MXPA00003644A - NOVEL 3,6-HEMIKETALS FROM THE CLASS OF 9a-AZALIDES - Google Patents
NOVEL 3,6-HEMIKETALS FROM THE CLASS OF 9a-AZALIDESInfo
- Publication number
- MXPA00003644A MXPA00003644A MXPA/A/2000/003644A MXPA00003644A MXPA00003644A MX PA00003644 A MXPA00003644 A MX PA00003644A MX PA00003644 A MXPA00003644 A MX PA00003644A MX PA00003644 A MXPA00003644 A MX PA00003644A
- Authority
- MX
- Mexico
- Prior art keywords
- group
- represent
- equal
- methyl
- hydrogen
- Prior art date
Links
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 133
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 107
- 239000001257 hydrogen Substances 0.000 claims abstract description 107
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 94
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 73
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 125000001033 ether group Chemical group 0.000 claims abstract description 32
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 24
- -1 L-cladinosyl group Chemical group 0.000 claims abstract description 19
- 238000007792 addition Methods 0.000 claims abstract description 14
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims abstract description 14
- 150000005676 cyclic carbonates Chemical class 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 239000003120 macrolide antibiotic agent Substances 0.000 claims abstract description 11
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 150000007524 organic acids Chemical class 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 7
- 235000005985 organic acids Nutrition 0.000 claims abstract description 7
- 230000008569 process Effects 0.000 claims abstract description 7
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 6
- 125000002252 acyl group Chemical group 0.000 claims abstract description 5
- 239000000543 intermediate Substances 0.000 claims abstract description 5
- 229960004099 azithromycin Drugs 0.000 claims description 64
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 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 20
- 239000000203 mixture Substances 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- 230000002829 reductive effect Effects 0.000 claims description 13
- 239000000741 silica gel Substances 0.000 claims description 13
- 229910002027 silica gel Inorganic materials 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 12
- 238000007069 methylation reaction Methods 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 10
- 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 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 235000019253 formic acid Nutrition 0.000 claims description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 8
- 150000001298 alcohols Chemical class 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000012442 inert solvent Substances 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000005917 acylation reaction Methods 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 229910004373 HOAc Inorganic materials 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 230000010933 acylation Effects 0.000 claims description 5
- 150000001735 carboxylic acids Chemical class 0.000 claims description 5
- 150000001805 chlorine compounds Chemical class 0.000 claims description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000003810 Jones reagent Substances 0.000 claims description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 2
- 230000000845 anti-microbial effect Effects 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000005828 desilylation reaction Methods 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 239000012022 methylating agents Substances 0.000 claims description 2
- 238000006884 silylation 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 239000012298 atmosphere Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 125000000369 oxido group Chemical group [*]=O 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000003981 vehicle Substances 0.000 claims 1
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 abstract 2
- 125000003107 substituted aryl group Chemical group 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 33
- 239000010410 layer Substances 0.000 description 26
- 239000000047 product Substances 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 229910001868 water Inorganic materials 0.000 description 23
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 19
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000284 extract Substances 0.000 description 14
- 101150041968 CDC13 gene Proteins 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 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 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 229960003276 erythromycin Drugs 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 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 3
- 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 3
- 241000894006 Bacteria Species 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229930006677 Erythromycin A Natural products 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 229960002626 clarithromycin Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 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 3
- 239000003835 ketolide antibiotic agent Substances 0.000 description 3
- 230000011987 methylation Effects 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- GAPYKZAARZMMGP-UHFFFAOYSA-N pyridin-1-ium;acetate Chemical compound CC(O)=O.C1=CC=NC=C1 GAPYKZAARZMMGP-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- ORVGLRAXIUNDTG-SBXXAWCKSA-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-dihydroxy-13-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-10-methoxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadec 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)([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 ORVGLRAXIUNDTG-SBXXAWCKSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 241000589989 Helicobacter Species 0.000 description 2
- 101000693444 Homo sapiens Zinc transporter ZIP2 Proteins 0.000 description 2
- 241000589248 Legionella Species 0.000 description 2
- 208000007764 Legionnaires' Disease Diseases 0.000 description 2
- YKFRUJSEPGHZFJ-UHFFFAOYSA-N N-trimethylsilylimidazole Chemical compound C[Si](C)(C)N1C=CN=C1 YKFRUJSEPGHZFJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 102100025451 Zinc transporter ZIP2 Human genes 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 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 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 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
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 150000003949 imides Chemical class 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 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
- MWBJRTBANFUBOX-SQYJNGITSA-N (3r,4s,5s,6r,7r,9r,10e,11s,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-12,13-dihydroxy-10-hydroxyimino-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-7-methoxy-3,5,7,9,11,13-hexamethyl-oxacyclot Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/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 MWBJRTBANFUBOX-SQYJNGITSA-N 0.000 description 1
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
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- 150000007513 acids Chemical class 0.000 description 1
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- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
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- AJSDVNKVGFVAQU-BIIVOSGPSA-N cladinose Chemical compound O=CC[C@@](C)(OC)[C@@H](O)[C@H](C)O AJSDVNKVGFVAQU-BIIVOSGPSA-N 0.000 description 1
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- 238000003113 dilution method Methods 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
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- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
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- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to compounds of general formula (I) characterized in that R1 individually stands for hydroxyl, L-cladinosyl group of formula (II) wherein R2 individually stands for hydrogen or a silyl group;R3 individually stands for hydrogen or together with R6 stands for an ether group;R4 individually stands for hydrogen, (C1-C4)acyl group or -COO-(CH2)n-Ar group, wherein n is 1-7 and Ar individually stands for unsubstituted or substituted aryl group with up to 18 carbon atoms;R5 individually stands for hydrogen, methyl group or -COO-(CH2)n-Ar group, wherein n is 1-7 and Ar individually stands for unsubstituted or substituted aryl group with up to 18 carbon atoms;R6 individually stands for a hydroxyl group or together with R3 stands for an ether group;R7 individually stands for hydrogen, (C1-C12)alkyl group, silyl group or together with R8 and C-11/C-12 carbon atoms stands for a cyclic carbonate, R8 individually stands for hydrogen, (C1-C12)alkyl group, silyl group or together with R7 and C-11/C-12 carbon atoms stands for a cyclic carbonate;and its pharmaceutically acceptable additions salts with inorganic or organic acids, to a process for the preparation thereof and to the use thereof as antibiotics or as intermediates for the synthesis of other macrolide antibiotics.
Description
NEW 3, 6-HEMICETALES OF THE CLASS OF THE 9a- AZALIDOS
TECHNICAL FIELD OF THE INVENTION Technical problem. The invention relates to new compounds of the class of macrolide antibiotics. Particularly, the invention relates to novel 3, 6 -hemi ce ta 1 is of the class of 9a-azalides, to its pharmaceutically acceptable addition salts with inorganic or organic acids, to a process for its preparation and to the use of the same as antibiotics or as intermediates for the synthesis of other macrolide antibiotics.
Previous technique The macrolide antibiotic erythromycin A has been considered for more than 40 years a safe and effective agent for the treatment of respiratory and genital infections caused by gram-positive and some gram-negative bacteria, some species of Legionella, Mycoplasma, Chlamidia and Helicobacter. Some changes observed in bioavailability after oral administration, gastric intolerance in many patients and loss of activity in an acid medium where the inactive metabolite anhydroerythromycin is formed, are basic disadvantages in the clinical use of erythromycin. However, the spirocyclization of the aglycone ring is successfully inhibited by means of a chemical transformation of the C-9 ketone or hydroxyl groups at the C-6 and / or C-12 positions. Thus, for ex. , by oximación of the C-9 ketone and subsequent transposition of Beckmann and reduction, 9-deoxo-9a-aza-9a-homoerythromycin A is obtained, the first 15-member macrolide antibiotic with a 9a-amino group incorporated into the ring aglycone (Kobrehel, G. et al., US 4,328,334; 5/1982). By means of reductive methylation of 9-amines according to the Esch eiler-Clark procedure, 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin (AZITHROMYCIN), a prototype of a new class, is synthesized. of macrolide antibiotics, namely, azalides (Kobrehel, G. et al., BE 892357; 7/1982). In addition to a broad antimicrobial spectrum that also includes gram-negative bacteria, azithromycin is also characterized by a prolonged biological half-life, a transport mechanism specific to the site of use and a short treatment period. Azithromycin readily penetrates and accumulates within human phagocytic cells resulting in improved action on the intracellular pathogenic microorganisms of the Legionella, Chlamidia and Helicobacter classes.
Furthermore, it is known that the C-6 / C-12 spirocyclicization of erythromycin A is successfully inhibited by O-methylation of the C-6 hydroxyl group of the aglycone ring (Watanabe Y. et al., US 4,331.8Q3; 5/1982). ). By the reaction of erythromycin with benzyloxycarbonyl chloride and subsequent methylation of the obtained 2'-O, 3'-N-bis (benzyloxycarbonyl) derivative, by removal of the protecting groups and by 3'-N-methylation, are furthermore formed of 6-O-methylerythromycin (CLARITHROMYCIN), also significant amounts of 11-O-methylerythromycin and multiply substituted analogues (Morimoto, S. et al., J. Antibiotics, 1984, 37, 187). With respect to erythromycin A, clarithromycin is considerably more stable in an acid medium and has better in vitro action with respect to strains of gram-positive bacteria (Kirst, H.A. et al., Antimicrobial Agents and Chemoter., 1989, 1419). In a similar manner a series of 0-methyl derivatives of azithromycin was also synthesized (K obrehel, G. et al., US 5,250,518; 10/1993). Although the main products of the O-methylation of azithromycin, namely, 11-O-methyl-azithromycin (Example 8) and 6-O-methyl-azithromycin (Example 6) present significant activity against strains of standard bacteria and isolates In clinical trials, and pharmacokinetic properties similar to those of azithromycin, obtaining products in larger quantities represents an additional technical problem due to the non-selectivity of O-methylation. The determination of the The structure of the O-methyl derivatives of azithromycin was based on the analysis of the 1H-1H and 1H-13C 2D NMR spectra (300 MHz). Subsequently, it was further determined by long-range NMR spectroscopy that the substitution of the C-6 hydroxyl group had been erroneously attributed to azithromycin and that in fact it was 12-0-methylazithromycin. It was further found that the use of suitable protecting groups on the hydroxyl groups at the 4"and 11 positions (especially of silyl protecting groups such as the trimethylsilyl groups) results in selective O-methylation and enables simple preparation of the -0-methyl-azithromycin (HR 970051A; 10/97). Later, Waddell, S.T. et al., (Biorg. Med. Chem. Letters 8 (1998), 549-555), independently of the last patent application, established the O-methylation of the hydroxyl group at the C-12 position. It is also known that recent research on 14-member macrolides led to the discovery of a new type of macrolide antibiotics, namely ketolides. Instead of the neutral L-cladinose sugar known for its instability even in a weakly acid medium, these compounds possess a keto group in the C-3 position (Agouridas, C. et al., EP 596802 Al, 5/1994; Le Martret , 0., FR 2697524 Al, 5/1994). The ketolides. they show significantly better activity against MLS-induced resistant organisms (Macrolide, lincosamide and e s t r ep t ogr amine B) (Jamjian, C., Antimicrob Agents Chemother., 1997, 41, 485). This important discovery has led to a large number of 3-keto derivatives of clarithromycin, largely substituted at positions C-ll / C-12, giving numerous carbonates, carbamates and, recently, carbazatos, cyclic. The first step of the synthesis of ketolides includes the hydrolysis of clarithromycin with the formation of a corresponding derivative 3-of c inos amines ilo, (3-de (2,6-dideoxy-3-C-methyl-3-0-methyl- aL-ribohexopyranosyl-oxy) -derivate), which is subject, after removal of the protection of the 2'-hydroxyl group (preferably by acylation with chlorides or anhydrides of carboxylic acids), to an oxidation and deprotection reaction of the position 2' . According to our knowledge, cetolides substituted in C-ll / C-12 of the class of 9a-azalide antibiotics have not been described so far. The first step, namely, the synthesis of the 3-de-1-adi-derivatives not 1 or 9-deoxo-9a-az a-9 a-homoeri tr omi ciña and azithromycin, is described in the US patent No 4,886,792, 12/1989. With the intention of oxidizing the C-3 hydroxyl group of 3-cladino if 1-azitr omi ci na and its derivatives 11-0-methyl and 12-O-methyl by the transannular addition of the 6-hydroxyl group on the ketone Recently formed C-3 has been obtained a series not described so far of 3,6-bicyclic and tricyclic hemicetales of the class of 9a-azalides. The synthesis of 3, 6 -hemi ce ta 1 is of azithromycin and O-methyl derivatives thereof comprises the preparation of corresponding 3-decladin derivatives i 1, the protection of the 2 'idroxyl group of basic sugar, D- of sos amine, by selective acylation, the oxidation of the hydroxyl group in position C-3, that of sprotecc ion of the 2 'position and the cyclization of the hydroxyl groups C-ll and C-12. Also the subject of the present invention are the pharmaceutically acceptable salts of the 3, 6 -hemi keta 1 is azithromycin and its O-methyl derivatives with organic and inorganic acids, methods and intermediates for its preparation, as well as methods of preparation and application of pharmaceutical preparations.
Description of the technical problems with examples. The invention relates to: i) new 3, 6-heiketa 1 is of the class of 9a-azalides, ii) a process for the preparation of new 3, 6-hemi ce ta 1 is of the class of 9a- az idos, iii) use of new 3, 6 - hemi ceta 1 is of the class of 9a-azalides' as antibiotics or as intermediates for the synthesis of other macrolide antibiotics. New 3, 6 -hemi c e t a 1 s of the class of 9a-azalides of the general formula (I):
> characterized in that: R1 represents individually hydroxyl, a group L - c 1 to d i not s i 1 or of formula II):
wherein: R2 represents individually hydrogen or a silyl, R3 individually represents hydrogen or together with R6 represents an ether group, 'R4 individually represents hydrogen, an acyl group (C? -C) or a group - COO- (CH2) n - Ar, where n is 1-7 and Ar individually represents a substituted or unsubstituted aryl group with up to 18 carbon atoms, R5 represents individually hydrogen, a methyl group or a group -COO- (C H2) n_ Ar, in where n is 1-7 and Ar individually represents a substituted or unsubstituted aryl group with up to 18 carbon atoms, R represents individually a hydroxyl group or together with R3 has the meaning of an ether group, R7 individually represents hydrogen, an alkyl group (C? -C? 2), a silyl group or together with R8 and carbon atoms C-ll / C-12 represents a cyclic carbonate, R8 represents individually hydrogen, an 'alkyl group (C i -C 12), a silyl group or together with R and carbon atoms C-ll / C- 12 represents a cyclic carbonate, and its pharmaceutically acceptable addition salts with inorganic or organic acids are obtained by the following steps.
1: Azithromycin of the general formula (I) wherein R 1 represents a group L - c 1 ad i not if 1 or of the formula (II), R 2, R 3, R 4, R 7 and R 8 are equal to each other and represent hydrogen, R5 is methyl and Rd is a hydroxyl group, is subjected to a reaction with chlorides of organic carboxylic acids of the f or rmul a (III): C1COO (CH2) nr (III) where n is 1-7 and Ar represents individually substituted or unsubstituted aryl groups with up to 18 carbon atoms, preferably with benzyloxycarbonyl chloride, in the presence of bases, preferably sodium hydrogen carbonate, in a solvent inert to the reaction, preferably in benzene or toluene, giving 2'-0,3'-N-bis (benzyloxycarbonyl) -3'-N-demethyl-1-azithromycin (Kobrehel, G. et al., US 5,250,518 5/1993) of the general formula (I ) wherein R1 represents a group L - c 1 adi no if 1 or of the formula ('II), R2, R3. R7 and R8 are equal to each other and represent hydrogen, R4 and R5 are equal to each other and represent a benzylcarbonyl group and R6 is a hydroxyl group, which is subsequently subjected to silylation of the hydroxyl groups in: A / 4"positions and 11 with equimolar 2-5 excess of a silylating agent, in an inert organic solvent, at the temperature of 0-5 ° C for 5-8 hours, giving a new 4", 11-0-bis (trimethylsilyl) -2 '- 0, 3' -vi-b is (benzyloxycarbonyl)
- 3 '-iV-deme t i 1 - a z i t r omi ciña of the general formula
(I), where R1 represents a group L - c 1 adi no if 1 or of the formula (II), R2 and R7 are equal to each other and represent a group tr ime ti 1 if 1 i lo R- and R ( they are equal to each other and represent hydrogen, R4 and R5 are equal to each other and represent a benzyloxycarbonyl group and R6 is a hydroxyl group, or in, B / 4"position with equimolar excess 1.1-2 of a silylating agent, in an inert organic solvent, at the temperature of 0-5 ° C for 1 hour, giving a new 4"-O- trimeti 1 if 1 i 1 - 2 '- O, 3' - N-bis (benzyloxycarbonyl) - 3'-W-e-t-azithromycin of the general formula (I), wherein R 1 represents a group L-c 1 to diene if 1 or of the formula (II), R 2 represents a group tr ime ti 1 if 1 i 1, R 3, R 7 and R 8 are equal to each other and represent hydrogen, R 4 and R 5 are equal to each other and represent a benzyloxycarbonyl group and R 6 is a hydroxyl group.
1,1,1,3,3,3-hexamethyldisilazane, trimethyl silyl chloride, bis (trimethi 1 si 1 i 1) acet ami da and similar agents to introduce a trimeti 1 group if 1 il or, preferably, a mixture of triethyl chloride 1 if 1 i and 1 and 1 imide. Suitable solvent is pyridine, ethyl acetate, N, N-d ime t 1 formamide, methylene chloride and the like, preferably pyridine.
Step 2 By a reaction of 4", 11-0-bis (trimethylsilyl) -2'-0, 3'-N-bis (benzyloxycarbonyl) -3'-iV-deme ti 1-azithioli from step 1A / o 4"-0-Trimethylsilyl-2'-0, 3'-N-bis (benzyloxycarbonyl) -3 '-N- dimethyl-1-azitr or step IB /, respectively with 1.3-10 moles of a corresponding alkylating agent, preferably a methylating agent, in the presence of 1.1-8.5 moles of a suitable base, at a temperature of -15 ° C to room temperature, preferably at 0-5 ° C, in an inert solvent the appropriate reaction is reached: A / a selective alkylation, preferably methylation of a C-12 hydroxyl group giving a new 4", ll-0-b? s (trimethylsilyl) -2 '-0, 3' -N- bis (benzyloxycarbonyl) -3 '-W-demethyl-12-0-methyl-1-azithroxy of the general formula (I), wherein R 1 represents a group L-c 1 adinos i 1 or of the formula ( II), R2 and R7 are equal to each other and represent a group tr ime ti 1 if 1 i 1 o, R "represents hydrogen, R and R- s on equal to each other and represent a benzyloxycarbonyl group, R is a hydroxyl group and R8 is methyl, or B / an alkylation, preferably methylation of a C-11 or C-12 hydroxyl group giving a mixture of a new 4"-0-trimethylsilyl-2'-0,3'-N-bis (benzyloxycarbonyl) -3 '-N-demethyl-11-O-methyl-azithromycin of the general formula (I), wherein R 1 represents a group L - c 1 adi no if 1 or of the formula (II), R2 represents a group tr ime ti 1 if 1 i 1 o, R3 and R8 are equal to each other and represent hydrogen, R4 and R5 are equal to each other and represent a benzyloxycarbonyl group, R5 represents a hydroxyl group and R7 is methyl, or 4"-O- trimeti 1 if 1 i 1-2'-O, 3'-N-bis (benzyloxycarbonyl) -3'-N -demethyl-12-O-methyl-azithromycin of the general formula (I), wherein R 1 represents a group L-c 1 adi not if that of the formula (II), R represents a trimethylsilyl group, R and R are the same each other and they represent hydrogen, R4 and R5 are equal among them and represent a benzyloxycarbonyl group, R6 represents a hydroxyl group and R8 is methyl. As suitable alkylating agents, alkyl halides (C? -C? 2) are used, preferably methyl iodide, dimethyl sulfate, methyl methane sulfonate or methyl p-toluene sulfonate, preferably methyl iodide. Suitable bases are alkali metal hydrides, lithium hydride, sodium hydride or potassium hydride), alkali metal hydroxides (potassium hydroxide or sodium hydroxide) or alkali metal methylamides (lithium amide, sodium amide or potassium amide) ), preferably sodium hydride. Suitable inert reaction solvents are dimethyl ether, N,? V-dimethylated sulfur, N, N-dimethylethyl amide, or triamide hexamethasone 1 -f or sphthalic, preferably N, N-dimethylformamide, dimethylsulphite or a mixture thereof with tetrahydrofuran.
Step 3: The 4", 11-O-bis (trimethylsilyl) -2 '-0,3'-iV-bis (benzyloxycarbonyl) -3'-W-demethyl-12-O-methyl-azithromycin from step 2A / o the mixture obtained from 4"-0-trimethylsilyl-2'-0, 3'-W-bis (benzyloxycarbonyl) -3'-W-demethi 1 -11-0-me ti 1-azitr omi ci na and 4" -0-trimethylsilyl-2'-0, 3'-N-h is (benzyloxycarbonyl) -3'-N-dimethylo-12-O-me ti-1-azitr omi cin of step 2B / is subjected to a hydrogenolysis reaction according to the method of EH Flynn et al (Journal of American Chemical Society, 77, 3104, 1950) to deprotect the protecting groups at the 2 'and 3' positions and then to desilylation according to the procedure conventional in lower alcohols, preferably isopropanol in the presence of formic acid: A / positions 4"and 11 in step 2 A / giving 3'-W-deme ti 1 -12-0-me ti 1-azitr omi ci na of the general formula ( I), wherein R1 represents an L-cladininosyl group of the formula (II), R2, R3, R4, R5 and R7 are equal to each other and represent hydrogen, R6 is a hydroxyl group and R8 is methyl, or in B / position 4"in step 2 B / giving a mixture of 3 '- N - give me 1 - 11 - 0 - me ti 1 - azitr omi ci na of the general formula (I), where R 1 represents a group L -cladinosyl of the formula (II), R2, R3, R4, R5 and R8, are equal to each other and represent hydrogen, R6 is a hydroxyl group and R7 is methyl, and 3 '- N- déme ti 1 - 12 - 0 -me ti 1-azitr omi ci na of the general formula (I), wherein R 1 represents an L-cladinosyl group of the formula (II), R 2, R 3, R 4, R 5 and R 7 are equal to each other and represent hydrogen, R6 is a hydroxyl group and R8 is methyl. The 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 carbon, at a hydrogen pressure of 20 bars, a room temperature.
Step 4: The 3 '-iV-deme t il - 12 - 0-me ti 1 -zitr omi ciña of step 3A / o the mixture obtained from 3' - N- give me ti 1 - 11 - 0-me ti 1 - azitr omi ci na and 3 '- N- of me ti 1 - 12 - 0-me ti 1-azithromycin from step 3B / is subjected to a 3' -? 7-methylation reductive with 1-3 equivalents of formaldehyde (37% ) in the presence of an equal or double amount of formic acid (98-100%) and hydrogenation catalyst 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 in the case of the compound of step 3A / -12-O-methyl-azithromycin of the general formula (I), wherein R represents an L-cladinosyl group of the formula
(II "), R2, R3, R4 and R7 are equal to each other and represent hydrogen, R5 and R8 are equal to each other and represent methyl and R6 is a hydroxyl group, or - in the case of the products of step 3B / - a mixture of 11-O-me ti 1-azitr omi c ina of the general formula (I), wherein R 1 represents an L-cladinosyl group of the formula (II), R 2, R 3, R 4 and R 8 are equal to each other and they represent hydrogen, R5 and R7 are equal to each other and represent methyl and R6 is a hydroxyl group, and of 12-0-me ti 1-azitr omi ci na of the general formula (I), wherein R1, R2, R3 , R4, R5, R6, R and R8 have the meanings given in the case of the 3'-lime-1-one of the compounds of step 3A /.
Step 5: The azithromycin of the general formula (I), wherein R 1 represents an L-cladinosyl group of the formula (II), R 2, R 3, R 4, R 7 and R 8 are equal to each other and represent hydrogen, R 5 is methyl and R6 is a hydroxyl group, or its 11-O-methyl and 12-O-methyl derivatives of step 4 are optionally subjected to hydrolysis with strong acids, preferably with dichloroacetic acid or C, 25-1.5N hydrochloric acid in a mixture of water and an alcohol, preferably methanol, ethanol or isopropanol, for 10-30 hours, at room temperature giving 3-di (2,6-di-soxy-3-C-methyl-3-O-methyl-α-ribohexopyranosyl- oxy) -3-oxy-azithromycin of the general formula (I), wherein R1 and Rd are equal to each other and represent a hydroxyl group, R3, R4, R7 and R8 are equal to each other and represent hydrogen, and R5 is methyl , or 3-de (2,6-dideoxy-3-C-methyl-3-0-methyl--L-ribohexopyranosyl-ox i) - 3-oxy-11-O-me ti 1-azitr omi c í na of the general formula (I), wherein R1 and R6 are equal to each other and represent a hydroxyl group R- R and R 'are equal to each other and represent hydrogen, and R5 and R7 are equal to each other and represent methyl, or 3-de (2,6-dideoxy-3-C) -methyl-3-0-methyl- -L-ribohexopyranosyl-oxy) -3-oxy-12-0-methyl-azithromycin of the general formula (I), wherein R1 and R6 are equal to each other and represent a hydroxyl group , R3, R4 and R7 are equal to each other and represent hydrogen, and R5 and R8 are equal to each other and represent methyl.
Step 6: 3-de (2,6-dideoxy-3-C-methyl-3-0-ethyl-aIr ib ohexop ira not if 1-ox i) - 3-ox i - azitr omi cin and its derivatives 11-O -methyl and 12-O-methyl from step 5 are subjected to a selective acylation of the hydroxyl group at the 2 'position. The acylation is carried out with chlorides or anhydrides of carboxylic acids with up to 4 carbon atoms, preferably with acetic acid anhydride, in the presence of inorganic or organic bases, in an organic solvent inert to the reaction, at a temperature of 0-30 °. C, giving 3-de (2,6-dideoxy-3-C-methyl-3-0-methyl-aLr ibohex-ap ani if 1-oxy) -3-oxy-azitr omi ci na 2'-0- acetate of the general formula (I), wherein R1 and R6 are equal to each other and represent a hydroxyl group, R3, R7 and R8 are equal to each other and represent hydrogen, R4 is acetyl and R5 is methyl, or 3-de ( 2,6-dideoxy-3-C-methyl-3-0-methyl-aI / -ribohexopyranosyl-oxy) -3-oxy-11-o-methyl-azithromycin 2 '-0-acetate of the general formula (I) , where R1 and R6 are equal to each other and represent a hydroxyl group, R3 and R8 are equal to each other and represent hydrogen, R4 is acetyl and R5 and R are equal to each other and represent methyl, or 3-de (2,6-dideoxy-3-C-methyl-3-0-methyl- a-ij-ribohexopyranosyl-oxy) -3-oxy-12-0-methyl-azithromycin 2 '-0-acetate of the general formula (I), wherein R1 and Rd are equal to each other and represent a hydroxyl group, R and R are equal to each other and represent hydrogen, R 4 is acetyl and R and R 8 are equal to each other and represent methyl. Suitable bases are sodium hydrogen carbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine, t-butadiene, preferably sodium hydrogen carbonate. As a suitable inert solvent, methylene chloride, d i c 1 or r or e t i 1, acetone, pyridine, ethyl acetate, tetrahydrofuran, preferably methylene chloride are used.
Step 7: 3-de (2,6-dideoxy-3-C-methyl-3-0-methyl-aL-ribohexopyranosyl-oxy) -3-oxy-azithromycin 2'-0 -acetate and its derivatives 11-0 methyl and 12-0-methyl of step 6 are subjected to oxidation of the hydroxyl group at the C-3 position with Jones reagent or diimides according to a modified Mof f at-Pf it zner procedure. [DMSO and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide in the presence of trifluoride or pyridineacetate] giving 3-de (2,6-dideoxy-3-C-methyl-3-0-methyl- aLr ib ohe x op iranosi 1-oi) - azitr omicum 3, 6-h emi ceta 1 2'-0-acetate of the general formula (I), wherein R1 represents a hydroxyl group, R3 together with R6 represents a ether group, R4 is acetyl, R5 is methyl and R7 and R8 are equal to each other and represent hydrogen, or 3 -de (2, 6 -di of s oxy-3-C-me ti 1 - 3 - 0-me ti 1 - -I-ribohexopyranosii-oxy) -11-0-methyl-azithromycin
3, 6-h emi c e t a 1 2'-0-acetate of the general formula
(I), wherein R 1 represents a hydroxyl group, R 3 together with R 6 represent an ether group, R 4 is acetyl, R 5 and R 7 are equal to each other and represent methyl and R is hydrogen, or 3-de (2,6-di of oxi-3-C-RETHYL-3-0-RETYL-α---RIBOHEXOPYRANSYL-OXY) -12-0-METHYL 1-ZINTRY OMYCIN 3, 6-H EMIKET 1 2'-0- acetate of the general formula (I), wherein R 1 represents a hydroxyl group, R 3 together with R 6 represent an ether group, R 4 is acetyl, R 5 and R 8 are equal to each other and represent methyl and R 7 is hydrogen.
Step 8: 3-De (2,6-dideoxy-3-C-methyl-3-0-raetyl-aI-ribohexopyranosyl-oxy) -azithromycin 3, 6-hemicetal 2 '-0-acetate and its derivatives 11-0 -methyl and 12-0-methyl from step 7 are subjected to solvolysis in lower alcohols, preferably in methanol, at a temperature from room temperature to reflux temperature of the solvent, giving 3-de (2,6-dideoxy-3-C) -methyl-3-0-methyl-oi-ribohexo-p not if 1-oxy) - azitr omi ciña 3, 6-h emi ceta 1 of the general formula (I), wherein R 1 represents a hydroxyl group, R3 together with R6 represents an ether group, R4, R7 and R8 are equal to each other and represent hydrogen, and R5 is methyl, or 3-de (2,6-di of s ox i -3-C-methyl-3- 0-methyl- -i-ribohexopyranosyl-oxy) -11-0-me ti-1-azithro-3, 6-h emi-keta 1 of the general formula (I), wherein R 1 represents a hydroxyl group, R 3 together with R6 represent an ether group, R4 and R8 are equal to each other and represent hydrogen and R5 and R7 are the same in and they represent methyl, or 3 -de (2,6 -dides oxy-3-C-me ti 1 -3-0- ethyl-aI-ribohexopiranosil-oxy) -12-0-methyl-azithromycin 3, 6 - hemi ceta 1 of the general formula (I), wherein R 1 represents a hydroxyl group, R 3 together with R 6 represent an ether group, R 4 and R 7 are equal to each other and represent hydrogen and R 5 and R 8 are equal to each other and represent methyl.
Step 9: 3-de (2,6-dideoxy-3-C-methyl-3-Q-methyl-oyl-ribohexopyranosyl-oxy) -acythromycin 3, 6-hemicetal from step 8 is subsequently optionally subjected to a reaction with ethylene carbonate in the presence of inorganic or organic bases, preferably potassium carbonate, in a reaction-inert solvent, preferably ethyl acetate, giving 3-di (2,6-di-soxy-3-C-methyl-3) -O-methyl-L-ribohexopyranosyl-oxy) -zithromycin 3, 6-hemi-keta-1-cyclic carbonate 11,12 of the general formula (I), wherein R 1 represents a hydroxyl group, R 3 together with R 6 represent an ether group , R4 is hydrogen, R5 is methyl and R7 and R8 together with the carbon atoms C-11 and C-12 represent a cyclic carbonate. The pharmaceutically acceptable addition salts, which are another object of the present invention, are obtained by means of a reaction of the novel compounds of the general formula (I) with at least an equimolar amount of a corresponding inorganic or organic acid, such as ex. , hydrochloric, hydriodic, sulfuric, phosphoric, acetic, propionic, trifluoroacetic acids, maleic, citric, stearic, succinic, ethyl, methanesulfonic, benzene, non-ionic, p -to 1 ueno s ulphonic, 1 au ri 1 s ucy icoy, in a solvent inert to the reaction. The addition salts are isolated by filtration if they are insoluble in the solvent inert to the reaction, by precipitation with a non-solvent or by evaporation of the solvent, more frequently by lyophilization. The antibacterial activity within the novel compounds of the general formula (I) and their pharmaceutically acceptable addition salts with inorganic or organic acids in a series of standard test microorganisms was determined in a medium of Mué 11 er -Hi nt on (Difco Laboratories, Detroit, MI) by means of a conventional double dilution method according to recommendations of NCCLS (The National Commitee for Clinical Laboratory Standards). Each test microorganism was inoculated to the final inoculum size of 5 x 105 cfu / ml and the incubation was performed anaerobically at 37 ° C for 18 hours. The MIC in the liquid medium was defined as the minimum concentration of an antibacterial agent that inhibits visible growth in containers of my cellulose. Control organisms were obtained from ATCC (The American Type Culture Collection). All standards were identified by means of a standard procedure and stored at -70 ° C. The results of 12-O-azitr omi on the standard test microorganisms and those isolated clinically in comparison with azithromycin are shown in Table 1 and Table 2. Determining the concentration of 12-0-me ti 1 - After a simple oral dose of 20 mg / kg in a group of 36 male rats at time intervals of 0.25 to 24 hours, it was established that the new antibiotic was absorbed very rapidly in the serum. An analysis of the peaks suggested the existence of entheopathic circulation. During 0.5 and 1 hour a rapid drop in concentration was observed, followed by a repeated increase. The maximum concentration of substance was reached after 2 hours (Cmax 248.8 ng / ml). A secondary maximum was reached 4 hours after the application. The half-life was 5.2 hours and the AUC was 1993.4 h ng / ml. Table 1: Antibacterial activity i n vi t r o of 12 - 0-me til-a zi tromycin on standard strains compared to azithromycin. Organism Compound MIC (μg / ml) (No. of copes) Range 50% 90% Staph. aurms 'Aatropñcina 0.25 - 8 1 4
S. epidermis A- thromycin 0.25- 16 0.25 8 (20) 12- (Methylazitropicin 0.12- 8 0.25 4
Streptococcus Azithromycin 0.03 - 0.25 0.06 0.12 pneumoniae 12- < Metib-ptromfcina 0.03-0.12 0.03 0.12 (25)
Eiaerococcus sμ Aatrormcin 0.25 - 16 1 16 (35) 12- &- ethylazxtrom? Iru. 0.12 - 8 0.5 8
Hae opMus Atropic Acid 0.12 - 0.5 0.25 0.5 Influenza * 12-O-Fctibzitropycin 0.06 - 0.5 0.12 0.25 (40)
Table 2: Antibacterial activity i n vi t r o of 12 -O-me t i 1 - a z i t r omi ciña in a series of clinically isolated organisms in c o m a r a c i o n s azithromycin
ClM (mcg? M) Organism Aatromycin 12-6 ^ Metylaromercimine Staphylococcus aurtvs ATCC 6538 P i 0.25 S. a re s ATCC 29213 0.25 0.25 S. epidrmidis A1CC 12228 0.5 0.03 Micrococcusflaw ATCC 10240 0.5 0.12 M. h? * Us ATCC 9341 0.06 0.03 Sireptococaufaecalis ATCC 8043 0.5 0.25 j? Cí // tíf jaitf? ATCC 6633 4 1 5- cetane ATCC U778 1 025 It is srtchxa coli ATCC 10536 1 0.5
The procedure for the preparation of new 3, 6-hemi ce t a 1 e s of the class of
9a-azalides is illustrated by the following examples, which in no way limit the scope of the invention.
Preparation 1. 2 '-0.3' -N-Bis (benzyloxycarbonyl) -3'-N-demethyl I - a z i t r omi ciña A A a solution of azithromycin (17 g,
0.0227 moles) in toluene (170 ml), NaHCO 3 (74.8 g, 0.890 moles) was added and then the reaction mixture was heated under stirring to reflux temperature.
(80-85 ° C). To the suspension of the reaction, 102 ml of 50% benzyloxycarbonyl chloride (104.04 g, 0.305 mol) in toluene were added dropwise with stirring for 1 hour. The reaction mixture was stirred at the same temperature for an additional 2 hours and allowed to rest overnight at room temperature. After filtration, the precipitate was rinsed with toluene (85 ml) and the toluene solution was extracted twice with 0.25 N HCl (170 ml) and twice with 1.5% aqueous NaCl solution (170 ml). . To toluene water (340 ml) was added (pH 3.1), the pH of the reaction mixture was brought to 2.0 with 6 N HCl, the layers were separated and the organic layer was further extracted three times with water. (340 ml) maintaining the pH at 2.0. To the combined water extracts CH2C12 (125 ml) was added, the pH was brought to 10 with a NaOH solution (20%), the layers were separated and the aqueous layer was extracted again with CH2C12 (125 ml). The combined organic extracts were dried over K2CO3, filtered and evaporated under reduced pressure to give 16.5 g of a coarse oily residue, which was optionally purified with low pressure chromatography on a column of silica gel 60 (230-400 ASTM mesh). For this purpose, the crude product was dissolved in CH2C12 (20 ml) and applied to a column of silica gel (50 g) under a nitrogen pressure of 0.5 bar. To remove the residual benzyl, and its decay products, CH2C12 (150 ml) was passed through the column and then, using the solvent system chloride of 1-ene-methylene chloride. , 9: 1 (200 ml) and evaporating the fractions containing the product of the chromatographically homogeneous title, 11.53 g of 2'-0, 3'-N-bis- (benzyloxycarbonyl) -W-demethyl-az- were obtained. Itine icina pure to the TLC with physical constants - such as described in the U.S. Patent No. 5,250,518 of 10/1993).
E j e lo 1. 4", 11-0- Bis (trimethylsilyl) -2 '-0, 3'-N-bis (benzyloxycarbonyl) -3'-N-demethyl-azithromycin To a 2'-O solution , 3'-N-bis (benzyloxycarbonyl) 3'- f / -demethyl azithromycin (5.0 g, 0.005 mole) in pyridine (50 ml), cooled to 0-5 ° C, trimethylsilyl imidazole (3 , 3 ml, 0.0226 moles) and trimethylsilyl chloride (3.0 ml, 0.0179 moles) under nitrogen stream.The reaction mixture was stirred at the same temperature for 6 hours, n-hexane (60 ml) was added. ) and water (100 ml), the layers were separated and the organic layer was rinsed with a saturated solution of NaHCO (60 ml) and water (60 ml) After drying over MgSO4., filtration and evaporation of the solvent under a reduced pressure, 5.48 g of a white amorphous precipitate was obtained, which was optionally purified by low pressure chromatography on a column on silica gel using the system C H2C 12-CH30H, 9: 1. The combination and evaporation of the chromatographically homogeneous fractions yielded the title product with the following constants: TLC, Chloride of me ti 1 e not-met ta 1, 90: 1, Rf 0.875; Ethyl acetate-N-hexane-diethylamine, 100: 100: 20 Rf 0.942.
(IR (KBr) crn 1: 3524, 2969, 2692, 1754, 1732, 1708, 1498, US6, 1382, 1335, 1252, 1168, 16, IOEO, 1005, 895, 841, 754, 696.
? NMR (300 M? Z, CDCfe) d: 7.32-7.23 (Ph), 5.12, .98 (CHa-Ph), 4.85 (Hl "), 4.70 (HO, 4.65 (H-2% 4.46 (H-31) , 426 (H-5"), 4.42 (H-3), 3.72 (H-5 *), 3.66 (H-ll), 3.49, 3.47 (H-5), 3.20 (H-4" 3.32, 3.18 ( 3"-OCÍÍ>, 2.83, 2.79 (3'-NCH3), 2.78 (H-2), 2.64 Oi-10), 2.35 (H-9a), 2.33 (H-2" a), 2.11 (9a -NCH3), 1.94 (H-9bX 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 ( 6-0%), 1.24 (5"-CH3), 1.19 (5» -CH3), 1.12 O'-CHá 1.16 (12-CH &1726 (2-CHj), 0.89 (10-CHs), 0.95 ( 8-CH3), 0.85 (14-CHj), 1.02 (4-CH3), 1.02 (4-CH,), 0.16 (11-OSi (CH,) ,, and 0.13 / 4"-OSi (CH3y.
13 C NMR (75 MHz, CDC? 3) d: 17 (C-1), 156.2, 156.4 (OCO), 154.5, 154.4 (NCC7), 136.7-127.5 (Ph), 100.2 (C-1 '), 97.3 (Cl "), 83.9 (C-5), 80.7 (C4n), 75.0 (C-3), 75.0 (C-2 ') f 75.3 (C-6), 73.2 (C-3"), 69.4, 69.2 , 67.1, 66.8 (CfiTa-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-41), 29.0 (3'-NCH3), 25.6 ( C-8), 27.8 (6-CH,), 21.9 (3"-CHj), 21.5 (8-CH3), 20.7 (^ -CHi), 23.4 (C-14), 18.4 (5" -CH3), 16.0 (2-CH3), 11.6 (14-CH,), 9.6, 9.5 (4-CH3), 8.3 (10-CHj), 1.2 / l-OSi (CH3) / j and 0.67
E S - S 11 4 7
E j e m p l o 2. 3 '-N-Demethyl-12-O-methyl-azithromycin. To a solution of the product of Example 1 (1.0 g, 0.0009 mole) in N, W-dimethylenediimide (20 mL), methyl iodide (0.43 mL, 0.0069 mole) was added. ) and 60% sodium hydride (0.23 g, 0.0058 mol) gradually over 3 hours at room temperature. The reaction mixture was stirred for another 30 minutes at the same temperature, the reaction was stopped by the addition of triethylamine (2 ml), transferred to a mixture of an aqueous solution of 10% NaHCO 3 (50 ml) and water ( 50 ml) and extracted with ethyl acetate. The combined organic extracts were rinsed with a saturated NaCl solution and water, dried over MgSO, filtered and evaporated under reduced pressure, giving 0.93 g of a yellow precipitate [Rf 0.832, methylene chloride-methanol, 90: 1; IR (KBr) cm "1: 3516, 1752, 1732, -1705, 1456, 1382, 1336, 1253, 1169, 1116, 1062, 1004, 896, 840, 754, 696.] The product was dissolved in ethanol (20%). ml), NaOAc / HOAc buffer with pH 5 (0.17 ml of acetic acid, 0.263 g of sodium acetate, 0.22 ml of ethanol and 1 ml of water) and 10% Pd / C (0.6 ml) were added. g), and the reaction mixture was hydrogenated under stirring for 5 hours in an autoclave at a hydrogen pressure of 5 bars.The catalyst was filtered, the filtrate was evaporated giving a thick syrup, CH2C12 (10 ml) and water were added. (15 ml), the pH of the mixture was adjusted to 4 with 2N HCl, the layers were separated and the aqueous layer was extracted with CH2C12 (3 x 10 ml) after adjusting to pH 9.5 with 20% NaOH. The combined organic extracts were dried over K2C03, filtered and evaporated The precipitate was dissolved in isopropanol (10 ml), water (10 ml) and a few drops of formic acid were added and stirred for 30 minutes at room temperature, extracted with isopropyl acetate at pH 9.5, which after evaporation under a reduced pressure gave 0.43 g of the title product with the following constants f i s i co -qu i m ca s:
IR (KBr) can "1: 3672, 3496, 2962, 1727, 1458, 1375, 1343, L2 * >, 12S3, 1118, 1085, 1048, 1005, 998.
l3C NMR (75 MHz, CDCla) d: 177.4 (C-1), 102.7 (Cf), 95.5 C-l'i 83.4 (C-5), 79.7 (C-12), 78.0 (C-3), 76.6 (C-11), 74.0 (C-13) .73.9 (C), 74.3 (C-2 73.3 (C-3 *), 68.3 (C-9), 65.7 (C-5"), 60.1 (C-) 31), 61.2 (C-10), 52.8 (12-O? 3jX 4S.8 (3'-OCHs), 45.5 (C-2), 41.5 (C-4), 33.1, 3'-NC? S, 36.8 (9a-NCH,), 35.1 (02 *), 28 (C- <), 27.0
(C-8). EI-MS m / z 748 E j e lo 3. 12-0-Methylazithromycin To a solution of 3'-N-dimetho 1 -12-0-me ti 1-azithromycin from Example 2 (0.43 g, , 0006 moles) in CHC13 (20 ml), formaldehyde (37%) (0.047 ml, 0.0006 moles) and formic acid (98-100%) were added.
(0.042 mL, 0.0011 moles). The reaction mixture was 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 were separated and the aqueous layer was extracted 2 more times with CHCI3. To the aqueous layer CHCI3 was added, the pH was adjusted to 9.5 (2N NaOH), the layers were separated and the aqueous layer was extracted 2 more times with CHCl3. The combined organic extracts at pH 9.5 were dried (K2CO3) and evaporated, yielding 0.38 g of the title product, which was purified, if necessary, by chromatography on a silica gel column using the CH2Cl2-CH3OH system -NH 4 OH conc., 90: 9: 1. TLC, Chloride of me t i 1 in o -me t a no 1 - amon i a co conc. 90: 9: 0.5 Rf 0.363; 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. 1 H NMR (300 MHz, CDC13) S: 5.39 (H-13), 5.00 (H-i'X 4.43 (HI 4.32 (H-3), 4.06 (H-5-), 3.68 (H-ll), 3.65 (H-5), 3.51 (H-51), 3.38 (12-OCHj), 3.32 (3"-OCH3? 3.24 (H-2 '), 3.02 (H-4") , 2.73 (H-2), 2.69 (H-10X 2.49 (H-3"), 2.34 (H-2" a), 2.31 (H-9a), 2.29 3'N (CHJ) 2, 2.30 (9 * -NCH3? 2.12 (H-9b), 2.04 (1 * 4), 2.01 (H-8), 1.73 (H-14t), 1.68 (H-4'a), 1.66 (H-7a), 1.56 (H-2"b? 1.52 (H-14b), 1.36 (H-7bX 1.29 (6-CH3? 1.21 (2-CH3? 1.30 (5" -CH3), 1.24 (H-4T>? 1.23 (3"-CHB), 1.22 (5'-CH3), 1.09 (12-CH3), 1.29 (4-CH3), 1.09 (10-CH3), 0.92 (8-CH3), 0.93 (14-CH3).
15C NMR (75 MHz, CDCfc) 6 177.5 (C-1), 103.1 (C-1'X 95.2 (Cl "), 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 (0-2-, 68.8 (C-9). '65.6 (C-5"), 65.7 (C-3) ), 61.6 (C-10X 52.8 (12-OCHs), 49.4 (3"-OCH3), 45.1 (C-2), 43.0 (C-7), 41.8 (C-4), 40.4 3-N (CH5y, 36.8 (9 »-NCH,), 35.0 (C-2"), 29.0 (C 26.9 (C-8), 26.9 (6-CH3), 22.0 (8 &?,). 22.0 (C-14), 21.6 (3 «-CI ^ X 21.3 (5'-CH3), '18.1 (5-CH,), 16.9 (12-CH, X 14.6 (2-CH, X 11.0 (14-CH3), 9.6 (4 -CHj), 9.4 (KK-C? Í,).
E j e m p l o 4. 3-De (2,6-dideoxy-3-C-methyl-3-0-methyl-a- -ribohexopyranosyl-oxy) -3-oxy-12-0-methyl-azithromycin. In 0.25 N hydrochloric acid (80 ml), 12-O-me t il-a z i t r omi c i na (1.7 g, 0.0022 mol) of Example 3 was dissolved and left to rest for 24 hours at room temperature. CH2C12 (pH 1.8) was added to the reaction mixture, the layers were separated and the aqueous layer was extracted twice more with CH2C12. CH2C12 was again added to the aqueous layer, the pH of the mixture was adjusted with conc. NH4OH. At 9.0, the layers were separated and the aqueous layer was extracted with CH2C12. The combined organic extracts at pH 9.0 were rinsed with 10% aqueous NaHCO3 solution and water, dried over K2CO3 and evaporated, yielding 1.25 g of the title product with the following physical-chemical constants: TLC , Chloride de me ti 1 eno -me t ano 1 - amoni a co conc. ', 90: 9: 0, 5, Rf 0.315; Ethyl acetate-N-hexane-diethylamine, 100: 100: 20, Rf 0.594.
IR (KBr) can "1: 3450.2971, 2933, 1711, 1648, 1460, 1381, 1272, 1261 1171 1113 1078, 1049.
* H NMR (300 MHz, CDOa) S: 5.32 (H-13X 4.47 (H-1.3.78 (H-3), 3.66 (HI I), 3.58 (H-5), 3.58 (HSX 3.41 (12 DOÍ, X 3.28 (H-2"X 2.67 (H-2), 2.80 (H-10), 2.53 (H-3- 2.53 (H-9a), 2.27 / 3tI (C 3) 2 /, 2.37 (9 *. NCHs), 2.07 (H-9b), 2 7 (H-4X 1.92 (H-8X 1.74 (H-14aX 1.68 (H-4'a), 1.59 (H-7a), 1.63 (H-14b), 1.51 (H-7b, 1.31 (6-CHj), 1.31 (2-CH3), 1.29 (H-4'b), 1.26 (5'-CHj), 1.08 (12-CH3), 1.05 (4-CHj), 1.19 (10-CH3), 0.93 (8-CHJX 0.92 (14-CH |).
l3C NMR (75 MHz, CDCH) S: 177.2 (C-1). 106.4 (C-11), 94.7 (C-5), 78.0 (C-12X 79.0 (C-3), 78.3 (C-11), 75.1 (C-13X 72.9 (C-6), 70.2 (-, 70.3 (C-9), 65.3 (03r),
62. 1 (C-10), 52.5 (12-OCHs) .44.3 (C-2X 41.8 (C-7), 35.7 (C-4) .39.9 ^ CHjy, 36.5 (9a-NCH3), 27.9 (C-4" )> 26.4 (C-ß? 25.5 (6-CH »X 20.8 (8-CH5), 20.7 (C-4), 20.8 (5'-CHj, 16.1 (12-CHs), 15.7 (2-CH3) , 10.3 (I4-CH3), 7.6 (4-CH3), 7.2 (10-CH3).
E j lo lo 5 3-De (2,6-dideoxy-3-C-methyl-3-0-methyl-aI > - ribohexopyranosyl-oxy) -3-oxy-12-Q-methyl-azithromycin-2 ' - O- acetate To a solution of 3-de (2, 6-di-oxo-3-C-methyl-3-O-methyl-aL-ribohexopyranosyl-oxy) -3-oxy-12-O-me 111-azithromycin (1.3 g, 0.0022 moles) of Example 4 in CH2C12 (20 ml), NaHCO3 (0.754 g, 0.009 mole) and acetic acid anhydride (0.221 ml, 0.0023 mole) were added and then stirred for 10 hours at room temperature. After resting overnight a saturated NaHCO 3 solution was added to the reaction mixture, the layers were separated and the aqueous layer was extracted with CH 2 C 12. The combined organic extracts were rinsed with a saturated NaHCO 3 solution and water, dried over K 2 CO 3, filtered and evaporated, yielding 1.29 g of a white amorphous precipitate. TLC, Chloride of me t i 1 e no-me t an o 1 - amo n í a c o conc., 90: 9: 0,5, Rf 0.489; Ethyl acetate-N-hexane-diethylamine, 100: 100: 20, Rf 0.661.
IR (KBr) ra "r • * .: 3448,2974, 1749, 1718, 1637, 1458, 1377, 1242, 1169, 1115, 1045.
lH NMR (300 MHz, CDC13) & 5.23 (H-13), 4.72 (H, 2), 4.70 (H-1'X 3.59 (Hl l), 3 Jd (H-5), 3.52 (H-3), 3.43 (H-S1), 3.33 (12-OCHj), 2.72 (H-10), 2.71 (H-3 «), 2.61 (H-2), 2.42 (H-9a), 2.30 (9a-NCH3), 2.20 2.12 (H-4, 1.99 (2'-COCff3), 1.96 (H-9b), 1.80 (H-8X 1.67 (H-14a), 1.67 (H-4'a), 1.58 (H-14bX 1.47 (H-7a), 1.31 (H -4T3), 1.21 (2-CH3), 1.18 (H-7bX 1.16 (5'-CH3), 1.15 (6-CHj), 1.10 (10-CH3? 0.97 (12 ^ H3), 0.86 (14-CH3? 0.84 (& H3), 0.81 (4-CH3).
"C NMR (75 MHz, CDCls) 5: 176.5 (C-1), 169.4 (T-COCH), 98.6 (Cl *), 84.3 (C-5), 77.3 (C-12), 78.3 (C-3X 76.7 (C-11), 74.6 (C-13), 72.4 (C-6X 70.7 (C-21), 69.9 (C-9), 62.2 (C-3'X 62.3 (C-10), 51.9 (12 -OCH3), 43.0 (C-2), 40.1 (C-7), 35.2 (G4), 39.6 / 3 * CH5 a /, 35.9 (9 * -NCH3), 30.0 (C-4 25.4 (C-8X 25.2 (6-CH3) .20.6 (r-COCHj) .20.4 (8-CH?), 20.0 (C-14X 20.2 (5'-CH3), 15.9 (12-CHsX 15.2 (2-CHj), 9.7 (14- CH5),
E j emp lo 6. 3-De (2,6-dideoxy-3-C-methyl-3-Q-methyl-α-β-ribohexyopyranosyl-oxy) -12-0-methyl-azithromycin 3, 6-hemicetal- 2 '-O-acetate. To a solution of 3-de (2,6-di-ox i -3-C-methyl-3-O-methyl-aL-ribohexopyranosyl-oxy) -3-oxy-12-O-me ti 1-azitr 2 '-O-acetate (1.3 g, 0.0020 mole) of Example 5 in CH2C12 (15 ml), dime ti 1 s ul f oxide (4.35 ml) and N, N-dime were added ti 1-ami not -pr op i 1 -eti 1 -ca rbodiimide (4.55 g). The reaction mixture was cooled to 15 ° C and then a solution of tri fluorine or pyridinium acetate (4.61 g, 0.0234 moles) was added dropwise over 30 minutes, with stirring and maintaining the temperature at 15 ° C. ) in CH2C12 (10 ml). The temperature of the reaction mixture was gradually raised to room temperature and stirred for another 2 hours, after which the reaction was stopped by the addition of a saturated NaCl solution (25 ml). After alkalizing with 2N NaOH to 9.5, the reaction mixture was extracted with CH2C12, the organic extracts were rinsed with a solution of saturated NaCl, NaHCO3 and water and dried over K2CO3. Evaporation of CH2C12 at a reduced pressure gave 1.78 g of an oily residue. TLC, Chloride of me t i 1 n o -me t a n 1 - ammon a c o conc., 90: 9: 0,5, Rf 0.176; Ethyl acetate-N-he-diethylane, 100: 100: 20, Rf 0.861.
E j emp lo 7 3-De (2, 6-dideoxy-3-C-methyl-3-0-methyl-a-β-ribohexopyranosyl-oxy) -12-O-methyl-azithromycin 3, 6 -hemicetal A solution of 3-de (2, 6-di of s ox i -3-C-methyl-3-O-methyl-aL-ribohexopyranosyl-oxy) -12-0-me ti 1-azitr omi c ina-2 '- O-aceto (1.78 g) of Example 6 in methanol (50 ml) was allowed to rest for 24 hours at room temperature. Methanol was evaporated at a reduced pressure, the obtained residue (1.65 g) was purified by low pressure chromatography on a silica gel column using the methylene chloride 1-methane 1-ammonia co-conc. , 90: 9: 0.5. Evaporating the combined extracts with Rf 0.082 gave 3-de (2,6-dideoxy-3-C-methyl-3-0-methyl-aI-ribohexopyranosyl-oxy) -12-O-methyl-azithromycin 3,6-hemicetal Chromatographically homogeneous with the following physiological constants co-quimi ca s: TLC, Chloride of me ti 1 e no-met ta no 1 - ammon í conc., 90: 9: 0,5, Rf 0.082; Ethyl acetate-N-he-diethylamine, 100: 100: 20, Rf 0.624. IR CDC13 cm 3450 2956 2940 171
1678, 1631, 1459, 1393, 1278, 1198, 1117, 1068, 1048, 1014, 963.
* HNMR (300 MHz, CDC) 3) d: 5.49 (H-13), 4.21 (H-l '), 3.83 (H-ll), 3.75 (H-5) .3.52 (H-5, 3.43 (12 -OCHb), 3.25 (H-2 *), 2.59 (H-2), 2.93 (H-10), 2.50 (H-31), 2.61 (H-9a), 2.29 ß'N, CHsX,) /, 2.40 (9a-NCH, X 2.10 (H-9b), 2.06 (H-4), 1.88 (H-8), 1.77 (H-14a), 1.67 (H-4 * aX 1.61 (H-7aX 1.64 (H-14b), 1.33 (H-7b), 1.31 (6-CH3), 1.05 (2-CHs), 1.27 (H-4"), 1-26 (5'-CHJX 1.08 (12-CH3), 1.05, (4-CH3), 1.19 (10-CHsX 0.92 (8-CH3), 0.93 (14-CH,).
l3C NMR (75 MHz. CDC13) d: 176.2 (Cl), 105.8 (Cl *? 94.6 (C-5), 78.3 (C-12), 102.7 (C-3), 71.2 (C-UX 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-OCHj), 49.2 (C-2) ), 41.4 (C-7X 48.6 (C-4), 40.0 ^ NICHl, 40.5 (9a NCH3), 28.2 (C-4, 29.1 (C-8), 26.5 (6-CHsX 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 (Cft 10.7 (? X? .3).
E je mp lo 8 4"-0-Trimethylsilyl-2 '-0-3' - N-bis (benzyloxycarbonyl) -3'-N-demethyl-azithromycin To a solution of 2'-0-3 '- N-bis (benzyloxycarbonyl) -3'-N-demethyl-azithromycin (5 g, 0.005 mole) in pyridine (30 ml) cooled to 0-5 ° C, trimethylsilyl imidazole (1.46 ml, 0.01 mole) and trimethylsilyl were added. chloride (1.64 ml, 0.01 mol) under a stream of nitrogen The reaction mixture was stirred for 1 hour at the same temperature, n-hexane (50 ml) and water (25 ml) were added, separated The layers were washed and the organic layer was rinsed with saturated NaHCO 3 solution (25 ml) and water (25 ml) After drying over MgSO 3, filtering and evaporating the solvent under reduced pressure gave an amorphous precipitate (3.65 g). ) which was optionally purified by low pressure chromatography on a column of silica gel using the methylene chloride system -method 1-ammonia co-conc., 90: 9: 0.5, combining and evaporating the fractions chromatographically homogeneous with Rf 0.670, the title product was obtained with the following constants and co-chemistries: TLC, Chloride of me t i 1 ene -method 1, 90: 1, Rf 0.525; Ethyl acetate-N-hexane-diethylamine, 100: 100: 20, Rf 0.862.
IR (KBr) cm1: 3502, 2969, 2938, 1753, 1732, Í708, 1454, 1383, 1365, 1254, 1169, 1118, 1063, 1001, 897, 839, 754, 696.
lH NMK. (300 MHz. CDClj) d: 7.34-7.26 (Ph). 5.13, 5.09, (CHa-Pti), 5.07 (H-I "), 4.78 (H-r), 4.68 (H-13), 4.66 (H-2"). 4.55 (H-31), 4.22 < H-5"), 4.13 (H-3), 3.96 (H-S *), 3.65 (H-I?), 3.58, 3.54 (H-5), 3.15 (H-4"), 3.37. 2.99 (3"-OCH,), 2.85, 2.81 (3'-NCH3), 2.70 (H-2), 2.68 (H-10), 2.54 (H-9a> 2.35 (H-2», 2.31 ( ? -NCHj), 2.04 (H-9b), 1.97 (H-8), 1.90 (H-14a), 1.85 (H-4), 1.62 (H-7a), 1.50, K-2 ^ \ 1.44 CH- 14b), 1.28, 1.27 (6-CH5), 1.23 (S "-CHj), 1.16 (5 * - H, 1.15 (H-7), 1.04 (3" -CH3), 1.15 (12-Cha). (2-CH3), 1.10 CIO-H3), 0.92 (8-CH3), 0.89 (14-CH3).
13 C NMR (75 MHz, CDCl 3) d: 178.8 (C-1), 156.6, 156.3 (OCO), 134.7, 154.6 (NCO), 136.8-127-5 (Pll), 99.2 (C-1), 94.8 (C-lm), 83.2, 83.1 (C-5), 80.5, 80.4 (C-4"). 77.3 (C-3), 75.1, 75.0 (C-2 *), 74.1 (C-12) 73.8 (C-11), 73.2 (C-6), 73.2 (C-3") f 69.2, 69.0, 67.2, 66.8 (Cffj-Pi), 64.8 (C-5"), 62.2 (C-10) , 54.6 (C-3 '), 49.3, 48.8 (3 -OCH3), 44.7 (C-2), 41.5 (C-7), 41.1 (C-4X 36.1 (9a-NCHj), 35.1, 35.0 (C- 2"), 36.3, 35.7 (C-41), 28.4 (3'-NCHs), 26.3 (C-8), 26.8 (6-CHa), 22.1 (3" -CH3), 21.6 (8-CH3), 21.4 (S'-CHs), 21.0 (C-14) .18.7 (5"-CH?). 15.9 (2-CH3 14.5 (12-CH3). 11.0 (14-CH3), 8.5 (4-CH3).
7. 1 (10-CHj), 0.63 / 4H-OSi (ClW-ES-MS 1075 E jan 9. 11-0-methyl-azithromycin JL 12 -O-me t-yl azithromycin To a solution of the product of Example 8 (3.0 g, 0.0028 mole) in N, f-dimethyldimide (50 ml), methyl iodide (1.29 ml, 0.0207 mole) and sodium hydride were added 60% (0.69 g, 0.0174 mol) for 3 hours at room temperature The reaction mixture was stirred for 1 hour at the same temperature, the reaction was stopped by addition of triethylamine
(5 ml), was transferred to a solution mixture of
% aqueous NaHC03 (100 ml) and water (100 ml) and extracted with ethyl acetate. The combined organic extracts were rinsed with a saturated NaCl solution and water and dried over MgSO4, filtered and evaporated under reduced pressure to give 2.9 g of a product mixture, which was optionally purified by low pressure chromatography on a column of silica gel using the chloride chloride system -method 1, 90: 1, giving a 4"-O- tr ime ti ls i 1 i 1 -2 '- 0 - 3' -iV-bi s (benzyloxycarbonyl) -3'-W-methyl-11-O-methyl-azithromycin chromatographically homogeneous with Rf 0.745 [IR (KBr): 3452, 2969, 1752, 1736, 1706, 1455, 1382, 1332, 1254, 1169 , 1117, 1063, 1002, 914, 897, 840, 754, 697] and 4"- O - tr ime ti 1 si 1 i 1 - 2 '- 0 - 3' - N-bis (benzyloxycarbonyl) -3 '- N- of me ti 1 - 12 -0-me ti 1-azithromycin with Rf 0.485 [IR (KBr): 3450, 2958, 1754, 1718, 1708, 1458, 1383, 1252, 1168, 1068, 1010, 896, 842, 753, 695]. The obtained mixture was dissolved in ethanol (50 ml), NaOAc / HOAc buffer with pH 5 (0.51 ml of HOAc, 0.789 g of NaOAc, 0.66 ml of ethanol and 3 ml of water) and Pd / C were added. to 10% (1.5 g) and the mixture was hydrogenated under stirring for 8 hours in an autoclave at a hydrogen pressure of 5 bars. The catalyst was filtered, the filtrate was evaporated to give a thick syrup, water (50 ml) and CHC13 (50 ml) were added and the product was isolated by a pH gradient extraction at pH 4.0 and 9.5 . The combined organic extracts combined at pH 9.5 were dried over K2C03 and evaporated to an amorphous precipitate. The precipitate was dissolved in isopropanol (20 ml), water (20 ml) and a few drops of formic acid were added and stirred for 30 minutes at room temperature, extracted with isopropyl acetate at pH 9.5, dried over Sodium sulfate and evaporated under reduced pressure. The product obtained was dissolved in CHC13 (50 ml), formaldehyde (37%) (0.24 ml) and formic acid (98-100%) (0.22 ml) were added. The reaction mixture was 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 were separated and the aqueous layer was extracted twice more with CHCI3. To the aqueous layer was added CHC13, the pH was adjusted to 9.5 (2N NaOH), the layers were separated and the aqueous layer was extracted twice more with CHC13. The combined organic extracts at pH 9.5 were dried
(K2CO3) and evaporated, yielding 1.25 g of a precipitate, which was spotted on a column of silica gel using the chloride 1-ene-1-monomeric chloride system. ., 90: 9: 1, yielding 0.40 g of chromatographically homogeneous 11-O-me ti-1-azithiomide with co-chemical physical constants as indicated in U.S. Patent 5,250,518 of 10/1993 and 0.52 g of 12 - -me ti 1-azitr omi with physical-chemical constants as given in Example 3.
E j emp lo 10 3-De (2, 6-dideoxy-3-C-methyl-3-0-methyl-aL-ribohexopyranosiloxy) -3-oxy) -11-0-methylazithromycin In methanol (30 ml) was dissolved 11-O-methyl-azithromycin (1.5 g), 0.25 N hydrochloric acid (50 ml) was added and allowed to rest for 24 hours at room temperature. The methanol was evaporated, CDC13 (pH 1.9) was added to the reaction mixture, the layers were separated and the aqueous layer was extracted twice more with CDC13. The aqueous solution was basified to pH 9.5 and extracted with CDC13. The combined organic extracts at pH 9.5 were dried over K2C03 and evaporated, yielding 0.95 g of the title product, which was optionally purified by low pressure chromatography on a silica gel column using the chloride solvent system. me ti 1 e no-me tano 1-ammonia conc., 90: 9: 0,5, giving a product of the title chromatographically homogeneous with the following constants f í yes co-qu icas: TLC, Chloride de me ti 1 e no-me ta no 1 - amon i a co conc., 90: 9: 0.5, Rf 0.382; Ethyl acetate-N-hexane-diethylamine, 100: 100: 20, Rf 0.594.
IR (KBr) em "1: 3448, 2972, 2937, 1730, 1638, 1458, 1377, 1165, 1113, 1078, 1050.
? NMR (300 MHz, CDC13) 5: 4.97 (H-13), 4.52 (H-11), 3.76 (H-3), 3.70 (1 l-OCH 3), 3.59 (H-5), 3.54 (H-5) '), 3.42 (Hl 1), 3.29 (H-21), 2.68 (H-2X 2.70 (H-10), 2.58 (H-3 *), 2.46 (H-9a), 2.35 (H-4), 2.29 / 3'N (CH3V, 2.30 (9 * -NCH3) 2.11 (H-9b), 1.94 (H-14a), 1.89 (H-8), 1-70 (H-4'l) 1.66 ( H-7aX 1.54 (H-7b), 1.52 (H-14), 1.33 (6-CH3), 1.30 (2-OIJX 1.27 (H-4T>), 1.25 (5'-CH3? 1.12 (12-CH3 ), 1.10 (4-CH3), 1.06 (IO-CH3), 0.92 (8-CHJX 0.86 (14-CH3).
13C NMR (75 MHz. CDC13) 8 175.7 (C-1), 106.1 (Cr), 94.7 (C-5), 74.2 (C-12), 78.1 (C-3 86.0 (C-11), 77.1 (C -13), 72.8 (C-6), 70.2 (C-2, 70.9 (C-9), 65.4 (C-31), 62.9 (CIO), 62.0 (ll-OCH3), 44.1 (C-2), 42.5 (C-7X 35.3 (C-4), 39.9 / 3"N (CH» V, 36.2 (ya-NCH,), 28.0 (C-4 *), 26.7 (C-8), 25.8 (6-CHs ), 20.9 (8-CH3), 21.2 (C-14), 20.8 (5'-CH3), 16.8 (12-CH,), 15.6 (2-CH,), 10.3 (14-CH3), 7.7 (4 -CH3), 6.8 (10-CH,).
E j emp lo 11 3-De (2,6-dideoxy-3-C-methyl-3-Q-methyl-aL-ribohexopyranosyl-oxy) -3-oxy-ll-0-methyl-azithromycin 2 '-O- acetate To a solution of 3 -de (2,6-di-des-oxy-3-C-methyl-3-O-methyl-aL-ribohexopyranosyl-oxy) -3-oxy-11-0-me ti 1-azitr omi cina (0.89 g) of Example 10 in CH2C12 (25 ml), NaHCO3 (0.52 g) and acetic acid anhydride (0.15 ml) were added, the reaction mixture was stirred for 10 hours at Room temperature was allowed to rest overnight and then isolated by extraction with CH2C12 as described in Example 5, giving 0.65 g of a white amorphous precipitate. TLC, Chloride of me t i 1 ene -me t a no 1 - amoní acó conc., 90: 9: 0,5, Rf 0.426; Ethyl acetate-N-hexane-diethylamine, 100: 100: 20, Rf 0.670. IR (KBr) cm "1 3525, 3475, 2968, 2937, 1724, 1647, 1458, 1376, 1265, 1168, 1113, 1081, 1050.
E je pl o 12 3-De (2,6-dideoxy-3-C-methyl-3-0-methyl-aL-ribohexopyranosyl-oxy) -11-0-met i.1 -azithromycin 3,6-hemicetal 2f -O-acetate To a solution of 3 -de (2,6-di-ox i -3-C-methyl-3-0-methyl-aL-ribohexopyranosyl-oxy) -3-oxy-11-O-me Tissue 1-azithiomine 2'-0-acetate (0.65 g) of Example 11 in CH 2 Cl 12 (20 ml) were added dimethyl ether (0.94 ml) and N, N-dimethyl-amine. nop r op i 1 - eti 1 - ca rbodi imide (1.16 g). The reaction mixture was cooled to 15 ° C and then, under stirring and keeping the temperature at 15 ° C, a solution of triforum or pyridinium acetate (1.15 g) in CH 2 Cl 2 (5 ml) was gradually added. Drop for 30 minutes. The temperature of the reaction mixture was raised to room temperature, stirred for an additional 4 hours and then the product was isolated according to the procedure described in Example 6, giving 0.6 g of the title product. TLC, Chloride of me t i 1 ene -method 1 -amoni a co conc., 90: 9: 0,5, Rf 0.606; Ethyl acetate-N-hexane-diethylamine, 100: 100: 20, Rf 0.861.
E xemployment 13 3-De (2, 6-dideoxy-3-C-methyl-3-0-methyl-aL-ribohexopyranosiloxil-11-O-methyl-azithromycin 3, 6-hemi ketal A solution of 3-de ( 2, 6-di-oxo-3-C-methyl-3-O-methyl-aL-ribohexopyranosiloxil-ll-C-me ti 1-azitr omicina 3, 6 - hemi ceta 1 2 '-O-acetate (0.6 g) of Example 12 in methanol (40 ml) was allowed to rest for 24 hours at room temperature The methanol was evaporated under reduced pressure, the obtained residue (0.53 g) was purified by low pressure chromatography over a column of silica gel using the chloride system of me t 1 ene-me t 1-ammonia conc 90: 9: 0,5.Over evaporation of the combined extracts with Rf 0,670, 0.22 g of 3-fold was obtained (2, 6-di-oxo-3-C-methyl-3-O-methyl-aL-ribohexopyranosyl-oxy) -11-0-me ti 1-azitr omi ci na 3, 6 -hemi ceta 1 chromatográ - homogeneously with the following physical-chemical constants:
ICDA, ap "1: 3471, 2975, .715, 1638, 1458, 1382, 1196, 1117, 1049, 1013, 963.
lll NMR (300 Hz, CDO ») d 5.01 (H-13X 4.22 OH-l1) .3.80 (H-5), 3.50 (H-5 '), 3.45 (ll-OCH3), 3.25 (H-2, 2.63 (H-2) .2.49 < -?), 2.77 (H-9a), 2.29 VCHa) a / t 2.20 (9a-NCHjX 2.24 (H-9b), 2.09 (H- X 1.85 (BJ), 1.83 (H-14a? 1.66 (H-4'a), 1.73 (H-14b), 1.36 (6-CHJ), 1.31 (2-CH3 1.26 I 'b 1.21 (5'-CH3), 1.25, (4 -CHj), 1.01 (10-CH3), 1.03 (8-CH3X 0.81 (14-CHj).
1JC NMR (75 MHz, CDCfe) é: 177.0 (C-1X 106.2 (C-1 * X 102.1 (C-3), 93.9 (C-5), 86.1 (C-11X 81.9 (C-), & 1 (020, 64J (C-9X 65.8 (C-3'X 62.1 (C-10), 61.9
(ll-OCHa), 49.6 (C-2), 43.3 < C-7), 40.1 / 3 * N (CHJV, 28.1 C ^ ', 28.7 (C-8X 25.5 (6-CHsX 20.9 (5, -CH3) .14.0 (2- BsX 11.7 (14-CHJX 12.3 (4- CHs), 8.5 (10-CH3).
E x emp. 14: 3-De (2,6-dideoxy-3-C-methyl-3-Q-methyl-aL-ribohexopyranosyloxy) -3-oxy-azithromycin 3-de (2,6-di s ox i -3-C-me ti 1 -3-methyl-aL-ribohexopyranosyloxy) -3-oxy-azithromycin from azithromycin according to the procedure of Djokic et al. US Pat. No. 4,886,792 of 12/1989, Example 3. By separation on a silica gel column using the solvent system methylene chloride-methylene ammonium conc. , 90: 9: 0, 5, a homogeneously chromatographic product with the following constants was obtained: TLC, Acetate e t i lo - t r i e t i 1 amine, 95: 5, Rf 0. 371.
IR (KBr) cm * 1: 3438, 2973, 2938, 1713, 1655, 1459, 1378, 1350, 1260, 1172, 1113, 1078, 1044, 957.
lH NMR (300 MHz, CDC) 8: 4.72 (H-I3), 4.47 (H-1 '), 3.78 (H-3), 3.58 (H-5) .3.56 (H-5 *), 3.65 (H -1IX 3.27 (H-2, 2.66 (H-2), 2.74 (H-10), 2.52 (H-3 '), 2.49 (H-9aX 2.28 (H-4), 2.26 ^ (CHaV.2.37 (9 ** JCH3X 2.06 (H-9b), 1.90 (H-14a), 1.90 (H-8), 1.67 (H-4 * aX 1.62 (H-7tX 1.47 (H-7b? 1.53 (H-I4b? 1.32 ( 6-CH3), 1.30 (2-Ctfe), 1.28 (H-4T>), 1.26 (S'-Cipe), 1.07 (12-CH3), 1.06 (4-CH3? 1.12 (10-CHj), 0.92 (8-CH3), 0.88 (14-CH3).
I3C NMR (75 MHz, CDC13) 8: 178.8 (C-1), 106.6 (CV), 94.7 (C-5), 72.9 (C-2), 79.2 (C-3), 75.5 (C-11) ), 77.1 (C-13), 74.0 (C-6), 70.3 (C-2-? 70.6 (C-9), 65.4 (C-3 '), 62.2 (C-10), 44.2 (C-2) ), 41.7 (C-7) .35.6 (C-4), 39.9 / 3 * N (CH3) 2, 36.8 (9a-NCH3), 27.7 (C-4 '), 26.3 (C-8), 25.5 ( 6-CHJX 20.8 (8-CH3), 20.5 (C-14), 20.9 S-Cí X 15.7 (I2-CH3), 15.8 (2-CH3), 10.5 (14-CH,), 7.5 (4-CHJ) 7.3 (10-CH3).
E j p lo 3 3-De (2,6-dideoxy-3-C-methyl-3-0-methyl-aL-ribohexopyranosiloxy) -3-oxy-azithro-icine 2'-0-acetate To a solution of 3 - of (2, 6-di-s-oxy-3-C-methyl-3-Q-methyl-aL-ribohexopyranosyloxy) -3-oxy-azithromycin 2'-O-acetate of Example 14 in CH2C12 (150 ml), NaHC03 5.84 g) and acetic acid anhydride (1.68 ml) were added. The reaction mixture was stirred for 12 hours at room temperature, allowed to rest overnight and then isolated according to the procedure described in Example 5, giving 11.21 g of an amorphous precipitate with the following physiological constants. my case: TLC Acetate 1 o - trieti 1 amine, 95: 5, Rf 0.54.
IR (KBr) c '1: 3485, 2973, 2937, 1748, 1716.1648, 1459, 1376, 1240.1170, 1114, 1081, 1045, 956.aH NMR (300 MHz, CDCIj) d: 4.71 (H-13), 4.79 (H-21), 4.71 (H-l '% 3.84 (H-3), 3.61 (H-5), 3.50 (H-5) *), 3.68 (H-li? 2.73 (H-10), 2.70 (H-2), 2.70 (H-31, 2.48 (H-9 *), 2.27 (H-), 2.26 mi C? 3W, 2.36 (9t-NCH3), 2.07 (COCHj), 2.05 (H-9 *> 1.90 (H-14a), 1.90 (H-8), 1.78 (H-4 '»), 1.56 (H-7»), 4 (H-7b), 134 (B-I4b), 1 ^ 3 (6-CH3), 1.29 (2-CHj), 1.32 (H-F'b), 1.24 (S'-CHj), 1.11 (tO) -CH,), 1.06 (12-CH3), 0.90 (4-CH3), 0.89 (8-CH3), 0.88 (14-CK?).
E j emp lo 16: 3-De (2, 6-dideoxy-3-C-methyl-3-0-methyl-aL-ribohexopyranosiloxi) -azithromycin 3, 6-hemicetal 2 '-O-ace tat o A solution of 3-De (2, 6-di-s-oxy-3-C-methyl-3-O-methyl-aL-ribohexopyranosyloxy) -3-azithromycin 2'-O-acetate (5.6 g) of Example 15 in CH2C12 (100 ml), dime ti 1 was added to its 1 f oxide (12.34 ml) and N, N-di me ti 1-ami nop r op i 1 -eti -carbodiimide (15.05 g). The reaction mixture was cooled to 15 ° C and then, under stirring and keeping the temperature at 15 ° C, a solution of trifluoride pyridinium oac (15.044 g) in CH2C12 (30 ml) was added gradually to drops for 30 minutes. The temperature of the reaction mixture was raised to room temperature, kept stirring for a further 4 hours and then a product was isolated according to the procedure described in Example 6, giving 5.26 g of the title compound. TLC Acetate of e t i 1 o - t r i e t i 1 amine, 95: 5, Rf
0.675.
E j p lo 17: 3-De (2, 6-dideoxy-3-C-methyl-3-Q-methyl-aL ribohexopyranosiloxy) -azithromycin 3, 6-hemicetal A solution of 3 -de (2,6-di of oxi-3-C-methyl-3-Q-methyl-α-L-ribohexopyranosyloxy) -azithromycin 3,6-hemi-acetic acid 1 2'-O-acetate (5.2 g) of Example 16 in methanol (100 ml ) was allowed to rest for 16 hours at room temperature. Methanol was evaporated at a reduced pressure and the product obtained was purified by low pressure chromatography on a silica gel column using the chloride system of 1-ene-1-amino-1-amino acid or conc. , 90: 9: 1, 5. Evaporating the fractions combined with Rf 0, 480 gave 3 - of (2, 6 - di of s ox 1 - 3 - C - me ti 1 - 3 - O - methyl - aL - ribohexopyranosyl-oxy) -azithromycin 3, 6 -hemicetal chromatographically homogeneous with the following physical constants: TIC: Acetate of eti 1 o-trieti 1 amine, 95: 5, Rf 0.447.
IR (CDC13) can "': 3468, 2976, 1713, 1638, 1459, 1382, 1197, 1116.1068, 1049, 1014, 963.
lH NMR (300 MHz, CDCl,) 8: 4.94 (H-13), 4"21 (H-11), 3.74 (H-3), 3.51 (HS"), 3.23 (H-2, 2.57 <jfci -2), 2.49 (H-3 ') 2.23 3Vf (C £ /, 2.06 (H-4), 1.74 (HS), 1.67 (H-4'a), 1.39 (6-CHs), 128 (2) -CH), 1.25 QH-4 * b), 1.22 (5, -CH3), 1.23, (4-CH3), 1.10 (l? -CH3), 1.04 (8-CHa) .0.92 (I4-CH3). 13C NMR (75 T? Hx, GDC? A) d: 176.9 (Cl), 106.1 (C-1 *), 102.3 (C-3), 94.8 (C-5), 82.4 (C-6), 69.7 ( C-2 *), 68.5 (C-11) .66.4 (C-9) .65.3 (CS *), 61.6 (C-10), 49.3 (C-2).
41. 6 (C-T), 40.1 / 3 * N < CÍ? »> »/, 3I.O (C-8), 28.2 (C-4"), 26.4 (6-CHj>, ZO.β (y-CH,), 13.6 (2 ~ C £? 3), 1X6 ( 4-CH,), 11.4 (14-CH3).
FAB-MS m / z 589
E x emp lo 18: 3-De (2,6-dideoxy-3-C-methyl-3-0-methyl-aL-ribohexopyranosyl-oxy) -acythromycin 3, 6 -hexyl cyclic ketal keto 11,12 A solution of 3-de (2,6-di-s-ox i -3-C-methyl-3-O-methyl-aL-ribohexopyranosyl-oxy) -azithromycin 3, 6 -hemi keta 1 (1 g) of Example 17 in ethyl acetate (30 ml) were added ethylene carbonate (0.5 g) and potassium carbonate (0.5 g). The suspension of the reaction was stirred under reflux for 10 hours, allowed to rest for 16 hours at room temperature and filtered. The ethyl acetate was rinsed with saturated NaCl solution and water, dried over CaCl2, filtered and evaporated, yielding 1.05 g of an oily residue. After separation on a column of silica gel using the chloride system of methyl ester and non-methyl ammonia conc., 90: 9: 0.5, the product of the chromatographically homogeneous title was obtained with the following Physical constants -Quimica: TLC Acetate of eti lo-trieti 1 amina, 95: 5, Rf 0.514.
IR ÍCDC and cm'1: 3498, 2975, 2941, 1812, 1724, 1638, 1459, 1381, 1359, 1333, 1292, 1234, 1173, 1115, 1082, 1045, 1015, 66.
lH NMR (300 MHz, CDC13) d: 5.03 (H-13), 4.61 (H-11X 4.23 (HV), 3.73 (H-5), 3.52 (H-5'X 3.25 (H- 3.18 (H-9t 2.90 (H-10), 2.54 (H-2), 2.50 (H-3 »X 2.28 ¡m (C? ¿, 2.10 (H-4), 2.07 (9a-NCH3), 1.76 (H-7a ? 1.95 (H-8), 1.86 (H-14a), 1.67 (H-4'a), 1.57 (H-9b), 1.55 (H-14b), 1.45 (12rCH3), 1.37 (6-CH3X 1 30 (2rCH3), 1.28 1.23 (5-CH, X 1.24 (4-CH3? 1.13 (H-7b), 1.18 (? 0-CH3), 0.90 (8-CH3), 0.92 (14-CH3).
l3C NMR (75 MHz, OJC!) d: 176.1 (C-1), 153.5 C-O carbonate). 106.1 (C-11), 101.6 (C-3), 93.6 (C-5), 83.7 (C-12), 82.7 (C-6), 78.9 (C-1). 77.9 (C-13X 69.6 (C-2? 69.4 (C-5'X 63.6 (C-9), 65.3 (C-3"X 60.1 (C-10), 49.9 (C-2), 46.6 (C- 4), 41.8 (C-7), 40.0 / 3"N (CHJ)? / .33.4 (9a-CH,). 28.0 (C-4 *), 26.8 (C-8), 25.1 (6-CHj) , 22.3 (C-14X 20.8 (S'-Cílj), 19.4 (8-CH3), 14.1 (12-CHj), 13.9 (2-CH3), 12.1 4- H3), 12.9 (10-CH?), 10.1 (4-CHj).
Claims (1)
1. Compound of the general formula (I CH3 a > bristling feature because: R represents individually hydroxyl, an L-cladinosyl group of the formula (II): (II) wherein: R represents individually hydrogen or a silyl group, R3 represents individually hydrogen or together with R6 represents an ether group, R4 represents individually hydrogen, an acyl group (Cj_-C4) or a group - COO - (C H2) n-Ar, wherein n is 1-7 and Ar individually represents a substituted or unsubstituted aryl group with up to 18 carbon atoms, R5 individually represents hydrogen, a methyl group or a group -COO- (CH2) n_ Ar , wherein n is 1-7 and Ar individually represents a substituted or unsubstituted aryl group with up to 18 carbon atoms, R6 represents individually a hydroxyl group or together with R3 has the meaning of an ether group, R7 individually represents hydrogen, alkyl group (C? -C? 2), a silyl group or together with R8 and the carbon atoms C-ll / C-12 represents a cyclic carbonate, R8 represents individually hydrogen, an alkyl group (C? -C? 2 ), a silyl group or together with R7 and the carbon C-11 / C-12 represents a cyclic carbonate, and its pharmaceutically acceptable addition salts with inorganic or organic acids, a process for the preparation thereof and the use thereof as antibiotics or as intermediates for the synthesis of other macrolide antibiotics.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HRP970551A | 1997-10-16 | ||
| HRP980497A | 1998-09-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00003644A true MXPA00003644A (en) | 2001-07-09 |
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