WO2023274313A1 - 两性霉素b半合成衍生物及其制备方法和用途 - Google Patents

两性霉素b半合成衍生物及其制备方法和用途 Download PDF

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WO2023274313A1
WO2023274313A1 PCT/CN2022/102461 CN2022102461W WO2023274313A1 WO 2023274313 A1 WO2023274313 A1 WO 2023274313A1 CN 2022102461 W CN2022102461 W CN 2022102461W WO 2023274313 A1 WO2023274313 A1 WO 2023274313A1
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French (fr)
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杨玉社
潜安然
郑亚洲
马慧君
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中国科学院上海药物研究所
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, and more specifically, the invention relates to a semi-synthetic derivative of amphotericin B, a synthesis method thereof and an application thereof in treating fungal infectious diseases.
  • invasive fungal infection accounts for a relatively low proportion of fungal infections, it has been widely valued because of its high mortality and morbidity.
  • invasive fungal infection has become one of the important causes of death from major diseases such as AIDS and malignant tumors clinically, and has risen to the third largest infectious disease, which seriously threatens human life and causes human health and economy. Huge damage.
  • Amphotericin B was the first drug used to treat invasive fungal infections, and it has been used clinically since the 1950s.
  • the advantages of amphotericin B are: broad antibacterial spectrum, strong antibacterial activity, bactericidal effect at high concentrations, low incidence of acquired drug resistance observed clinically, and is still the last treatment for severe invasive aspergillus infection. means.
  • the application of AmB is limited by its poor water solubility and serious side effects, such as hemolytic toxicity, nephrotoxicity, and infusion site-related reactions. Due to the toxic and side effects of amphotericin B (especially hemolytic toxicity and nephrotoxicity), its therapeutic window is very narrow, and its clinically administered dosage often cannot reach its optimal therapeutic concentration. Based on this, currently amphotericin B is generally only used for the treatment of life-threatening invasive fungal infections.
  • the second solution is to modify the structure of amphotericin B, conduct structure-activity relationship research and structure-toxicity relationship research, control and improve or even eliminate its toxicity from the source, so as to develop the next generation of high activity and low toxicity polyene antifungal drugs. Due to the relatively complex structure of amphotericin B, structural modification of amphotericin B is generally carried out at the carboxyl end of the macrocycle and the amino end of trehalose.
  • the present invention provides a class of amphotericin B bisamidated modified derivatives with novel structure, stronger antibacterial activity and greatly reduced hemolytic activity.
  • the compound of the invention is novel in structure, and its therapeutic index is significantly better than that of amphotericin B, and it may become a new type of antifungal drug with high efficiency and low toxicity.
  • the first aspect of the present invention provides a compound described in the following formula V, or a pharmaceutically acceptable salt thereof:
  • Each R 1 is independently selected from the group consisting of -NR 4 -(L) p -Ra; wherein, Ra is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 amino, -NH 2 , substituted or unsubstituted -NH-C 1 -C 10 alkyl, substituted or unsubstituted -NH-C (O)C 1 -C 10 alkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted benzo 5-6 membered heteroaryl Base, and -COR 3 ;
  • L is selected from the group consisting of (CH 2 ) n , (CH 2 OCH 2 ) m , NH, NHC(O); wherein, when each of CH 2 and NH appears alone or as part of other groups, it can be optionally replaced;
  • Each R 2 is independently selected from the following group: H, -C(O)(L) p -Rc; wherein, each Rc is independently selected from the following group: (CH 2 ) n NHR 4 , NHR 4 , or substituted or not A substituted 3-8 membered heterocyclic group (preferably a nitrogen-containing heterocyclic group); and when R 2 is H, R 1 is -NR 4 -(L) p -Ra, and at least one L in the R 1 group is NH or NHC(O);
  • Each R 3 is independently selected from the group consisting of NH 2 , substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted five-membered or six-membered heteroaryl, or Substituted or unsubstituted benzo five-membered or six-membered heteroaryl;
  • Each R 4 is independently selected from the following group: H, substituted or unsubstituted C 1 -C 6 alkyl;
  • R 4 and (L) p -Ra and the connected N atoms together constitute a substituted or unsubstituted 5-12 membered heterocyclic group, or a substituted or unsubstituted 5-12 membered heteroaryl group;
  • the The 5-12-membered heterocyclic group or the 5-12-membered heteroaryl group may have one Rb substituent, and the Rb substituent is selected from the group consisting of hydroxyl, unsubstituted or hydroxyl-substituted C 1 -C 10 alkyl, Substituted or unsubstituted 5-12 membered heterocyclic groups;
  • p is selected from the group consisting of 0, 1, 2 or 3;
  • n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • substituted means that one or more hydrogen atoms on the group are replaced by substituents selected from the following group: halogen, oxo, carboxyl, cyano, hydroxyl, 5-6 membered heterocycle, C1- C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl substitution, amino, N,N-dimethylamino, mercapto, C 1 -C 6 sulfone, -(CH 2 OCH 2 ) n OH, (CH 2 OCH 2 ) n OR 4 , (CH 2 OCH 2 ) n NH 2 , (CH 2 OCH 2 ) n NHR 4 , (CH 2 OCH 2 ) n N(R 4 ) 2 .
  • each of the R 1s is independently selected from the following group: -NR 4 -(L) p -Ra; wherein, Ra is selected from the following group: -NH 2 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -COR 3 ;
  • L is selected from the group consisting of (CH 2 ) n , (CH 2 OCH 2 ) m , NH, NHC(O); wherein, when each of CH 2 and NH appears alone or as part of other groups, it can be optionally replaced;
  • p is 0 or 1;
  • Each R 4 is independently selected from the following group: H, substituted or unsubstituted C 1 -C 6 alkyl;
  • R 4 and (L) p -Ra and the connected N atoms together constitute a substituted or unsubstituted 5-12 membered heterocyclic group, or a substituted or unsubstituted 5-12 membered heteroaryl group; wherein, the The 5-12-membered heterocyclic group or the 5-12-membered heteroaryl group may have a Rb substituent, and the Rb substituent is selected from the group consisting of hydroxyl, unsubstituted or hydroxyl-substituted C1-C10 alkyl, substituted or Unsubstituted 5-12 membered heterocyclic group.
  • the R 2s are each independently selected from the following group: H, -C(O)(L) p -Rc; wherein, each Rc is independently selected from the following group: NHR 4 , or substituted Or an unsubstituted 3-8 membered heterocyclic group (preferably a nitrogen-containing heterocyclic group);
  • L is selected from the group consisting of (CH 2 ) n , (CH 2 OCH 2 ) m , NH, NHC(O); wherein, when each of CH 2 and NH appears alone or as part of other groups, it can be optionally replaced;
  • p 0 or 1.
  • said n is selected from the group: 0, 1, 2, 3, 4 or 5.
  • said m is selected from the group consisting of 0, 1, 2, 3, 4 or 5.
  • the R 1 is selected from the group consisting of -NR 4 (CH 2 ) n R 5 , -NHCH 2 CH 2 NH 2 ,
  • R 5 is selected from the following group: H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 5-12 membered heterocyclic group;
  • R 6 is selected from the group consisting of H, OH, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 5-12 membered heterocyclic group.
  • the R 2 is selected from the following group: -CO(CH 2 ) n NHR 4 , -CO(CH 2 OCH 2 ) m (CH 2 ) n NHR 4 ,
  • the substituted alkyl group is selected from the group consisting of C 1 -C 6 alkyl, N,N-dimethylamino, mercapto, and C 1 -C 6 alkyl substituted by sulfone.
  • R2 is selected from the following group:
  • said R is selected from the following group:
  • R2 is selected from the following group:
  • the compound is selected from the following table:
  • the second aspect of the present invention provides a method for preparing the compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, the method comprising the steps of:
  • the protecting group is removed with the compound M-2 to obtain the compound of formula V;
  • the method also includes steps (1) and (2):
  • the PG is an amine protecting group
  • the R2' is selected from the following group: chemical bond, -C (O)(L) p -Rc'; wherein, Rc' is formed by the loss of a hydrogen atom from Rc group; and when R 2 ' is a chemical bond, R 1 is -NR 4 -(L) p -Ra, and at least one L in the R 1 group is NH or NHC(O);
  • the amino group N connected to the PG and its linker constitutes a carbamate, amide, N-alkylamine or N-arylamine.
  • the above-mentioned protecting group is selected from Fmoc, Boc, Cbz, Alloc, Teoc, methoxycarbonyl or ethoxycarbonyl, Tfa, Pht, Tos, Ns, pivaloyl, benzoyl, Bn, PMB, Trt, Dmb; more preferably selected from the group consisting of Fmoc, Boc, Tos, Cbz.
  • the third aspect of the present invention provides a method for preparing the compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, the method comprising the steps of:
  • the method also includes steps (a) and (b):
  • the PG is an amino protecting group
  • the R 1 ' is a group formed by R 1 losing one H atom
  • the R 2 ' is selected from the following group: chemical bond, -C(O)(L) p -Rc'; wherein, Rc' is a group formed by Rc losing a hydrogen atom; and when R 2 ' is a chemical bond, R 1 is -NR 4 -(L) p -Ra, and at least one L in the R 1 group is NH or NHC(O);
  • the fourth aspect of the present invention provides a pharmaceutical composition, which comprises the following components:
  • the fifth aspect of the present invention provides a use of the compound described in the first aspect of the present invention, or its optical isomers, pharmaceutically acceptable salts, hydrates, and solvates thereof, characterized in that, for A pharmaceutical composition for preventing or treating infectious diseases caused by fungal infections is prepared.
  • the fungus is selected from the group consisting of Candida, Cryptococcus neoformans, Aspergillus (preferably Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger), combined bacteria, dermatophytes, or a combination thereof.
  • the sixth aspect of the present invention provides a preparation intermediate of the compound of formula V as described in the first aspect of the present invention, and the intermediate is selected from the following group:
  • the PG is an amine protecting group, and the amine N connected to it constitutes a carbamate, amide, N-alkylamine or N-arylamine.
  • the above-mentioned protecting group is selected from Fmoc, Boc, Cbz, Alloc, Teoc, methoxycarbonyl or ethoxycarbonyl, Tfa, Pht, Tos, Ns, pivaloyl, benzoyl, Bn, PMB, Trt, Dmb;
  • Fmoc, Boc, Tos, Cbz Preferably selected from the group: Fmoc, Boc, Tos, Cbz; more preferably Fmoc;
  • the R 1 ' is a group formed by R 1 losing a H atom
  • R 2 ' is selected from the following group: chemical bond, -C(O)(L) p -Rc'; wherein, Rc' is Rc losing a hydrogen A group formed by atoms; and when R 2 ' is a chemical bond, R 1 is -NR 4 -(L) p -Ra, and at least one L in the R 1 group is NH or NHC(O); the remaining groups
  • R 1 is a group formed by R 1 losing a H atom
  • R 2 ' is selected from the following group: chemical bond, -C(O)(L) p -Rc'; wherein, Rc' is Rc losing a hydrogen A group formed by atoms
  • R 2 ' is a chemical bond
  • R 1 is -NR 4 -(L) p -Ra, and at least one L in the R 1 group is NH or NHC(O); the remaining groups
  • the inventor has synthesized a series of compounds through extensive research, and through antibacterial activity screening and pharmacokinetic screening, it is first found that the following general formula (I) represents that the compound has strong antibacterial activity and good pharmacokinetics It is especially suitable as a drug for anti-infection treatment.
  • the present inventors have completed the present invention on this basis.
  • the halogen is F, Cl, Br or I.
  • C1-C6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, including without limitation methyl, ethyl, propyl, isopropyl, butyl, base, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • C1-C6 alkoxy refers to a straight-chain or branched alkoxy group with 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, Isopropoxy and butoxy, etc.
  • C2-C6 alkenyl refers to a straight chain or branched chain alkenyl group with 2 to 6 carbon atoms containing a double bond, including non-limiting ethenyl, propenyl, butenyl , Isobutenyl, Pentenyl and Hexenyl etc.
  • C2-C6 alkynyl refers to a straight-chain or branched-chain alkynyl group with 2 to 6 carbon atoms containing a triple bond, including without limitation ethynyl, propynyl, butynyl, group, isobutynyl, pentynyl and hexynyl, etc.
  • C3-C10 cycloalkyl refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, cycloheptyl, cyclooctyl and cyclodecyl, etc.
  • C3-C8 cycloalkyl “C3-C7 cycloalkyl”
  • C3-C6 cycloalkyl have similar meanings.
  • C3-C10 cycloalkenyl refers to a cyclic alkenyl group having 3 to 10 carbon atoms in the ring, including without limitation cyclopropenyl, cyclobutenyl, cyclopentenyl , cyclohexenyl, cycloheptenyl, cyclooctenyl and cyclodecylene, etc.
  • C3-C7 cycloalkenyl has a similar meaning.
  • aryl ring or “aryl” has the same meaning, preferably "aryl” is “C6-C12 aryl” or “C6-C10 aryl”.
  • C6-C12 aryl refers to an aromatic ring group having 6 to 12 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl and the like.
  • C6-C10 aryl has a similar meaning.
  • heteroaryl has the same meaning and refers to a heteroaromatic group containing one to more heteroatoms.
  • the heteroatoms referred to herein include oxygen, sulfur and nitrogen.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • 3-12 membered heterocyclic group refers to a saturated or unsaturated 3-12 membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, for example Dioxolyl, etc.
  • 3-7 membered heterocyclyl has a similar meaning.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • a cyclic substituent, such as a heterocycloalkyl can be attached to another ring, such as a cycloalkyl, to form a spirobicyclic ring system, eg, two rings having a common carbon atom.
  • substituents contemplated by this invention are those that are stable or chemically feasible.
  • the substituents are for example (but not limited to): C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, Heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, amino, alkoxy, C1-10 sulfonyl, etc.
  • protecting group refers to a group that protects the substituted or unsubstituted amino group at the non-reactive site in the reaction, so that the amino group N connected to it forms a carbamate, amide, N-alk arylamines or N-arylamines, such as Fmoc, Boc, Cbz, Alloc, Teoc, methoxycarbonyl or ethoxycarbonyl, Tfa, Pht, Tos, Ns, pivaloyl, benzoyl, Bn, PMB, Trt, Dmb et al.
  • a pharmaceutically acceptable salt refers to a salt formed of a compound of the present invention and an inorganic acid or an organic acid.
  • the above-mentioned inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, and the above-mentioned organic acid is selected from chiral isomers or Racemic glutamic acid, L-glutamic acid, DL-aspartic acid, proline, alanine, citric acid, L-malic acid, tartaric acid, mandelic acid, lactic acid, succinic acid, deoxycholic acid , benzoic acid, or acetic acid, oxalic acid, maleic acid, fumaric acid.
  • Another aspect of the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound selected from the above general formula V, its pharmaceutically acceptable salts, enantiomers, diastereoisomers or exosomes One or more of the racemates, and optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and/or diluents.
  • the excipients are, for example, flavoring agents, flavoring agents, sweetening agents, and the like.
  • the pharmaceutical composition provided by the present invention preferably contains active ingredients in a weight ratio of 1-99%, and its preferred ratio is that the compound of general formula V accounts for 35wt% to 99wt% of the total weight as the active ingredient, and the rest is pharmaceutically acceptable carrier, diluent or solution or saline solution.
  • the compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or diluents Neutralize in suitable sterile equipment for injection or infusion.
  • the unit dose of the preparation formula contains 1 mg-700 mg of the compound of general formula V, preferably, the unit dose of the preparation formula contains 5 mg-300 mg of the compound of general formula V.
  • the compounds and pharmaceutical compositions of the present invention can be clinically used in mammals, including humans and animals, and can be administered through oral, nasal, dermal, pulmonary or gastrointestinal routes. Oral administration is most preferred.
  • the most preferred daily dose is 0.1-140 mg/kg body weight, taken once, or 0.1-70 mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dosage for an individual should depend on the specific treatment. Usually, start with a small dose and gradually increase the dose until you find the most suitable dose.
  • the present invention also provides a fungal infection inhibitor, which comprises a compound selected from the above general formula V, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or their One or more of the mixtures, and optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and/or diluents.
  • a fungal infection inhibitor which comprises a compound selected from the above general formula V, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or their One or more of the mixtures, and optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and/or diluents.
  • the compounds and compositions of the present invention can be used to inhibit fungi, and thus can be used as therapeutic drugs for diseases or conditions associated with fungal infections, such as Candida, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, conjunctiva, dermatophytes Wait.
  • diseases or conditions associated with fungal infections such as Candida, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, conjunctiva, dermatophytes Wait.
  • another aspect of the present invention provides compounds represented by the above general formula, their pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or their mixtures for the preparation of Diseases related to fungal infection, such as application in medicine for diseases related to fungal infection such as Candida albicans, Candida krusei, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Aspergillus fumigatus and the like.
  • Another aspect of the present invention provides a method for treating diseases associated with fungal infections, which comprises administering a compound selected from the above general formula V, its pharmaceutically acceptable salts, racemic compounds to patients in need of the treatment.
  • a compound selected from the above general formula V its pharmaceutically acceptable salts, racemic compounds to patients in need of the treatment.
  • 1 H-NMR is recorded by Varian Mercury 400 nuclear magnetic resonance instrument or Varian Mercury 600 nuclear magnetic resonance instrument, and the chemical shift is expressed in ⁇ (ppm); low-resolution mass spectrum is determined by Finnigan MAT95 type mass spectrometer; column chromatography uses silica gel It is 200-300 mesh.
  • FmocOSu 9-fluorenylmethyl-N-succinimidyl carbonate
  • DMA N,N-dimethylacetamide
  • HPLC high performance liquid Phase chromatography
  • DMSO dimethylsulfoxide
  • PyAOP (3H-1,2,3-triazolo[4,5-B]pyridin-3-oxyl)tris-1-pyrrolidinyl hexafluorophosphate
  • TLC thin-layer chromatography
  • HONSu N-hydroxysuccinimide
  • DCC dicyclohexylcarbodiimide
  • PyBOP 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate salt
  • DIPEA N,N-diisopropylethylamine
  • DMF N,N-dimethylformamide.
  • step 1
  • Amphotericin B (2.26g, 2.446mmol, 1eq), FmocOSu (1.5g, 4.4mmol, 1.8eq) and pyridine (0.6mL, 7.4mmol, 3eq) were sequentially added to a single-necked bottle containing DMA (220mL), The outer wall of the one-necked bottle was wrapped with aluminum foil, protected by argon, stirred overnight at room temperature, and the reaction progress was monitored by HPLC. After the reaction was complete, the reaction solution was poured into vigorously stirred methyl tert-butyl ether (1000 mL), filtered under normal pressure, and the filter cake was the crude product of compound 1-2.
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 1-2 (180mg, 0.157mmol, 1eq), PyAOP (130mg, 0.25mmol, 1.6eq), ethoxyacylhydrazine (28mg, 0.314mmol , 2eq) and N-methylmorpholine (47.6mg, 0.471mmol, 3eq) were used as raw materials to obtain compound 2-1 (90mg) as a pale yellow solid.
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 1-2 (180mg, 0.157mmol, 1eq), PyAOP (130mg, 0.25mmol, 1.6eq), aminoacylhydrazine (24mg, 0.314mmol, 2eq ) and N-methylmorpholine (47.6mg, 0.471mmol, 3eq) were used as raw materials to obtain compound 3-1 (85mg) as a pale yellow solid.
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 1-2 (180mg, 0.157mmol, 1eq), PyAOP (130mg, 0.25mmol, 1.6eq), phenylhydrazine (43mg, 0.314mmol, 2eq) and N-methylmorpholine (47.6mg, 0.471mmol, 3eq) were used as raw materials to synthesize compound 4-1 (102mg) as a pale yellow solid.
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 1-2 (180mg, 0.157mmol, 1eq), PyAOP (130mg, 0.25mmol, 1.6eq), pyridine-3-acylhydrazine (43mg, 0.314 mmol, 2eq) and N-methylmorpholine (47.6mg, 0.471mmol, 3eq) were used as raw materials to synthesize compound 5-1 (100mg) as a pale yellow solid.
  • 1-2 180mg, 0.157mmol, 1eq
  • PyAOP 130mg, 0.25mmol, 1.6eq
  • pyridine-3-acylhydrazine 43mg, 0.314 mmol, 2eq
  • N-methylmorpholine 47.6mg, 0.471mmol, 3eq
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 1-2 (180mg, 0.157mmol, 1eq), PyAOP (130mg, 0.25mmol, 1.6eq), pyrazinylacylhydrazine (43mg, 0.314mmol , 2eq) and N-methylmorpholine (47.6mg, 0.471mmol, 3eq) were used as raw materials to obtain compound 6-1 (86mg) as a pale yellow solid.
  • 1-2 180mg, 0.157mmol, 1eq
  • PyAOP 130mg, 0.25mmol, 1.6eq
  • pyrazinylacylhydrazine 43mg, 0.314mmol , 2eq
  • N-methylmorpholine 47.6mg, 0.471mmol, 3eq
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 1-2 (180mg, 0.157mmol, 1eq), PyAOP (130mg, 0.25mmol, 1.6eq), furan-2-acylhydrazine (40mg, 0.314 mmol, 2eq) and N-methylmorpholine (47.6mg, 0.471mmol, 3eq) were used as raw materials to synthesize compound 7-1 (112mg) as a pale yellow solid.
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 1-2 (180mg, 0.157mmol, 1eq), PyAOP (130mg, 0.25mmol, 1.6eq), hydrazine (32mg, 0.314mmol, 2eq) Using N-methylmorpholine (47.6mg, 0.471mmol, 3eq) as raw material, compound 8-1 (91mg) was synthesized as a pale yellow solid.
  • step 1
  • step 2 in Example 1 compound 9-2 (200mg, 0.164mmol, 1eq), PyAOP (137mg, 0.262mmol, 1.6eq), methylacylhydrazine (24mg, 0.328mmol, 2eq) and N -Methylmorpholine (50mg, 0.492mmol, 3eq) was sequentially added to a one-necked bottle containing DMA (5mL), the outer wall of the one-necked bottle was wrapped with aluminum foil, protected by argon, stirred overnight at room temperature, and the reaction progress was monitored by HPLC.
  • step 3 in Example 1 compound 9-3 (101mg) and piperidine (0.1mL) were sequentially added to a one-necked bottle filled with DMSO (3mL), the outer wall of the one-necked bottle was wrapped with aluminum foil, and argon protection, stirred the reaction at room temperature for 2 hours, and monitored the progress of the reaction by HPLC. After the reaction was complete, the reaction solution was poured into vigorously stirred methyl tert-butyl ether (100mL), filtered, and the resulting solid was washed with methyl tert-butyl ether (40mL x 2), filtered, and vacuum-dried to obtain the target Product V-9 (31 mg), pale yellow solid.
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 9-2 (200mg, 0.164mmol, 1eq), PyAOP (137mg, 0.262mmol, 1.6eq), 3-amino-1,2-propanediol ( 30mg, 0.328mmol, 2eq) and N-methylmorpholine (50mg, 0.492mmol, 3eq) were used as raw materials to synthesize compound 10-1 (96mg) as a pale yellow solid.
  • 9-2 200mg, 0.164mmol, 1eq
  • PyAOP 137mg, 0.262mmol, 1.6eq
  • 3-amino-1,2-propanediol 30mg, 0.328mmol, 2eq
  • N-methylmorpholine 50mg, 0.492mmol, 3eq
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 9-2 (200mg, 0.164mmol, 1eq), PyAOP (137mg, 0.262mmol, 1.6eq), 4-hydroxypiperidine (33mg, 0.328mmol , 2eq) and N-methylmorpholine (50mg, 0.492mmol, 3eq) were used as raw materials to obtain compound 11-1 (97mg) as a pale yellow solid.
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 9-2 (200mg, 0.164mmol, 1eq), PyAOP (137mg, 0.262mmol, 1.6eq), 1-(2-hydroxyethyl)piperidine Using oxazine (43mg, 0.328mmol, 2eq) and N-methylmorpholine (50mg, 0.492mmol, 3eq) as raw materials, compound 12-1 (97mg) was synthesized as a pale yellow solid.
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 9-2 (200mg, 0.164mmol, 1eq), PyAOP (137mg, 0.262mmol, 1.6eq), 1-(3-hydroxypropyl)piperene Using oxazine (47mg, 0.328mmol, 2eq) and N-methylmorpholine (50mg, 0.492mmol, 3eq) as raw materials, compound 13-1 (102mg) was synthesized as a pale yellow solid.
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 9-2 (200mg, 0.164mmol, 1eq), PyAOP (137mg, 0.262mmol, 1.6eq), 1-(2,2-dimethyl -2-Hydroxyethyl)piperazine (52mg, 0.328mmol, 2eq) and N-methylmorpholine (50mg, 0.492mmol, 3eq) were used as raw materials to synthesize compound 14-1 (95mg) as a pale yellow solid.
  • 9-2 200mg, 0.164mmol, 1eq
  • PyAOP 137mg, 0.262mmol, 1.6eq
  • 1-(2,2-dimethyl -2-Hydroxyethyl)piperazine 52mg, 0.328mmol, 2eq
  • N-methylmorpholine 50mg, 0.492mmol, 3eq
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 9-2 (200mg, 0.164mmol, 1eq), PyAOP (137mg, 0.262mmol, 1.6eq), 1-(1,1-dimethyl -2-Hydroxyethyl)piperazine (52mg, 0.328mmol, 2eq) and N-methylmorpholine (50mg, 0.492mmol, 3eq) were used as raw materials to synthesize compound 15-1 (100mg) as a pale yellow solid.
  • 9-2 200mg, 0.164mmol, 1eq
  • PyAOP 137mg, 0.262mmol, 1.6eq
  • 1-(1,1-dimethyl -2-Hydroxyethyl)piperazine 52mg, 0.328mmol, 2eq
  • N-methylmorpholine 50mg, 0.492mmol, 3eq
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 9-2 (200mg, 0.164mmol, 1eq), PyAOP (137mg, 0.262mmol, 1.6eq), 4-(4-piperidinyl)morphine Phenyl (56mg, 0.328mmol, 2eq) and N-methylmorpholine (50mg, 0.492mmol, 3eq) were used as raw materials to synthesize compound 16-1 (112mg) as a pale yellow solid.
  • 9-2 200mg, 0.164mmol, 1eq
  • PyAOP 137mg, 0.262mmol, 1.6eq
  • 4-(4-piperidinyl)morphine Phenyl 56mg, 0.328mmol, 2eq
  • N-methylmorpholine 50mg, 0.492mmol, 3eq
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 9-2 (200mg, 0.164mmol, 1eq), PyAOP (137mg, 0.262mmol, 1.6eq), 2,6-dimethyl-1- (2-Hydroxyethyl)piperazine (52mg, 0.328mmol, 2eq) and N-methylmorpholine (50mg, 0.492mmol, 3eq) were used as raw materials to synthesize compound 17-1 (102mg light yellow solid).
  • 9-2 200mg, 0.164mmol, 1eq
  • PyAOP 137mg, 0.262mmol, 1.6eq
  • 2,6-dimethyl-1- (2-Hydroxyethyl)piperazine 52mg, 0.328mmol, 2eq
  • N-methylmorpholine 50mg, 0.492mmol, 3eq
  • step 1
  • step 1 in Example 1 using DMA as a solvent, amphotericin B (2.26g, 2.446mmol, 1eq), 18-1 (1.7g, 4.4mmol, 1.8eq; Chemical Science.2014, 5 , 2747-2753) and pyridine (0.6mL, 7.4mmol, 3eq) were used as raw materials to obtain compound 18-2 (1.02g) as a pale yellow solid.
  • step 2 in Example 1 using DMA as a solvent, 18-2 (200mg, 0.166mmol, 1eq), PyAOP (139mg, 0.266mmol, 1.6eq), 1-(2-hydroxyethyl)piper Using oxazine (42mg, 0.332mmol, 2eq) and N-methylmorpholine (50mg, 0.498mmol, 3eq) as raw materials, compound 18-3 (115mg) was synthesized as a pale yellow solid.
  • step 1
  • step 2 in Example 1 using DMSO as a solvent, 19-7 (200mg, 0.166mmol, 1eq), PyAOP (139mg, 0.266mmol, 1.6eq), 1-(2-hydroxyethyl)piper Using oxazine (42mg, 0.332mmol, 2eq) and N-methylmorpholine (50mg, 0.498mmol, 3eq) as raw materials, compound 19-8 (103mg) was synthesized as a pale yellow solid.
  • step 1
  • step 1 in Example 1 using DMA as a solvent, amphotericin B (2.26g, 2.446mmol, 1eq), 20-1 (1.8g, 4.4mmol, 1.8eq; WO2014068443) and pyridine (0.6 mL, 7.4mmol, 3eq) was used as raw material to obtain compound 20-2 (1.3g).
  • step 2 in Example 1 using DMA as a solvent, 20-2 (200mg, 0.164mmol, 1eq), PyAOP (137mg, 0.262mmol, 1.6eq), 1-(2-hydroxyethyl)piperidine Using oxazine (43mg, 0.328mmol, 2eq) and N-methylmorpholine (50mg, 0.492mmol, 3eq) as raw materials, compound 20-3 (97mg) was synthesized as a pale yellow solid. MS (ESI) m/z: 1329.0 [M+H] + .
  • step 1
  • step 1 in Example 19 Referring to the synthesis method of step 1 in Example 19, using dichloromethane/water as solvent, 19-1 (5mL, 0.0342mmol), 21-1 (3g, 0.0171mmol) as raw materials, prepared 21-2 (2.7 g), colorless oil. MS(ESI)m/z:290.2[M+H] + .
  • 21-4 (7 g) was prepared as a colorless oily substance using water/1,4-dioxane as a solvent and 21-3 (5 g) as a raw material.
  • step 2 in Example 1 using DMA as a solvent, 21-6 (200mg, 0.158mmol, 1eq), PyAOP (132mg, 0.254mmol, 1.6eq), 1-(2-hydroxyethyl)piper Using oxazine (41mg, 0.316mmol, 2eq) and N-methylmorpholine (48mg, 0.474mmol, 3eq) as raw materials, compound 21-7 (104mg) was synthesized as a pale yellow solid.
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 18-2 (200mg, 0.166 mmol, 1eq), PyAOP (139mg, 0.266mmol, 1.6eq), 2,6-dimethyl-1- (2-Hydroxyethyl)piperazine (53mg, 0.332mmol, 2eq) and N-methylmorpholine (50mg, 0.498mmol, 3eq) were used as raw materials to synthesize compound 22-1 (103mg) as a pale yellow solid.
  • 18-2 200mg, 0.166 mmol, 1eq
  • PyAOP 139mg, 0.266mmol, 1.6eq
  • 2,6-dimethyl-1- (2-Hydroxyethyl)piperazine 53mg, 0.332mmol, 2eq
  • N-methylmorpholine 50mg, 0.498mmol, 3eq
  • step 1
  • step 1 in Example 1 using DMA as a solvent, amphotericin B (2.26g, 2.446mmol, 1eq), 23-1 (1.9g, 4.4mmol, 1.8eq; CN106589069) and pyridine (0.6 mL, 7.4mmol, 3eq) was used as raw material to obtain compound 23-2 (1.32g) as a pale yellow solid.
  • step 2 in Example 1 using DMA as a solvent, 23-2 (200mg, 0.16mmol, 1eq), PyAOP (134mg, 0.257mmol, 1.6eq), 2,6-dimethyl-1- (2-Hydroxyethyl)piperazine (51mg, 0.32mmol, 2eq) and N-methylmorpholine (49mg, 0.48mmol, 3eq) were used as raw materials to synthesize compound 23-3 (106mg) as a pale yellow solid.
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 24-4 (200mg, 0.16mmol, 1eq), PyAOP (134mg, 0.257mmol, 1.6eq), 2,6-dimethyl-1- (2-Hydroxyethyl)piperazine (51mg, 0.32mmol, 2eq) and N-methylmorpholine (49mg, 0.48mmol, 3eq) were used as raw materials to synthesize compound 24-5 (95mg) as a pale yellow solid.
  • step 1
  • the crude product 25-2 (10 g, 57.8 mmol) was dissolved in dichloromethane (40 mL), stirred under an ice-water bath. Trifluoroacetic acid (43 mL, 578 mmol) was added dropwise to the above solution. After the addition was complete, the mixture was moved to room temperature and stirred for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, toluene (30mL x 3) was added to the reaction solution, and trifluoroacetic acid was removed by azeotropic distillation to obtain 19.4 g of crude product as a colorless oil. Dissolve the above crude product in water, and then add solid sodium carbonate to adjust the pH of the solution to 8-9.
  • step 2 in Example 1 using DMA as a solvent, 25-5 (200mg, 0.16mmol, 1eq), PyAOP (134mg, 0.257mmol, 1.6eq), 2,6-dimethyl-1- (2-Hydroxyethyl)piperazine (51mg, 0.32mmol, 2eq) and N-methylmorpholine (49mg, 0.48mmol, 3eq) were used as raw materials to synthesize compound 25-6 (97mg) as a pale yellow solid.
  • 25-5 200mg, 0.16mmol, 1eq
  • PyAOP 134mg, 0.257mmol, 1.6eq
  • 2,6-dimethyl-1- (2-Hydroxyethyl)piperazine 51mg, 0.32mmol, 2eq
  • N-methylmorpholine 49mg, 0.48mmol, 3eq
  • step 1
  • step 2 in Example 1 using DMA as a solvent, 20-2 (200mg), PyAOP (137mg), 1-(3-hydroxypropyl)piperazine (44mg) and N-methylmorpholine (49 mg) of the starting material, and synthesized to obtain compound 26-1 (102 mg) as a pale yellow solid.
  • step 1
  • step 2 in Example 1 18-2 (100mg, 0.083mmol, 1eq), PyBOP (52mg, 0.1mmol, 1.2eq), 27-1 (40mg, 0.125mmol, 1.5eq, ACS Infect Dis .2020,14,2029-2044) and DIPEA (49 ⁇ L, 0.291mmol, 3.5eq) were sequentially added to a one-necked bottle filled with DMF (3mL), the outer wall of the one-necked bottle was wrapped with aluminum foil, protected by argon, and stirred at room temperature for reaction Overnight, the progress of the reaction was monitored by HPLC.
  • step 3 in Example 1 27-2 (65mg) and piperidine (0.1mL) were sequentially added to a one-necked bottle filled with DMSO (3mL), and the outer wall of the one-necked bottle was wrapped with aluminum foil and protected by argon.
  • the reaction was stirred at room temperature for 2 hours, and the progress of the reaction was monitored by HPLC.
  • the reaction solution was poured into vigorously stirred methyl tert-butyl ether (100mL), filtered, and the resulting solid was washed with methyl tert-butyl ether (40mL x 2), filtered, and vacuum-dried to obtain the target Product V-27 (29 mg), pale yellow solid.
  • step 1
  • step 1 in Example 27 Referring to the synthesis method of step 1 in Example 27, with DMF as solvent, 20-2 (100mg, 0.082mmol, 1eq), PyBOP (52mg, 0.099mmol, 1.2eq), 27-1 (40mg, 0.123mmol, 1.5 eq, ACS Infect Dis.2020, 14, 2029-2044) and DIPEA (49 ⁇ L, 0.288mmol, 3.5eq) raw materials were synthesized to obtain compound 28-1 (55mg), a pale yellow solid.
  • step 1
  • step 1 in Example 27 Referring to the synthesis method of step 1 in Example 27, with DMF as solvent, 20-2 (100mg, 0.082mmol, 1eq), PyBOP (52mg, 0.099mmol, 1.2eq), 27-1 (40mg, 0.123mmol, 1.5 eq, ACS Infect Dis.2020, 14, 2029-2044) and DIPEA (49 ⁇ L, 0.288mmol, 3.5eq) raw materials were synthesized to obtain compound 29-1 (47mg), a pale yellow solid.
  • Example 30 Referring to the synthesis method in Example 30, to a solution of L-glutamic acid (29mg, 0.193mmol, 2eq) in water (10mL), add compound V-29 (100mg, 0.097mmol, 1eq), and stir at room temperature for 5min , filtered, and the filtrate was lyophilized under vacuum to obtain the target product V-31 (118 mg) as a yellow solid.
  • step 1
  • step 1 in Example 27 Referring to the synthesis method of step 1 in Example 27, with DMF as solvent, 9-2 (100mg, 0.083mmol, 1eq), PyBOP (52mg, 0.1mmol, 1.2eq), 33-1 (39mg, 0.125mmol, 1.5 eq, Synlett.2004, 3, 453-456) and DIPEA (28 ⁇ L, 0.166 mmol, 2 eq) were synthesized to obtain compound 33-2 (54 mg) as a light yellow solid.
  • 9-2 100mg, 0.083mmol, 1eq
  • PyBOP 52mg, 0.1mmol, 1.2eq
  • 33-1 39mg, 0.125mmol, 1.5 eq, Synlett.2004, 3, 453-456
  • DIPEA 28 ⁇ L, 0.166 mmol, 2 eq
  • test example 1 The in vitro antifungal activity experiment of test example 1 preferred compound
  • Candida albicans CA
  • Candida krusei CK
  • CP Candida parapsilosis
  • CT Candida tropicalis
  • Candida krusei ATCC6258 CK (ATCC6285)) 1 plant
  • Cryptococcus neoformans ATCC32609(CN(ATCC32609)) 1 plant Aspergillus fumigatus ATCC96918(AF(ATCC96918)) 1 plant
  • MIC Minimum Inhibitory Concentration
  • Amphotericin B for injection was used as the quality control compound
  • Candida krusei ATCC 6258 was used as the quality control strain.
  • the MIC reference value standard refers to CLSI2016 (Reference Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts; Fourth Informational Supplement; M27-S4), and the MIC reference range of amphotericin B for injection to standard quality control strains is shown in Table 2 below.
  • V-29 increased the activity of Candida albicans by 62-250 times, the activity of Candida krusei by 4-8 times, the activity of Candida parapsilosis by 2-16 times, and the activity of Candida tropicalis by 16- 32 times.
  • the compound of the present invention has excellent in vitro antibacterial activity, which means that the in vitro antibacterial activity of the compound is significantly better than that of amphotericin B.
  • Test example 2 In vitro hemolytic activity test of the compound of the present invention
  • the cells used in this experiment were human red blood cells (Human Red Blood Cells), which were prepared as a suspension (concentration of 4 x 10 8 cells/mL) for use. All compounds to be tested were dissolved in dimethyl sulfoxide for use. Add 736 ⁇ L of PBS solution and 14 ⁇ L of dimethyl sulfoxide solution of the test compound to a 1.5 mL PCR tube, and finally add 750 ⁇ L of human erythrocyte suspension. In the final solution, the solubility of the compound to be tested is 200, 150, 100, 80, 50, 30, 20, 10, 5, 1 ⁇ M (choose the highest drug concentration according to the actual situation).
  • the hemolytic activity of the compound of the present invention in vitro is greatly improved, especially the hemolytic activity of compound V-15 and V-29 compared with amphotericin B.
  • the activities were reduced by 19 times and 56 times, respectively. It shows that the compound of the present invention has lower hemolytic toxicity compared with amphotericin B, and the safety is greatly improved.
  • Test example 3 pharmacokinetic test of compound of the present invention in mice
  • Table 6 shows the pharmacokinetic parameters of compounds V-15, V-27 and V-29 and amphotericin B administered to mice intravenously.
  • Test example 4 antifungal activity test of the compound of the present invention in vivo
  • mice healthy KM mice, weighing 18-22 g, were selected into random groups after isolation and quarantine, free to eat and drink, and free to drink water.
  • Candida albicans strain 20-1 was selected as the source of infection, and a single intravenous injection of compound V-31 and the control drug Ammphamide glutamate (ACS Infect. Dis. Efficacy in mice.
  • the drug to be tested is prepared with physiological saline and diluted to the required concentration solution, which is prepared and used immediately.
  • mice Healthy mice were taken and divided into random groups, with 5 mice in each group, half male and half male.
  • the mice were immunosuppressed by intraperitoneal injection of 150 and 100 mg/kg cyclophosphamide 4 days before infection and 1 day before infection respectively.
  • draw the above-mentioned bacterial solutions of different dilution concentrations inject them into the mice through the tail vein respectively, 0.5ml per mouse, observe for 7-14 days after infection, and record the number of mouse deaths, so as to cause the lowest bacterial concentration of 100% death of mice.
  • the amount was taken as the minimum lethal dose (MLD, Minimal Lethad Dose), which was used as the amount of infectious bacteria in the in vivo test.
  • MLD minimum lethal dose
  • mice were deprived of food and water supply 18 hours before the test, and were divided into random groups, with 8 mice in each group, half male and half male.
  • 150 and 100 mg/kg cyclophosphamide were injected intraperitoneally, respectively, and on the day of infection, the bacterial liquid with the lowest lethal amount was absorbed and injected into the mice through the tail vein, 0.5ml per mouse, to establish Candida albicans.
  • a mouse model of systemic infection One hour after the animals in each treatment group were infected with the bacterial solution, the drug was given by single tail vein injection according to the designed dose.
  • the representative compound V-29 of the present invention has greatly reduced toxicity and significantly improved activity, which can greatly expand the therapeutic window and show better efficacy. Pharmacokinetic properties, with obvious pharmaceutical advantages.

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Abstract

本发明提供了两性霉素B半合成衍生物及其制备方法和用途。具体地，本发明公开了结构如式(V)所示的化合物，以及水溶性盐和复合物、药物组合物，以及包含该衍生物的植物和机体治疗产品和他们作为抗真菌抗生素的用途。本发明还公开了上述化合物的制备方法。

Description

两性霉素B半合成衍生物及其制备方法和用途 技术领域
本发明属于药物学合成领域，更具体而言，本发明涉及两性霉素B半合成衍生物及其合成方法和其在治疗真菌感染性疾病中的用途。
背景技术
侵袭性真菌感染虽然在真菌感染所占的比例较低,但是由于它的高致死率和致病率，一直受到人们的广泛重视。目前，侵袭性真菌感染在临床上已经成为艾滋病和恶性肿瘤等重大疾病死亡的重要原因之一，已经上升为第三大传染性疾病，严重威胁着人类的生命，给人类的健康和经济造成了巨大的损害。
两性霉素B(AmB)是首个应用于治疗侵袭性真菌感染的药物，上世纪50年代就已经用于临床。两性霉素B的优点在于：抗菌谱广，抗菌活性强，在高浓度下具有杀菌作用，临床上观察到的获得性耐药发生率较低,至今依然是治疗严重侵袭性曲霉菌感染的最后手段。然而，AmB的应用受到其水溶性差和严重副作用的限制，如溶血毒性、肾毒性以及输液部位相关反应。由于两性霉素B的毒副反应(特别溶血毒性和肾毒性)，使得它的治疗窗很窄，临床上的给药剂量往往达不到它的最优治疗浓度。基于此，目前两性霉素B一般仅用于那些危及生命的侵袭性真菌感染的治疗。
目前临床上严重侵袭性曲霉菌感染如果不使用两性霉素B治疗，死亡率高达50％，每年造成150万死亡，这说明人类健康极度需要低毒性两性霉素B。尽管全世界的科学家为此做了不懈的能力，但目前还没有高效低毒的两性霉素B衍生物上市。研究开发低毒，高效两性霉素B类药物的方法包括，将其制成两性霉素B的脂质体制剂，这样降低了两性霉素B聚合物含量，改善了它在体内的代谢与分布情况，降低了它的毒性，目前已有3款两性霉素B的脂质体制剂上市，但这类脂质体工艺复杂，价格昂贵，最重要的是毒性降低效果有限。第二种解决方案是对两性霉素B进行结构改造，进行构效关系研究和结构毒性关系研究，从源头上把控和改善甚至消除它的毒性，从而开发出下一代的高活性、低毒性的多烯类抗真菌药物。由于两性霉素B的结构比较复杂，目前针对两性霉素B的结构改造一般在大环上的羧基端和海藻糖上的氨基端进行。
本领域已有较多针对羧基端改造的新衍生物研究，主要是羧基酯化或者酰胺化，而海藻糖氨基主要进行酰胺化或者烷基化修饰。这样的衍生物相比于两性霉素B而言，结构改变不大，有的依旧是两亲性质，因此，总体毒性虽有降低，但是大部分活性均降低了好几倍，安全窗并没有明显改善。针对两性霉素B的结构改造一直是多烯大环抗生素科学的研究的难点和热点，目前还没有基于两性霉素B的结构改造而衍生出的新化学实体用于真菌感染的治疗。其主要原因是因为这些新衍生物很难在抗菌活性、毒性、代谢取得平衡，没有达到理想的程度，治疗窗和两性霉素相比没有实质性提高。
综上所述，本领域迫切需要提供结构新颖、抗菌活性更强，溶血活性大幅降低的的两性霉素B新衍生物。
发明内容
针对本领域存在的上述问题，本发明提供了一类结构新颖、抗菌活性更强，溶血活性大幅降低的的两性霉素B双酰胺化修饰衍生物。本发明的化合物结构新颖，治疗指数显著优于两性霉素B，有可能成为一类新型、高效、低毒的抗真菌药物。
本发明的第一方面，提供了一种如下式V所述的化合物，或其药学上可接受的盐：
Figure PCTCN2022102461-appb-000001
其中，
各个R 1各自独立地选自下组：-NR 4-(L) p-Ra；其中，Ra选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基，取代或未取代的C 1-C 6氨基、-NH 2、取代或未取代的-NH-C 1-C 10烷基、取代或未取代的-NH-C(O)C 1-C 10烷基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、或取代或未取代的苯并5-6元杂芳基、以及-COR 3；
L选自下组：(CH 2) n、(CH 2OCH 2) m、NH、NHC(O)；其中，当所述的各个CH 2和NH单独或作为其他基团的一部分出现时，可以任选地被取代；
R 2各自独立地选自下组：H、-C(O)(L) p-Rc；其中，Rc各自独立地选自下组：(CH 2) nNHR 4、NHR 4、或取代或未取代的3-8元杂环基(优选为含氮杂环基)；且当R 2为H时，R 1为-NR 4-(L) p-Ra，且R 1基团中至少一个L为NH或NHC(O)；
R 3各自独立地选自下组：NH 2、取代的或未取代的C 1-C 10烷基、取代或未取代的苯基、取代或未取代的五元或六元杂芳香基、或取代或未取代的苯并五元或六元杂芳香基；
R 4各自独立地选自下组：H、取代或未取代的C 1-C 6烷基；
或R 4与(L) p-Ra，以及相连的N原子共同构成取代或未取代的5-12元杂环基、或取代或未取代的5-12元杂芳基；其中，所述的5-12元杂环基或5-12元杂芳基可以具有一个Rb取代基，且所述的Rb取代基选自下组：羟基、未取代或羟基取代的C 1-C 10烷基、取代或未取代的5-12元杂环基；
p选自下组：0、1、2或3；
n选自下组：0、1、2、3、4、5、6、7或8；
m选自下组：0、1、2、3、4、5、6、7、8、9或10；
除非特别说明，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、氧代、羧基、氰基、羟基、5-6元杂环、C1-C6烷基、C1-C6烷氧基、C3-C8环烷基取代、氨基、N，N-二甲基氨基、巯基、C 1-C 6砜基、-(CH 2OCH 2) nOH、 (CH 2OCH 2) nOR 4、(CH 2OCH 2) nNH 2、(CH 2OCH 2) nNHR 4、(CH 2OCH 2) nN(R 4) 2。
在另一优选例中，所述的R 1各自独立地选自下组：-NR 4-(L) p-Ra；其中，Ra选自下组：-NH 2、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基，取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、-COR 3；
L选自下组：(CH 2) n、(CH 2OCH 2) m、NH、NHC(O)；其中，当所述的各个CH 2和NH单独或作为其他基团的一部分出现时，可以任选地被取代；
p为0或1；
R 4各自独立地选自下组：H、取代或未取代的C 1-C 6烷基；
或R 4与(L) p-Ra，以及相连的N原子共同构成取代或未取代的5-12元杂环基、或取代或未取代的5-12元杂芳基；其中，所述的5-12元杂环基或5-12元杂芳基可以具有一个Rb取代基，且所述的Rb取代基选自下组：羟基、未取代或羟基取代的C1-C10烷基、取代或未取代的5-12元杂环基。
在另一优选例中，所述的R 2各自独立地选自下组：H、-C(O)(L) p-Rc；其中，Rc各自独立地选自下组：NHR 4、或取代或未取代的3-8元杂环基(优选为含氮杂环基)；
L选自下组：(CH 2) n、(CH 2OCH 2) m、NH、NHC(O)；其中，当所述的各个CH 2和NH单独或作为其他基团的一部分出现时，可以任选地被取代；
p为0或1。
在另一优选例中，所述的n选自下组：0、1、2、3、4或5。
在另一优选例中，所述的m选自下组：0、1、2、3、4或5。
在另一优选例中，所述的R 1选自下组：-NR 4(CH 2) nR 5、-NHCH 2CH 2NH 2、
Figure PCTCN2022102461-appb-000002
其中，R 5选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的5-12元杂环基；
R 6选自下组：H、OH、取代或未取代的C 1-C 6烷基、取代或未取代的5-12元杂环基。
在另一优选例中，所述的R 2选自下组：-CO(CH 2) nNHR 4、-CO(CH 2OCH 2) m(CH 2) nNHR 4、
Figure PCTCN2022102461-appb-000003
在另一优选例中，所述的取代的烷基选自下组：C 1-C 6烷基、N，N-二甲基氨基、巯基、砜基取代的C 1-C 6烷基。
在另一优选例中，所述的R 2选自下组：
Figure PCTCN2022102461-appb-000004
Figure PCTCN2022102461-appb-000005
在另一优选例中，所述的R 1选自下组：
Figure PCTCN2022102461-appb-000006
在另一优选例中，所述的R 2选自下组：
Figure PCTCN2022102461-appb-000007
在另一优选例中，或其药学上可接受的盐，其特征在于，所述的化合物选自下表：
Figure PCTCN2022102461-appb-000008
Figure PCTCN2022102461-appb-000009
Figure PCTCN2022102461-appb-000010
Figure PCTCN2022102461-appb-000011
本发明的第二方面，提供了一种如本发明第一方面所述的化合物，或其药学上可接受的盐的制备方法，所述方法包括步骤：
Figure PCTCN2022102461-appb-000012
在惰性溶剂中，用M-2化合物脱除保护基，得到式V化合物；
较佳地，所述方法还包括步骤(1)和(2)：
Figure PCTCN2022102461-appb-000013
(1)在惰性溶剂中，用AmB与化合物
Figure PCTCN2022102461-appb-000014
反应，得到式M-1化合物；
Figure PCTCN2022102461-appb-000015
(2)在惰性溶剂中，用M-1与化合物R 1H反应，得到式M-2化合物；
其中，所述的PG为胺基保护基；所述的R 2'选自下组：化学键，-C(O)(L) p-Rc'；其中，Rc'为Rc失去一个氢原子形成的基团；且当R 2'为化学键时，R 1为-NR 4-(L) p-Ra，且R 1基团中至少一个L为NH或NHC(O)；
其余各基团的定义如本发明第一方面中所述。
在另一优选例中，所述的PG与其相连的胺基N构成氨基甲酸酯、酰胺、N-烷基胺或N-芳基胺优选地，上述保护基选自Fmoc，Boc，Cbz，Alloc，Teoc，甲氧羰基或乙氧羰基，Tfa，Pht，Tos，Ns，特戊酰基，苯甲酰基，Bn，PMB，Trt，Dmb；更佳地选自下组：Fmoc、Boc、Tos、Cbz。
本发明的第三方面，提供了一种如本发明第一方面所述的化合物，或其药学上可接受的盐的制备方法，所述方法包括步骤：
Figure PCTCN2022102461-appb-000016
在惰性溶剂中，用M-4化合物脱除保护基，得到式V化合物；
较佳地，所述的方法还包括步骤(a)和(b)：
Figure PCTCN2022102461-appb-000017
(a)在惰性溶剂中，用AmB与化合物
Figure PCTCN2022102461-appb-000018
反应，得到式M-3化合物；
Figure PCTCN2022102461-appb-000019
(b)在惰性溶剂中，用式M-3化合物与化合物PG-R 1'H反应，得到式M-4化合物；
其中，所述的PG为胺基保护基；
所述的R 1'为R 1失去一个H原子形成的基团；
所述的R 2'选自下组：化学键，-C(O)(L) p-Rc'；其中，Rc'为Rc失去一个氢原子形成的基团；且当R 2'为化学键时，R 1为-NR 4-(L) p-Ra，且R 1基团中至少一个L为NH或NHC(O)；
其余各基团的定义如本发明第一方面中所述。
本发明的第四方面，提供了一种药物组合物，所述的药物组合物包含如下组分：
1)治疗有效量的一种或多种本发明第一方面所述化合物、或其光学异构体、其药学上可接受的盐、水合物、溶剂合物；和
2)药学上可接受的载体或赋形剂。
本发明的第五方面，提供了一种本发明第一方面所述化合物，或其光学异构体、其药学上可接受的盐、水合物、溶剂合物的用途，其特征在于，用于制备预防或治疗治疗真菌感染引起的感染性疾病的药物组合物。
在另一优选例中，所述的真菌选自下组：念珠菌、新型隐球菌、曲霉菌(优选黄曲霉菌、烟曲霉菌、土曲霉菌、黑曲霉菌)、结合菌、皮肤真菌，或其组合。
本发明的第六方面，提供了一种如本发明第一方面所述的式V化合物的制备中间体，所述的中间体选自下组：
Figure PCTCN2022102461-appb-000020
其中，所述的PG为胺基保护基，与其相连的胺基N构成氨基甲酸酯、酰胺、N-烷基胺或N-芳基胺。优选地，上述保护基选自Fmoc，Boc，Cbz，Alloc，Teoc，甲氧羰基或乙氧羰基，Tfa，Pht，Tos，Ns，特戊酰基，苯甲酰基，Bn，PMB，Trt，Dmb；较佳地选自下组：Fmoc、Boc、Tos、Cbz；更佳地为Fmoc；
所述的R 1'为R 1失去一个H原子形成的基团；R 2'选自下组：化学键，-C(O)(L) p-Rc'；其中，Rc'为Rc失去一个氢原子形成的基团；且当R 2'为化学键时，R 1为-NR 4-(L) p-Ra，且R 1基团中至少一个L为NH或NHC(O)；其余各基团的定义如本发明第一方面中所述。
所述的中间体化合物进行脱保护后，得到如本发明第一方面所述的式V化合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛的研究，合成了一系列的化合物，并通过抗菌活性筛选、药物代谢动力学筛选，首次发现以下通式(Ⅰ)表示化合物具有很强的抗菌活性、很好的药物代谢动力学性质，特别适合作为抗感染治疗的药物。本发明人在此基础上完成了本发明。
术语
在本发明中，所述卤素为F、Cl、Br或I。
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等；优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本发明中，术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明中，术语“C2-C6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中，术语“C2-C6炔基”是指具有2至6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中，术语“C3-C10环烷基”是指在环上具有3至10个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基等。术语“C3-C8环烷基”、“C3-C7环烷基”、和“C3-C6环烷基”具有类似的含义。
在本发明中，术语“C3-C10环烯基”是指在环上具有3至10个碳原子的环状烯基，非限制性地包括环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基和环癸基烯等。术语“C3-C7环烯基”具有类似的含义。
在本发明中，术语“芳环”或“芳基”具有相同的含义，优选地“芳基”为“C6-C12芳基”或“C6-C10芳基”。术语“C6-C12芳基”是指在环上不含杂原子的具有6至12个碳原子的芳香族环基，如苯基、萘基等。术语“C6-C10芳基”具有类似的含义。
在本发明中，术语“芳香杂环”或“杂芳基”具有相同的含义，指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中，术语“3-12元杂环基”是指在环上含有1～3个选自氧、硫和氮中的杂原子的饱和或不饱和的3-12元环基，例如二氧杂环戊基等。术语“3-7元杂环基”具有类似的含义。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环烷基，可以与另一个环相连，例如环烷基，从而形成螺二环系，例如，两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-8醛基、C2-10酰基、C2-10酯基、氨基、烷氧基、C1-10磺酰基等。
在本发明中，术语“保护基”是指对反应中非反应位点的取代或未取代氨基进行保护的基团，使之与其相连的胺基N构成氨基甲酸酯、酰胺、N-烷基胺或N-芳基胺，例如Fmoc、Boc、Cbz、Alloc、Teoc、甲氧羰基或乙氧羰基、Tfa、Pht、Tos、Ns、特戊酰基、苯甲酰基、Bn、PMB、Trt、Dmb等。
在本发明中，药学上可接受的盐指的是本发明化合物与无机酸或有机酸所成的盐，上述无机酸选自盐酸，硫酸，磷酸，上述有机酸选自手性异构体或消旋体的谷氨酸，L-谷氨酸，DL-天冬氨酸，脯氨酸，丙氨酸，柠檬酸，L-苹果酸，酒石酸，扁桃酸，乳酸，琥珀酸，脱氧胆酸，安息香酸，或醋酸，草酸，马来酸，富马酸。
药物组合物及其制备
本发明的另一方面提供了一种药物组合物，其含有治疗有效量的选自上述通式V的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体中的一种或多种，以及任选地，一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。所述辅料例如为气味剂、香味剂、甜味剂等。
本发明所提供的药物组合物优选含有重量比为1-99％的活性成份，其优选的比例是，通式V化合物作为活性成分占总重量的35wt％～99wt％，其余部分为药学可接受的载体、稀释液或溶液或盐溶液。
本发明所提供的化合物和药物组合物可以是多种形式，如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等，并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位计量中包含1mg-700mg通式V化合物，优选地，制剂配方的单位计量中包含5mg-300mg通式V化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺或者胃肠道等的给药途径。最优选为口服。最优选日剂量为0.1-140mg/kg体重，一次性服用，或0.1-70mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直 到找到最适合的剂量。
本发明还提供了一种真菌感染抑制剂，其包含选自上述通式V所示的化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种，以及任选地一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
本发明的化合物和组合物可以用于抑制真菌，因此可以用作与真菌感染相关的疾病或病症的治疗药物，例如念珠菌、新型隐球菌、黄曲霉菌、烟曲霉菌、结合菌、皮肤真菌等。
因此，本发明的又一方面提供了上述通式所示的化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物在制备用于治疗与真菌感染相关的疾病，例如白色念珠菌、克柔念珠菌、近平滑念珠菌、热带念珠菌、新型隐球菌、烟曲霉等真菌感染相关的疾病的药物中的用途。
本发明的又一个方面提供了一种治疗与真菌感染相关的疾病的方法，其包括向需要该治疗的患者给药选自上述通式V所示的化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
所有实施例中， 1H-NMR用Varian Mercury 400核磁共振仪或Varian Mercury 600核磁共振仪记录，化学位移以δ(ppm)表示；低分辨质谱由Finnigan MAT95型质谱仪测定；柱层析用硅胶为200-300目。实施例中出现的缩写及其全称如下(按出现顺序)：FmocOSu，9-芴甲基-N-琥珀酰亚胺基碳酸酯；DMA，N,N-二甲基乙酰胺；HPLC，高效液相色谱；DMSO，二甲基亚砜；PyAOP，(3H-1,2,3-三唑并[4,5-B]吡啶-3-氧基)三-1-吡咯烷基六氟磷酸盐；TLC，薄层层析色谱；HONSu，N-羟基丁二酰亚胺；DCC，二环己基碳二亚胺；PyBOP，1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐；DIPEA，N,N-二异丙基乙胺；DMF，N,N-二甲基甲酰胺。
实施例1化合物V-1的合成
Figure PCTCN2022102461-appb-000021
步骤1:
将两性霉素B(2.26g，2.446mmol,1eq)，FmocOSu(1.5g，4.4mmol,1.8eq)和吡 啶(0.6mL,7.4mmol,3eq)依次加入装有DMA(220mL)的单口瓶中，并用铝箔纸包裹单口瓶外壁，氩气保护，于室温下搅拌过夜，HPLC监测反应进度。反应完全后，将反应液倾入剧烈搅拌的甲基叔丁基醚(1000mL)中，常压过滤，滤饼即为化合物1-2的粗品。粗品经硅胶柱层析纯化(洗脱剂为二氯甲烷/甲醇＝6:1)，得化合物1-2(1.6g)为淡黄色固体，收率56.4％。MS(ESI)m/z:1143.3[M-H] -.HRMS(ESI):Anal.Calcd for C 62H 82NO 19[M-H] -:1144.5487,Found:1144.5468.
步骤2:
将化合物1-2(180mg,0.157mmol,1eq),PyAOP(130mg,0.25mmol,1.6eq),乙酰基肼(23mg,0.314mmol,2eq)和N-甲基吗啉(47.6mg,0.471mmol,3eq)依次加入装有DMA(5mL)的单口瓶中，单口瓶的外壁用铝箔纸包裹，氩气保护，于室温下搅拌过夜，HPLC监测反应进度。反应完全后，将反应液倾入剧烈搅拌的甲基叔丁基醚(100mL)中，过滤得化合物1-3的粗品，经硅胶柱层析(洗脱剂为二氯甲烷/甲醇＝10:1～5:1)纯化，得化合物1-3(100mg)，为淡黄色固体，收率53％。MS(ESI)m/z:1200.5[M-H] -.
步骤3:
将化合物1-3(100mg,0.083mmol)和哌啶(0.1mL)依次加入装有DMSO(3mL)的单口瓶中，单口瓶的外壁用铝箔纸包裹，氩气保护，于室温下搅拌反应2小时，HPLC监测反应进度。反应完全后，将反应液倾入剧烈搅拌的甲基叔丁基醚(100mL)中，过滤，将所得固体用甲基叔丁基醚(40mL x 2)搅洗，过滤，真空干燥，即得目标产物V-1(52mg)，为淡黄色固体，收率64％。 1H NMR(600MHz,DMSO-d 6)δ6.51-6.03(m,12H),5.96(dd,J＝15.2,8.9Hz,1H),5.88(s,1H),5.46-5.39(m,2H),5.23(m,1H),4.82-4.77(m,2H),4.76(d,J＝3.8Hz,1H),4.70(d,J＝4.9Hz,1H),4.67(d,J＝4.9Hz,1H),4.49-4.42(m,2H),4.35(m,1H),4.29-4.20(m,2H),4.09-4.00(m,2H),3.56-3.45(m,3H),3.17(m,1H),2.85(m,1H),2.33-2.25(m,2H),2.19-2.14(m,2H),2.01-1.88(m,3H),1.84(s,3H),1.72(m,1H),1.64-1.37(m,7H),1.37-1.20(m,6H),1.15-1.09(m,7H),1.07-1.02(m,3H),0.92(d,J＝7.1Hz,1H). 13C NMR(126MHz,DMSO-d 6)δ171.63,171.06,169.11,137.33,137.22,134.37,134.17,133.94,133.67,132.96,132.92,132.67,132.36,132.31,131.75,130.11,128.81,97.60,96.73,77.70,74.72,74.35,74.02,73.96,72.96,70.24,69.56,69.26,68.32,66.64,65.54,65.21,56.79,49.20,47.15,46.64,45.27,45.06,42.94,42.47,40.98,39.49,35.59,29.51,20.90,18.98,18.58,17.41,12.58.MS(ESI)m/z:980.5[M+H] +.HRMS(ESI):Anal.Calcd for C 49H 78N 3O 17[M+H] +:980.5331,Found:980.5304.
实施例2化合物V-2的合成
Figure PCTCN2022102461-appb-000022
步骤1:
参照实施例1中步骤2的合成方法，以DMA为溶剂，以1-2(180mg,0.157mmol,1eq),PyAOP(130mg,0.25mmol,1.6eq),乙氧基酰基肼(28mg,0.314mmol,2eq)和N-甲基吗啉(47.6mg,0.471mmol,3eq)为原料，合成得到化合物2-1(90mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以2-1(100mg)和哌啶(0.1mL)为原料，合成得到目标产物V-2(41mg)，淡黄色固体。 1H NMR(600MHz,DMSO-d 6)δ6.48-6.03(m,12H),5.97(m,1H),5.84(s,1H),5.45-5.37(m,2H),5.21(m,1H),4.85-4.72(m,4H),4.69-4.61(m,2H),4.50-4.41(m,2H),4.35(m,1H),4.30-4.18(m,2H),4.08-3.96(m,2H),3.58(s,2H),3.54-3.43(m,2H),3.23(m,1H),3.12-3.02(m,3H),2.90(d,J＝32.0Hz,1H),2.84(m,1H),2.74(d,J＝31.8Hz,1H),2.41(m,1H),2.32-2.24(m,2H),2.19-2.12(m,2H),1.94(s,1H),1.92-1.85(m,2H),1.70(m,1H),1.61-1.34(m,6H),1.35-1.18(m,4H),1.14-1.05(m,7H),1.02(d,J＝5.8Hz,3H),0.90(d,J＝6.7Hz,3H). 13C NMR(126MHz,DMSO d 6)δ172.11,171.05,157.28,137.53,137.22,134.42,134.19,134.02,133.68,132.93,132.86,132.65,132.59,132.37,132.20,131.73,128.64,97.59,96.60,77.68,74.50,74.35,74.05(2C,overlap),72.92,70.38,69.59,69.30,68.30,66.66,65.56,65.15,56.85,55.31,52.32,46.69,45.33,45.24,42.93,42.49,40.92,40.08,36.45,35.58,29.51,18.96,18.59,17.42,12.56.MS(ESI)m/z:996.5[M+H]+.HRMS(ESI):Anal.Calcd for C 49H 78N 3O 18[M+H]+:996.5280,Found:996.5266.
实施例3化合物V-3的合成
Figure PCTCN2022102461-appb-000023
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以1-2(180mg,0.157mmol,1eq),PyAOP(130mg,0.25mmol,1.6eq),氨基酰基肼(24mg,0.314mmol,2eq)和N-甲基吗啉(47.6mg,0.471mmol,3eq)为原料，合成得到化合物3-1(85mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以3-1(85mg)和哌啶(0.1mL)为原料，合成得到目标产物V-3(30mg)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ6.51-6.05(m,12H),5.95(m,1H),5.87(s,1H),5.45(m,1H),5.37(s,1H),5.23(m,1H),4.95(m,1H),4.83-4.77(m,2H),4.75(m,1H),4.72-4.62(m,2H),4.49-4.40(m,2H),4.35(m,1H),4.30-4.21(m,2H),4.12-3.97(m,2H),3.60-3.43(m,3H),3.19(m,1H),3.16-3.04(m,3H),2.87(m,1H),2.75(m,1H),2.44(m,1H),2.29(m,1H),2.22-2.13(m,2H),2.00-1.87(m,2H),1.73(m,1H),1.64-1.39(m,7H),1.37-1.22(m,5H),1.18-1.08(m,7H),1.05(d,J＝5.5Hz,3H),0.92(d,J＝6.4Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ172.34,171.04,159.48,137.45,137.24,134.40,134.19,134.02,133.69,132.92,132.86,132.61,132.36,132.21,131.69,130.11,128.95,97.61,97.19,77.65,74.71,74.23,74.07,73.92,73.09,70.26,69.62,69.36,68.18,66.67,65.85,65.38,56.70,55.18,46.68,45.27,44.89,42.92,42.52,40.92,40.07,36.94,35.56,29.47,18.96,18.54,17.45,12.55.MS(ESI)m/z:981.2[M+H]+.HRMS(ESI):Anal.Calcd for C 48H 77N 4O 17[M+H]+:981.5284,Found:981.5300.
实施例4化合物V-4的合成
Figure PCTCN2022102461-appb-000024
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以1-2(180mg,0.157mmol,1eq),PyAOP(130mg,0.25mmol,1.6eq),苯基酰基肼(43mg,0.314mmol,2eq)和N-甲基吗啉(47.6mg,0.471mmol,3eq)为原料，合成得到化合物4-1(102mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以4-1(102mg)和哌啶(0.1mL)为原料，合成得到目标产物V-4(36mg)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ7.94(d,J＝7.1Hz,2H),7.56(m,1H),7.51-7.42(m,2H),6.53-6.07(m,12H),6.02(m,1H),5.88(s,1H),5.49-5.37(m,2H),5.24(m,1H),4.90-4.70(m,4H),4.69-4.61(m,2H),4.52-4.41(s,2H),4.36-4.23(m,2H),4.14-4.03(m,2H),3.60-3.46(m,4H),3.17-3.04(m,3H),2.91(m,1H),2.79(m,1H),2.65(m,1H),2.36-2.25(m,2H),2.23-2.15(m,2H),2.04(m,1H),1.94(m,1H),1.73(m,1H),1.68-1.47(m,6H),1.48-1.23(m,4H),1.18(d,J＝5.0Hz,3H),1.16-1.08(m,4H),1.05(d,J＝5.2Hz,3H),0.93(d,J＝6.1Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ171.81,171.05,166.11,137.58,137.22,134.43,134.19,134.05,133.68,132.93,132.87,132.80,132.66,132.60,132.37,132.20,132.09,131.73,128.80(2C,overlap),128.75,128.12(2C,overlap),97.61,96.67,77.68,74.63,74.33,74.06,73.53,73.01,70.07,69.61,69.31,68.29,66.67,65.63,65.29,56.63,55.60,46.72,45.32,45.18,42.92,42.49,40.92,40.03,36.73,35.59,29.52,18.96,18.60,17.43,12.56.MS(ESI)m/z:1042.3[M+H]+.HRMS(ESI):Anal.Calcd for C 54H 80N 3O 17[M+H]+:1042.5488,Found:1042.5466.
实施例5化合物V-5的合成
Figure PCTCN2022102461-appb-000025
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以1-2(180mg,0.157mmol,1eq),PyAOP(130mg,0.25mmol,1.6eq),吡啶-3-酰基肼(43mg,0.314mmol,2eq)和N-甲基吗啉(47.6mg,0.471mmol,3eq)为原料，合成得到化合物5-1(100mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以5-1(100mg)和哌啶(0.1mL)为原料，合成得到目标产物V-5(53mg)，淡黄色固体。 1H NMR(500MHz, DMSO-d 6)δ9.07(s,1H),8.73(d,J＝3.2Hz,1H),8.27(d,J＝7.2Hz,1H),7.50(m,1H),6.53-6.06(m,12H),6.02(m,1H),5.89(s,1H),5.50-5.38(m,2H),5.23(m,1H),4.88-4.72(m,5H),4.68(m,1H),4.61(m,1H),4.51-4.40(m,2H),4.36-4.24(m,3H),4.15-4.01(m,2H),3.64-3.46(m,3H),3.18-3.01(m,3H),2.88(m,1H),2.35-2.23(m,2H),2.18(d,J＝4.7Hz,2H),2.05(m,1H),1.94(m,1H),1.73(m,1H),1.67-1.48(m,5H),1.47-1.22(m,7H),1.17(d,J＝5.5Hz,3H),1.15-1.08(m,4H),1.05(d,J＝5.3Hz,3H),0.92(d,J＝6.3Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ171.74,171.05,164.74,152.78,149.09,137.50,137.22,135.80,134.42,134.19,134.02,133.68,132.94,132.87,132.66,132.62,132.37,132.24,131.73,128.76,128.49,123.97,97.62,96.71,77.69,74.61,74.34,74.06,73.78,73.05,70.20,69.60,69.31,68.30,66.66,65.57,65.28,56.77,55.57,46.70,45.31,45.20,42.92,42.49,40.90,40.02,36.70,35.57,29.52,18.96,18.60,17.42,12.55.MS(ESI)m/z:1043.3[M+H]+.HRMS(ESI):Anal.Calcd for C 53H 79N 4O 17[M+H]+:1043.5440,Found:1043.5432.
实施例6化合物V-6的合成
Figure PCTCN2022102461-appb-000026
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以1-2(180mg,0.157mmol,1eq),PyAOP(130mg,0.25mmol,1.6eq),吡嗪基酰基肼(43mg,0.314mmol,2eq)和N-甲基吗啉(47.6mg,0.471mmol,3eq)为原料，合成得到化合物6-1(86mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以6-1(86mg)和哌啶(0.1mL)为原料，合成得到目标产物(31mg)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ9.19(m,1H),8.89(m,1H),8.75(m,1H),6.52-6.06(m,12H),6.03(m,1H),5.89(s,1H),5.49-5.39(m,2H),5.23(m,1H),4.85-4.73(m,3H),4.69(m,1H),4.60(m,1H),4.51-4.39(m,2H),4.35-4.24(m,2H),4.14-4.03(m,2H),3.60-3.47(m,3H),3.16-3.06(m,3H),2.85(m,1H),2.34-2.24(m,2H),2.18(d,J＝5.3Hz,2H),2.04(m,1H),1.95(m,1H),1.79(m,1H),1.73(m,1H),1.66-1.48(m,5H),1.47-1.21(m,7H),1.20-1.15(m,3H),1.14-1.08(m,4H),1.05(d,J＝6.0Hz,3H),0.93(d,J＝6.8Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ173.44,171.04,162.50,148.16,145.08,144.27,143.98,137.49,137.22,134.43,134.20,134.05,133.69,132.92,132.86,132.65,132.61,132.37,132.24,131.72, 128.80,97.61,96.84,77.67,74.72,74.64,74.32,74.07,73.11,70.27,69.60,69.31,68.28,66.67,65.57,65.32,56.88,55.68,46.72,45.31,45.04,42.94,42.50,40.91,40.04,36.75,35.58,29.55,18.97,18.60,17.43,12.55.MS(ESI)m/z:1044.3[M+H]+.
实施例7化合物V-7的合成
Figure PCTCN2022102461-appb-000027
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以1-2(180mg,0.157mmol,1eq),PyAOP(130mg,0.25mmol,1.6eq),呋喃-2-酰基肼(40mg,0.314mmol,2eq)和N-甲基吗啉(47.6mg,0.471mmol,3eq)为原料，合成得到化合物7-1(112mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以7-1(112mg)和哌啶(0.1mL)为原料，合成得到目标产物V-7(45mg)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ7.86(m,1H),7.21(m,1H),6.64(m,1H),6.54-6.06(m,12H),6.00(m,1H),5.88(s,1H),5.51-5.35(m,2H),5.24(m,1H),4.84-4.74(m,3H),4.73-4.68(m,2H),4.66(m,1H),4.60(m,1H),4.46(m,1H),4.41(m,1H),4.33-4.24(m,2H),4.17(m,1H),4.13-4.02(m,2H),3.59-3.45(m,3H),3.17-3.05(m,2H),2.84(m,1H),2.36-2.24(m,2H),2.18(d,J＝4.6Hz,2H),2.01(m,1H),1.94(m,1H),1.73(m,1H),1.67-1.46(m,5H),1.45-1.22(m,6H),1.16(d,J＝5.3Hz,3H),1.14-1.08(m,4H),1.05(d,J＝5.4Hz,3H),0.93(d,J＝6.4Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ171.86,171.05,157.78,146.78,146.03,137.59,137.22,134.42,134.20,134.04,133.68,132.93,132.86,132.66,132.59,132.37,132.19,131.72,128.72,115.19,112.27,97.61,96.89,77.68,74.72,74.29,74.12,74.07,72.96,70.42,69.61,69.33,68.25,66.67,65.69,65.28,56.63,55.56,46.72,45.31,45.14,42.92,42.50,40.91,40.03,36.78,35.58,29.50,18.97,18.63,17.43,12.56.MS(ESI)m/z：1032.3[M+H]+.HRMS(ESI):Anal.Calcd for C 52H 78N 3O 18[M+H]+:1032.5280,Found:1032.5256.
实施例8化合物V-8的合成
Figure PCTCN2022102461-appb-000028
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以1-2(180mg,0.157mmol,1eq),PyAOP(130mg,0.25mmol,1.6eq),奥肼(32mg,0.314mmol,2eq)和N-甲基吗啉(47.6mg,0.471mmol,3eq)为原料，合成得到化合物8-1(91mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以8-1(91mg)和哌啶(0.1mL)为原料，合成得到目标产物V-8(28mg)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ6.52-6.02(m,12H),5.96(m,1H),5.84(s,1H),5.50-5.34(m,2H),5.21(m,1H),4.85-4.73(m,3H),4.69(m,1H),4.46(m,1H),4.42-4.33(m,2H),4.32-4.20(m,2H),4.13-4.00(m,2H),3.63-3.45(m,3H),3.17-3.05(m,3H),2.85(m,1H),2.39-2.25(m,3H),2.22-2.13(m,2H),1.98-1.87(m,2H),1.73(m,1H),1.68-1.37(m,8H),1.36-1.20(m,6H),1.18-1.08(m,7H),1.05(d,J＝4.8Hz,3H),0.92(d,J＝6.0Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ173.22,171.02,160.72,158.13,137.55,137.24,134.39,134.20,134.00,133.72,132.93,132.86,132.66,132.62,132.38,132.22,131.65,129.14,97.56,97.39,77.58,74.71,74.33,74.09,73.43,71.81,69.70,69.41,69.09,68.27,66.71,65.35,64.99,56.79,55.63,46.81,45.39,45.11,42.91,42.51,40.91,40.03,36.72,35.57,29.53,18.98,18.57,17.46,12.54.MS(ESI)m/z:1009.2[M+H]+.HRMS(ESI):Anal.Calcd for C 49H 77N 4O 18[M+H]+:1009.5233,Found:1009.5213.
实施例9化合物V-9的合成
Figure PCTCN2022102461-appb-000029
步骤1：
参照实施例1中步骤1的合成方法，将两性霉素B(2.26g，2.446mmol,1eq)，9-1(1.8g，4.4mmol,1.8eq；Tetrahedron.2000,56,8119-8131)和吡啶(0.6mL,7.4mmol,3eq)依次加入装有DMA(220mL)的单口瓶中，用铝箔纸包裹单口瓶外壁，氩气保护，于室温下搅拌过夜，HPLC监测反应进度。反应完全后，将反应液倾入剧烈搅拌的甲基叔丁基醚(1000mL)中，常压过滤，滤饼即为化合物9-2的粗品。粗品经硅胶柱层析纯化(洗脱剂为二氯甲烷/甲醇＝6:1)，得化合物9-2(1.2g)为淡黄色固体。MS(ESI)m/z:1215.4[M-H] -。HRMS(ESI):Anal.Calcd for C 65H 87N 2O 20[M-H] -:1215.5858,Found:1215.5859.
步骤2：
参照实施例1中步骤2的合成方法，将化合物9-2(200mg,0.164mmol,1eq),PyAOP(137mg,0.262mmol,1.6eq),甲基酰基肼(24mg,0.328mmol,2eq)和N-甲基吗啉(50mg,0.492mmol,3eq)依次加入装有DMA(5mL)的单口瓶中，单口瓶的外壁用铝箔纸包裹，氩气保护，于室温下搅拌过夜，HPLC监测反应进度。反应完全后，将反应液倾入剧烈搅拌的甲基叔丁基醚(100mL)中，过滤得化合物9-3的粗品，经硅胶柱层析(洗脱剂为二氯甲烷/甲醇＝10:1～5:1)纯化，得到化合物9-3(101mg)，淡黄色固体。
步骤3：
参照实施例1中步骤3的合成方法，将化合物9-3(101mg)和哌啶(0.1mL)依次加入装有DMSO(3mL)的单口瓶中，单口瓶的外壁用铝箔纸包裹，氩气保护，于室温下搅拌反应2小时，HPLC监测反应进度。反应完全后，将反应液倾入剧烈搅拌的甲基叔丁基醚(100mL)中，过滤，将所得固体用甲基叔丁基醚(40mL x 2)搅洗，过滤，真空干燥，得到目标产物V-9(31mg)，淡黄色固体。 1H NMR(600MHz,DMSO-d 6)δ6.51-6.05(m,12H),5.96(dd,J＝15.1,8.9Hz,1H),5.89(s,1H),5.43(m,2H),5.23(m,1H),4.81-4.77(m,1H),4.76(m,1H),4.69(m,1H),4.66-4.60(m,2H),4.57(m,1H),4.47(m,1H),4.35(m,1H),4.30-4.22(m,2H),4.10-3.99(m,2H),3.70(m,1H),3.57-3.44(m,3H),3.04(d,J＝7.3Hz,2H),2.32-2.23(m,4H),2.19-2.13(m,2H),1.98-1.86(m,4H),1.72(m,1H),1.64-1.36(m,7H),1.35-1.19(m,6H),1.16-1.06(m,7H),1.04(d,J＝5.9Hz,3H),0.92(d,J＝6.9Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ171.65,171.23,171.06,169.53,137.23,137.07,134.36,134.17,133.89,133.67,132.97,132.95,132.71,132.40,132.37,131.75,130.11,128.96,97.61,96.40,77.69,75.08,74.33,74.02,72.97,72.03,69.68,69.55,69.25,68.31,66.64,65.59,65.21,55.33,54.92,49.21,46.64,45.35,45.10,43.00,42.47,40.91,39.50,36.82,36.69,35.59,29.50,20.86,18.99,18.53,17.41,12.58.MS(ESI)m/z:1051.6[M+H]+.HRMS(ESI):Anal.Calcd for C 52H 83N 4O 18[M+H]+:1051.5702,Found:1051.5714.
实施例10化合物V-10的合成
Figure PCTCN2022102461-appb-000030
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以9-2(200mg,0.164mmol,1eq),PyAOP(137mg,0.262mmol,1.6eq),3-氨基-1,2-丙二醇(30mg,0.328mmol,2eq)和N-甲基吗啉(50mg,0.492mmol,3eq)为原料，合成得到化合物10-1(96mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以10-1(96mg)和哌啶(0.1mL)为原料，合成得到目标产物V-10(22mg)，淡黄色固体。 1H NMR(600MHz,DMSO-d 6)δ6.47-6.01(m,12H),5.93(m,1H),5.81(s,1H),5.46-5.38(m,1H),5.34(s,1H),5.19(m,1H),4.83-4.60(m,7H),4.43(m,1H),4.38(m,1H),4.33(m,1H),4.25-4.16(m,2H),4.08-3.97(m,2H),3.70(m,1H),3.56(m,1H),3.54-3.47(m,2H),3.44(m,1H),3.15(m,1H),3.13-3.00(m,6H),2.31-2.21(m,3H),2.19-2.12(m,2H),2.01-1.90(m,2H),1.85(m,1H),1.70(m,1H),1.60-1.34(m,7H),1.32-1.18(m,5H),1.13(d,J＝4.2Hz,3H),1.11-1.05(m,4H),1.02(d,J＝5.4Hz,3H),0.90(d,J＝6.3Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ172.86,171.53,171.04,137.34,137.26,134.39,134.18,133.99,133.69,132.93,132.88,132.66,132.36,132.30,131.68,130.11,129.13,97.56,97.47,77.64,75.70,75.56,74.18,74.07,73.56,71.03,70.95,69.76,69.64,69.36,68.15,66.68,65.92,65.18,64.30,64.13,57.26,54.86,54.50,46.77,45.25,45.04,42.88,42.53,40.92,37.33,36.61,35.56,29.46,18.97,18.54,17.46,12.55.MS(ESI)m/z:1068.3[M+H]+.HRMS(ESI):Anal.Calcd for C 53H 86N 3O 19[M+H] +:1068.5856,Found:1068.5853.
实施例11化合物V-11的合成
Figure PCTCN2022102461-appb-000031
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以9-2(200mg,0.164mmol,1eq),PyAOP(137mg,0.262mmol,1.6eq),4-羟基哌啶(33mg,0.328mmol,2eq)和N-甲基吗啉(50mg,0.492mmol,3eq)为原料，合成得到化合物11-1(97mg)，淡黄色固体。
步骤3：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以11-1(96mg)和哌啶(0.1mL)为原料，合成得到目标产物V-11(24mg)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ6.50-6.05(m,12H),5.97(m,1H),5.86(s,1H),5.48-5.37(m,2H),5.23(m,1H),4.83-4.69(m,6H),4.65(m,1H),4.46(m,1H),4.41-4.22(m,4H),4.12-3.97(m,3H),3.88(m,1H),3.76-3.67(m,2H),3.62(m,1H),3.57-3.45(m,2H),3.21-2.99(m,5H),2.95(m,1H),2.83-2.75(m,2H),2.35-2.25(m,3H),2.18(m,1H),1.97(m,1H),1.89(m,1H),1.81(m,1H),1.73(m,1H),1.64-1.38(m,8H),1.37-1.21(m,6H),1.21-1.15(m,4H),1.12(d,J＝5.6Hz,3H),1.05(d,J＝5.9Hz,3H),0.92(d,J＝6.8Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ171.28,171.18,171.04,137.25,136.88,134.34,134.15,133.85,133.66,132.99,132.95,132.75,132.70,132.47,132.35,131.68,129.12,97.68,97.01,77.66,75.06,74.86,74.24,74.04,73.75,70.96,69.69,69.61,69.32,68.21,66.66,66.24,54.89,54.43,51.67,51.59,46.69,45.29,45.03,43.52,42.91,42.45,40.92,40.06,37.87,36.60,35.57,35.40,35.00,34.64,29.49,18.98,18.54,17.43,12.55.MS(ESI)m/z:1078.3[M+H]+.HRMS(ESI):Anal.Calcd for C 55H 88N 3O 18[M+H]+:1078.6063,Found:1078.6075.
实施例12化合物V-12的合成
Figure PCTCN2022102461-appb-000032
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以9-2(200mg,0.164mmol,1eq),PyAOP(137mg,0.262mmol,1.6eq),1-(2-羟乙基)哌嗪(43mg,0.328mmol,2eq)和N-甲基吗啉(50mg,0.492mmol,3eq)为原料，合成得到化合物12-1(97mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以12-1(97mg)和哌啶(0.1mL)为原料，合成得到目标产物V-12(26mg)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ6.51-6.05(m,12H),5.96(dd,J＝14.9,9.1Hz,1H),5.87(s,1H),5.49-5.37(m,2H),5.23(m,1H),4.82-4.63(m,6H),4.47(m,1H),4.39-4.29(m,2H),4.26(m,1H),4.11-3.97(m,2H),3.69(m,1H),3.67-3.58(m,3H),3.56-3.43(m,6H),3.20-3.02(m,6H),2.43-2.38(m,2H),2.33-2.25(m,3H),2.18(d,J＝5.3Hz,2H),1.93-1.81(m,2H),1.73(m,1H),1.64-1.38(m,7H),1.37-1.23(m,5H),1.17(d,J＝5.5Hz,3H),1.15-1.09(m,4H),1.05(d,J＝5.7Hz,3H),0.92(d,J＝6.6Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ171.39,171.20,171.04,137.26,136.82,134.34,134.15,133.85,133.66,132.99,132.95,132.75,132.70,132.47,132.34,131.70,129.22,97.68,96.93,77.65,75.01,74.25,74.05,73.82,70.88,69.71,69.61,69.32,68.22,66.67,66.56,66.22,60.61,58.96,54.91,54.46,54.27,53.82,51.47,46.79,45.99,45.28,45.03,42.86,42.50,41.77,40.92,40.05,36.76,36.61,35.56,29.49,18.98,18.56,17.43,12.55.MS(ESI)m/z:1107.3[M+H]+.HRMS(ESI):Anal.Calcd for C 56H 91N 4O 18[M+H]+:1107.6328,Found:1107.6308.
实施例13化合物V-13的合成
Figure PCTCN2022102461-appb-000033
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以9-2(200mg,0.164mmol,1eq),PyAOP(137mg,0.262mmol,1.6eq),1-(3-羟丙基)哌嗪(47mg,0.328mmol,2eq)和N-甲基吗啉(50mg,0.492mmol,3eq)为原料，合成得到化合物13-1(102mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以13-1(102mg)和哌啶(0.1mL)为原料，合成得到目标产物V-13(32mg)，淡黄色固体。 1H NMR(600MHz,DMSO-d 6)δ6.51-6.00(m,12H),5.93(m,1H),5.86(s,1H),5.50-5.30(m,2H),5.20(m,1H),4.89-4.57(m,6H),4.45(m,1H),4.38-4.16(m,4H),4.10-3.91(m,2H),3.74-3.55(m,4H),3.54-3.39(m,5H),3.17-2.92(m,6H),2.40-2.18(m,6H),2.17-2.04(m,3H),1.94-1.77(m,2H),1.70(m,1H),1.64-1.44(m,7H),1.42-1.20(m,8H),1.20-0.94(m,13H),0.93-0.77(m,3H). 13C NMR(151MHz,DMSO-d 6)δ171.35,171.11,171.02,137.20,136.77,134.33,134.10,133.76,133.57,132.98,132.94,132.74,132.68,132.51,132.34,131.65,129.16,97.63,96.89,77.62,74.97,74.20,73.98,73.78,70.75,69.72,69.58,69.20,68.13,66.62,66.53,66.10,59.66,55.37,54.80,54.36,53.90,53.51,51.48,46.67,45.82,45.23,44.93,42.87,42.43,41.79,40.84,36.70,39.97,36.54,35.51,29.99,29.47,18.96,18.53,17.38,12.52.MS(ESI)m/z:1121.3[M+H]+.HRMS(ESI):Anal.Calcd for C 57H 93N 4O 18[M+H]+:1121.6485,Found:1121.6487.
实施例14化合物V-14的合成
Figure PCTCN2022102461-appb-000034
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以9-2(200mg,0.164mmol,1eq),PyAOP(137mg,0.262mmol,1.6eq),1-(2,2-二甲基-2-羟乙基)哌嗪(52mg,0.328mmol,2eq)和N-甲基吗啉(50mg,0.492mmol,3eq)为原料，合成得到化合物14-1(95mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以14-1(102mg)和哌啶(0.1mL)为原料，合成得到目标产物V-14(28mg)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ6.51-6.03(m,12H),5.96(m,1H),5.86(s,1H),5.45(m,1H),5.38(s,1H),5.22(m,1H),4.84-4.67(m,6H),4.63(m,1H),4.45(m,1H),4.38-4.29(m,3H),4.25(m,1H),4.16-3.97(m,3H),3.70(m,1H),3.66-3.56(m,3H),3.55-3.41(m,4H),3.21-2.97(m,7H),2.28(br,4H),2.24-2.11(m,4H),1.94-1.79(m,2H),1.73(m,1H),1.67-1.47(m,5H),1.48-1.22(m,8H),1.18(d,J＝4.7Hz,3H),1.15-1.07(m,4H),1.05(d,J＝4.8Hz,3H),0.92(d,J＝5.8Hz,3H). 13C NMR(126MHz,DMSO-d 6)170.85,170.67,170.54,136.76,136.33,133.83,133.65,133.36,133.16,132.49,132.45,132.24,132.21,131.96,131.84,131.19,128.72,97.18,96.48,77.16,74.52,73.73,73.55,73.32,72.04,70.39,70.22,69.24,69.11,68.83,68.32,67.70,66.17,65.71,55.29,54.94,54.40,53.94,50.92,48.70,46.26,45.70,44.78,44.48,42.00,41.67,40.42,39.51,36.23,36.11,35.06,28.98,28.06,27.96,26.81,18.47,18.06,16.93,12.05.MS(ESI)m/z:1135.3[M+H]+.HRMS(ESI):Anal.Calcd for C 58H 95N 4O 18[M+H]+:1135.6636,Found:1135.6636.
实施例15化合物V-15的合成
Figure PCTCN2022102461-appb-000035
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以9-2(200mg,0.164mmol,1eq),PyAOP(137mg,0.262mmol,1.6eq),1-(1,1-二甲基-2-羟乙基)哌嗪(52mg,0.328mmol,2eq)和N-甲基吗啉(50mg,0.492mmol,3eq)为原料，合成得到化合物15-1(100mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以15-1(100mg)和哌啶(0.1mL)为原料，合成得到目标产物V-15(31mg)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ6.49-6.01(m,12H),5.94(m,1H),5.85(s,1H),5.47-5.35(m,2H),5.21(m,1H),4.81-4.63(m,7H),4.44(m,1H),4.37-4.19(m,4H),4.09-3.95(m,2H),3.68(m,1H),3.34-3.55(s,3H),3.54-3.41(m,4H),3.17-3.00(m,6H),2.79(m,1H),2.26(br,4H),2.20-2.12(m,2H),1.90-1.77(m,2H),1.71(m,1H),1.63-1.42(m,6H),1.42-1.20(m,7H),1.15(d,J＝5.0Hz,3H),1.12-1.06(m,4H),1.02(d,J＝6.0Hz,3H),0.95-0.87(m,6H). 13C NMR(126MHz,DMSO-d 6)δ170.69,170.65,170.54,136.76,136.26,133.84,133.66,133.35,133.16,132.50,132.45,132.25,132.21,132.01,131.85,131.21,128.73,97.18,96.37,77.15,74.47,73.77,73.55,73.37,70.40,69.21,69.11,68.81,67.73,66.98,66.17,66.03,65.66,65.25,56.95,55.16,54.77,54.35,53.98,51.00,50.93,48.71,46.46,46.24,45.90,45.64,45.31,44.78,44.49,42.43,42.17,42.00,40.42,39.51,36.20,36.07,35.06,28.99,26.81,20.71,20.59,18.49,18.07,16.93,12.05.MS(ESI)m/z:1135.2[M+H]+.HRMS(ESI):Anal.Calcd for C 58H 95N 4O 18[M+H]+:1135.6636,Found:1135.6641.
实施例16化合物V-16的合成
Figure PCTCN2022102461-appb-000036
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以9-2(200mg,0.164mmol,1eq),PyAOP(137mg,0.262mmol,1.6eq),4-(4-哌啶基)吗啡啉(56mg,0.328mmol,2eq)和N-甲基吗啉(50mg,0.492mmol,3eq)为原料，合成得到化合物16-1(112mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以16-1(112mg)和哌啶(0.1mL)为原料，合成得到目标产物V-16(38mg)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ6.51-6.05(m,12H),5.97(m,1H),5.86(s,1H),5.50-5.35(m,2H),5.23(m,1H),4.86-4.68(m,6H),4.64(m,1H),4.49(m 1H),4.45(m,1H),4.37(m,1H),4.35-4.21(m,3H),4.13(m,1H),4.10-3.95(m,2H),3.72(m,1H),3.65-3.44(m,7H),3.19-3.03(m,6H),2.96(m,1H),2.49-2.35(m,6H),2.34-2.24(m,4H),2.22-2.14(m,2H),1.94-1.81(m,2H),1.80-1.68(m,2H),1.68-1.47(m,5H),1.46-1.22(m,9H),1.21-1.14(m,3H),1.12(d,J＝5.7Hz,3H),1.05(d,J＝5.6Hz,3H),0.92(d,J＝6.5Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ171.23,171.04,170.58,137.27,136.81,134.32,134.15,133.83,133.65,133.00,132.97,132.77,132.71,132.49,132.35,131.69,129.27,97.68,96.98,77.66,74.97,74.28,74.04,73.81,70.83,69.70,69.62,69.34,68.23,66.99(2C,overlap),66.67,66.41,66.06,61.54,54.55,54.39,51.51,49.99,49.89,46.74,45.29,45.00,42.91,42.50,41.06,40.91,39.52,36.75,36.27,35.57,29.49,29.23,29.00,28.22,18.98,18.55,17.43,12.55.MS(ESI)m/z:1147.2[M+H]+.HRMS(ESI):Anal.Calcd for C 59H 95N 4O 18[M+H]+:1147.6641,Found:1147.6619.
实施例17化合物V-17的合成
Figure PCTCN2022102461-appb-000037
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以9-2(200mg,0.164mmol,1eq),PyAOP(137mg,0.262mmol,1.6eq),2,6-二甲基-1-(2-羟乙基)哌嗪(52mg,0.328mmol,2eq)和N-甲基吗啉(50mg,0.492mmol,3eq)为原料，合成得到化合物17-1(102mg淡黄色固体)。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以17-1(102mg)和哌啶(0.1mL)为原料，合成得到目标产物V-17(29mg)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ6.52-6.04(m,12H),5.98(m,1H),5.88(s,1H),5.49-5.36(m,2H),5.23(m,1H),4.87-4.73(m,4H),4.72-4.64(m,2H),4.47(m,1H),4.42-4.34(m,2H),4.32-4.22(m,3H),4.07(m,1H),4.00(m,1H),3.69(m,1H),3.61(m,1H),3.57-3.49(m,3H),3.17-3.02(m,7H),2.84(m,1H),2.71-2.59(m,3H),2.40(m,1H),2.34-2.22(m,5H),2.21-2.12(m,2H),1.97-1.85(m,2H),1.74(m,1H),1.66-1.46(m,6H),1.46-1.22(m,8H),1.20-1.15(m,3H),1.14-1.08(m,6H),1.07-0.98(m,7H),0.92(d,J＝6.2Hz,3H).MS(ESI)m/z:1135.2[M+H]+.HRMS(ESI):Anal.Calcd for C 58H 95N 4O 18[M+H]+:1135.6641,Found:1135.6624.
实施例18化合物V-18的合成
Figure PCTCN2022102461-appb-000038
步骤1：
参照实施例1中步骤1的合成方法，以DMA为溶剂，以两性霉素B(2.26g，2.446mmol,1eq)，18-1(1.7g，4.4mmol,1.8eq；Chemical Science.2014,5,2747-2753)和吡啶(0.6mL,7.4mmol,3eq)为原料，合成得到化合物18-2(1.02g)，淡黄色固体。MS(ESI)m/z:1201.5[M-H] -。HRMS(ESI):Anal.Calcd for C 64H 85N 2O 20[M-H] -:1201.5701,Found:1201.5685.
步骤2：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以18-2(200mg,0.166mmol,1eq),PyAOP(139mg,0.266mmol,1.6eq),1-(2-羟乙基)哌嗪(42mg,0.332mmol,2eq)和N-甲基吗啉(50mg,0.498mmol,3eq)为原料，合成得到化合物18-3(115mg)，淡黄色固体。
步骤3：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以18-3(115mg)和哌啶(0.1mL)为原料，合成得到目标产物V-18(36mg)，淡黄色固体。 1H NMR(600MHz,DMSO-d 6)δ6.50-6.01(m,12H),5.95(m,1H),5.84(s,1H),5.46-5.39(m,1H),5.37(s,1H),5.20(m,1H),4.80-4.65(m,5H),4.61(m,1H),4.42(m,1H),4.36-4.18(m,3H),4.09-3.95(m,2H),3.71-3.56(m,3H),3.55-3.38(m,5H),3.17-3.01(m,6H),2.40-2.22(m,7H),2.15(s,2H),1.99(m,1H),1.91-1.78(m,2H),1.71(m,1H),1.61-1.43(m,6H),1.41-1.19(m,8H),1.15(d,J＝4.7Hz,3H),1.11-1.06(m,4H),1.02(d,J＝5.0Hz,3H),0.90(d,J＝4.9Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ172.92,171.38,171.05,137.26,136.80,134.32,134.14,133.83,133.66,132.98,132.77,132.70,132.49,132.35,131.96,131.71,129.23,97.67,96.94,77.65,74.99,74.24,74.03,73.79,71.00,69.63,69.57,69.31,68.21,66.65,66.56,66.21,60.61,58.88,54.64,54.28,53.81,51.45,46.71,45.89,45.31,44.97,42.92,42.49,41.83,40.90,39.99,36.66,35.52,29.42,25.59,18.98,18.56,17.43,12.56.MS(ESI)m/z:1093.2[M+H]+.HRMS(ESI):Anal.Calcd for C 55H 89N 4O 18[M+H] +:1093.6172,Found:1093.6192.
实施例19化合物V-19的合成
Figure PCTCN2022102461-appb-000039
步骤1：
将19-1(1.88mL,13mmol)，四丁基硫酸氢铵(440mg，1.3mmol)和氢氧化钠溶液(5M,4mL)加入装有二氯甲烷/水(1:1,40mL)的单口瓶中，而后向上述反应液中滴加19-2(1mL,6.46mmol)，加毕，于室温下搅拌反应5小时后，向反应液中加入溴乙酸叔丁酯(1.88mL,13mmol),继续于室温搅拌过夜，TLC监测反应进度。反应完全后，向上述反应液中加入二氯甲烷稀释至100mL，依次用水和饱和食盐水洗涤有机层，无水硫酸钠干燥，过滤，柱层析(石油醚/乙酸乙酯＝5:1)纯化，得19-3(1.37g)，无色油状物。MS(ESI)m/z:276.2[M+H] +.
步骤2：
将19-3(13.7g,0.0498mol)溶于二氯甲烷(40mL)中，于冰水浴下搅拌。向上述溶液中滴加三氟乙酸(57g,0.498mmol)，加毕，移至室温下搅拌反应2小时，TLC监测反应进度。反应完全后，向反应液中加入甲苯(30mL x 3)，共沸蒸馏除去三氟乙酸，得19-4粗品(14g)，无色油状物，直接用于下一步反应。MS(ESI)m/z:118[M-H] -.
步骤3：
将上述粗品19-4溶于水中，加入碳酸钠固体，直至溶液的PH在8～9之间。而后向上述反应液中滴加FmocOSu(20g,60.7mmol)的1,4-二氧六环(30mL)溶液，加毕，于室温下搅拌过夜，TLC监测反应进度。反应完全后，减压浓缩除去有机溶剂，残留的水相用碳酸钠固体调节溶液的PH至8～9，而后用乙酸乙酯萃取(20mL x 3)，保留水相，水相再用6M的稀盐酸调节溶液的PH至2～3，再次用乙酸乙酯萃取(20mL x 3)，有机层合并，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得19-5(13.2g)，白色固体。MS(ESI)m/z:340[M-H] -.
步骤4：
将19-5(1g，2.93mmol),HONSu(0.4g,3.52mmol)和DCC(0.73g,3.52mmol)依次加入装有二氯甲烷(50mL)的单口瓶中，于室温下搅拌过夜，TLC监测反应进度。反应完全后，过滤取滤液，将滤液减压浓缩除去溶剂，残留物用乙酸乙酯稀释至100mL，出现白色固体，再次过滤取滤液，依次用饱和碳酸氢钠溶液，水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，柱层析，得19-6(0.66g)，白色固体。MS(ESI)m/z:439.2[M+H] +.
步骤5：
参照实施例1中步骤1的合成方法，以DMA为溶剂，以两性霉素B(2.26g，2.446mmol,1eq)，19-6(1.9g，4.4mmol,1.8eq)和吡啶(0.6mL,7.4mmol,3eq)为原料，合成得到化合物19-7(1.3g)，淡黄色固体。MS(ESI)m/z:1245.4[M-H] -.HRMS(ESI):Anal.Calcd for C 66H 89N 2O 21[M-H] -:1245.5963,Found:1245.5959.
步骤6：
参照实施例1中步骤2的合成方法，以DMSO为溶剂，以19-7(200mg,0.166mmol,1eq),PyAOP(139mg,0.266mmol,1.6eq),1-(2-羟乙基)哌嗪(42mg,0.332mmol,2eq)和N-甲基吗啉(50mg,0.498mmol,3eq)为原料，合成得到化合物19-8(103mg)，淡黄色固体。
步骤7：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以19-8(103mg)和哌啶(0.1mL)为原料，合成得到目标产物V-19(33mg)，淡黄色固体。 1H NMR(500MHz, DMSO-d 6)δ6.50-6.04(m,12H),5.96(m,1H),5.88(s,1H),5.48-5.36(m,2H),5.22(m,1H),4.85-4.61(m,6H),4.47(m,1H),4.40-4.28(m,3H),4.25(m,1H),4.04(m,2H),3.91(s,2H),3.72(m,1H),3.69-3.58(m,3H),3.21-3.05(m,5H),2.89-2.77(m,2H),2.43-2.36(m,2H),2.35-2.25(m,2H),2.21-2.13(m,2H),1.93-1.79(m,2H),1.73(m,1H),1.64-1.46(m,6H),1.45-1.22(m,7H),1.20-1.14(m,3H),1.13-1.09(m,4H),1.04(d,J＝4.4Hz,3H),0.92(d,J＝5.7Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ171.39,171.03,169.37,137.26,136.81,134.34,134.16,133.86,133.66,132.97,132.94,132.74,132.69,132.47,132.31,131.69,129.22,97.68,96.86,77.65,75.00,74.23,74.05,73.85,71.87,71.69,70.32,70.17,69.60,69.52,69.32,68.20,66.66,66.56,66.23,60.61,58.95,54.79,54.26,53.84,51.48,46.67,45.94,45.27,44.91,42.86,42.51,41.83,40.92,40.60,36.69,35.63,29.47,18.98,18.59,17.43,12.55.MS(ESI)m/z:1137.4[M+H]+.HRMS(ESI):Anal.Calcd for C 57H 93N 4O 19[M+H]+:1137.6434.Found:1137.6460.
实施例20化合物V-20的合成
Figure PCTCN2022102461-appb-000040
步骤1：
参照实施例1中步骤1的合成方法，以DMA为溶剂，以两性霉素B(2.26g，2.446mmol,1eq)，20-1(1.8g，4.4mmol,1.8eq；WO2014068443)和吡啶(0.6mL,7.4mmol,3eq)为原料，合成得到化合物20-2(1.3g)。MS(ESI)m/z:1215.9[M-H] -。HRMS(ESI):Anal.Calcd for C 65H 87N 2O 20[M-H] -:1215.5858,Found:1215.5839.
步骤2：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以20-2(200mg,0.164mmol,1eq),PyAOP(137mg,0.262mmol,1.6eq),1-(2-羟乙基)哌嗪(43mg,0.328mmol,2eq)和N-甲基吗啉(50mg,0.492mmol,3eq)为原料，合成得到化合物20-3(97mg)，淡黄色固体。MS(ESI)m/z:1329.0[M+H] +。
步骤3：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以20-3(103mg)和哌啶(0.1mL)为原料，合成得到目标产物V-20(27mg)，淡黄色固体。 1H NMR(600MHz,DMSO-d 6)δ6.48-6.02(m,12H),5.93(dd,J＝14.9,8.9Hz,1H),5.84(s,1H),5.42(dd,J＝14.9,10.2Hz,1H),5.32(m,1H),5.20(m,1H),4.79-4.75m,2H),4.73(d,J＝3.7Hz,1H),4.68(d,J＝5.8Hz,1H),4.61(d,J＝5.1Hz,1H),4.47-4.39(m,2H),4.34-4.27(m,2H),4.23 (m,1H),4.08-3.95(m,3H),3.69-3.55(m,4H),3.53-3.40(m,6H),3.14-3.05(m,5H),2.84-2.74(m,2H),2.41-2.35(m,4H),2.35-2.22(m,6H),2.19-2.12(m,2H),2.02-1.92(m,2H),1.90-1.77(m,3H),1.71(m,1H),1.64-1.37(m,11H),1.34-1.18(m,9H),1.18-1.12(m,3H),1.11-1.06(m,4H),1.02(d,J＝6.2Hz,3H),0.90(d,J＝7.0Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ171.72,171.38,171.05,137.25,136.90,134.33,134.14,133.85,133.66,132.96,132.73,132.44,132.35,131.71,130.11,129.17,128.51,97.68,96.90,77.60,74.95,74.27,74.08,73.90,70.50,69.56,69.31,68.20,66.65,66.60,66.26,60.61,58.91,55.12,54.31,53.77,51.43,49.16,46.75,45.89,45.29,45.02,42.96,42.43,41.77,40.06,38.46,37.89,35.55,29.48,27.26,25.52,19.01,18.69,17.40,12.52.MS(ESI)m/z:1107.5[M+H]+.HRMS(ESI):Anal.Calcd for C 56H 91N 4O 18[M+H]+:1107.6328.Found:1107.6328.
实施例21化合物V-21的合成
Figure PCTCN2022102461-appb-000041
步骤1：
参照实施例19中步骤1的合成方法，以二氯甲烷/水为溶剂，以19-1(5mL,0.0342mmol)，21-1(3g，0.0171mmol)为原料，制得21-2(2.7g)，无色油状物。MS(ESI)m/z:290.2[M+H] +.
步骤2：
参照实施例19中步骤2的合成方法，以二氯甲烷为溶剂，以21-2(5g,0.0173mol)为原料，制得21-3(5g)，无色油状物。MS(ESI)m/z:132[M-H] -.
步骤3：
参照实施例19中步骤3的合成方法，以水/1,4-二氧六环为溶剂，以21-3(5g)为原料，制得21-4(7g)，无色油状物。MS(ESI)m/z:354[M-H] -.
步骤4：
参照实施例19中步骤4的合成方法，以二氯甲烷为溶剂，以21-4(7g)为原料，制得21-5(3.5g)无色油状物。MS(ESI)m/z:452.2[M+H]+.
步骤5：
参照实施例1中步骤1的合成方法，以DMA为溶剂，以两性霉素B(2.26g，2.446mmol,1eq)，21-5(2g，4.4mmol,1.8eq)和吡啶(0.6mL,7.4mmol,3eq)为原料，合成得到化合物21-6(1.12g)，淡黄色固体。MS(ESI)m/z:1259.4[M-H] -.HRMS(ESI):Anal.Calcd for C 67H 91N 2O 21[M-H] -:1259.6120,Found:1259.6134.
步骤6：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以21-6(200mg,0.158mmol,1eq),PyAOP(132mg,0.254mmol,1.6eq),1-(2-羟乙基)哌嗪(41mg,0.316mmol,2eq)和N-甲基吗啉(48mg,0.474mmol,3eq)为原料，合成得到化合物21-7(104mg)，淡黄色固体。
步骤7：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以21-7(104mg)和哌啶(0.1mL)为原料，合成得到目标产物V-21(31mg)，为淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ6.51-6.03(m,12H),5.96(m,1H),5.87(s,1H),5.50-5.34(m,2H),5.23(m,1H),4.85-4.59(m,6H),4.50-4.41(m,2H),4.39-4.29(m,3H),4.26(m,1H),4.11-3.97(m,2H),3.93-3.86(m,2H),3.72(m,1H),3.67-3.60(m,2H),3.59-3.44(m,6H),3.19-3.04(m,4H),2.78-2.66(m,2H),2.42-2.24(m,8H),2.22-2.10(m,2H),1.94-1.79(m,2H),1.73(m,1H),1.65-1.38(m,8H),1.36-1.22(m,5H),1.21-1.15(m,3H),1.14-1.08(m,4H),1.07-1.00(m,3H),0.97-0.88(m,3H). 13C NMR(126MHz,DMSO-d 6)δ171.38,171.04,169.43,137.26,136.81,134.33,134.15,133.84,133.66,132.97,132.95,132.73,132.70,132.47,132.35,131.69,129.21,97.67,96.89,77.70,75.02,74.23,74.05,73.84,70.31,70.24,69.59,69.56,69.32,68.20,66.66,66.57,66.22,60.61,58.96,54.64,54.26,53.88,51.48,50.61,46.65,45.95,45.21,45.05,43.02,42.57,41.93,40.92,40.07,36.83,35.92,35.63,29.40,27.23,18.97,18.59,17.43,12.55.MS(ESI)m/z:1151.6[M+H]+.HRMS(ESI):Anal.Calcd for C 58H 95N 4O 19[M+H]+:1151.6591.Found:1151.6601.
实施例22化合物V-22的合成
Figure PCTCN2022102461-appb-000042
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以18-2(200mg,0.166 mmol,1eq),PyAOP(139mg,0.266mmol,1.6eq),2,6-二甲基-1-(2-羟乙基)哌嗪(53mg,0.332mmol,2eq)和N-甲基吗啉(50mg,0.498mmol,3eq)为原料，合成得到化合物22-1(103mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以22-1(104mg)和哌啶(0.1mL)为原料，合成得到目标产物V-22(28mg)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ6.51-6.03(m,12H),5.95(m,1H),5.86(s,1H),5.48-5.35(m,2H),5.21(m,1H),4.84-4.72(m,4H),4.71-4.60(m,2H),4.46(m,1H),4.40-4.32(m,2H),4.31-4.20(m,3H),4.10-3.93(m,3H),3.72-3.56(m,3H),3.55-3.43(m,2H),3.19-3.01(m,5H),2.70-2.58(m,2H),2.33-2.21(m,2H),2.19-2.09(m,2H),1.93-1.82(m,2H),1.78-1.67(m,2H),1.65-1.44(m,5H),1.43-1.20(m,8H),1.19-1.13(m,3H),1.12-1.08(m,6H),1.07-0.96(m,7H),0.91(d,J＝4.8Hz,3H).MS(ESI)m/z:1121.1[M+H]+.HRMS(ESI):Anal.Calcd for C 57H 93N 4O 18[M+H]+:1121.6485,Found:1121.6488.
实施例23化合物V-23的合成
Figure PCTCN2022102461-appb-000043
步骤1：
参照实施例1中步骤1的合成方法，以DMA为溶剂，以两性霉素B(2.26g，2.446mmol,1eq)，23-1(1.9g，4.4mmol,1.8eq；CN106589069)和吡啶(0.6mL,7.4mmol,3eq)为原料，合成得到化合物23-2(1.32g)，淡黄色固体。MS(ESI)m/z:1241.5[M-H] -.HRMS(ESI):Anal.Calcd for C 67H 89N 2O 20[M-H] -:1241.6014,Found:1241.6002.
步骤2：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以23-2(200mg,0.16mmol,1eq),PyAOP(134mg,0.257mmol,1.6eq),2,6-二甲基-1-(2-羟乙基)哌嗪(51mg,0.32mmol,2eq)和N-甲基吗啉(49mg,0.48mmol,3eq)为原料，合成得到化合物23-3(106mg)，淡黄色固体。
步骤3：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以23-4(106mg)和哌啶(0.1mL)为原料，合成得到目标产物V-23(25mg)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ6.52-6.04(m,12H),5.97(m,1H),5.86(s,1H),5.49-5.36(m,2H),5.23(m, 1H),4.86-4.73(m,4H),4.72-4.61(m,2H),4.46(m,1H),4.42-4.34(m,2H),4.33-4.21(m,3H),4.11-3.94(m,3H),3.68-3.44(m,6H),3.19-3.02(m,5H),2.87(m,1H),2.81-2.72(m,2H),2.71-2.59(m,3H),2.34-2.23(m,2H),2.22-2.12(m,2H),2.04-1.84(m,3H),1.82-1.69(m,3H),1.68-1.48(m,7H),1.49-1.23(m,8H),1.21-1.14(m,4H),1.13-1.10(m,4H),1.09-0.99(m,7H),0.92(d,J＝6.2Hz,3H).MS(ESI)m/z:1161.4[M+H]+.HRMS(ESI):Anal.Calcd for C 60H 97N 4O 18[M+H]+:1161.6798.Found:1161.6774.
实施例24化合物V-24的合成
Figure PCTCN2022102461-appb-000044
步骤1：
参照实施例19中步骤3的合成方法，以水/1,4-二氧六环为溶剂，以24-1(1.5g)为原料，制得24-2(3.8g)，无色油状物。MS(ESI)m/z:350[M-H] -.
步骤2：
参照实施例19中步骤4的合成方法，以二氯甲烷为溶剂，以24-2(3.8g)为原料，制得24-3(3.2g)，无色油状物。MS(ESI)m/z:449.1[M+H]+
步骤3：
参照实施例1中步骤1的合成方法，以DMA为溶剂，以两性霉素B(2.26g，2.446mmol,1eq)，24-3(1.97g，4.4mmol,1.8eq)和吡啶(0.6mL,7.4mmol,3eq)为原料，合成得到化合物24-4(1.25g)，淡黄色固体。MS(ESI)m/z:1255.6[M-H] -.HRMS(ESI):Anal.Calcd for C 68H 91N 2O 20[M-H] -:1255.6171,Found:1255.6139.
步骤4：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以24-4(200mg,0.16mmol,1eq),PyAOP(134mg,0.257mmol,1.6eq),2,6-二甲基-1-(2-羟乙基)哌嗪(51mg,0.32mmol,2eq)和N-甲基吗啉(49mg,0.48mmol,3eq)为原料，合成得到化合物24-5(95mg)，淡黄色固体。
步骤5：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以24-5(106mg)和哌啶(0.1mL)为原料，合成得到目标产物V-24(23mg)，淡黄色固体。 1H NMR(500MHz, DMSO-d 6)δ6.50-6.04(m,12H),5.96(m,1H),5.87(s,1H),5.49-5.36(m,2H),5.23(m,1H),4.83-4.71(m,4H),4.70-4.61(m,2H),4.45(m,1H),4.42-4.34(m,2H),4.33-4.21(m,3H),4.11-3.95(m,3H),3.71-3.51(m,2H),3.56-3.45(m,2H),3.19-3.04(m,5H),2.94(m,1H),2.70-2.59(m,3H),2.34-2.22(m,2H),2.18(d,J＝5.3Hz,2H),1.94-1.85(m,2H),1.83-1.66(m,4H),1.65-1.44(m,7H),1.44-1.23(m,10H),1.22-1.15(m,3H),1.14-1.10(m,4H),1.09-0.98(m,9H),0.92(d,J＝6.8Hz,3H).MS(ESI)m/z:1175.4[M+H]+.HRMS(ESI):Anal.Calcd for C 61H 99N 4O 18[M+H]+:1175.6954.Found:1175.6957.
实施例25化合物V-25的合成
Figure PCTCN2022102461-appb-000045
步骤1：
将25-1(2.64mL,0.03076mol)溶于乙腈(30mL)中，于冰水浴下搅拌。向上述溶液中滴加19-1(1.5mL,0.01025mol)，加毕，移至室温下搅拌过夜，TLC监测反应进度。反应完全后，减压浓缩除去溶剂，残留物用二氯甲烷稀释至100mL，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得25-2粗品(1g)，无色油状物。MS(ESI)m/z:174.2[M+H]+.
步骤2：
将粗品25-2(10g,57.8mmol)溶于二氯甲烷(40mL)中，于冰水浴下搅拌。向上述溶液中滴加三氟乙酸(43mL,578mmol)，加毕，移至室温下搅拌2小时，TLC监测反应进度。反应完全后，向反应液中加入甲苯(30mL x 3)，共沸蒸馏除去三氟乙酸，得粗品19.4g，无色油状物。将上述粗品溶于水中，而后加入碳酸钠固体，调节溶液PH至8～9。向上述溶液中滴加FmocOSu(20g,60.7mmol)的1,4-二氧六环(30mL)溶液，加毕，于室温下搅拌过夜，TLC监测反应进度。反应完全后，减压浓缩除去有机溶剂，残留的水相用碳酸钠固体调节溶液的PH至8～9，而后用乙酸乙酯萃取(20mL x 3)，保留水相，水相再用6M的稀盐酸调节溶液的PH至2～3，再次用乙酸乙酯萃取(20mL x 3)，合并有机层，有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得25-3(7.6g)，固体。MS(ESI)m/z:340.2[M+H]+
步骤3：
参照实施例19中步骤4的合成方法，以二氯甲烷为溶剂，以25-3(7.6g)为原料，制得25-4(8.1g)，白色固体。MS(ESI)m/z:437.2[M+H]+.
步骤4：
参照实施例1中步骤1的合成方法，以DMA为溶剂，以两性霉素B(2.26g，2.446mmol,1eq)，25-4(1.97g，4.4mmol,1.8eq)和吡啶(0.6mL,7.4mmol,3eq)为原料，合成得到化合物25-5(1.1g)，淡黄色固体。MS(ESI)m/z:1243.5[M-H] -.HRMS(ESI):Anal.Calcd for C 67H 91N 2O 20[M-H] -:1243.6171,Found:1243.6163.
步骤5：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以25-5(200mg,0.16mmol,1eq),PyAOP(134mg,0.257mmol,1.6eq),2,6-二甲基-1-(2-羟乙基)哌嗪(51mg,0.32mmol,2eq)和N-甲基吗啉(49mg,0.48mmol,3eq)为原料，合成得到化合物25-6(97mg)，淡黄色固体。
步骤6：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以25-6(97mg)和哌啶(0.1mL)为原料，合成得到目标产物V-25(26mg)。 1H NMR(500MHz,DMSO-d 6)δ6.50-6.06(m,12H),5.96(m,1H),5.87(s,1H),5.49-5.36(m,2H),5.23(m,1H),4.82-4.71(m,4H),4.70-4.62(m,2H),4.45(m,1H),4.42-4.22(m,5H),4.11-3.94(m,3H),3.69(m,1H),3.60(m,1H),3.57-3.45(m,2H),3.44-3.36(m,2H),3.18-3.04(m,6H),2.71-2.59(m,3H),2.36(m,1H),2.33-2.21(m,2H),2.18(d,J＝5.5Hz,2H),2.05-1.85(m,2H),1.74(m,1H),1.66-1.38(m,7H),1.38-1.14(m,9H),1.14-1.10(m,3H),1.10-1.01(m,8H),0.99(d,J＝6.1Hz,6H),0.93(d,J＝6.8Hz,3H).MS(ESI)m/z:1163.4[M+H]+.HRMS(ESI):Anal.Calcd for C 60H 99N 4O 18[M+H]+:1163.6954.Found:1163.6943.
实施例26化合物V-26的合成
Figure PCTCN2022102461-appb-000046
步骤1：
参照实施例1中步骤2的合成方法，以DMA为溶剂，以20-2(200mg),PyAOP(137mg),1-(3-羟丙基)哌嗪(44mg)和N-甲基吗啉(49mg)原料，合成得到化合物26-1(102mg)， 淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以26-1(102mg)和哌啶(0.1mL)为原料，合成得到目标产物V-26(35mg)。MS(ESI)m/z:1121.3[M+H]+.HRMS(ESI):Anal.Calcd for C 57H 93N 4O 18[M+H]+:1121.6441.Found:1121.6438.
实施例27化合物V-27的合成
Figure PCTCN2022102461-appb-000047
步骤1：
参照实施例1中步骤2的合成方法，将18-2(100mg,0.083mmol,1eq),PyBOP(52mg,0.1mmol,1.2eq),27-1(40mg,0.125mmol,1.5eq，ACS Infect Dis.2020,14,2029-2044)和DIPEA(49μL,0.291mmol,3.5eq)依次加入装有DMF(3mL)的单口瓶中，单口瓶外壁用铝箔纸包裹，氩气保护，于室温下搅拌反应过夜，HPLC监测反应进度。反应完全后，将反应液倾入剧烈搅拌的甲基叔丁基醚(60mL)中，过滤得27-2的粗品，经硅胶柱层析(洗脱剂为二氯甲烷/甲醇＝10:1～5:1)纯化后，得到化合物27-2(65mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，将27-2(65mg)和哌啶(0.1mL)依次加入装有DMSO(3mL)的单口瓶中，单口瓶外壁用铝箔纸包裹，氩气保护，于室温下搅拌反应2小时，HPLC监测反应进度。反应完全后，将反应液倾入剧烈搅拌的甲基叔丁基醚(100mL)中，过滤，将所得固体用甲基叔丁基醚(40mL x 2)搅洗，过滤，真空干燥，得到目标产物V-27(29mg)，淡黄色固体。 1H NMR(600MHz,DMSO-d 6)δ8.25(br,1H),8.12–7.94(m,1H),6.50–6.02(m,12H),5.93(dd,J＝15.3,9.0Hz,2H),5.43(dd,J＝14.9,10.2Hz,1H),5.28–5.15(m,1H),5.03–4.49(m,8H),4.42–4.29(m,4H),4.28–4.14(m,4H),4.13–3.93(m,6H),3.74–3.65(m,2H),3.63(s,2H),3.56–3.49(m,2H),3.46(s,1H),3.45(s,1H),3.22–3.09(m,4H),2.88–2.73(m,1H),2.36–2.22(m,1H),2.16(d,J＝6.1Hz,2H),1.98–1.88(m,2H),1.87(s,1H),1.75–1.68(m,1H),1.62–1.35(m,8H),1.34–1.21(m,3H),1.18–1.14(m,3H),1.12–1.10(m,3H),1.03(d,J＝6.1Hz,3H),0.91(d,J＝7.0Hz,3H). 13C NMR(151MHz,DMSO-d 6)δ172.71,170.60(2C),136.83,136.29,133.86,133.72,133.34,133.22,132.56(2C),132.40,132.27,132.11,131.92,131.24,129.00,97.15,97.05,77.20,75.18,73.80,73.59,73.34,69.98,69.20,69.04,68.88,67.77,66.24,65.24,64.79,57.20,54.76,46.23,44.79,44.45,43.72,43.04,42.51(2C),42.06,40.06,37.75,37.00,35.10,29.04,18.56,18.12,17.01,12.12.MS(ESI)m/z:1023.1[M+H] +. HRMS(ESI):Anal.Calcd for C 51H 83N 4O 17[M+H] +:1023.5748,Found:1023.5776.
实施例28化合物V-28的合成
Figure PCTCN2022102461-appb-000048
步骤1：
参照实施例27中步骤1的合成方法，以DMF为溶剂，以20-2(100mg,0.082mmol,1eq),PyBOP(52mg,0.099mmol,1.2eq),27-1(40mg,0.123mmol,1.5eq，ACS Infect Dis.2020,14,2029-2044)和DIPEA(49μL,0.288mmol,3.5eq)原料，合成得到化合物28-1(55mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以28-1(55mg)和哌啶(0.1mL)为原料，合成得到目标产物V-28(21mg)，淡黄色固体。 1H NMR(600MHz,DMSO-d 6)δ8.10–7.99(m,1H),7.94–7.84(m,1H),6.55–5.82(m,12H),5.50–5.37(m,1H),5.27–5.14(m,1H),4.94–4.52(m,4H),4.41–4.30(m,2H),4.28–4.16(m,2H),4.13–3.97(m,4H),3.24–3.01(m,8H),2.93–2.78(m,2H),2.74–2.58(m,2H),2.42–2.21(m,3H),2.17–2.14(m,2H),2.01–1.85(m,2H),1.84–1.81(m,2H),1.76–1.66(m,1H),1.64–1.21(m,11H),1.16–1.13(m,3H),1.12–1.09(m,3H),1.05–1.02(m,3H),0.97–0.85(m,3H).MS(ESI)m/z:1059.4[M+Na] +.HRMS(ESI):Anal.Calcd for C 52H 85N 4O 17[M+H] +:1037.5904,Found:1037.5924.
实施例29化合物V-29的合成
Figure PCTCN2022102461-appb-000049
步骤1：
参照实施例27中步骤1的合成方法，以DMF为溶剂，以20-2(100mg,0.082mmol,1eq),PyBOP(52mg,0.099mmol,1.2eq),27-1(40mg,0.123mmol,1.5eq，ACS Infect Dis.2020,14,2029-2044)和DIPEA(49μL,0.288mmol,3.5eq)原料，合成得到化合物29-1(47mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以29-1(47mg)和哌啶(0.1mL)为原料，合成得到目标产物V-29(21mg)，淡黄色固体。 1H NMR(600MHz,DMSO-d 6)δ7.99(br,1H),7.64(d,J＝9.0Hz,1H),6.51–6.01(m,12H),5.97–5.89(m,1H),5.85(br,1H),5.43(dd,J＝14.9,10.0Hz,2H),5.27–5.17(m,1H),4.99–4.53(m,4H),4.39–4.32(m,2H),4.27–4.18(m,2H),4.10–4.04(m,1H),4.04–4.00(m,1H),3.69(t,J＝9.3Hz,2H),3.61–3.56(s,2H),3.55–3.49(m,2H),3.48–3.43(m,2H),3.20–3.09(m,4H),2.63(dt,J＝12.5,6.2Hz,1H),2.27(s,3H),2.26(s,1H),2.16(d,J＝6.1Hz,2H),2.00–1.80(m,3H),1.75–1.68(m,1H),1.64–1.44(m,5H),1.43–1.35(m,2H),1.31(d,J＝13.5Hz,2H),1.28–1.21(m,2H),1.15(d,J＝6.0Hz,3H),1.12–1.11(m,3H),1.03(d,J＝6.2Hz,3H),0.91(d,J＝7.0Hz,3H). 13C NMR(151MHz,DMSO-d 6)δ172.17,170.85,170.60,136.80,136.60,133.89,133.72,133.42,133.23,132.53(2C),132.24(2C),131.92(2C),131.25,128.92,97.12(2C),77.21,75.22,73.82,73.59,73.29,70.41,69.24(2C),68.88,67.77,66.25,65.40,64.69,57.12,54.36,54.06,46.30,44.78,44.58,42.49,42.05,41.16,41.00,40.43,40.06,36.95,36.12,35.12,29.07,18.55,18.10,17.01,12.11.MS(ESI)m/z:1037.0[M+H] +.HRMS(ESI):Anal.Calcd for C 52H 85N 4O 17[M+H] +:1037.5904,Found:1037.5926.
实施例30化合物V-30的合成
Figure PCTCN2022102461-appb-000050
向扁桃酸(9mg,0.058mmol,2eq)的水(3mL)溶液中，加入化合物V-29(30mg,0.029mmol,1eq)，于室温下搅拌3min，过滤，滤液于真空条件下冻干，目标产物V- 30(38mg)，黄色固体。 1H NMR(500MHz,DMSO-d 6)δ8.42(s,1H),8.30(d,J＝8.4Hz,1H),7.39(d,J＝7.5Hz,4H),7.26(t,J＝7.5Hz,4H),7.19(t,J＝7.3Hz,2H),6.51–6.02(m,12H),5.97–5.83(m,2H),5.44(dd,J＝14.9,9.9Hz,2H),5.21(d,J＝7.1Hz,1H),4.71(s,5H),4.35(s,2H),4.31(s,2H),4.23(t,J＝9.4Hz,3H),4.10–3.99(m,4H),3.70(s,1H),3.65(s,1H),3.57–3.49(m,2H),3.49–3.40(m,4H),3.38(d,J＝5.2Hz,1H),3.35(d,J＝5.2Hz,1H),3.30(d,J＝5.7Hz,1H),3.28(d,J＝5.9Hz,1H),3.17(t,J＝7.5Hz,2H),3.09(d,J＝8.0Hz,2H),2.92–2.78(m,2H),2.54(s,1H),2.41(s,3H),2.28(q,J＝7.6,7.2Hz,2H),2.16(d,J＝6.2Hz,2H),1.95–1.83(m,3H),1.72(d,J＝7.8Hz,1H),1.62–1.49(m,4H),1.48–1.21(m,9H),1.17(d,J＝5.2Hz,3H),1.11(d,J＝6.1Hz,3H),1.04(d,J＝6.1Hz,3H),0.91(d,J＝7.0Hz,3H). 13C NMR(126MHz,DMSO)δ174.89(2C),172.84,170.59,167.33,142.55(2C),136.84,136.25,133.83,133.69,133.29,133.22,132.55(2C),132.39,132.26,132.10,131.90,131.22,129.03,127.62(4C),126.59(2C),126.43(4C),97.14,97.00,75.12,73.82,73.59,73.38,73.25(2C),72.51(2C),69.63,69.22,68.91,67.78,66.24,65.26,64.77,63.09,57.73,54.99,51.24,46.35,44.76,44.41,42.51,42.06,40.43,38.87,37.01,36.83,35.09,33.85,29.05,18.52,18.09,16.99,12.09.MS(ESI)m/z:1037.2[M+H] +.HRMS(ESI):Anal.Calcd for C 52H 85N 4O 17[M+H] +:1037.5909,Found:1037.5904.
实施例31化合物V-31的合成
Figure PCTCN2022102461-appb-000051
参照实施例30中的合成方法，向L-谷氨酸(29mg,0.193mmol,2eq)的水(10mL)溶液中，加入化合物V-29(100mg,0.097mmol,1eq)，于室温下搅拌5min，过滤，滤液于真空条件下冻干，得目标产物V-31(118mg)，黄色固体。 1H NMR(500MHz,Deuterium Oxide)δ6.78–5.91(m,13H),5.38(s,1H),5.26(s,1H),4.84(s,2H),4.74(s,2H),4.60(s,1H),4.52(s,1H),4.43(s,1H),4.38(s,1H),4.28(s,2H),4.05–3.92(m,4H),3.80(dd,J＝7.0,5.1Hz,4H),3.52–3.38(m,3H),3.30–3.16(m,3H),2.87–2.80(m,4H),2.75(s,1H),2.46(d,J＝3.3Hz,2H),2.44(d,J＝3.0Hz,2H),2.43(d,J＝2.6Hz,2H),2.25–2.06(m,9H),1.96–1.66(m,6H),1.55(s,2H),1.35(d,J＝5.3Hz,3H),1.26(d,J＝5.7Hz,3H),1.18(s,3H),1.05(s,3H).MS(ESI)m/z:1037.2[M+H] +.HRMS(ESI):Anal.Calcd for C 52H 85N 4O 17[M+H] +:1037.5900,Found:1037.5904.
实施例32化合物V-32的合成
Figure PCTCN2022102461-appb-000052
参照实施例30中的合成方法，以水为溶剂，以化合物V-29(30mg,0.029mmol,1eq)和DL-天冬氨酸(8mg,0.058mmol,2eq)为原料，合成得到目标产物V-32(37mg)，黄色固体。 1H NMR(500MHz,Deuterium Oxide)δ6.76–6.00(m,13H),5.47–5.20(m,1H),4.84(s,2H),4.60(s,1H),4.55–4.46(m,1H),4.43(s,2H),4.33–4.22(m,2H),4.00(s,2H),3.95(dd,J＝8.4,3.9Hz,4H),3.80(td,J＝6.5,3.2Hz,1H),3.69(d,J＝4.4Hz,1H),3.67(d,J＝4.4Hz,1H),3.60(d,J＝6.5Hz,1H),3.57(d,J＝6.5Hz,1H),3.51–3.41(m,3H),3.28–3.16(m,3H),2.88(d,J＝3.9Hz,1H),2.86–2.81(m,5H),2.79–2.70(m,4H),2.53–2.34(m,1H),2.26–2.04(m,3H),1.96–1.66(m,5H),1.55(s,3H),1.37–1.33(m,3H),1.28–1.24(m,3H),1.21(t,J＝7.2Hz,2H),1.19–1.15(m,3H),1.07–1.03(m,3H).MS(ESI)m/z:1037.2[M+H] +.HRMS(ESI):Anal.Calcd for C 52H 85N 4O 17[M+H] +:1037.5896,Found:1037.5904.
实施例33化合物V-33的合成
Figure PCTCN2022102461-appb-000053
步骤1：
参照实施例27中步骤1的合成方法，以DMF为溶剂，以9-2(100mg,0.083mmol,1eq),PyBOP(52mg,0.1mmol,1.2eq),33-1(39mg,0.125mmol,1.5eq,Synlett.2004,3,453-456)和DIPEA(28μL,0.166mmol,2eq)原料，合成得到化合物33-2(54mg)，淡黄色固体。
步骤2：
参照实施例1中步骤3的合成方法，以DMSO为溶剂，以33-2(54mg)和哌啶(0.1mL)为原料，合成得到目标产物V-33(32mg)，淡黄色固体。MS(ESI)m/z:1062.5[M+H] +.HRMS(ESI):Anal.Calcd for C 54H 87N 4O 17[M+H] +:1062.6032,Found:1062.6054.
测试例1优选化合物的体外抗真菌活性实验
1.1方法：采用美国临床和实验室标准协会(Clinical and Laboratory Standards Institute,CLSI)抗菌药物敏感性试验操作规程【M44-A2，2013】推荐的琼脂二倍稀释法测定受试样品对所试菌株的最低抑菌浓度(Minimal Inhibitory Concentration，MIC)。
培养基及培养条件：
培养基：沙氏琼脂培养基
培养条件：35-37℃孵育48h观察结果。
表1.体外抗菌活性筛选的受试临床分离菌株
菌株名称 株数
白色念珠菌(CA) 3株
克柔念珠菌(CK) 3株
近平滑念珠菌(CP) 4株
热带念珠菌(CT) 4株
克柔念珠菌ATCC6258(CK(ATCC6285)) 1株
新型隐球菌ATCC32609(CN(ATCC32609)) 1株
烟曲霉菌ATCC96918(AF(ATCC96918)) 1株
1.2实验方案：
采用美国临床和实验室标准协会(Clinical and Laboratory Standards Institute,CLSI)抗真菌药物敏感性试验操作规程【Method for Antifungal Disk Diffusion Susceptibility Testing of Yeast；Approved Guideline-Second Edition(Vol,29,No.17)；M44-A2】推荐的琼脂二倍稀释法测定化合物对真菌的最低抑菌浓度(Minimal Inhibitory Concentration，MIC)；具体方法：于无菌平皿内加入1ml药液，再加入融化的50℃沙氏琼脂培养基14ml，混匀，使其每皿内所含药物终浓度依次为128、64、32、16、8、4、2、1、0.5、0.25、0.125、0.06、0.03、0.015、0.008mg/L；待冷却后用多点接种仪(MIT-P,SUKUMA)接种真菌，接种菌量约为10 4CFU/ml，盖上皿盖。置于35-37℃培养箱内培养。培养48h后观察记录结果。以平皿内未见菌生长的药物最低浓度，判断为最低抑菌浓度(Minimal Inhibitory Concentration，MIC)。质控化合物采用注射用两性霉素B，质控菌株采用克柔念珠菌ATCC 6258。其MIC参考值标准参考CLSI2016(Reference Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts；Fourth Informational Supplement；M27-S4)，注射用两性霉素B对标准质控菌株的MIC参考范围见下表2。
表2两性霉素B对标准质控菌的MIC范围(CLSI2012的判断标准)
Figure PCTCN2022102461-appb-000054
1.3本发明化合物的体外抗真菌实验结果
结果见表3中所示：
表3双酰胺修饰的两性霉素B衍生物的体外抗真菌活性(MIC,μg/mL)
Figure PCTCN2022102461-appb-000055
Figure PCTCN2022102461-appb-000056
续表3双酰胺修饰的两性霉素B衍生物的体外抗真菌活性(MIC,μg/mL)
Figure PCTCN2022102461-appb-000057
续表3双酰胺修饰的两性霉素B衍生物的体外抗真菌活性(MIC,μg/mL)
Figure PCTCN2022102461-appb-000058
Figure PCTCN2022102461-appb-000059
续表3双酰胺修饰的两性霉素B衍生物的体外抗真菌活性(MIC,μg/mL)
Figure PCTCN2022102461-appb-000060
由表3可知，羧基端进行酰基肼衍生化的化合物V-(1-9)对白色念珠菌，克柔念珠菌，新型新球菌的活性优于两性霉素B，其中，化合物V-2在该系列中抗菌活性最强，抗菌活性明显优于两性霉素B。双酰胺取代的两性霉素B衍生物V-(10-29)，大部分化合物相比于两性霉素B对于各类真菌均有更强的体外抗菌活性。尤其是化合物V-12,V-13,V-17,V-18,V-20,V-22，V-25，V-26，V-27，V-28和V-29的综合抗菌活性显著优于两性霉素B。其中V-29与两性霉素B相比白色念珠菌活性提高62-250倍，克柔念珠菌活性提高4-8倍，近平滑念珠菌活性提高2-16倍，热带念珠菌活性提高16-32倍。
总之，本发明的化合物具有优良的体外抗菌活性，代表化合物的体外抗菌活性明显优于两性霉素B。
测试例2本发明化合物体外溶血活性实验
2.1实验方案：
本实验所用细胞为人血红细胞(Human Red Blood Cell)，将其制备为悬浮液(浓度为4 x 10 8cells/mL)待用。所有待测化合物均用二甲亚砜溶解待用。在1.5mL的PCR管中加入736μL的PBS溶液和14μL的代测化合物的二甲亚砜溶液，最后加入750μL的人红细胞悬浮液。在最终的溶液中，使得待测化合物的溶度为200,150,100,80,50,30,20,10,5,1μM(根据实际情况选取最高药物浓度)。每个实验均开展一个空白对照实验(只有二甲亚砜，不加待测化合物)和一个阳性对照试验(加入1％Triton X100)。而后，将PCR管在37℃下孵化培养1h后，在4℃下离心(1500g)5分钟。取上清液于560nm处观测它们的光密度(OD 560)。化合物在特定浓度下的裂解率的计算公式如下：
Figure PCTCN2022102461-appb-000061
其中，阳性对照实验组计为100％的人红细胞裂解。最后，用GraphPad Prism 6计算出各个化合物裂解50％的人血红细胞的浓度，并计为EC 50(μM)。
2.2本发明化合物的体外溶血活性实验结果
表4部分两性霉素B衍生物的体外溶血活性
Figure PCTCN2022102461-appb-000062
从上表可知，本发明的化合物相比于两性霉素B而言，本发明化合物体外溶血活性有大幅度的改善，尤其是化合物V-15,V-29相比于两性霉素B其溶血活性分别降低了19倍、56倍。表明本发明的化合物相比于两性霉素B具有更低的溶血毒性，安全性达到大幅提升。
结合上述表3的体外抗菌活性结果，充分说明本发明的化合物相比于两性霉素B具有更大的治疗窗，更高的疗效指数。
测试例3本发明化合物小鼠体内药代动力学试验
3.1实验方案：
本实验选取健康雄性CD-1小鼠，体重18-22g(来自中国科学院上海实验动物中心)，静脉注射给予被试化合物和两性霉素B。给药方案如下表5所示：
表5待测化合物的给药方案
化合物 动物数 给药途径 给药剂量
V-15 3 静脉注射 1mg/kg
V-27 3 静脉注射 1mg/kg
V-29 3 静脉注射 1mg/kg
两性霉素B 3 静脉注射 1mg/kg
试验前禁食12h，自由饮水。给药(药物以DMSO:PEG300:EtOH:NaCl＝5:40:5:50,v/v/v溶解)后2h统一进食。每只动物经股静脉取血约25μL,置于肝素抗凝管中，血液样本置于冰上，并于30分钟之内离心分离血浆(5000rpm，10分钟，4℃)。采血时间点为：给药后0.05h,0.25h,0.75h,2h,4h,8h和24h。收集的血浆于-20℃冰箱中保存。
3.2本发明化合物小鼠体内药代动力学试验结果
小鼠静脉注射给予化合物V-15、V-27和V-29、两性霉素B的药代动力学参数见表6。
表6小鼠静脉注射V-15、V-27和V-29、两性霉素B的主要药动力学参数(1mg/kg，N＝3)
Figure PCTCN2022102461-appb-000063
从表6可知，经静脉注射给药后，本发明代表性化合物V-15,V-27和V-29与两性霉素B相比，清除率分别降低了76％、77％和87％。分别达到了0.95，0.91和0.53mL/min/kg,从而导致药物暴露量增加4.3、4.6和7.1倍。特别是V-29代谢性质最优，明显优于两性霉素B。这些数据表明本发明化合物代谢性质更优，更好的成药性质，而这可能是因为本发明化合物双酰胺取代，破坏了两性霉素B分子的两性性质，从而降低了它形成分子间聚集物的能力，使其更有利于结合麦角固醇产生抗菌活性而非胆固醇产生毒性。
测试例4本发明化合物体内抗真菌活性试验
4.1实验方案：
本实验选取健康KM小鼠，体重18-22g，经隔离检疫后，随机分组，自由饮食，自由饮水。感染源选用白色念珠菌(菌株为20-1)，分别测试化合物V-31及对照药Amphamide glutamate(ACS Infect.Dis.2020,6,2029-2044)单次静脉注射给予对白色念珠菌系统感染小鼠的疗效。待测药物用生理盐水进行配制并稀释成所需浓度溶液，现配现用。
4.1.1菌液配备
从24h培养的沙氏琼脂平皿中挑选几个菌落直接在无菌生理盐水中制成菌悬液。调整菌悬液的浓度为0.5-2.0麦氏比浊度。将校正后的菌液用生理盐水进行稀释备用，现配现用。
4.1.2最低致死菌量测定
取健康小白鼠，随机分组，每组5只小鼠，雌雄各半。感染前4天和感染前1天分别腹腔注射150、100mg/kg的环磷酰胺致小鼠免疫抑制。感染当天，吸取上述不同稀释浓度菌液，分别尾静脉注射入小鼠体内，每鼠0.5ml，感染后观察7-14天，并记录小鼠死亡数，以引起小鼠100％死亡的最低菌量作为最小致死菌量(MLD,Minimal Lethad Dose)，用该菌量作为体内试验的感染菌量。
4.1.3体内抗真菌活性实验
将小鼠于试验前18小时停食供水，随机分组，每组8只小鼠，雌雄各半。在接种前第4天和第1天分别腹腔注射150、100mg/kg环磷酰胺，感染当天吸取最低致死菌量菌液，尾静脉注射入小鼠体内，每鼠0.5ml，建立白色念珠菌所致系统感染小鼠模型。各给药组动物感染菌液后1h，按照设计剂量单次尾静脉注射给予药物。感染对照组动物感染后1h单次尾静脉注射给予等体积生理盐水。给药后7-14天，每天观察并记录动物的存活情况。根据小鼠死亡数，按Bliss法计算半数有效剂量ED 50及95％可信限，并进行统计学处理。
4.2本发明化合物小鼠体内抗真菌活性试验结果
[根据细则91更正 13.07.2022]　
化合物V-31和Amphamide glutamate对白色念珠菌感染小鼠的体内抗真菌活性(单次静脉注射给药，N＝8)见表7。
[根据细则91更正 13.07.2022]　
表7化合物V-31和Amphamide glutamate对白色念珠菌感染小鼠的体内抗真菌活性(单次静脉注射给药，N＝8)
[根据细则91更正 13.07.2022]　
Figure WO-DOC-FIGURE-1
[根据细则91更正 13.07.2022]　
从表7可知，单次静脉给药时，本发明代表性化合物V-31与对照药Amphamide glutamate相比，对白色念珠菌感染小鼠的体内抗真菌活性提高了约1.5倍，与两性霉素B(ED 50＝1.08mg/kg，ACS Infect.Dis.2020,6,2029-2044)相比，体内抗真菌活性 更是提高了约4倍。
结合溶血活性实验和体内药代动力学试验结果，本发明代表性化合物V-29与两性霉素B相比，毒性大幅降低，同时活性明显提高，可大幅扩大治疗窗，并表现出更优的药代动力学性质，具有明显的成药优势。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种如下式V所述的化合物，或其药学上可接受的盐：
    Figure PCTCN2022102461-appb-100001
    其中，
    各个R 1各自独立地选自下组：-NR 4-(L) p-Ra；其中，Ra选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基，取代或未取代的C 1-C 6氨基、-NH 2、取代或未取代的-NH-C 1-C 10烷基、取代或未取代的-NH-C(O)C 1-C 10烷基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、或取代或未取代的苯并5-6元杂芳基、以及-COR 3；
    L选自下组：(CH 2) n、(CH 2OCH 2) m、NH、NHC(O)；其中，当所述的各个CH 2和NH单独或作为其他基团的一部分出现时，可以任选地被取代；
    R 2各自独立地选自下组：H、-C(O)(L) p-Rc；其中，Rc各自独立地选自下组：(CH 2) nNHR 4、NHR 4、或取代或未取代的3-8元杂环基(优选为含氮杂环基)；且当R 2为H时，R 1为-NR 4-(L) p-Ra，且R 1基团中至少一个L为NH或NHC(O)；
    R 3各自独立地选自下组：NH 2、取代的或未取代的C 1-C 10烷基、取代或未取代的苯基、取代或未取代的五元或六元杂芳香基、或取代或未取代的苯并五元或六元杂芳香基；
    R 4各自独立地选自下组：H、取代或未取代的C 1-C 6烷基；
    或R 4与(L) p-Ra，以及相连的N原子共同构成取代或未取代的5-12元杂环基、或取代或未取代的5-12元杂芳基；其中，所述的5-12元杂环基或5-12元杂芳基可以具有一个Rb取代基，且所述的Rb取代基选自下组：羟基、未取代或羟基取代的C 1-C 10烷基、取代或未取代的5-12元杂环基；
    p选自下组：0、1、2或3；
    n选自下组：0、1、2、3、4、5、6、7或8；
    m选自下组：0、1、2、3、4、5、6、7、8、9或10；
    除非特别说明，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、氧代、羧基、氰基、羟基、5-6元杂环、C1-C6烷基、C1-C6烷氧基、C3-C8环烷基取代、氨基、N，N-二甲基氨基、巯基、C 1-C 6砜基、-(CH 2OCH 2) nOH、(CH 2OCH 2) nOR 4、(CH 2OCH 2) nNH 2、(CH 2OCH 2) nNHR 4、(CH 2OCH 2) nN(R 4) 2。
  2. 如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述的R 1选自下组：-NR 4(CH 2) nR 5、-NHCH 2CH 2NH 2、
    Figure PCTCN2022102461-appb-100002
    Figure PCTCN2022102461-appb-100003
    其中，R 5选自下组：H、取代或未取代的C 1-C 6烷基、取代或未取代的5-12元杂环基；
    R 6选自下组：H、OH、取代或未取代的C 1-C 6烷基、取代或未取代的5-12元杂环基。
  3. 如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述的R 2选自下组：
    Figure PCTCN2022102461-appb-100004
    Figure PCTCN2022102461-appb-100005
  4. 如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述的化合物选自下表：
    Figure PCTCN2022102461-appb-100006
    Figure PCTCN2022102461-appb-100007
    Figure PCTCN2022102461-appb-100008
    Figure PCTCN2022102461-appb-100009
  5. 如权利要求1所述的化合物，或其药学上可接受的盐的制备方法，其特征在于，包括步骤：
    Figure PCTCN2022102461-appb-100010
    在惰性溶剂中，用M-2化合物脱除保护基，得到式V化合物；
    较佳地，所述方法还包括步骤(1)和(2)：
    Figure PCTCN2022102461-appb-100011
    (1)在惰性溶剂中，用AmB与化合物
    Figure PCTCN2022102461-appb-100012
    反应，得到式M-1化合物；
    Figure PCTCN2022102461-appb-100013
    (2)在惰性溶剂中，用M-1与化合物R 1H反应，得到式M-2化合物；
    其中，所述的PG为胺基保护基；所述的R 2'选自下组：化学键，-C(O)(L) p-Rc'；其 中，Rc'为Rc失去一个氢原子形成的基团；且当R 2'为化学键时，R 1为-NR 4-(L) p-Ra，且R 1基团中至少一个L为NH或NHC(O)；
    其余各基团的定义如权利要求1中所述。
  6. 如权利要求1所述的化合物，或其药学上可接受的盐的制备方法，其特征在于，包括步骤：
    Figure PCTCN2022102461-appb-100014
    在惰性溶剂中，用M-4化合物脱除保护基，得到式V化合物；
    较佳地，所述的方法还包括步骤(a)和(b)：
    Figure PCTCN2022102461-appb-100015
    (a)在惰性溶剂中，用AmB与化合物
    Figure PCTCN2022102461-appb-100016
    反应，得到式M-3化合物；
    Figure PCTCN2022102461-appb-100017
    (b)在惰性溶剂中，用式M-3化合物与化合物PG-R 1'H反应，得到式M-4化合物；
    其中，所述的PG为胺基保护基；
    所述的R 1'为R 1失去一个H原子形成的基团；
    所述的R 2'选自下组：化学键，-C(O)(L) p-Rc'；其中，Rc'为Rc失去一个氢原子形成的基团；且当R 2'为化学键时，R 1为-NR 4-(L) p-Ra，且R 1基团中至少一个L为NH或NHC(O)；
    其余各基团的定义如权利要求1中所述。
  7. 一种药物组合物，其特征在于，包含如下组分：
    1)治疗有效量的一种或多种权利要求1所述化合物、或其光学异构体、其药学上可接受的盐、水合物、溶剂合物；和
    2)药学上可接受的载体或赋形剂。
  8. 一种权利要求1所述化合物，或其光学异构体、其药学上可接受的盐、水合物、溶剂合物的用途，其特征在于，用于制备预防或治疗治疗真菌感染引起的感染性疾病的药物组合物。
  9. 如权利要求8所述的用途，其特征在于，所述的真菌选自下组：念珠菌、新型隐球菌、曲霉菌(优选黄曲霉菌、烟曲霉菌、土曲霉菌、黑曲霉菌)、结合菌、皮肤真菌，或其组合。
  10. 一种如权利要求1所述的式V化合物的制备中间体，其特征在于，所述的中间体选自下组：
    Figure PCTCN2022102461-appb-100018
    其中，所述的PG为胺基保护基，与其相连的胺基N构成氨基甲酸酯、酰胺、N-烷基胺或N-芳基胺优选地，上述保护基选自Fmoc，Boc，Cbz，Alloc，Teoc，甲氧羰基或乙氧羰基，Tfa，Pht，Tos，Ns，特戊酰基，苯甲酰基，Bn，PMB，Trt，Dmb；较佳地选自下组：Fmoc、Boc、Tos、Cbz；更佳地为Fmoc；
    所述的R 1'为R 1失去一个H原子形成的基团；R 2'选自下组：化学键，-C(O)(L) p-Rc'；其中，Rc'为Rc失去一个氢原子形成的基团；且当R 2'为化学键时，R 1为-NR 4-(L) p-Ra，且R 1基团中至少一个L为NH或NHC(O)；其余各基团的定义如权利要求1中所述。
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WO1993017034A1 (en) * 1992-02-19 1993-09-02 Smithkline Beecham Plc Amphotericin b derivatives
WO1999051274A1 (fr) * 1998-04-07 1999-10-14 Universite Pierre Et Marie Curie (Paris Vi) Derives de macrolide polyenique, utilisation pour la vectorisation de molecules
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