WO1993014100A1 - Derives d'amphotericine b, leur preparation et leur utilisation - Google Patents

Derives d'amphotericine b, leur preparation et leur utilisation Download PDF

Info

Publication number
WO1993014100A1
WO1993014100A1 PCT/GB1993/000076 GB9300076W WO9314100A1 WO 1993014100 A1 WO1993014100 A1 WO 1993014100A1 GB 9300076 W GB9300076 W GB 9300076W WO 9314100 A1 WO9314100 A1 WO 9314100A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
decarboxy
hydrogen
amphotericin
Prior art date
Application number
PCT/GB1993/000076
Other languages
English (en)
Inventor
David Kenneth Dean
David Timothy Macpherson
Original Assignee
Smithkline Beecham Plc
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 Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of WO1993014100A1 publication Critical patent/WO1993014100A1/fr

Links

Classifications

    • 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):
  • EP-A-0375223 (Beecham Group p.l.c.) describes derivatives of amphotericin B having a 16-position aldehyde or ketone function of formula (B):
  • Rj is a group -X-Y where X is a carbonyl group and Y is hydrogen, C ⁇ _g alkyl, C2-8 alkenyl, or optionally substituted aryl or heteroaryl; R2 is hydroxy or C _8 alkoxy; R3 is hydrogen or an a ine protection group; and each R4 is hydrogen which compounds have been prepared in attempts to satisfy the need for a less toxic antifungal agent than amphotericin B.
  • Novel derivatives of amphotericin B have now been prepared in which the 16-position aldehyde or ketone group is replaced by a novel substituent 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:
  • R2 is C .g alkoxy or hydroxy
  • R3 is an amino group or a derivative thereof
  • R4 is hydrogen
  • R5 is hydrogen or hydroxy or 2 and R5 together represent a bond.
  • an alkyl or alkenyl group preferably has from 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms and may be straight-chain or branched.
  • the group j can exist in two geometric isomeric forms i.e. the E and Z isomers.
  • the present invention includes both the E and Z isomers and any mixtures thereof.
  • 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, alkoxy, aryl C ⁇ _galkyl, heteroarylC ⁇ _galkyl, aryl and heteroaryl groups may be selected from OH, C ⁇ _6 alkyl, C ⁇ _g alkoxy, carboxy, nitro, halogen, and amino optionally substituted by C ⁇ _ alkyl, C ⁇ .g acyl or aryl.
  • acyl refers to variables of the formula -COR wherein R is optionally substituted C ⁇ _8 alkyl, C ⁇ _ alkenyl, aryl C ⁇ _8 alkyl, aryl or heteroaryl.
  • Values for Rg in variable R include those mentioned for the variable Y in Ri in EP-A-0375223 (Beecham Group p.l.c.)
  • Rg is hydrogen
  • R2 is hydroxy and R5 is hydrogen.
  • R3 is primary amino
  • R7 examples include hydrogen, methoxycarbonyl, allyloxycarbonyl, hydroxycarbonyl and hydroxymethyL
  • R3 is an amine group or a derivative thereof including acyl derivatives bearing a basic substituent such as M-D-lysyl and -D-ornithyl derivatives, guarddine derivatives, andM-glycosyl derivatives.
  • acyl derivatives bearing a basic substituent such as M-D-lysyl and -D-ornithyl derivatives, guarddine derivatives, andM-glycosyl derivatives.
  • the preparation of further amino group derivatives is described in European Patent Publication 0 010 297 (Schering), European Patent Publication 0 031 722 (Dumex), US 4 195 172 and European Patent Publication 0 428 440.
  • 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 R3 is primary amine may 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
  • the present invention also provides a process for the preparation of compounds of formula (I) which process comprises the reaction of a compound of formula (II):
  • A is a group -X-Rg where X is a carbonyl group and Rg is as defined in relation to formula (I), R2' is alkoxy and ⁇ .5 is hydrogen or R2' and R5' together represent a bond; R3' is an amine protecting group; and each 4 * is hydrogen or a silyl protecting group; with a compound of formula (IIIA); or formula (IIIB) in the presence of a base;
  • Ph 3 P CHR 7 (IIIA) (R 8 0) 2 P(0)CH 2 R7 (IIIB)
  • R7 is as defined in relation to formula (I) and ⁇ .Q is alkyl, aryl, arylC ⁇ _8alkyl and thereafter optionally or as necessary in any appropriate order, separating any geometric isomers, converting R2' to R2 and R5' to hydrogen or hydroxy when R2' and R5' together are a bond, converting
  • the reaction between a compound of formula (II) and a compound of formula (IIIA) is a Wittig reaction as such the conditions used are conventional for Wittig reactions in general such as those described in Descriptions 1 and 2.
  • R3 * amine protection groups are chosen such that they are readily removable subsequent to the initial reaction between a compound of formula (II) and a compound of formula (III) to provide a compound of formula (I) in which R3 is primary amine.
  • Values for R3 * include trifluoracetyl, 9-fluorenylmethoxycarbonyl, trichloroethoxycarbonyl, 2-methylsulphonylethoxycarbonyl, 2-trimethylsilylethoxycarbonyl and allyloxycarbonyl.
  • R3' is tiifluoroacetyl and 9-fluorenylmethoxy- carbonyl.
  • Suitable R4' silyl protecting groups include trimethylsilyl, triethylsilyl and i-butyldimethylsilyl.
  • R4' is triethylsilyl.
  • R3' amine protection group to give an R3 primary amine may be carried out under basic conditions.
  • R3' amine protection group such as trifluoroacetyl maybe removed using a base such as ammonia or potassium carbonate in anhydrous methanol.
  • An R3' amine protection group such as 9-fiuorenylmethoxycarbonyl, 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, trialkylamines such as triethylamine, cyclic amines and especially cyclic secondary amines such as morpholine, piperazine and more especially piperidine, and diazabicyclic bases such as l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and preferably l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • DBN diazabicyclic bases
  • 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.
  • R4 1 silyl protecting groups in compounds of formula (II) may be removed using known deprotection methods, for example using a solution of hydrogen fiuoride-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 temperature, over a time period up to 60 hours and preferably from 4 to 24 hours.
  • Intermediate compounds of formula (II) in may be prepared from amphotericin B according to the procedures outlined in EP-A-0375223 (Beecham Group p.l.c).
  • the compounds of formula (IIIB) are commercially available or may be prepared according to the procedures outlined by W.S. Wadsworth, Organic Reactions (1977), Vol.25, p.73.
  • Rj, R2 and R5 are as defined in relation to formula (I) and R3 is a protected amine group and each R4 is a silyl protecting group.
  • R3 is a protected amine group and each R4 is a silyl protecting group.
  • the 13-position anomeric hydroxyl group wherein R5' is hydrogen may be selectively exchanged using the appropriate C ⁇ _8 alkyl alcohol in the presence of an acid catalyst such as 10-camphorsulphomc acid or pyridinium p.- toluene sulphonate under anhydrous conditions.
  • an acid catalyst such as 10-camphorsulphomc acid or pyridinium p.- toluene sulphonate under anhydrous conditions.
  • 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 H2 ⁇ -scavenger such as molecular sieves and/or under an inert atmosphere.
  • R3' amine protection groups may be introduced by standard procedures.
  • an R3' trifluoroacetyl amine protection group may be introduced by reaction of the primary amine with ethyl trifluoroacetate in the presence of base such as d ⁇ sopropylethylamine, in a methanol-dimethyl sulphoxide or methanol- dimethylformamide solvent mixture at reduced to normal temperatures, for example at 0°C.
  • An R3' 9-fluorenylmethoxycarbonyl 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 3' 9-fluorenylmethoxycarbonyl group may be introduced by addition of N-(9-fluorenylmethoxycarbonyloxy)succinimide to a slurry of the primary amine in methanol-dimethylformamide under anhydrous conditions in the presence of a base such as pyridine.
  • Free hydroxyl groups may be silylated using standard procedures.
  • the reaction with silyating agents such as trimethylsilyl 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.
  • R7 CO2H group can be converted to an R7-C ⁇ 2alkyl group by conventional esterification methods such as utilising an appropriate alcohol under acidic conditions.
  • R2 maybe converted to hydroxy under acid-catalysed conditions after removal of the R4' silyl protecting groups, using water or a mixture of water and tetrahydrofuran as solvent, preferably using a solvent mixture containing up to 50% water in tetrahydrofuran.
  • compounds of formula (I) where R2 and R5 together are a bond may be hydrated under acid-catalysed conditions to give compounds of formula (I) in which R2 is hydroxy and R5 is hydrogen.
  • a suitable acid catalyst for these reactions is 10-camphorsulphonic acid or pyridinium p.-toluene-sulphonate.
  • R2 * and R ⁇ may be C ⁇ _8 alkoxy and hydrogen respectively or R2' and R5' may together be a bond.
  • R4' is TES the extent of the elimination varies according to the solvent; it is significant when the solvent is dichloromethane, but negligible when the solvent is n-hexane or diethyl ether.
  • 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.
  • they are potentially useful in treating topical fungal infections in man caused by, among other organisms, species of Candida, Trichophyton, M ⁇ crosporum or Epidermophyton, or in mucosal infections caused by 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, Cryptococcus neoformans, Aspergill s fumigatus, Coccidioides, Paracoccidioides, Histoplasma or Blastomyces spp.
  • They may also be of use in treating eumycotic mycetoma, chromoblastomycosis, and phycomycosis.
  • 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 crea form.
  • the antifungal compounds of the formula (I) or 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, intramuscularly or subcutaneously.
  • parenteral administration they are best used in the for of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic.
  • 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 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 may be 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 (I) or a pharmaceutically acceptable salt thereof to the animal.
  • 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.
  • the present invention also provides a pharmaceutical composition for use in the treatment of fungal infections in animals, including humans, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof admixed with a pharmaceutically acceptable carrier.
  • N-(9-Fluorenylmethoxycarbonyl)-16-decarboxy-16-formyl-13-0-methyl- 3,5,8,9, ll,15,35,2 ⁇ 4 -nona-0-triethylsilyl- amphotericin B ⁇ (108mg, O.O ⁇ mmol) was stirred at 10°C in dry benzene (5ml) under nitrogen and methylenetriphenylphosphorane (0.5ml of 0.1M solution in benzene, O.O ⁇ mmol, prepared according to reference 2 from methyltriphenylphosphonium bromide and n-butyl Hthium) was added via syringe.
  • IR vmax (KBr disc): 3450 (b), 2940, 2900, 2860, 1730, 1500, 1450, 1410, 1375, 1230, 1060, 1000, 730, 720, cm "1 .
  • UV ⁇ max (n-hexane): 408, 384, 365, 347 nm.
  • Mass spectrum FAB (3-NOBA/Na matrix) observed mass MNa+ 2191.5, calculated for 2191.4.
  • Patent EP-A-0375223 (Beecham Group p.l.c) page 29, Description 10.
  • IR vmax (KBr disc): 3446, 2955, 2910, 2875, 1730, 1629, 1509, 1460, 1415, 1375, 1238, 1190, 1163, 1082, 1007, 838, 740, 729 cm" 1 .
  • IRvmax (KBr disc): 3400, 2955, 2920, 2875, 1730, 1500, 1450, 1410, 1370, 1230, 1070, 1000, 735, 720 cm- 1 .
  • Mass spectrum FAB (3-NOBA/Na matrix) observed mass MNa + 2275.4, calculated
  • IR vmax (KBr disc): 2955, 2612, 2876, 1734, 1695, 1636, 1509, 1457, 1414, 1380, 1239, 1108, 1082, 1005, 740, 727 cm" 1 .
  • UV ⁇ max (n-hexane): 408, 384, 365, 347 nm.
  • Mass spectrum FAB (3-NOBA/Na matrix) observed mass MNa + 2219.5, calculated for C ⁇ 9H2i3NSi9 ⁇ gNa 2219.4.
  • IR vmax (KBr disc): 3447, 2954, 2910, 2876, 1735, 1635, 1512, 1460, 1410, 1380, 1238, 1104, 1080, 1000, 740, 727 cm" 1 .
  • UV ⁇ max (n-hexane): 408, 384, 365, 347 nm.
  • Mass spectrum FAB (3-NOBA/Na) observed mass MNa + 2221.5, calculated for C ⁇ 19 H2i5Si 9 NOi8Na 2221.4.
  • the powder was stirred in tetrahydrofiiran (6ml)/water (1ml) under nitrogen in the dark with pyridinium para-toluene sulphonate (174mg, 0.69mmol). After 75 minutes, triethylamine (0.128ml, 0.92mmol) was added and the tetrahydrofiiran was removed in ⁇ acuo. Water was added and the solid was filtered. Washing the solid with water and drying gave a yellow powder.
  • the powder was stirred in tetrahydrofuran (12ml)/water (2ml) under nitrogen in the dark with pyridinium para-toluene sulphonate (377mg, l. ⁇ mmol). After 90 minutes, triethylamine (0.28ml, 2mmol) was added and the tetrahydrofiiran was removed in ⁇ acuo. Water was added and the solid was filtered. Washing the solid with water and drying gave a yellow powder.
  • IR vmax (KBr disc): 3400 (b), 2920, 1700, 1640, 1380, 1060, 1010 cm “1 .
  • UV ⁇ max (methanol): 405, 382, 363, 345 nm.
  • IR vmax (KBr disc): 3420 (b), 2926, 1717, 1636, 1560, 1384, 1071,
  • IRvmax (KBr disc): 3420 (b), 2929, 1701, 1636, 1400,1384, 1190, 1171, 1070, 1012 cm “1 .
  • 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 ⁇ 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

Composé répondant à la formule (1), ou son sel pharmaceutiquement acceptable. Dans ladite formule, R1 représente un groupe -CR6=CHR7 dans lequel R6 représente hydrogène, alkyle C1-8, alcényle C2-8, hétéroarylalkyle C1-8, arylalkyle C1-8, aryle ou hétéroaryle; R7 représente hydrogène, alcoxycarbonyle C1-8, alcényloxycarbonyle C2-8, hydroxycarbonyle, hydroxyméthyle ou formyle; où toute fraction aryle, hétéroaryle ou alkyle est éventuellement substituée; R2 représente alcoxy C1-6 ou hydroxy; R3 représente un groupe amino ou un dérivé de celui-ci; R4 représente hydrogène; et R5 représente hydrogène ou hydroxy, ou R2 et R5 représentent ensemble une liaison.
PCT/GB1993/000076 1992-01-14 1993-01-14 Derives d'amphotericine b, leur preparation et leur utilisation WO1993014100A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929200713A GB9200713D0 (en) 1992-01-14 1992-01-14 Novel compounds
GB9200713.7 1992-01-14

Publications (1)

Publication Number Publication Date
WO1993014100A1 true WO1993014100A1 (fr) 1993-07-22

Family

ID=10708562

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/000076 WO1993014100A1 (fr) 1992-01-14 1993-01-14 Derives d'amphotericine b, leur preparation et leur utilisation

Country Status (3)

Country Link
AU (1) AU3358093A (fr)
GB (1) GB9200713D0 (fr)
WO (1) WO1993014100A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003200284B2 (en) * 1998-03-27 2006-11-02 The Regents Of The University Of California Pharmacophore recombination for the identification of small molecule drug lead compounds

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0350164A2 (fr) * 1988-06-13 1990-01-10 Beecham Group Plc Dérivés-amphotéricine
EP0375222A2 (fr) * 1988-12-19 1990-06-27 Beecham Group Plc Dérivés d'amphotericin B
EP0375223A2 (fr) * 1988-12-19 1990-06-27 Beecham Group Plc Dérivés de l'amphotéricine B, leur préparation et leur utilisation comme médicaments
EP0431870A1 (fr) * 1989-12-08 1991-06-12 Beecham Group p.l.c. DÀ©rivés d'amphotéricine B
EP0431874A1 (fr) * 1989-12-08 1991-06-12 Beecham Group p.l.c. Nouveaux composés
WO1991009047A1 (fr) * 1989-12-08 1991-06-27 Beecham Group Plc Derives d'amphotericine b, leur production et leur utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0350164A2 (fr) * 1988-06-13 1990-01-10 Beecham Group Plc Dérivés-amphotéricine
EP0375222A2 (fr) * 1988-12-19 1990-06-27 Beecham Group Plc Dérivés d'amphotericin B
EP0375223A2 (fr) * 1988-12-19 1990-06-27 Beecham Group Plc Dérivés de l'amphotéricine B, leur préparation et leur utilisation comme médicaments
EP0431870A1 (fr) * 1989-12-08 1991-06-12 Beecham Group p.l.c. DÀ©rivés d'amphotéricine B
EP0431874A1 (fr) * 1989-12-08 1991-06-12 Beecham Group p.l.c. Nouveaux composés
WO1991009047A1 (fr) * 1989-12-08 1991-06-27 Beecham Group Plc Derives d'amphotericine b, leur production et leur utilisation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003200284B2 (en) * 1998-03-27 2006-11-02 The Regents Of The University Of California Pharmacophore recombination for the identification of small molecule drug lead compounds

Also Published As

Publication number Publication date
GB9200713D0 (en) 1992-03-11
AU3358093A (en) 1993-08-03

Similar Documents

Publication Publication Date Title
US20030060609A1 (en) Novel aromatic amides, preparation method and application as medicines
US5066646A (en) Amphotericin derivatives
US4150220A (en) Semi-synthetic 4"-erythromycin A derivatives
EP0201166B1 (fr) Dérivés d'érythromycine
US5204330A (en) Antifungal compounds
US6284736B1 (en) Amphotericin derivatives
US5100876A (en) 16-decarboxy-16-hydroxy derivatives of amphotericin b
US5116960A (en) Amphotericin b derivatives
US6451768B1 (en) Macrolide antiinfective agents
US4436729A (en) 23-Demycinosyltylosin compounds, pharmaceutical compositions and method of use
WO1993014100A1 (fr) Derives d'amphotericine b, leur preparation et leur utilisation
ES2208334T3 (es) Derivados cetolida de 6-0 carbamato.
WO1993017034A1 (fr) Derives d'amphothericine b
EP0184921A2 (fr) Dérivés d'érythromycine
JPH0649072A (ja) ６’−アルキルスペクチノマイシン用中間体の製法
IE46661B1 (en) Erythromycin a derivatives
WO1993016090A1 (fr) Derive d'amphotericine b
US4851518A (en) Di and tri-O-acetyl-"O-iso-valeryl-23-O-demycinosyl tylosins, hydrazone derivatives thereof and processes for their preparation
US4576931A (en) 23-C-Substituted mycaminosyl tylonolide, pharmaceutical compositions and method of use
US7144866B2 (en) Avermectin derivatives
JPH0136834B2 (fr)
EP0362267A1 (fr) Derives antibacteriens 3-o-glycosyle de macrolides a 16 membres et substances apparentees
AU2002300839B2 (en) Novel aromatic amides, preparation method and application as medicines
WO1991009047A1 (fr) Derives d'amphotericine b, leur production et leur utilisation
HU195820B (en) Process for producing new 6-alkyl-analogues of spectinomycin and pharmaceutical compositions containing them as active components

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP KR NZ US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA