CN115160343B - 一种雷帕霉素衍生物及其制备方法和应用 - Google Patents
一种雷帕霉素衍生物及其制备方法和应用 Download PDFInfo
- Publication number
- CN115160343B CN115160343B CN202210644186.9A CN202210644186A CN115160343B CN 115160343 B CN115160343 B CN 115160343B CN 202210644186 A CN202210644186 A CN 202210644186A CN 115160343 B CN115160343 B CN 115160343B
- Authority
- CN
- China
- Prior art keywords
- rapamycin
- ethyl
- derivative
- activity
- drug
- 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
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical class C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 229960002930 sirolimus Drugs 0.000 claims abstract description 40
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims abstract description 38
- 241000894006 Bacteria Species 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 11
- 241000233866 Fungi Species 0.000 claims abstract description 9
- 229940079593 drug Drugs 0.000 claims abstract description 9
- -1 ethyl rapamycin Chemical compound 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
- RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 241000222122 Candida albicans Species 0.000 claims description 9
- 229940095731 candida albicans Drugs 0.000 claims description 9
- 241000191967 Staphylococcus aureus Species 0.000 claims description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims description 5
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 claims description 5
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 5
- WVVLSMXNNHBIMX-UHFFFAOYSA-N CCOC(C(CC1)CCN1C#CC)=O Chemical compound CCOC(C(CC1)CCN1C#CC)=O WVVLSMXNNHBIMX-UHFFFAOYSA-N 0.000 claims description 4
- 241000588724 Escherichia coli Species 0.000 claims description 4
- 241000191963 Staphylococcus epidermidis Species 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- XXFUZSHTIOFGNV-UHFFFAOYSA-N 1-bromoprop-1-yne Chemical compound CC#CBr XXFUZSHTIOFGNV-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- DHBCPZKZOIVYER-UHFFFAOYSA-N C(=O)O.C(C)C1CCNCC1 Chemical compound C(=O)O.C(C)C1CCNCC1 DHBCPZKZOIVYER-UHFFFAOYSA-N 0.000 claims description 2
- 229940124350 antibacterial drug Drugs 0.000 claims description 2
- 230000003385 bacteriostatic effect Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 2
- 241000192023 Sarcina Species 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 5
- 230000004071 biological effect Effects 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000000338 in vitro Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000001580 bacterial effect Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 229940126062 Compound A Drugs 0.000 description 5
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- VOLGAXAGEUPBDM-UHFFFAOYSA-N $l^{1}-oxidanylethane Chemical compound CC[O] VOLGAXAGEUPBDM-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000191938 Micrococcus luteus Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 3
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 2
- 125000005999 2-bromoethyl group Chemical group 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000123650 Botrytis cinerea Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000018679 Tacrolimus Binding Proteins Human genes 0.000 description 2
- 108010027179 Tacrolimus Binding Proteins Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 238000009630 liquid culture Methods 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 235000010378 sodium ascorbate Nutrition 0.000 description 2
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 2
- 229960005055 sodium ascorbate Drugs 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-UHFFFAOYSA-N 0.000 description 1
- QSECPQCFCWVBKM-UHFFFAOYSA-N 2-iodoethanol Chemical compound OCCI QSECPQCFCWVBKM-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001153358 Micrococcus luteus NCTC 2665 Species 0.000 description 1
- 241000893976 Nannizzia gypsea Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241000187391 Streptomyces hygroscopicus Species 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003409 anti-rejection Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- 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
-
- 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
- A61P31/10—Antimycotics
-
- 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
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及药物合成领域，尤其涉及一种雷帕霉素衍生物及其制备方法和应用。所述雷帕霉素衍生物为40‑O‑(3‑(4–哌啶甲酸乙酯基)‑1H‑1,2,3‑三氮唑‑1‑基))乙基雷帕霉素，其结构式如下：
Description
技术领域
本发明涉及药物合成领域，尤其涉及一种雷帕霉素衍生物及其制备方法和应用。
背景技术
雷帕霉素(Rapamycin，RAP)，又名西罗莫司(Sirolimus)，是吸水链霉菌产生的三十六元环含氮三烯大环内酯类抗生素，其结构中包含非常特殊的被α,β-二酮已哌啶酸胺分子所掩盖的半缩酮。最初雷帕霉素产生菌在智利的复活节岛(Easter Island)上分离获得，发现其对白色念珠菌、石膏样小孢子菌及颗粒发癣菌等真菌具有显著的杀菌活性。近年来，研究人员逐渐发现雷帕霉素还具有其他治疗功效，例如免疫抑制活性、抗排斥反应作用、抗衰老、抗肿瘤、改善神经退行性疾病等，但其抗菌研究反而因此被忽视。
雷帕霉素的主要作用机制是它能与FKBP蛋白(FK506-binding protein)结合，然后再结合细胞的TOR激酶(target of rapamycin)形成复合体，使TOR激酶失去磷酸化活性而失活。TOR激酶负责调控细胞生长和凋亡，其失活后，细胞将呈现与饥饿和凋亡相似的生理表现。据研究发现雷帕霉素对番茄灰霉病菌、水稻恶苗病菌及小麦赤霉病菌等具有明显拮抗活性，并在电镜下观察到雷帕霉素能显著影响这些病菌菌丝结构，使菌丝呈现早期衰老症状，这现象与其作用机制及作用方式相符。但是未见雷帕霉素及其衍生物有抑制细菌生长的相关研究报道。
发明内容
本发明要解决的技术问题，在于提供一种雷帕霉素衍生物及其制备方法和在制备抑菌药物中的应用。
本发明是这样实现的：
本发明首先提供了一种雷帕霉素衍生物，所述雷帕霉素衍生物为40-O-(3-(4–哌啶甲酸乙酯基)-1H-1,2,3-三氮唑-1-基))乙基氧雷帕霉素，其结构式如下：
本发明还提供了所述雷帕霉素衍生物的制备方法，包括如下步骤：
步骤A：雷帕霉素与含磺酸酯基侧链(化合物2)在50-60℃下反应，制备40-卤乙基氧雷帕霉素，即化合物3。
步骤B：将40-卤乙基氧雷帕霉素(化合物3)与叠氮化钠在55-60℃下反应，制备40-O-(2-叠氮乙基)氧雷帕霉素，即化合物4；
步骤C：将4-哌啶甲酸乙酯与溴丙炔加热回流反应，制备1-丙炔基-4-哌啶甲酸乙酯，即化合物1；
步骤D：将与40-O-(2-叠氮乙基)氧雷帕霉素(化合物4)与1-丙炔基-4-哌啶甲酸乙酯(化合物1)反应，制备40-O-(3-(4–哌啶甲酸乙酯基)-1H-1,2,3-三氮唑-1-基))乙基氧雷帕霉素，即化合物A。
进一步地：
步骤A中，加入二异丙基乙胺作为缚酸剂，也可以用三乙胺、2,6-二甲基吡啶、三甲胺。
步骤A中，所述含磺酸酯基侧链的制备是通过卤乙醇与三氟甲磺酸酐反应，卤乙醇包括溴乙醇、氟乙醇、氯乙醇或碘乙醇。
步骤B中，加入催化剂碘化钾。
步骤C中，加入碳酸钠作为缚酸剂，也可以用碳酸钾、碳酸铯
步骤C中，以五水硫酸铜和抗坏血酸钠为催化体系。
最后，本发明提供了所述雷帕霉素衍生物在制备抑制细菌或真菌生长药物中的应用。
进一步地，所述真菌包括白色念珠菌、啤酒酵母。
进一步地，所述细菌包括藤黄八叠球菌、金黄色葡萄球菌、白色葡萄球菌、大肠埃希菌。
本发明具有如下优点：本发明的40-O-(3-(4–哌啶甲酸乙酯基)-1H-1,2,3-三氮唑-1-基))乙基氧雷帕霉素，体外抑菌生物学活性显示其具有一定的抗菌活性。与雷帕霉素相比，不仅具有抑制真菌的活性，还具有较好的抑制细菌的活性。
具体实施方式
实施例旨在阐述而不是限制本发明的范围。本发明中所制备化合物的核磁共振氢谱用Bruker ARX-300测定，质谱用Agi lent 1100LC/MSD测定；所用试剂均为分析纯或化学纯。
实施例1
一、雷帕霉素衍生物的制备
步骤A：C-40-(2-溴乙基)氧雷帕霉素的制备
将溴乙醇12.50g(100mmol)加入到100mL二氯甲烷溶液中，加料完毕后冷却至-30℃，加入2,6-二甲基吡啶16.10g(150mmol)，然后滴加三氟甲磺酸酐33.86g(120mmol)，磁力搅拌反应2小时。做TLC跟踪反应完全，加入1mL水后继续搅拌10分钟，将反应液倾入80mL水中，二氯甲烷提取，合并提取液再水洗，用无水硫酸钠干燥。蒸干得油状物，继续做柱层析分离，分离得到17.3g(67.58mmol)磺酸酯侧链产物，收率67.5％。
将雷帕霉素6g(6.60mmol)加入到60mL甲苯溶液中，加入5.1g(20mmol)磺酸酯侧链和8mL二异丙基乙胺(DIPEA)，升温至60℃反应3小时，做TLC跟踪反应完全后，将反应液倾入100mL水中，分别经水洗，稀盐酸、饱和碳酸氢钠和饱和食盐水萃取，有机层经无水硫酸钠干燥。蒸干得油状物4.66g(4.6mmol)，即C-40-(2-溴乙基)氧雷帕霉素，收率为69.3％，MS：1044.2(M+Na)。
步骤B：C-40-(2-叠氮乙基)氧雷帕霉素的的制备
将C-40-(2-溴乙基)氧雷帕霉素2.04g(2mmol)逐渐加入到30mL N,N-二甲基甲酰胺溶液中，在室温条件下，加入叠氮化钠的水溶液(34.4mmol,2.24g,5mL H2O)，加料完毕后，在60℃下反应1小时。反应完毕后，将反应液倒入大量水中，用乙酸乙酯萃取，萃取的有机相进行干燥减压浓缩，经柱层析(PE/Ac＝3:1)分离得到淡黄色固体1.2g(1.2mmol)，即C-40-(2-叠氮乙基)氧雷帕霉素，收率：61.2％，MS:1006.2(M+Na)。
步骤C：40-O-(3-(4–哌啶甲酸乙酯基)-1H-1,2,3-三氮唑-1-基))乙基氧雷帕霉素的制备
在100mL的单口瓶中分别加入4-哌啶甲酸乙酯(1.56g,10mmol)、溴丙炔(1.78g,15mmol)、碳酸钠(2.76g,20mmol)和100mLDMF。将反应液加热回流8小时后冷却至室温，TLC跟踪检测反应结束，减压蒸去溶剂，用200mL乙酸乙酯提取，30mL水洗有机相3次，经无水硫酸钠干燥后抽滤、减压蒸去溶剂，再柱层析分离得淡黄色液体1.5g(7.7mmol)，即1-丙炔基-4-哌啶甲酸乙酯，收率76.92％，MS:218.2(M+Na)。
在50mL干燥的圆底烧瓶中，加入C-40-(2-叠氮乙基)氧雷帕霉素0.98g(1mmo1)、2mLDMF，2mLH20溶解，然后依次加入1-丙炔基-4-哌啶甲酸乙酯0.30mg(1.5mmol)、CuSO4·5H2O 0.8mg(0.032mmol)、抗坏血酸钠22mg(0.11mmol)，室温下搅拌1个小时。TLC跟踪检测反应结束，加入100mL水，再用200mL乙酸乙酯提取，100mL水洗有机相3次，经无水硫酸钠干燥后抽滤、减压蒸去溶剂，再柱层析分离得白色粉末状物0.85g(0.73mmol)，即40-O-(3-(4–哌啶甲酸乙酯基)-1H-1,2,3-三氮唑-1-基))乙基氧雷帕霉素，收率73.4％，MS:1187.5(M+Na)。
以上柱层析均以石油醚:丙酮为洗脱剂。
化合物A的构象特征如下：
1H NMR(500MHz,CDCl3)δ7.90(s,1H),6.39(dd,J＝14.8,10.8Hz,1H),6.35–6.26(m,1H),6.14(dd,J＝15.1,10.2Hz,1H),5.97(d,J＝10.6Hz,1H),5.54(dd,J＝15.0,8.7Hz,1H),5.41(d,J＝9.9Hz,1H),5.28(d,J＝5.1Hz,1H),5.16(d,J＝4.3Hz,1H),4.52(t,J＝4.9Hz,2H),4.18(d,J＝5.4Hz,1H),4.13(dt,J＝7.0,4.8Hz,3H),3.99–3.92(m,2H),3.87(s,1H),3.84(s,2H),3.76(d,J＝5.6Hz,1H),3.66(t,J＝7.6Hz,1H),3.59–3.54(m,1H),3.43(d,J＝10.7Hz,1H),3.38(s,1H),3.36(s,2H),3.33(s,3H),3.13(d,J＝3.0Hz,3H),3.02(dd,J＝7.6,3.1Hz,4H),2.75–2.66(m,2H),2.57(dd,J＝16.8,6.5Hz,1H),2.34(d,J＝12.5Hz,4H),2.05(s,2H),2.02–1.96(m,3H),1.94–1.83(m,5H),1.76(s,4H),1.74(s,1H),1.65(s,4H),1.61(d,J＝5.3Hz,3H),1.47(s,5H),1.32(d,J＝4.6Hz,2H),1.28(s,1H),1.26(s,3H),1.25(s,2H),1.23(s,1H),1.21(s,1H),1.18(s,1H),1.15(s,2H),1.09(d,J＝6.7Hz,3H),1.05(d,J＝6.4Hz,3H),0.99(d,J＝6.4Hz,3H),0.95(d,J＝6.5Hz,3H),0.90(d,J＝6.7Hz,3H)。
13C NMR(125MHz,CDCl3)δ215.20,208.21,192.75,174.41,169.26,166.73,140.60,140.00,136.04,135.73,133.53,130.20,130.00,129.43,126.56,126.47,98.47,84.73,84.28,83.13,82.73,77.27,77.16,75.52,68.24,67.17,60.55,60.41,59.28,57.27,55.89,51.25,50.80,46.57,44.21,41.50,40.85,40.53,40.20,38.94,38.27,35.83,35.08,33.79,33.11,32.79,31.49,31.19,29.89,29.69,27.21,27.05,25.27,21.49,21.07,20.66,16.24,15.97,15.85,14.20,13.64,13.25,10.18。
二、抑菌活性应用
1、真菌
试验菌株:白假丝酵母(Candida albicans CPCC360003)、白假丝酵母(Candidaalbicans CMCC(F)98001(CICC 1965))、啤酒酵母(Saccharomyces cerevisiaeATCC9763)。
待测菌悬液的制备：将上述试验菌分别接种于SDA培养基上，置28℃培养48h后，各取1接种环新培养物分别混悬于2ml无菌生理盐水中震荡15秒，使之充分混合均匀后，用血细胞计数板计数，用SDB液体培养基稀释至1×105-5×105CFU/ml(终浓度)。
2、细菌：
试验菌株:藤黄八叠球菌(Micrococcus luteus ATCC4698)、金黄色葡萄球菌(Staphylococcus aureus ATCC 6538)、金黄色葡萄球菌(Staphylococcus aureus ATCC27217)、白色葡萄球菌Staphylococcus albus ATCC8032(CICC 10897)及大肠埃希菌CMCC(B)44102。
待测菌悬液的制备：将上述试验菌分别接种于TSA培养基上，置37℃培养18h后，各取1接种环新培养物分别混悬于2ml无菌生理盐水中震荡15秒，使之充分混合均匀后，用血细胞计数板计数，用TSB液体培养基稀释至1×105-5×105CFU/ml(终浓度)。
3、检测步骤：
(1)待测药物配置：将待测药物用DMSO稀释至200ug/ml；
(2)检测：取无菌圆底96孔板，先在各排孔中加入100ul空白液体培养液(真菌SDB培养基；细菌TSB培养基)，第1行第1孔加入100ul待测药物200ug/ml，混合均匀后，吸取第1孔100ul药液至第2孔，依次至12号孔进行倍比稀释，最后每孔添加100ul终浓度1×105-5×105CFU/ml待测菌悬液，实验设置3组平行实验，2组不加药物作为阴性对照实验。细菌(37℃培养)24h后观察结果；真菌(28℃培养)48h后观察结果。
(3)结果判断:检查对照管的受试菌生长情况是否良好，肉眼观察，药物最低浓度管无菌生长者，即为受试菌的MIC。
4、结果：
表1药物的抑菌活性
检测结果(见表1)表明在对真菌方面，化合物A稍弱于Rapamycin。具体表现为白色念珠菌CPCC360003、白色念珠菌CMCC(F)98001及啤酒酵母ATCC9763对化合物A及Rapamycin敏感，显示其具有一定的抗真菌活性。在细菌方面，化合物A强于Rapamycin，具体表现为金黄色葡萄球菌ATCC6538、金黄色葡萄球菌ATCC 27217对化合物A敏感，藤黄八叠球菌ATCC4698、白色葡萄球菌8032对化合物A介于耐药与敏感之间，大肠埃希菌CMCC(B)44102对化合物A耐药，但在检测范围内，各细菌测试菌均对Rapamycin耐药。表明化合物A具有较好的抗细菌活性。
虽然以上描述了本发明的具体实施方式，但是熟悉本技术领域的技术人员应当理解，我们所描述的具体的实施例只是说明性的，而不是用于对本发明的范围的限定，熟悉本领域的技术人员在依照本发明的精神所作的等效的修饰以及变化，都应当涵盖在本发明的权利要求所保护的范围内。
Claims (3)
1.一种雷帕霉素衍生物，其特征在于：所述雷帕霉素衍生物为40-O-(3-(4–哌啶甲酸乙酯基)-1H-1,2,3-三氮唑-1-基))乙基雷帕霉素，其结构式如下：
2.一种如权利要求1所述的雷帕霉素衍生物的制备方法，其特征在于：包括如下步骤：
步骤A：雷帕霉素与含磺酸酯基侧链在50-60℃下反应，制备40-卤乙基氧雷帕霉素；
步骤B：将40-卤乙基氧雷帕霉素与叠氮化钠在55-60℃下反应，制备40-O-(2-叠氮乙基)雷帕霉素；
步骤C：将4-哌啶甲酸乙酯与溴丙炔加热回流反应，制备1-丙炔基-4-哌啶甲酸乙酯；
步骤D：将40-O-(2-叠氮乙基)雷帕霉素与1-丙炔基-4-哌啶甲酸乙酯反应，制备40-O-(3-(4–哌啶甲酸乙酯基)-1H-1,2,3-三氮唑-1-基))乙基雷帕霉素。
3.一种如权利要求1所述的雷帕霉素衍生物在制备抑菌药物中的应用，其特征在于：所述抑菌药物为抑制细菌或抑制真菌的药物；所述真菌为白色念珠菌或啤酒酵母；所述细菌为藤黄八叠球菌、金黄色葡萄球菌、白色葡萄球菌或大肠埃希菌。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210644186.9A CN115160343B (zh) | 2022-06-09 | 2022-06-09 | 一种雷帕霉素衍生物及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210644186.9A CN115160343B (zh) | 2022-06-09 | 2022-06-09 | 一种雷帕霉素衍生物及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115160343A CN115160343A (zh) | 2022-10-11 |
| CN115160343B true CN115160343B (zh) | 2023-11-14 |
Family
ID=83486111
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210644186.9A Active CN115160343B (zh) | 2022-06-09 | 2022-06-09 | 一种雷帕霉素衍生物及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115160343B (zh) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5262423A (en) * | 1992-10-29 | 1993-11-16 | American Home Products Corporation | Rapamycin arylcarbonyl and alkoxycarbonyl carbamates as immunosuppressive and antifungal agents |
| CN104327097A (zh) * | 2014-10-11 | 2015-02-04 | 福建省微生物研究所 | 雷帕霉素的三氮唑衍生物和用途 |
| CN104341434A (zh) * | 2014-10-16 | 2015-02-11 | 福建省微生物研究所 | 取代的雷帕霉素三氮唑衍生物和用途 |
| CN104854112A (zh) * | 2012-11-30 | 2015-08-19 | 杭州归创生物医药有限公司 | 雷帕霉素类似物及其制备方法 |
| CN107501294A (zh) * | 2017-05-17 | 2017-12-22 | 福建省微生物研究所 | 雷帕霉素胍基衍生物和用途 |
| CN107827908A (zh) * | 2017-11-20 | 2018-03-23 | 福建省微生物研究所 | 一种雷帕霉素三氮唑衍生物及其制备方法和用途 |
| CN108484637A (zh) * | 2018-03-13 | 2018-09-04 | 福建省微生物研究所 | 靶向抗癌新药x-76成盐化合物及其用途、制备方法 |
| CN111388427A (zh) * | 2020-04-09 | 2020-07-10 | 类承斌 | 一种治疗胰腺癌用特异靶向药剂配方及其制备工艺 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110098241A1 (en) * | 2008-04-14 | 2011-04-28 | Poniard Pharmaceuticals, Inc. | Rapamycin analogs as anti-cancer agents |
-
2022
- 2022-06-09 CN CN202210644186.9A patent/CN115160343B/zh active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5262423A (en) * | 1992-10-29 | 1993-11-16 | American Home Products Corporation | Rapamycin arylcarbonyl and alkoxycarbonyl carbamates as immunosuppressive and antifungal agents |
| CN104854112A (zh) * | 2012-11-30 | 2015-08-19 | 杭州归创生物医药有限公司 | 雷帕霉素类似物及其制备方法 |
| CN104327097A (zh) * | 2014-10-11 | 2015-02-04 | 福建省微生物研究所 | 雷帕霉素的三氮唑衍生物和用途 |
| CN104341434A (zh) * | 2014-10-16 | 2015-02-11 | 福建省微生物研究所 | 取代的雷帕霉素三氮唑衍生物和用途 |
| CN107501294A (zh) * | 2017-05-17 | 2017-12-22 | 福建省微生物研究所 | 雷帕霉素胍基衍生物和用途 |
| CN107827908A (zh) * | 2017-11-20 | 2018-03-23 | 福建省微生物研究所 | 一种雷帕霉素三氮唑衍生物及其制备方法和用途 |
| CN108484637A (zh) * | 2018-03-13 | 2018-09-04 | 福建省微生物研究所 | 靶向抗癌新药x-76成盐化合物及其用途、制备方法 |
| CN111388427A (zh) * | 2020-04-09 | 2020-07-10 | 类承斌 | 一种治疗胰腺癌用特异靶向药剂配方及其制备工艺 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115160343A (zh) | 2022-10-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| UA125800C2 (uk) | Похідні азахіноліну | |
| Hallock et al. | Triticones, spirocyclic lactams from the fungal plant pathogen Drechslera tritici-repentis | |
| CN115160343B (zh) | 一种雷帕霉素衍生物及其制备方法和应用 | |
| CN110551072A (zh) | 具有抑制dna拓扑异构酶活性的喹噁啉-n1,n4-二氧化物衍生物、制备方法及应用 | |
| CN101691368A (zh) | 喹啉酮生物碱衍生物的脱水甲基化产物及制备方法与应用 | |
| CN111269220A (zh) | 具有胡椒碱骨架结构化合物、制备及其应用 | |
| CN104725447A (zh) | 一种3-S-四羟基-β-D-葡萄糖苷-1,2,4-三唑类化合物 | |
| US9944607B2 (en) | Thiohydantoin derivatives and uses thereof | |
| CN114920717A (zh) | 海松烷二萜化合物及其制备方法与应用 | |
| CN111011388B (zh) | 一种二甲基黄青霉素在抗植物致病真菌中的应用 | |
| CN110862374B (zh) | 一种萘酰亚胺苯并咪唑类化合物及其制备方法与应用 | |
| CN114539161A (zh) | 一种奥拉帕尼-尿素共晶及其制备方法 | |
| CN108342325B (zh) | 一种蝉虫草来源的蒽醌类化合物及其制备方法和应用 | |
| CN101265214B (zh) | 甲基黄青霉素酯及其盐类、其制备方法和应用、以及药物组合物 | |
| CN107746423B (zh) | 麦角甾-7，22-二烯-3-酮肟及其制备方法和在制备抗菌药物中的应用 | |
| US20080096856A1 (en) | Antibiotic Compound | |
| EP1644380B1 (en) | Biologically active neopeltolide compounds | |
| CN113620882B (zh) | 一种含硒咪唑类化合物及其在制备抗菌药物中的应用 | |
| CN115160213B (zh) | 一种大黄酸吡啶季铵盐类化合物及其合成方法和应用 | |
| CN112521435B (zh) | 一种罗红霉素类似物在制备抗菌药物中的应用 | |
| RU2806097C1 (ru) | Противотуберкулезное средство на основе 4'-гидрокси-1'-(2-гидроксифенил)-3'-ацил-спиро[бензо[b][1,4]тиазин-2,2'-пиррол]-3,5'(1'H,4H)-дионов | |
| CN116283867A (zh) | 氮杂取代苍耳亭或氯代苍耳亭类衍生物及其应用 | |
| CN112239483B (zh) | 一种化合物及药物组合物 | |
| WO2022253297A1 (zh) | 一种阿尼芬净衍生物的制备方法 | |
| CN100500668C (zh) | 格尔德霉素衍生物及其制备方法和制备药物的用途 |
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 |