CN1109890A - 9-脱氧-9a-氮杂-9a-高红霉素,A的9a-N-(N′-氨基甲酰基)和9a-N-(N′-硫代氨基甲酰基衍生物 - Google Patents
9-脱氧-9a-氮杂-9a-高红霉素,A的9a-N-(N′-氨基甲酰基)和9a-N-(N′-硫代氨基甲酰基衍生物 Download PDFInfo
- Publication number
- CN1109890A CN1109890A CN94112765A CN94112765A CN1109890A CN 1109890 A CN1109890 A CN 1109890A CN 94112765 A CN94112765 A CN 94112765A CN 94112765 A CN94112765 A CN 94112765A CN 1109890 A CN1109890 A CN 1109890A
- Authority
- CN
- China
- Prior art keywords
- compound
- homoerythromycin
- deoxidation
- azepine
- represent
- 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.)
- Granted
Links
- 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 class 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 title abstract description 3
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- 150000007524 organic acids Chemical class 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 20
- 239000000654 additive Substances 0.000 claims description 9
- 230000000996 additive effect Effects 0.000 claims description 9
- -1 4-methyl-5-oxazolyl Chemical group 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 241000894006 Bacteria Species 0.000 claims description 5
- 230000000845 anti-microbial effect Effects 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 230000008707 rearrangement Effects 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 13
- 150000007522 mineralic acids Chemical class 0.000 abstract description 7
- 239000003120 macrolide antibiotic agent Substances 0.000 abstract description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
- 208000035143 Bacterial infection Diseases 0.000 abstract 1
- 208000022362 bacterial infectious disease Diseases 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 235000005985 organic acids Nutrition 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 229960003276 erythromycin Drugs 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
- 229930006677 Erythromycin A Natural products 0.000 description 7
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- BDQNKCYCTYYMAA-UHFFFAOYSA-N 1-isocyanatonaphthalene Chemical compound C1=CC=C2C(N=C=O)=CC=CC2=C1 BDQNKCYCTYYMAA-UHFFFAOYSA-N 0.000 description 1
- GSLTVFIVJMCNBH-UHFFFAOYSA-N 2-isocyanatopropane Chemical class CC(C)N=C=O GSLTVFIVJMCNBH-UHFFFAOYSA-N 0.000 description 1
- ZIXUNDOOBLSXPE-UHFFFAOYSA-N 4-methyl-1,3-oxazole-5-carboxylic acid Chemical compound CC=1N=COC=1C(O)=O ZIXUNDOOBLSXPE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 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 1
- 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 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000193755 Bacillus cereus Species 0.000 description 1
- 241000194103 Bacillus pumilus Species 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 238000006237 Beckmann rearrangement reaction Methods 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000192041 Micrococcus Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- MDKCFLQDBWCQCV-UHFFFAOYSA-N benzyl isothiocyanate Chemical compound S=C=NCC1=CC=CC=C1 MDKCFLQDBWCQCV-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 235000018927 edible plant Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 244000144992 flock Species 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 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 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- YDNLNVZZTACNJX-UHFFFAOYSA-N isocyanatomethylbenzene Chemical compound O=C=NCC1=CC=CC=C1 YDNLNVZZTACNJX-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000004893 oxazines Chemical class 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 238000000247 postprecipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000004076 pyridyl group Chemical group 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
- 238000006485 reductive methylation reaction Methods 0.000 description 1
- 238000006049 ring expansion reaction Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Engineering & Computer Science (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)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明涉及上列通式(I)新的氮杂大环内酯系
列的半合成大环内酯抗生素9-脱氧-9a-氮杂-9a-
高红霉素A的9a-N-(N′-氮基甲酰基)和9a-N-
(N′-硫代氨基甲酰基)衍生物,它们与无机和有机酸
形成的药物上可接受的加成盐,中间体及它们的制备
方法,药物组合物的制备方法以及此药物在治疗细菌
感染中的应用。
其中R表示C1—C3烷基,芳基或芳烷基以及X表示O或S。
Description
本发明涉及下列通式具有抗菌活性的新的氮杂大环内酯系列的半合成大环内酯抗生素9-脱氧-9a-氮杂-9a-高红霉素A的9a-N-(N′-氨基甲酰基)和9a-N-(N′-硫代氨基甲酰基)衍生物,它们与无机和有机酸形成的药物上可接受的加成盐,它们的制备方法,药物组合物的制备方法以及此药物组合物在治疗细菌感染中的应用,
其中R表示C1-C3烷基、芳基或芳烷基以及X表示O或S。
红霉素A是一种大环内酯类抗生素,其结构特点在于它是一个C-9位具有羰基的14元大环内酯环。它由McGuire在1952年发现(Antibiot Chemother,1952;2:281)并且在40多年中一直被认为是治疗由革兰氏阳性菌和某些革兰氏阴性菌引起的感染中较可靠和有效的抗菌剂。但是,在酸性介质中,其易转变成脱水红霉素A,一种无活性螺酮缩醇结构的C-6/C-12代谢物(Kurath P.等人,Experientia 1971;27:362)。从所周知,C-9酮或C-6和/或C-12位上羟基的化学转变可成功地抑制红霉素A糖苷配基环的螺环形成。通过C-9酮的肟化作用(Diokic S,等人,Tetrahedron Lett,1967;1945)以及随后通过将所得9(E)-肟转变成9-[0-(2-甲氧乙氧基)甲基肟]红霉素A(ROKSITROMICIN)(Ambrieres,G.S.FR2,473,525/1981)或9(S)-红霉素基胺(Egan R.S.等人,J.Org.Chem.,1974;39:2492)或者其更复杂噁嗪衍生物,可以合成得与母体抗生素红霉素A相比除了在酸性介质中具有更强的稳定性以外,具有较好的药物动力学和较长半衰期基本特性的,新的半合成大环内酯类化合物9-脱氧-11-脱氧-9,11-{亚氨基[2-(2-甲氧乙氧基)1,2-亚乙基]氧}-9(S)-红霉素A(DIRITROMICIN)(Lugar P.等人,J.Crist.MOl.Strut.1979;9:329),C-9酮的第3种修饰方法是使用9(E)-肟的贝克曼重排反应以及在14元酮内酯环扩环成15元氮杂内酯环的条件下,将所得亚氨基醚(Kobrehel G.等人,U.S.Pat.4,328,334,5/1982)还原成11-氮杂-10-脱氧-二氢红霉素A(9-脱氧-9a-氮杂-9a-高红霉素A)。通过用Eschweiler-Clak方法将9a-氨基还原性甲基化(Kobrehel G.等人,BE Pat,892,357,7/1982)或者通过先用转变成相应的N-氧化物的方法保护氨基,然后通过烷基化和还原作用(Bright G.M.,U.S.Pat.4,474,768,10/1984),可以合成得N-甲基-11-氮杂-10-脱氧-10-二氢红霉素A(9-脱氧-9a-甲基-9a-氮杂-9a-高红霉素A,AZITROMICIN),一种氮杂大环内酯型抗生素,其除了具有较宽的抗菌谱(包括革氏兰阴性菌和细胞外微生物)以外,还具有向作用部位特异性转移机制、较长的生物半衰期和较短的治疗周期等特性。在欧洲专利公开316 128(Bright G.M.)中公开了新的9-脱氧-9a-氮杂-9a-高红霉素A的9a-烯丙基和9a-炔丙基衍生物,而在美国专利4,492,688,1/1985(Bright G.M.)中公开了相应的环醚的合成和抗菌活性。在克罗地亚专利申请381-03\93-05\041(559-93-1)中进一步公开了新的9-脱氧-9a-氮杂-11-脱氧-9a-高红霉素A、其9a,11-环氨基甲酸酯和0-甲基衍生物的合成及其抗菌谱。
根据现有的和发现的现有技术,还没有公开过9-脱氧-9a-氮杂-9a-高红霉素A的9a-N-(N′-氨基甲酰基)和9a-N-(N′-硫代氨基甲酰基)衍生物,它们与无机和有机酸形成的药物上可接受的加成盐,它们的制备方法以及药物组合物的制备方法和应用。
现已发现即本发明的一个目的在于,通过将9-脱氧-9a-氮杂-9a-高红霉素A与异氰酸酯或硫代异氰酸酯反应并且任意地通过9-脱氧-9a-氮杂-9a-高红霉素A的9a-N-(N′-氨基甲酰基)和9a-N-(N′-硫代氨基甲酰基)衍生物与无机和有机酸反应可以制得9-脱氧-9a-氮杂-9a-高红霉素A的9a-N-(N′-氨基甲酰基)和9a-N-(N′-硫代氨基甲酰基)衍生物,新的氮杂大环内酯系列半合成大环内酯类抗生素,及其与无机和有机酸形成的药物上可接受的加成盐。
现已发现,新的下列式(Ⅰ)9-脱氧-9a-氮杂-9a-高红霉素A的9a-N-(N′-氨基甲酰基)和9a-N-(N′-硫代氨基甲酰基)衍生物,它们与无机和有机酸形成的药物上可接受的加成盐,
其中R表示C1-C3烷基、芳基或芳烷基以及X表示O或S,可以在甲苯、二甲苯或某些其它非质子传递溶剂中,于20-110℃下通过将9-脱氧-9a-氮杂-9a-高红霉素A与下列通式(Ⅱ)的异氰酸酯或硫代异氰酸酯反应制得,
其中R和X如上定义,其中R表示苯基、1-萘基或含有一或两个杂原子的未取代或取代的芳香族5-元和6-元环,通式(Ⅱ)的异氰酸酯可在升高的温度下用库尔提斯重排方法在原位制备。
药物上可接受的加成盐,作为本发明的目的,可以通过将9-脱氧-9a-氮杂-9a-高红霉素A的9a-N-(N′-氨基甲酰基)和9a-N-(N′-硫代氨基甲酰基)衍生物与至少等摩尔量的相应的无机或有机酸在惰性溶剂中反应获得,此无机或有机酸例如盐酸、氢碘酸、硫酸、磷酸、乙酸、三氟乙酸、丙酸、苯甲酸、苯磺酸、甲磺酸、月桂基磺酸、硬脂酸、棕榈酸、琥珀酸、乙基琥珀酸、乳酸、草酸、水杨酸等。加成盐可以通过蒸发溶剂或者可以通过加入非极性共溶剂产生絮状沉淀或沉淀后过滤分离出。
式(Ⅰ)9-脱氧-9a-氮杂-9a-高红霉素A的9a-N-(N′-氨基甲酰基)和9a-N-(N′-硫代氨基甲酰基)衍生物及其与无机和有机酸形成的药物上可接受的加成盐具有体外抗菌活性。根据National Committee For Clinical Laboratory Standards(NCCLS,M7-A2)推荐,通过微滴板稀释法测定最低抑制浓度(MIC,mcg/ml)。表1表明,常规所试常规菌株的临床分离物对新合成的化合物敏感。这样,它们可以用于对室内、外科器具和人进行消毒以及作为治疗剂用于治疗由对式(Ⅰ)化合物敏感的广谱革兰氏阳性菌、支原体和常规致病微生物引起的动物,特别是哺乳动物和人的感染性疾病。为此,上述化合物及其药物上可接受的加成盐可以以0.2mg/每公斤体重/天-250mg/kg/天,最优选5-50mg/kg/天常用剂量口服或者以皮下和肌内注射的形式经非肠道作用。
表1
9-脱氧-9a-氮杂-9a-高红霉素A的9a-N-(N′-氨基甲酰基,和9a-N-(N′-硫代氨基甲酰基)衍生物在与原料胺的对比试验中的体外抗菌活性
MIC(mcg/ml)
供试微生物 9a-NH*1 4 5 6 7**
表皮葡萄球菌
ATCC 12228 3.12 6.25 25.0 3.12 6.25 6.25
金黄色葡萄球菌
ATCC 6538P 3.12 1.56 12.5 6.25 3.12 3.12
细球菌
ATCC 10240 1.56 3.12 12.5 6.25 3.12 1.56
类链球菌
ATCC 8043 3.12 3.12 6.25 3.12 3.12 1.56
枯草杆菌
NCTC 8236 12.5 1.56 25.0 6.25 3.12 1.56
杆菌(Bacillus pumilus)
NCTC 8241 12.5 6.25 12.5 6.25 3.12 1.56
蜡样芽胞杆菌
ATCC 11778 3.12 6.25 12.5 12.5 6.25 6.25
绿脓假单胞菌
NCTC 10490 25.0 25.0 50.0 50.0 50.0 50.0
大肠杆菌
ATCC 10536 3.12 12.5 12.5 12.5 25.0 12.5
沙门菌
6117 3.12 6.25 25.0 25.0 >100.0 >100.0
BHS-A 链球菌
pyogenes J-21 3.12 12.5 3.12
BHS-B 链球菌
Agalactiae J-22 1.56 12.5 1.56
* 9-脱氧-9a-氮杂-9a-高红霉素A
** 该数字代表相应的实施例中新合成的化合物
下列实施例详细说明了本发明9-脱氧-9a-氮杂-高红霉素A的9a-N-(N′-氨基甲酰基)和9a-N-(N′-硫代氨基甲酰基)衍生物的制备方法,但对本发明的保护范围并无限制作用。
实施例1
9-脱氧-9a-N-(N′-异丙基-氨基甲酰基)-9a-氮杂-9a-高红霉素A
于30℃下将9-脱氧-9a-氮杂-9a-高红霉素A(7.27g;0.01mol)、异氰酸异丙基酯(094g;0.011mol)和甲苯(40ml)的混合物搅拌1小时。将此反应混合物减压(40℃)蒸发至干,得到9-脱氧-9a-N-(N′-异丙基-氨基甲酰基)-9a-氮杂-9a-高红霉素A粗品(7.0g;86.2%),m.p.128-136℃。所得产物将于甲醇-水混合物中重结晶,得到具有下列理化常数的色谱分析均相产物:
m.p.135~144℃
TLC,EtAc-(n-C6H6)-NHEt2(100∶100∶20),Rf0.351.
CHCl3-CH3OH-浓.NH4OH(6∶1∶0.1),Rf0.553.
IR(KBr)cm-11730,1625,1515,1455,1380,1270,1165,1050,950.
1HNMR(300MHz,CDCl3)δ 5.00(1H,H-13),4.85(1H,H-1"),4.47(1H,H-1'),4.02(1H,H-3),3.91(1H,-CH(CH3)2),3.50(1H,H-5),3.43(1H,H-9a),3.28(3H,3"-OCH3),2.49(1H,H-9b),2.32[6H,3'-N(CH3)2,2.31(1H,H-8),1.62(1H,H-7a),1.29(3H,10-CH3),1.14[6H,-CH(CH3)2],1.13(1H,H-7b),1.04(3H,8-CH3).
13CNMR(75MHz,CDCl3)δ 175.5(C-1),158.2(9a-NCONH),103.8(C-1'),96.0(C-1"),87.9(C-5),78.8(C-3),48.8(3"-OCH3),45.5(C-2),42.2[-CH(CH3)2],39.9[3'-N(CH3)2],27.4(C-8),22.9[-CH(CH3)2,20.5(8-CH3),12.2(10-CH3).
实施例2
9-脱氧-9a-N-{N′-[(4-甲基-5-噁唑基)-氨基甲酰基]}-9a-氮杂-9a-高红霉素A
沸腾温度下将9-脱氧-9a-氮杂-9a-高红霉素A(4.8g;0.0065mol)4-甲基-5-噁唑基-甲酸叠氮化物(1.0g;0.0066mol)和无水甲苯(30ml)的混合物加热15分钟,然后减压(40℃)蒸馏,蒸发至干。将所得残余物悬浮于丙酮(20ml)中,于室温搅拌,然后过滤所得结晶,得到9-脱氧-9a-N-{N′[(4-甲基-5-噁唑基)-氨基甲酰基]}-9a-氮杂-9a-高红霉素A(5.4g;93.3%),m.p174-177℃,经于热丙酮中重结晶,得到具有下列理化常数的色谱分析均相产物。
m.p.181~183℃
TLC,EtAc-(n-C6H6)-NHEt2(100∶100∶20),Rf0.149.
CHCl3-CH3OH-浓.NH4OH(6∶1∶0.1),Rf0.491.
IR(KBr)cm-11730,1680,1655,1490,1460,1380,1170,1050,755,660.
1H NMR(300MHz,Pyd5,50℃)δ 9.02(9a-N-CONH),7.95(-CH=N)5.71(1H,H-13),5.15(1H,H-1"),4.94(1H,H-1'),4.77(1H,H-3),4.07(1H,H-5),3.96(1H,H-9a),3.44(3H,3"-OCH3),2.50(1H,H-9b),2.32[6H,3'-N(CH3)2],2.34(1H,H-8),2.35(1H,H-7a),1.68(3H,10-CH3),1.97(1H,H-7b),1.09(3H,8-CH3).
13C NMR(75MHz,Pyd5,50℃)δ 177.2(C-1),157.2(9a-NCONH),104.2(C-1'),96.9(C-1"),86.6(C-5),80.5(C-3),50.1(3"-OCH3),46.5(C-2),42.2(C-4),41.0[3'-N(CH3)2],29.1(C-8),21.2(8-CH3),14.1(10-CH3),149.9,142.2,128.2和12.2(4-甲基-5-噁唑).
实施例3
9-脱氧-9a-N-[N′-(2-呋喃基)-氨基甲酰基]-9a-氮杂-9a-高红霉素A
用实施例2所述相似的方法,由9-脱氧-9a-氮杂-9a-高红霉素A(2.18g;0.003mol)、2-呋喃甲酸叠氮化物(0.5g;0.0036mol)和甲苯(15ml)得到树脂状残余物(2.1g),经用溶剂系统CHCl3-CH3OH(7∶3)进行硅胶柱色谱分离,得到具有下列理化常数的9-脱氧-9a-N-[N′-(2-呋喃基)-氨基甲酰基]-9a-氮杂-9a-高红霉素A(1.7g;77.0%):
m.p.155~159℃
TLC,EtAc-(n-C6H6)-NHEt2(100∶100∶20),Rf0.262.
CHCl3-CH3OH-浓.NH4OH(6∶1∶0.1),Rf0.574.
IR(CHCl3)cm-11730,1655,1520,1460,1380,1270,1165,1050,1000,955,900,830,730.
1H NMR(300MHz,DMSO)δ 8.51(9a-N-CONH),7.24(-O-CH=)6.34(-O-CH=CH-),6.00(-CH=C-NH),5.04(1H,H-13),4.77(1H,H-1"),4.47(1H,H-1'),4.01(1H,H-3),3.42(1H,H-5),3.47(1H,H-9a),3.35(3H,3"-OCH3),3.25(1H,H-9b),2.50[6H,3'-N(CH3)2],2.07(1H,H-8),1.45(1H,H-7a),1.20(1H,H-7b),1.15(3H,10-CH3),0.90(3H,8-CH3).
13C NMR(75MHz,DMSO)δ 175.5(C-1),155.4(9a-NCONH),101.9(C-1'),95.3(C-1"),84.4(C-5),78.6(C-3),48.8(3"-OCH3),44.6(C-2),40.0(C-4),40.1[3'-N(CH3)2],27.7(C-8),19.7(8-CH3),13.2(10-CH3),147.7,136.5,118.9,98.0(5-呋喃甲酰基)
实施例4
9-脱氧-9a-N-[N′-(4-吡啶基)-氨基甲酰基]-9a-氮杂-9a-高红霉素A
用实施例2所述相似的方法,由9-脱氧-9a-氮杂-9a-高红霉素A(2.18g;0.003mol)、异烟酸叠氮化物(0.53g;0.0036mol)和甲苯(15ml)得到树脂状残余物(2.26g),经用甲醇和水混合物进行重结晶,得到具有下列理化常数的9-脱氧-9a-N-[N′-(4-吡啶基)-氨基甲酰基]-9a-氮杂-9a-高红霉素A(1.9g;74.8%):
实施例5
9-脱氧-9a-N-(N′-苯基-氨基甲酰基)-9a-氮杂-9a-高红霉素A
用实施例2所述相似的方法,由9-脱氧-9a-氮杂-9a-高红霉素A(2.0g;0.0027mol)、苯甲酸叠氮化物(0.5g;0.0034mol)和甲苯(15ml)得到树脂状残余物(2.43g),经用溶剂系统CH2Cl2-CH3OH(85∶15)进行硅胶柱色谱分离,得到具有下列理化常数的9-脱氧-9a-N-(N′-苯基-氨基甲酰基)-9a-氮杂-9a-高红霉素A(1.4g;61.4%):
m.p.126~130℃
TLC,EtAc-(n-C6H6)-NHEt2(100∶100∶20),Rf0.345.
CHCl3-CH3OH-浓.NH4OH(6∶1∶0.1),Rf0.637.
IR(KBr)cm-11730,1645,1600,1539,1510,1455,1380,1315,1240,1165,1045,950,895,755,690.
1H NMR(300MHz,DMSO)δ 8.11(9a-N-CONH),7.30,7.35(苯基),5.05(1H,H-13),4.79(1H,H-1"),4.46(1H,H-1'),4.04(1H,H-3),3.46(1H,H-5),3.28(1H,H-9a),3.23(3H,3"-OCH3),3.16(1H,H-9b),2.34[6H,3'-N(CH3)2],2.16(1H,H-8),1.58(1H,H-7a),1.15(1H,H-7b),1.25(3H,10-CH3),0.90(3H,8-CH3).
13C NMR(75MHz,DMSO)δ 175.6(C-1),156.1(9a-NCONH),102.0(C-1'),95.4(C-1"),84.4(C-5),78.5(C-3),48.9(3"-OCH3),44.6(C-2),39.4(C-4),40.1[3'-N(CH3)2],27.3(C-8),20.0(8-CH3),14.0(10-CH3),140.6,127.9和114.4(苯基).
(接P9下-P10上数据1)
实施例6
9-脱氧-9a-N-(N′-苄基-氨基甲酰基)-9a-氮杂-9a-高红霉素A
用实施例1所述相似的方法,由9-脱氧-9a-氮杂-9a-高红霉素A(7.27g;0.01mol)、异氰酸苄基酯(1.33g;0.10mol)和甲革(15ml)得到树脂状残余物(8.4g),经用溶剂系统CHCl3-CH3OH(7∶3)进行硅胶柱色谱分离,得到具有下列理化常数的9-脱氧-N-(N′-苄基-氨基甲酰基)-9a-氮杂-9a-高红霉素A(6.5g;75.6%):
m.p.142~144℃
TLC,EtAc-(n-C6H6)-NHEt2(100∶100∶20),Rf0.355.
CHCl3-CH3OH-浓NH4OH(6∶1∶0.1),Rf0.621.
IR(KBr)cm-11730,1630,1525,1410,1380,1270,1165,1045,950,895,755,700.
1H NMR(300MHz,CDCl3)δ 7.30,5.00,4.40(-CH2-C6H5),5.04(1H,H-13),4.83(1H,H-1"),4.48(1H,H-1'),4.00(1H,H-3),3.52(1H,H-5),3.48(1H,H-9a),3.28(3H,3"-OCH3),2.51(1H,H-9b),2.56[6H,3'-N(CH3)2],2.34(1H,H-8),1.66(1H,H-7a),1.10(1H,H-7b),0.99(3H,10-CH3),1.36(3H,8-CH3).
13C NMR(75MHz,CDCl3)δ 175.7(C-1),159.3(9a-NCONH),103.8(C-1'),96.5(C-1"),88.8(C-5),78.8(C-3),48.9(3"-OCH3),45.9(C-2),40.4(C-4),40.2[3'-N(CH3)2],27.3(C-8),20.5(8-CH3),12.3(10-CH3),139.1,128.3,127.2和126.8,45.9(-CH2-C6H5).
实施例7
9-脱氧-9a-N-(N′-苄基-硫代氨基甲酰基)-9a-氮杂-9a-高红霉素A
用实施例1所述相似的方法,于30℃搅拌反应混合物8小时,由9-脱氧-9a-氮杂-9a-高红霉素A(7.27g;0.01mol)、硫代异氰酸苄基酯(1.50g;0.01mol)和甲苯(30ml)得到树脂状残余物(8.6g),经用溶剂系统CHCl3-CH3OH(7∶3)进行硅胶柱色谱分离,得到具有下列理化常数的9-脱氧-9a-N-(N′-苄基-硫代氨基甲酰基)-9a-氮杂-9a-高红霉素A(7.2g;82.1%):
m.p.119~122℃
TLC,EtAc-(n-C6H6)-NHEt2(100∶100∶20),Rf0.370.
CHCl3-CH3OH-浓.NH4OH(6∶1∶0.1),Rf0.689.
IR(KBr)cm-11730,1630,1525,1410,1380,1270,1165,1045,950,895,755,700.
1H NMR(300MHz,CDCl3)δ 7.36,4.85,4.72(-CH2-C6H5),4.75(1H,H-13),4.87(1H,H-1"),4.41(1H,H-1'),4.10(1H,H-3),3.81(1H,H-11),3.49(1H,H-5),3.30(3H,3"-OCH3),3.03(1H,H-4"),2.34[6H,3'-N(CH3)2],2.31(1H,H-8),1.52(1H,H-7a),1.26(1H,H-7b),1.31(3H,10-CH3),0.96(3H,8-CH3).
实施例8
9-脱氧-9a-N-[N′-(1-荼基)-氨基甲酰基]-9a-氮杂-9a-高红霉素A
用实施例1所述相似的方法,于20℃搅拌反应混合物1小时,由9-脱氧-9a-氮杂-9a-高红霉素A(7.27g;0.01mol)、异氰酸1-萘基酯(1.7g;0.01mol)和甲苯(40ml)得到树脂状残余物(9.0g),经用溶剂系统CHCl3CH3OH-浓NH4OH(6∶1∶0.1)进行硅胶柱色谱分离,得到具有下列理化常数的9-脱氧-9a-N-[N′-萘基-氨基甲酰基]-9a-氮杂-9a-高红霉素A(7.8g;86.6%):
m.p.134~137℃
TLC,EtAc-(n-C6H6)-NHEt2(100∶100∶20),Rf0.335.
CHCl3-CH3OH-浓.NH4OH(6∶1∶0.1),Rf0.658.
IR(CHCl3)cm-11740,1635,1530,1500,1455,1380,1340,1265,1160,1050,1010,960,890,795,775,735;700.
Claims (17)
2、根据权利要求1的化合物,其特征在于R表示C1-C3烷基和X表示O。
3、根据权利要求2的化合物,其特征在于C1-C3烷基表示异丙基。
4、根据权利要求1的化合物,其特征在于R表示芳基和X表示O。
5、根据权利要求4的化合物,其特征在于芳基表示苯基。
6、根据权利要求4的化合物,其特征在于芳基表示1-萘基。
7、根据权利要求4的化合物,其特征在于芳基表示含有一或两个杂原子的未取代的和取代的5-元或6-元环和X表示O。
8、根据权利要求7的化合物,其特征在于杂芳基表示4-甲基-5-噁唑基。
9、根据权利要求7的化合物,其特征在于杂芳基表示呋喃基。
10、根据权利要求7的化合物,其特征在于杂芳基表示4-吡啶基。
11、根据权利要求1的化合物,其特征在于R表示芳烷基和X表示O。
12、根据权利要求11的化合物,其特征在于R表示苄基。
13、根据权利要求1的化合物,其特征在于R表示芳烷基和X表示S。
14、根据权利要求13的化合物,其特征在于R表示苄基。
16、含有药物上可接受的载体和抗菌活性有效量的权利要求1化合物的药物组合物。
17、权利要求1-14的化合物在制备治疗细菌感染的药物组合物中的应用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HRP931480A | 1993-12-08 | ||
HR931480A HRP931480B1 (en) | 1993-12-08 | 1993-12-08 | 9a-N-(N'-CARBAMONYL) and 9a-N-(N'-THIOCARBAMONYL) DERIVATES OF 9-DEOXO-9a-HOMOERYTHROMYCIN A |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1109890A true CN1109890A (zh) | 1995-10-11 |
CN1039417C CN1039417C (zh) | 1998-08-05 |
Family
ID=10946045
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN94112765A Expired - Fee Related CN1039417C (zh) | 1993-12-08 | 1994-12-07 | 新的9a-N-取代的氮杂大环内酯化合物及其制备方法和应用 |
Country Status (18)
Country | Link |
---|---|
US (1) | US5629296A (zh) |
EP (1) | EP0657464B1 (zh) |
JP (1) | JP3131546B2 (zh) |
CN (1) | CN1039417C (zh) |
AT (1) | ATE144778T1 (zh) |
BG (1) | BG61571B1 (zh) |
CA (1) | CA2137395C (zh) |
CZ (1) | CZ288554B6 (zh) |
DE (1) | DE69400817T2 (zh) |
ES (1) | ES2096401T3 (zh) |
HR (1) | HRP931480B1 (zh) |
HU (1) | HU213611B (zh) |
PL (1) | PL176696B1 (zh) |
RO (1) | RO113854B1 (zh) |
RU (1) | RU2131878C1 (zh) |
SI (1) | SI9400434A (zh) |
SK (1) | SK281200B6 (zh) |
UA (1) | UA39870C2 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100345860C (zh) * | 2003-05-14 | 2007-10-31 | 普利瓦研究院有限公司 | 新的9-脱氧-9-二氢-9A-氮杂-9A-高红霉素A的3-去红霉糖基9a-N-氨基甲酰基和9a-N-硫代氨基甲酰基衍生物 |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HRP970714B1 (en) * | 1997-12-31 | 2003-08-31 | Pliva Pharm & Chem Works | Beta,beta-disubstituted derivatives of 9-deoxo-9a-n-ethenyl-9a-aza-9a-homoerythromycin a |
KR20010083944A (ko) * | 1998-11-03 | 2001-09-03 | 실버스타인 아써 에이. | 신규 마크롤라이드 항생물질 |
UA70972C2 (uk) * | 1998-11-20 | 2004-11-15 | Пфайзер Продактс Інк. | 13-членні азаліди і їх застосування як антибіотиків |
HRP990130B1 (en) * | 1999-05-03 | 2004-06-30 | Pliva D D | HALOGEN DERIVATIVES 9a-N-(N'-ARYLCARBAMOYL)- AND 9a-N-(N'-ARYLTHIOCARBAMOYL)-9-DEOXO-9a-AZA-9a OF HOMOERYTHROMYCIN A |
EE200100613A (et) * | 1999-05-24 | 2003-02-17 | Pfizer Products Inc. | 13-metüülerütromütsiini derivaadid |
KR100428703B1 (ko) * | 2000-02-02 | 2004-04-30 | 한국과학기술연구원 | 헬리코박터 파이로리의 성장 억제 효과를 지닌 신규 마크로라이드 화합물 |
US6787342B2 (en) * | 2000-02-16 | 2004-09-07 | Merial Limited | Paste formulations |
HRP20010146B1 (en) * | 2001-02-28 | 2005-10-31 | Pliva D.D. | 9a-N-(N'-(PHENYLSULFONYL)CARBAMOYL) DERIVATIVES OF 9-DEOXO-9-DIHYDRO-9a-AZA-9a-HOMOERYTHROMYCIN A AND OF 5-O-DESOSAMINYL-9-DEOXO-9-DIHYDRO-9a-AZA-9a-HOMOERYTHRONOLIDE A |
HRP20020885B1 (en) * | 2002-11-11 | 2007-05-31 | GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. | SUBSTITUTED 9a-N-{N'-[4-(SULFONYL)PHENYLCARBAMOYL]}DERIVATIVES 9-DEOXO-9-DIHYDRO-9a-AZA-9a-HOMOERITHROMYCIN A AND 5-O-DESOZAMINYL-9-DEOXO-9-DIHYDRO-9a-AZA-9a-HOMOERITHRONOLIDE A |
HRP20020991A2 (en) * | 2002-12-12 | 2005-02-28 | Pliva-Istra�iva�ki institut d.o.o. | N"-Substituted 9a-N-(N'-carbamoyl-Gamma-aminopropyl), 9a-N-(N'? -thiocarbamoyl-Gamma-aminopropyl), 9a-N-(N'-((Beta-cyanoethyl)-N'-carbamoyl-Gamma? -aminopropyl) and 9a-N-(N'-(Beta-cyanoethyl)-N'-thiocarbamoyl-Gamma? -aminopropyl) derivatives of 9-de |
US20080200403A1 (en) * | 2005-01-14 | 2008-08-21 | Glaxosmithkline | 9A-Carbamoyl and Thiocarbamoyl Azalides with Anti-Inflammatory Activity |
ATE429921T1 (de) * | 2005-01-14 | 2009-05-15 | Glaxosmithkline Zagreb | 9a-carbamoyl- und thiocarbamoylazalide mit antimalariawirkung |
US8362086B2 (en) | 2005-08-19 | 2013-01-29 | Merial Limited | Long acting injectable formulations |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4464527A (en) * | 1983-06-30 | 1984-08-07 | Pfizer Inc. | Antibacterial 9-deoxo-9a-alkyl-9a-aza-9a-homoerythromycin A derivatives and intermediates therefore |
GB8521402D0 (en) * | 1985-08-28 | 1985-10-02 | Beecham Group Plc | Chemical compounds |
SI9011409A (en) * | 1990-07-18 | 1995-10-31 | Pliva Pharm & Chem Works | O-methyl azitromycin derivates, methods and intermediates for their preparation and methods for preparation of pharmaceuticals products which comprise them |
EP0549040A1 (en) * | 1991-12-20 | 1993-06-30 | Merck & Co. Inc. | Methods of making 4" derivatives of 9-deoxo-8a-aza-8a-alkyl-8a-homoerythromycin A |
FR2697524B1 (fr) * | 1992-11-05 | 1994-12-23 | Roussel Uclaf | Nouveaux dérivés de l'érythromycine, leur procédé de préparation et leur application comme médicaments. |
HRP930014A2 (en) * | 1993-01-08 | 1994-08-31 | Pliva Pharm & Chem Works | 9-deoxo-9a-aza-11-deoxy-9a-homoeritromycin a 9a, 11-cyclic carbamates |
-
1993
- 1993-12-08 HR HR931480A patent/HRP931480B1/xx not_active IP Right Cessation
-
1994
- 1994-11-29 US US08/350,990 patent/US5629296A/en not_active Expired - Fee Related
- 1994-11-30 SK SK1469-94A patent/SK281200B6/sk unknown
- 1994-12-01 EP EP94118984A patent/EP0657464B1/en not_active Expired - Lifetime
- 1994-12-01 AT AT94118984T patent/ATE144778T1/de not_active IP Right Cessation
- 1994-12-01 DE DE69400817T patent/DE69400817T2/de not_active Expired - Fee Related
- 1994-12-01 ES ES94118984T patent/ES2096401T3/es not_active Expired - Lifetime
- 1994-12-06 RU RU94042916A patent/RU2131878C1/ru active
- 1994-12-06 CA CA002137395A patent/CA2137395C/en not_active Expired - Fee Related
- 1994-12-07 RO RO94-01958A patent/RO113854B1/ro unknown
- 1994-12-07 PL PL94306154A patent/PL176696B1/pl unknown
- 1994-12-07 CZ CZ19943082A patent/CZ288554B6/cs not_active IP Right Cessation
- 1994-12-07 JP JP06303945A patent/JP3131546B2/ja not_active Expired - Fee Related
- 1994-12-07 BG BG99242A patent/BG61571B1/bg unknown
- 1994-12-07 HU HU9403502A patent/HU213611B/hu not_active IP Right Cessation
- 1994-12-07 CN CN94112765A patent/CN1039417C/zh not_active Expired - Fee Related
- 1994-12-08 SI SI9400434A patent/SI9400434A/sl unknown
- 1994-12-08 UA UA94129154A patent/UA39870C2/uk unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100345860C (zh) * | 2003-05-14 | 2007-10-31 | 普利瓦研究院有限公司 | 新的9-脱氧-9-二氢-9A-氮杂-9A-高红霉素A的3-去红霉糖基9a-N-氨基甲酰基和9a-N-硫代氨基甲酰基衍生物 |
Also Published As
Publication number | Publication date |
---|---|
UA39870C2 (uk) | 2001-07-16 |
RU94042916A (ru) | 1996-10-10 |
US5629296A (en) | 1997-05-13 |
JP3131546B2 (ja) | 2001-02-05 |
HRP931480A2 (en) | 1996-08-31 |
CZ308294A3 (en) | 1995-07-12 |
HRP931480B1 (en) | 1997-08-31 |
BG61571B1 (bg) | 1997-12-30 |
HU213611B (en) | 1997-08-28 |
DE69400817T2 (de) | 1997-05-22 |
CA2137395A1 (en) | 1995-06-09 |
PL176696B1 (pl) | 1999-07-30 |
JPH07252292A (ja) | 1995-10-03 |
HU9403502D0 (en) | 1995-02-28 |
BG99242A (en) | 1995-09-29 |
ES2096401T3 (es) | 1997-03-01 |
CN1039417C (zh) | 1998-08-05 |
ATE144778T1 (de) | 1996-11-15 |
HUT69283A (en) | 1995-09-28 |
SK281200B6 (sk) | 2001-01-18 |
SI9400434A (en) | 1995-06-30 |
CA2137395C (en) | 2000-02-22 |
SK146994A3 (en) | 1995-07-11 |
RU2131878C1 (ru) | 1999-06-20 |
CZ288554B6 (cs) | 2001-07-11 |
PL306154A1 (en) | 1995-06-12 |
EP0657464A1 (en) | 1995-06-14 |
EP0657464B1 (en) | 1996-10-30 |
RO113854B1 (ro) | 1998-11-30 |
DE69400817D1 (de) | 1996-12-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1039417C (zh) | 新的9a-N-取代的氮杂大环内酯化合物及其制备方法和应用 | |
CN1033273C (zh) | 新型红霉素衍生物及其制备方法和作为药物的用途 | |
JPH05255342A (ja) | 4a−置換アベルメクチン誘導体 | |
KR850000962B1 (ko) | 20-아미노 틸로신 유도체의 제조방법 | |
CN1280585A (zh) | 从9a-氮杂大环内酯类衍生的新3,6-半缩酮类 | |
AU597194B2 (en) | Antibacterial 9-deoxo-9a-allyl and propargyl-9a-aza-9a-homoerythromycin a derivatives | |
CN1140535C (zh) | 9-脱氧-9a-氮杂-9a-高红霉素A的卤代衍生物 | |
CN1362964A (zh) | 新型8a-和9a-15-元内酰胺 | |
CN1059212C (zh) | 9(s)-红霉素胺的9-n-乙烯基衍生物 | |
RU2328503C2 (ru) | N''-ЗАМЕЩЕННЫЕ 9a-N-(N'-КАРБАМОИЛ-ГАММА-АМИНОПРОПИЛЬНЫЕ) И 9a-N-(N'-ТИОКАРБАМОИЛ-ГАММА-АМИНОПРОПИЛЬНЫЕ), ПРОИЗВОДНЫЕ 9-ДЕЗОКСО-9-ДИГИДРО-9a-АЗА-9a-ГОМОЭРИТРОМИЦИНА A И 5-O-ДЕЗОЗАМИНИЛ-9-ДЕЗОКСО-9-ДИГИДРО-9a-АЗА-9a-ГОМОЭРИТРОНОЛИДА A | |
RU2205185C2 (ru) | β, β-ДИЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ 9-ДЕЗОКСО-9А-N-ЭТЕНИЛ-9А-АЗА-9А-ГОМОЭРИТРОМИЦИНА А | |
NZ204940A (en) | 5-o-mycaminosyl tylonolide derivatives and veterinary compositions | |
US7365056B2 (en) | Substituted 9a-N-(N′-(sulfonyl)phenylcarbamoyl)derivatives of 9-deoxo-9-dihydro-9a-aza-9a-homoerithomycin A and 5-0-desosaminyl-9-deoxo-9-dihydro-9-a-aza-9a-homoerithronolide A |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |