WO1993017034A1 - Derives d'amphothericine b - Google Patents

Derives d'amphothericine b Download PDF

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Publication number
WO1993017034A1
WO1993017034A1 PCT/GB1993/000306 GB9300306W WO9317034A1 WO 1993017034 A1 WO1993017034 A1 WO 1993017034A1 GB 9300306 W GB9300306 W GB 9300306W WO 9317034 A1 WO9317034 A1 WO 9317034A1
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formula
alkyl
hydrogen
compound
group
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PCT/GB1993/000306
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English (en)
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Colin Thomas Shanks
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Smithkline Beecham Plc
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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

Definitions

  • the present invention relates to novel compounds, their preparation and their use in the treatment of fungal infections in animals, including humans.
  • the polyene macrolide amphotericin B produced by Streptomyces nodosus, is widely used for the treatment of fungal infections.
  • Amphotericin B is the only complex polyene macrolide whose molecular structure and absolute configuration have been firmly established by x-ray crystallographic analysis. Amphotericin B has the formula (A):
  • amphotericin B has now been prepared which have novel substituents at the 16-position and which derivatives have been shown to have anti-fungal activity and have potential utility as anti-fungal agents.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 is a group CO.N(R 5 )OR 6 in which R 5 is hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl -C 1-6 alkyl, aryl C 1-6 alkyl, heteroaryl C 1-6 alkyl, aryl, heteroaryl in which any aryl or heteroaryl moiety is optionally substituted,
  • s and r together represent 3, 4 or 5 and X represents oxygen, sulphur CH 2 , or NR in which R is hydrogen or C 1-6 alkyl;
  • R 6 is a group of formula (ii);
  • t is 1 to 6 and R 9 is hydrogen, C 1-6 alkyl or C 3-6 alkenyl;
  • R 6 is a group of formula (iii);
  • u is 1 to 6 and R 10 and R 11 independently represent hydrogen, or C 1-6 alkyl;
  • R 2 is hydroxy or C 1-6 alkoxy;
  • R 3 is amino or a derivative thereof;
  • R 4 is hydrogen or hydroxy; or R 2 and R 4 together represent a bond.
  • an alkyl moiety or group or an alkenyl group preferably has from 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms and may be straight-chain or branched.
  • aryl includes aromatic carbocyclic groups such as phenyl and naphthyl, preferably phenyl.
  • heteroaryl includes 5- or 6- membered monocyclic and 9- or 10-membered bicyclic heteroaryl.
  • 5- or 6- membered monocyclic and 9- or 10- membered bicyclic heteroaryl preferably contain one or two heteroatoms selected from nitrogen, oxygen and sulphur which in the case of there being more than one heteroatom may be the same or different.
  • 9- or 10- membered bicyclic heteroaryl the two rings are fused, preferably with one 5- or 6-membered ring containing a single heteroatom.
  • Optional substituents for alkyl, alkenyl, arylC 1-8 alkyl, aryl and heteroaryl groups may be selected from OH, C 1-6 alkyl, C 1-6 alkoxy, carboxy, nitro, halogen, and amino optionally substituted by C 1-6 alkyl, C 1-6 acyl or aryl.
  • R 5 in the variable R 1 is preferably hydrogen or methyl.
  • R 6 in the variable R 1 is preferably hydrogen, methyl, prop-2-enyl, hydroxyethyl or N-ethylmorpholino.
  • R 2 is preferably hydroxy and R 4 is preferably hydrogen.
  • R 3 is primary amino
  • R 3 is an amine group or derivative thereof
  • acyl derivatives bearing a basic substituent such as N-D-lysyl and N-D-ornithyl derivatives, guanidine derivatives, and N-glycosyl derivatives.
  • the preparation of further amino group derivatives is described in European Patent Publication 0 010 297 (Schering), European Patent Publication 0 031722 (Dumex) US 4 195 172 and European Patent Publication O 428440.
  • pharmaceutically acceptable salt encompasses solvates and hydrates.
  • compounds of formula (I) or pharmaceutically acceptable salts thereof form solvates or hydrates, these also form an aspect of the invention.
  • the compounds of formula (I) wherein R 3 is hydrogen can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, oxalic, methanesulphonic, aspartic and ascorbic.
  • acids such as conventional pharmaceutically acceptable acids, for example hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, oxalic, methanesulphonic, aspartic and ascorbic.
  • acids such as conventional pharmaceutically acceptable acids, for example hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, oxalic, methanesulphonic, aspartic and ascorbic.
  • the invention also extends to quaternary salts.
  • R 2 is hydroxy or C 1-6 alkoxy
  • R 3 ' is an amine protecting group and R 4 is hydrogen or hydroxy or R 2 and R 4 together represent a bond and each R 12 is hydrogen or a silyl protecting group; with a compound of formula (III) or, an acid addition salt thereof; in the presence of an amide coupling reagent;
  • R 5 is as defined in relation to formula (I)
  • R 6 ' is R 6 as defined in relation to formula (I) or a group convertible thereto, and thereafter optionally or as necessary in any appropriate order, converting R 6 ' when other than R 6 to R 6 , converting NHR 3 ' to R 3 , removing the R 12 silyl protecting groups, interconverting R 2 and R 4 , and forming a
  • R 6 ' is alkyl
  • the reaction between a compound of formula (II) and formula (III) is suitably carried out in an inert solvent such as
  • dimethylformamide at ambient temperature in the presence of a buffer such as sodiuim acetate or a base such as pyridine and further in the presence of dicyclohexylcarbodiimide (DCCI) as the amide coupling reagent.
  • a buffer such as sodiuim acetate or a base such as pyridine
  • DCCI dicyclohexylcarbodiimide
  • R 6 ' is other than alkyl
  • the reaction between a compound of formula (II) and formula (III) is suitably carried out in an inert solvent such as dimethylformamide in the presence of a base such as N,N-di-isopropylethylamine and in the presence of bromo-tris-pyrrolidinophosphonium-hexafluoro-phosphate as the amide coupling reagent.
  • Addition salts of the compound of formula (III) include the hydrochloric and hydrobromic salt thereof.
  • the acid addition salt is the hydrochloric salt thereof.
  • R 6 ' when a group convertible to R 6 include conventional protecting groups which may be converted to R 6 using conventional deprotection methods such as those described in Greene, T.W. 'Protective groups in Organic Synthesis' New York, Wiley (1981).
  • a suitable group convertible to R 6 is hydrogen is a silyl protected group such as i-butyldimethyl silyl which may be converted to a hydrogen by treatment with a salt of a strong acid and a weak base such as pyridinium para-toluene sulphate in a suitable solvent such as a water/THF mixture.
  • R 2 is alkoxy and R 4 is hydrogen this reaction converts the alkoxy function to R 2 is hydroxy and this is an example of interconversion of R 2 from alkoxy to hydroxy.
  • R 3 ' amine protection groups are chosen such that they are readily removable subsequent to the initial reaction between a compound of formula (II) and a comound of formula (III) or an acid addition salt thereof to provide a compound of formula (I) in which R 3 is hydrogen.
  • R 3 ' include trifluoracetyl, 9-fluorenylmethoxycarbonyl, trichloroethoxycarbonyl, 2-methylsulphonylethoxycarbonyl
  • R 3 ' is 9-fluorenylmethoxycarbonyl.
  • Suitable R 12 silyl protecting groups include trimethylsilyl, triethylsilyl andt-butyldimethylsilyl.
  • R 12 is triethylsilyl.
  • R 2 hydroxy function can be converted to an alkoxy function using procedures analogous to those outlined in WO/91/0947.
  • R 4 Interconversion of R 4 can be carried out according to the procedures outlined in EP-A-0431874 (Beecham Group p.l.c.). Where R 3 in compounds of formula (I) is primary amine the removal of an R 3 ' amine protecting group to give an R 3 primary amine may be carried out under basic conditions.
  • An R 3 ' amine protection group such as 9-fluorenylmethoxycarbonyl, may be removed under basic conditions in a solvent such as methanolic dimethyl sulphoxide.
  • Suitable bases for amine deprotection include ammonia, dialkylamines such as dimethylamine and diethylamine, trial-kylamines such as triethylamine, cyclic amines and especially cyclic secondary amines such as morpholine, piperazine and more especially piperidine, and diazabicyclic bases such as
  • DBN 1,5-diazabicyclo[4.3.0]non-5-ene
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • the deprotection may be carried out using from 1-10 equivalents of base, preferably from 1-2 equivalents, at reduced or elevated temperatures, for example from -30°C to 50°C and preferably from 0°C to room temperature, over a time period ranging from 1 minute to 5 hours and preferably from 30 minutes to 2.5 hours.
  • R 12 silyl protecting groups in compounds of formula (II) may be removed using known deprotection methods, for example using a solution of hydrogen fluoride-pyridine in tetrahydrofuran or
  • tetrahydrofuran/methanol mixtures at normal or reduced temperature, for example from -10°C to 50°C and preferably from 0°C to room
  • Intermediate compounds of formula (II) in which R 4 is hydrogen and R 2 is alkoxy may be prepared from amphotericin B according to the procedures outlined in WO 91/09047 (Beecham Group p.l.c).
  • the reaction may be carried out in an inert solvent such as tetrahydrofuran and the alcohol may act either wholly or partially as the solvent.
  • the reaction is conveniently carried out in the presence of an H 2 O-scavenger such as molecular sieves and/or under an inert atmosphere.
  • R 3 ' amine protection groups may be introduced by standard procedures.
  • an R 3 ' trifluoroacetyl amine protection group may be introduced by reaction of the primary amine with ethyl trifluoroacetate in the presence of base such as diisopropylethylamine, in a
  • An R 3 ' 9-fiuorenylmethoxycarbonyl amine protection group may be introduced by addition of 9-fluorenylmethyl chloroformate to a solution of the primary amine in methanol-dimethylformamide under anhydrous conditions, in the presence of a base such as potassium carbonate.
  • an R 3 ' 9-fluorenylmethoxycarbonyl group maybe introduced by addition of N-(9-fluorenyln ⁇ ethoxycarbonyloxy)sucdnimide to a slurry of the primary amine in rnethanol-diniethylformamide under anhydrous conditions in the presence of a base such as pyridine.
  • Free hydroxyl groups may be silylated using standard procedures.
  • trifluoromethanesulphonate and triethylsilyl trifluoromethanesulphonate may be carried out in an inert solvent, for example dichloromethane, hexane or diethyl ether, under an inert atmosphere at ambient or reduced temperatures, for example from 0°C to 25°C.
  • the reaction is conveniently effected using an excess of the silylating agent in the presence of a base, for example a pyridine derivative such as 2,6-lutidine. Alternatively, when a liquid, the base may replace the solvent.
  • the reaction time is dependent on the size of the silyl group, ranging from a few minutes for a trimethylsilyl group to several hours for larger silyl groups.
  • the compounds of the formula (I) and their pharmaceutically acceptable salts are anti-fungal agents, potentially useful in combating fungal infections in animals, including humans. For example they are
  • Candida albicans e.g. thrush and vaginal candidiasis
  • They may also be used in the treatment of systemic fungal infections caused by, for example Candida albicans.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.
  • the composition is preferably for human use in tablet, capsule, injectable or cream form.
  • pharmaceutically acceptable salts thereof can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they may be administered orally in the form of a tablet containing such excipients as starch or lactose, or in a capsule or ovule either alone or in admixture with excipients, or in the form of an elixir or suspension containing a flavouring or colouring agent.
  • They may be injected parenterally, for example, intravenously,
  • the daily dosage level of the antifungal compounds of the formula (I) will be from 0.1 to 1 mg/kg (in divided doses) when administered by either the oral or parenteral route.
  • tablets or capsules of the compounds can be expected to contain from 5 mg to 0.5 g of active compound for administration singly or two or more at a time as appropriate.
  • the physician in any event will determine the actual dosage which will be most suitable for an individual patient and will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the antifungal compounds of formula (I) can be
  • a suppository or pessary administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be incorporated, at a concentration between 1 and 10%, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as maybe required.
  • the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance.
  • a compound for use as an active therapeutic substance is intended for use in the treatment of disorders in animals including humans.
  • compounds of formula (I) and their pharmaceutically acceptable salts have anti-fungal activity and are potentially useful in combating fungal infections in animals including humans.
  • the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of fungal infections.
  • the present invention additionally provides a method of treatment of fungal infections in animals, including humans, which comprises administering an effective anti-fungal amount of a compound of formula
  • the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of fungal infections in animals, including humans.
  • Characteristic signals include:- 1.15 (3H, d, J7.12 Hz), 1.24 (3H, d, J6.59 Hz), 1.35 (3H, d, J6.35 Hz), 1.47 (3H, d, J6.02 Hz), 3.25 (3H, s), 3.90 (3H, s), 4.80 (1H, multiplet), 4.84 (1H, s), 5.47 (1H, multiplet), 5.63 (1H, dd, J14.1 and 9.63 Hz), 6.14 (1H, dd, J14.24 and 6.84 Hz), 6.23-6.61 (12H, complex), 7.30 (2H, t, J7.45 Hz), 7.42 (2H, t, J7.4 Hz), 7.71 (2H, t, J7.08 Hz) and 7.83 (2H, d, J7.51 Hz) ppm.
  • amphotericin B 16-(N-methoxy)carboxamide (0.183g, 0.154mmol) in tetrahydrofuran-water (6:1, 7mL) under nitrogen was added pyridinium p-toluenesulphonate (0.292g, 1.16mmol). After stirring in a sealed flask for 1.5 hours triethylamine (0.23mL, 0.167g, 1.65mmol) was added, and the mixture poured into diethyl ether (1L). The precipitate was filtered and washed with diethyl ether (500mL), dry distilled tetrahydrofuran (50ml) then diethyl ether (500mL).
  • Characteristic signals include:- 0.95 (3H, d, J7.07 Hz), 1.06 (3H, d, J6.5 Hz), 1.15 (3H, d, J6.3 Hz), 1.21 (3H, d, J4.12 Hz), 3.61 (3H, s), 4.49 (2H, multiplet), 5.03 (1H, multiplet), 5.59 (1H, dd, J14.41 and 9.22 Hz), 5.91 (1H, dd, J14.13 and 6.42 Hz), 6.05-6.45 (12H, complex), 7.35 (2H, t, J7.4 Hz), 7.42 (2H, t, J7.38 Hz), 7.76 (2H, d, J7.09 Hz), and 7.88 (2H, d, J7.5 Hz) ppm.
  • amphotericin B (0.29g, 0.25mmol) in dry N,N-dimethyflformamide (2mL) under nitrogen was added successively N,N-diiopropylethylamine (0.15ml, 0.111g, 0.86mmol), O-(tert-butyldimethylsilyl) hydroxylamine (0.038g, 0.25mmol) and bromo-trispyrrolidino-phosphonium hexafluorophosphate [PyBroP] (0.12g, 0.25mmol) and the mixture stirred in a sealed flask for 3 hours.
  • Characteristic signals include:- 0.15 (3H, s), 0.16 (3H, s), 0.94 (12H, complex), 1.05 (3H, d, J6.45 Hz), 1.14 (3H, d, J6.45 Hz), 1.18 (3H, d, J6.10 Hz), 2.30 (1H, multiplet), 3.08 (3H, s), 3.60 (1H, multiplet), 4.46 (1H, s), 4.50 (1H, multiplet), 5.04 (1H, multiplet), 5.58 (1H, dd, J14.83 and 9.67 Hz), 5.87 (1H, dd, J14.19 and 7.09 Hz), 6.04-6.45 (12H, complex), 7.34 (2H, t, J7.43 Hz), 7.41 (2H, t, J7.35 Hz), 7.74 (2H, multiplet), and 7.86 (2H, d, 7.60 Hz) ppm.
  • Characteristic signals include:- 0.94 (3H, d, J7.07 Hz), 1.06 (3H, d, J6.47 Hz), 1.14 (3H, d, J6.31 Hz), 1.18 (3H, d, J5.43 Hz), 2.30 (1H, multiplet), 3.59 (1H, multiplet), 4.38 (1H, multiplet), 4.48 (1H, s), 5.26 (1H, multiplet), 5.42 (1H, dd, J14 and 10 Hz), 5.98 (1H, dd, J15.05 and 8.70 Hz), 6.12-6.50 (12H, complex), 7.33 (2H, multiplet), 7.41 (2H, t, J7.4 Hz), 7.74 (2H, multiplet) and 7.86 (2H, d, J7.5 Hz) ppm.
  • This intermediate was prepared from N-(9-fluorenylmethoxycarbonyl)-13-0-methyl amphotericin B and 0-allyl hydroxylamine in two steps by the methods outlined in descriptions 3 and 4.
  • Characteristic signals include:- 0.94 (3H, d, J 7.1Hz), 1.05 (3H, d, J 6.3Hz), 1.13 (3H, d, J 6.4Hz), 1.18 (3H, d, J 5Hz), 3.70 (1H, d, J 2.8Hz), 4.43 (1H, s), 5.43 (1H, dd, J 10, MHz).
  • N-(9-fluorenylmethoxycarbonyl) amphotericin B (286 mg, 0.25 mmol) in N,N-dimethylformamide (2.5 ml) was added N,N- diisopropylethylamine (0.225 ml), N-O-dimethyl hydroxylamine
  • This material was prepared by the method of description 6.
  • Characteristic signals include:- 0.03 (6H, s), 0.85 (9H, s), 0.93 (3H, d, J 7.3Hz), 1.05 (3H, d, J 6.3Hz), 1.13 (3H, d, J 6.4Hz), 1.17 (3H, d, J 5.9Hz), 3.67 (1H, d, J 2.5Hz), 5.44 (1H, dd, J 10.1, 14.3Hz), 5.96 (1H, dd, J 15.0, 8.8Hz).
  • N-(9-fluorenylmethoxycarbonyl) amphotericin B 16-[N-(2-t-butyldimethylsilyloxy) ethoxy] carboxamide (0.66 g, 0.5 mmol) in tetrahydrofuran: dimethylformamide (10:1) (33 ml) was added tetra-n-butylammonium fluoride (0.24 g, 0.75 mmol) and the solution stirred at room temperature for 2 hours. The solution was poured into ether (1l) and the solid filtered and washed with water (200 ml), ethyl acetate (500 ml) and ether (500 ml).
  • Characteristic signals include:- 0.93 (3H, d, J 7.1Hz), 1.05 (3H, d, J 6.4Hz), 1.13 (3H, d, J 6.4Hz), 1.17 (3H, d, J 5.6Hz), 3.69 (1H, d, J 2.5Hz), 5.43 (1H, dd, J 14.3, 10.1Hz), 5.95 (1H, dd, J 15.1, 9.0Hz).
  • N-[2-(4-Morpholino)] ethoxyphthalimide D11
  • N-hydroxyphthalimide 2.44 g, 15 mmol
  • N-(2-hydroxyethyl) morpholine 1.96 g, 15 mmol
  • tri (p-methoxy phenyl) phosphine 5.26 g, 15 mmol
  • diisopropylazodicarboxylate 3.33 ml, 17 mmol
  • This material was prepared by the mehhod of description 8. ⁇ max (film) 3300 cm -1 .
  • This material was prepared by the method of description 6. ⁇ max (MeOH) 405, 382, 363 nm.
  • Characteristic signals include:- 0.93 (3H, d, J 7.1Hz), 1.05 (3H, d, J 6.4 Hz), 1.13 (3H, d, J 6.4Hz), 1.18 (3H, d, J 5.9 Hz), 3.68 (1H, d, J 2.7Hz), 4.42 (1H, s), 5.43 (1H, dd, J 14.4, 10.0Hz), 5.96 (1H, dd, J l5.2, 8.9Hz).
  • Characteristic signals include;- 0.94 (3H, d, J6.91 Hz), 1.16 (3H, d, J6.15 Hz), 3.63 (3H, s), 4.36 (1H, s), 5.26 (1H, multiplet), 5.42 (1H, dd, J14.36 and 9.96 Hz), 5.98 (1H, dd, J15.36 and 8.85 Hz) and 6.07-6.50 (12H, complex) ppm.
  • Characteristic signals include:- 0.94 (3H, d, J6.97 (Hz), 1.06 (3H, d, J6.27 Hz), 1.13 (3H, d, J6.14 Hz), 1.17 (3H, d, J6.01 Hz), 2.31 (1H, multiplet), 4.38 (2H, multiplet), 5.26 (1H, multiplet), 5.43 (1H, dd, J13.71 and 10.26 Hz), 5.99 (1H, dd, J15.13 and 8.66 Hz) and 6.11-6.50 (12H, complex) ppm.
  • Characteristic signals include 0.93 (3H, d, J 7.1Hz), 1.05 (3H, d, J 6.4Hz), 1.13 (3H, d, J 6.4Hz), 1.16 (3H, d, J 6.1Hz), 2.39 (1H, d, J 9.5, 3Hz), 2.94 (1H, t, J 9.2Hz), 3.65 (1H, d, J 3Hz), 5.43 (1H, dd, J 14,10Hz).
  • Characteristic signals include 0.93 (3H, d, J 7.1Hz), 1.05 (3H, d, J 6.3Hz), 1.13 (3H, d, J 6.3Hz), 1.17 (3H, d, J 6.1Hz), 3.61 (1H, d, J 2.6Hz), 3.72 (3H, s), 5.25 (1H, dd, J 6.3, 2Hz), 5.43 (1H, dd, J 14.4, 10.1Hz), 5.97 (1H, dd, J 15.2, 9Hz).
  • the Minimum Inhibitory Concentration was determined by diluting the test compound in a broth medium in a microtitre tray. The organisms, which had been grown previously in a broth medium, were diluted and added to the wells to provide a final inoculum of approximately 10 5 colony-forming units per well. The trays were incubated at 37°C and the turbidity of each well noted at intervals. The MIC was taken as the lowest concentration (in ⁇ g/ml) which prevented significant growth.
  • YNB Yeast Nitrogen Base Broth

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Abstract

L'invention concerne un composé de la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, dans laquelle R1 représente un groupe CO.N(R5)OR6 dans lequel R5 représente hydrogène, alkyle C1-6, alcényle C3-6, cycloalkyle C3-6, C3-6 cycloalkyle -C1-6 alkyle, aryle C1-6 alkyle, hétéoaryle C1-6 alkyle, aryle, hétéroaryle dans lesquels n'importe quelle fraction d'aryle ou d'hétéoaryle est éventuellement substituée; R6 représente hydrogène, alkyle C1-6, alcényle C3-6, cycloalkyle C3-6, C3-6 cycloalkyle -C1-6 alkyle, aryle C1-6 alkyle, hétéroaryle C1-6 alkyle, aryle, hétéroaryle, dans lesquels n'importe quelle fraction d'aryle ou d'hétéroaryle est éventuellement substituée, hydroxyalkyle C2-6, un groupe (CH2)nNR7R8 dans lequel n = 2 à 6; R7 et R8 représentent indépendamment hydrogène ou alkyle C1-6 ou les deux avec l'azote auquel il sont rattachés à partir d'un groupe de la formule (i), dans laquelle s et r réunis représentent 3, 4 ou 5 et X représente oxygène, soufre CH2, ou NR dans lequel R représente hydrogène ou alkyle C1-6; où R6 est un groupe de la formule (ii) dans laquelle t est 1 à 6 et R9 représente hydrogène, alkyle C1-6; ou alcényle C3-6; ou R6 est un groupe de la formule (iii) dans laquelle u est 1 à 6 et R10 et R11 représentent indépendamment hydrogène, ou alkyle C1-6; R2 représente hydroxy ou alcoxy C1-6; R3 représente amino ou un dérivé de celui-ci; et R4 représente hydrogène ou hydroxy; ou R2 et R4 réunis représentent une liaison.
PCT/GB1993/000306 1992-02-19 1993-02-12 Derives d'amphothericine b WO1993017034A1 (fr)

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GB929203476A GB9203476D0 (en) 1992-02-19 1992-02-19 Novel compounds
GB9203476.8 1992-02-19

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Cited By (7)

* Cited by examiner, † Cited by third party
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FR2776927A1 (fr) * 1998-04-07 1999-10-08 Univ Paris Curie Compositions pour la vectorisation de molecules
WO2015190587A1 (fr) * 2014-06-12 2015-12-17 塩野義製薬株式会社 Dérivé de macrolide de polyène
US9447136B2 (en) 2012-03-09 2016-09-20 Blirt S.A. Semisynthetic derivatives of Nystatin A1
WO2016168568A1 (fr) 2015-04-15 2016-10-20 Revolution Medicines, Inc. Dérivés d'amphotéricine b
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
CN111875653A (zh) * 2020-08-11 2020-11-03 深圳市儿童医院 一种含二硫键的两性霉素b衍生物及其用途
WO2023274313A1 (fr) * 2021-06-29 2023-01-05 中国科学院上海药物研究所 Dérivé semi-synthétique d'amphotéricine b, son procédé de préparation et son utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0375223A2 (fr) * 1988-12-19 1990-06-27 Beecham Group Plc Dérivés de l'amphotéricine B, leur préparation et leur utilisation comme médicaments
EP0431874A1 (fr) * 1989-12-08 1991-06-12 Beecham Group p.l.c. Nouveaux composés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0375223A2 (fr) * 1988-12-19 1990-06-27 Beecham Group Plc Dérivés de l'amphotéricine B, leur préparation et leur utilisation comme médicaments
EP0431874A1 (fr) * 1989-12-08 1991-06-12 Beecham Group p.l.c. Nouveaux composés

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF ANTIBIOTICS. vol. 35, no. 2, February 1982, TOKYO JP pages 220 - 229 A.JARZEBSKI ET AL. 'Synthesis and Structure-Activity Relationships of Amides of Amphotericin B.' *

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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
FR2776927A1 (fr) * 1998-04-07 1999-10-08 Univ Paris Curie Compositions pour la vectorisation de molecules
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
CN106414473B (zh) * 2014-06-12 2020-03-13 盐野义制药株式会社 多烯大环内酯衍生物
WO2015190587A1 (fr) * 2014-06-12 2015-12-17 塩野義製薬株式会社 Dérivé de macrolide de polyène
EA037093B1 (ru) * 2014-06-12 2021-02-04 Сионоги Энд Ко., Лтд. Производное полиенового макролида
KR20170016957A (ko) 2014-06-12 2017-02-14 시오노기 앤드 컴파니, 리미티드 폴리엔 마크로라이드 유도체
CN106414473A (zh) * 2014-06-12 2017-02-15 盐野义制药株式会社 多烯大环内酯衍生物
JPWO2015190587A1 (ja) * 2014-06-12 2017-04-20 塩野義製薬株式会社 ポリエンマクロライド誘導体
US10696707B2 (en) 2014-06-12 2020-06-30 Shionogi & Co., Ltd. Polyene macrolide derivative
US10246478B2 (en) 2014-06-12 2019-04-02 Shionogi & Co., Ltd. Polyene macrolide derivative
JP2018514522A (ja) * 2015-04-15 2018-06-07 スファンガ セラピューティクス インコーポレイテッドＳｆｕｎｇａ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｉｎｃ． アムホテリシンｂの誘導体
US10597420B2 (en) 2015-04-15 2020-03-24 Sfunga Therapeutics, Inc. Derivatives of amphotericin B
US9957290B2 (en) 2015-04-15 2018-05-01 Sfunga Therapeutics, Inc. Derivatives of amphotericin B
US10882883B2 (en) 2015-04-15 2021-01-05 Sfunga Therapeutics, Inc. Derivatives of amphotericin B
WO2016168568A1 (fr) 2015-04-15 2016-10-20 Revolution Medicines, Inc. Dérivés d'amphotéricine b
JP2021075570A (ja) * 2015-04-15 2021-05-20 スファンガ セラピューティクス インコーポレイテッドＳｆｕｎｇａ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｉｎｃ． アムホテリシンｂの誘導体
EP3929203A1 (fr) * 2015-04-15 2021-12-29 Sfunga Therapeutics, Inc. Dérivés d'amphotéricine b
JP7240811B2 (ja) 2015-04-15 2023-03-16 スファンガ セラピューティクス インコーポレイテッド アムホテリシンｂの誘導体
CN111875653A (zh) * 2020-08-11 2020-11-03 深圳市儿童医院 一种含二硫键的两性霉素b衍生物及其用途
WO2023274313A1 (fr) * 2021-06-29 2023-01-05 中国科学院上海药物研究所 Dérivé semi-synthétique d'amphotéricine b, son procédé de préparation et son utilisation

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