CN117304241B - 一种大环内酯类化合物及其制备方法与应用 - Google Patents
一种大环内酯类化合物及其制备方法与应用 Download PDFInfo
- Publication number
- CN117304241B CN117304241B CN202311620585.2A CN202311620585A CN117304241B CN 117304241 B CN117304241 B CN 117304241B CN 202311620585 A CN202311620585 A CN 202311620585A CN 117304241 B CN117304241 B CN 117304241B
- Authority
- CN
- China
- Prior art keywords
- tylosin
- macrolide compound
- acid
- macrolide
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 43
- 239000003120 macrolide antibiotic agent Substances 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 9
- 244000052769 pathogen Species 0.000 claims abstract description 7
- 208000015181 infectious disease Diseases 0.000 claims abstract description 6
- 230000001717 pathogenic effect Effects 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 239000000273 veterinary drug Substances 0.000 claims abstract description 4
- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 30
- -1 (R) -prolyl alcohol Chemical compound 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 150000001414 amino alcohols Chemical class 0.000 claims description 10
- 239000003814 drug Substances 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 6
- 241000193998 Streptococcus pneumoniae Species 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229940031000 streptococcus pneumoniae Drugs 0.000 claims description 6
- 241000588724 Escherichia coli Species 0.000 claims description 5
- 239000012454 non-polar solvent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 4
- 244000037640 animal pathogen Species 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000004182 Tylosin Substances 0.000 description 27
- 229960004059 tylosin Drugs 0.000 description 27
- 229930194936 Tylosin Natural products 0.000 description 26
- 235000019375 tylosin Nutrition 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000243 solution Substances 0.000 description 14
- 230000000844 anti-bacterial effect Effects 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 10
- 244000144972 livestock Species 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000001580 bacterial effect Effects 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 244000144977 poultry Species 0.000 description 7
- 235000013594 poultry meat Nutrition 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000192125 Firmicutes Species 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 241000282898 Sus scrofa Species 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 150000002466 imines Chemical class 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000204031 Mycoplasma Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- ICVKYYINQHWDLM-KBEWXLTPSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;2-[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4 Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 ICVKYYINQHWDLM-KBEWXLTPSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 238000009631 Broth culture Methods 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000204045 Mycoplasma hyopneumoniae Species 0.000 description 2
- 206010028470 Mycoplasma infections Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 241000187438 Streptomyces fradiae Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 229960004099 azithromycin Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- ONUMZHGUFYIKPM-MXNFEBESSA-N telavancin Chemical compound O1[C@@H](C)[C@@H](O)[C@](NCCNCCCCCCCCCC)(C)C[C@@H]1O[C@H]1[C@H](OC=2C3=CC=4[C@H](C(N[C@H]5C(=O)N[C@H](C(N[C@@H](C6=CC(O)=C(CNCP(O)(O)=O)C(O)=C6C=6C(O)=CC=C5C=6)C(O)=O)=O)[C@H](O)C5=CC=C(C(=C5)Cl)O3)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](NC(=O)[C@@H](CC(C)C)NC)[C@H](O)C3=CC=C(C(=C3)Cl)OC=2C=4)O[C@H](CO)[C@@H](O)[C@@H]1O ONUMZHGUFYIKPM-MXNFEBESSA-N 0.000 description 2
- 229960005240 telavancin Drugs 0.000 description 2
- 108010089019 telavancin Proteins 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229960001717 tylosin tartrate Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- VWAMTBXLZPEDQO-UZSBJOJWSA-N (2r,3s,4r,5s,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-7-propyl-1-oxa-7-azacyclopentadeca Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@H](CC)[C@@](C)(O)[C@H](O)[C@@H](C)CN([C@@H](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)CCC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 VWAMTBXLZPEDQO-UZSBJOJWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- OLLVTRJWJCUNEY-IAGPQMRQSA-N 2-[(4R,5S,6S,7R,9R,11E,13E,15R,16R)-6-[(2R,3R,4R,5S,6R)-5-[(2S,4R,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13-trimethyl-2,10-dioxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde hydrochloride Chemical compound Cl.CC[C@H]1OC(=O)C[C@@H](O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](O)[C@H](C)O3)[C@@H]([C@H]2O)N(C)C)[C@@H](CC=O)C[C@@H](C)C(=O)\C=C\C(\C)=C\[C@@H]1CO[C@@H]1O[C@H](C)[C@@H](O)[C@@H](OC)[C@H]1OC OLLVTRJWJCUNEY-IAGPQMRQSA-N 0.000 description 1
- NBOODGNJLRRJNA-IAGPQMRQSA-N 2-[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl Chemical compound OP(O)(O)=O.O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 NBOODGNJLRRJNA-IAGPQMRQSA-N 0.000 description 1
- RYUPCWUNGWONDQ-IAGPQMRQSA-N 2-[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl Chemical compound CC(O)C(O)=O.O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 RYUPCWUNGWONDQ-IAGPQMRQSA-N 0.000 description 1
- 241000606750 Actinobacillus Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000014085 Chronic respiratory disease Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 241000186810 Erysipelothrix rhusiopathiae Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241001148567 Lawsonia intracellularis Species 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 241001138504 Mycoplasma bovis Species 0.000 description 1
- 241000204022 Mycoplasma gallisepticum Species 0.000 description 1
- 241000606856 Pasteurella multocida Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000282849 Ruminantia Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010047697 Volvulus Diseases 0.000 description 1
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000001775 anti-pathogenic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000005262 decarbonization Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229960002314 gamithromycin Drugs 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 201000007647 intestinal volvulus Diseases 0.000 description 1
- 229950007634 kitasamycin Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- XYJOGTQLTFNMQG-KJHBSLKPSA-N leucomycin V Chemical compound CO[C@H]1[C@H](O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1 XYJOGTQLTFNMQG-KJHBSLKPSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000004396 mastitis Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000005142 microbroth dilution method Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-dimethylbenzene Natural products CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 229940051027 pasteurella multocida Drugs 0.000 description 1
- 238000009304 pastoral farming Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- XBXHCBLBYQEYTI-UHFFFAOYSA-N piperidin-4-ylmethanol Chemical compound OCC1CCNCC1 XBXHCBLBYQEYTI-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000009374 poultry farming Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 229960000223 tilmicosin Drugs 0.000 description 1
- JTSDBFGMPLKDCD-XVFHVFLVSA-N tilmicosin Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCN1C[C@H](C)C[C@H](C)C1)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O JTSDBFGMPLKDCD-XVFHVFLVSA-N 0.000 description 1
- 229940031989 tylosin phosphate Drugs 0.000 description 1
- 208000025301 tympanitis Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Communicable Diseases (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种大环内酯类化合物及其制备方法与应用。本发明提供的大环内酯类化合物具有如式I所示的结构，本发明还提供了一种药物组合物或兽药组合物，其包括如式I所示结构的大环内酯类化合物。本发明还提供了一种药物制剂，其包括如式I所示结构的大环内酯类化合物。本发明提供的大环内酯类化合物、兽药组合物及药物制剂可用于治疗病原体感染，特别是治疗动物病原体感染，效果显著。
Description
技术领域
本发明属于杂环化合物合成及动物药学技术领域，具体涉及一种大环内酯类化合物及其制备方法与应用。
背景技术
大环内酯类化合物是一类重要的抗生素，具有抗感染性好、副作用小等优点，广泛应用于畜禽兽医临床（王秀茹 大环内酯类药物的性质、特点及应用.兽医导刊2018, 54-55. 匡宝晓. 新型动物专用抗生素-泰地罗新.今日养猪业,2022, 98-100.）。按照化学结构分类，大环内酯类抗生素分为14元环、15元环与16元环大环内酯类药物。主要品种有红霉素、阿奇霉素、吉他霉素、泰乐菌素、替米考星、泰万菌素、加米霉素等（于志超. 兽用抗生素加米霉素的研究进展.当代畜禽养殖业2020, 22-23. 刘旺; 裴巍. 阿奇霉素的最新研究进展.畜牧兽医科技信息2014, 15.）。主要用于治疗牛支原体感染引起的牛呼吸道疾病、乳腺炎、关节炎和中耳炎，由猪肺炎支原体引起的猪气喘病，由胞内劳森氏菌引起的猪增生性肠炎，鸡支原体引起的鸡慢性呼吸道疾病等疾病（贺承光; 孔令聪; 孙喆. 牛支原体抗生素耐药性的研究进展.吉林畜牧兽医2018,39, 11-13. 万进; 马妮妮; 王聪. 酒石酸泰万菌素对特定畜禽疫病防治功效研究进展. 中国动物检疫,2021,38, 75-78.）。
泰乐菌素，英文名称为Tylosin，是一种重要的大环内酯类畜禽专用抗生素，具有16元大环内酯结构，最早于1959年从弗氏链霉菌（Streptomyces fradiae）的培养液中提取获得。畜禽兽医临床使用产品主要包括酒石酸泰乐菌素、乳酸泰乐菌素、硫酸泰乐菌素、盐酸泰乐菌素与磷酸泰乐菌素（陈东; 张晓强; 纳奇; 锁嘉伟. 泰乐菌素纯化工艺优化研究.当代化工研究,2023, 170-172. 刘佳; 郝生燕; 潘发明. 动物产品中泰乐菌素残留规律研究进展.畜牧与兽医2022,54, 148-152.）。泰乐菌素对于革兰氏阴性菌、革兰阳性菌与支原体等病原体均具有良好的抗菌活性，不仅可以用于治疗猪痢疾、家禽支原体感染、反刍动物肺炎等疾病，而且可以作为饲料添加剂，促进动物生长（王丽霞; 李生龙; 陈砀桐; 王君. 泰乐菌素高效液相色谱检测方法的建立.安徽农业科学2020,48, 206-209.）。
为开发新的大环内酯类抗生素，国内外学者对泰乐菌素的结构进行了各种改造，已合成出一系列泰乐菌素衍生物（赵东峰; 任翔; 朱丽. 泰乐菌素及其衍生物研究进展.医药产业资讯, 2006, 46-48.）。例如，10,11,12,13-四氢-脱碳霉糖泰乐菌素衍生物（Narandja, A.; Kelneric, K.; Kolacny-Babic, L.; Djokic, S. 10,11,12,13-Tetrahydro Derivatives of Tylosin. Ii. Synthesis, Antibacterial Activity andTissue Distribution of 4'-Deoxy-10,11,12,13-Tetrahydrodesmycosin.Journal of Antibiotics.1995,48, 248-253. Narandja, A.; Djokic, S. Derivatives of 10,11,12,13-tetra-hydrodesmycosin, processes for preparation, and use thereof inobtaining pharmaceuticals. Patent EP0490311, 1992-06-17）、9-肟泰乐菌素衍生物（王焕焕; 杨璞; 翟洪进; 张烁; 曹亚权; 杨莹雪; 吴春丽 新型泰乐菌素衍生物的设计合成和活性评价.有机化学2022,42, 557-571.）、12,13-环氧泰乐菌素（Narandja, A.;Lopotar, N. Derivatives of 12,13-Epoxy-tylosin and processes of manufacturethereof. Patent US5688924, 1997-11-18）、泰地罗新（Zhang, C.; Song, M.; Qi, P.;Zhang, G.; Ge, X.; Zhao, M.; Wu, J.; Ma, J.; Wang, D.; Process forpreparation of 20,23-dipiperidinyl-5-O-mycaminosyl-tylonolide. Patent CN104892704 B, 2017-08-08.）、泰万菌素（酒石酸泰万菌素对特定畜禽疫病防治功效研究进展. 中国动物检疫,2021,38, 75-78.）等。
发明内容
本发明的目的是提供一种大环内酯类化合物及其制备方法与应用，该化合物可用于治疗或预防动物病原体感染，效果显著。
为实现上述目的，本发明提供如下技术方案：
第一方面，本发明提供一种大环内酯类化合物，具有如式I所示的结构：
其中：R选自2-羟基乙氨基、3-羟基丙氨基、二(2-羟基乙氨基)、二(3-羟基丙氨基)、(R)-2-羟甲基四氢吡咯基、(S)-2-羟甲基四氢吡咯基、4-羟基哌啶基、4-羟甲基哌啶基。
具体地，所述大环内酯类化合物为：20-(2-羟基乙氨基)泰乐菌素、20-(3-羟基丙氨基)泰乐菌素、20-(二(2-羟基乙氨基) )泰乐菌素、20-(二(3-羟基丙氨基))泰乐菌素、20-((R)-2-羟甲基四氢吡咯基)泰乐菌素、20-((S)-2-羟甲基四氢吡咯基)泰乐菌素、20-(4-羟基哌啶基)泰乐菌素、20-(4-羟甲基哌啶基)泰乐菌素。
优选地，所述大环内酯类化合物具有如式Ia、式Ib、式Ic或式Id中任一项所示的结构：
。
本发明还提供上述大环内酯类化合物在药学上可接受的盐。
所述药学上可接受的盐是指，所述大环内酯化合物与酸生成的盐。
所述酸包括：酒石酸、盐酸、磷酸、硫酸、水杨酸、甲磺酸、乳酸、苹果酸、甲酸、乙酸、丙酸、富马酸、柠檬酸、草酸盐、马来酸、琥珀酸、苯甲酸、乙二磺酸等。
第二方面，本发明进一步提供上述大环内酯类化合物的制备方法，包括如下步骤：
S1、泰乐菌素A与氨基醇反应；
S2、向步骤S1反应得到的体系中加入还原剂或酸，反应得到所述大环内酯类化合物。
进一步地，所述制备方法包括合成路径1和合成路径2：
所述合成路径1包括如下步骤：
（1）泰乐菌素A与氨基醇在极性溶剂中反应，得到亚胺溶液；
（2）向所述亚胺溶液中加入还原剂，反应得到羟基仲氨基修饰的大环内酯类化合物。
步骤（1）中，所述氨基醇为2-氨基乙醇、3-氨基丙醇。
步骤（1）中，所述氨基醇与所述泰乐菌素A的摩尔比为2~5：1，优选为3~3.5：1。
步骤（1）中，所述极性溶剂为甲醇、乙醇、丙醇、异丙醇、正丁醇和乙二醇中的一种或多种。
步骤（1）中，所述反应的条件为：温度为室温，时间为12~13 h。
步骤（2）中，所述还原剂为硼氢化钠、三乙酰氧基硼氢化钠和LiAlH4中的一种或多种。
步骤（2）中，所述还原剂与所述泰乐菌素A的摩尔比为1~4：1，优选为2~2.5：1。
步骤（2）中，所述反应的条件为：温度为室温，时间为2~3h。
进一步地，所述合成路径1还包括：在加入所述还原剂之前，进行TLC监测反应，确保原料完全转化为亚胺。
进一步地，所述合成路径1还包括后处理步骤；所述后处理按照下述操作进行：向反应体系内加入碱的水溶液淬灭反应，然后减压浓缩除去醇溶剂；剩余水溶液用有机溶剂萃取，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩；其中，碱选自碳酸钾、碳酸钠、氢氧化钾或氢氧化钠中的一种或多种；有机溶剂选自二氯甲烷、乙酸乙酯或乙醚中的一种或多种。
示例性地，上述合成路径1的合成路线如下：
所述合成路径2包括如下步骤：
（A）泰乐菌素A与氨基醇在非极性溶剂中反应，得到反应液；
（B）向步骤（A）得到的反应液中加入酸，反应得到羟基叔氨基修饰的大环内酯类化合物。
步骤（A）中，所述氨基醇为2-氨基乙醇、3-氨基丙醇、(R)-脯氨醇、(S)-脯氨醇、4-羟基哌啶、4-羟甲基哌啶。
步骤（A）中，所述氨基醇与所述泰乐菌素A的摩尔比为2~5：1，优选为2.5~3.5:1。
步骤（A）中，所述非极性溶剂为乙二醇二甲醚、苯和甲苯中的一种或多种。
步骤（B）中，所述酸为甲酸。
步骤（B）中，所述酸的加入时机为：反应体系的温度达到75~85℃，优选为80℃。
步骤（B）中，所述酸与所述泰乐菌素A的摩尔比为3~6：1，优选为5~6：1。
步骤（B）中，所述反应的条件为：温度为78~80℃，时间为2~2.5h。
进一步地，所述合成路径2还包括后处理步骤；所述后处理按照下述操作进行：向反应体系内加入蒸馏水，分液后的水相用碱调pH至9~11，水溶液用有机溶剂萃取，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩；其中，碱选自碳酸钾、碳酸钠、氢氧化钾或氢氧化钠中的一种或多种；有机溶剂选自二氯甲烷、乙酸乙酯或乙醚中的一种或多种。
进一步地，本发明提供的大环内酯类化合物的制备方法还包括纯化步骤：将所得粗产物加到硅胶色谱柱内，选两种有机溶剂配成不同极性的洗脱剂，利用梯度洗脱将粗品内的杂质除去，从而得到大环内酯类化合物纯品；其中所述洗脱剂可选自乙醚、乙酸乙酯、甲醇、异丙醇、丙酮或二氯甲烷中的任意两种。
示例性地，上述合成路径2的合成路线如下：
第三方面，本发明进一步提供一种兽药组合物，所述兽药组合物包括上述如式I所示结构的大环内酯类化合物。
第四方面，本发明还进一步提供一种药物制剂，所述药物制剂包括上述如式I所示结构的大环内酯类化合物。
所述药物制剂的剂型为散剂、片剂、预混剂、可溶性粉剂、注射液。
第五方面，本发明进一步提供上述大环内酯类化合物、兽药组合物及药物制剂在制备抗病原体感染药品中的应用。示例性地，所述抗病原体感染药品如畜禽兽医临床使用产品。
所述应用中，所述病原体为支原体、巴氏杆菌、多杀氏巴氏杆菌、噬组织菌、金黄色葡萄球菌、无乳链球菌、肺炎链球菌、乙型溶血性链球菌、大肠杆菌、流感嗜血杆菌、肺炎放线杆菌、沙门氏菌、曼氏杆菌、猪丹毒杆菌。
本发明取得的有益效果如下：
本发明提供了一种大环内酯类化合物及其制备方法与应用，该化合物或其药学上可接受的盐可用于治疗或预防细菌或支原体感染，为畜牧兽医临床提供更多的选择性。
具体实施方式
下面结合具体实施例对本发明作进一步阐述，但本发明并不限于以下实施例。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的试剂、材料、仪器等，如无特殊说明，均可从商业途径得到。
以下实施例中使用的原料来源如下：
实施例1
将泰乐菌素A（3.00 g, 3.27 mmol）加入50 mL史莱克瓶，加入甲醇（18 mL），然后用注射器缓慢加入3-氨基-1-丙醇（0.74 g, 9.85 mmol），室温下搅拌反应12 h。
TLC检测原料完全转化为亚胺后，室温下缓慢加入三乙酰氧基硼氢化钠（1.39 g,6.56 mmol），室温下继续搅拌反应2 h。
TLC检测反应完全后，加入1 M的NaOH 水溶液 (3 mL) 淬灭反应。然后减压浓缩除去MeOH，残余物用二氯甲烷（10 mL×3）萃取。合并的萃取液用饱和NaCl水溶液 (10 mL)洗涤，无水硫酸钠干燥。过滤，将滤液减压浓缩得到粗产物。最后，经过硅胶柱色谱纯化（二氯甲烷/甲醇 = 8:1），得到白色固体大环内酯化合物Ia（1.40 g，产率44%）。
1H NMR (500 MHz, CDCl3) δ 7.37 (d,J= 14.7 Hz, 1H), 6.30 (d,J= 14.8 Hz,1H), 5.95 (s, 1H), 5.08 (d,J= 9.6 Hz, 1H), 4.96 (d,J= 10.6 Hz, 1H), 4.58 (t,J= 10.5 Hz, 1H), 4.33 – 4.25 (s, 4H), 4.09 – 4.08 (m, 1H), 4.01 – 3.99 (m,1H), 3.80 – 3.75 (m, 4H), 3.67 – 3.61 (m, 4H), 3.56 (s, 2H), 3.49 – 3.47 (m,2H), 3.29 (t,J= 10.5 Hz, 2H), 3.19 (d,J= 10.4 Hz, 1H), 3.02 – 2.95 (m, 4H),2.87 – 2.80 (m, 3H), 2.72 – 2.68 (m, 4H), 2.51 – 2.44 (m, 8H), 2.06 – 1.95(m, 3H), 1.87 – 1.74 (m, 8H), 1.63 – 1.62 (m, 3H), 1.53 – 1.48 (m, 2H), 1.31– 1.23 (m, 14H), 1.16 – 1.11 (m, 4H), 1.03 (s, 3H), 0.93 (d,J= 8.2 Hz, 3H)。
13C NMR (126 MHz, CDCl3) δ 203.84, 173.60, 148.26, 142.99, 134.55,117.88, 103.71, 101.01, 96.38, 81.69, 79.83, 79.50, 76.32, 75.03, 74.88,72.84, 72.67, 71.67, 70.34, 69.39, 69.02, 68.70, 66.59, 65.88, 61.88, 61.66,59.51, 47.26, 46.07, 45.94, 44.97, 41.91, 41.05, 40.85, 39.32, 33.47, 32.41,30.42, 29.55, 26.14, 25.34, 25.18, 19.03, 18.18, 17.69, 17.52, 12.82, 10.52,9.55。
TLC Rf = 0.4（二氯甲烷/甲醇 = 8:1）
HRMS (ESI, m/z): [M + H]+calcd for C49H87N2O17, 975.59993; found975.60059。
实施例2
将泰乐菌素A（0.50 g, 0.55 mmol）加入装有冷凝管的50 mL三口瓶，加入甲苯（6mL），搅拌溶解。然后加入二乙醇胺（0.17 g, 1.62 mmol），升温至80 ℃，再加入甲酸（0.14g, 3.04 mmol），在80 ℃下继续搅拌反应2 h。
TLC检测反应完全后，加入蒸馏水（5 mL）淬灭反应，分液。水相用5 M的氢氧化钠水溶液调pH至10，然后用二氯甲烷（15 mL×3）萃取。合并的萃取液用无水硫酸钠干燥。过滤，将滤液减压浓缩得到粗产物。最后，经过硅胶柱色谱纯化（二氯甲烷/甲醇=8：1）得到白色固体大环内酯化合物Ib（0.27 g，产率49%）。
1H NMR (500 MHz, CDCl3) δ 7.44 (d,J= 14.4 Hz, 1H), 6.31 (d,J= 15.7 Hz,1H), 5.98 (s, 1H), 5.08 (d,J= 10.2 Hz, 1H), 4.93 (d,J= 9.9 Hz, 1H), 4.58 (t,J= 9.1 Hz, 1H), 4.33 – 4.29 (m, 2H), 4.11 – 4.08 (m, 1H), 4.03 – 3.99 (m, 1H),3.79 – 3.57 (m, 13H), 3.47 – 3.45 (m, 2H), 3.32 – 3.28 (m, 2H), 3.21 – 3.17(m, 1H), 3.05 – 2.95 (m, 3H), 2.72 – 2.60 (m, 7H), 2.51 – 2.49 (m, 8H), 2.42– 2.38 (m, 2H), 2.28 – 2.26 (m, 1H), 2.06 – 2.01 (m, 1H), 1.95 – 1.75 (m,7H), 1.66 – 1.59 (m, 3H), 1.50 – 1.46 (m, 2H), 1.32 – 1.21 (m, 16H), 1.12 –1.05 (m, 7H), 0.96 – 0.91 (m, 3H)。
13C NMR (126 MHz, CDCl3) δ 205.13, 173.62, 149.18, 143.77, 134.55,117.45, 103.57, 101.03, 96.33, 81.66, 80.09, 79.83, 76.33, 75.15, 75.07,72.76, 72.68, 71.74, 70.36, 69.40, 69.10, 68.75, 66.33, 65.89, 61.64, 59.58,59.47, 59.43, 57.17, 53.02, 45.97, 45.94, 45.27, 44.89, 41.93, 41.01, 40.88,39.39, 33.80, 33.65, 26.06, 25.34, 25.25, 19.10, 18.18, 17.69, 17.46, 12.76,10.89, 9.66。
TLC Rf = 0.2（二氯甲烷/甲醇 = 8:1）
HRMS (ESI, m/z): [M + H]+calcd for C50H89N2O18, 1005.61049; found1005.62402。
实施例3
将泰乐菌素A（0.50 g, 0.55 mmol）加入装有冷凝管的50 mL三口瓶，加入甲苯（6mL），然后加入(R)-脯氨醇（0.17 g, 1.68 mmol），搅拌溶解。升温至80 ℃，加入甲酸（0.14g, 3.04 mmol），在80 ℃下继续反应2 h。
TLC检测反应完全后，加入蒸馏水（5 mL）淬灭反应，分液。水相用5 M的氢氧化钠水溶液调pH至10，然后用二氯甲烷（15 mL×3）萃取。合并的萃取液用无水硫酸钠干燥。过滤，将滤液减压浓缩得到粗产物。最后，经过硅胶柱色谱纯化（二氯甲烷/甲醇=8：1），得到白色固体大环内酯化合物Ic（0.32 g，产率58%）。
1H NMR (500 MHz, CDCl3) δ 7.36 (d,J= 17.5 Hz, 1H), 6.30 (d,J= 14.8 Hz,1H), 5.94 (s, 1H), 5.09 – 5.07 (m, 1H), 4.97 – 4.94 (m, 1H), 4.58 – 4.55 (m,1H), 4.29 – 4.26 (m, 2H), 4.11 – 4.06 (m, 1H), 4.02 – 3.98 (m, 1H), 3.83 –3.81 (m, 1H), 3.76 – 3.73 (m, 1H), 3.62 – 3.53 (m, 7H), 3.47 – 3.44 (m, 4H),3.33 – 3.29 (m, 2H), 3.19 – 3.17 (m, 2H), 3.03 – 2.93 (m, 3H), 2.72 – 2.63(m, 3H), 2.59 – 2.54 (m, 6H), 2.50 – 2.46 (m, 5H), 2.36 – 2.26 (m, 2H), 2.04– 2.01 (m, 2H), 1.89 – 1.83 (m, 3H), 1.79 – 1.72 (m, 7H), 1.63 – 1.55 (m,4H), 1.31 – 1.19 (m, 16H), 1.08 – 1.06 (m, 5H), 1.01 – 0.99 (m, 2H), 0.93 –0.91 (m, 3H)。
13C NMR (126 MHz, CDCl3) δ 203.98, 173.63, 162.63, 161.84, 148.07,143.06, 134.38, 117.97, 103.97, 101.01, 96.36, 82.44, 81.69, 79.86, 76.32,75.01, 74.91, 72.95, 72.66, 71.65, 70.35, 69.37, 69.07, 68.80, 66.48, 65.89,65.12, 63.03, 61.64, 59.50, 55.00, 54.69, 46.01, 45.11, 41.93, 41.63, 40.87,39.36, 34.95, 34.22, 27.64, 26.75, 25.34, 25.17, 23.48, 19.13, 18.18, 17.69,12.76, 11.16, 9.60, 9.33。
TLC Rf = 0.3（二氯甲烷/甲醇 = 8:1）
HRMS (ESI, m/z): [M + H]+calcd for C51H89N2O17, 1001.61558; found1001.61896。
实施例4
将泰乐菌素A（1.00 g, 1.09 mmol）加入装有冷凝管的50 mL三口瓶，加入甲苯（8mL），然后加入 (S)-脯氨醇（0.33 g, 3.26 mmol），搅拌溶解。升温至80 ℃，加入甲酸（0.27g, 5.86 mmol），在80 ℃下继续反应2 h。
TLC检测反应完全后，加入蒸馏水（8 mL）淬灭反应，分液。水相用5 M的氢氧化钠水溶液调pH至10，然后用二氯甲烷（15 mL×3）萃取。合并的萃取液用无水硫酸钠干燥。过滤，将滤液减压浓缩得到粗产物。最后，经过硅胶柱色谱（二氯甲烷/甲醇=8：1）纯化得到白色固体大环内酯化合物Id（0.64 g，产率59%）。
1H NMR (500 MHz, CDCl3) δ 7.31 (d,J= 15.4 Hz, 1H), 6.29 (d,J= 15.5 Hz,1H), 5.92 (s, 1H), 5.11 – 5.06 (m, 1H), 4.97 – 4.91 (m, 1H), 4.59 – 4.55 (m,1H), 4.32 – 4.26 (m, 2H), 4.11 – 4.07 (m, 1H), 4.02 – 3.97 (m, 1H), 3.76 –3.72 (m, 2H), 3.65 – 3.61 (m, 4H), 3.57 – 3.53 (m, 3H), 3.50 – 3.42 (m, 4H),3.33 – 3.27 (m, 2H), 3.21 – 3.17 (m, 2H), 3.02 – 2.93 (m, 3H), 2.87 – 2.68(m, 3H), 2.61 – 2.42 (m, 13H), 2.16 – 2.09 (m, 2H), 1.88 – 1.74 (m, 10H),1.65 – 1.56 (m, 4H), 1.33 – 1.19 (m, 16H), 1.10 – 1.02 (m, 7H), 0.96 – 0.90(m, 3H)。
13C NMR (126 MHz, CDCl3) δ 203.54, 172.99, 162.58, 161.82, 147.71,142.84, 134.41, 117.96, 103.63, 100.97, 96.28, 81.63, 79.82, 79.45, 76.29,75.01, 74.77, 72.76, 72.64, 71.71, 70.29, 69.33, 69.12, 68.71, 66.41, 65.83,65.56, 61.65, 61.58, 59.45, 53.48, 53.38, 45.95, 45.14, 41.91, 41.17, 40.84,39.62, 33.60, 32.58, 26.98, 26.66, 25.31, 23.27, 23.21, 19.05, 18.14, 17.65,12.79, 11.10, 9.59。
TLC Rf = 0.3（二氯甲烷/甲醇 = 8:1）
HRMS (ESI, m/z): [M + H]+calcd for C51H89N2O17, 1001.61558; found1001.61746。
测试例1 本发明化合物抗菌活性测定
以泰乐菌素为阳性对照，采用微量肉汤稀释法，测定本发明中实施例1-4获得化合物的抗菌活性。
测试方法如下：
在96孔板加入肉汤培养基，将己经配制药液作微量二倍递减浓度稀释，然后接种适量菌液，经24 h孵育后，观察药物最低抑菌浓度。
试验用培养基为CAMHB肉汤、CAMHB+5%脱纤维羊血肉汤。
将保存菌种接种于血清板培养基，37℃培养16-18小时，将传代培养完毕的适量细菌和生理盐水置于比浊管中，用麦氏比浊仪校正到麦氏比浊标准，将细菌悬浊液以生理盐水稀释10倍，制得一定浓度（5×105~5×106cfu/mL）的试验用菌液，待用。
将泰乐菌素及实施例所获得的化合物用甲醇溶解，使各化合物浓度至所需浓度（1.0 mg/mL），储于灭菌的棕色西林瓶中，加塞、封口待用。其中针对革兰氏阴性菌工作浓度范围0.25 μg/mL~128 μg/mL；针对革兰氏阳性菌工作浓度范围0.098μg/mL~50 μg/mL。
采用96孔板微量二倍稀释法。在96孔板中加入肉汤培养基，将已配制好的药液作微量二倍递减浓度稀释，使第一个孔至第十个孔中的药液浓度呈现二倍递减关系，第十一个孔和第十二个孔不加药液。最后向第一个孔至第十一个孔中加入己配置好的菌液（浓度为5×105～5×106cfu/mL），第十二个孔不加菌液作为空白对照。将96孔板放置于37℃的恒温箱中，静置培养24小时，观察每个孔的细菌生长情况。抑制细菌生长的孔中溶液为透明，不能抑制细菌生长的孔中溶液为浑浊。选择溶液透明的孔所对应的浓度即为即为该样品的最小抗菌浓度(MIC)。
结果如下表。
结果表明：与泰乐菌素相比，实施例1-4中获得化合物对肺炎链球菌（革兰氏阳性菌代表）和大肠杆菌（革兰氏阴性菌代表）的体外抗菌活性表现出优于或相当的效果，说明式I所示化合物对革兰氏阳性菌、部分革兰氏阴性菌和支原体等有抗菌活性。具体来讲，经过3-氨基-1-丙醇反应得到衍生物Ia，对肺炎链球菌ATCC 49169略优于泰乐菌素，对大肠杆菌8099的抗菌效果与泰乐菌素相当，推测R位基团增加了与肺炎链球菌的结合，提升了抗菌活性；经过与（R）-脯氨醇反应得到的衍生物Ic，其对肺炎链球菌ATCC 49169和大肠杆菌8099的抗菌效果均优于泰乐菌素；而(S)-脯氨醇的反应得到的衍生物Id，含N的吡咯环引入虽能进一步增加了抗菌活性，但可能因空间位阻原因，其抗菌活性的增加没有得到实现。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
Claims (5)
1.一种大环内酯类化合物，其特征在于：所述大环内酯类化合物具有如式Ic所示的结构：
2.权利要求1所述大环内酯类化合物的制备方法，其特征在于：包括如下步骤：
(A)泰乐菌素A与氨基醇在非极性溶剂中反应，得到反应液；所述氨基醇为(R)-脯氨醇，所述氨基醇与所述泰乐菌素A的摩尔比为2～5：1；所述非极性溶剂为甲苯；
(B)向所述反应液中加入酸，反应得到羟基叔氨基修饰的大环内酯类化合物；所述酸为甲酸；所述酸的加入时机为：反应体系的温度达到75～85℃；所述酸与所述泰乐菌素A的摩尔比为3～6：1；
步骤(B)中，所述反应的条件为：温度为78～80℃，时间为2～3h。
3.一种兽药组合物，其特征在于：所述兽药组合物包括权利要求1所述的大环内酯类化合物。
4.一种药物制剂，其特征在于：所述药物制剂包括权利要求1所述的大环内酯类化合物。
5.权利要求1所述的大环内酯类化合物、权利要求3所述的兽药组合物或权利要求4所述的药物制剂在制备抗病原体感染药品中的应用，所述病原体为肺炎链球菌和/或大肠杆菌。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311620585.2A CN117304241B (zh) | 2023-11-30 | 2023-11-30 | 一种大环内酯类化合物及其制备方法与应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311620585.2A CN117304241B (zh) | 2023-11-30 | 2023-11-30 | 一种大环内酯类化合物及其制备方法与应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN117304241A CN117304241A (zh) | 2023-12-29 |
| CN117304241B true CN117304241B (zh) | 2024-03-01 |
Family
ID=89260790
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311620585.2A Active CN117304241B (zh) | 2023-11-30 | 2023-11-30 | 一种大环内酯类化合物及其制备方法与应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117304241B (zh) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0103465A1 (en) * | 1982-09-13 | 1984-03-21 | Eli Lilly And Company | 20-Amino macrolide derivatives |
| US4440759A (en) * | 1982-02-25 | 1984-04-03 | Satoshi Omura | 20-Amino tylosin derivatives and pharmaceutical compositions containing same |
| CN87102397A (zh) * | 1986-03-31 | 1987-10-07 | 伊莱利利公司 | 制备大环内酯类衍生物的改进方法 |
| US4820695A (en) * | 1982-09-13 | 1989-04-11 | Eli Lilly And Company | C-20-dihydro-deoxy-(cyclic amino)-derivatives of macrolide antibiotics |
| US4933439A (en) * | 1988-06-21 | 1990-06-12 | Sanraku Incorporated | Tylosin derivatives and processes for producing the same |
| CN1083068A (zh) * | 1992-07-15 | 1994-03-02 | 美国辉瑞有限公司 | 16节环抗菌的大环内酯的衍生物 |
| CN103059084A (zh) * | 2013-01-18 | 2013-04-24 | 郑州大学 | 乙酰异戊酰泰乐菌素胺化物、制备方法及应用 |
| CN103130848A (zh) * | 2013-02-22 | 2013-06-05 | 中国人民解放军第二军医大学 | 一种大环内酯类抗菌化合物及其制备方法和应用 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2012211760A1 (en) * | 2011-01-31 | 2013-08-15 | Meiji Seika Pharma Co., Ltd. | Novel macrolide derivative |
-
2023
- 2023-11-30 CN CN202311620585.2A patent/CN117304241B/zh active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4440759A (en) * | 1982-02-25 | 1984-04-03 | Satoshi Omura | 20-Amino tylosin derivatives and pharmaceutical compositions containing same |
| EP0103465A1 (en) * | 1982-09-13 | 1984-03-21 | Eli Lilly And Company | 20-Amino macrolide derivatives |
| US4820695A (en) * | 1982-09-13 | 1989-04-11 | Eli Lilly And Company | C-20-dihydro-deoxy-(cyclic amino)-derivatives of macrolide antibiotics |
| CN87102397A (zh) * | 1986-03-31 | 1987-10-07 | 伊莱利利公司 | 制备大环内酯类衍生物的改进方法 |
| US4933439A (en) * | 1988-06-21 | 1990-06-12 | Sanraku Incorporated | Tylosin derivatives and processes for producing the same |
| CN1083068A (zh) * | 1992-07-15 | 1994-03-02 | 美国辉瑞有限公司 | 16节环抗菌的大环内酯的衍生物 |
| CN103059084A (zh) * | 2013-01-18 | 2013-04-24 | 郑州大学 | 乙酰异戊酰泰乐菌素胺化物、制备方法及应用 |
| CN103130848A (zh) * | 2013-02-22 | 2013-06-05 | 中国人民解放军第二军医大学 | 一种大环内酯类抗菌化合物及其制备方法和应用 |
Non-Patent Citations (3)
| Title |
|---|
| Chemical modification of tylosin: synthesis of amino derivatives at C-20 position of tylosin and demycarosyltylosin;HAJIME MATSUBAR et al.;《Journal of Antibiotics》;第36卷;第1713-1721页 * |
| HAJIME MATSUBAR et al..Chemical modification of tylosin: synthesis of amino derivatives at C-20 position of tylosin and demycarosyltylosin.《Journal of Antibiotics》.1983,第36卷第1713-1721页. * |
| SYNTHESIS AND ANTIMICROBIAL EVALUATION OF 20-DEOXO-20-(3，5-DIMETHYLPIPERIDIN-l-YL)DESMYCOSIN (TILMICOSIN，EL-870) AND RELATED CYCLIC AMINO DERIVATIVES;Manuel Debono et al.;《Journal of Antibiotics》;第8卷;第1253-1267页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117304241A (zh) | 2023-12-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Debono et al. | Synthesis and antimicrobial evaluation of 20-deoxo-20-(3, 5-dimethylpiperidin-l-yl) desmycosin (tilmicosin, EL-870) and related cyclic amino derivatives | |
| DK2125850T3 (en) | MACROCYCLIC POLYMORPHS, COMPOSITIONS INCLUDING SUCH POLYMORPHS, PROCEDURES FOR PREPARING AND USING THEREOF | |
| KR100486053B1 (ko) | 신규에리트로마이신유도체,그의제조방법및약제로서의그의용도 | |
| US8518899B2 (en) | Macrocyclic polymorphs, compositions comprising such polymorphs and methods of use and manufacture thereof | |
| US20190211003A1 (en) | Novel 16-member triamilide derivatives and uses thereof | |
| CN117304241B (zh) | 一种大环内酯类化合物及其制备方法与应用 | |
| CN117510561B (zh) | 一种泰乐菌素衍生物及其制备方法与应用 | |
| KR20160014656A (ko) | 틸로신 유도체 및 그의 제조 방법 | |
| CN110590885A (zh) | 20-取代-5-o-碳霉胺糖基-泰乐内酯衍生物 | |
| CN108864228B (zh) | 十六元环三胺内酯衍生物及其应用 | |
| CN116731096A (zh) | 20-醛基-23-哌啶基-5-o-碳霉胺糖基-泰乐内酯及其合成方法及它的用途 | |
| AU2008209580B2 (en) | Macrocyclic polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof | |
| AU2012244278B2 (en) | Macrocyclic polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof | |
| EA003776B1 (ru) | Производные 6-деоксиэритромицина, способ их получения и их применение в качестве лекарственных средств | |
| JPH09132590A (ja) | １０位含窒素置換メチル１４員環マクロライド誘導体 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |