CN1280585A - 从9a-氮杂大环内酯类衍生的新3,6-半缩酮类 - Google Patents
从9a-氮杂大环内酯类衍生的新3,6-半缩酮类 Download PDFInfo
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- CN1280585A CN1280585A CN98811624A CN98811624A CN1280585A CN 1280585 A CN1280585 A CN 1280585A CN 98811624 A CN98811624 A CN 98811624A CN 98811624 A CN98811624 A CN 98811624A CN 1280585 A CN1280585 A CN 1280585A
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- hydrogen
- represent hydrogen
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- 239000001257 hydrogen Substances 0.000 claims abstract description 102
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 102
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 88
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 68
- -1 L-cladinosyl group Chemical group 0.000 claims abstract description 46
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 31
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 17
- 125000001033 ether group Chemical group 0.000 claims abstract description 16
- 150000005676 cyclic carbonates Chemical class 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 150000007524 organic acids Chemical class 0.000 claims abstract description 10
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 125000002252 acyl group Chemical group 0.000 claims abstract description 4
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 4
- 229960004099 azithromycin Drugs 0.000 claims description 113
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 86
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 75
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 38
- YHVUVJYEERGYNU-UHFFFAOYSA-N 4',8-Di-Me ether-5,7,8-Trihydroxy-3-(4-hydroxybenzyl)-4-chromanone Natural products COC1(C)CC(O)OC(C)C1O YHVUVJYEERGYNU-UHFFFAOYSA-N 0.000 claims description 37
- 239000002585 base Substances 0.000 claims description 37
- AJSDVNKVGFVAQU-BIIVOSGPSA-N cladinose Chemical compound O=CC[C@@](C)(OC)[C@@H](O)[C@H](C)O AJSDVNKVGFVAQU-BIIVOSGPSA-N 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 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 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 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
- 239000002253 acid Substances 0.000 claims description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 16
- 238000007069 methylation reaction Methods 0.000 claims description 14
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 14
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 13
- 235000010755 mineral Nutrition 0.000 claims description 13
- 239000011707 mineral Substances 0.000 claims description 13
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000000741 silica gel Substances 0.000 claims description 12
- 229910002027 silica gel Inorganic materials 0.000 claims description 12
- 229960001866 silicon dioxide Drugs 0.000 claims description 12
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000654 additive Substances 0.000 claims description 10
- 230000000996 additive effect Effects 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 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 8
- 239000003513 alkali Substances 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 235000019253 formic acid Nutrition 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 5
- 229910004373 HOAc Inorganic materials 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 5
- NRTYMEPCRDJMPZ-UHFFFAOYSA-N pyridine;2,2,2-trifluoroacetic acid Chemical compound C1=CC=NC=C1.OC(=O)C(F)(F)F NRTYMEPCRDJMPZ-UHFFFAOYSA-N 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 5
- 241000894006 Bacteria Species 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YKFRUJSEPGHZFJ-UHFFFAOYSA-N N-trimethylsilylimidazole Chemical compound C[Si](C)(C)N1C=CN=C1 YKFRUJSEPGHZFJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000013016 damping Methods 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 238000006884 silylation reaction Methods 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 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
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000005828 desilylation reaction Methods 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 238000003797 solvolysis reaction Methods 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 6
- 241001465754 Metazoa Species 0.000 claims 3
- 230000000845 anti-microbial effect Effects 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 239000003960 organic solvent Substances 0.000 claims 2
- 239000003810 Jones reagent Substances 0.000 claims 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 claims 1
- 238000005947 deacylation reaction Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- XDKYAFZLRAPNOQ-UHFFFAOYSA-N n-methyl-n-(pentan-2-yliminomethylideneamino)methanamine Chemical compound CCCC(C)N=C=NN(C)C XDKYAFZLRAPNOQ-UHFFFAOYSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000003120 macrolide antibiotic agent Substances 0.000 abstract description 3
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 229940088710 antibiotic agent Drugs 0.000 abstract description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 abstract 3
- 125000003107 substituted aryl group Chemical group 0.000 abstract 2
- 238000007792 addition Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 150000007522 mineralic acids Chemical class 0.000 abstract 1
- 235000005985 organic acids Nutrition 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 description 66
- 229910052760 oxygen Inorganic materials 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 239000000126 substance Substances 0.000 description 16
- 238000001704 evaporation Methods 0.000 description 15
- 230000008020 evaporation Effects 0.000 description 15
- 230000003115 biocidal effect Effects 0.000 description 13
- 239000012071 phase Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 10
- 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 9
- 238000004587 chromatography analysis Methods 0.000 description 8
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
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- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
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- 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
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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Classifications
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- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
Abstract
本发明涉及通式(Ⅰ)化合物,其中R1代表羟基式(Ⅱ)L-二脱氧甲基已糖基,其中R2代表氢或甲硅烷基;R3代表氢,或者与R6一起代表醚基;R4代表氢,(C1-C4)酰基或-COO-(CH2)n-Ar,其中n是1-7,Ar代表未取代或取代的最多可达18个碳原子的芳基;R5代表氢,甲基或-COO-(CH2)n-Ar,其中n是1-7,Ar代表未取代或取代的最多可达18个碳原子的芳基;R6代表氢,或者与R3一起代表醚基;R7代表氢,(C1-C12)烷基,甲硅烷基,或者与R8和C-11/C-12碳原子一起代表环状碳酸酯,R8代表氢,(C1-C12)烷基,甲硅烷基,或者与R7和C-11/C-12碳原子一起代表环状碳酸酯;涉及式(Ⅰ)化合物与无机酸或有机酸形成的可药用酸加成盐,涉及制备它们的方法,以及它们作为抗菌素或合成其它大环内酯抗菌素的中间体的用途。
Description
本发明涉及从一类大环内酯抗菌素衍生的新化合物,特别是从9a-氮杂大环内酯(azalide)类衍生的新3,6-半缩酮类,它们与无机酸或有机酸形成的可药用酸加成盐,它们的制备方法,以及它们作为抗菌素或合成其它大环内酯抗菌素的中间体的用途。
大环内酯抗菌素红霉素A被认为是治疗由革兰氏阳性菌或一些革兰氏阴性菌如Legionella,枝原体属,Chlamidia和卷旋杆菌属(Helicobacter)引起的呼吸系统和生殖系统感染的安全有效的药物已经有40多年了。口服给药后生物利用度发生显著变化,许多患者出现胃不适现象,以及在酸性介质中由于无活性的代谢无水红霉素的形成使活性丧失,上述是红霉素临床应用中的基本缺点。但是,通过C-9酮或羟基在C-6和/或C-12位的化学转变可以成功地抑制糖苷配基环的螺环化作用。这样,例如,通过C-9酮的肟化反应,然后进行Beckmann重排和还原反应,得到9-脱氧-9a-氮杂-9a-高红霉素A-第一个15员大环内酯抗菌素,其在糖苷配基环中带有9a-氨基,(Kobrehel,G.等人,US 4,328,334;5/1982)。根据Eschweiler-Clark方法,通过9-胺的还原性甲基化反应,合成9-脱氧-9a-甲基-9a-氮杂-9a-高红霉素(阿齐霉素)-一种新型大环内酯抗菌素的原型,即氮杂大环内酯(Kobrehel,G.等人,BE 892357;7/1982)。除具有包括革兰氏阴性菌在内的广谱抗菌性之外,阿齐霉素还具有长生物半衰期-抵达使用部位的特殊传输机理-和短治疗周期的特性。阿齐霉素很容易穿透并积累在人的吞噬细胞中,结果改善了对Legionella,Chlamidia和卷旋杆菌属的细胞内病原微生物的作用。
另外,已知通过糖苷配基环C-6羟基的0-甲基化作用成功地抑制了红霉素AC-6/C-12的螺环化作用(Watanabe,Y.等人,US 4,331,803;5/1982)。通过红霉素与苄氧羰基氯反应及随后对所得2’-0,3’-N-双(苄氧羰基)衍生物进行的甲基化反应,通过去掉保护基及3’-N-甲基化反应,除了形成6-0-甲基红霉素(克红霉素)外还形成了大量11-0-甲基红霉素和多取代的类似物(Morimoto,S.等人,《抗菌素杂志》(J.Antibiotics),37:187(1984))。关于红霉素A,克红霉素在酸性介质中更加稳定,而且对革兰氏阳性菌株表现出更好的体外活性(Kirst,H.A.等人,《抗菌剂和化疗剂》(Antimicrobial Agent and Chemoter.),1419(1989))。以类似的方式还可以合成一系列阿齐霉素的0-甲基衍生物(Kobrehel,G.等人,US 5,250,518;10/1993)。虽然阿齐霉素的0-甲基化反应的主要产物11-0-甲基-阿齐霉素(实施例8)和6-0-甲基-阿齐霉素(实施例6)表现出显著的抗标准菌株活性,而且临床分离和药动学性质与阿齐霉素的相似,但是,由于0-甲基化反应的非选择性,大量获得产物表明还有其它技术问题存在。0-甲基衍生物结构的测定是建立在1H-1H和1H-13C 2D NMR谱分析(300MHz)的基础上。然后,还要用远程NMR谱仪测定对已经被错误地归咎于阿齐霉素的C-6羟基上的取代作用而实际上是12-0-甲基-阿齐霉素问题。另外,已经发现,对4”-和11-位羟基使用适当保护基(尤其是甲硅烷基保护基如三甲基甲硅烷基)可以得到选择性0-甲基化反应,并且可以简化12-0-甲基阿齐霉素的制备(HR 970051A;10/1997)。后来,Waddell,S.T.等人(《生物医药化学通讯》(Biorg.Med.Chem.Letters),8:549-555(1998))(与后来的专利申请无关)建立了C-12位羟基的0-甲基化反应。
人们还知道,最近对14员大环内酯的研究使人们发现了一种新型大环内酯抗菌素,即酮内酯。已知的天然糖L-二脱氧甲基己糖即使在弱酸性介质也是不稳定的,而这些化合物在C-3位具有酮基(Agouridas,C.等人,EP 596802 A1,5/1994;Le Martret,O.,FR2697524 A1,5/1994)。酮内酯在抵抗诱发耐生物体(引起抗药性)的MLS(大环内酯,林可酰胺(lincosamide)和链阳性菌素B)方面表现了很好的作用(Jamjian,C.,《抗生素化疗剂》(Antimicrob.AgentsChemother.),41:485(1997))。这个重要发现使几乎所有在C-11/C-12位被取代的大量克红霉素的3-酮衍生物都产生大量环状碳酸酯,氨基甲酸酯,以及最近出现的肼基甲酸酯。合成酮内酯的第一步是在形成相应的3-脱二脱氧甲基己糖基衍生物(3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)衍生物)条件下进行克红霉素水解,在除去2’-羟基保护之后(优选用氯化物或羧酸酐进行酰化)进行氧化反应和2’-位的脱保护反应。根据我们的知识,从9a-氮杂大环内酯抗菌素得到的C-11/C-12位取代的酮内酯迄今还没有文献论述。第一步,即9-脱氧-9a-氮杂-9a-高红霉素的3-脱二脱氧甲基己糖基衍生物与阿齐霉素的合成在US 4,886,792,12/1989中有所描述。其通过将6-羟基跨环加合到新形成的C-3酮上来氧化3-脱二脱氧甲基己糖基-阿齐霉素及其11-0-甲基-和12-0-甲基-衍生物的C-3羟基,但其中没有描述由9a-氮杂大环内酯类得到了一系列至今还没有文献论述的双环和三环3,6-半缩酮类。
阿齐霉素的3,6-半缩酮类及其0-甲基衍生物的合成反应包括制备相应的3-脱二脱氧甲基己糖基衍生物,通过选择性酰化反应对该碱性糖-D-脱氧糖胺的2’-羟基进行保护,C-3位羟基的氧化反应,2’-位的脱保护反应,及C-11和C-12羟基的环化反应。本发明的目的还包括阿齐霉素的3,6-半缩酮类及其0-甲基衍生物与有机酸和无机酸形成的可药用酸加成盐,制备方法和中间体,以及药物制剂和及应用方法。
本发明涉及ⅰ)从9a-氮杂大环内酯类衍生的新3,6-半缩酮类,ⅱ)从9a-氮杂大环内酯类制备新3,6-半缩酮类的方法,ⅲ)从9a-氮杂大环内酯类衍生的新3,6-半缩酮类作为抗菌素或合成其它大环内酯抗菌素的中间体的用途。
从9a-氮杂大环内酯类衍生的通式(Ⅰ)新3,6-半缩酮类及其与无机酸或有机酸形成的可药用加成盐,特征在于R1代表羟基,式(Ⅱ)L-二脱氧甲基己糖基,其中R2代表氢或甲硅烷基,R3代表氢,或者与R6一起代表醚基,R4代表氢,(C1-C4)酰基或-COO-(CH2)n-Ar,其中n是1-7,及Ar
代表未取代或取代的最多可达18个碳原子的芳基,R5代表氢,甲基或-COO-(CH2)n-Ar,其中n是1-7,及Ar代表未
取代或取代的最多可达18个碳原子的芳基,R6代表氢,或者与R3一起代表醚基,R7代表氢,(C1-C12)烷基,甲硅烷基,或者与R8和C-11/C-12碳
原子一起代表环状碳酸酯,R8代表氢,(C1-C12)烷基,甲硅烷基,或者与R7和C-11/C-12碳
原子一起代表环状碳酸酯,制备步骤如下:步骤1
将通式(Ⅰ)的阿齐霉素,其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,R2,R3,R4,R7和R8相同并都代表氢,R5是甲基及R6是羟基,与式(Ⅲ)的有机羧酰氯反应,
-ClCOO-(CH2)n-Ar (Ⅲ)其中n是1-7,及Ar代表未取代或取代的最多可达18个碳原子的芳基,优选与苄氧羰基氯在碱,优选碳酸氢钠存在下,在对反应惰性的溶剂,优选苯或甲苯中反应,生成通式(Ⅰ)的2’-0,3’-N-双(苄氧羰基)-3’-N-脱甲基-阿齐霉素(Kobrehel,G.等人,US 5,250,518;5/1993),其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,R2,R3,R7和R8相同并都代表氢,R4和R5相同并都代表苄氧羰基,及R6是羟基,然后在下列位置进行羟基的甲硅烷基化反应:A/4”-和11-位与2-5等摩尔过量甲硅烷基化剂在有机惰性溶剂
中在0-5℃反应5-8小时,生成新的通式(Ⅰ)4”-11-0-双
(三甲基甲硅烷基)-2’-0,3’-N-双(苄氧羰基)-3’-N-
脱甲基-阿齐霉素,其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,
R2和R7相同并都代表三甲基甲硅烷基,R3和R8相同并都代表氢,
R4和R5相同并都代表苄氧羰基,及R6是羟基,或在B/4”-位与1.1-2等摩尔过量甲硅烷基化剂在有机惰性溶剂中在0
-5℃反应1小时,生成新的通式(Ⅰ)4”-O-三甲基甲硅烷基
-2’-0,3’-N-双(苄氧羰基)-3’-N-脱甲基-阿齐霉素,
其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,R2代表三甲基甲硅
烷基,R3,R7和R8相同并都代表氢,R4和R5相同并都代表苄氧羰
基,及R6是羟基。
作为甲硅烷基化剂使用的有:1,1,1,3,3,3-六甲基二甲硅氮烷,三甲基甲硅烷基氯,双(三甲基甲硅烷基)乙酰胺和能引入三甲基甲硅烷基的类似试剂,优选三甲基甲硅烷基氯和三甲基甲硅烷基咪唑的混合物。合适的溶剂包括吡啶,乙酸乙酯,N,N-二甲基甲酰胺,二氯甲烷等,优选吡啶。步骤2
通过步骤1A/所得4”-11-0-双(三甲基甲硅烷基)-2’-0,3’-N-双(苄氧羰基)-3’-N-脱甲基-阿齐霉素,或步骤1B/所得4”-0-三甲基甲硅烷基-2’-0,3’-N-双(苄氧羰基)-3’-N-脱甲基-阿齐霉素分别与1.3-10摩尔相应的烷基化剂,优选甲基化剂,在1.1-8.5 mol适当碱存在下,在-15℃至室温,优选0-5℃,在适当的对反应惰性的溶剂中进行以下反应:A/选择性烷基化反应,优选C-12羟基的甲基化反应,生成新的通
式(Ⅰ)4”-11-0-双(三甲基甲硅烷基)-2’-0,3’-N-双(苄
氧羰基)-3’-N-脱甲基-12-0-甲基-阿齐霉素,其中R1代
表式(Ⅱ)L-二脱氧甲基己糖基,R2和R7相同并都代表三甲基
甲硅烷基,R3代表氢,R4和R5相同并都代表苄氧羰基,R6是羟基,
及R8是甲基,或B/烷基化反应,优选C-11或C-12羟基的甲基化反应,生成新的通
式(Ⅰ)4”-0-三甲基甲硅烷基-2’-0,3’-N-双(苄氧羰基)
-3’-N-脱甲基-11-0-甲基-阿齐霉素,其中R1代表式(Ⅱ)
L-二脱氧甲基己糖基,R2代表三甲基甲硅烷基,R3和R8相同并
都代表氢,R4和R5相同并都代表苄氧羰基,R6是羟基,及R7是
甲基,或通式(Ⅰ)4”-0-三甲基甲硅烷基-2’-0,3’-N-双(苄
氧羰基)-3’-N-脱甲基-12-0-甲基-阿齐霉素,其中R1代
表式(Ⅱ)L-二脱氧甲基己糖基,R2代表三甲基甲硅烷基,R3
和R7相同并都代表氢,R4和R5相同并都代表苄氧羰基,R6是羟
基,及R8是甲基的混合物。
作为合适的烷基化剂使用的有:(C1-C12)烷基卤化物,优选甲基碘,硫酸二甲酯,甲磺酸甲酯或对甲苯磺酸甲酯,更优选甲基碘。合适的碱包括碱金属氢化物(氢化锂,氢化钠或氢化钾)或碱金属甲基氨化物(氨化锂,氨化钠或氨化钾),优选氢化钠。合适的对反应惰性的溶剂有二甲亚砜,N,N-二甲基甲酰胺,N,N-二甲基乙酰胺或六甲基磷酰三酰胺,优选N,N-二甲基甲酰胺,二甲亚砜,或它们与四氢呋喃的混合物。步骤3
为了去除2’-和3’-位的保护基,根据Flynn,E.H.等人(《美国化学会志》(Journal of American Chemical Society),77:3104(1950))所述方法,将步骤2A/所得4”-11-0-双(三甲基甲硅烷基)-2’-0,3’-N-双(苄氧羰基)-3’-N-脱甲基-12-0-甲基-阿齐霉素,或者步骤2B/所得4”-0-三甲基甲硅烷基-2’-0,3’-N-双(苄氧羰基)-3’-N-脱甲基-11-0-甲基-阿齐霉素和4”-0-三甲基甲硅烷基-2’-0,3’-N-双(苄氧羰基)-3’-N-脱甲基-12-0-甲基-阿齐霉素的混合物进行氢解反应,然后,采用常规方法,在低级醇,优选异丙醇中,在甲酸存在下在下列位置进行脱甲硅烷基化反应:A/步骤2A/中的4”-和11-位反应,生成通式(Ⅰ)3’-N-脱甲基
-12-0-甲基-阿齐霉素,其中R1代表式(Ⅱ)L-二脱氧甲基
己糖基,R2,R3,R4,R5和R7相同并都代表氢,R6是羟基,及R8
是甲基,或B/步骤2B/中的4”-位反应,生成通式(Ⅰ)3’-N-脱甲基-11-
0-甲基-阿齐霉素,其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,
R2,R3,R4,R5和R8相同并都代表氢,R6是羟基,及R7是甲基,
和3’-N-脱甲基-12-0-甲基-阿齐霉素,其中R1代表式(Ⅱ)
L-二脱氧甲基己糖基,R2,R3,R4,R5和R8相同并都代表氢,R6
是羟基,及R8是甲基,的混合物。
氢解反应在低级醇,优选乙醇中,在含有催化剂如钯黑或活性炭的NaOAc/HOAc缓冲液(pH 5)存在下,在1-20 bar氢气压力和室温下进行。步骤4
将步骤3A/所得3’-N-脱甲基-12-0-甲基-阿齐霉素,或者步骤3B/所得3’-N-脱甲基-11-0-甲基-阿齐霉素和3’-N-脱甲基-12-0-甲基-阿齐霉素的混合物用1-3当量甲醛(37%)在等量或两倍数量的甲酸(98-100%)和氢化催化剂或其它氢源存在下,在对反应惰性的溶剂如卤代烃,低级醇或低级酮,优选氯仿中,在反应混合物的回流温度下进行还原性3’-N-甲基化反应,得到在使用步骤3A/化合物的情况下:
通式(Ⅰ)12-0-甲基-阿齐霉素,其中R1代表式(Ⅱ)L-二
脱氧甲基己糖基,R2,R3,R4和R7相同并都代表氢,R5和R8相同
并都代表甲基,及R6是羟基,或在使用步骤3B/化合物的情况下:
通式(Ⅰ)11-0-甲基-阿齐霉素,其中R1代表式(Ⅱ)L-二
脱氧甲基己糖基,R2,R3,R4和R8相同并都代表氢,R5和R7相同
并都代表甲基,及R6是羟基,和12-0-甲基-阿齐霉素,其中
R1,R2,R3,R4,R5,R6,R7和R8与用步骤3A/所得化合物进行3’
-N-甲基化反应的情况中定义相同的混合物。步骤5
将步骤4所得通式(Ⅰ)阿齐霉素,其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,R2,R3,R4,R7和R8相同并都代表氢,R5是甲基,及R6是羟基,或其11-0-甲基-和12-0-甲基-衍生物,与强酸,优选0.25-1.5N盐酸或二氯乙酸,在水和醇,优选甲醇,乙醇或异丙醇的混合物中,在室温下进行水解反应10-30小时,得到通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-阿齐霉素,其中R1和R6相同并都代表羟基,R3,R4,R7和R8相同并都代表氢,及R5是甲基,或生成通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-11-0-甲基-阿齐霉素,其中R1和R6相同并都代表羟基,R3,R4和R8相同并都代表氢,及R5和R7相并都代表甲基,或生成通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-12-0-甲基-阿齐霉素,其中R1和R6相同并都代表羟基,R3,R4和R7相同并都代表氢,及R5和R8相同并都代表甲基。步骤6
将步骤5所得通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-阿齐霉素及其11-0-甲基-和12-0-甲基-衍生物进行2’-位羟基的选择性酰化反应。酰化反应是用最多可达4个碳原子的羧酸的氯化物或酸酐,优选乙酸酐,在无机碱或有机碱存在下,在对反应惰性的溶剂中,在0-30℃进行,生成通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-阿齐霉素2’-0-乙酸酯,其中R1和R6相同并都代表羟基,R3,R7和R8相同并都代表氢,R4是乙酰基,及R5是甲基,或生成通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-11-0-甲基-阿齐霉素2’-0-乙酸酯,其中R1和R6相同并都代表羟基,R3和R8相同并都代表氢,R4是乙酰基,及R5和R7相同并都代表甲基,或生成通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-12-0-甲基-阿齐霉素2’-0-乙酸酯,其中R1和R6相同并都代表羟基,R3和R7相同并都代表氢,R4是乙酰基,及R5和R8相同并都代表甲基。
可用的合适碱是碳酸氢钠,碳酸钠,碳酸钾,三乙胺,吡啶,三丁胺,优选碳酸氢钠。可用的合适的惰性溶剂是二氯甲烷,二氯乙烷,丙酮,吡啶,乙酸乙酯,四氢呋喃,优选二氯甲烷。步骤7
根据改进的Moffat-Pfitzner方法[三氟乙酸吡啶的DMSO和1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺],将步骤6所得通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-阿齐霉素2’-0-乙酸酯及其11-0-甲基-和12-0-甲基-衍生物进行C-3位羟基的氧化反应,生成通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-阿齐霉素3,6-半缩酮2’-0-乙酸酯,其中R1代表羟基,R3和R6一起代表醚基团,R4是乙酰基,R5是甲基,及R7和R8相同并都代表氢,或生成通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-11-0-甲基-阿齐霉素3,6-半缩酮2’-0-乙酸酯,其中R1代表羟基,R3和R6一起代表醚基团,R4是乙酰基,R5和R7相同并都代表甲基,及R8是氢,或生成通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-12-0-甲基-阿齐霉素3,6-半缩酮2’-0-乙酸酯,其中R1代表羟基,R3和R6一起代表醚基团,R4是乙酰基,R5和R8相同并都代表甲基,及R7是氢。步骤8
将步骤7所得通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟(氧)-阿齐霉素3,6-半缩酮2’-0-乙酸酯及其11-0-甲基-和12-0-甲基-衍生物在低级醇,优选甲醇中,在室温至溶剂回流温度进行溶剂分解反应,生成通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-阿齐霉素3,6-半缩酮,其中R1代表羟基,R3和R6一起代表醚基团,R4,R7和R8相同并都代表氢,及R5是甲基,或生成通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-11-0-甲基-阿齐霉素3,6-半缩酮,其中R1代表羟基,R3和R6一起代表醚基团,R4和R8相同并都代表氢,R5和R7相同并都代表甲基,或生成通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-12-0-甲基-阿齐霉素3,6-半缩酮,其中R1代表羟基,R3和R6一起代表醚基团,R4和R7相同并都代表氢,R5和R8相同并都代表甲基。步骤9
接着,任选将步骤8所得通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-阿齐霉素3,6-半缩酮与碳酸1,2-亚乙酯在无机碱或有机碱,优选碳酸钾存在下,在对反应惰性的溶剂,优选乙酸乙酯中反应,生成通式(Ⅰ)3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-阿齐霉素3,6-半缩酮11,12环状碳酸酯,其中R1代表羟基,R3和R6一起代表醚基团,R4是氢,R5是甲基,及R7和R8与C-11和C-12碳原子一起代表环状碳酸酯。
作为本发明另一目的的可药用加成盐可以通过通式(Ⅰ)新化合物与至少等摩尔的相应无机酸或有机酸在对反应惰性的溶剂中反应得到,所说无机酸和有机酸的实例有盐酸,氢碘酸,硫酸,磷酸,乙酸,丙酸,三氟乙酸,马来酸,柠檬酸,硬脂酸,琥珀酸,乙基琥珀酸,甲磺酸,苯磺酸,对甲苯磺酸,月桂基磺酸,以及类似的酸。如果这些加成盐在对反应惰性的溶剂中不溶解,则可以通过过滤,从非溶剂中沉淀或通过从溶剂中蒸发将其分离,最常用的是通过冻干。
新的通式(Ⅰ)化合物及其与无机酸或有机酸形成的可药用加成盐在一系列标准微生物试验所表现的体外抗菌活性是根据NCCLS(临床实验室标准全国委员会)推荐的两倍稀释的常规方法在Mueller-Hinton培养基(Difco-Laboratories,Detroit,MI)中测定的。每种受试微生物被接种成最终接种物体积为5×105cfu/ml,并以厌氧方式在37℃培养18小时。液体培养基中的MIC被定义为抗菌素在微量容器中抑制可见生长的最低浓度。对比生物得自ATCC(The AmericanType Culture Collection)。所有标准(物质)是用标准方法认定并被存放在-70℃。与阿齐霉素相比12-0-甲基-阿齐霉素对标准试验微生物和临床分离菌的结果示于表1和表2。
通过测定以0.25-24小时的时间间隔给一组36只雄性鼠一次性口服20mg/kg剂量后12-0-甲基-阿齐霉素在血清中的浓度发现新的抗菌素很快被血清吸收。对(吸收)峰的分析结果表明存在(胆盐)肠肝循环。在0.5和1小时处浓度迅速下降,以后便重复性地增加。2小时后浓度达到最大(Cmax 248.8ng/ml)。第二最大浓度是在4小时后达到。半衰期为5.2小时,整个AUC为1993.4h ng/ml。表1与阿齐霉素相比12-0-甲基-阿齐霉素对标准菌株的体外抗菌活性
表2与阿齐霉素相比12-0-甲基-阿齐霉素对一系列临床分离菌的体外抗菌活性
MIC(mcg/ml) | ||
微生物 | 阿齐霉素 | 12-0-甲基-阿齐霉素 |
金黄色葡萄球菌ATCC6538P金黄色葡萄球菌ATCC29213表皮葡萄球菌ATCC12228黄色微球菌ATCC10240藤黄微球菌ATCC9341粪链球菌ATCC8043枯草芽孢杆菌ATCC6633蜡状芽孢杆菌ATCC11778大肠埃希氏杆菌ATCC10536 | 10.250.50.50.060.5411 | 0.250.250.30.120.030.2510.250.5 |
微生物 | 化合物 | MIC(μg/ml) |
(菌株编号) | 范围 50% 90% | |
金黄色葡萄球菌(77)表皮葡萄球菌(20)肺炎链球菌(25) | 阿齐霉素12-O-甲基-阿齐霉素阿齐霉素12-0-甲基-阿齐霉素阿齐霉素12-0-甲基-阿齐霉素 | 0.25-8 1 40.12-2 0.25 10.25-16 0.25 80.12-8 0.25 40.03-0.25 0.06 0.120.03-0.12 0.03 0.12 |
肠球菌属(Sp.)(35)流感嗜血杆菌(40) | 阿齐霉素12-0-甲基-阿齐霉素阿齐霉素12-0-甲基-阿齐霉素 | 0.25-160.12-80.12-0.50.06-0.5 | 10.50.250.12 | 1680.50.25 |
制备从9a-氮杂大环内酯类衍生的新的3,6-半缩酮类的方法用下列实施例加以说明,这些实施例不以任何方式限制本发明范围。制备例12’-0,3’-N-双(苄氧羰基)-3’-N-脱甲基-阿齐霉素A
在阿齐霉素(17g,0.0227mol)的甲苯(170ml)溶液中加入NaHCO3(74.8g,0.890mol),然后将反应混合物搅拌加热至回流温度(80-85℃)。搅拌的同时用1小时向反应悬浮液中滴加102ml 50%苄氧羰基氯(104.04g,0.305mol)的甲苯。在同一温度搅拌反应混合物2小时,然后在室温放置过夜。过滤后用甲苯(85ml)漂洗沉淀物,然后用0.25NHCl(170ml)萃取甲苯溶液两次,1.5%NaCl水溶液(170ml)萃取两次。在甲苯中加水(340ml)(pH 3.1),用6N HCl将反应混合物的pH调至2.0。分离各相,在保持pH为2.0的情况下用水(340ml)萃取有机相三次。在合并的水萃取液中加CH2Cl2(125ml),用NaOH水溶液(20%)将pH调至10。分离各相,水相再用CH2Cl2(125ml)萃取。合并的有机萃取液用K2CO3干燥,过滤并加压蒸发,得到16.5g粘稠油,任选在硅胶60柱(230-400目ASTM)上用低压色谱纯化。为此目的,将上述粗产物溶解于CH2Cl2(20ml),并在0.5bar氮气下加到硅胶柱(50g)上。为了除去残余的氯甲酸苄酯及其分解产物,要将CH2Cl2(150ml)贯穿整个柱,用二氯甲烷/甲醇(9∶1,200ml)的溶剂系统洗脱,然后蒸发含有色谱相同的标题化合物的馏分,得到11.53g TLC纯的2’-0,3’-N-双(苄氧羰基)-N-脱甲基-阿齐霉素,其物理-化学常数如美国专利5,250,518(10/1993)所述。
实施例14”,11-0-双(三甲基甲硅烷基)-2’-0,3’-N-双(苄氧羰基)-3’-N-脱甲基-阿齐霉素
氮气流下在冷却到0-5℃的2’-0,3’-N-双(苄氧羰基)-3’-N-脱甲基-阿齐霉素(5.0g,0.005mol)的吡啶(50ml)溶液中加入三甲基甲硅烷基咪唑(3.3ml,0.0226mol)和三甲基甲硅烷基氯(3.0ml,0.0179mol)。将反应混合物在同样温度搅拌6小时,然后加入正己烷(60ml)和水(100ml)。分离各相,有机相用饱和NaHCO3水溶液(60ml)和水(60ml)漂洗,MgSO4干燥,过滤,减压蒸发除去溶剂,得到5.48g白色非晶状沉淀。任选在硅胶柱上用低压色谱纯化,用CH2Cl2/CH3OH(9∶1)的溶剂系统洗脱。合并及蒸发色谱相同的馏分,得到具有下列物理-化学常数的标题产物:TLC 二氯甲烷/甲醇,90∶1 Rf=0.875
乙酸乙酯/正己烷/二乙胺,100∶100∶20 Rf=0.942(IR(KBr)cm-1:3524,2969,2692,1754,1732,1708,1498,1456,1382,1335,1252,1168,1116,1060,1005,895,841,754,696。1H NMR(300MHz,CDCl3)δ:7.32-7.23(Ph),5.12,4.98(CH2-Ph),4.85(H-1″),4.70(H-1'),4.65(H-2'),4.46(H-3'),4.26(H-5″),4.42(H-3),3.72(H-5'),3.66(H-11),3.49,3.47(H-5),3.20(H-4″),3.32,3.18(3″-OCH3),2.83,2.79(3′-NCH3),2.78(H-2),2.64(H-10),2.35(H-9a),2.33(H-2″a),2.11(9a-NCH3),1.94(H-9b),1.91(H-8),1.64(H-14a),1.94(H-4),1.50(H-2″b),1.50(H-14b),1.27,1.25(6-CH3),1.24(5″-CH3),1.19(5′-CH3),1.12(3″-CH3),1.16(12-CH3),1.26(2-CH3),0.89(10-CH3),0.95(8-CH3),0.85(14-CH3),1.02(4-CH3),1.02(4-CH3),0.16(11-OSi(CH3)3,和0.13/4″-OSi(CH3)3/。13CNMR(75MHz,CDCl3)δ:176.2(C-1),156.2,156.4(OCO),154.5,154.4(NCO),136.7-127.5(Ph),100.2(C-1′),97.3(C-1″),83.9(C-5),80.7(C-4″),75.0(C-3),75.0(C-2′),75.3(C-6),73.2(C-3″),69.4,69.2,67.1,66.8(CH2-Ph),64.8(C-5″),62.3(C-10),54.8(C-3′),49.4,49.2(3″-OCH3),46.2(C-2),38.5(C-7),39.4(C-4),34.2(9a-NCH3),35.9,35.6(C-2″),36.2,36.1(C-4′),29.0(3′-NCH3),25.6(C-8),27.8(6-CH3),21.9(3″-CH3),21.5(8-CH3),20.7(5′-CH3),23.4(C-14),18.4(5″-CH3),16.0(2-CH3),11.6(14-CH3),9.6,9.5(4-CH3),8.3(10-CH3),1.2/11-OSi(CH3)/3和0.67/4″-OSi(CH3)3/。ES-MS 1147
实施例23’-N-脱甲基-12-0-甲基-阿齐霉素
室温下用3小时在实施例1产物(1.0g,0.0009mol)的N,N-二甲基甲酰胺(20ml)溶液中缓缓加入甲基碘(0.43ml,0.0069mol)和60%氢化钠(0.23g,0.0058mol)。将反应混合物在同样温度继续搅拌30分钟,然后通过加入三乙胺(2ml)终止反应。将反应物转入10%NaHCO3水溶液(50ml)和水(50ml)的混合物,然后用乙酸乙酯萃取。合并的有机萃取液用饱和NaCl溶液和水漂洗,MgSO4干燥,过滤并减压蒸发,得到0.93g黄色沉淀[Rf=0.832,二氯甲烷/甲醇90∶1,IR(KBr)cm-1:3516,1752,1732,1705,1456,1382,1336,1253,1169,1116,1062,1004,896,840,754,696]。
将产物溶解于乙醇(20ml),加入pH 5的NaOAc/HOAc缓冲液(0.17ml乙酸,0.263g乙酸钠,0.22ml乙醇和1ml水)和Pd/C 10%(0.6g)。将反应混合物在5bar氢气反应釜中边搅拌边氢化5小时。滤除结晶,蒸发滤液至粘稠浆液。加入CH2Cl2(10ml)和水(15ml),用2N HCl将混合物的pH调至4。分离各相,在用20%NaOH将水相pH调至9.5的基础上用CH2Cl2萃取(3×10ml)水相。合并的有机相用K2CO3干燥,过滤并蒸发。将所得沉淀溶解于异丙醇(10ml),加入水(10ml)和几滴甲酸,然后在室温下搅拌30分钟。用pH 9.5的乙酸异丙酯萃取,减压蒸发后得到0.43g具有下列物理-化学常数的标题产物:IR(KBr)cm-1:3672,3496,2962,1727,1458,1375,1343,1280,1263,1118,1085,1048,1005,998。13CNMR(75MHz,CDCl3)δ:177.4(C-1),102.7(C-1′),95.5(C-1″),83.4(C-5),79.7(C-12),78.0(C-3),76.6(C-11),74.0(C-13),73.9(C-6),74.3(C-2′),73.0(C-3″),68.8(C-9),65.7(C-5″),60.1(C-3′),61.2(C-10),52.8(12-OCH3),49.8(3″-OCH3),45.5(C-2),41.5(C-4),33.1,3′-NCH3,36.8(9a-NCH3),35.1(C-2″),28.8(C-4′),27.0(C-8)。EI-MS m/z 748。
实施例312-0-甲基-阿齐霉素
在实施例2所得3’-N-脱甲基-12-0-甲基-阿齐霉素(0.43g,0.0006mol)的CHCl3(20ml)溶液中加入甲醛(37%,0.047ml,0.0006mol)和甲酸(98-100%,0.042ml,0.0011mol)。将反应混合物搅拌回流3小时,然后冷却到室温。将反应物倒入水(20ml)中,将pH调至4.0。分离各相,水相用CHCl3萃取两次以上。在水相中加入CHCl3萃取,用2N NaOH将pH调至9.5。分离各相,水相用CHCl3萃取两次以上。将pH 9.5的合并的有机相用K2CO3干燥并蒸发,得到0.38g标题产物。如果需要,将产物在硅胶柱上进行色谱纯化,用CH2Cl2/CH3OH/浓NH4OH(90∶9∶1)溶剂系统洗脱。TLC 二氯甲烷/甲醇/浓氨水,90∶9∶0.5 Rf=0.363
乙酸乙酯/正己烷/二乙胺,100∶100∶20 Rf=0.745IR(KBr)cm-1:3499,2972,2940,1736,1633,1460,1381,1259,1168,1110,1059,1082,1054,1013,999。1H NMR(300MHz,CDCl3)δ:5.39(H-13),5.00(H-1″),4.43(H-1′),4.32(H-3),4.06(H-5″),3.68(H-11),3.65(H-5),3.51(H-5′),3.38(12-OCH3),3.32(3″-OCH3),3.24(H-2′),3.02(H-4″),2.73(H-2),2.69(H-10),2.49(H-3′),2.34(H-2″a),2.31(H-9a),2.29/3′N(CH3)2/,2.30(9a-NCH3),2.12(H-9b),2.04(H-4),2.01(H-8),1.73(H-14a),1,68(H-4′a),1.66(H-7a),1.56(H-2″b),1.52(H-14b),1.36(H-7b),1.29(6-CH3),1.21(2-CH3),1.30(5″-CH3),1.24(H-4′b),1.23(3″-CH3),1.22(5′-CH3),1.09(12-CH3),1.29(4-CH3),1.09(10-CH3),0.92(8-CH3),0.93(14-CH3)。13C NMR(75MHz,CDCl3)δ177.5(C-1),103.1(C-1′),95.2(C-1″),83.6(C-5),79.2(C-12),78.1(C-3),76.6(C-11),74.7(C-13),73.8(C-6),70.9(C-2′),68.8(C-9),65.6(C-5″),65.7(C-3′),61.6(C-10),52.8(12-OCH3),49.4(3″-OCH3),45.1(C-2),43.0(C-7),41.8(C-4),40.4/3′N(CH3)2/,36.8(9a-NCH3),35.0(C-2″),29.0(C-4′),26.9(C-8),26.9(6-CH3),22.0(8-CH3),22.0(C-14),21.6(3″-CH3),21.3(5′-CH3),18.1(5″-CH3),16.9(12-CH3),14.6(2-CH3),11.0(14-CH3),9.6(4-CH3),9.4(10-CH3)。
实施例43-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-12-O-甲基-阿齐霉素
将实施例3所得12-O-甲基-阿齐霉素(1.7g,0.0022mol)溶解于0.25N盐酸(80ml),并将其在室温放置24小时。在反应混合物中加入CH2Cl2(pH 1.8)。分离各相,水相用CH2Cl2萃取两次以上。再在水相中加入CH2Cl2萃取,用浓NH4OH将混合物的pH调至9.0。分离各相,水相再用CH2Cl2萃取。将pH 9.0的合并的有机相用10%NaHCO3水溶液和水漂洗,K2CO3干燥并蒸发,得到1.25g具有下列物理-化学常数的标题产物:TLC 二氯甲烷/甲醇/浓氨水,90∶9∶0.5 Rf=0.315
乙酸乙酯/正己烷/二乙胺,100∶100∶20 Rf=0.594IR(KBr)cm-1:3450,2971,2933,1711,1648,1460,1381,1272,1261,1171,1113,1078,1049。1H NMR(300 MHz,CDCl3)δ:5.32(H-13),4.47(H-1′),3.78(H-3),3.66(H-11),3.58(H-5),3.58(H-5′),3.41(12-OCH3),3.28(H-2′),2.67(H-2),2.80(H-10),2.53(H-3′),2.53(H-9a),2.27/3′N(CH3)2/,2.37(9a-NCH3),2.07(H-9b),2,27(H-4),1.92(H-8),1.74(H-14a),1.68(H-4′a),1.59(H-7a),1.63(H-14b),1.51(H-7b),1.31(6-CH3),1.31(2-CH3),1.29(H-4′b),1.26(5′-CH3),1.08(12-CH3),1.05(4-CH3),1.19(10-CH3),0.93(8-CH3),0.92(14-CH3)。13C NMR(75 MHz,CDCl3)δ:177.2(C-1),106.4(C-1′),94.7(C-5),78.0(C-12),79.0(C-3),78.3(C-11),75.1(C-13),72.9(C-6),70.2(C-2′),70.3(C-9),65.3(C-3′),62.1(C-10),52.5(12-OCH3),44.3(C-2),41.8(C-7),35.7(C-4),39.9/3′N(CH3)2/,36.5(9a-NCH3),27.9(C-4′),26.4(C-8),25.5(6-CH3),20.8(8-CH3),20.7(C-14),20.8(5′-CH3,16.1(12-CH3),15.7(2-CH3),10.3(14-CH3),7.6(4-CH3),7.2(10-CH3)。
实施例53-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-12-0-甲基-阿齐霉素-2’-0-乙酸酯
在实施例4所得3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-12-0-甲基-阿齐霉素(1.3g,0.0022mol)的CH2Cl2(20ml)溶液中加入NaHCO3(0.754g,0.009mol)和乙酸酐(0.221ml,0.0023mol),然后在室温搅拌10小时。放置过夜后在反应混合物中加入饱和NaHCO3。分离各相,水相用CH2Cl2萃取。合并的有机萃取液用饱和NaHCO3溶液漂洗,K2CO3干燥,过滤并蒸发,得到1.29g白色非晶状沉淀。TLC 二氯甲烷/甲醇/浓氨水,90∶9∶0.5 Rf=0.489
乙酸乙酯/正己烷/二乙胺,100∶100∶20 Rf=0.661IR(KBr)cm-1:3448,2974,1749,1718,1637,1458,1377,1242,1169,1115,1045。1H NMR(300 MHz,CDCl3)δ:5.23(H-13),4.72(H-2'),4.70(H-1′),3.59(H-11),3.56(H-5),3.52(H-3),3.43(H-5′),3.33(12-OCH3),2.72(H-10),2.71(H-3′),2.61(H-2),2.42(H-9a),2.30(9a-NCH3),2.20/3′N(CH3)2/,2.12(H-4,1.99(2′-COCH3),1.96(H-9b),1.80(H-8),1.67(H-14a),1.67(H-4′a),1.58(H-14b),1.47(H-7a),1.31(H-4′b),1.21(2-CH3),1.18(H-7b),1.16(5′-CH3),1.15(6-CH3),1.10(10-CH3),0.97(12-CH3),0.86(14-CH3),0.84(8-CH3),0.81(4-CH3)。13C NMR(75 MHz,CDCl3)δ:176.5(C-1),169.4(2′-COCH3),98.6(C-1'),84.3(C-5),77.3(C-12),78.3(C-3),76.7(C-11),74.6(C-13),72.4(C-6),70.7(C-2'),69.9(C-9),62.2(C-3'),62.3(C-10),51.9(12-OCH3),43.0(C-2),40.1(C-7),35.2(C-4),39.6/3′N(CH3)2/,35.9(9a-NCH3),30.0(C-4′),25.4(C-8),25.2(6-CH3),20.6(2′-COCH3),20.4(8-CH3),20.0(C-14),20.2(5′-CH3),15.9(12-CH3),15.2(2-CH3),9.7(14-CH3),7.0(4-CH3),6.4(10-CH3)。实施例63-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-12-0-甲基-阿齐霉素3,6-半缩酮-2’-0-乙酸酯
在实施例5所得3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-12-0-甲基-阿齐霉素2’-0-乙酸酯(1.3g,0.0020mol)的CH2Cl2(15ml)溶液中加入二甲亚砜(4.35ml)和N,N-二甲基-氨基-丙基-乙基-碳化二亚胺(4.55g)。将反应混合物冷却到15℃,在搅拌和保持15℃的情况下用30分钟滴加三氟乙酸吡啶鎓(4.61g,0.0234mol)的CH2Cl2(10ml)溶液。将反应混合物的温度逐渐升至室温,然后将其搅拌2小时。通过加入饱和NaCl溶液(25ml)终止反应。加入2N NaOH使反应碱性化至pH9.5。用CH2Cl2萃取反应混合物,依次用饱和NaCl溶液,NaHCO3和水漂洗有机萃取液,K2CO3干燥。减压蒸发CH2Cl2,得到1.78g油状剩余物。TLC 二氯甲烷/甲醇/浓氨水,90∶9∶0.5 Rf=0.176
乙酸乙酯/正己烷/二乙胺,100∶100∶20 Rf=0.861
实施例73-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-12-0-甲基-阿齐霉素3,6-半缩酮
将实施例6所得3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-12-0-甲基-阿齐霉素2’-0-乙酸酯(1.78g)的甲醇(50ml)溶液在室温下放置24小时。减压蒸发除去甲醇,得到的剩余物(1.65g)在硅胶柱上进行低压色谱纯化,用二氯甲烷/甲醇/浓氨水(90∶9∶0.5)溶剂系统洗脱。经过蒸发Rf=0.082的合并萃取液,得到具有下列物理-化学常数的色谱相同的3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-12-0-甲基-阿齐霉素-3,6-半缩酮:TLC 二氯甲烷/甲醇/浓氨水,90∶9∶0.5 Rf=0.082
乙酸乙酯/正己烷/二乙胺,100∶100∶20 Rf=0.624IR(CDCl3)cm-1:3450,2956,2940,1718,1678,1631,1459,1383,1278,1198,1117,1068,1048,1014,963。1H NMR(300 MHz,CDCl3)δ:5.49(H-13),4.21(H-1′),3.83(H-11),3.75(H-5),3.52(H-5′),3.43(12-OCH3),3.25(H-2′),2.59(H-2),2.93(H-10),2.50(H-3′),2.61(H-9a),2.29/3′N(CH3)2)/,2.40(9a-NCH3),2.10(H-9b),2.06(H-4),1.88(H-8),1.77(H-14a),1.67(H-4′a),1.61(H-7a),1.64(H-14b),1.33(H-7b),1.31(6-CH3),1.05(2-CH3),1.27(H-4′b),1.26(5′-CH3),1.08(12-CH3),1.05,(4-CH3),1.19(10-CH3),0.92(8-CH3),0.93(14-CH3)。13C NMR(75 MHz,CDCl3)δ:176.2(C-1),105.8(C-1′),94.6(C-5),78.3(C-12),102.7(C-3),71.2(C-11),74.8(C-13),82.9(C-6),69.6(C-2′),64.5(C-9),65.1(C-3′),60.7(C-10),52.2(12-OCH3),49.2(C-2),41.4(C-7),48.6(C-4),40.0/3′N(CH3)2/,40.5(9a-NCH3),28.2(C-4′),29.1(C-8),26.5(6-CH3),21.5(8-CH3),21.6(C-14),20.8(5′-CH3),16.3(12-CH3),13.6(2-CH3),10.7(14-CH3),12.8(4-CH3),10.7(10-CH3)。
实施例84”-0-三甲基甲硅烷基-2’-0-3’-N-双(苄氧羰基)-3’-N-脱甲基-阿齐霉素
氮气流下在冷却到0-5℃的2’-0-3’-N-双(苄氧羰基)-3’-N-脱甲基-阿齐霉素(5g,0.005mol)的吡啶(30ml)溶液中加入三甲基甲硅烷基咪唑(1.46ml,0.01mol)和三甲基甲硅烷基氯(1.64ml,0.01mol)。将反应混合物在同样温度搅拌1小时,加入正己烷(50ml)和水(25ml)。分离各相,有机相用饱和NaHCO3溶液(25ml)和水(25ml)漂洗。MgSO4干燥,过滤并减压蒸发溶剂,得到非晶状沉淀物(3.65g)。任选在硅胶柱上进行低压色谱纯化,用二氯甲烷/甲醇/浓氨水(90∶9∶0.5)溶剂系统洗脱。经过合并及蒸发Rf=0.670的色谱相同馏分,得到具有下列物理-化学常数的标题产物:TLC 二氯甲烷/甲醇,90∶1 Rf=0.525乙酸乙酯/正己烷/二乙胺,100∶100∶20 Rf=0.862IR(KBr)cm-1:3502,2969,2938,1753,1732,1708,1454,1383,1365,1254,1169,1118,1063,1001,897,839,754,696。1H NMR(300 MHz,CDCl3)δ:7.34-7.26(Ph),5.13,5.09,(CH2-Ph),5.07(H-1″),4.78(H-1′),4.68(H-13),4.66(H-2′),4.55(H-3′),4.22(H-5″),4.13(H-3),3.96(H-5′),3.65(H-11),3.58,3.54(H-5),3.15(H-4″),3.37,2.99(3″-OCH3),2.85,2.81(3′-NCH3),2.70(H-2),2.68(H-10),2.54(H-9a),2.35(H-2″a),2.31(9a-NCH3),2.04(H-9b),1.97(H-8),1.90(H-14a),1.85(H-4),1.62(H-7a),1.50(H-2″b),1.44(H-14b),1.28,1.27(6-CH3),1.23(5″-CH3),1.16(5′-CH3),1.15(H-7b),1.04(3″-CH3),1.15(12-CH3),1.10(2-CH3),1.10(10-CH3),0.92(8-CH3),0.89(14-CH3),1.10(4-CH3)。13C NMR(75 MHz,CDCl3)δ:178.8(C-1),156.6,156,3(OCO),154.7,154.6(NCO),136.8-127-5(Ph),99.2(C-1′),94.8(C-1′″),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″),69.2,69.0,67.2,66.8(CH2-Ph),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-4),36.1(9a-NCH3),35.1,35.0(C-2″),36.3,35.7(C-4′),28.4(3′-NCH3),26.3(C-8),26.8(6-CH3),22.1(3″-CH3),21.6(8-CH3),21.4(5′-CH3),21.0(C-14),18.7(5″-CH3),15.9(2-CH3),14.5(12-CH3),11.0(14-CH3),8.5(4-CH3),7.1(10-CH3),0.63/4″-OSi(CH3)3/。ES-MS 1075。实施例911-0-甲基-阿齐霉素和12-0-甲基-阿齐霉素
室温下用3小时向实施例8产物(3.0g,0.0028mol)的N,N-二甲基甲酰胺(50ml)溶液中缓缓加入甲基碘(1.29ml,0.0207mol)和60%氢化钠(0.69g,0.0174mol)。将反应混合物在同样温度搅拌1小时。通过加入三乙胺(5ml)终止反应,然后将其转移到10%NaHCO3水溶液(100ml)和水(100ml)的混合物中,并用乙酸乙酯萃取。合并的有机萃取液用饱和NaCl溶液和水漂洗。MgSO4干燥,过滤并减压蒸发,得到2.9g各种产物的混合物。任选在硅胶柱上进行低压色谱纯化,用二氯甲烷/甲醇(90∶1)溶剂系统洗脱,得到Rf=0.745的色谱相同的4”-0-三甲基甲硅烷基-2’-0-3’-N-双(苄氧羰基)-3’-N-脱甲基-11-0-甲基-阿齐霉素[IR(KBr):3452,2969,1752,1736,1706,1455,1382,1332,1254,1169,1117,1063,1002,914,897,840,754,697]和Rf=0.485的4”-0-三甲基甲硅烷基-2’-0-3’-N-双(苄氧羰基)-3’-N-脱甲基-12-0-甲基-阿齐霉素[IR(KBr):3450,2958,1754,1718,1708,1458,1383,1252,1168,1068,1010,896,842,753,695]。
将所得混合物溶解于乙醇(50ml),加入pH 5的NaOAc/HOAc缓冲液(0.51ml HOAc,0.789g NaOAc,0.66ml乙醇和3ml)和10%Pd/C(1.5g),然后在5bar氢气的反应釜中搅拌8小时进行氢化。滤除催化剂,将滤液蒸发成粘稠的浆液。加水(50ml)和CHCl3(50ml),通过pH 4.0和pH 9.5的梯度萃取分离产物。将合并的pH 9.5的有机萃取液用K2CO3干燥,蒸发得到非晶状沉淀物。将沉淀物溶解于异丙醇(20ml),加入水(20ml)和几滴甲酸,然后在室温下搅拌30分钟。用pH 9.5的乙酸异丙酯萃取,硫酸钠干燥并减压蒸发。将所得产物溶解于CHCl3(50ml),加入甲醛(37%,0.24ml)和甲酸(98-100%,0.22ml)。将反应混合物搅拌回流3小时,冷却到室温,倒入水(20ml)中,将pH调至4.0后分离各相,水相用CHCl3萃取两次以上。在水相中加入CHCl3,用2N NaOH将pH调至9.5。分离各相,水相用CHCl3萃取两次以上。将合并的pH 9.5的有机萃取液用K2CO3干燥,蒸发得到1.25g沉淀物。将其在硅胶柱上进行色谱纯化,用二氯甲烷/甲醇/浓氨水(90∶9∶1)溶剂系统洗脱,得到0.40g色谱相同的11-0-甲基-阿齐霉素,其物理-化学常数在美国专利5,250,518(10/1993)中给出,和0.52g 12-0-甲基-阿齐霉素,其物理-化学常数在实施例3中给出。
实施例103-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-氧-11-0-甲基-阿齐霉素
将11-0-甲基-阿齐霉素(1.5g)溶解于甲醇(30ml),加入0.25N盐酸(50ml),然后在室温下放置24小时。蒸除甲醇,在反应混合物中加入CDCl3(pH 1.9)。分离各相,水相用CDCl3萃取两次以上。将水溶液碱化至pH 9.5,再用CDCl3萃取。将合并的pH 9.5的有机萃取液用K2CO3干燥,蒸发得到0.95g标题产物。任选在硅胶柱上进行低压色谱纯化,用二氯甲烷/甲醇/浓氨水(90∶9∶0.5)溶剂系统洗脱,得到具有下列物理-化学常数的色谱相同的标题产物:TLC 二氯甲烷/甲醇/浓氨水,90∶9∶0.5 Rf=0.382乙酸乙酯/正己烷/二乙胺,100∶100∶20 Rf=0.594IR(KBr)cm-1:3448,2972,2937,1730,1638,1458,1377,1165,1113,1078,1050。1H NMR(300 MHz,CDCl3)δ:4.97(H-13),4.52(H-1′),3.76(H-3),3.70(11-OCH3),3.59(H-5),3.54(H-5′),3.42(H-11),3.29(H-2′),2.68(H-2),2.70(H-10),2.58(H-3′),2.46(H-9a),2.35(H-4),2.29/3′N(CH3)2/,2.30(9a-NCH3),2.11(H-9b),1.94(H-14a),1.89(H-8),1.70(H-4′a),1.66(H-7a),1.54(H-7b),1.52(H-14b),1.33(6-CH3),1.30(2-CH3),1.27(H-4′b),1.25(5′-CH3),1.12(12-CH3),1.10(4-CH3),1.06(10-CH3),0.92(8-CH3),0.86(14-CH3)。13C NMR(75 MHz,CDCl3)δ:175.7(C-1),106.1(C-1′),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-3′),62.9(C-10),62.0(11-OCH3),44.1(C-2),42.5(C-7),35.3(C-4),39.9/3′N(CH3)2/,36.2(9a-NCH3),28.0(C-4′),26.7(C-8),25.8(6-CH3),20.9(8-CH3),21.2(C-14),20.8(5′-CH3),16.8(12-CH3),15.6(2-CH3),10.3(14-CH3),7.7(4-CH3),6.8(10-CH3)。
实施例113-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-羟基(氧)-11-0-甲基-阿齐霉素2’-0-乙酸酯
在实施例10所得3-脱(2,6-二脱氧-3-C-甲基-3-0-甲基-α-L-核糖吡喃己糖基-氧)-3-氧(羟基)-11-0-甲基-阿齐霉素(0.89g)的CH2Cl2(25ml)溶液中加入NaHCO3(0.52g)和乙酸酐(0.15ml),然后在室温下搅拌反应混合物10小时。放置过夜后用实施例5所述方法,通过用CH2Cl2萃取分离反应混合物,得到0.65g非晶状沉淀物。TLC 二氯甲烷/甲醇/浓氨水,90∶9∶0.5 Rf=0.426
乙酸乙酯/正己烷/二乙胺,100∶100∶20 Rf=0.670IR(KBr)cm-1 3525,3475,2968,2937,1724,1647,1458,1376,1265,1168,1113,1081,1050。
实施例123-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-11-O-甲基-阿齐霉素3,6-半缩酮2’-O-乙酸酯
在实施例11所得3-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-3-氧(羟基)-11-O-甲基-阿齐霉素2’-O-乙酸酯(0.65g)的CH2Cl2(20ml)溶液中加入二甲亚砜(0.94ml)和N,N-二甲基-氨基丙基-乙基-碳化二亚胺(1.16g)。将反应混合物冷却到15℃,在搅拌和保持15℃的情况下用30分钟缓缓加入三氟乙酸吡啶鎓(1.15g)的CH2Cl2(5ml)溶液。将反应混合物的温度升至室温,再搅拌4小时,然后根据实施例6所述方法分离产物,得到0.6g标题产物。TLC 二氯甲烷/甲醇/浓氨水,90∶9∶0.5 Rf=0.606
乙酸乙酯/正己烷/二乙胺,100∶100∶20 Rf=0.861
实施例133-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-11-O-甲基-阿齐霉素3,6-半缩酮
将实施例12所得3-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-11-O-甲基-阿齐霉素3,6-半缩酮2’-O-乙酸酯(0.6g)的甲醇(40ml)溶液在室温下放置24小时。减压蒸除甲醇,将所得剩余物(0.53g)在硅胶柱上进行低压色谱纯化,用二氯甲烷/甲醇/浓氨水(90∶9∶1.5)溶剂系统洗脱。通过蒸发Rf=0.670的合并萃取液,得到0.22g具有下列物理-化学常数的色谱相同的3-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-11-O-甲基-阿齐霉素3,6-半缩酮:IR(CDCl3)cm-1:3471,2975,1715,1638,1458,1382,1196,1117,1049,1013,963。1H NMR(300 MHz,CDCl3)δ:5.01(H-13),4.22(H-1′),3.80(H-5),3.50(H-5′),3.45(11-OCH3),3.25(H-2′),2.63(H-2),2.49(H-3′),2.77(H-9a),2.29/3′N(CH3)2/,2.20(9a-NCH3),2.24(H-9b),2.09(H-4),1.85(H-8),1.83(H-14a),1.66(H-4′a),1.73(H-14b),1.36(6-CH3),1.31(2-CH3),1.26(H-4′b),1.21(5′-CH3),1.25,(4-CH3),1.01(10-CH3),1.03(8-CH3),0.81(14-CH3)。13C NMR(75 MHz,CDCl3)δ:177.0(C-1),106.2(C-1′),102.1(C-3),93.9(C-5),86.1(C-11),81.9(C-6),69.7(C-2′),64.9(C-9),65.8(C-3′),62.1(C-10),61.9(11-OCH3),49.6(C-2),43.3(C-7),40.1/3′N(CH3)2/,28.1(C-4′),28.7(C-8),25.5(6-CH3),20.9(5′-CH3),14.0(2-CH3),11.7(14-CH3),12.3(4-CH3),8.5(10-CH3)。实施例143-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-L-核糖吡喃己糖基-氧)-3-氧-阿齐霉素
根据Djokic等人在美国专利4,886,792(12/1989)实施例3所述方法从阿齐霉素制备3-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-3-氧-阿齐霉素。经硅胶柱色谱分离,用二氯甲烷/甲醇/浓氨水(90∶9∶0.5)溶剂系统洗脱,得到具有下列物理-化学常数的色谱相同的产物:TLC 乙酸乙酯/三乙胺,95∶5 Rf=0.371IR(KBr)cm-1:3438,2973,2938,1713,1655,1459,1378,1350,1260,1172,1113,1078,1044,957。1H NMR(300 MHz,CDCl3)δ:4.72(H-13),4.47(H-1′),3.78(H-3),3.58(H-5),3.56(H-5′),3.65(H-11),3.27(H-2′),2.66(H-2),2.74(H-10),2.52(H-3′),2.49(H-9a),2.28(H-4),2.26/3′N(CH3)2/,2.37(9a-NCH3),2.06(H-9b),1.90(H-14a),1.90(H-8),1.67(H-4′a),1.62(H-7a),1.47(H-7b),1.53(H-14b),1.32(6-CH3),1.30(2-CH3),1.28(H-4′b),1.26(5′-CH3),1.07(12-CH3),1.06(4-CH3),1.12(10-CH3),0.92(8-CH3),0.88(14-CH3)。13C NMR(75 MHz,CDCl3)δ:178.8(C-1),106.6(C-1′),94.7(C-5),72.9(C-12),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-CH3),20.8(8-CH3),20.5(C-14),20.9(5′-CH3),15.7(12-CH3),15.8(2-CH3),10.5(14-CH3),7.5(4-CH3),7.3(10-CH3)。实施例153-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-3-氧-阿齐霉素2’-O-乙酸酯
在实施例14所得3-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-3-氧-阿齐霉素(10g)的CH2Cl2(150ml)溶液中加入NaHCO3(5.84g)和乙酸酐(1.68ml),然后在室温下搅拌反应混合物12小时。放置过夜后用实施例5所述方法进行分离,得到11.21g具有下列物理-化学常数的非晶状沉淀物:TLC 乙酸乙酯/三乙胺,95∶5 Rf=0.547IR(KBr)cm-1:3485,2973,2937,1748,1716,1648,1459,1376,1240,1170,1114,1081,1045,956。1H NMR(300 MHz,CDCl3)δ:4.71(H-13),4.79(H-2′),4.71(H-1′),3.84(H-3),3.61(H-5),3.50(H-5′),3.68(H-11),2.73(H-10),2.70(H-2),2.70(H-3′),2.48(H-9a),2.27(H-4),2.26/3′N(CH3)2/,2.36(9a-NCH3),2.07(COCH3),2.05(H-9b),1.90(H-14a),1.90(H-8),1.78(H-4′a),1.56(H-7a),1.24(H-7b),1.54(H-14b),1.23(6-CH3),1.29(2-CH3),1.32(H-4′b),1.24(5′-CH3),1.11(10-CH3),1.06(12-CH3),0.90(4-CH3),0.89(8-CH3),0.88(14-CH3)。
实施例163-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-阿齐霉素3,6-半缩酮2’-O-乙酸酯
在实施例15所得3-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-3-氧-阿齐霉素2’-O-乙酸酯(5.6g)的CH2Cl2(100ml)溶液中加入二甲亚砜(12.34ml)和N,N-二甲基-氨基-丙基-乙基-碳化二亚胺(15.05g)。将反应混合物冷却到15℃,在搅拌和保持15℃的情况下用30分钟缓缓加入三氟乙酸吡啶鎓(15.04g)的CH2Cl2(30ml)溶液。将反应混合物的温度升至室温,再搅拌4小时,然后根据实施例6所述方法分离产物,得到5.26g标题产物。TLC 乙酸乙酯/三乙胺,95∶5 Rf=0.675
实施例173-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-阿齐霉素3,6-半缩酮
将实施例16所得3-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-阿齐霉素3,6-半缩酮2’-O-乙酸酯(5.2g)的甲醇(100ml)溶液在室温下放置16小时。减压蒸除甲醇,将所得产物在硅胶柱上进行低压色谱纯化,用二氯甲烷/甲醇/浓氨水(90∶9∶1.5)溶剂系统洗脱。通过蒸发Rf=0.480的合并馏分,得到具有下列物理-化学常数的色谱相同的3-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-阿齐霉素3,6-半缩酮:TLC 乙酸乙酯/三乙胺,95∶5 Rf=0.447IR(CDCl3)cm-1:3468,2976,1713,1638,1459,1382,1197,1116,1068,1049,1014,963。1H NMR(300 MHz,CDCl3)δ:4.94(H-13),4.21(H-1′),3.74(H-5),3.51(H-5′),3.23(H-2′),2.57(H-2),2.49(H-3′),2.23/3′N(CH3)2/,2.06(H-4),1.74(H-8),1.67(H-4′a),1.39(6-CH3),1.28(2-CH3),1.25(H-4′b),1.22(5′-CH3),1.23,(4-CH3),1.10(10-CH3),1.04(8-CH3),0.92(14-CH3)。13C NMR(75 MHz,CDCl3)δ:176.9(C-1),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(C-3′),61.6(C-10),49.3(C-2),41.6(C-7),40.1/3′N(CH3)2/,31.0(C-8),28.2(C-4′),26.4(6-CH3),20.8(5′-CH3),13.6(2-CH3),12.6(4-CH3),11.4(14-CH3)。实施例183-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-阿齐霉素3,6-半缩酮11,12-环状碳酸盐
在实施例17所得3-脱(2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核糖吡喃己糖基-氧)-阿齐霉素3,6-半缩酮(1g)的乙酸乙酯(30ml)溶液中加入碳酸亚乙酯(0.5g)和碳酸钾(0.5g)。将反应悬浮液搅拌回流10小时,在室温下放置16小时,然后过滤。用饱和NaCl溶液和水漂洗乙酸乙酯相,CaCl2干燥,过滤并蒸发,得到1.05g油状残余物。在硅胶柱上分离,用二氯甲烷/甲醇/浓氨水(90∶9∶0.5)溶剂系统洗脱后,得到具有下列物理-化学常数的色谱相同的标题产物:TLC 乙酸乙酯/三乙胺,95∶5 Rf=0.514IR(CDCl3)cm-1:3498,2975,2941,1812,1724,1638,1459,1381,1359,1333,1292,1234,1173,1115,1082,1045,1015,966。1H NMR(300 MHz,CDCl3)δ:5.03(H-13),4.61(H-11),4.23(H-1′),3.73(H-5),3.52(H-5′),3.25(H-2′),3.18(H-9a),2.90(H-10),2.54(H-2),2.50(H-3′),2.28/3′N(CH3)2/,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(12-CH3),1.37(6-CH3),1.30(2-CH3),1.28(H-4′b),1.23(5′-CH3),1.24(4-CH3),1.13(H-7b),1.18(10-CH3),0.90(8-CH3),0.92(14-CH3)。13C NMR(75 MHz,CDCl3)δ:176.1(C-1),153.5 C=O碳酸盐),106. 1(C-1'),101.6(C-3),93.6(C-5),83.7(C-12),82.7(C-6),78.9(C-11),77.9(C-13),69.6(C-2′),69.4(C-5′),63.6(C-9),65.3(C-3′),60.1(C-10),49.9(C-2),46.6(C-4),41.8(C-7),40.0/3′N(CH3)2/,33.4(9a-CH3),28.0(C-4′),26.8(C-8),25.1(6-CH3),22.3(C-14),20.8(5′-CH3),19.4(8-CH3),14.1(12-CH3),13.9(2-CH3),12.1(4-CH3),12.9(10-CH3),10.1(14-CH3)。
Claims (23)
1.通式(Ⅰ)化合物及其与无机酸或有机酸形成的可药用加成盐,特征在于R1分别代表羟基,式(Ⅱ)L-二脱氧甲基己糖基,其中R2分别代表氢或甲硅烷基,R3分别代表氢,或者与R6一起代表醚基,R4分别代表氢,(C1-C4)酰基或-COO-(CH2)n-Ar,其中n是1-7,及Ar代表未取代或取代的最多可达18个碳原子的芳基,R5分别代表氢,甲基或-COO-(CH2)n-Ar,其中n是1-7,及Ar分别代表未取代或取代的最多可达18个碳原子的芳基,R6分别代表氢,或者与R3一起代表醚基,R7分别代表氢,(C1-C12)烷基,甲硅烷基,或者与R8和C-11/C-12碳原子一起代表环状碳酸酯,R8分别代表氢,(C1-C12)烷基,甲硅烷基,或者与R7和C-11/C-12碳原子一起代表环状碳酸酯。
2.根据权利要求1的化合物,特征是:R1代表L-二脱氧甲基己糖基,R2和R7相同并都代表三甲基甲硅烷基,R3和R8相同并都代表氢,R4和R5相同并都代表苄氧羰基,及R6代表羟基。
3.根据权利要求1的化合物,特征是:R1代表L-二脱氧甲基己糖基,R2代表三甲基甲硅烷基,R3,R7和R8相同并都代表氢,R4和R5相同并都代表苄氧羰基,及R6代表羟基。
4.根据权利要求1的化合物,特征是:R1代表L-二脱氧甲基己糖基,R2和R7相同并都代表三甲基甲硅烷基,R3代表氢,R4和R5相同并都代表苄氧羰基,R6代表羟基,及R8代表甲基。
5.根据权利要求1的化合物,特征是:R1代表L-二脱氧甲基己糖基,R2代表三甲基甲硅烷基,R3和R8相同并都代表氢,R4和R5相同并都代表苄氧羰基,R6代表羟基,及R7代表甲基。
6.根据权利要求1的化合物,特征是:R1代表L-二脱氧甲基己糖基,R2代表三甲基甲硅烷基,R3和R7相同并都代表氢,R4和R5相同并都代表苄氧羰基,R6代表羟基,及R8代表甲基。
7.根据权利要求1的化合物,特征是:R1代表L-二脱氧甲基己糖基,R2,R3,R4,R5和R7相同并都代表氢,R8代表甲基,及R6代表羟基。
8.根据权利要求1的化合物,特征是:R1代表L-二脱氧甲基己糖基,R2,R3,R4和R7相同并都代表氢,R5和R8相同并都代表甲基,及R6代表羟基。
9.根据权利要求1的化合物,特征是:R1和R6相同并都代表羟基,R3,R4和R8相同并都代表氢,及R5和R7相同并都代表甲基。
10.根据权利要求1的化合物,特征是:R1和R6相同并都代表羟基,R3,R4和R7相同并都代表氢,及R5和R8相同并都代表甲基。
11.根据权利要求1的化合物,特征是:R1和R6相同并都代表羟基,R3,R7和R8相同并都代表氢,R4代表乙酰基,及R5代表甲基。
12.根据权利要求1的化合物,特征是:R1和R6相同并都代表羟基,R3和R8相同并都代表氢,R4代表乙酰基,及R5和R7相同并都代表甲基。
13.根据权利要求1的化合物,特征是:R1和R6相同并都代表羟基,R3和R7相同并都代表氢,R4代表乙酰基,及R5和R8相同并都代表甲基。
14.根据权利要求1的化合物,特征是:R1代表羟基,R3与R6一起代表醚基,R4代表乙酰基,R5代表甲基,及R7和R8相同并都代表氢。
15.根据权利要求1的化合物,特征是:R1代表羟基,R3与R6一起代表醚基,R4代表乙酰基,R5和R7相同并都代表甲基,及R8代表氢。
16.根据权利要求1的化合物,特征是:R1代表羟基,R3与R6一起代表醚基,R4代表乙酰基,R5和R8相同并都代表甲基,及R7代表氢。
17.根据权利要求1的化合物,特征是:R1代表羟基,R3与R6一起代表醚基,R4,R7和R8相同并都代表氢,及R5代表甲基。
18.根据权利要求1的化合物,特征是:R1代表羟基,R3与R6一起代表醚基,R4和R8相同并都代表氢,及R5和R7相同并都代表甲基。
19.根据权利要求1的化合物,特征是:R1代表羟基,R3与R6一起代表醚基,R4和R7相同并都代表氢,及R5和R8相同并都代表甲基。
20.根据权利要求1的化合物,特征是:R1代表羟基,R3与R6一起代表醚基,R4代表氢,R5代表甲基。及R7和R8与C-11/C-12碳原子一起代表环状碳酸酯。
21.通式(Ⅰ)化合物及其与无机酸或有机酸形成的可药用加成盐的制备方法,特中R1代表羟基,式(Ⅱ)L-二脱氧甲基己糖基,其中R2分别代表氢或甲硅烷基,R3分别代表氢,或者与R6一起代表醚基,R4分别代表氢,(C1-C4)酰基或-COO-(CH2)n-Ar,其中n是1-7,及Ar分别代表未取代或取代的最多可达18个碳原子的芳基,R5分别代表氢,甲基或-COO-(CH2)n-Ar,其中n是1-7,及Ar分别代表未取代或取代的最多可达18个碳原子的芳基,R6分别代表氢,或者与R3一起代表醚基,R7分别代表氢,(C1-C12)烷基,甲硅烷基,或者与R8和C-11/C-12碳原子一起代表环状碳酸酯,R8分别代表氢,(C1-C12)烷基,甲硅烷基,或者与R7和C-11/C-12碳原子一起代表环状碳酸酯,
特征在于(Ⅰ)将通式(Ⅰ)的阿齐霉素,其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,R2,R3,R4,R7和R8相同并都代表氢,R5是甲基,及R6是羟基,与式(Ⅲ)的有机羧酰氯反应,
-ClCOO-(CH2)n-Ar (Ⅲ)其中n是1-7,及Ar代表未取代或取代的最多可达18个碳原子的芳基,优选与苄氧羰基氯在碱,优选碳酸氢钠存在下,在对反应惰性的溶剂,优选苯或甲苯中反应,生成通式(Ⅰ)化合物,其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,R2,R3,R7和R8相同并都代表氢,R4和R5相同并都代表苄氧羰基,及R6是羟基,然后在下列位置进行羟基的选择性甲硅烷基化反应:A/4”-和11-位与2-5等摩尔过量甲硅烷基化剂,优选与三甲基
甲硅烷基氯和三甲基甲硅烷基咪唑的混合物,在有机惰性溶剂如
吡啶,乙酸乙酯,N,N-二甲基甲酰胺或二氯甲烷,优选吡啶中,
在0-5℃反应5-8小时,生成通式(Ⅰ)化合物,其中R1代表
式(Ⅱ)L-二脱氧甲基己糖基,R2和R7相同并都代表三甲基甲
硅烷基,R3和R8相同并都代表氢,R4和R5相同并都代表苄氧羰
基,及R6是羟基,或B/4”-位与1.1-2等摩尔过量甲硅烷基化剂,在有机惰性溶剂,
优选吡啶中,在0-5℃反应1小时,生成通式(Ⅰ)化合物,其
中R1代表式(Ⅱ)L-二脱氧甲基己糖基,R2代表三甲基甲硅烷
基,R3,R7和R8相同并都代表氢,R4和R5相同并都代表苄氧羰基,
及R6是羟基,然后,与1.3-10摩尔过量的相应的烷基化剂,优选甲基化剂,更优选甲基碘,在1.1-8.5mol适当的碱如碱金属氢化物,优选氢化钠存在下,在适当的对反应惰性的溶剂如二甲亚砜,四氢呋喃,N,N-二甲基甲酰胺或它们的混合物中,在-15℃至室温,优选在0-5℃,进行O-烷基化反应,生成A/通式(Ⅰ)化合物,其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,
R2和R7相同并都代表三甲基甲硅烷基,R3代表氢,R4和R5相同并
都代表苄氧羰基,R6是羟基,及R8是甲基,或B/通式(Ⅰ)化合物,其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,
R2代表三甲基甲硅烷基,R3和R8相同并都代表氢,R4和R5相同并
都代表苄氧羰基,R6是羟基,及R7是甲基,和通式(Ⅰ)化合物,
其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,R2代表三甲基甲硅
烷基,R3和R7相同并都代表氢,R4和R5相同并都代表苄氧羰基,
R6是羟基,及R8是甲基,的混合物,然后,在低级醇,优选乙醇中,在NaOAc/HOAc缓冲液(pH 5)和催化剂存在下,在1-20 bar氢气压下进行2’-和3’-位保护基的脱保护反应,分离后在低级醇,优选异丙醇中,在甲酸存在下,进行4”-和11-位的脱甲硅烷基化反应,生成A/通式(Ⅰ)化合物,其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,
R2,R3,R4,R5和R7相同并都代表氢,R6是羟基,及R8是甲基,
或B/通式(Ⅰ)化合物,其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,
R2,R3,R4,R5和R8相同并都代表氢,R6是羟基,及R7是甲基,
和通式(Ⅰ)化合物,其中R1,R2,R3,R4,R5,R7和R8与A/中
脱保护反应所定义的相同,的混合物,然后,用1-3当量甲醛(37%),在等量或两倍数量的甲酸(98-100%)和氢化催化剂或其它氢源存在下,在对反应惰性的溶剂,优选氯仿中,加热,优选在回流温度下,进行还原性3’-N-甲基化反应,得到A/通式(Ⅰ)化合物,其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,
R2,R3,R4和R7相同并都代表氢,R5和R8相同并都代表甲基,及
R6是羟基,或B/通式(Ⅰ)化合物,其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,
R2,R3,R4和R8相同并都代表氢,R5和R7相同并都代表甲基,及
R6是羟基,和通式(Ⅰ)化合物,其中R1,R2,R3,R4,R5,R6,R7
和R8与3’-N-甲基化反应的A/情况定义相同,的混合物,任选在硅胶柱上进行分离,得到色谱相同的通式(Ⅰ)化合物,其中R1代表式(Ⅱ)L-二脱氧甲基己糖基,R2,R3,R4和R8相同并都代表氢,R5和R7相同并都代表甲基,及R6是羟基(11-0-甲基-阿齐霉素),和通式(Ⅰ)化合物,其中R1,R2,R3,R4,R5,R6,R7和R8与3’-N-甲基化反应的A/情况定义相同(12-0-甲基-阿齐霉素),或者(Ⅱ)任选将根据方法(Ⅰ)得到的阿齐霉素或其11-0-甲基-和12-0-甲基-衍生物用稀无机酸,优选用0.25N盐酸进行水解反应,得到通式(Ⅰ)化合物,其中R1和R6相同并都代表羟基,R3,R4,R7和R8相同并都代表氢,及R5是甲基,或通式(Ⅰ)化合物,其中R1和R6相同并都代表羟基,R3,R4和R8相同并都代表氢,及R5和R7相同并都代表甲基,或通式(Ⅰ)化合物,其中R1和R6相同并都代表羟基,R3,R4和R7相同并都代表氢,及R5和R8相同并都代表甲基,然后,用最多可达4个碳原子的羧酸的氯化物或酸酐,优选乙酸酐,在对反应惰性的有机溶剂,优选二氯甲烷中,进行2’-位羟基的选择性酰化反应,生成通式(Ⅰ)化合物,其中R1和R6相同并都代表羟基,R3,R7和R8相同并都代表氢,R4是乙酰基,及R5是甲基,或通式(Ⅰ)化合物,其中R1和R6相同并都代表羟基,R3和R8相同并都代表氢,R4是乙酰基,及R5和R7相同并都代表甲基,或通式(Ⅰ)化合物,其中R1和R6相同并都代表羟基,R3和R7相同并都代表氢,R4是乙酰基,及R5和R8相同并都代表甲基,然后,用Jones试剂或根据改进的Moffat-Pfitzner方法,优选用N,N-二甲氨基丙基-乙基-碳化二亚胺,在作为催化剂的二甲亚砜和三氟乙酸吡啶鎓存在下,在惰性有机溶剂,优选二氯甲烷中,在10℃至室温进行氧化反应,生成通式(Ⅰ)化合物,其中R1代表羟基,R3和R6一起代表醚基团,R4是乙酰基,R5是甲基,及R7和R8相同并都代表氢,或通式(Ⅰ)化合物,其中R1代表羟基,R3和R6一起代表醚基团,R4是乙酰基,R5和R7相同并都代表甲基,及R8是氢,或通式(Ⅰ)化合物,其中R1代表羟基,R3和R6一起代表醚基团,R4是乙酰基,R5和R8相同并都代表甲基,及R7是氢,然后,在低级醇,优选甲醇中,在室温下进行溶剂分解反应,完成2’-位的脱酰基化反应,生成通式(Ⅰ)化合物,其中R1代表羟基,R3和R6一起代表醚基团,R4,R7和R8相同并都代表氢,及R5是甲基,或通式(Ⅰ)化合物,其中R1代表羟基,R3和R6一起代表醚基团,R4和R8相同并都代表氢,R5和R7相同并都代表甲基,或通式(Ⅰ)化合物,其中R1代表羟基,R3和R6一起代表醚基团,R4和R7相同并都代表氢,R5和R8相同并都代表甲基,然后,任选将通式(Ⅰ)化合物与碳酸亚乙酯,在无机碱或有机碱,优选碳酸钾存在下,在对反应惰性的溶剂,优选乙酸乙酯中反应,生成通式(Ⅰ)化合物,其中R1代表羟基,R3和R6一起代表醚基团,R4是氢,R5是甲基,及R7和R8与C-11和C-12碳原子一起代表环状碳酸酯。
22.用于治疗人和动物细菌感染的药物组合物,包括根据权利要求1的抗菌有效量的通式(Ⅰ)化合物或其可药用加成盐以及可药用载体。
23.治疗人和动物细菌感染的方法,包括给人类和动物施用根据权利要求1的抗菌有效量的通式(Ⅰ)化合物或其与无机酸或有机酸形成的可药用加成盐以及可药用载体。
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HR970551A HRP970551B1 (en) | 1997-10-16 | 1997-10-16 | Novel o-methyl azythromycin derivatives |
HRP970551A | 1997-10-16 | ||
HR980497A HRP980497B1 (en) | 1998-09-10 | 1998-09-10 | NOVEL 3,6-HEMIKETALS FROM THE CLASS OF 9a-AZALIDES |
HRP980497A | 1998-09-10 |
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US (1) | US6369035B1 (zh) |
EP (2) | EP1437359B1 (zh) |
JP (1) | JP2001520234A (zh) |
KR (1) | KR100554549B1 (zh) |
CN (1) | CN1281615C (zh) |
AR (1) | AR018014A1 (zh) |
AT (2) | ATE267835T1 (zh) |
AU (1) | AU755315B2 (zh) |
BG (1) | BG64650B1 (zh) |
BR (1) | BR9812808A (zh) |
CA (1) | CA2306963C (zh) |
DE (2) | DE69824201T2 (zh) |
DK (2) | DK1437359T3 (zh) |
EE (1) | EE04681B1 (zh) |
ES (2) | ES2222610T3 (zh) |
HK (1) | HK1032785A1 (zh) |
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IL (2) | IL135648A0 (zh) |
NO (1) | NO20001871L (zh) |
NZ (1) | NZ503897A (zh) |
PL (1) | PL191087B1 (zh) |
PT (2) | PT1036083E (zh) |
RU (1) | RU2220148C2 (zh) |
SI (2) | SI1437359T1 (zh) |
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CN100381453C (zh) * | 2003-05-30 | 2008-04-16 | 葛兰素伊斯特拉齐瓦基森塔萨格勒布公司 | O-烷基大环内酯和氮杂内酯衍生物和制备这些化合物的区域选择性方法 |
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CZ20011512A3 (cs) * | 1998-11-03 | 2001-09-12 | Pfizer Products Inc. | Nová makrolidová antibiotika |
KR100361397B1 (ko) * | 2000-03-15 | 2002-11-23 | 한미약품공업 주식회사 | 에리스로마이신 에이 9-오-트로필옥심 유도체를 이용한클라리스로마이신의 제조방법 |
AU2003211113B2 (en) | 2002-02-15 | 2007-08-09 | Merckle Gmbh | Antibiotic conjugates |
AU2003215245A1 (en) | 2002-02-15 | 2003-09-09 | Sympore Gmbh | Conjugates of biologically active compounds, methods for their preparation and use, formulation and pharmaceutical applications thereof |
US7579324B2 (en) | 2002-02-15 | 2009-08-25 | C-A-I-R Biosciences Gmbh | Conjugates of biologically active compounds, methods for their preparation and use, formulation and pharmaceutical applications thereof |
HRP20020779A2 (en) | 2002-09-27 | 2005-02-28 | Pliva-Istra�iva�ki institut d.o.o. | NEW 3-DECLADINOSYL DERIVATIVES OF 9-DEOXO-9-DIHYDRO-9a-AZA-9a-HOMOERYTHROMICIN A 9a, 11-CYCLIC CARBAMATES |
ITMI20022292A1 (it) * | 2002-10-29 | 2004-04-30 | Zambon Spa | 9a-azalidi ad attivita' antiinfiammatoria. |
US7435805B2 (en) * | 2003-05-30 | 2008-10-14 | Glaxpsmithkline Istrazivacki | O-alkyl macrolide and azalide derivatives and regioselective process for their preparation |
WO2005030227A1 (en) | 2003-09-23 | 2005-04-07 | Enanta Pharmaceuticals, Inc. | 9a, 11-3C-BICYCLIC 9a-AZALIDE DERIVATIVES |
US20060116336A1 (en) * | 2004-03-17 | 2006-06-01 | American Pharmaceutical Partners, Inc. | Lyophilized azithromycin formulation |
US7468428B2 (en) * | 2004-03-17 | 2008-12-23 | App Pharmaceuticals, Llc | Lyophilized azithromycin formulation |
US7402568B2 (en) | 2004-09-29 | 2008-07-22 | Enanta Pharmaceuticals, Inc. | Bicyclic 9a-azalide derivatives |
US7271155B2 (en) | 2005-01-07 | 2007-09-18 | Enanta Pharmaceuticals, Inc. | 9A, 11-2C-bicyclic 9a-azalide derivatives |
WO2008143729A2 (en) * | 2007-02-28 | 2008-11-27 | Rib-X Pharmaceuticals, Inc. | Macrolide compounds and methods of making and using the same |
EP2625185A4 (en) * | 2010-10-10 | 2014-03-26 | Synovo Gmbh | INFLAMMATORY MAKROLIDE |
CA2869461A1 (en) * | 2012-03-27 | 2013-10-03 | Michael W. BURNET | Anti-inflammatory macrolides |
JP7184520B2 (ja) * | 2018-01-22 | 2022-12-06 | 旭化成株式会社 | トランス型脂環式カーボネートの製造方法 |
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SI8110592A8 (en) * | 1981-03-06 | 1996-06-30 | Pliva Pharm & Chem Works | Process for preparing of n-methyl-11-aza-10-deoxo-10-dihydroerythromycine a and derivatives thereof |
US4474768A (en) * | 1982-07-19 | 1984-10-02 | Pfizer Inc. | N-Methyl 11-aza-10-deoxo-10-dihydro-erytromycin A, intermediates therefor |
UA27040C2 (uk) * | 1987-07-09 | 2000-02-28 | Пфайзер Інк. | Кристалічhий дигідрат азитроміциhу та спосіб одержаhhя кристалічhого дигідрату азитроміциhу |
EP0283055B1 (en) * | 1987-09-03 | 1990-08-29 | SOUR PLIVA farmaceutska, Kemijska prehrambena i kozmeticka industrija, n.sol.o. | 10-dihydro-10-deoxo-11-azaerythronolide-a-compounds, methods and intermediates for the manufacture thereof and their use in pharmaceuticals and in the manufacture thereof |
WO1989002271A1 (en) * | 1987-09-10 | 1989-03-23 | Pfizer | Azithromycin and derivatives as antiprotozoal agents |
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 |
FR2691464B1 (fr) * | 1992-05-21 | 1995-06-02 | Roussel Uclaf | Nouveaux dérivés de la 1-oxa 6-azacyclopentadécane 13,15-dione, leur procédé de préparation et leur application comme médicaments. |
WO1999000124A1 (en) * | 1997-06-26 | 1999-01-07 | Merck & Co., Inc. | 9a-azalides, compositions containing such compounds and methods of treatment |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN100381453C (zh) * | 2003-05-30 | 2008-04-16 | 葛兰素伊斯特拉齐瓦基森塔萨格勒布公司 | O-烷基大环内酯和氮杂内酯衍生物和制备这些化合物的区域选择性方法 |
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