WO1996035701A1 - Antibiotiques - Google Patents

Antibiotiques Download PDF

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Publication number
WO1996035701A1
WO1996035701A1 PCT/GB1996/001144 GB9601144W WO9635701A1 WO 1996035701 A1 WO1996035701 A1 WO 1996035701A1 GB 9601144 W GB9601144 W GB 9601144W WO 9635701 A1 WO9635701 A1 WO 9635701A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
polyene macrolide
antibiotics
salts
methyl
Prior art date
Application number
PCT/GB1996/001144
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English (en)
Inventor
Edward Borowski
Jolanta Grzybowska
Pawel Sowinski
Jerzy Gumieniak
Andrzej Czerwinski
Original Assignee
British Technology Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by British Technology Group Limited filed Critical British Technology Group Limited
Priority to MX9708637A priority Critical patent/MX9708637A/es
Priority to JP8533895A priority patent/JPH11504647A/ja
Priority to AU56983/96A priority patent/AU716883B2/en
Priority to EP96915094A priority patent/EP0825995A1/fr
Priority to KR1019970708187A priority patent/KR19990014843A/ko
Priority to NZ307592A priority patent/NZ307592A/xx
Publication of WO1996035701A1 publication Critical patent/WO1996035701A1/fr
Priority to US08/857,281 priority patent/US5942495A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to N-alkyl-N-glycosyl derivatives of alkyl esters of antifungal antibiotics of the polyene macrolide group of general formula 1(a), wherein M represents polyene macrolide antibiotics residues, R represents a variable part of sugar residue, and each of R* and R which may be the same or different, represents a C j _4 alkyl group; to salts of compound 1(a), represented by the general formula 2(a), wherein M, R, R ⁇ and R ⁇ are as defined above and A represents an anion of an inorganic or organic acid; to methods of preparation of compounds of general formula 1(a) and 2(a) and their use in medicine.
  • Compounds of particular interest include N-methyl-N-glycosyl derivatives of methyl esters of antifungal antibiotics of polyene macrolide group of general formula 1(b), wherein M represents polyene macrolide antibiotics residues, wherein R represents a variable part of sugar residue, and their salts of general formula 2(b), wherein M represents polyene macrolide antibiotics residues, wherein R represents a variable part of sugar residue, and A represents an anion of inorganic or organic acid, and to methods of their preparation, and use in medicine.
  • N-alkyl derivatives of antibiotics of polyene macrolide group wherein the amino group of the parent antibiotic is substituted by an alkyl group are known.
  • N-glycosyl derivatives of polyene macrolides wherein amino group of the parent antibiotic is substituted with a residue of sugar are also known (J. Antibiotics 28, 244 (1975), L. Falkowski, J. Golik, P. Kolodziejczyk, J. Pawlak, J. Zieli ⁇ ski, T. Zimi ⁇ ski, E. Borowski; Acta Polon. Pharm. 37, 517 (1980), L. Falkowski, J. Pawlak, J. Golik, P. Kolodziejczyk, B. Stefa ⁇ ska, E. Bylec, E. Borowski).
  • sugars used in the preparation of these derivatives include D-glucose, D-mannose, L-rhamnose, D-ribose and maltose.
  • sugars used in the preparation of these derivatives include D-glucose, D-mannose, L-rhamnose, D-ribose and maltose.
  • Upon reaction of polyene macrolides with the appropriate sugar a simultaneous Amadori rearrangement occurs to give the corresponding N-glycosyl derivatives.
  • the compounds have the advantage that they exhibit a biological activity similar to those of the starting antibiotics and form water soluble salts.
  • the high toxicity associated therewith represents a significant disadvantage.
  • N-glycosyl derivatives of polyene macrolides in which the amino group of the parent antibiotic is substituted with a residue of sugar, such as D-glucose, D-mannose, L-rhamnose, D-ribose, maltose.
  • the compounds are prepared by reaction of polyene macrolides with the listed sugars, and simultaneous Amadori rearrangement.
  • the compounds exhibit the biological activity similar to those of the starting antibiotics and form water soluble salts. However, they exhibit high toxicity.
  • Trimemyl-unmonium derivatives of polyene macrolides methyl esters wherein the amino group of the parent antibiotic is fully methylated to give a quaternary ammonium salt are also known (J. Antibiotics 32, 1080 (1979), L. Falkowski, B. Stefa ⁇ ska, J. Zieli ⁇ ski, E. Bylec, J. Golik, P. Kolodziejczyk, E. Borowski).
  • the compounds are prepared by exhaustive methylation of the parent antibiotic with dimethyl sulphate.
  • Advantageous properties of the derivatives include their solubility in water and an antifungal activity similar to that of the starting antibiotics. Unfortunately they are very toxic and unstable.
  • Another type of derivatives are trimethylammonium derivatives of polyene macrolides methyl esters, which are known from a paper - J. Antibiotics 32, 1080 (1979), L. Falkowski, B. Stefa ⁇ ska, J. Zieli ⁇ ski, E. Bylec, J. Golik, P. Kolodziejczyk, E. Borowski and in these compounds the amino group of the antibiotic methyl esters is fully methylated to give quaternary ammonium salt.
  • the compounds are prepared by exhaustive methylation of the parent antibiotic with dimethyl sulphate.
  • the derivatives are soluble in water and are characterized by antifungal activity similar to the activity of the starting antibiotics, but they are very toxic and unstable.
  • N-alkyl derivatives include the N-succinimidyl derivatives formed by Michael addition reaction of the antibiotics and N-substituted maleimides, such as: N-ethylmaleimide, N,N'-hexamethylenedimaleimide, N-(3-dimethylaminopropyl)- maleimide; the compounds are known from a paper - J. Antibiotics, 44, 979 (1991), A. Czerwi ⁇ ski, W.A. K ⁇ nig, T. Zieniawa, P. Sowi ⁇ ski, V. Sinnwell, S. Milewski, E. Borowski. Such compounds are less toxic than the parent antibiotics, but their antifungal activity is diminished.
  • N-alkyl derivatives of polyene macrolides are N-enamine and amidine derivatives, formed by reaction of the antibiotics with acetylacetone, ethyl acetylacetate, dimethylacetal or dimethylformamide; the compounds are presented in a paper - Acta Polonica Phann. 45, 71 (1988), B. Stefa ⁇ ska, J. Zieli ⁇ ski, E. Borowski, L. Falkowski.
  • the derivatives exhibit antifungal activity similar to those of the parent antibiotics and improved solubility in organic solvents, however, they are still significantly toxic and very unstable.
  • the present inventors have now prepared mixed N-alkyl-N-glycosyl derivatives of alkyl esters of polyene macrolide antibiotics. Methods of preparation of these mixed compounds have also been established. These novel compounds have been found to have high anti-fungal activity, similar to those of the parent antibiotics; form water soluble salts with acids; and are significantly less toxic. These properties are unexpected since all of the N-alkyl derivatives of polyene macrolides of the prior art exhibit a high toxicity, which is a considerable disadvantage. The compounds comprised by the invention are devoid of this disadvantage.
  • N-methyl-N-glycosyl derivatives of methyl esters of polyene macrolide antibiotics and methods of their preparation were unknown. Surprisingly, such compounds preserve high antifungal activity, similar to those of the parent antibiotics, they form water soluble salts with acids, and are dramatically less toxic. These compounds do not exhibit the same toxicity as the N-alkyl derivatives of the prior art. A high toxicity constitutes the basic drawback of all known before N-alkyl derivatives of polyene macrolides, and the compounds comprised by the invention are devoid of this disadvantage.
  • a first aspect of the invention provides N-alkyl-N-glycosyl derivatives of alkyl esters of antibiotics of polyene macrolide group of general formula 1(a), wherein M represents residue of an antibiotic of polyene macrolide group, R represents a part of sugar residue formed by reaction of the antibiotic with a mono or oligosaccharide, and each of R* and R-2, which may be the same or different, represents C ] _4 alkyl group.
  • the residue of the antibiotic of polyene macrolide group M is selected from amphotericin B, candidin, candidoin, candidinin, mycoheptin, nystatin, polyfungin, aureofacin, vacidin, trichomycin or candicidin.
  • the mono or oligosaccharide from which the sugar residue R is derived is selected from D-glucose, or L-glucose, or D-mannose, or D-galactose, or lactose, or maltose.
  • Amadori rearrangement occurs to give the N-glycosyl precursors to the compounds of the invention.
  • a preferred embodiment of the invention comprises N-methyl-N-glycosyl derivatives of methyl esters of antibiotics of polyene macrolide group presented by general formula 1(b), wherein M represents residue of an antibiotic of polyene macrolide group, wherein R represents a part of sugar residue formed by reaction of the antibiotic with mono or oligosaccharide, preferably with D-glucose, or L-glucose, or D-mannose, or D-galactose, or lactose, or maltose, and by simultaneous Amadori rearrangement.
  • the invention in its preferred form relates to the derivatives wherein the antibiotic of polyene macrolide group is amphotericin B, or candidin, or candidoin, or candidinin, or mycoheptin, or nystatin, or polyfungin, or aureofacin, or vacidin, or trichomycin or candicidin.
  • a second aspect of the invention provides salts of N-alkyl-N-glycosyl derivatives of antibiotics of polyene macrolide group of general formula 2(a) wherein M, R, R ⁇ and R ⁇ are as defined above for the first aspect of the invention and A represents an anion of an organic or inorganic acid. It is preferred that the salt is a physiologically acceptable salt and compounds wherein A is the anion of L-aspartic acid are especially preferred. Salts wherein R ] and R2 are methyl groups are especially preferred.
  • a preferred embodiment of the second aspect of the invention comprises salts of N- methyl-N-glycosyl derivatives of antibiotics of polyene macrolide group presented by general formula 2(b) wherein M represents residue of an antibiotic of polyene macrolide group, wherein R represents a part of sugar residue formed by reaction of the antibiotic with mono or oligosaccharide, preferably with D-glucose, or L-glucose, or D-mannose, or D- galactose, or lactose, or maltose, and by simultaneous Amadori rearrangement, and A represents an anion of organic or inorganic acid.
  • the invention in its preferred form relates to the salts wherein the antibiotic of polyene macrolide group is amphotericin B, or candidin, or candidoin, or candidinin, or mycoheptin. or nystatin, or polyfungin, or aureofacin, or vacidin, or trichomycin or candicidin, and also preferably A relates to the anion of L-aspartic acid.
  • a third aspect of the invention comprises a method of preparation of compounds of formula 1 (a) wherein M, R, R* and R ⁇ are as defined above for the first and second aspects of the invention and which comprises the steps of reacting a polyene macrolide antibiotic with a mono or oligosaccharide, the reaction being characterised by the occurrence of a simultaneous Amadori rearrangement, to give the N-glycosyl derivatives of the polyene macrolide antibiotics; isolating the product of the Amadori rearrangement; treating the product with an alkylating agent and purifying the crude product.
  • the product of the Amadori rearrangement is isolated in the form of a suspension by precipitation from the solution in which the rearrangement occurs.
  • Organic solvents such as N,N-dimethylformamide are preferred to support the Amadori rearrangement.
  • Organic solvents such as diethyl ether are suitable to effect formation of a suspension by precipitation of the product of the Amadori rearrangement.
  • alkylation of the product of the Amadori rearrangement is carried out at reduced temperature. Temperatures of between -5°C and +5°C are preferred. Alkylating agents such as diazo alkanes may be used. An ethereal solution of diazomethane is the preferred alkylating agent.
  • Crude N-alkyl-N-glycosyl products can be isolated upon removal of the solvent and precipitation from diethyl ether.
  • the pure product may be isolated using known purification procedures.
  • a preferred embodiment of the third aspect of the invention comprises a process for preparation of the N-methyl-N-glycosyl derivatives of methyl esters of antibiotics of polyene macrolide group presented by general formula 1(b), wherein M represents residue of an antibiotic of polyene macrolide group, wherein R represents a part of sugar residue formed by reaction of the antibiotic with mono or oligosaccharide, preferably with D- glucose, or L-glucose, or D-mannose, or D-galactose, or lactose, or maltose, and by simultaneous Amadori rearrangement, wherein the obtained by Amadori rearrangement N- glycosyl derivatives of antibiotics of polyene macrolide group are transformed into suspension by precipitation with solvent, preferably diethyl ether, from a solution of the derivatives in organic solvent, preferably in N,N-dimethylformamide, and subsequently treated with ethereal solution of diazomethane at lowered temperature, preferably in the range from -5°
  • the preparation of salts of N-methyl-N-glycosyl derivatives of methyl esters of polyene macrolide antibiotics is especially preferred.
  • Organic or inorganic acids may be used to acidify the suspension.
  • L-aspartic acid is preferred.
  • Isolation of the pure product may be effected by precipitation of the crude product with an organic solvent which is then washed with an additional appropriate solvent and dried. It is preferred that the solvent used to precipitate the crude product is miscible with water; acetone is preferred. Typical solvents employed for washing the product include acetone and diethyl ether. It is preferred that the product is dried under reduced pressure.
  • a preferred embodiment of the fourth aspect of the invention comprises a process for preparation of salts of N-methyl-N-glycosyl derivatives of methyl esters of antibiotics of polyene macrolide group presented by general formula 2(b), wherein M represents residue of an antibiotic of polyene macrolide group, wherein R represents a part of sugar residue formed by reaction of the antibiotic with mono or oligosaccharide, preferably with D- glucose, or L-glucose, or D-mannose, or D-galactose, or lactose, or maltose, and by simultaneous Amadori rearrangement, wherein the obtained by Amadori rearrangement N- glycosyl derivatives of antibiotics of polyene macrolide group are transformed into suspension by precipitation with solvent, preferably diethyl ether, from a solution of the derivative in organic solvent, preferably in N,N-dimethylformamide, and subsequently treated with ethereal solution of diazomethane at lowered temperature, preferably in the range from -5
  • a fifth aspect of the present invention comprises N-alkyl-N-glycosyl derivatives of formula 1(a) or salts thereof for use in therapy.
  • a sixth aspect of the invention provides a method for the treatment of fungal infections in humans and animals which comprises the administration thereto of N-alkyl-N- glycosyl derivatives of formula 1(a) or salts thereof as herein before defined. N-methyl-N- glycosyl derivatives of formula 1(b) or the salts thereof are of particular interest.
  • a first preferred embodiment of the sixth aspect of the invention comprises a method for treatment of external and internal fungal infections in humans and animals, wherein N- methyl-N-glycosyl derivatives of methyl esters of antibiotics of polyene macrolide group presented by general formula 1(b), wherein M represents residue of an antibiotic of polyene macrolide group, wherein R represents a part of sugar residue formed by reaction of the antibiotic with mono or oligosaccharide, preferably with D-glucose, or L-glucose, or D- mannose, or D-galactose, or lactose, or maltose, and by simultaneous Amadori rearrangement are used to treat the infections.
  • a second preferred embodiment of the sixth aspect of the invention comprises a method for treatment of external and internal fungal infections in humans and animals, wherein salts of N-methyl-N-glycosyl derivatives of methyl esters of antibiotics of polyene macrolide group presented by general formula 2(b), wherein M represents residue of an antibiotic of polyene macrolide group, wherein R represents a part of sugar residue formed by reaction of the antibiotic with mono or oligosaccharide, preferably with D-glucose, or L-glucose, or D-mannose, or D-galactose, or lactose, or maltose, and by simultaneous Amadori rearrangement, and A represents an anion of organic or inorganic acid are used to treat the infections.
  • a seventh aspect of the invention provides N-alkyl-N-glycosyl derivatives of formula
  • N-methyl-N-glycosyl derivatives of formula 1(b) or the salts thereof are of particular interest.
  • the infections for which treatment is provided may be internal or external.
  • the mode of administration will depend upon the nature of the infection.
  • the compounds of the invention may be formulated for intravenous, intra peritoneal, oral, topical, subcutaneous, rectal or vaginal administration.
  • a eighth aspect of the invention provides compositions for use in the treatment of fungal infections comprising an N-alkyl-N-glycosyl derivatives of formula 1(a) or a salt thereof and a physiologically acceptable carrier.
  • the nature of the N-alkyl-N-glycosyl derivative and the carrier will depend upon the mode of administration.
  • the composition may be formulated from one or more compounds according to the invention, optionally in combination with other known antifungal agents, according to requirements.
  • Compositions containing N-methyl-N-glycosyl derivatives of formula 1(b) or the salts thereof are of particular interest.
  • An ninth aspect of the invention provides a unit dosage form comprising one or more
  • the unit dosage form may be formulated from one or more compounds according to the invention optionally in combination with other known antifungal agents.
  • unit dosage forms containing N-methyl-N-glycosyl derivatives of formula 1(b) are of particular interest.
  • the nature of the unit dosage form will depend upon the mode of administration. Typically tablets and capsules are suitable for oral administration; creams and patches are suitable for topical administration with pessaries being suitable for rectal and vaginal administration.
  • a tenth aspect of the invention provides the use of N-alkyl-N-glycosyl derivative of formula 1(a) or salts thereof for the preparation of a medicament for use in the treatment of fungal infections.
  • Compounds wherein the N-alkyl and alkyl ester substituents are both methyl groups are of particular interest. Structural determinations carried out on the compounds of the invention using spectroscopic methods indicate that the integrity of the parent antibiotic is preserved during the reaction.
  • Absorption infrared spectrum of the N-methyl-N-D-fructosylamphotericin B methyl ester demonstrates the band related to stretching vibrations of the ester carbonyl group at 1730 cm and lack of band of free carboxylic group, what means that the carboxylic group was completely transformed into methyl ester group.
  • Table 1 presents chemical shifts *H and ROE effects of the disaccharide fragment of the N-methyl-N-D-fructosylamphotericin B methyl ester.
  • Table 3 presents coupling constants J jj JJ for protons of the disaccharide fragment of the N-methyl-N-D-fructosylamphotericin B methyl ester (py ⁇ dme-d$: methanol-d4 9 : 1), coupling constants and chemical shifts of closely coupled spin system H3" - H6" were refined iteratively by computer simulation.
  • the antifungal activity of compounds was determined following the standard for polyene macrolides procedure.
  • the liquid Sabouraud medium was inoculated with 10 4 cells/ml of test organism Candida albicans ATCC 262778 and incubated for 24 hours at 30 °C with the tested antibiotic (serial dilutions).
  • Amphotericin B was used as the reference.
  • Compounds were dissolved in DMF and suitable amounts of the solutions were added to the medium.
  • Turbidimetric method (660 nm) was applied to determine the degree of growth inhibition.
  • the concentration of antibiotic at which the growth of fungi was inhibited by 50% was determined from the dose response curve.
  • the obtained IC50 value characterized antifungal activity of the compound.
  • Toxicity of compounds in vitro against animal cells was determined using standard for polyene macrolides procedure, by the determination of the degree of haemolysis of human erythrocytes.
  • Human erythrocytes isolated from fresh, citrated human blood were washed twice with cold saline. The cells were diluted 250 times with saline and equilibrated for 30 minutes at 37 °C. Samples of erythrocytes were incubated with various concentrations of antibiotics (the base solution in DMF) for 30 minutes at 37°C. After centrifugation the lysis of erythrocytes was assessed by determination of the haemoglobin released to the solution. Optical density of the supernatant was measured at 550 nm.
  • EH50 value concentration of antibiotic at which 50% of hemolysis occurred.
  • the values of EH50 were read from a curve relating the degree of hemolysis with antibiotic dose.
  • MTD maximum tolerated dose
  • LD50 acute toxicity
  • the maximum multiple tolerated dose for intraperitoneal administration of 100 mg/kg for 5 days was much higher. For such dose, toxic effects were not observed during 20 days of observation.
  • the acute toxicity, LD50 of methyl ester of N-methyl-N-D-fructosylamphotericin B L-aspartate was determined for Swiss Webster female mice of average weight of 20 g.
  • Various doses of the tested compound, and for comparison, amphotericin B in form of Fungizone, dissolved in 5% glucose were given intravenously to the animals.
  • the administered volume of the solution was 0.5 ml.
  • 0.5 ml of 5 % solution of glucose was administered to mice as a control. Every dose of both preparations was administered to 5 mice. The animals were observed for 7 days.
  • Chemotherapeutic efficacy of methyl ester of N-methyl-N-D-fructosylamphotericin B L-aspartate was determined using systemic murine candidose model.
  • Candida albicans was grown overnight in Sabouraud dextrose broth at room temperature. The fungal cells were centrifuged, washed twice with 0.9 % solution of sodium chloride, and suspended in physiological salt solution.
  • mice Three days post-infection, animals were treated intravenously, twice a day, for 5 consecutive days with a 5 to 6 hours interval. Preparation was administered as a solution in 5% glucose. The animals were observed for 5 weeks starting from the day of infection. After this time, the surviving animals were sacrificed , their kidneys were removed, homogenized in sterile water, and the homogenate was plated on Sabouraud dextrose agar, and the grown colonies of Candida were counted. The chemotherapeutic effectiveness was represented as a dose of mg/kg, which in the above test resulted in a survival of 50 % of animals, and on clearance of Candida from kidneys of half of the mice. The dose, called ED50, was calculated using a method given in J. Hyg.
  • the product was dissolved, with stirring, in 10 ml of N,N-dimethylformamide and 50 ml of diethyl ether was added to the solution, to give a fine suspension.
  • the suspension was cooled in ice to 0 - 2°C, and freshly prepared diethyl ether solution of 2.5 mole of diazomethane per 1 mole of N-D-fructosylamphotericin B, was added with vigorous stirring.
  • the reaction was followed by thin layer chromatography on silica gel in chloroform - methanol - water 10:6:1 v/v solvent system.
  • the obtained derivative was methylated using diazomethane, as in the Example I to give 0.5 g of crude product.
  • Pure N-methyl-N-D-fructosylvacidin methyl ester was isolated by chromatography on silica gel column similarly as it was described in the Example I, but the column was developed with chloroform - methanol - water 30 : 8 : 1 solvent system.

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Abstract

L'invention porte: sur des dérivés N-alkyle-N-glycosyle d'alkylesters d'antibiotiques fongicides du groupe des polyènes macrolides, de formule générale (1a) dans laquelle M représente des résidus d'antibiotiques du type des polyènes macrolides, R représente une portion variable d'un résidu de sucre et chacun des R1 et R2 représente un groupe alkyle C¿1-4?; sur leurs sels de formule générale (2a) dans laquelle R, R?1, R2¿ et M sont tels que définis dans la description et A représente un anion d'acide organique ou minéral. Des composés de formule (1b) et (2b) dans lesquels les groupes N-alkyle et alkylester sont représentés par méthyle, présentent un intérêt particulier. L'invention porte également sur le procédé de préparation de ces composés, sur des compositions les contenant et sur leur emploi dans la thérapie et le traitement de mycoses externes ou internes chez l'homme et chez l'animal.
PCT/GB1996/001144 1995-05-13 1996-05-10 Antibiotiques WO1996035701A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
MX9708637A MX9708637A (es) 1995-05-13 1996-05-10 Antibioticos.
JP8533895A JPH11504647A (ja) 1995-05-13 1996-05-10 抗生物質
AU56983/96A AU716883B2 (en) 1995-05-13 1996-05-10 Antibiotics
EP96915094A EP0825995A1 (fr) 1995-05-13 1996-05-10 Antibiotiques
KR1019970708187A KR19990014843A (ko) 1995-05-13 1996-05-10 항생물질
NZ307592A NZ307592A (en) 1995-05-13 1996-05-10 N-alkyl-n-glycosyl derivatives of alkyl esters of antifungal antibiotics of polyene macrolides
US08/857,281 US5942495A (en) 1996-05-10 1997-05-16 Antibiotics

Applications Claiming Priority (2)

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PL95308583A PL180253B1 (pl) 1995-05-13 1995-05-13 Pochodne N-metylo-N-glikozylowe estrów metylowych antybiotyków z grupy makrolidów polienowych i ich sole oraz sposób ich otrzymywania PL PL PL PL PL PL
PLP.308583 1995-05-13

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KR (1) KR19990014843A (fr)
AU (1) AU716883B2 (fr)
CA (1) CA2220771A1 (fr)
IL (1) IL118233A0 (fr)
MX (1) MX9708637A (fr)
NZ (1) NZ307592A (fr)
PL (1) PL180253B1 (fr)
WO (1) WO1996035701A1 (fr)
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Cited By (8)

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US5981721A (en) * 1997-10-23 1999-11-09 Karykion Corporation Polyene macrolide schiff bases, their alkyl esters and processes for preparing polyene macrolide alkyl ester salts thereof
EP1278527A1 (fr) * 2000-01-14 2003-01-29 IntraBiotics Pharmaceuticals, Inc. Derives de macrolides de polyene, preparation et utilisations correspondantes
WO2009004322A2 (fr) * 2007-07-03 2009-01-08 Biosergen As Composés
US9447136B2 (en) 2012-03-09 2016-09-20 Blirt S.A. Semisynthetic derivatives of Nystatin A1
KR20170016957A (ko) 2014-06-12 2017-02-14 시오노기 앤드 컴파니, 리미티드 폴리엔 마크로라이드 유도체
US9745335B2 (en) 2012-06-15 2017-08-29 Blirt S.A. N-substituted second generation derivatives of antifungal antibiotic amphotericin B and methods of their preparation and application
CN112920238A (zh) * 2021-01-27 2021-06-08 河南农业大学 一种糖胺类Amadori衍生物及其制备方法和应用
EP3929203A1 (fr) * 2015-04-15 2021-12-29 Sfunga Therapeutics, Inc. Dérivés d'amphotéricine b

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Publication number Priority date Publication date Assignee Title
KR100687748B1 (ko) * 2005-06-23 2007-02-27 한국전자통신연구원 이동 단말에 독립적인 빠른 핸드오버 수행을 위한 방법 및그 시스템

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US5981721A (en) * 1997-10-23 1999-11-09 Karykion Corporation Polyene macrolide schiff bases, their alkyl esters and processes for preparing polyene macrolide alkyl ester salts thereof
EP1278527A1 (fr) * 2000-01-14 2003-01-29 IntraBiotics Pharmaceuticals, Inc. Derives de macrolides de polyene, preparation et utilisations correspondantes
EP1278527A4 (fr) * 2000-01-14 2003-04-09 Intrabiotics Pharmaceuticals Derives de macrolides de polyene, preparation et utilisations correspondantes
US6562796B2 (en) 2000-01-14 2003-05-13 Micrologix Biotech Inc. Derivatives of polyene macrolides and preparation and use thereof
US8415312B2 (en) 2007-07-03 2013-04-09 Biosergen As Compound which is a nystatin derivative
WO2009004322A3 (fr) * 2007-07-03 2009-04-23 Biosergen As Composés
WO2009004322A2 (fr) * 2007-07-03 2009-01-08 Biosergen As Composés
KR101462301B1 (ko) 2007-07-03 2014-11-14 바이오써젠 에이에스 나이스타틴의 유도체 및 항진균제로서 그것의 용도
US9447136B2 (en) 2012-03-09 2016-09-20 Blirt S.A. Semisynthetic derivatives of Nystatin A1
US9745335B2 (en) 2012-06-15 2017-08-29 Blirt S.A. N-substituted second generation derivatives of antifungal antibiotic amphotericin B and methods of their preparation and application
KR20170016957A (ko) 2014-06-12 2017-02-14 시오노기 앤드 컴파니, 리미티드 폴리엔 마크로라이드 유도체
US10246478B2 (en) 2014-06-12 2019-04-02 Shionogi & Co., Ltd. Polyene macrolide derivative
US10696707B2 (en) 2014-06-12 2020-06-30 Shionogi & Co., Ltd. Polyene macrolide derivative
EP3929203A1 (fr) * 2015-04-15 2021-12-29 Sfunga Therapeutics, Inc. Dérivés d'amphotéricine b
CN112920238A (zh) * 2021-01-27 2021-06-08 河南农业大学 一种糖胺类Amadori衍生物及其制备方法和应用

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EP0825995A1 (fr) 1998-03-04
PL180253B1 (pl) 2001-01-31
JPH11504647A (ja) 1999-04-27
ZA963787B (en) 1997-11-13
PL308583A1 (en) 1996-11-25
MX9708637A (es) 1998-02-28
CA2220771A1 (fr) 1996-11-14
IL118233A0 (en) 1996-09-12
KR19990014843A (ko) 1999-02-25
AU5698396A (en) 1996-11-29
AU716883B2 (en) 2000-03-09

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