WO2020119773A1 - Dérivé peptidique de l'amphotéricine b - Google Patents

Dérivé peptidique de l'amphotéricine b Download PDF

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WO2020119773A1
WO2020119773A1 PCT/CN2019/124970 CN2019124970W WO2020119773A1 WO 2020119773 A1 WO2020119773 A1 WO 2020119773A1 CN 2019124970 W CN2019124970 W CN 2019124970W WO 2020119773 A1 WO2020119773 A1 WO 2020119773A1
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gly
aeeac
pharmaceutically acceptable
acceptable salt
compound according
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PCT/CN2019/124970
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English (en)
Chinese (zh)
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东圆珍
冯军
张喜全
张金华
赵文杰
朱冰
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上海医药工业研究院
正大天晴药业集团股份有限公司
上海多米瑞生物技术有限公司
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Priority to CN201980079769.8A priority Critical patent/CN113166188B/zh
Publication of WO2020119773A1 publication Critical patent/WO2020119773A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • 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
    • 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
    • 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
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicine, and relates to amphotericin B peptide derivatives, preparation methods and applications thereof, and specifically relates to a series of amphotericin B peptide derivatives with high solubility, low toxicity and good antibacterial activity And its synthetic preparation and application.
  • Amphotericin B is a polyene broad-spectrum antifungal drug, suitable for the treatment of the following fungal infection diseases: Candidiasis, Cryptococcosis, Blastomycosis ), coccidioidomycosis, mucormycosis caused by Mucor, sporothrichosis caused by Sporothrix, and most of Aspergillus ) Caused by aspergillosis (aspergillosis) and so on.
  • amphotericin B Since the amphotericin B was isolated from metabolites of Streptomyces in 1955, this compound has attracted much attention.
  • amphotericin B is the gold standard for clinical treatment of deep fungal infections and systemic systemic infections, and it is the only effective therapeutic drug for certain fatal systemic fungal infections; on the other hand, at therapeutic doses, Amphotericin B has serious toxic and side effects, such as hemolytic toxicity, nephrotoxicity, neurotoxicity, etc., and amphotericin B has very poor water solubility. After oral administration of this product, it is less and unstable from the gastrointestinal tract. The application of amphotericin B is greatly restricted.
  • amphotericin B liposomes are made of vesicles formed by phospholipid bilayer membranes wrapped with drug molecules and targeted
  • the new drug with drug delivery function is better tolerated than ordinary preparations. On the one hand, it can be distributed more in the liver, spleen, and lungs, while in other organs, especially in kidney tissue, the concentration is lower.
  • the cholesterol component in liposomes can reduce the binding of drugs to cholesterol in human cells and enhance the binding of ergosterol to fungal cells, with relatively few side effects on the kidneys and the like.
  • amphotericin B liposome preparations also have the following disadvantages: First, the antibacterial activity of liposome preparations is inferior to amphotericin B, and the therapeutic dose needs to be increased. Second, the cost of liposome preparations is higher. The price is relatively expensive. 3. The instability of the liposome itself. 4. The liposome preparation has not fundamentally eliminated the nephrotoxicity and side effects of amphotericin B.
  • amphotericin B used as the lead compound, a solid phase and liquid phase combined experimental method ,Peptide reaction of amphotericin B to synthesize a series of amphotericin B peptide derivatives, including H-(Gly)n-OH or hydrophilicity formed by combining AEEAc and Gly (n is an integer, the range is 2-10) Series of amphotericin B peptide derivatives, while retaining their antibacterial activity, improve their water solubility, and even further reduce their hemolytic toxicity, nephrotoxicity and other toxic side effects.
  • the present invention relates to amphotericin B peptide derivatives and their synthetic preparation methods and applications, in particular to improving the solubility of amphotericin B and reducing the toxicity of amphotericin B, while retaining the antibacterial activity of amphotericin B Amphotericin B peptide derivative and its synthetic preparation method and application.
  • amphotericin B peptide derivative specifically refers to the synthesis of R 2 -(Gly)n-OH or AEEAc combined with Gly by using R 2 -AEEAc-OH and R 2- Gly-OH as raw materials and adopting the solid phase synthesis method
  • the resulting series of compounds are then coupled with amphotericin B through an amide bond, and finally the amino protecting group is removed, and then purified to obtain the target compound.
  • the invention relates to compounds of general formula [I] or derivatives thereof:
  • R 1 is a hydrophilic polymer part
  • R 2 is an amino protecting group such as Fmoc, Boc or H
  • R 3 is H or C 1-4 hydrocarbon group or phenyl
  • R 4 is OH or H
  • the hydrophilic polymer part may be a H-(Gly)n-OH polymer part containing H-Gly-OH monomer, where n takes an integer of 2-20, preferably n takes 2 -15 integer, optimally, n is 5
  • the hydrophilic polymer part may also be a polypeptide part composed of Gly and AEEAc through a peptide bond, the length of the polypeptide part is 2-20 peptides, preferably 2- 15 peptides, optimally, 5 peptides.
  • the present invention relates to the synthetic preparation of amphotericin B peptide derivatives.
  • the present invention relates to the derivative having improved anti-fungal activity while improving solubility and even further reducing toxicity.
  • the present invention relates to water-soluble polypeptide compounds, including but not limited to H-(Gly)n-OH or a polypeptide composed of Gly and AEEAc through a peptide bond.
  • amphotericin B derivative referred to in the present invention is connected by an amide bond.
  • the amphotericin B derivative mentioned in the present invention comprises: a water-soluble polypeptide part, which is connected to the sugar amine structure on the amphotericin B through a stable amide bond, so this type of compound It can be referred to as amphotericin B polypeptide derivative (DTY-AMB) for short.
  • the water-soluble polypeptide refers to a polypeptide in which H-(Gly)n-OH or AEEAc is combined with Gly
  • the water-soluble polypeptide part refers to a part formed by removing the -OH and -H from the terminal amino acid in the corresponding polypeptide .
  • DTY-AMB also contains a class of derivatives where the carboxyl group on C 16 is esterified, such as hydrocarbyl esters.
  • T is a polymer containing Gly or Gly derivatives, or a combination polypeptide composed of AEEAc and Gly and derivatives thereof.
  • R 1 is selected from -(Gly)n-, -(AEEAc)n-Gly-, -(AEEAc-Gly)n-AEEAc-, -AEEAc-Gly-, -(AEEAc-Gly)n -, -(Gly-AEEAc)n-Gly-, -(AEEAc)n-Gly-(AEEAc)m-, -(AEEAc)n-(Gly)m- and -(Gly)n-AEEAc-(Gly) m-, where n and m are each independently an integer of 2-9.
  • R 1 is selected from -(AEEAc)n-Gly-, -(AEEAc-Gly)n-AEEAc-, -(AEEAc-Gly)n-, -(Gly-AEEAc)n-Gly- and -(AEEAc ) n-Gly-(AEEAc)m-, wherein n and m are each independently an integer of 2-9 and at the same time satisfy the number of AEEAc in R 1 is greater than or equal to 3.
  • R 2 is H.
  • R 3 is H.
  • R 2 is an amino protecting group such as Fmoc, Boc or H
  • R 3 is H or C 1-4 hydrocarbon group or phenyl
  • R 4 is OH or H
  • the hydrophilic polypeptide part may be T (T is composed of Gly or a combination of AEEA and Gly), where the length of T is 2-10 peptides, preferably 3-7 peptides, and most preferably 5 peptides.
  • the hydrophilic polypeptide part of DTY-AMB has different lengths, and may contain 2-20 monomers, preferably, 2-10 monomers, and optimally, 5 monomers, In the present invention, DTY-AMB may contain 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 monomers .
  • the monomer may be Gly, or Gly and AEEAc.
  • the hydrophilic polypeptide part of DTY-AMB is T, and T has different lengths, and may contain 2-10 monomers, preferably, 3-7 monomers, and optimally, 5 Monomers, in some specific embodiments, DTY-AMB may contain 2, 3, 4, 5, 6, 7, 8, 9, 10 monomers.
  • the monomer may be Gly, or Gly and AEEAc.
  • the C 16 position of DTY-AMB contains a free carboxyl group or a hydrocarbyl ester of carboxyl group, including methyl ester, ethyl ester, propyl ester, butyl ester, phenyl ester and the like.
  • the DTY-AMB containing the hydrophilic polypeptide part T has good bacteriostatic activity, and at the same time, it is not easily hydrolyzed by enzymes because it is connected by an amide bond.
  • the invention relates to compounds of formula [II] or derivatives thereof, wherein: R 3 is H; R 2 -T- is selected from:
  • the present invention relates to compounds of formula [II] or derivatives thereof, wherein R 3 is H; R 2 -T- is H-AEEAc-XYZ-AEEAc-; X is AEEAc or Gly, and Y is AEEAc Or Gly, and Z is AEEAc or Gly.
  • the invention relates to compounds of formula [III] or derivatives thereof:
  • the invention relates to compounds of formula [IV] or derivatives thereof:
  • the compound of the present invention is a compound of the following formula or a derivative thereof, wherein the peptide modification site may be an amino group in AMB, that is, an amino group of a glycosamino group:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method for preventing and/or treating fungal infections in a subject in need thereof, wherein the subject is administered a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof.
  • the fungal infection is selected from fungal infections such as Cryptococcus, Blastomyces dermatitis, Candida albicans, Candida krusei, and Candida parapsilosis, Coccidioides immitis, Mucor, Sporothrix schenckii, and Aspergillus fumigatus.
  • the subject has Cryptococcosis, Blastomycosis, Candidiasis, Coccidioidomycosis, mucormycosis caused by Mucor , Sporrotrichosis caused by Sporothrix, aspergillosis caused by most Aspergillus.
  • the present invention relates to the use of the above compounds or pharmaceutically acceptable salts thereof for the preparation of medicaments, such as antifungal drugs.
  • the fungus is selected from, for example, Cryptococcus, dermatitis, Candida albicans, Candida krusei, Candida parapsilosis, Coccidioides sphaeroides, Mucor spp., S. sclerotiorum and Aspergillus fumigatus.
  • the above-mentioned compound of the present invention or a pharmaceutically acceptable salt thereof has considerable antifungal activity, and has improved solubility, and may even further have reduced toxicity.
  • the present invention relates to the above compounds or pharmaceutically acceptable salts thereof for preventing and/or treating fungal infections.
  • the fungal infection is selected from the group of fungal infections such as Cryptococcus, Blastodermatitis, Candida albicans, Candida krusei, Candida parapsilosis, Coccidioides, Mucor, Mycet Schenck or Aspergillus fumigatus.
  • the above compound or a pharmaceutically acceptable salt thereof is used to treat diseases caused by fungal infections selected from the group consisting of cryptococcosis, blastomycosis, candidiasis, coccidioidomycosis, and mucormycosis caused by mucormycosis , Spore hyphae caused by spore hyphae, aspergillosis caused by most aspergillus.
  • diseases caused by fungal infections selected from the group consisting of cryptococcosis, blastomycosis, candidiasis, coccidioidomycosis, and mucormycosis caused by mucormycosis , Spore hyphae caused by spore hyphae, aspergillosis caused by most aspergillus.
  • the above-mentioned compound of the present invention or a pharmaceutically acceptable salt thereof has considerable antifungal activity, and has improved solubility, and may even further have reduced toxicity.
  • the present invention relates to a method for preparing the above compound or a pharmaceutically acceptable salt thereof.
  • the method includes: (1) solid-phase synthesis of a polypeptide on a resin, cleaving the resulting polypeptide product with a weak acid, and filtering, Rotate steam, then add the first organic solvent to dissolve, spin steam, precipitate with the second organic solvent, and dry to obtain the polypeptide containing the amino protecting group; (2) Activate the polypeptide containing the amino protecting group, and then in anhydrous The reaction with amphotericin B in the solvent is carried out in the presence of a catalyst amount of base; and optionally, (3) the amino protecting group of the polypeptide portion containing the amino protecting group is removed.
  • the weak acid described in step (1) includes but is not limited to trifluoroethanol, and the weak acid can be formulated with dichloromethane at 1:4 (V/V) as a weak acid solution.
  • the first organic solvent in step (1) may be selected from DCM and THF.
  • the second organic solvent in step (1) may be selected from diethyl ether, isopropyl ether, and methyl tert-butyl ether.
  • the anhydrous solvent described in step (2) is selected from DMF and DMSO.
  • the base described in step (2) includes but is not limited to N,N-diisopropylethylamine (DIEA).
  • DIEA N,N-diisopropylethylamine
  • a removal agent selected from the following group is used to remove the amino protecting group: piperidine (PIP) solution, preferably 10 wt% to 40 wt% PIP in DMF solution, more preferably 20 wt% to 25 wt% PIP Of DMF solution.
  • PIP piperidine
  • the invention relates to a compound selected from the following or a pharmaceutically acceptable salt thereof:
  • HT- is any one selected from the following:
  • the main pathogen of deep fungal infections is still Candida albicans, and the phenomenon of drug resistance is also the most prominent. Therefore, the prevention and treatment of deep infections of Candida albicans is also the focus of the research field of antifungal infections.
  • the water-soluble polymer part T DTY-AMB has a good antibacterial effect on Candida albicans.
  • DTY-AMB can be in the form of a pharmaceutically acceptable salt.
  • DTY-AMB can be used as an effective pharmaceutical ingredient for oral preparations; it can also be used as an effective pharmaceutical ingredient for injections, such as intravenous injection, subcutaneous injection, intramuscular injection, etc.; and can also be used as an effective pharmaceutical ingredient for topical medications.
  • DTY-AMB can be made into an effective dosage unit of medicine through the existing medical technology.
  • the effective dosage unit can be in the form of oral, tablet, capsule or liquid.
  • the pharmaceutical ingredient can be made into a preparation containing water, wherein the water content is not less than 50%.
  • Oral preparations can be in the form of liquids, suspensions, powders, tablets, and capsules; tablets containing various excipients (such as calcium carbonate, calcium phosphate, etc.) can also be made into disintegrating preparations.
  • excipients such as calcium carbonate, calcium phosphate, etc.
  • the pharmaceutical ingredients can be released in a controlled manner, including slow release or rapid release, and the controlled release dosage of the relevant pharmaceutical ingredients can be achieved by known pharmaceutical techniques.
  • the pharmaceutical composition may contain 0.1%-99.9% DTY-AMB (DTY-AMB is calculated by weight), and the optimal content is 1%-70%.
  • Figure 3 is the general route of DTY-AMB chemical synthesis.
  • the chemical synthesis of DTY-AMB includes the first, second and third steps below.
  • the first step includes solid phase synthesis of polypeptide R 2 -T and activation of the series of polypeptides.
  • the present invention provides a method for synthesizing the series of polypeptides. In some aspects, the method includes: synthesizing the series of polypeptides. In some schemes, solid-phase synthesis technology can be used to prepare the series of polypeptides, including:
  • step (1) The product of step (1) is cleaved with a weak acid, filtered, and rotary evaporation, then the appropriate amount of organic solvent is added to dissolve the peptide, rotary evaporation is repeated, repeated 2-3 times, and finally the organic solvent is precipitated and dried to obtain the target polypeptide .
  • the step (1) includes the following steps:
  • the amino protecting group includes but is not limited to tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenyl-methylcarbonyl (Fmoc), preferably 9-fluorenyl-methylcarbonyl (Fmoc), etc.
  • the protective group includes but is not limited to this, and a reasonable choice can be made according to specific circumstances.
  • an appropriate amount of R 2 -AEEAc-OH or R 2 -Gly-OH is weighed and an appropriate amount of high steric hindered base is taken, added with DCM, for example, 10 mL of DCM to dissolve, and then put into the reactor.
  • the high steric hindrance reagents include but are not limited to N,N-diisopropylethylamine (DIEA).
  • an amino protecting group removing agent for example 1mL 20% PIP/DMF
  • the solvent used in the liquid phase environment of the step (a) is selected from dimethylformamide (DMF), dichloromethane (DCM), N-methylpyrrolidone (NMP), preferably DCM and DMF.
  • DMF dimethylformamide
  • DCM dichloromethane
  • NMP N-methylpyrrolidone
  • the removal agent of the amino protecting group needs to be added with a removal agent of the amino protection group.
  • the removal agent of the amino protection group is a piperidine (PIP) solution with a concentration of 10%-40% (PIP/DMF).
  • PIP piperidine
  • the removal time is 20-50 min; the preferred concentration is 20%-25% (PIP/DMF) and the removal time is 25-35 min.
  • the coupling of the amino acid in the step (a) requires the addition of a coupling reagent.
  • the coupling reagent is composed of a carbodiimide type reagent or a benzotriazolium salt type reagent and 1-hydroxybenzotriazole (HOBt).
  • the carbodiimide type reagents include but are not limited to dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or N-diaminopropyl-N-ethylcarbodiimide (EDC).
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDC N-diaminopropyl-N-ethylcarbodiimide
  • the benzotriazonium salt type reagents include but are not limited to 2-(1H-benzotriazo L-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate (TBTU), O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), hexafluorophosphate benzotriazole-1-oxytris(dimethylamino) Phosphorus (BOP) or hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidinyl phosphorus (PyBOP).
  • 2-(1H-benzotriazo L-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate TBTU
  • HBTU O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate
  • BOP hexaflu
  • the coupling reagent is preferably diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBt), or 2-(1H-benzotriazo L-1-yl)-1,1 , 3,3-tetramethylurea tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole (HOBt), further preferably DIC (diisopropylcarbodiimide) and 1-hydroxybenzotriazole (HOBt).
  • DIC diisopropylcarbodiimide
  • HOBt 2-(1H-benzotriazo L-1-yl)-1,1 , 3,3-tetramethylurea tetrafluoroborate
  • TBTU 3,3-tetramethylurea tetrafluoroborate
  • TBTU 3,3-tetramethylurea tetrafluoroborate
  • TBTU 3,3-tetramethylurea tetrafluoroborate
  • HBt 1-hydroxybenz
  • the "monitoring" in the step (a) uses a ninhydrin detection method to monitor the condensation reaction of the polypeptide.
  • the sequential coupling of amino acids in the step (a) refers to linking amino acids one by one from the C-terminus to the N-terminus according to the amino acid sequence of the polypeptide.
  • the weak acid described in step (2) includes but is not limited to trifluoroethanol, and the weak acid can be formulated with dichloromethane at 1:4 (V/V) as a weak acid solution.
  • the other part of the reaction in the first step is the activation of a polypeptide containing an amino protecting group, wherein the polypeptide T is a 2-10 peptide, preferably a 3-7 peptide, and most preferably a 5 peptide.
  • the activation of the polypeptide carboxyl group includes: activated ester method, symmetric anhydride method, azide method, etc., preferably a milder activated ester method; used activation reagent: carbodiimide type reagent or benzotriazonium salt type reagent It is composed of 1-hydroxybenzotriazole (HOBt) or succinimide (HOSU).
  • the carbodiimide type reagents include but are not limited to dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or N-diaminopropyl-N-ethylcarbodiimide (EDC).
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDC N-diaminopropyl-N-ethylcarbodiimide
  • the benzotriazonium salt type reagents include but are not limited to 2-(1H-benzotriazo L-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate ( TBTU), O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), hexafluorophosphate benzotriazole-1-oxytris(dimethylamino) Phosphorus (BOP) or hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidinyl phosphorus (PyBOP), preferably diisopropylcarbodiimide (DIC) and hydroxysuccinimide (HOSU);
  • the solvent in the liquid phase system used for activation is preferably an organic solvent, including DMF, DMSO, DCM, THF, etc., preferably THF (tetrahydrofuran).
  • the amino protecting group includes but is not limited to tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenyl-methylcarbonyl (Fmoc), preferably 9-fluorenyl-methylcarbonyl (Fmoc);
  • the activation of the ester is at 30°C for 1-2 hours.
  • the addition of a catalyst amount of base is beneficial to complete activation.
  • the base reagents include but are not limited to N,N-diisopropylethylamine (DIEA); after rotary evaporation, Compound 2 can be obtained by removing the organic solvent.
  • DIEA N,N-diisopropylethylamine
  • compound 2 is reacted with amphotericin B in an anhydrous solvent such as DMF and DMSO at room temperature for 1-2 hours.
  • the reaction requires protection from light.
  • a catalyst amount of base is beneficial to complete the reaction.
  • the base reagents include but are not limited to N,N-diisopropylethylamine (DIEA); compound 4 and compound 4 can be obtained
  • DIEA N,N-diisopropylethylamine
  • compound 4 and compound 4 can be obtained
  • Preparative purification can be performed by semi-preparative RP-HPLC.
  • the third step is to perform a deamino protecting group on the polypeptide containing an amino protecting group.
  • the amino protecting group includes but is not limited to tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenyl-methylcarbonyl (Fmoc), preferably 9-fluorenyl-methylcarbonyl (Fmoc); removal of the amino protecting group requires the addition of an amino protecting group removing agent.
  • the amino protecting group removing agent is piperidine (PIP) solution with a concentration of 10% -40% (PIP/DMF), the removal time is 20-50min; the preferred concentration is 20%-25% (PIP/DMF), the removal time is 25-35min.
  • 5-deoxyamphophilic B can also be used as a starting material instead of amphotericin B, 5-deoxyamphophilic B, that is, the group OH at the R 4 position of amphotericin B becomes H; related 5- Deoxyamphophilic B can be synthesized.
  • the preparation method of the amphotericin B peptide derivative provided by the present invention may further include a purification step.
  • the purification method used includes but is not limited to reverse phase chromatography or ion exchange chromatography, preferably reverse phase chromatography.
  • the in vitro antibacterial activity of the amphotericin B peptide derivative of the present invention can be identified by measuring its minimum inhibitory concentration (MIC).
  • MIC minimum inhibitory concentration
  • NCCLS National Committee for Clinical Laboratory Standardization
  • Amphotericin B was used as a positive control.
  • the in vitro activity measurement shows that the amphotericin B peptide derivative provided by the present invention has good activity against Candida albicans.
  • ethyl is "optionally” substituted with halogen, meaning that ethyl can be unsubstituted (CH 2 CH 3 ), mono-substituted (such as CH 2 CH 2 F), poly-substituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ).
  • halogen meaning that ethyl can be unsubstituted (CH 2 CH 3 ), mono-substituted (such as CH 2 CH 2 F), poly-substituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ).
  • C mn means that there are mn carbon atoms in this part.
  • carbon 3-10 cycloalkyl means that the cycloalkyl has 3-10 carbon atoms.
  • Carbon 0-6 alkylene means that the alkylene has 0-6 carbon atoms, and when the alkylene has 0 carbon atoms, the group is a bond.
  • C 1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. So, for example, if a group is replaced by 2 Rs, then each R has an independent option.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • acyl refers to a -CO- group.
  • hydroxyl refers to the -OH group.
  • amino refers to the -NH 2 group.
  • alkyl refers to a hydrocarbon group of the formula C n H 2n +.
  • the alkyl group may be linear or branched.
  • hydrocarbon 1-6 alkyl refers to a monovalent straight or branched chain aliphatic group containing 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl , Hexyl, 2-methylpentyl, etc.).
  • the alkyl portion (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.
  • alkoxy refers to -O-alkyl.
  • alkylthio refers to -S-alkyl.
  • alkylamino refers to -NH (alkyl).
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and can exist as a single ring, a condensed ring, or a spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3 to 10 membered ring, preferably a 3 to 8 membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamant Alkyl and so on.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ electron system.
  • the aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C, and has at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially 5 to 8 membered ring, or have multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , Tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced with a substituent, as long as the valence state of the specific atom is normal and the compound after substitution is stable.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive The toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • metal salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like can be mentioned .
  • metal salts include, but are not limited to, alkali metal salts, such as sodium salt, potassium salt, etc.; alkaline earth metal salts, such as calcium salt, magnesium salt, barium salt, etc.; aluminum salt, etc.
  • Non-limiting examples of salts with organic bases include, but are not limited to, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, Salt formed by dicyclohexylamine, etc.
  • Non-limiting examples of salts with inorganic acids include, but are not limited to, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Non-limiting examples of salts with organic acids include, but are not limited to, with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzene Salts formed by sulfonic acid, p-toluenesulfonic acid, etc.
  • Non-limiting examples of salts with basic amino acids include, but are not limited to, salts with arginine, lysine, ornithine, and the like.
  • Non-limiting examples of salts with acidic amino acids include, but are not limited to, salts with aspartic acid, glutamic acid, and the like.
  • pharmaceutical ingredient refers to one or more compounds of the present application or salts thereof and excipients, diluents, or carriers commonly used in the art for delivering biologically active compounds to organisms (eg, humans) Of the preparation.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to an organism.
  • pharmaceutically acceptable excipients, diluents, or carriers refers to those excipients, diluents, or carriers that do not have a significant stimulating effect on the organism and do not impair the biological activity and performance of the active compound.
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include such materials as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oil, Solvent, water and other raw materials.
  • polypeptide refers to a compound formed by connecting more than two amino acids through peptide bonds, such as but not limited to 2 peptide, 3 peptide, 4 peptide, 5 peptide, 6 peptide, 7 peptide, 8 peptide, 9 peptide, 10 Peptide, 15 peptide, 20 peptide.
  • AEEAc refers to 2-(2-(2-aminoethoxy)ethoxy)acetic acid.
  • Gly refers to glycine.
  • the present application also includes compounds of the present application that are the same as those described herein, but one or more atoms are replaced by an isotope labeled with an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature.
  • isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, 36 Cl, etc.
  • Certain isotopically-labeled compounds of the present application can be used in the analysis of compound and/or substrate tissue distribution. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred because of their ease of preparation and detection. In addition, substitution with heavier isotopes (such as deuterium (ie, 2 H)) can provide certain therapeutic advantages resulting from higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations The following may be preferred. Positron emission isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • PET positron emission tomography
  • the isotopically labeled compounds of the present application can generally be prepared by isotopically labeled reagents instead of unisotopically labeled reagents by the following procedures similar to those disclosed in the schemes and/or examples below.
  • the compounds of the present application can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthetic methods, and equivalents well known to those skilled in the art Alternatively, preferred embodiments include but are not limited to the examples of the present application.
  • Figure 1 shows the chemical structure of amphotericin B.
  • FIG. 2 shows the overall chemical structure of DTY-AMB containing T.
  • This structure contains a sugar amine structure with an amino group in the sugar amine.
  • the hydrophilic polypeptide part T (T is composed of Gly-OH or AEEAc-OH and Gly-OH (Combined) can be coupled to amphotericin B through a stable amide bond, which is not easily hydrolyzed by enzymes and is more stable in the body.
  • the solubility of amphotericin B is improved, on the other hand, the amphotericin B is reduced. Toxicity of mycin B.
  • Figure 3 depicts the general route of DTY-AMB chemical synthesis.
  • Figure 4 is a chemical structure diagram of the target product DMR078.
  • Figure 5 is the absorption spectrum of DMR078 and AMB;
  • Figure 5A shows the absorption spectrum of DMR078 and AMB (12.7 ⁇ g/mL) in methanol;
  • Figure 5B shows the DMR078 and AMB (in PBS buffer) 12.7 ⁇ g/mL);
  • FIG. 5C shows the absorption spectrum of DMR078 (62.4 ⁇ g/mL) in PBS buffer.
  • Amino acids are: Fmoc-AEEAc-OH and Fmoc-Gly-OH
  • Synthetic reagents HATU, DMF, DCM, DIEA, piperidine.
  • CS-BIO type peptide synthesizer Waters600 semi-preparative high-performance liquid chromatograph, Beckman centrifuge, Buchi rotary evaporator.
  • the crude product was purified by semi-preparative RP-HPLC under the following conditions.
  • the collected product was analyzed by Agilent 1260 HPLC under the following conditions.
  • the target components with a purity greater than 90% are collected, rotary evaporated, and freeze-dried.
  • Amino acid sequence 2-10 peptide containing Gly-OH, or AEEAc-OH and Gly-OH
  • amphotericin B peptide derivative of HT-AMB the synthesis method refers to compound DMR078, namely 1Fmoc-T (T is Gly, or a combination of AEEAc and Gly hydrophilic peptide, peptide Length range is 2-10); 2 Preparation of Fmoc-T-Osu; 3 Fmoc-T-Osu modifies the amino group of amphotericin B, piperidine removes Fmoc, and finally obtains the crude product of amphotericin B peptide derivative of HT-AMB.
  • the crude product was purified by RP-HPLC; according to the general formula [II], Table 3 lists the abbreviations and relative molecular masses of the compounds of this example:
  • amphotericin B and amphotericin B peptide derivative prepared by the same method as in Example 1.
  • their solubility was measured using double distilled water. The results are shown in Table 4.
  • H-G-A-G-A-G-AMB ⁇ 0.5 H-A-G-A-G-A-AMB(DMR078) >60 H-A-A-G-A-AMB(DMR079) >60 H-A-G-A-G-AMB >60 H-G-A-G-A-G-AMB >60 H-G-A-G-A-G-AMB >70 H-(AEEAc) 9 -Gly-AMB >100
  • A refers to AEEAc
  • G refers to Gly
  • AMB is almost insoluble in water; when the number of AEEAc is less than 3, Gly is increased, and the solubility is not improved. If all are Gly, H-(Gly) 5 -AMB is dissolved in water and left at room temperature for half an hour , Will form micelles; when the number of AEEAc is more than 3, the amount of Gly increases and decreases, AMB peptide derivatives have higher solubility, DMR078 significantly improves water solubility; however, with the hydrophilic peptide After prolonged, the solubility of amphotericin B peptide derivatives increases, but the antibacterial activity can be significantly reduced, or even no antibacterial activity.
  • Unstable three parts AMB parent structure are C 13 ketal structure and a half, seven and a conjugated double bond structure of C 19-bit ⁇ - glycosidic bond, so the Chinese Pharmacopoeia amphotericin B using a predetermined dark, refrigerated Storage.
  • the amphotericin B peptide derivative prepared by the invention is modified on the structure of amphotericin B, so similar degradation pathways also exist.
  • the minimum inhibitory concentration (MIC) of each antibacterial drug was determined according to the micro-broth dilution method recommended by the National Committee for Clinical Laboratory Standardization (NCCLS).
  • the bacterial culture medium was Mueller-Hinton (MH) broth medium and Candida albicans medium Hyclone modified RPMI-1640 medium was used.
  • the fungal growth medium is modified Martin medium, and the specific preparation method is as follows: 1L medium contains 2% glucose, 0.2% yeast extract powder, 0.5% fish meal peptone, 0.05% magnesium sulfate, 0.1% dipotassium hydrogen phosphate, according to the above ratio Weigh each substance in a corresponding amount, dissolve it in a certain amount of purified water, adjust the volume to 1 L, adjust the pH to 7.2, add 2% agar, and sterilize at 121°C for 30 min at high temperature.
  • the fungal MIC test uses Hyclone modified RPMI-1640 medium.
  • the specific preparation method is as follows: Weigh 18.00g of glucose dissolved in a certain amount of purified water, dilute to 500mL, and sterilize at 115°C for 15min. In a sterile environment, add 500 mL of RPMI-1640 medium to the sterilized glucose solution, store it at 4°C, and store it until use.
  • Hyclone modified RPMI-1640 liquid The turbidity of the culture medium is adjusted to 0.5 McLay standard, which is equivalent to containing 1 ⁇ 10 6 ⁇ 5 ⁇ 10 6 CFU (colony-forming unit) per milliliter. Take this bacterial suspension with Hyclone modified RPMI-1640 liquid medium After 1:20 dilution, a further 1:50 dilution is used as the inoculum. The bacterial suspension concentration is equivalent to 1 ⁇ 10 3 ⁇ 5 ⁇ 10 3 CFU/ml.
  • the drug concentrations in wells 1-10 were 32 ⁇ g/mL, 16 ⁇ g/mL, 8 ⁇ g/mL, 4 ⁇ g/mL, 2 ⁇ g/mL, 1 ⁇ g/mL, 0.5 ⁇ g/mL, 0.25 ⁇ g/mL, 0.125 ⁇ g/mL, 0.0625 ⁇ g /mL, hole 11 is a blank control without antibacterial drugs and inoculants, and hole 12 is a negative control without antibacterial drugs.
  • the 96-well plate inoculated with fungi was placed in an air incubator at 28°C and incubated for 40-50 hours.
  • the minimum drug concentration without fungal growth is the minimum inhibitory concentration (MIC) of the sample.
  • the MIC measurement results of each antibacterial drug are shown in Table 5.
  • A refers to AEEAc
  • G refers to Gly
  • PBS buffer solution take 100mL 0.2mol/L Na 2 HPO 4 ⁇ 12H 2 O mother liquor, and adjust its pH value to 7.4 with 0.2mol/L NaH 2 PO 4 ⁇ 2H 2 O mother liquor Measure 50 mL of the above buffer and dilute it with purified water 20 times, then weigh 9.00 g of NaCl and add it.
  • pH8.0 PBS buffer solution take 100mL 0.2mol/L Na 2 HPO 4 ⁇ 12H 2 O mother liquor, and adjust its pH value to 8.0 with 0.2mol/L NaH 2 PO4 ⁇ 2H 2 O mother liquor Take 50mL of the above buffer solution and dilute it with purified water 20 times, then weigh and add 9.00g NaCl to it.
  • the drug concentration of antimicrobial drugs in holes 1-10 is 640 ⁇ g/mL, 320 ⁇ g/mL, 160 ⁇ g/mL, 80 ⁇ g/mL, 40 ⁇ g/mL, 20 ⁇ g/mL, 10 ⁇ g/mL, 5 ⁇ g/mL, 2.5 ⁇ g/mL, 1.25 ⁇ g/mL
  • the drug concentration of the amphotericin B of the control drug is 12.8 ⁇ g/mL, 6.4 ⁇ g/mL, 3.2 ⁇ g/mL, 1.6 ⁇ g/mL, 0.8 ⁇ g/mL, 0.4 ⁇ g/mL, 0.2 ⁇ g/mL, 0.1 ⁇ g/mL, 0.05 ⁇ g/mL, 0.025 ⁇ g/mL
  • the 11th well is the negative control of red blood cell suspension + PBS
  • the 12th well is the positive control of red blood cell suspension + double distilled water. Finally, it was placed in a 37°C incubator for 1 hour.
  • A refers to AEEAc
  • G refers to Gly
  • Example 7 Spectral properties and self-aggregation characteristics of AMB and DMR078
  • Disodium hydrogen phosphate Na 2 HPO 4 ⁇ 12H 2 O: 3.58g
  • FIG. 5A shows the spectrum of DMR078 and AMB (12.7 ⁇ g/mL) in methanol
  • Figure 5B shows the spectrum of DMR078 and AMB (12.7 ⁇ g/mL) in PBS buffer
  • Figure 5C shows The spectrum of DMR078 (62.4 ⁇ g/mL) in PBS buffer is shown.
  • Example 8 In vitro HEK293T cytotoxicity assay
  • HEK293T cells NaCl, KCl, Na 2 HPO 4 ⁇ 12H 2 O, KH 2 PO 4 , MTT, DMEM
  • Disodium hydrogen phosphate Na 2 HPO 4 ⁇ 12H 2 O: 3.58g
  • Collect the logarithmic phase cells adjust the concentration of the cell suspension, add 100 ⁇ L to each well, plate the density of the cells to be tested to 0.5 ⁇ 10 4 cells/well (the edge wells are filled with sterile PBS), 5% CO 2 , and incubate at 37°C overnight. Cover the bottom of the cell monolayer with a well (96-well flat bottom plate), discard the supernatant, and then add the drug with a gradient concentration, a total of 8 concentration gradients, 100 ⁇ L per well, set a double well, 5% CO 2 , 37 Incubate for 24-48 hours at °C, and observe under an inverted microscope.
  • compositions and/or methods disclosed and claimed herein can be prepared and implemented without undue experimentation.
  • compositions and methods of the present invention have been described according to preferred embodiments, it will be apparent to those skilled in the art that without departing from the concept, spirit and scope of the present invention, the compositions and/or methods described herein can be Or the method and the steps of the method or the order of the steps are changed.

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Abstract

La présente invention se rapporte au domaine de la médecine et concerne particulièrement un dérivé peptidique de l'amphotéricine B ainsi qu'un procédé de préparation associé. Le dérivé peptidique de l'amphotéricine B a un effet bactéricide à large spectre et à efficacité élevée sur des bactéries et des champignons résistants aux médicaments.
PCT/CN2019/124970 2018-12-13 2019-12-13 Dérivé peptidique de l'amphotéricine b WO2020119773A1 (fr)

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CN114133428B (zh) * 2021-12-09 2023-10-27 华东理工大学 两性霉素b亲水性多肽衍生物及其应用

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