by methylation of the obtained 2'-0,3'-N-bis(benzyloxycarbonyl)-derivative, elimination of protective groups and N-methylation, significant amounts of 11- O-methylerythromycin and multiple substituted analogs (Morimo S. et al., J. Antibiotics 1984, 37, 187). Compared to erythromycin A, clarithromycin is significantly more stable in an acidic environment and shows increased in vitro activity against Gram-positive bacterial strains (Kirst H. A. et al., Antimicrobial Agents and Chemother., 1989, 1419). A series of O-methyl derivatives of azithromycin was also synthesized in a similar way (Kobrehel G. et al., U.S. 5,250,518 5/1993). Although the main products, 6- and 11-O-methyl-azithromycin derivatives show significant activity against standard bacterial strains and clinical isolates, and pharmacokinetic properties similar to azithromycin, due to the non-selectivity of the substitution, the separation of the products on a larger scale represents an additional technical problem. Subsequent HPLC analysis of the mixture of 2'-O,3'-N-bis(benzyloxycarbonyl)-0-methyl derivatives, an intermediate in the second stage of the synthesis of O-methyl-azithromycin, revealed that in addition to the already described biologically active derivatives, 12-O -methyl-azithromycin with similar physico-chemical characteristics as the 6-O-methyl-derivative. It has now been found that the application of appropriate protecting groups and reaction conditions results in selective O-methylation of the C-12 hydroxyl group of azithromycin.
Prema poznatom i utvrđenom stanju tehnike 12-O-metil derivati azitromicina i njihove farmaceutski prihvatljive adicione soli s organskim ili anorganskim kiselinama, metode i intermedijeri za njihovo dobivanje, te metode priprave i upotrebe kao farmaceutskih preparata nisu do danas opisani. Predmet ovog izuma je također sinteza odgovarajućeg 3-keto derivata 12-O-metil-3-O-de kladinozil-azitromicina, novog predstavnika antibakterijskih supstancija iz reda ketolida, kao i novih intermedijera u njihovoj sintezi. According to the known and established state of the art, 12-O-methyl derivatives of azithromycin and their pharmaceutically acceptable addition salts with organic or inorganic acids, methods and intermediates for their preparation, and methods of preparation and use as pharmaceutical preparations have not been described to date. The subject of this invention is also the synthesis of the corresponding 3-keto derivative 12-O-methyl-3-O-decladinosyl-azithromycin, a new representative of antibacterial substances from the class of ketolides, as well as new intermediates in their synthesis.
Opis tehničkog problema s primjerima Description of the technical problem with examples
Novi O-metil derivati azitromicina opće formule (I) New O-methyl derivatives of azithromycin of the general formula (I)
[image] [image]
gdje where
R1 ima individualno značenje hidroksila, L-kladinozil grupe formule (II) R1 has the individual meaning of hydroxyl, L-cladinosyl group of formula (II)
[image] [image]
gdje where
R2 ima individualno značenje vodika ili silil grupe, ili R1 zajedno s R3 ima značenje ketona, R2 individually means hydrogen or a silyl group, or R1 together with R3 means ketone,
R3 ima individualno značenje vodika ili zajedno s R1 ima značenje ketona ili zajedno s R6 ima značenje eterske grupe R3 individually means hydrogen or together with R1 means a ketone or together with R6 means an ether group
R4 ima individualno značenje vodika, (C1-C4) acil grupe ili -COO-(CH2)n-Ar grupe, gdje je n 1 - 7, a R4 has the individual meaning of hydrogen, (C1-C4) acyl group or -COO-(CH2)n-Ar group, where n is 1 - 7, and
Ar ima individualno značenje nesupstituirane ili supstituirane aril grupe do 18 ugljikovih atoma, Ar has the individual meaning of an unsubstituted or substituted aryl group of up to 18 carbon atoms,
R5 ima individualno značenje vodika, metil grupe ili -COO-(CH2)n-Ar grupe, gdje je n 1 - 7, a Ar ima individualno značenje nesupstituirane ili supstituirane aril grupe do 18 ugljikovih atoma, R5 has the individual meaning of hydrogen, methyl group or -COO-(CH2)n-Ar group, where n is 1 - 7, and Ar has the individual meaning of an unsubstituted or substituted aryl group of up to 18 carbon atoms,
R6 ima individualno značenja hidroksilne grupe ili zajedno s R3 ima značenje eterske grupe, R6 individually means a hydroxyl group or together with R3 means an ether group,
R7 ima individualno značenje vodika ili silil grupe, R7 has the individual meaning of hydrogen or silyl group,
R8 ima individualno značenje vodika ili (C1-C12) alkil grupe, R8 has the individual meaning of hydrogen or (C1-C12) alkyl group,
ili njegove farmaceutski prihvatljive adicione soli s anorganskim ili organskim kiselinama, dobivaju se: or its pharmaceutically acceptable addition salts with inorganic or organic acids, are obtained:
Stupanj 1: Level 1:
Podvrgavanjem azitromicina opće formule (I), gdje R1 ima značenje L-kladinozil grupe formule (II), gdje su R2, R3, R4, R5, R7 i R8 međusobno isti i imaju značenje vodika, a R6 je hidroksilna skupina, reakciji s kloridima organskih karboksilnih kiselina formule (III) By subjecting azithromycin of the general formula (I), where R1 has the meaning of the L-cladinosyl group of the formula (II), where R2, R3, R4, R5, R7 and R8 are the same and have the meaning of hydrogen, and R6 is a hydroxyl group, to reaction with chlorides organic carboxylic acids of formula (III)
ClCOO(CH2)n-Ar (III), ClCOO(CH2)n-Ar (III),
gdje je n 1 - 7, a Ar ima individualno značenje nesupstituirane ili supstituirane aril grupe do 18 ugljikovih atoma, preferirano s benziloksikarbonil kloridom, uz prisustvo baza, preferirano natrij hidrogenkarbonata, u reakcijski inertnom otapalu, preferirano u benzenu ili toluenu, dajući 2'-O,3'-N-bis(benziloksikarbonil)-N-demetil-azitromicin (Kobrehel G. i sur., U. S. 5,250,518 5/1993) formule (I), gdje R1 ima značenje L-kladinozil grupe formule (II), R2, R3, R7 i R8 su međusobno isti i imaju značenje vodika, R4 i R5 su međusobno isti i imaju značenje benziloksikarbonil grupe, a R6 ima značenje hidroksilne grupe, koji se zatim podvrgne selektivnom sililiranju 4"- i 11-hidroksilnih grupa, u organski inertnom otapalu, na temperaturi 0 - 5 °C, dajući novi 4",11-O-bis(trimetilsilil)-2'-O,3'-N-bis(benziloksikarbonil)-N-demetil-azitromicin opće formule (I), gdje R1 ima značenje L-kladinozil grupe formule (II), R2 i R7 su međusobno isti i imaju značenje trimetilsilil grupe, R3 i R8 su međusobno isti i imaju značenje vodika, R4 i R5 su međusobno isti i imaju značenje benziloksikarbonil grupe, a R6 je hidroksilna grupa. Kao reagensi za sililiranje koriste se 1,1,1,3,3,3-heksametildisilazan, trimetilsilil klorid, bis(trimetilsilil)acetamid i slični reagensi za uvođenje trimetilsilil grupe, preferirano smjesa trimetilsilil klorida i trimetilsililimidazola. Kao pogodno otapalo upotrebljava se piridin, etilacetat, N,N-dimetilformamid, metilenklorid i slično, preferirano piridin. where n is 1 - 7, and Ar has the individual meaning of an unsubstituted or substituted aryl group of up to 18 carbon atoms, preferably with benzyloxycarbonyl chloride, in the presence of bases, preferably sodium hydrogencarbonate, in a reaction-inert solvent, preferably in benzene or toluene, giving 2'- O,3'-N-bis(benzyloxycarbonyl)-N-demethyl-azithromycin (Kobrehel G. et al., U.S. 5,250,518 5/1993) of formula (I), where R1 has the meaning of L-cladinosyl group of formula (II), R2 , R3, R7 and R8 are the same and have the meaning of hydrogen, R4 and R5 have the same meaning as the benzyloxycarbonyl group, and R6 has the meaning of the hydroxyl group, which is then subjected to selective silylation of the 4"- and 11-hydroxyl groups, in organic in an inert solvent, at a temperature of 0 - 5 °C, giving a new 4",11-O-bis(trimethylsilyl)-2'-O,3'-N-bis(benzyloxycarbonyl)-N-demethyl-azithromycin of the general formula (I) , where R1 has the meaning of the L-cladinosyl group of the formula (II), R2 and R7 are the same as each other and have the meaning of the trimethylsilyl group, R3 and R8 are are mutually the same and have the meaning of hydrogen, R4 and R5 are mutually the same and have the meaning of a benzyloxycarbonyl group, and R6 is a hydroxyl group. 1,1,1,3,3,3-hexamethyldisilazane, trimethylsilyl chloride, bis(trimethylsilyl)acetamide and similar reagents for introducing the trimethylsilyl group, preferably a mixture of trimethylsilyl chloride and trimethylsilylimidazole, are used as silylation reagents. Suitable solvents are pyridine, ethyl acetate, N,N-dimethylformamide, methylene chloride and the like, preferably pyridine.
Stupanj 2: Stage 2:
Reakcijom 4'',11-O-bis(trimetilsilil)-2'-O,3'-N-bis(benziloksikarbonil)-N-demetil-azitromicina dobivenog u Stupnju 1. s 1.3 - 10 mola odgovarajućeg sredstva za metiliranje i 1.1 - 8.5 mola odgovarajuće baze, na temperaturi od -15 °C do sobne temperature, preferirano na 0 - 5 °C, u prikladnom aprotičnom otapalu, dolazi do selektivnog metiliranja na hidroksilnoj skupini u C-12 položaju uz nastajanje novog 4'',11-O-bis(trimetilsilil)-2'-O,3'-N-bis(benziloksikarbonil)-N-demetil-12-O-metil azitromicina opće formule (I), gdje R1 ima značenje L-kladinozil grupe formule (II), R2 i R7 su međusobno isti i imaju značenje trimetilsilil grupe, R3 je vodik, R4 i R5 su međusobno isti i imaju značenje benziloksikarbonil grupe, R6 je hidroksilna grupa, a R8 je metil. Odgovarajuće sredstvo za metiliranje je metiljodid, dimetilsulfat, metilmetan sulfonat ili metil p-toluensulfonat, preferirano metiljodid. Odgovarajuća baza je alkalij metalni hidrid (litij hidrid, natrij hidrid ili kalij hidrid), alkalij hidroksid (kalij hidroksid ili natrij hidroksid) ili alkalij metalni amid (litij amid, natrij amid ili kalij amid), preferirano natrij hidrid. Prikladno aprotično otapalo je dimetilsulfoksid, N,N-dimetilformamid, N,N-dimetilacetamid, ili heksametilfosforni triamid, preferirano N,N-dimetilformamid, dimetil-sulfoksid ili njihova smjesa s tetrahidrofuranom. By reacting 4'',11-O-bis(trimethylsilyl)-2'-O,3'-N-bis(benzyloxycarbonyl)-N-demethyl-azithromycin obtained in Step 1 with 1.3 - 10 moles of the appropriate methylating agent and 1.1 - 8.5 moles of the corresponding base, at a temperature from -15 °C to room temperature, preferably at 0 - 5 °C, in a suitable aprotic solvent, selective methylation occurs on the hydroxyl group in the C-12 position with the formation of a new 4'',11 -O-bis(trimethylsilyl)-2'-O,3'-N-bis(benzyloxycarbonyl)-N-demethyl-12-O-methyl azithromycin of the general formula (I), where R1 has the meaning of the L-cladinosyl group of the formula (II ), R2 and R7 are the same and have the meaning of the trimethylsilyl group, R3 is hydrogen, R4 and R5 are the same and have the meaning of the benzyloxycarbonyl group, R6 is the hydroxyl group, and R8 is methyl. A suitable methylating agent is methyl iodide, dimethyl sulfate, methyl methane sulfonate or methyl p-toluenesulfonate, preferably methyl iodide. A suitable base is an alkali metal hydride (lithium hydride, sodium hydride or potassium hydride), an alkali hydroxide (potassium hydroxide or sodium hydroxide) or an alkali metal amide (lithium amide, sodium amide or potassium amide), preferably sodium hydride. A suitable aprotic solvent is dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, or hexamethylphosphoric triamide, preferably N,N-dimethylformamide, dimethylsulfoxide or a mixture thereof with tetrahydrofuran.
Stupanj 3: Level 3:
Prema metodi E. H. Flynn-a i sur. (Journal of American Chemical Society, 77, 3104, 1950) dobiveni 12-O-metil derivat azitromicina iz Stupnja 2. podvrgava se reakciji hidrogenolize u svrhu uklanjanja zaštitnih benziloksikarbonil grupa u 2'- i 3'-položaju uz istovremeno desililiranje 4"- i 11-položaja, dajući 3'-de-N-metil-12-O-metil-azitromicin opće formule (I), gdje R1 ima značenje L-kladinozil grupe formule (II), R2, R3, R4, R5 i R7 su međusobno isti i imaju značenje vodika, R6 je hidroksilna grupa, a R8 je metil. Hidrogenoliza se provodi u otopini nižih alkohola, preferirano u etanolu, uz prisustvo NaOAc/HOAc pufera (pH 5), uz katalizator, kao što je paladijsko crnilo ili paladij na ugljenu, pod pritiskom vodika od l do 20 bara, na sobnoj temperaturi. According to the method of E. H. Flynn et al. (Journal of American Chemical Society, 77, 3104, 1950) the obtained 12-O-methyl derivative of azithromycin from Step 2 is subjected to a hydrogenolysis reaction in order to remove the protective benzyloxycarbonyl groups in the 2'- and 3'-positions while desilylating the 4"- and 11-position, giving 3'-de-N-methyl-12-O-methyl-azithromycin of the general formula (I), where R1 has the meaning of the L-cladinosyl group of the formula (II), R2, R3, R4, R5 and R7 are the same and have the meaning of hydrogen, R6 is a hydroxyl group and R8 is methyl.Hydrogenolysis is carried out in a solution of lower alcohols, preferably in ethanol, in the presence of NaOAc/HOAc buffer (pH 5), with a catalyst, such as palladium black or palladium on coal, under hydrogen pressure from 1 to 20 bar, at room temperature.
Stupanj 4: Stage 4:
3'-De-N-metil-12-O-metil-azitromicin dobiven u Stupnju 3. podvrgne se reduktivnom N-metiliranju u 3'-položaju s 1-3 ekvivalenata formaldehida (37%), uz prisustvo jednake odnosno dvostruke količine mravlje kiseline (98-100%) ili nekog drugog izvora vodika, u reakcijski inertnom otapalu, kao što su halogenirani ugljikovodici, niži alkoholi ili niži ketoni, preferirano kloroform, na temperaturi refluksiranja reakcijske smjese, dajući 12-O-metil-azitromicin opće formule (I), gdje je R1 ima značenje L-kladinozil grupe formule (II), R2, R3, R4 i R7 su međusobno isti i imaju značenje vodika, a R5 i R8 su međusobno isti i imaju značenje metila, a R6 je hidroksilna grupa. 3'-De-N-methyl-12-O-methyl-azithromycin obtained in Step 3 is subjected to reductive N-methylation in the 3'-position with 1-3 equivalents of formaldehyde (37%), in the presence of an equal or double amount of acid (98-100%) or some other source of hydrogen, in a reaction-inert solvent, such as halogenated hydrocarbons, lower alcohols or lower ketones, preferably chloroform, at the reflux temperature of the reaction mixture, giving 12-O-methyl-azithromycin of the general formula ( I), where R1 has the meaning of the L-cladinosyl group of the formula (II), R2, R3, R4 and R7 are the same and have the meaning of hydrogen, and R5 and R8 have the same meaning and have the meaning of methyl, and R6 is a hydroxyl group.
Alternativno, 12-O-metil-azitromicin dobiva se provođenjem hidrogenolize i reduktivnog metiliranja u jednom reakcijskom stupnju bez izolacije intermedijera iz Stupnja 3. Alternatively, 12-O-methyl-azithromycin is obtained by performing hydrogenolysis and reductive methylation in one reaction step without isolating the intermediate from Step 3.
Stupanj 5: Level 5:
12-O-Metil-azitromicin iz Stupnja 4. podvrgne se po potrebi hidrolizi s razrijeđenim anorganskim kiselinama, preferirano s 0.25 N kloridnom kiselinom, kroz 10 - 30 sati, kod sobne temperature, dajući spoj 3-de(2,6-dideoksi-3-C-metil-3-O-metil-α-L-riboheksopiranozil-oksi)-3-oksi-12-O-metil-azitromicin opće formule (I), gdje su R1 i R6 međusobno isti i imaju značenje hidroksilne grupe, R3, R4 i R7 su međusobno isti i imaju značenje vodika, a R5 i R8 su međusobno isti i imaju značenje metila. 12-O-Methyl-azithromycin from Step 4 is subjected to hydrolysis with dilute inorganic acids, preferably with 0.25 N hydrochloric acid, for 10 - 30 hours, at room temperature, giving the compound 3-de(2,6-dideoxy- 3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl-oxy)-3-oxy-12-O-methyl-azithromycin of the general formula (I), where R1 and R6 are the same and have the meaning of a hydroxyl group , R 3 , R 4 and R 7 are mutually identical and have the meaning of hydrogen, and R 5 and R 8 are mutually the same and have the meaning of methyl.
Stupanj 6: Level 6:
3-De(2,6-dideoksi-3-C-metil-3-O-metil-α-L-riboheksopiranozil-oksi)-3-oksi-12-O-metil-azitromicin iz Stupnja 5. podvrgne se selektivnom aciliranju 2'-hidroksilne grupe. Aciliranje se provodi s anhidridima karbonskih kiselina do 4 ugljikova atoma, preferirano s anhidridom octene kiseline, uz prisustvo anorganskih ili organskih baza, u inertnom organskom otapalu, na temperaturi od 0 -30 °C, dajući 3-de(2,6-dideoksi-3-C-metil-3-O-metil-α-L-riboheksopiranozil-oksi)-3-oksi-12-O-metil-azitromicin 2'-O-acetat opće formule (I), gdje su R1 i R6 međusobno isti i imaju značenje hidroksilne grupe, R3 i R7 su međusobno isti i imaju značenje vodika, R4 je acetil, a R5 i R8 su međusobno isti i imaju značenje metila. Kao odgovarajuće baze upotrebljavaju se natrij hidrogenkarbonat, natrij karbonat, kalij karbonat, trietilamin, piridin, tributilamin, preferirano natrij hidrogenkarbonat. Kao prikladno inertno otapalo upotrebljava se metilenklorid, dikloretan, aceton, piridin, etilacetat, tetrahidrofuran, preferirano metilenklorid. 3-De(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl-oxy)-3-oxy-12-O-methyl-azithromycin from Step 5 undergoes selective acylation 2'-hydroxyl groups. Acylation is carried out with carboxylic acid anhydrides of up to 4 carbon atoms, preferably with acetic anhydride, in the presence of inorganic or organic bases, in an inert organic solvent, at a temperature of 0-30 °C, giving 3-de(2,6-dideoxy- 3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl-oxy)-3-oxy-12-O-methyl-azithromycin 2'-O-acetate of the general formula (I), where R1 and R6 are mutually are the same and have the meaning of a hydroxyl group, R3 and R7 are the same as each other and have the meaning of hydrogen, R4 is acetyl, and R5 and R8 are the same as each other and have the meaning of methyl. Suitable bases are sodium hydrogencarbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine, tributylamine, preferably sodium hydrogencarbonate. Suitable inert solvents are methylene chloride, dichloroethane, acetone, pyridine, ethyl acetate, tetrahydrofuran, preferably methylene chloride.
Stupanj 7: Level 7:
2'-Zaštićeni produkt iz Stupnja 6. podvrgne se oksidaciji hidroksilne skupine u C-3 položaju po modificiranom Moffat-Pfitzner-ovom postupku (DMSO i 1-(3-dimetilaminopropil)-3-etil-karbodiimid u prisustvu piridin trifluoracetata) dajući 3-de(2,6-dideoksi-3-C-metil-3-O-metil-α-L-ribohekso-piranozil-oksi)-3-okso-12-O-metil-azitromicin 2'-O-acetat opće formule (I), gdje R1 i R3 imaju zajedno značenje ketona, R4 je acetil, R5 i R8 su međusobno isti i imaju značenje metila, R6 je hidroksilna grupa, a R7 je vodik. The 2'-protected product from Step 6 undergoes oxidation of the hydroxyl group at the C-3 position by a modified Moffat-Pfitzner procedure (DMSO and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in the presence of pyridine trifluoroacetate) to give 3 -de(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexo-pyranosyl-oxy)-3-oxo-12-O-methyl-azithromycin 2'-O-acetate general of formula (I), where R1 and R3 together have the meaning of ketone, R4 is acetyl, R5 and R8 are the same and have the meaning of methyl, R6 is a hydroxyl group, and R7 is hydrogen.
Stupanj 8: Level 8:
Spoj dobiven u Stupnju 7. podvrgne se zatim solvolizi u nižim alkoholima, preferirano u metanolu, na sobnoj temperaturi do temperature refluksiranja otapala, dajući smjesu 3-de(2,6-dideoksi-3-C-metil-3-0-metil-α-L-riboheksopiranozil-oksi)-3-oksi-12-O-metil-azitromicina opće formule (I), gdje R1 zajedno s R3 ima značenje ketona, R4 i R7 su međusobno isti i imaju značenje vodika, R5 i R8 su međusobno isti i imaju značenje metila, a R6 je hidroksilna grupa i 3-de(2,6-dideoksi-3-C-metil-3-O-metil-α-L-riboheksopiranozil-oksi)-3-oksi-12-O-metil-azitromicina 3,6-hemi-ketala opće formule (I), gdje je R1 hidroksilna grupa, R3 zajedno s R6 ima značenje eterske grupe, R4 i R7 su međusobno isti i imaju značenje vodika, a R5 i R8su međusobno isti i imaju značenje metila. The compound obtained in Step 7 is then subjected to solvolysis in lower alcohols, preferably in methanol, at room temperature to the reflux temperature of the solvent, giving a mixture of 3-de(2,6-dideoxy-3-C-methyl-3-0-methyl- α-L-ribohexopyranosyl-oxy)-3-oxy-12-O-methyl-azithromycin of the general formula (I), where R1 together with R3 has the meaning of ketone, R4 and R7 are the same and have the meaning of hydrogen, R5 and R8 are mutually the same and have the meaning of methyl, and R6 is a hydroxyl group and 3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl-oxy)-3-oxy-12- O-methyl-azithromycin 3,6-hemi-ketal of the general formula (I), where R1 is a hydroxyl group, R3 together with R6 has the meaning of an ether group, R4 and R7 are the same and have the meaning of hydrogen, and R5 and R8 are the same and have the meaning of methyl.
Farmaceutski prihvatljive adicione soli, koje su također predmet ovog izuma, dobivaju se reakcijom novih O-metil derivata azitromicina opće formule (I) s najmanje ekvimolarnom količinom odgovarajuće anorganske ili organske kiseline, kao stoje kloridna, jodidna, sulfatna fosforna, octena, propionska, trifluoroctena, maleinska, limunska, stearinska, jantarna, etiljantarna, metansulfonska, benzensulfonska, p-toluensulfonska, laurilsulfonska i slično, u reakcijski inertnom otapalu. Adicione soli izoliraju se filtracijom, ukoliko su netopive u reakcijski inertnom otapalu, taloženjem pomoću neotapala ili otparavanjem otapala, najčešće procesom liofilizacije. Pharmaceutically acceptable addition salts, which are also the subject of this invention, are obtained by the reaction of new O-methyl derivatives of azithromycin of the general formula (I) with at least an equimolar amount of a suitable inorganic or organic acid, such as chloride, iodide, sulfate phosphoric, acetic, propionic, trifluoroacetic , maleic, citric, stearic, amber, ethylamber, methanesulfonic, benzenesulfonic, p-toluenesulfonic, laurylsulfonic and the like, in a reaction-inert solvent. Salt additions are isolated by filtration, if they are insoluble in a reaction-inert solvent, by precipitation using a non-solvent or by evaporation of the solvent, most often by the lyophilization process.
Anti bakterijska in vitro aktivnost novih O-metil azitromicina opće formule (I) i njegovih farmaceutski prihvatljivih adicionih soli s anorganskim ili organskim kiselinama na seriji standardnih test mikroorganizama određena je u Mueller-Hinton mediju (Difco-Laboratories, Detroit, MI) uobičajenom metodom dvostrukog razrjeđenja prema preporukama NCCLS (The National Commitee for Clinical Laboratory Standards). Svaki test mikroorganizam inokuliran je do konačne veličine inokuluma od 5 x 105 cfu/ml, a inkubacija je provedena anaerobno na 37 °C kroz 18 sati. MIK u tekućem mediju je definiran kao najniža koncentracija antibakterijskog sredstva koja inhibira vidljiv porast u mikrodilucijskim posudama. Organizmi za kontrolu dobiveni su od ATCC (The American Type Culture Collection). Svi standardi identificirani su standardnim postupkom i čuvani su na -70 °C. Rezultati testiranja 12-O-metil-azitromicina na standardnim test mikroorganizmima i kliničkim izolatima u komparaciji s azitromicinom prikazani su u Tabeli 1. i Tabeli 2. The antibacterial in vitro activity of the new O-methyl azithromycin of the general formula (I) and its pharmaceutically acceptable addition salts with inorganic or organic acids on a series of standard test microorganisms was determined in Mueller-Hinton medium (Difco-Laboratories, Detroit, MI) by the usual method of double dilutions according to NCCLS (The National Committee for Clinical Laboratory Standards) recommendations. Each test microorganism was inoculated to a final inoculum size of 5 x 105 cfu/ml, and the incubation was carried out anaerobically at 37 °C for 18 hours. The MIC in a liquid medium is defined as the lowest concentration of an antibacterial agent that inhibits visible growth in microdilution vessels. Control organisms were obtained from ATCC (The American Type Culture Collection). All standards were identified by standard procedure and stored at -70 °C. The results of testing 12-O-methyl-azithromycin on standard test microorganisms and clinical isolates in comparison with azithromycin are shown in Table 1 and Table 2.
Određivanjem koncentracije u serumu 12-O-metil-azitromicina nakon jednokratne oralne doze od 20 mg/kg na skupini od 36 mužjaka štakora u vremenskom intervalu od 0.25 do 24 sata utvrđeno je da se novi antibiotik vrlo brzo apsorbira u serumu. Analiza pikova sugerira postojanje enterohepatične cirkulacije. Između 0.5 i 1 sata dolazi do naglog pada koncentracije, nakon čega slijedi ponovni porast. Maksimalna koncentracija supstancije postiže se nakon 2 sata (Cmax 248.8 ng/ml). Sekundarni maksimum postiže se 4 sata nakon aplikacije. Poluživot iznosi 5.2 sata, a totalni AUC 1993.4 h ng/ml. By determining the serum concentration of 12-O-methyl-azithromycin after a single oral dose of 20 mg/kg in a group of 36 male rats in the time interval from 0.25 to 24 hours, it was determined that the new antibiotic is very quickly absorbed in the serum. Peak analysis suggests the existence of an enterohepatic circulation. Between 0.5 and 1 hour there is a sudden drop in concentration, followed by a re-increase. The maximum concentration of the substance is reached after 2 hours (Cmax 248.8 ng/ml). The secondary maximum is reached 4 hours after application. The half-life is 5.2 hours, and the total AUC is 1993.4 h ng/ml.
Tabela 1. Anti bakterijska in vitro aktivnost 12-O-metil-azitromicina na standardnim sojevima u usporedbi s azitromicinom Table 1. Antibacterial in vitro activity of 12-O-methyl-azithromycin on standard strains compared to azithromycin
[image] [image]
Tabela 2. Antibakterijska in vitro aktivnost 12-O-metil-azitromicina na seriji kliničkih izolata u usporedbi s azitromicinom Table 2. Antibacterial in vitro activity of 12-O-methyl-azithromycin on a series of clinical isolates compared to azithromycin
[image] [image]
Postupak priprave novih O-metil derivata azitromicina ilustriran je slijedećim primjerima koji ni u čemu ne ograničavaju širinu pronalaska. The procedure for the preparation of new O-methyl derivatives of azithromycin is illustrated by the following examples, which in no way limit the scope of the invention.
Priprava 1. Preparation 1.
2’-O,3'-N-Bis(benziloksikarbonil)-N-demetilazitromicin A 2'-O,3'-N-Bis(benzyloxycarbonyl)-N-demethylazithromycin A
U otopinu azitromicina (17 g, 0.0227 mola) u toluenu (170 ml) doda se NaHCO3 (74.8 g, 0.890 mol), a zatim reakcijska smjesa zagrije uz miješanje do temperature refluksiranja (80-85 °C). U reakcijsku suspenziju dokapa se uz miješanje, kroz 1 sat, 102 ml (104.04.g, 0.305 mol) 50%-tnog benziloksikarbonil klorida u toluenu. Reakcijska smjesa miješa se daljnjih 2 sata kod iste temperature, te ostavi da stoji preko noći na sobnoj temperaturi. Nakon filtracije, talog se pere s 85 ml toluena, a toluenska otopina ekstrahira dva puta s 170 ml 0.25 N HCl i dva puta s 170 ml 1.5%-tne vodene otopine NaCl-a. Na toluen se doda 340 ml vode (pH 3.1), pH reakcijske smjese podesi se s 6 N HCl na 2.0, slojevi odvoje, a organski ekstrahira još tri puta s 340 ml vode uz održavanje pH na 2.0. Na sjedinjene vodene ekstrakte doda se 125 ml CH2Cl2, pH podesi s vodenom otopinom NaOH (20%) na 10.0, slojevi odvoje, a vodeni ekstrahira još jedanput s 125 ml CH2Cl2. Sjedinjeni organski ektrakti suše se nad K2CO3, filtriraju, te upare kod smanjenog pritiska dajući 16.5 g gustog uljastog ostatka koji se po potrebi čisti niskotlačnom kromatografijom na stupcu silikagela 60 (230-400 mesh ATSM). U tu svrhu sirovi produkt se otopi u 20 ml CH2Cl2, te nanese pod pritiskom dušika od 0.5 bara na stupac silikagela (50 g). Zbog uklanjanja zaostalog benzilklorformata i njegovih razgradnih produkata, preko kolone se propusti najprije 150 ml CH2Cl2, a zatim uz upotrebu sistema metilenklorid-metanol, 9 : 1 (200 ml) te uparavanja frakcija koje sadrže kromatografski homogen naslovni produkt dobiva 11.53 g TLC čistog 2'-O,3'-N-bis-(benziloksikarbonil)-N-demetil-azitromicina s fizikalno-kemijskim konstantama kao stoje opisano u US patentu 5,250,518 10/1993. NaHCO3 (74.8 g, 0.890 mol) was added to a solution of azithromycin (17 g, 0.0227 mol) in toluene (170 ml), and then the reaction mixture was heated with stirring to the reflux temperature (80-85 °C). 102 ml (104.04 g, 0.305 mol) of 50% benzyloxycarbonyl chloride in toluene was added dropwise to the reaction suspension with stirring for 1 hour. The reaction mixture is stirred for another 2 hours at the same temperature, and left to stand overnight at room temperature. After filtration, the precipitate is washed with 85 ml of toluene, and the toluene solution is extracted twice with 170 ml of 0.25 N HCl and twice with 170 ml of 1.5% aqueous NaCl solution. 340 ml of water (pH 3.1) is added to toluene, the pH of the reaction mixture is adjusted to 2.0 with 6 N HCl, the layers are separated, and the organics are extracted three more times with 340 ml of water while maintaining the pH at 2.0. 125 ml of CH2Cl2 is added to the combined aqueous extracts, the pH is adjusted to 10.0 with an aqueous solution of NaOH (20%), the layers are separated, and the aqueous extract is extracted once more with 125 ml of CH2Cl2. The combined organic extracts are dried over K2CO3, filtered, and evaporated under reduced pressure to give 16.5 g of a thick oily residue which is purified if necessary by low pressure chromatography on a silica gel 60 column (230-400 mesh ATSM). For this purpose, the crude product is dissolved in 20 ml of CH2Cl2, and applied under nitrogen pressure of 0.5 bar to a column of silica gel (50 g). Due to the removal of residual benzylchloroformate and its decomposition products, first 150 ml of CH2Cl2 is passed through the column, and then with the use of the methylene chloride-methanol system, 9:1 (200 ml) and the pairing of the fractions containing the chromatographically homogeneous title product, 11.53 g of TLC pure 2' is obtained. -O,3'-N-bis-(benzyloxycarbonyl)-N-demethyl-azithromycin with physicochemical constants as described in US patent 5,250,518 10/1993.
Primjer 1. Example 1.
4’’,11-O-Bis(trimetilsilil)-2’-O,3’-N-bis(benziloksikarbonil)-N-demetil-azitromicin 4'',11-O-Bis(trimethylsilyl)-2'-O,3'-N-bis(benzyloxycarbonyl)-N-demethyl-azithromycin
U otopinu 2'-O,3'-N-bis(benziloksikarbonil)-N-demetil-azitromicina (5.0 g, 0.005 mol) u piridinu (50 ml) ohlađenu na 0 - 5 °C doda se pod strujom dušika 3.3 ml (0.0226 mol) trimetilsililimidazola i 3.0 ml (0.0179 mol) trimetilsililklorida. Reakcijska smjesa miješa se 6 sati kod iste temperature, razrijedi s 60 ml n-heksana, doda voda (100 ml), slojevi odvoje, a organski pere s zasićenom otopinom NaHCO3 (60 ml) i vodom (60 ml). Nakon sušenja nad MgSO4, filtracije i otparavanja otapala kod sniženog pritiska dobiva se 5.48 g bijelog amorfnog taloga koji se po potrebi čisti niskotlačnom na stupcu silikagela uz upotrebu sistema metilenklorid-metanol, 9:1. Sjedinjavanjem i uparavanjem kromatografski homogenih frakcija dobiven je naslovni produkt sa slijedećim fizikalno-kemijskim konstantama: 3.3 ml ( 0.0226 mol) of trimethylsilylimidazole and 3.0 ml (0.0179 mol) of trimethylsilyl chloride. The reaction mixture is stirred for 6 hours at the same temperature, diluted with 60 ml of n-hexane, water (100 ml) is added, the layers are separated, and the organics are washed with saturated NaHCO3 solution (60 ml) and water (60 ml). After drying over MgSO4, filtration and evaporation of the solvent under reduced pressure, 5.48 g of a white amorphous precipitate is obtained, which, if necessary, is purified by low pressure on a silica gel column using the methylene chloride-methanol system, 9:1. By combining and comparing the chromatographically homogeneous fractions, the title product was obtained with the following physicochemical constants:
TLC, Metilenklorid-metanol, 90 : l Rf 0.875 TLC, Methylene chloride-methanol, 90:1 Rf 0.875
Etilacetat-n-heksan-dietilamin, 100 : 100 : 20 Rf 0.942 Ethyl acetate-n-hexane-diethylamine, 100 : 100 : 20 Rf 0.942
(IR (KBr) cm-1 3524, 2969, 2692, 1754, 1732, 1708, 1498, 1456, 1382, 1335, 1252, 1168, 1116, 1060, 1005, 895, 841, 754, 696. (IR (KBr) cm-1 3524, 2969, 2692, 1754, 1732, 1708, 1498, 1456, 1382, 1335, 1252, 1168, 1116, 1060, 1005, 895, 841, 754, 696.
1H NMR (300 MHz, CDCl3) δ 7.32-7.23 (Ph), 5.12, 4.98 (CH2-Ph), 4.85 (H-1"), 4.70 (H-T), 4.65 (H-2'), 4.46 (H-3’), 4.26 (H-5"), 4.42 (H-3), 3.72 (H-5'), 3.66 (H-11), 3.49, 3.47 (H-5), 3.20 (H-4"), 3.32, 3.18 (3"-OCH3), 2.83, 2.79 (3'-NCH3), 2.78 (H-2), 2.64 (H-10), 2.35 (H-9a), 2.33 (H-2"a), 2.11 (9a-NCH3), 1.94 (H-9b), 1.91 (H-8), 1.64 (H-14a), 1.94 (H-4), 1.50 (H-2"b), 1.50 (H-14b), 1.27, 1.25 (6-CH3), 1.24 (5"-CH3), 1.19 (5'-CH3), 1.12 (3"-CH3), 1.16 (12-CH3), 1.26 (2-CH3), 0.89 (10-CH3), 0.95 (8-CH3), 0.85 (14-CH3), 1.02 (4-CH3), 0.16 /4"-OSi(CH3)3/, 0.13 /2'-OSi(CH3)3/. 1H NMR (300 MHz, CDCl3) δ 7.32-7.23 (Ph), 5.12, 4.98 (CH2-Ph), 4.85 (H-1"), 4.70 (H-T), 4.65 (H-2'), 4.46 (H- 3'), 4.26 (H-5"), 4.42 (H-3), 3.72 (H-5'), 3.66 (H-11), 3.49, 3.47 (H-5), 3.20 (H-4") , 3.32, 3.18 (3"-OCH3), 2.83, 2.79 (3'-NCH3), 2.78 (H-2), 2.64 (H-10), 2.35 (H-9a), 2.33 (H-2"a) , 2.11 (9a-NCH3), 1.94 (H-9b), 1.91 (H-8), 1.64 (H-14a), 1.94 (H-4), 1.50 (H-2"b), 1.50 (H-14b ), 1.27, 1.25 (6-CH3), 1.24 (5"-CH3), 1.19 (5'-CH3), 1.12 (3"-CH3), 1.16 (12-CH3), 1.26 (2-CH3), 0.89 (10-CH3), 0.95 (8-CH3), 0.85 (14-CH3), 1.02 (4-CH3), 0.16 /4"-OSi(CH3)3/, 0.13 /2'-OSi(CH3)3/ .
13C NMR (75 MHz, CDCl3) δ 176.2 (C-1), 156.2, 156.4 (OCO), 154.5, 154.4 (NCO), 136.7-127.5 (Ph), 100.2 (C-1'), 97.3 (C-1"), 83.9 (C-5), 80.7 (C-4"), 75.0 (C-3), 75.0 (C-2'), 80.6 (C-12), 77.3 (C-11), 75.3 (C-6), 73.2 (C-3"), 69.4 69.2, 67.1, 66.8 (CH2-Ph), 64.8 (C-5"), 62.3 (C-10), 54.8 (C-3'), 49.4, 49.2 (3"-OCH3), 46.2 (C-2), 38.5 (C-7), 39.4 (C-4), 34.2 (9a-NCH3), 35.9, 35.6 (C-2"), 36.2, 36.1 (C-4'), 29.0 (3'-NCH3), 25.6 (C-8), 27.8 (6-CH3), 21.9 (3"-CH3), 21.5 (8-CH3), 20.7 (5'-CH3), 23.4 (C-14), 18.4 (5"-CH3), 16.0 (2-CH3), 21.5 (12-CH3), 11.6 (14-CH3), 9.6, 9.5 (4-CH3),8.3(10-CH3), 1.2 /2'-OSi(CH3)3/, 0.67/4"-OSi(CH3)3/. 13C NMR (75 MHz, CDCl3) δ 176.2 (C-1), 156.2, 156.4 (OCO), 154.5, 154.4 (NCO), 136.7-127.5 (Ph), 100.2 (C-1'), 97.3 (C-1 "), 83.9 (C-5), 80.7 (C-4"), 75.0 (C-3), 75.0 (C-2'), 80.6 (C-12), 77.3 (C-11), 75.3 (C -6), 73.2 (C-3"), 69.4 69.2, 67.1, 66.8 (CH2-Ph), 64.8 (C-5"), 62.3 (C-10), 54.8 (C-3'), 49.4, 49.2 (3"-OCH3), 46.2 (C-2), 38.5 (C-7), 39.4 (C-4), 34.2 (9a-NCH3), 35.9, 35.6 (C-2"), 36.2, 36.1 (C -4'), 29.0 (3'-NCH3), 25.6 (C-8), 27.8 (6-CH3), 21.9 (3"-CH3), 21.5 (8-CH3), 20.7 (5'-CH3), 23.4 (C-14), 18.4 (5"-CH3), 16.0 (2-CH3), 21.5 (12-CH3), 11.6 (14-CH3), 9.6, 9.5 (4-CH3), 8.3 (10-CH3 ), 1.2 /2'-OSi(CH3)3/, 0.67/4"-OSi(CH3)3/.
Primjer 2. Example 2.
3'-De-N-metil-12-O-metil-azitromicin 3'-De-N-methyl-12-O-methyl-azithromycin
U otopinu produkta iz Primjera 1. (1.0 g, 0.0009 mol) u 20 ml N,N-dimetilformamida doda se postepeno kroz 3 sata, na sobnoj temperaturi, 0.43 ml (0.0069 mol) metiljodida i 0.23 g (0.0058 mol) 60%-tnog natrij hidrida. Reakcijska smjesa miješa se daljnjih 30 minuta kod iste temperature, reakcija prekine dodatkom trietilamina (2 ml), prebaci u smjesu 10%-tne vodene otopine NaHCO3 (50 ml) i vode (50 ml), te ekstrahira s etilacetatom. Sjedinjeni organski ekstrakti peru se sa zasićenom otopinom NaCl i vodom, suše nad MgSO4, filtriraju, te upare kod sniženog pritiska dajući 0.93 g žuto obojenog uljastog ostatka. Produkt se otopi u 20 ml etanola, doda se NaOAc/HOAc pufer pH 5 (0.17 ml HOAc, 0.263 g NaOAc, 0.22ml etanola i l ml vode) i Pd/C 10% (0.6 g), te reakcijska smjesa hidrira uz miješanje 5 h u autoklavu, kod pritiska vodika od 5 bara. Katalizator se filtrira, filtrat upari do gustog sirupa, doda se 10 ml CH2Cl2 i 15 ml vode, pH smjese podesi s 2 N HCl na 4, slojevi odvoje, a vodeni ekstrahira nakon podešavanja pH s 20%-tnom NaOH na 9.5 s CH2Cl2 (3x10 ml). Sjedinjeni organski ekstrakti suše se nad K2CO3, filtriraju, te upare dajući 0.43 g naslovnog produkta sa slijedećim fizikalno-kemijskim konstantama: 0.43 ml (0.0069 mol) of methyl iodide and 0.23 g (0.0058 mol) of 60%- of sodium hydride. The reaction mixture is stirred for a further 30 minutes at the same temperature, the reaction is stopped by the addition of triethylamine (2 ml), transferred to a mixture of 10% aqueous NaHCO3 solution (50 ml) and water (50 ml), and extracted with ethyl acetate. The combined organic extracts are washed with saturated NaCl solution and water, dried over MgSO4, filtered, and evaporated under reduced pressure to give 0.93 g of a yellow colored oily residue. The product is dissolved in 20 ml of ethanol, NaOAc/HOAc buffer pH 5 (0.17 ml of HOAc, 0.263 g of NaOAc, 0.22 ml of ethanol and 1 ml of water) and Pd/C 10% (0.6 g) are added, and the reaction mixture is hydrated with stirring for 5 h in an autoclave, at a hydrogen pressure of 5 bar. The catalyst is filtered, the filtrate is evaporated to a thick syrup, 10 ml of CH2Cl2 and 15 ml of water are added, the pH of the mixture is adjusted to 4 with 2 N HCl, the layers are separated, and the aqueous is extracted after adjusting the pH with 20% NaOH to 9.5 with CH2Cl2 ( 3x10 ml). The combined organic extracts are dried over K2CO3, filtered, and evaporated to give 0.43 g of the title product with the following physicochemical constants:
EI-MS m/z 748 EI-MS m/z 748
IR (KBr) cm-1 3672, 3496, 2962, 1727, 1458, 1375, 1343, 1280, 1263, 1118, 1085, 1048, 1005, 998. IR (KBr) cm-1 3672, 3496, 2962, 1727, 1458, 1375, 1343, 1280, 1263, 1118, 1085, 1048, 1005, 998.
13C NMR (75 MHz, CDCl3) δ 177.4 (C-1), 102.7 (C-1'), 95.5 (C-1"), 83.4 (C-5), 79.7 (C-12), 78.0 (C-3), 76.6 (C-11), 74.0 (C-13), 73.9 (C-6), 74.3 (C-2'), 73.0 (C-3"), 68.8 (C-9), 65.7 (C-5"), 60.1 (C-3'), 61.2 (C-10), 52.8 (12-OCH3), 49.8 (3"-OCH3), 45.5 (C-2), 41.5 (C-4), 33.1 3'-NCH3, 36.8 (9a-NCH3), 35.1 (C-2"), 28.8 (C-4'), 27.0 (C-8). 13C NMR (75 MHz, CDCl3) δ 177.4 (C-1), 102.7 (C-1'), 95.5 (C-1"), 83.4 (C-5), 79.7 (C-12), 78.0 (C- 3), 76.6 (C-11), 74.0 (C-13), 73.9 (C-6), 74.3 (C-2'), 73.0 (C-3"), 68.8 (C-9), 65.7 (C -5"), 60.1 (C-3'), 61.2 (C-10), 52.8 (12-OCH3), 49.8 (3"-OCH3), 45.5 (C-2), 41.5 (C-4), 33.1 3'-NCH3, 36.8 (9a-NCH3), 35.1 (C-2"), 28.8 (C-4'), 27.0 (C-8).
Primjer 3. Example 3.
12-O-Metil-azitromicin 12-O-Methyl-azithromycin
U otopinu od 0.43 g (0.0006 mola) 3'-de-N-metil-12-O-metil-azitromicin iz Primjera 2. otopi se u CHCl3(20 ml), doda se 0.047 ml formaldehida (37%) (0.0006 mol) i 0.042 ml (0.0011 mol) mravlje kiseline (98-100%). Reakcijska smjesa miješa se 3 sata uz refluksiranje, ohladi na sobnu temperaturu, izlije na vodu (20 ml), te nakon podešavanja pH na 4.0, slojevi odvoje, a vodeni dio ekstrahira još dva puta s CHCl3. Na vodeni sloj doda se svježi CHCl3, pH podesi s 2N NaOH na 9.5, slojevi odvoje, a vodeni ekstrahira još dva puta s CHCl3. Sjedinjeni organski ekstrakti kod pH 9.5 se suše (K2CO3), te upare dajući 0.38 g naslovnog produkta, koji se po potrebi čisti kromatografijom na stupcu silikagela uz upotrebu sistema metilenklorid-metanol-conc. amonijak, 90 : 9 : 1. In a solution of 0.43 g (0.0006 mol) of 3'-de-N-methyl-12-O-methyl-azithromycin from Example 2, dissolve in CHCl3 (20 ml), add 0.047 ml of formaldehyde (37%) (0.0006 mol ) and 0.042 ml (0.0011 mol) of formic acid (98-100%). The reaction mixture is stirred for 3 hours under reflux, cooled to room temperature, poured into water (20 ml), and after adjusting the pH to 4.0, the layers are separated, and the aqueous part is extracted two more times with CHCl3. Fresh CHCl3 is added to the aqueous layer, the pH is adjusted to 9.5 with 2N NaOH, the layers are separated, and the aqueous layer is extracted two more times with CHCl3. The combined organic extracts at pH 9.5 are dried (K2CO3) and evaporated to give 0.38 g of the title product, which, if necessary, is purified by chromatography on a silica gel column using the system methylene chloride-methanol-conc. ammonia, 90 : 9 : 1.
TLC, Metilenklorid-metanol-conc. amonijak, 90 : 9 : 0.5 Rf 0.363 TLC, Methylene chloride-methanol-conc. ammonia, 90 : 9 : 0.5 Rf 0.363
Etilacetat-n-heksan-dietilamin, 100 : 100 : 20 Rf 0.745 Ethyl acetate-n-hexane-diethylamine, 100 : 100 : 20 Rf 0.745
IR (KBr) cm-1 3499, 2972, 2940, 1736, 1633, 1460, 1381, 1259, 1168, 1110, 1059, 1082, 1054, 1013, 999. IR (KBr) cm-1 3499, 2972, 2940, 1736, 1633, 1460, 1381, 1259, 1168, 1110, 1059, 1082, 1054, 1013, 999.
1H NMR (300 MHz, CDCl3) δ 5.39 (H-13), 5.00 (H-1"), 4.43 (H-P), 4.32 (H-3), 4.06 (H-5"), 3.68 (H-11), 3.65 (H-5), 3.51 (H-5'), 3.38 (12-OCH3), 3.32 (3"-OCH3), 3.24 (H-2'), 3.02 (H-4"), 2.73 (H-2), 2.69 (H-10), 2.49 (H-3'), 2.34 (H-2"a), 2.31 (H-9a), 2.29 /3'N(CH3)2/, 2.30 (9a-NCH3), 2.12 (H-9b), 2.04 (H-4), 2.01 (H-8), 1.73 (H-14a), 1.68 (H-4'a), 1.66 (H-7a), 1.56 (H-2"b), 1.52 (H-14b), 1.36 (H-7b), 1.29 (6-CH3), 1.21 (2-CH3), 1.30 (5"-CH3), 1.24 (H-4'b), 1.23 (3"-CH3), 1.22 (5'-CH3), 1.09 (12-CH3), 1.29, (4-CH3), 1.09 (10-CH3), 0.92 (8-CH3), 0.93 (14-CH3). 1H NMR (300 MHz, CDCl3) δ 5.39 (H-13), 5.00 (H-1"), 4.43 (H-P), 4.32 (H-3), 4.06 (H-5"), 3.68 (H-11) , 3.65 (H-5), 3.51 (H-5'), 3.38 (12-OCH3), 3.32 (3"-OCH3), 3.24 (H-2'), 3.02 (H-4"), 2.73 (H -2), 2.69 (H-10), 2.49 (H-3'), 2.34 (H-2"a), 2.31 (H-9a), 2.29 /3'N(CH3)2/, 2.30 (9a- NCH3), 2.12 (H-9b), 2.04 (H-4), 2.01 (H-8), 1.73 (H-14a), 1.68 (H-4'a), 1.66 (H-7a), 1.56 (H -2"b), 1.52 (H-14b), 1.36 (H-7b), 1.29 (6-CH3), 1.21 (2-CH3), 1.30 (5"-CH3), 1.24 (H-4'b) , 1.23 (3"-CH3), 1.22 (5'-CH3), 1.09 (12-CH3), 1.29, (4-CH3), 1.09 (10-CH3), 0.92 (8-CH3), 0.93 (14- CH3).
13C NMR (75 MHz, CDCl3) δ 177.5 (C-1), 103.1 (C-P), 95.2 (C-1"), 83.6 (C-5), 79.2 (C-12), 78.1 (C-3), 76.6 (C-11), 74.7 (C-13), 73.8 (C-6), 70.9 (C-2'), 68.8 (C-9), 65.6 (C-5"), 65.7 (C-3'), 61.6 (C-10), 52.8 (12-O CH3), 49.4 (3"-O CH3), 45.1 (C-2), 43.0 (C-7), 41.8 (C-4), 40.4 /3'N(CH3)2/, 36.8 (9a-NCH3), 35.0 (C-2"), 29.0 (C-4'), 26.9 (C-8), 26.9 (6-CH3), 22.0 (8-CH3), 22.0 (C-14), 21.6 (3"-CH3), 21.3 (5'-CH3), 18.1 (5" -CH3), 16.9 (12-CH3), 14.6 (2-CH3), 11.0 (14-CH3), 9.6 (4- CH3), 9.4(10-CH3). 13C NMR (75 MHz, CDCl3) δ 177.5 (C-1), 103.1 (C-P), 95.2 (C-1"), 83.6 (C-5), 79.2 (C-12), 78.1 (C-3), 76.6 (C-11), 74.7 (C-13), 73.8 (C-6), 70.9 (C-2'), 68.8 (C-9), 65.6 (C-5"), 65.7 (C-3' ), 61.6 (C-10), 52.8 (12-O CH3), 49.4 (3"-O CH3), 45.1 (C-2), 43.0 (C-7), 41.8 (C-4), 40.4 /3 'N(CH3)2/, 36.8 (9a-NCH3), 35.0 (C-2"), 29.0 (C-4'), 26.9 (C-8), 26.9 (6-CH3), 22.0 (8-CH3 ), 22.0 (C-14), 21.6 (3"-CH3), 21.3 (5'-CH3), 18.1 (5"-CH3), 16.9 (12-CH3), 14.6 (2-CH3), 11.0 (14 -CH3), 9.6 (4-CH3), 9.4(10-CH3).
Primjer 4. Example 4.
3-De(2,6-dideoksi-3-C-metil-3-O-metil-α-L-riboheksopiranozil-oksi)-3-oksi-12-O-metil-azitromicin 3-De(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl-oxy)-3-oxy-12-O-methyl-azithromycin
U 80 ml 0.25N solne kiseline otopi se 1.7 g (0.0022 mol) 12-O-metil-azitromicina iz Primjera 3. te ostavi da stoji 24 sata na sobnoj temperaturi. Na reakcijsku smjesu doda se metilenklorid (pH 1.8), pH smjese podesi s koncentriranim amonijakom na 9.0, slojevi odvoje, a vodeni ekstrahira s CH2Cl2. Sjedinjeni organski ekstrakti peru se s 10%-tnom vodenom otopinom NaHCO3 i vodom, suše nad K2CO3, te upare dajući 1.25 g naslovnog produkta sa slijedećim fizikalno-kemijskim konstantama: 1.7 g (0.0022 mol) of 12-O-methyl-azithromycin from Example 3 is dissolved in 80 ml of 0.25N hydrochloric acid and left to stand for 24 hours at room temperature. Methylene chloride (pH 1.8) is added to the reaction mixture, the pH of the mixture is adjusted to 9.0 with concentrated ammonia, the layers are separated, and the aqueous is extracted with CH2Cl2. The combined organic extracts are washed with 10% aqueous NaHCO3 solution and water, dried over K2CO3, and evaporated to give 1.25 g of the title product with the following physicochemical constants:
TLC, Metilenklorid-metanol-conc. amonijak, 90 : 9 : 0.5 Rf 0.315 TLC, Methylene chloride-methanol-conc. ammonia, 90 : 9 : 0.5 Rf 0.315
Etilacetat-n-heksan-dietilamin, 100: 100 : 20 Rf 0.594 Ethyl acetate-n-hexane-diethylamine, 100: 100: 20 Rf 0.594
IR(KBr)cm-1 3450,2971,2933, 1711, 1648, 1460, 1381, 1272, 1261, 1171, 1113, 1078, 1049. IR(KBr)cm-1 3450,2971,2933, 1711, 1648, 1460, 1381, 1272, 1261, 1171, 1113, 1078, 1049.
1H NMR (300 MHz, CDCl3) δ 5.32 (H-13), 4.47 (H-P), 3.78 (H-3), 3.66 (H-11), 3.58 (H-5), 3.58 (H-5'), 3.41 (12-OCH3), 3.28 (H-2'), 2.67 (H-2), 2.80 (H-10), 2.53 (H-3'), 2.53 (H-9a), 2.27 /3'N(CH3)2/, 2.37 (9a-NCH3), 2.07 (H-9b), 2.27 (H-4), 1.92 (H-8), 1.74 (H-14a), 1.68 (H-4'a), 1.59 (H-7a), 1.63 (H-14b), 1.51 (H-7b), 1.31 (6-CH3), 1.31 (2-CH3), 1.29 (H-4'b), 1.26 (5'-CH3), 1.08 (12-CH3), 1.05, (4-CH3), 1.19 (10-CH3), 0.93 (8-CH3), 0.92 (14-CH3). 1H NMR (300 MHz, CDCl3) δ 5.32 (H-13), 4.47 (H-P), 3.78 (H-3), 3.66 (H-11), 3.58 (H-5), 3.58 (H-5'), 3.41 (12-OCH3), 3.28 (H-2'), 2.67 (H-2), 2.80 (H-10), 2.53 (H-3'), 2.53 (H-9a), 2.27 /3'N( CH3)2/, 2.37 (9a-NCH3), 2.07 (H-9b), 2.27 (H-4), 1.92 (H-8), 1.74 (H-14a), 1.68 (H-4'a), 1.59 (H-7a), 1.63 (H-14b), 1.51 (H-7b), 1.31 (6-CH3), 1.31 (2-CH3), 1.29 (H-4'b), 1.26 (5'-CH3) , 1.08 (12-CH3), 1.05, (4-CH3), 1.19 (10-CH3), 0.93 (8-CH3), 0.92 (14-CH3).
13C NMR (75 MHz, CDCl3) δ 177.2 (C-1), 106.4 (C-P), 94.7 (C-5), 78.0 (C-12), 79.0 (C-3), 78.3 (C-11), 75.1 (C-13), 72.9 (C-6), 70.2 (C-2'), 70.3 (C-9), 65.3 (C-3'), 62.1 (C-10), 52.5 (12-OCH3), 44.3 (C-2), 41.8 (C-7), 35.7 (C-4), 39.9 /3'N(CH3)2/, 36.5 (9a-NCH3), 27.9 (C-4'), 26.4 (C-8), 25.5 (6-CH3), 20.8 (8-CH3), 20.7 (C-14), 20.8 (5'-CH3), 16.1 (12-CH3), 15.7 (2-CH3), 10.3 (14-CH3), 7.6 (4-CH3), 7.2 (10-CH3). 13C NMR (75 MHz, CDCl3) δ 177.2 (C-1), 106.4 (C-P), 94.7 (C-5), 78.0 (C-12), 79.0 (C-3), 78.3 (C-11), 75.1 (C-13), 72.9 (C-6), 70.2 (C-2'), 70.3 (C-9), 65.3 (C-3'), 62.1 (C-10), 52.5 (12-OCH3), 44.3 (C-2), 41.8 (C-7), 35.7 (C-4), 39.9 /3'N(CH3)2/, 36.5 (9a-NCH3), 27.9 (C-4'), 26.4 (C -8), 25.5 (6-CH3), 20.8 (8-CH3), 20.7 (C-14), 20.8 (5'-CH3), 16.1 (12-CH3), 15.7 (2-CH3), 10.3 (14 -CH3), 7.6 (4-CH3), 7.2 (10-CH3).
Primjer 5. Example 5.
3-De(2,6-dideoksi-3-C-metiI-3-O-metil-α-L-riboheksopiranoziI-oksi)-3-oksi-12-O-metil-azitromicin 2'-O-acetat 3-De(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosiI-oxy)-3-oxy-12-O-methyl-azithromycin 2'-O-acetate
U otopinu 3-de(2,6-dideoksi-3-C-metil-3-O-metil-α-L-riboheksopiranozil-oksi)-3-oksi-12-O-metil-azitromicina (1.3 g, 0.0022 mol) u metilenkloridu (20 ml) iz Primjera 4. doda se 0.754 (0.009 mol) NaHCO3 i 0.221 ml (0.0023 mol) anhidrida octene kiseline, a zatim miješa 10 sati na sobnoj temperaturi. Nakon stajanja preko noći, na reakcijsku smjesu doda se zasićena otopina NaHCO3, slojevi odvoje, a vodeni ekstrahira s CH2Cl2 Sjedinjeni organski ekstrakti peru se sa zasićenom otopinom NaHCO3 i vodom, suše nad K2CO3, filtriraju te upare dajući 1.29 g bijelog amorfnog taloga. In a solution of 3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl-oxy)-3-oxy-12-O-methyl-azithromycin (1.3 g, 0.0022 mol ) in methylene chloride (20 ml) from Example 4, add 0.754 (0.009 mol) NaHCO3 and 0.221 ml (0.0023 mol) acetic anhydride, and then stir for 10 hours at room temperature. After standing overnight, a saturated solution of NaHCO3 is added to the reaction mixture, the layers are separated, and the aqueous one is extracted with CH2Cl2. The combined organic extracts are washed with a saturated solution of NaHCO3 and water, dried over K2CO3, filtered and evaporated to give 1.29 g of a white amorphous precipitate.
TLC, Metilenklorid-metanol-conc. amonijak, 90 : 9 : 0.5 Rf 0.489 TLC, Methylene chloride-methanol-conc. ammonia, 90 : 9 : 0.5 Rf 0.489
Etilacetat-n-heksan-dietilamin, 100 : 100 : 20 Rf 0.661 Ethyl acetate-n-hexane-diethylamine, 100 : 100 : 20 Rf 0.661
IR (KBr) cm-1 3448, 2974, 1749, 1718, 1637, 1458, 1377, 1242, 1169, 1115, 1045. IR (KBr) cm-1 3448, 2974, 1749, 1718, 1637, 1458, 1377, 1242, 1169, 1115, 1045.
1H NMR (300 MHz, CDCl3) δ 5.23 (H-13), 4.72 (H-2'), 4.70 (H-1'), 3.59 (H-11), 3.56 (H-5), 3.52 (H-3), 3.43 (H-5'), 3.33 (12-OCH3), 2.72 (H-10), 2.71 (H-3'), 2.61 (H-2), 2.42 (H-9a), 2.30 (9a-NCH3), 2.20 /3'N(CH3)2/, 2.12 (H-4), 1.99 (2'-COCH3), 1.96 (H-9b), 1.80 (H-8), 1.67 (H-14a), 1.67 (H-4'a), 1.58 (H-14b), 1.47 (H-7a), 1.31 (H-4'b), 1.21 (2-CH3), 1.18 (H-7b), 1.16 (5'-CH3), 1.15 (6-CH3), 1.10 (10-CH3), 0.97 (12-CH3), 0.86 (14-CH3), 0.84 ( 8-CH3), 0.81 (4-CH3). 1H NMR (300 MHz, CDCl3) δ 5.23 (H-13), 4.72 (H-2'), 4.70 (H-1'), 3.59 (H-11), 3.56 (H-5), 3.52 (H- 3), 3.43 (H-5'), 3.33 (12-OCH3), 2.72 (H-10), 2.71 (H-3'), 2.61 (H-2), 2.42 (H-9a), 2.30 (9a -NCH3), 2.20 /3'N(CH3)2/, 2.12 (H-4), 1.99 (2'-COCH3), 1.96 (H-9b), 1.80 (H-8), 1.67 (H-14a) , 1.67 (H-4'a), 1.58 (H-14b), 1.47 (H-7a), 1.31 (H-4'b), 1.21 (2-CH3), 1.18 (H-7b), 1.16 (5 '-CH3), 1.15 (6-CH3), 1.10 (10-CH3), 0.97 (12-CH3), 0.86 (14-CH3), 0.84 (8-CH3), 0.81 (4-CH3).
13C NMR (75 MHz, CDCl3) δ 176.5 (C-1), 169.4 (2'-COCH3), 98.6 (C-1'), 84.3 (C-5), 77.3 (C-12), 78.3 (C-3), 76.7 (C-11), 74.6 (C-13), 72.4 (C-6), 70.7 (C-2'), 69.9 (C-9), 62.2 (C-3'), 62.3 (C-10), 51.9 (12-OCH3), 43.0 (C-2), 40.1 (C-7), 35.2 (C-4), 39.6 /3'N(CH3)2/, 35.9 (9a-NCH3), 30.0 (C-4'), 25.4 (C-8), 25.2 (6-CH3), 20.6 (2'-COCH3), 20.4 (8-CH3), 20.0 (C-14), 20.2 (5'-CH3), 15.9 (12-CH3), 15.2 (2-CH3), 9.7 (14-CH3), 7.0 (4-CH3), 6.4 (10-CH3). 13C NMR (75 MHz, CDCl3) δ 176.5 (C-1), 169.4 (2'-COCH3), 98.6 (C-1'), 84.3 (C-5), 77.3 (C-12), 78.3 (C- 3), 76.7 (C-11), 74.6 (C-13), 72.4 (C-6), 70.7 (C-2'), 69.9 (C-9), 62.2 (C-3'), 62.3 (C -10), 51.9 (12-OCH3), 43.0 (C-2), 40.1 (C-7), 35.2 (C-4), 39.6 /3'N(CH3)2/, 35.9 (9a-NCH3), 30.0 (C-4'), 25.4 (C-8), 25.2 (6-CH3), 20.6 (2'-COCH3), 20.4 (8-CH3), 20.0 (C-14), 20.2 (5'-CH3 ), 15.9 (12-CH3), 15.2 (2-CH3), 9.7 (14-CH3), 7.0 (4-CH3), 6.4 (10-CH3).
Primjer 6. Example 6.
3-De(2,6-dideoksi-3-C-metil-3-0-metil-α-L-riboheksopirazonil-oksi)-3-okso-12-O-metil-azitromicin 2'-O-acetat 3-De(2,6-dideoxy-3-C-methyl-3-0-methyl-α-L-ribohexopyrazonyl-oxy)-3-oxo-12-O-methyl-azithromycin 2'-O-acetate
U otopinu 3-de(2,6-dideoksi-3-C-metil-3-O-metil-α-L-riboheksopiranozil-oksi)-3-oksi-12-O-metil-azitromicin 2'-O-acetata (1.3 g, 0.0020 mol) iz Primjera 5. u metilenkloridu (15 ml) doda se 4.35 ml dimetilsulfoksida i 4.55 g N-dimetil-aminopropil-etil-karbodiimida. Reakcijska smjesa ohladi se na 15 °C, a zatim se uz miješanje i održavanje temperature postepeno kroz 30 minuta dokapa otopina od 4.61 g (0.0234) piridinium trifluoracetata u 10 ml metilenklorida. Temperatura reakcijske smjese postepeno se povisi na sobnu, miješanje nastavi daljnjih 2 sata, a zatim reakcija prekine dodatkom 25 ml zasićene otopine NaCl. Nakon zaluživanja s 2 N NaOH na 9.5, reakcijska smjesa ekstrahira se CH2Cl2, organski ekstrakti peru zasićenom otopinom NaCl, NaHCO3 i vodom te suše nad K2CO3. Otparavanjem CH2Cl2 kod sniženog pritiska dobiva se 1.78 g uljastog ostatka koji se po potrebi čisti niskotlačnom kromatografijom na stupcu silikagela uz upotrebu sistemu otapala etilacetat-trietilamin, 95 : 5. Uparavanjem sjedinjenih ekstrakta s Rf 0.425 dobiva se kromatografski homogeni naslovni produkt sa slijedećim fizikalno-kemijski konstantama: In a solution of 3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl-oxy)-3-oxy-12-O-methyl-azithromycin 2'-O-acetate (1.3 g, 0.0020 mol) from Example 5 in methylene chloride (15 ml) were added 4.35 ml of dimethyl sulfoxide and 4.55 g of N-dimethyl-aminopropyl-ethyl-carbodiimide. The reaction mixture is cooled to 15 °C, and then, while stirring and maintaining the temperature, a solution of 4.61 g (0.0234) pyridinium trifluoroacetate in 10 ml of methylene chloride is gradually added dropwise over 30 minutes. The temperature of the reaction mixture was gradually raised to room temperature, the mixing continued for another 2 hours, and then the reaction was stopped by the addition of 25 ml of saturated NaCl solution. After alkalinization with 2 N NaOH at 9.5, the reaction mixture is extracted with CH2Cl2, the organic extracts are washed with a saturated solution of NaCl, NaHCO3 and water and dried over K2CO3. By evaporating CH2Cl2 under reduced pressure, 1.78 g of an oily residue is obtained, which, if necessary, is purified by low-pressure chromatography on a silica gel column using the solvent system ethyl acetate-triethylamine, 95 : 5. Evaporation of the combined extracts with Rf 0.425 gives the chromatographically homogeneous title product with the following physico-chemical constants:
TLC, Metilenklorid-metanol-conc. amonijak, 90 : 9 : 0.5 Rf 0.176 TLC, Methylene chloride-methanol-conc. ammonia, 90 : 9 : 0.5 Rf 0.176
Etilacetat-n-heksan-dietilamin, 100 : 100 : 20 Rf 0.861 Ethyl acetate-n-hexane-diethylamine, 100 : 100 : 20 Rf 0.861
IR (CDCl3) cm-1 3441, 2975, 2939, 1743, 1720, 1655, 1560, 1456, 1406, 1372, 1241, 1196, 1115, 1048, 952. IR (CDCl3) cm-1 3441, 2975, 2939, 1743, 1720, 1655, 1560, 1456, 1406, 1372, 1241, 1196, 1115, 1048, 952.
13C NMR (75 MHz, CDCl3) δ 211.4 (C-3), 176.0 (C-1), 169.8 (C=O acetat), 104.2 (C-1'), 95.1 (C-5), 72.7 (C-6), 78.4 (C-12), 74.8 (C-13), 70.6 (C-2'), 68.8 (C-5'), 64.5 (C-9), 62.9 (C-3'), 60.7 (C-10), 52.0 (12-OCH3), 41.3 (C-7), 40.2 (9a-NCH3), 20.5 (2'-COCH3), 26.5 (6-CH3), 26.3 (C-8), 21.6 (C-14) 20.8 (8-CH3), 20.5 (5'-CH3), 20.5 (2'-COCH3), 10.6 (14-CH3). 13C NMR (75 MHz, CDCl3) δ 211.4 (C-3), 176.0 (C-1), 169.8 (C=O acetate), 104.2 (C-1'), 95.1 (C-5), 72.7 (C- 6), 78.4 (C-12), 74.8 (C-13), 70.6 (C-2'), 68.8 (C-5'), 64.5 (C-9), 62.9 (C-3'), 60.7 ( C-10), 52.0 (12-OCH3), 41.3 (C-7), 40.2 (9a-NCH3), 20.5 (2'-COCH3), 26.5 (6-CH3), 26.3 (C-8), 21.6 ( C-14) 20.8 (8-CH3), 20.5 (5'-CH3), 20.5 (2'-COCH3), 10.6 (14-CH3).
Primjer 7. Example 7.
3-De(2,6-dideoksi-3-C-metil-3-O-metil-α-L-riboheksopirazonil-oksi)-3-okso-12-O-metil-azitromicin 3-De(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyrazonyl-oxy)-3-oxo-12-O-methyl-azithromycin
3-De(2,6-dideoksi-3-C-metil-3-O-metil-α-L-ribboheksopirazonil-oksi)-3-oksi-12-O-metil-azitromicin 3-De(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribbohexopyrazonyl-oxy)-3-oxy-12-O-methyl-azithromycin
3,6-hemiketal 3,6-hemiketal
Otopina od 1.78 g 3-de(2,6-dideoksi-3-C-metil-3-O-metil-α-L-riboheksopiranozil-oksi)-3-okso-12-O--metil-azitromicin 2'-O-acetata iz Primjera 6. u metanolu (50 ml) ostavi se da stoji 24 sati na sobnoj temperaturi. Metanol se otpari kod sniženog pritiska, a dobiveni ostatak (1.65 g) čisti niskotlačnom kromatografijom na stupcu silikagela uz upotrebu sistemu metilenklorid-metanol-conc. amonijak, 90 : 9 : 0.5. Uparavanjem sjedinjenih ekstrakta s Rf 0.152 dobiva se 0.237 g kromatografski homogenog 3-de(2,6-dideoksi-3-C-metil-3-O-metil-α-L-riboheksopiranozil-oksi)-3-okso-12-O-metil-azitromicina sa slijedećim fizikalno-kemijski konstantama: A solution of 1.78 g of 3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl-oxy)-3-oxo-12-O--methyl-azithromycin 2'- O-acetate from Example 6 in methanol (50 ml) is left to stand for 24 hours at room temperature. Methanol is evaporated under reduced pressure, and the resulting residue (1.65 g) is purified by low-pressure chromatography on a silica gel column using the system methylene chloride-methanol-conc. ammonia, 90 : 9 : 0.5. Evaporation of combined extracts with Rf 0.152 yields 0.237 g of chromatographically homogeneous 3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl-oxy)-3-oxo-12-O -methyl-azithromycin with the following physical and chemical constants:
TLC, Metilenklorid-metanol-conc. amonijak, 90 : 9 : 0.5 Rf 0.152 TLC, Methylene chloride-methanol-conc. ammonia, 90 : 9 : 0.5 Rf 0.152
Etilacetat-n-heksan-dietilamin, 100 : 100 : 20 Rf 0.814 Ethyl acetate-n-hexane-diethylamine, 100 : 100 : 20 Rf 0.814
IR (CDCl3) cm-1 3469, 2976, 1719, 1651, 1459, 1382, 1192, 1115, 1047, 1014, 965, IR (CDCl3) cm-1 3469, 2976, 1719, 1651, 1459, 1382, 1192, 1115, 1047, 1014, 965,
te 0.162 g kromatografski homogenog 3-de(2,6-dideoksi-3-C-metil-3-O-metil-α-L-riboheksopiranozil-oksi)-3-oksi-12-O-metil-azitromicin 3,6-hemiketala sa slijedećim fizikalno-kemijski konstantama: and 0.162 g of chromatographically homogeneous 3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl-oxy)-3-oxy-12-O-methyl-azithromycin 3,6 - hemiketal with the following physico-chemical constants:
TLC, Metilenklorid-metanol-conc. amonijak, 90 : 9 : 0.5 Rf 0.082 TLC, Methylene chloride-methanol-conc. ammonia, 90 : 9 : 0.5 Rf 0.082
Etilacetat-n-heksan-dietilamin, 100 : 100 : 20 Rf 0.624 Ethyl acetate-n-hexane-diethylamine, 100 : 100 : 20 Rf 0.624
IR (CDC13) cm-1 3450, 2956, 2940, 1718, 1678, 1631, 1459, 1383, 1278, 1198, 1117, 1068, 1048, 1014, 963. IR (CDC13) cm-1 3450, 2956, 2940, 1718, 1678, 1631, 1459, 1383, 1278, 1198, 1117, 1068, 1048, 1014, 963.
1H NMR (300 MHz, CDCl3) δ 5.49 (H-13), 4.21 (H-1'), 3.83 (H-11), 3.75 (H-5), 3.52 (H-5'), 3.43 (12-OCH3), 3.25 (H-2'), 2.59 (H-2), 2.93 (H-10), 2.50 (H-3'), 2.61 (H-9a), 2.29 /3'N(CH3)2/, 2.40 (9a-NCH3), 2.10 (H-9b), 2.06 (H-4), 1.88 (H-8), 1.77 (H-14a), 1.67 (H-4'a), 1.61 (H-7a), 1.64 (H-14b), 1.33 (H-7b), 1.31 (6-CH3), 1.05 (2-CH3), 1.27 (H-4'b), 1.26 (5'-CH3), 1.08 (12-CH3), 1.05, (4-CH3), 1.19 (10-CH3), 0.92 (8-CH3), 0.93 (14-CH3). 1H NMR (300 MHz, CDCl3) δ 5.49 (H-13), 4.21 (H-1'), 3.83 (H-11), 3.75 (H-5), 3.52 (H-5'), 3.43 (12- OCH3), 3.25 (H-2'), 2.59 (H-2), 2.93 (H-10), 2.50 (H-3'), 2.61 (H-9a), 2.29 /3'N(CH3)2/ , 2.40 (9a-NCH3), 2.10 (H-9b), 2.06 (H-4), 1.88 (H-8), 1.77 (H-14a), 1.67 (H-4'a), 1.61 (H-7a ), 1.64 (H-14b), 1.33 (H-7b), 1.31 (6-CH3), 1.05 (2-CH3), 1.27 (H-4'b), 1.26 (5'-CH3), 1.08 (12 -CH3), 1.05, (4-CH3), 1.19 (10-CH3), 0.92 (8-CH3), 0.93 (14-CH3).
I3C NMR (75 MHz, CDCl3) δ 176.2 (C-1), 105.8 (C-1'), 94.6 (C-5), 78.3 (C-12), 102.7 (C-3), 71.2 (C-11), 74.8 (C-13), 82.9 (C-6), 69.6 (C-2'), 64.5 (C-9), 65.1 (C-3'), 60.7 (C-10), 52.2 (12-OCH3), 49.2 (C-2), 41.4 (C-7), 48.6 (C-4), 40.0 /3'N(CH3)2/, 40.5 (9a-NCH3), 28.2 (C-4'), 29.1 (C-8), 26.5 (6-CH3), 21.5 (8-CH3), 21.6 (C-14), 20.8 (5'-CH3), 16.3 (12-CH3), 13.6 (2-CH3), 10.7 (14-CH3), 12.8 (4-CH3), 10.7 (10-CH3). I3C NMR (75 MHz, CDCl3) δ 176.2 (C-1), 105.8 (C-1'), 94.6 (C-5), 78.3 (C-12), 102.7 (C-3), 71.2 (C-11 ), 74.8 (C-13), 82.9 (C-6), 69.6 (C-2'), 64.5 (C-9), 65.1 (C-3'), 60.7 (C-10), 52.2 (12- OCH3), 49.2 (C-2), 41.4 (C-7), 48.6 (C-4), 40.0 /3'N(CH3)2/, 40.5 (9a-NCH3), 28.2 (C-4'), 29.1 (C-8), 26.5 (6-CH3), 21.5 (8-CH3), 21.6 (C-14), 20.8 (5'-CH3), 16.3 (12-CH3), 13.6 (2-CH3), 10.7 (14-CH3), 12.8 (4-CH3), 10.7 (10-CH3).
Claims (13)
Priority Applications (35)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HR970551A HRP970551B1 (en) | 1997-10-16 | 1997-10-16 | Novel o-methyl azythromycin derivatives |
| EP04004844A EP1437359B1 (en) | 1997-10-16 | 1998-10-13 | Novel 3,6-Hemiketals from the Class of 9a-Azalides |
| CNB988116243A CN1281615C (en) | 1997-10-16 | 1998-10-13 | Novel 3.6-hemiketals from the class of 9a-azalides |
| SK552-2000A SK285914B6 (en) | 1997-10-16 | 1998-10-13 | 3,6-Hemiketals, preparation method thereof, pharmaceutical composition comprising the same and their use |
| DE69836697T DE69836697T2 (en) | 1997-10-16 | 1998-10-13 | New 3,6-hemiketals of the 9a-azalid class |
| ES98946627T ES2222610T3 (en) | 1997-10-16 | 1998-10-13 | NEW 9A-AZALIDAS. |
| AT98946627T ATE267835T1 (en) | 1997-10-16 | 1998-10-13 | NEW 9A AZALIDE |
| JP2000516980A JP2001520234A (en) | 1997-10-16 | 1998-10-13 | Novel 3,6-hemiketals derived from 9a-azalides |
| ES04004844T ES2279242T3 (en) | 1997-10-16 | 1998-10-13 | NEW 3,6-HEMICETALS OF THE CLASS OF 9A-AZALIDAS. |
| KR1020007004079A KR100554549B1 (en) | 1997-10-16 | 1998-10-13 | NOVEL 3,6-HEMIKETALS FROM THE CLASS OF 9a-AZALIDES |
| CA002306963A CA2306963C (en) | 1997-10-16 | 1998-10-13 | Novel 3,6-hemiketals from the class of 9a-azalides |
| AU93622/98A AU755315B2 (en) | 1997-10-16 | 1998-10-13 | Novel 3,6-hemiketals from the class of 9a-azalides |
| HU0004085A HUP0004085A3 (en) | 1997-10-16 | 1998-10-13 | Novel 3,6-hemiketals from the class of 9a-azalides |
| RU2000111996/04A RU2220148C2 (en) | 1997-10-16 | 1998-10-13 | Derivatives of azithromycin and method for their preparing |
| EEP200000226A EE04681B1 (en) | 1997-10-16 | 1998-10-13 | 3,6-Half-Ketals of the 9a-Azalides, Method of Preparation and Pharmaceutical Composition |
| SI9830675T SI1036083T1 (en) | 1997-10-16 | 1998-10-13 | Novel 9a-azalides |
| DK98946627T DK1036083T5 (en) | 1997-10-16 | 1998-10-13 | New 9A azalides |
| EP98946627A EP1036083B9 (en) | 1997-10-16 | 1998-10-13 | Novel 9a-azalides |
| US09/529,642 US6369035B1 (en) | 1997-10-16 | 1998-10-13 | 3,6-hemiketals from the class of 9A-azalides |
| NZ503897A NZ503897A (en) | 1997-10-16 | 1998-10-13 | 3,6-hemiketals from the class of 9a-azalides |
| IL13564898A IL135648A0 (en) | 1997-10-16 | 1998-10-13 | Novel 3, 6-hemiketals from the class of 9a-azalides |
| AT04004844T ATE348836T1 (en) | 1997-10-16 | 1998-10-13 | NEW 3,6-HEMIKETALS OF THE 9A AZALIDE CLASS |
| PT98946627T PT1036083E (en) | 1997-10-16 | 1998-10-13 | NEW 9A-AZALIDOS |
| BR9812808-6A BR9812808A (en) | 1997-10-16 | 1998-10-13 | 9a-azalide class 3,6 hemicetals, process for preparing same, pharmaceutical use as well as pharmaceutical composition comprising the same |
| DK04004844T DK1437359T3 (en) | 1997-10-16 | 1998-10-13 | New 3,6 hemiketals of the 9α-azalide class |
| PT04004844T PT1437359E (en) | 1997-10-16 | 1998-10-13 | Novel 3,6-hemiketals from the class of 9a-azalides |
| SI9830878T SI1437359T1 (en) | 1997-10-16 | 1998-10-13 | Novel 3,6-Hemiketals from the Class of 9a-Azalides |
| DE69824201T DE69824201T2 (en) | 1997-10-16 | 1998-10-13 | NEW 9A AZALIDE |
| PCT/HR1998/000005 WO1999020639A2 (en) | 1997-10-16 | 1998-10-13 | NOVEL 3,6-HEMIKETALS FROM THE CLASS OF 9a-AZALIDES |
| PL340372A PL191087B1 (en) | 1997-10-16 | 1998-10-13 | Novel 3,6x-hemiketals of 9a-azalydes class |
| ARP980105155A AR018014A1 (en) | 1997-10-16 | 1998-10-16 | COMPOUNDS DERIVED FROM 3,6-HEMICETALS OF THE CLASS OF 9A-AZALIDOS, A PROCEDURE TO PREPARE THEM AND PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM. |
| NO20001871A NO20001871L (en) | 1997-10-16 | 2000-04-11 | New 3,6-hemiacetals from the class 9a-azalides |
| IL135648A IL135648A (en) | 1997-10-16 | 2000-04-13 | Azithromycin derivatives, their preparation and antibacterial pharmaceutical compositions containing them |
| BG104445A BG64650B1 (en) | 1997-10-16 | 2000-05-16 | 9a-azalides |
| HK01103498A HK1032785A1 (en) | 1997-10-16 | 2001-05-22 | Novel 3,6-hemiketals from the class of 9a-azalides |
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| HR970551A HRP970551B1 (en) | 1997-10-16 | 1997-10-16 | Novel o-methyl azythromycin derivatives |
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