WO2016040779A1 - Dérivés d'urée d'antibiotiques macrolides polyéniques - Google Patents

Dérivés d'urée d'antibiotiques macrolides polyéniques Download PDF

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Publication number
WO2016040779A1
WO2016040779A1 PCT/US2015/049647 US2015049647W WO2016040779A1 WO 2016040779 A1 WO2016040779 A1 WO 2016040779A1 US 2015049647 W US2015049647 W US 2015049647W WO 2016040779 A1 WO2016040779 A1 WO 2016040779A1
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Prior art keywords
polyene macrolide
macrolide antibiotic
urea derivative
certain embodiments
tetrin
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PCT/US2015/049647
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English (en)
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Martin D. Burke
Stephen Davis
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The Board Of Trustees Of The University Of Illinois
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Publication of WO2016040779A1 publication Critical patent/WO2016040779A1/fr

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • amphotericin B (AmB) has served as the gold standard for treating systemic fungal infections.
  • AmB has a broad spectrum of activity, is fungicidal, and is effective even against fungal strains that are resistant to multiple other agents.
  • clinically significant microbial resistance has remained exceptionally rare while resistance to next generation antifungals has appeared within just a few years of their clinical introduction.
  • AmB is also highly toxic.
  • the effective treatment of systemic fungal infections is all too often precluded, not by a lack of efficacy, but by dose-limiting side effects.
  • Some progress has been made using liposome delivery systems, but these treatments are prohibitively expensive and significant toxicities remain.
  • AmB derivatives stand to have a major impact on human health.
  • AmB is representative of a whole class of polyene macro lide antibiotics useful for the treatment of fungal infections. Similar to AmB, less toxic, but equally effective, derivatives of other polyene macrolide antibiotics stand to have a major impact on human health.
  • An aspect of the invention is a urea derivative of a polyene macrolide antibiotic or a pharmaceutically acceptable salt thereof, comprising a urea-containing substructure represented by
  • R represents hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aminoalkyl, or -(CH 2 ) n -COOH;
  • n 1, 2, 3, 4, 5, or 6;
  • said urea derivative has antifungal activity
  • An aspect of the invention is a pharmaceutical composition, comprising a urea derivative of the invention; and a pharmaceutically acceptable carrier.
  • An aspect of the invention is a method of inhibiting growth of a yeast or fungus, comprising contacting the yeast or fungus with an effective amount of a urea derivative of a polyene macrolide antibiotic or a pharmaceutically acceptable salt thereof; wherein said urea derivative comprises a urea-containing substructure represented by
  • R represents hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aminoalkyl, -(CH 2 ) n -COOH;
  • n 1, 2, 3, 4, 5, or 6;
  • said urea derivative has antifungal activity
  • An aspect of the invention is a method of treating a fungal infection, comprising administering to a subject in need thereof a therapeutically effective amount of a urea derivative of a polyene macrolide antibiotic or a pharmaceutically acceptable salt thereof; wherein said urea derivative comprises a urea-containing substructure represented by
  • R represents hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aminoalkyl, -(CH 2 ) n -COOH;
  • n 1, 2, 3, 4, 5, or 6;
  • said urea derivative has antifungal activity
  • An aspect of the invention is a method of making a urea derivative of a polyene m
  • each R is independently selected from the group consisting of hydrogen, halogen, straight- or branched-chain alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxyl, sulfhydryl, carboxyl, amino, amido, azido, nitro, cyano, aminoalkyl, and alkoxyl;
  • polyene macrolide antibiotic is not amphotericin B.
  • the polyene macrolide antibiotic is selected from the group consisting of amphotericin A, arenomycin B, candicidin D, candidin, candidoin, CE-108, etruscomycin, eurocidin D, eurocidin E, FR-008-VI, HA-2-91, hamycin A, levorin AO, levorin A3, mycoheptin, natamycin (pimaricin), nystatin Al, nystatin A2, nystatin A3, partricin A, polyfungin B, rimocidin, tetramycin A, tetramycin B, tetrin A, tetrin B, tetrin C, trichomycin A, trichomycin B, vacidin A, YS-822A, 3874 HI, 3874 H2, 3874 H3, and 67- 121-A.
  • Amphotericin B (AmB), a widely known and used representative antifungal polyene macrolide antibiotic, comprises a polyhydroxylated, polyunsaturated macrolactone ring core, decorated with a mycosamine "appendage". Mycosamine is 3-amino-3,6-dideoxy-P- D-mannopyranose. The mycosamine portion of the molecule plays a key role in both the desired biological effects and the undesirable side-effects of Amphotericin B.
  • this crystal structure may represent the ground state conformation of AmB which is capable of binding both ergosterol and cholesterol.
  • nucleophiles efficiently opens the oxazolidinone while concomitantly cleaving the Fmoc protecting group. For example, exposure of 1 to ethylene diamine, followed by methyl ketal hydrolysis in acidic water generates aminoethylurea (AmBAU) 2 in 42% yield.
  • AmBAU aminoethylurea
  • methyl urea (AmBMU) 3 in 36% yield from 1.
  • This versatile synthetic strategy allows efficient access to a diverse array of AmB urea derivatives and is capable of generating large quantities of urea derivatives due to its synthetic efficiency.
  • oxazolidinone 1 with a variety of nucleophiles (e.g., amines, alcohols, and phenols) could efficiently access a wide range of urea or carbamate derivatives.
  • nucleophiles e.g., amines, alcohols, and phenols
  • Oxazolidinone 1 could be intercepted with primary amines to generate primary ureas, secondary amines to generate secondary ureas, and primary amines with alpha branching to create ureas with stereochemistry introduced at the alpha position.
  • oxazolidinone 1 could be opened with anilines to create aryl ureas, phenols to create aryl carbamates, or alcohols to generate alkyl carbamates.
  • amines include, without limitation, 1-(1-Naphthyl)ethylamine; l-(2- Naphthyl)ethylamine; l-(4-Bromophenyl)ethylamine; l,l-Diphenyl-2-aminopropane; 1,2,2- Triphenylethylamine; 1 ,2,3 ,4-Tetrahydro- 1 -naphthylamine; 1 ,2-Bis(2- hydroxyphenyl)ethylenediamine; l-Amino-2-benzyloxycyclopentane; 1-Aminoindane; 1- Benzyl-2,2-diphenylethylamine; 1-Cyclopropylethylamine; 1-Phenylbutylamine; 2-(3- Chloro-2,2-dimethyl-propionylamino)-3-methylbutanol; 2-
  • the instant invention provides urea derivatives of any suitable mycosamine-containing polyene macrolide antibiotic.
  • the present invention expressly excludes, however, the urea derivatives of AmB just described, namely, AmBAU, AmBMU, and AmBCU.
  • the compounds shown above can be generally characterized as comprising a C25-
  • the compounds of the invention i.e., urea derivatives of polyene macrolide antibiotics, comprise a corresponding motif or substructure represented by
  • R represents hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aminoalkyl, or -(CH 2 ) deliberately-COOH;
  • n 1, 2, 3, 4, 5, or 6.
  • An aspect of the invention is a urea derivative of a polyene macrolide antibiotic or a pharmaceutically acceptable salt thereof, comprising a urea-containing substructure represented by
  • R represents hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aminoalkyl, or -(CH 2 ) n -COOH;
  • n 1, 2, 3, 4, 5, or 6;
  • said urea derivative has antifungal activity
  • the binding avidity for ergosterol of said urea derivative is at least 75 percent of the binding avidity for ergosterol of the counterpart polyene macrolide antibiotic. In various individual embodiments, the binding avidity for ergosterol of a compound of the invention is at least 80 percent, at least 85 percent, at least 90 percent, or at least 95 percent of the binding avidity for ergosterol of the counterpart polyene macrolide. In certain embodiments, the binding avidity for ergosterol of a compound of the invention is at least 100 percent of the binding avidity for ergosterol of the counterpart polyene macrolide.
  • the binding avidity for cholesterol of said urea derivative is less than or equal to 25 percent of the binding avidity for cholesterol of the counterpart polyene macrolide antibiotic. In various individual embodiments, the binding avidity for cholesterol of a compound of the invention is less than or equal to 20 percent, less than or equal to 15 percent, less than or equal to 10 percent, or less than or equal to 5 percent, of the binding avidity for cholesterol of the counterpart polyene macrolide. In an
  • a compound of the invention has essentially no binding avidity for cholesterol.
  • the binding avidity for ergosterol of a compound of the invention is at least 75 percent of the binding avidity for ergosterol of the counterpart polyene macrolide; and the binding avidity for cholesterol of the compound of the invention is less than or equal to 25 percent of the binding avidity for cholesterol of the counterpart polyene macrolide.
  • R represents alkyl, aminoalkyl, or -(CH 2 ) n -COOH.
  • R represents alkyl
  • R represents aminoalkyl
  • R represents -(CH 2 ) n -COOH.
  • R represents -(CH 2 ) n -COOH, and n is 1.
  • R represents -(CH 2 ) n -COOH, and n is 2.
  • R represents -(CH 2 ) n -COOH, and n is 3.
  • R represents -(CH 2 ) n -COOH, and n is 4.
  • R represents -(CH 2 ) n -COOH, and n is 5.
  • R represents -(CH 2 ) n -COOH, and n is 6.
  • the polyene macrolide antibiotic is selected from the group consisting of amphotericin A, arenomycin B, candicidin D, candidin, candidoin, CE-108, etruscomycin, eurocidin D, eurocidin E, FR-008-VI, HA-2-91, hamycin A, levorin AO, levorin A3, mycoheptin, natamycin (pimaricin), nystatin Al, nystatin A2, nystatin A3, partricin A, polyfungin B, rimocidin, tetramycin A, tetramycin B, tetrin A, tetrin B, tetrin C, trichomycin A, trichomycin B, vacidin A, YS-822A, 3874 HI, 3874 H2, 3874 H3, and 67- 121-A.
  • the polyene macrolide antibioti c is amphotericin A.
  • the polyene macrolide antibioti c is arenomycin B.
  • the polyene macrolide antibioti c is candicidin D.
  • the polyene macrolide antibioti c is candidin.
  • the polyene macrolide antibioti c is candidoin.
  • the polyene macrolide antibioti c is CE-108.
  • the polyene macrolide antibioti c is etruscomycin.
  • the polyene macrolide antibioti c is eurocidin D.
  • the polyene macrolide antibioti c is eurocidin E.
  • the polyene macrolide antibioti c is FR-008-VI.
  • the polyene macrolide antibioti c is HA-2-91.
  • the polyene macrolide antibioti c is hamycin A.
  • the polyene macrolide antibioti c is levorin AO.
  • the polyene macrolide antibioti c is levorin A3.
  • the polyene macrolide antibioti c is mycoheptin.
  • the polyene macrolide antibioti c is natamycin (pimaricin)
  • the polyene macrolide antibioti c is nystatin Al .
  • the polyene macrolide antibioti c is nystatin A2.
  • the polyene macrolide antibioti c is nystatin A3.
  • the polyene macrolide antibioti c is partricin A.
  • the polyene macrolide antibioti c is polyfungin B.
  • the polyene macrolide antibioti c is rimocidin.
  • the polyene macrolide antibioti c is tetramycin A.
  • the polyene macrolide antibioti c is tetramycin B.
  • the polyene macrolide antibioti c is tetrin A.
  • the polyene macrolide antibioti c is tetrin B.
  • the polyene macrolide antibioti c is tetrin C.
  • the polyene macrolide antibioti c is trichomycin A. In certain embodiments, the polyene macrolide antibiotic is trichomycin B.
  • the polyene macrolide antibiotic is vacidin A.
  • the polyene macrolide antibiotic is YS-822A.
  • the polyene macrolide antibiotic is 3874 HI .
  • the polyene macrolide antibiotic is 3874 H2.
  • the polyene macrolide antibiotic is 3874 H3.
  • the polyene macrolide antibiotic is 67-121 -A.
  • a "compound of the invention” refers to a urea derivative of a polyene macrolide antibiotic or a pharmaceutically acceptable salt thereof, as set forth herein. Without meaning to be limiting, compounds of the invention include the following
  • a compound of the invention is purified, i.e., isolated from other compounds and components including the corresponding (i.e., unmodified) polyene macrolide.
  • a compound of the invention is present in a mixture together with the corresponding polyene macrolide.
  • a compound of the invention represents at least 50 percent of the polyene macrolide present in such mixture.
  • a compound of the invention represents at least 50 percent, at least 60 percent, at least 70 percent, at least 75 percent, at least 80 percent, at least 85 percent, at least 90 percent, or at least 95 percent of the polyene macrolide present in such mixture.
  • An aspect of the invention is a pharmaceutical composition, comprising a compound of the invention; and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means one or more compatible solid or liquid filler, diluent or encapsulating substances which are suitable for administration to a human or other subject.
  • the pharmaceutical composition is formulated for systemic administration.
  • the pharmaceutical composition is formulated for intravenous administration.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for intraperitoneal administration.
  • the pharmaceutical composition is formulated for topical administration.
  • the pharmaceutical composition is formulated for local administration.
  • the pharmaceutical composition is formulated for intrathecal administration.
  • An aspect of the invention is a method of inhibiting growth of a yeast or fungus.
  • the method includes the step of contacting the yeast or fungus with an effective amount of a urea derivative of a polyene macrolide antibiotic or a pharmaceutically acceptable salt thereof; wherein said urea derivative comprises a urea-containing substructure represented by
  • R represents hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aminoalkyl, or -(CH 2 ) deliberately-COOH;
  • n 1, 2, 3, 4, 5, or 6;
  • said urea derivative has antifungal activity
  • AmBMU AmBAU, or AmBCU.
  • Yeasts are eukaryotic organisms classified in the kingdom Fungi. Yeasts are typically described as budding forms of fungi. Of particular importance in connection with the invention are species of yeast that can cause infections in mammalian hosts. Such infections most commonly occur in immunocompromised hosts, including hosts with compromised barriers to infection (e.g., burn victims) and hosts with compromised immune systems (e.g., hosts receiving chemotherapy or immune suppressive therapy, and hosts infected with HIV).
  • Pathogenic yeast include, without limitation, various species of the genus Candida, as well as of Cryptococcus . Of particular note among pathogenic yeasts of the genus Candida are C albicans, C tropicalis, C stellatoidea, C. glabrata, C. krusei, C. parapsilosis, C. guilliermondii, C. viswanathii, and C. lusitaniae.
  • Cryptococcus specifically includes Cryptococcus neoformans.
  • Yeast can cause infections of mucosal membranes, for example oral, esophageal, and vaginal infections in humans, as well as infections of bone, blood, urogenital tract, and central nervous system. This list is exemplary and is not limiting in any way.
  • Fungi include other eukaryotic organisms including molds and mushrooms.
  • a number of fungi can cause infections in mammalian hosts. Such infections most commonly occur in immunocompromised hosts, including hosts with compromised barriers to infection (e.g., burn victims) and hosts with
  • Pathogenic fungi include, without limitation, species of Aspergillus, Rhizopus, Mucor, Histoplasma, Coccidioides,
  • Blastomyces, Trichophyton, Microsporum, and Epidermophyton are A. fumigatus, A.flavus, A. niger, H. capsulatum, C. immitis, and B.
  • Fungi can cause deep tissue infections in lung, bone, blood, urogenital tract, and central nervous system, to name a few. Some fungi are responsible for infections of the skin and nails.
  • the phrase "effective amount” refers to any amount that is sufficient to achieve a desired biological effect.
  • inhibit or inhibiting means reduce by at least a statistically significant amount compared to control. In one embodiment, inhibit or inhibiting means reduce by at least 5 percent compared to control. In various individual embodiments, inhibit or inhibiting means reduce by at least 10, 15, 20, 25, 30, 33, 40, 50, 60, 67, 70, 75, 80, 90, or 95 percent compared to control.
  • the binding avidity for ergosterol of said urea derivative is at least 75 percent of the binding avidity for ergosterol of the counterpart polyene macrolide antibiotic. In various individual embodiments, the binding avidity for ergosterol of a compound of the invention is at least 80 percent, at least 85 percent, at least 90 percent, or at least 95 percent of the binding avidity for ergosterol of the counterpart polyene macrolide. In certain embodiments, the binding avidity for ergosterol of a compound of the invention is at least 100 percent of the binding avidity for ergosterol of the counterpart polyene macrolide.
  • the binding avidity for cholesterol of said urea derivative is less than or equal to 25 percent of the binding avidity for cholesterol of the counterpart polyene macrolide antibiotic. In various individual embodiments, the binding avidity for cholesterol of a compound of the invention is less than or equal to 20 percent, less than or equal to 15 percent, less than or equal to 10 percent, or less than or equal to 5 percent, of the binding avidity for cholesterol of the counterpart polyene macrolide. In an
  • a compound of the invention has essentially no binding avidity for
  • the binding avidity for ergosterol of a compound of the invention is at least 75 percent of the binding avidity for ergosterol of the counterpart polyene macrolide; and the binding avidity for cholesterol of the compound of the invention is less than or equal to 25 percent of the binding avidity for cholesterol of the counterpart polyene macrolide.
  • R represents alkyl, aminoalkyl, or -(CH 2 ) n -COOH.
  • R represents alkyl
  • R represents aminoalkyl
  • R represents -(CH 2 ) n -COOH.
  • R represents -(CH 2 ) n -COOH, and n is 1.
  • R represents -(CH 2 ) n -COOH, and n is 2.
  • R represents -(CH 2 ) n -COOH, and n is 3.
  • R represents -(CH 2 ) n -COOH, and n is 4.
  • R represents -(CH 2 ) n -COOH, and n is 5.
  • R represents -(CH 2 ) n -COOH, and n is 6.
  • the polyene macrolide antibiotic is selected from the group consisting of amphotericin A, arenomycin B, candicidin D, candidin, candidoin, CE-108, etruscomycin, eurocidin D, eurocidin E, FR-008-VI, HA-2-91, hamycin A, levorin AO, levorin A3, mycoheptin, natamycin (pimaricin), nystatin Al, nystatin A2, nystatin A3, partricin A, polyfungin B, rimocidin, tetramycin A, tetramycin B, tetrin A, tetrin B, tetrin C, trichomycin A, trichomycin B, vacidin A, -822A, 3874 HI, 3874 H2, 3874 H3, and 67- 121-A.
  • the polyene macro ide antibioti c is amphotericin A.
  • the polyene macro ide antibioti c is arenomycin B.
  • the polyene macro ide antibioti c is candicidin D.
  • the polyene macro ide antibioti c is candidin.
  • the polyene macro ide antibioti c is candidoin.
  • the polyene macro ide antibioti c is CE-108.
  • the polyene macro ide antibioti c is etruscomycin.
  • the polyene macro ide antibioti c is eurocidin D.
  • the polyene macro ide antibioti c is eurocidin E.
  • the polyene macro ide antibioti c is FR-008-VI.
  • the polyene macro ide antibioti c is HA-2-91.
  • the polyene macro ide antibioti c is hamycin A.
  • the polyene macro ide antibioti c is levorin AO.
  • the polyene macro ide antibioti c is levorin A3.
  • the polyene macro ide antibioti c is mycoheptin.
  • the polyene macro ide antibioti c is natamycin (pimaricin)
  • the polyene macro ide antibioti c is nystatin Al .
  • the polyene macro ide antibioti c is nystatin A2.
  • the polyene macro ide antibioti c is nystatin A3.
  • the polyene macro ide antibioti c is partricin A.
  • the polyene macro ide antibioti c is polyfungin B.
  • the polyene macro ide antibioti c is rimocidin.
  • the polyene macro ide antibioti c is tetramycin A.
  • the polyene macro ide antibioti c is tetramycin B.
  • the polyene macro ide antibioti c is tetrin A.
  • the polyene macro ide antibioti c is tetrin B.
  • the polyene macro ide antibioti c is tetrin C.
  • the polyene macro ide antibioti c is trichomycin A.
  • the polyene macro ide antibioti c is trichomycin B.
  • the polyene macro ide antibioti c is vacidin A.
  • the polyene macro ide antibioti c is YS-822A. In certain embodiments, the polyene macro lide antibiotic is 3874 HI .
  • the polyene macrolide antibiotic is 3874 H2.
  • the polyene macrolide antibiotic is 3874 H3.
  • the polyene macrolide antibiotic is 67-121 -A.
  • An aspect of the invention is a method of treating a fungal infection, comprising administering to a subject in need thereof a therapeutically effective amount of a urea derivative of a polyene macrolide antibiotic or a pharmaceutically acceptable salt thereof; wherein said urea derivative comprises a urea-containing substructure represented by
  • R represents hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aminoalkyl, or -(CH 2 ) n -COOH;
  • n 1, 2, 3, 4, 5, or 6;
  • said urea derivative has antifungal activity
  • AmBMU AmBAU, or AmBCU.
  • treating and “treat” refer to performing an intervention that results in (a) preventing a condition or disease from occurring in a subject that may be at risk of developing or predisposed to having the condition or disease but has not yet been diagnosed as having it; (b) inhibiting a condition or disease, e.g., slowing or arresting its development; or (c) relieving or ameliorating a condition or disease, e.g., causing regression of the condition or disease.
  • treating and “treat” refer to performing an intervention that results in (a) inhibiting a condition or disease, e.g., slowing or arresting its development; or (b) relieving or ameliorating a condition or disease, e.g., causing regression of the condition or disease.
  • yeast or fungal infection refers to an infection with a yeast or fungus as defined herein.
  • a "subject” refers to a living mammal.
  • a subject is a non-human mammal, including, without limitation, a mouse, rat, hamster, guinea pig, rabbit, sheep, goat, cat, dog, pig, horse, cow, or non-human primate.
  • a subject is a human.
  • a "subject having a yeast or fungal infection” refers to a subject that exhibits at least one objective manifestation of a yeast or fungal infection.
  • a subject having a yeast or fungal infection is a subject that has been diagnosed as having a yeast or fungal infection and is in need of treatment thereof.
  • administering has its usual meaning and encompasses
  • administering by any suitable route of administration, including, without limitation, intravenous, intramuscular, intraperitoneal, intrathecal, subcutaneous, direct injection (for example, into a tumor), mucosal, inhalation, oral, and topical.
  • routes of administration including, without limitation, intravenous, intramuscular, intraperitoneal, intrathecal, subcutaneous, direct injection (for example, into a tumor), mucosal, inhalation, oral, and topical.
  • terapéuticaally effective amount refers to any amount that is sufficient to achieve a desired therapeutic effect, e.g., to treat a yeast or fungal infection.
  • the binding avidity for ergosterol of said urea derivative is at least 75 percent of the binding avidity for ergosterol of the counterpart polyene macrolide antibiotic. In various individual embodiments, the binding avidity for ergosterol of a compound of the invention is at least 80 percent, at least 85 percent, at least 90 percent, or at least 95 percent of the binding avidity for ergosterol of the counterpart polyene macrolide. In certain embodiments, the binding avidity for ergosterol of a compound of the invention is at least 100 percent of the binding avidity for ergosterol of the counterpart polyene macrolide.
  • the binding avidity for cholesterol of said urea derivative is less than or equal to 25 percent of the binding avidity for cholesterol of the counterpart polyene macrolide antibiotic. In various individual embodiments, the binding avidity for cholesterol of a compound of the invention is less than or equal to 20 percent, less than or equal to 15 percent, less than or equal to 10 percent, or less than or equal to 5 percent, of the binding avidity for cholesterol of the counterpart polyene macrolide. In an
  • a compound of the invention has essentially no binding avidity for cholesterol.
  • the binding avidity for ergosterol of a compound of the invention is at least 75 percent of the binding avidity for ergosterol of the counterpart polyene macrolide; and the binding avidity for cholesterol of the compound of the invention is less than or equal to 25 percent of the binding avidity for cholesterol of the counterpart polyene macrolide.
  • R represents alkyl, aminoalkyl, or -(CH 2 ) n -COOH.
  • R represents alkyl
  • R represents aminoalkyl
  • R represents -(CH 2 ) n -COOH.
  • R represents -(CH 2 ) n -COOH, and n is 1.
  • R represents -(CH 2 ) n -COOH, and n is 2.
  • R represents -(CH 2 ) n -COOH, and n is 3.
  • R represents -(CH 2 ) n -COOH, and n is 4.
  • R represents -(CH 2 ) n -COOH, and n is 5.
  • R represents -(CH 2 ) n -COOH, and n is 6.
  • the polyene macrolide antibiotic is selected from the group consisting of amphotericin A, arenomycin B, candicidin D, candidin, candidoin, CE-108, etruscomycin, eurocidin D, eurocidin E, FR-008-VI, HA-2-91, hamycin A, levorin AO, levorin A3, mycoheptin, natamycin (pimaricin), nystatin Al, nystatin A2, nystatin A3, partricin A, polyfungin B, rimocidin, tetramycin A, tetramycin B, tetrin A, tetrin B, tetrin C, trichomycin A, trichomycin B, vacidin A, YS-822A, 3874 HI, 3874 H2, 3874 H3, and 67- 121-A.
  • the polyene macrolide antibiotic is amphotericin A.
  • the polyene macrolide antibiotic is arenomycin B.
  • the polyene macrolide antibiotic is candicidin D.
  • the polyene macrolide antibiotic is candidin.
  • the polyene macrolide antibiotic is candidoin.
  • the polyene macrolide antibiotic is CE-108.
  • the polyene macrolide antibiotic is etruscomycin.
  • the polyene macrolide antibiotic is eurocidin D.
  • the polyene macrolide antibiotic is eurocidin E.
  • the polyene macrolide antibiotic is FR-008-VI.
  • the polyene macrolide antibiotic is HA-2-91. In certain embodiments, the polyene macrolide antibiotic is hamycin A.
  • the polyene macrolide antibiotic is levorin AO.
  • the polyene macrolide antibiotic is levorin A3.
  • the polyene macrolide antibiotic is mycoheptin.
  • the polyene macrolide antibiotic is natamycin (pimaricin)
  • the polyene macrolide antibiotic is nystatin Al .
  • the polyene macrolide antibiotic is nystatin A2.
  • the polyene macrolide antibiotic is nystatin A3.
  • the polyene macrolide antibiotic is partricin A.
  • the polyene macrolide antibiotic is polyfungin B.
  • the polyene macrolide antibiotic is rimocidin.
  • the polyene macrolide antibiotic is tetramycin A.
  • the polyene macrolide antibiotic is tetramycin B.
  • the polyene macrolide antibiotic is tetrin A.
  • the polyene macrolide antibiotic is tetrin B.
  • the polyene macrolide antibiotic is tetrin C.
  • the polyene macrolide antibiotic is trichomycin A.
  • the polyene macrolide antibiotic is trichomycin B.
  • the polyene macrolide antibiotic is vacidin A.
  • the polyene macrolide antibiotic is YS-822A.
  • the polyene macrolide antibiotic is 3874 HI .
  • the polyene macrolide antibiotic is 3874 H2.
  • the polyene macrolide antibiotic is 3874 H3.
  • the polyene macrolide antibiotic is 67-121 -A.
  • the urea derivative is administered systemically.
  • the urea derivative is administered intravenously.
  • the urea derivative is administered orally.
  • the urea derivative is administered intraperitoneally.
  • the urea derivative is administered intrathecally.
  • the urea derivative is administered locally.
  • the urea derivative is administered topically.
  • an "effective amount” refers to any amount that is sufficient to achieve a desired biological effect.
  • an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject.
  • the effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition.
  • One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and/or other therapeutic agent without necessitating undue experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds.
  • Appropriate systemic levels can be determined by, for example, measurement of the patient's peak or sustained plasma level of the drug. "Dose” and “dosage” are used interchangeably herein.
  • daily intravenous doses of compounds of the invention will be, for human subjects, similar to or greater than usual daily intravenous doses of corresponding polyene macrolide comprising a mycosaminyl moiety.
  • daily other parenteral doses of compounds of the invention will be, for human subjects, similar to or greater than usual daily other parenteral doses of corresponding polyene macrolide comprising a mycosaminyl moiety.
  • intravenous administration of a compound of the invention may typically be from 0.1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of a compound of the invention may typically be from 0.1 mg/kg/day to 2 mg/kg/day. In one embodiment, intravenous administration of a compound of the invention may typically be from 0.5 mg/kg/day to 5 mg/kg/day. In one embodiment, intravenous administration of a compound of the invention may typically be from 1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of a compound of the invention may typically be from 1 mg/kg/day to 10 mg/kg/day. Intravenous dosing thus may be similar to, or advantageously, may exceed maximal tolerated doses of a given
  • daily oral doses of active compounds will be, for human subjects, from about 0.01 milligrams/kg per day to 1000 milligrams/kg per day. It is expected that oral doses in the range of 0.5 to 50 milligrams/kg, in one or more administrations per day, will yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
  • the therapeutically effective amount can be initially determined from animal models.
  • a therapeutically effective dose can also be determined from human data for compounds of the invention which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration.
  • the applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.
  • compositions of the invention are administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.
  • an effective amount of the compound of the invention can be administered to a subject by any mode that delivers the compound of the invention to the desired surface.
  • Administering the pharmaceutical composition of the present invention may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical.
  • a compound of the invention generally may be formulated similarly to the corresponding polyene macrolide comprising a mycosaminyl moiety.
  • C2'epiAmB can be formulated as a lyophilized preparation with desoxycholic acid, as a lyophilized preparation of liposome- intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a cholesteryl sulfate complex.
  • Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration.
  • the compounds of the invention can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or
  • polyvinylpyrrolidone PVP
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers.
  • oral dosage forms of the above component or components may be chemically modified so that oral delivery of the derivative is efficacious.
  • contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine.
  • moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts", In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp.
  • the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine.
  • the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.
  • a coating impermeable to at least pH 5.0 is essential.
  • examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as mixed films.
  • a coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow.
  • Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used.
  • the shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used.
  • the therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm.
  • the formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets.
  • the therapeutic could be prepared by compression.
  • Colorants and flavoring agents may all be included.
  • the compound of the invention (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.
  • these diluents could include carbohydrates, especially mannitol, a-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch.
  • Certain inorganic salts may be also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride.
  • Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.
  • Disintegrants may be included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate,
  • Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used.
  • Another form of the disintegrants are the insoluble cationic exchange resins.
  • Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.
  • Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin.
  • MC methyl cellulose
  • EC ethyl cellulose
  • CMC carboxymethyl cellulose
  • PVP polyvinyl pyrrolidone
  • HPMC hydroxypropylmethyl cellulose
  • Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.
  • the glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.
  • Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride.
  • Non-ionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios.
  • compositions which can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • compounds of the invention for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • pulmonary delivery of a compound of the invention is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream.
  • inhaled molecules include Adjei et al, Pharm Res 7:565-569 (1990); Adjei et al, Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al, J
  • Contemplated for use in the practice of this invention are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.
  • Ultravent nebulizer manufactured by Mallinckrodt, Inc., St. Louis, Mo.
  • Acorn II nebulizer manufactured by Marquest Medical Products, Englewood, Colo.
  • the Ventolin metered dose inhaler manufactured by Glaxo Inc., Research Triangle Park, North Carolina
  • the Spinhaler powder inhaler manufactured by Fisons Corp., Bedford, Mass.
  • each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated.
  • Chemically modified compound of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.
  • Formulations suitable for use with a nebulizer will typically comprise compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution.
  • the formulation may also include a buffer and a simple sugar (e.g., for compound of the invention stabilization and regulation of osmotic pressure).
  • the nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol.
  • Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant.
  • the propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a
  • hydrochlorofluorocarbon a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2- tetrafluoroethane, or combinations thereof.
  • Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.
  • Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation.
  • the compound of the invention (or derivative) should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers ( ⁇ ), most preferably 0.5 to 5 ⁇ , for most effective delivery to the deep lung.
  • Nasal delivery of a pharmaceutical composition of the present invention is also contemplated.
  • Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung.
  • Formulations for nasal delivery include those with dextran or cyclodextran.
  • a useful device is a small, hard bottle to which a metered dose sprayer is attached.
  • the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed.
  • the chamber is compressed to administer the pharmaceutical composition of the present invention.
  • the chamber is a piston arrangement.
  • Such devices are commercially available.
  • a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used.
  • the opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation.
  • the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.
  • the compounds when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
  • a suitable vehicle e.g., sterile pyrogen- free water
  • the compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • compounds of the invention may also be formulated as a depot preparation.
  • Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto
  • the pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above.
  • the pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249: 1527- 33 (1990).
  • a compound of the invention and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt.
  • the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof.
  • Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic.
  • such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
  • Suitable buffering agents include: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5%) w/v); and phosphoric acid and a salt (0.8- 2%> w/v).
  • Suitable preservatives include benzalkonium chloride (0.003-0.03%) w/v);
  • chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v) and thimerosal (0.004-0.02% w/v).
  • compositions of the invention contain an effective amount of a compound of the invention and optionally other therapeutic agents included in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal.
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
  • the therapeutic agent(s), including specifically but not limited to compounds of the invention, may be provided in particles.
  • Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound of the invention or the other therapeutic agent(s) as described herein.
  • the particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating.
  • the therapeutic agent(s) also may be dispersed throughout the particles.
  • the therapeutic agent(s) also may be adsorbed into the particles.
  • the particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc.
  • the particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof.
  • the particles may be microcapsules which contain the compound of the invention in a solution or in a semi-solid state.
  • the particles may be of virtually any shape.
  • Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s).
  • Such polymers may be natural or synthetic polymers.
  • the polymer is selected based on the period of time over which release is desired.
  • Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein.
  • polyhyaluronic acids casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).
  • the therapeutic agent(s) may be contained in controlled release systems.
  • controlled release is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release
  • sustained release also referred to as “extended release”
  • extended release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.
  • delayed release is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”
  • Long-term sustained release implant may be particularly suitable for treatment of chronic conditions.
  • Long-term release as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days.
  • Long-term sustained release implants are well- known to those of ordinary skill in the art and include some of the release systems described above.
  • An aspect of the invention is a method of making a urea derivative of a polyene macr lide antibiotic according to any one of the six transformations shown in Scheme 2
  • each R is independently selected from the group consisting of hydrogen, halogen, straight- or branched-chain alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxyl, sulfhydryl, carboxyl, amino, amido, azido, nitro, cyano, aminoalkyl, and alkoxyl;
  • polyene macro lide antibiotic is not amphotericin B.
  • the polyene macrolide antibiotic is selected from the group consisting of amphotericin A, arenomycin B, candicidin D, candidin, candidoin, CE-108, etruscomycin, eurocidin D, eurocidin E, FR-008-VI, HA-2-91, hamycin A, levorin AO, levorin A3, mycoheptin, natamycin (pimaricin), nystatin Al, nystatin A2, nystatin A3, partricin A, polyfungin B, rimocidin, tetramycin A, tetramycin B, tetrin A, tetrin B, tetrin C, trichomycin A, trichomycin B, vacidin A, YS-822A, 3874 HI, 3874 H2, 3874 H3, and 67- 121-A.
  • the polyene macrolide antibiotic is amphotericin A.
  • the polyene macrolide antibiotic is arenomycin B.
  • the polyene macrolide antibiotic is candicidin D.
  • the polyene macrolide antibiotic is candidin.
  • the polyene macrolide antibiotic is candidoin.
  • the polyene macrolide antibiotic is CE-108.
  • the polyene macrolide antibiotic is etruscomycin.
  • the polyene macrolide antibiotic is eurocidin D.
  • the polyene macrolide antibiotic is eurocidin E.
  • the polyene macrolide antibiotic is FR-008-VI.
  • the polyene macrolide antibiotic is HA-2-91.
  • the polyene macrolide antibiotic is hamycin A.
  • the polyene macrolide antibiotic is levorin AO.
  • the polyene macrolide antibiotic is levorin A3.
  • the polyene macrolide antibiotic is mycoheptin.
  • the polyene macrolide antibiotic is natamycin (pimaricin)
  • the polyene macrolide antibiotic is nystatin Al .
  • the polyene macrolide antibiotic is nystatin A2.
  • the polyene macrolide antibiotic is nystatin A3.
  • the polyene macrolide antibiotic is partricin A.
  • the polyene macrolide antibiotic is polyfungin B.
  • the polyene macrolide antibiotic is rimocidin.
  • the polyene macrolide antibiotic is tetramycin A. In certain embodiments, the polyene macro lide antibiotic is tetramycin B.
  • the polyene macrolide antibiotic is tetrin A.
  • the polyene macrolide antibiotic is tetrin B.
  • the polyene macrolide antibiotic is tetrin C.
  • the polyene macrolide antibiotic is trichomycin A.
  • the polyene macrolide antibiotic is trichomycin B.
  • the polyene macrolide antibiotic is vacidin A.
  • the polyene macrolide antibiotic is YS-822A.
  • the polyene macrolide antibiotic is 3874 HI .
  • the polyene macrolide antibiotic is 3874 H2.
  • the polyene macrolide antibiotic is 3874 H3.
  • the polyene macrolide antibiotic is 67-121 -A.
  • the method of making comprises treating a protected variant of a macrolide antibiotic with diphenyl phosphoryl azide (DPP A) to promote a stereospecific Curtius rearrangement in which the C16-C41 bond (numbering according to AmB structure) is cleaved and the resulting isocyanate is intramolecularly trapped by the neighboring C15 alcohol to form an oxazolidinone (1).
  • DPP A diphenyl phosphoryl azide
  • This oxazolidinone is surprisingly reactive to ring-opening with primary amines under mild conditions to yield urea-containing derivatives having a C16-nitrogen bond.
  • 2-oxazolidinone is unreactive under the same conditions.
  • the method entails directly converting the parent macrolide antibiotic to a corresponding urea derivative in a scalable one-pot operation involving serial addition of diphenyl phosphoryl azide (DPP A), an amine, and aqueous acid.
  • DPP A diphenyl phosphoryl azide
  • alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer.
  • cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, about 6, or about 7 carbons in the ring structure.
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • lower alkyl refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • aryl is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • Those aryl groups having heteroatoms in the ring structure may also be referred to as "heteroaryls" or "aryl heterocycles" or
  • heterocyclyl aromatic or heteroaromatic moieties
  • the aromatic ring may be substituted at one or more ring positions with such substituents as, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF 3 , -CN, or the like.
  • substituents as, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • Nonlimiting examples of polycyclic aryls include naphthalene, anthracene, purines, and pyrene.
  • heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • alkoxyl or "alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • aralkyl is art-recognized and refers to an alkyl group substituted with an aryl group (i.e., an aromatic or heteroaromatic group).
  • azido is art-recognized and refers to -N 3 .
  • cyano is art-recognized and refers to -CN.
  • halogen is art-recognized and refers to -F, -CI, -Br or -I.
  • hydroxyl is art-recognized and refers -OH.
  • nitro is art-recognized and refers to -N0 2 .
  • sulfhydryl is art-recognized and refers to -SH.
  • sulfonyl is art-recognized and refers to -S0 2 .
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:
  • R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R61 , or R50 and R51 , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
  • R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
  • R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH 2 ) m -R61.
  • alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
  • amino is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:
  • aminoalkyl is art recognized and refers to an alkyl group, as defined above, having an amino radical, as defined above, attached thereto.
  • Representative aminoalkyl groups include aminomethyl, aminoethyl, and aminopropyl.
  • Camphorsulfonic acid was recrystallized from ethanol. Water was doubly distilled or obtained from a Millipore (Billerica, MA) MilliQ water purification system.
  • the purity of compounds is determined by HPLC analysis using an Agilent Zorbax Eclipse C 18 1.8-um, 2.1 x 50 mm column with detection at 383 nm and an eluent of acetonitrile and 0.1% formic acid in water unless otherwise indicated.
  • the resulting powder was dissolved in 1 : 1 THF:MeOH (150 mL) and cooled to 0 °C. To this solution was added camphorsulfonic acid (964 mg, 4.15 mmol, 0.55 equiv.) and the resulting mixture was stirred for 1 hour at 0 °C. The reaction was then quenched at 0 °C with triethylamine (0.58 mL, 4.15 mmol, 0.55 equiv.). The reaction was concentrated in vacuo, removing approximately half of the solvent. The resulting saturated solution was poured into 1 :1 hexanes: diethyl ether (5.0 L). The white precipitate was collected via Buchner filtration using Whatman #50 filter paper and washed with diethyl ether (200 mL) to yield a white solid that was then stored under vacuum for one hour.
  • Oxazolidinone intermediate I (200 mg, 0.22 mmol, 1 equiv.) was dissolved in THF (2.2 mL). To the resulting yellow solution was added methylamine (2 M in THF, 1.1 mL, 2.2 mmol, 10 equiv.), and the resulting mixture was left to stir at room temperature for 16 hours. After 16 hours, the reaction was diluted with methyl ter t-butyl ether (10 mL). The resulting precipitate was collected via Buchner filtration using Whatman #50 filter paper and washed with methyl tert-butyl ether.
  • the collected solid was stored under vacuum for one hour before it was dissolved in a minimal amount of DMSO and purified by a single prep-HPLC purification (Interchim Strategy C 18 , 5 ⁇ , 30 x 100 mm, 30 mL/min, 10:90 to 60:40 H 2 0:MeCN (both containing 0.3% HC0 2 H) over 60 min).
  • prep-HPLC purification the fractions containing the desired compound were stirred at 40 °C for 30 min before they were frozen and lyophilized to give NatMU 5 as a fluffy white solid (92.3 mg, 61%).
  • Compound 6 was synthesized in a manner similar to NatMU 5, except methylamine was replaced with piperidine.
  • Oxazolidinone intermediate I (200 mg, 0.22 mmol, 1 equiv.) was dissolved in THF (2.2 mL). To the resulting yellow solution was added ethylenediamine (0.147 mL, 2.2 mmol, 10 equiv.), and the resulting mixture was warmed to 50 °C and stirred for two hours. After two hours, the reaction was cooled to room temperature and diluted with methyl tert- butyl ether (10 mL). The resulting precipitate was collected via Buchner filtration using Whatman #50 filter paper and washed with methyl tert-butyl ether.
  • ethylenediamine was replaced with 2-(2-methoxyethoxy)ethanamine.
  • ethylenediamine was replaced with N,N-dimethylethylenediamine.
  • ethylenediamine was replaced with benzylamine.
  • ethylenediamine was replaced with 1-phenylpiperazine.
  • each derivative proposed herein is tested for biological activity against both yeast and human cells to determine its therapeutic index.
  • a broth microdilution experiment determines the MIC (minimum inhibitory concentration) of each derivative against S. cerevisiae and the clinically relevant C. albicans, thereby establishing the antifungal activity of each novel derivative.
  • each compound is exposed to a hemolysis assay against red blood cells which determines the concentration required to cause 90% lysis of human red blood cells (EH 90 ). Additionally, each compound is exposed to human primary renal tubule cells to determine the toxicity of each compound against kidney cells.
  • Saccharomyces cerevisiae are grown to stationary phase (OD -1.7) in YPD media at 30 °C, shaking. 49.5 mL of this culture is transferred to a 50 mL Falcon centrifuge tube.
  • Cells are treated with 500 of DMSO, 500 ⁇ test compound (final compound concentration of 5 ⁇ ).
  • Falcon tubes are incubated in the shaking incubator at 30 °C for 2 hours. Tubes are inverted at the 1 hour timepoint to resuspend.
  • Yeast membranes are isolated using a modified version of Haas' spheroplasting and isosmotic cell lysis protocol and differential ultracentrifugation. After treatment time, tubes are centrifuged for 5 minutes at 3000 g at 23 °C. The supernatant is decanted and 5 mL of wash buffer (milliQ H 2 0 (89%), 1M aq. DTT (1%), and 1M aq. Tris buffer pH 9.4 (10%)) is added. Tubes are vortexed to resuspend and incubated in a 30 °C water bath for 10 minutes. Tubes are then centrifuged for 5 minutes at 3000 g at 23 °C and the supernatant decanted.
  • wash buffer milliQ H 2 0 (89%), 1M aq. DTT (1%), and 1M aq. Tris buffer pH 9.4 (10%)
  • spheroplasting buffer (1M aq. potassium phosphate buffer pH 7.5 (5%>), 4M aq. sorbitol (15%>), and YPD media (80%>)
  • 100 of a 5 mg/mL aq. solution of lyticase from Arthrobacter luteus (L2524 Sigma- Aldrich) is added to each tube, vortexed to resuspend. Tubes are incubated in a 30 °C shaking incubator for 30 minutes. After incubation, tubes are centrifuged for 10 minutes at 1080 g at 4 °C and the supernatant decanted.
  • the suspensions are transferred to 2 mL Eppendorf tubes, vortexed to ensure complete lysis, and centrifuged at 15,000 g at 4 °C to remove un-lysed cells and cell debris.
  • the resulting supernatants are transferred to thick-wall polycarbonate ultracentrifuge tubes (3.5 mL, 13 x 51 mm, 349622 Beckman Coulter).
  • PBS buffer is added to the tubes to bring the volume up to ⁇ 3 mL.
  • the tubes are centrifuged for 1 hour at 100,000 g at 4 °C in a Beckman Coulter TLA- 100.3 fixed-angle rotor in a tabletop ultracentrifuge.
  • the suspension is allowed to warm to room temperature and 20 of internal standard (4 mg/mL cholesterol in chloroform) is added. They are dissolved in 3 mL 2.5% ethanolic KOH, which is vortexed gently, capped, and heated in a heat block on a hot plate at 90 °C for 1 hour.
  • the vials are allowed to cool to room temperature. 1 mL of brine is added to the contents of each vial. Extraction is performed three times, each with 2 mL of hexane. Organic layers are combined, dried over MgS0 4 , filtered through Celite ® 545, and transferred to another 7 mL vial. The contents of the vial are concentrated in vacuo.
  • the lipid films are dried on high vac with P 2 O 5 for 30 minutes to remove residual water.
  • the injector volume is 2
  • the column temperature is initially held at 250 °C for 0.5 min, then ramped to 265 °C at a rate of 10 °C /min with a final hold time of 12.5 min.
  • the injector and detector temperature are maintained at 270 °C and 290 °C, respectively.
  • the organisms are maintained, grown, subcultured, and quantified on Sabouraud dextrose agar (SDA; Difco Laboratories, Detroit, MI). 24 hours prior to the study, the organisms are subcultured at 35 °C. MIC determinations are performed in duplicate on at least two occasions using the Clinical and Laboratory Standards Institute M27-A3 microbroth methodology.
  • SDA Sabouraud dextrose agar
  • C. albicans is generally grown and maintained as described previously. Stocks are stored in 15% glycerol at -80 °C; strains are generally grown in YPD media at 30 °C. Drugs are added directly to media from DMSO stocks.
  • C. neoformans MIC is determined as previously reported after 48 hours. Cruz MC et al, Antimicrob Agents Chemother 44: 143-149 (2000).
  • the organisms are maintained, grown, subcultured, and quantified on potato dextrose agar (PDA; Difco Laboratories, Detroit, MI). MIC determinations are performed in duplicate on at least two occasions using the Clinical and Laboratory Standards Institute M28-A2 microbroth methodology at 48 hours.
  • PDA potato dextrose agar
  • geldanamycin and radicicol (A.G. Scientific) is determined in flat bottom, 96-well microtiter plates (Costar) using a broth microdilution protocol adapted from CLSI M27-A3. Overnight cultures (14-20 hr) are grown at 30 °C in YPD, and approximately 5xl0 3 cells are seeded per well. For test compounds, MIC assays are performed at 37 °C in RPMI buffered with MOPS (0.165M) with 10% fetal bovine serum (Sigma- Aldrich) added; for tert-butyl peroxide, geldanamycin, and radicicol, MIC's are determined in YPD at 30 °C.
  • MIC's are determined after 24h incubation as the concentration of compound resulting in no visible growth in wells.
  • OD 6 oo is measured in a spectrophotometer (Tecan) and displayed as heat maps using Java TreeView 1.1.3.
  • RPTECs Primary human renal proximal tubule epithelial cells
  • TERT1 human renal proximal tubule epithelial cells are purchased from ATCC (CRL-4031 , Manassas, VA) and immediately cultured upon receipt. Complete growth media is prepared using DMEM:F12 media (ATCC, 30-2006), triiodo-L-thyronine (Sigma, T6397), recombinant human EGF (Life Technologies, PHG031 1), ascorbic acid (Sigma, A4403), human transferrin (Sigma, T8158), insulin (Sigma 19278), prostaglandin El (Sigma, P7527), hydrocortisone (Sigma, H0888), sodium selenite (Sigma, S5261), and G418 (Sigma, A1720). Complete media is stored at 4 °C and used within 28 days. TERT1 RPTECs are grown in C0 2 incubator at 37 °C with an atmosphere of 95% air/5% C0 2 .
  • WST-8 reagent is prepared and stored following known procedures 9 . Wilcock BC et al, J Am Chem Soc 135 :8488-8491 (2013).
  • a suspension of primary or TERT1 RPTECs in complete growth media is brought to a concentration of 1 x 10 5 cells/mL.
  • a 96-well plate is seeded with 99 of the cell suspension and incubated at 37 °C with an atmosphere of 95%> air/5%> C0 2 for 3 hours.
  • Positive and negative controls are prepared by seeding with 100 of the cell suspension or 100 of the complete media.
  • Compounds are prepared as 5 mM stock solutions in DMSO and serially diluted to the following concentrations with DMSO: 8000, 6000, 4000, 3000, 2000, 1500, 1000, 800, 600, 400, 300, 200, 100, 50, 25, 10, 5, 2.5, 1 , 0.5, 0.25, and 0.1 ⁇ .
  • the 96-well plate is mixed in a shaking incubator at 200 rpm for 1 minute and absorbances are read at 450 nm using a Biotek HI Synergy Hybrid Reader (Wanooski, VT). Experiments are performed in triplicate and the reported cytotoxicity represents an average of three experiments.
  • Percent hemolysis is determined according to the following equation:
  • Concentration vs. percent hemolysis is plotted and fitted to 4-parameter logistic (4PL) dose response fit using OriginPro 8.6.
  • the MTC is defined as the concentration to cause 90% loss of cell viability.
  • CFU Candida albicans
  • mice Six- week-old ICR/Swiss specific-pathogen- free female mice are obtained from Harlan Sprague Dawley (Madison, WI). The mice are weighed (23-27 g) and given intraperitoneal injections of cyclophosphamide to render neutropenia (defined as ⁇ 100 polymorphonuclear leukocytes/mm 3 ). Each mouse is dosed with 150 mg/kg of cyclophosphamide 4 days prior to infection and 100 mg/kg 1 day before infection. Disseminated candidiasis is induced via tail vein injection of 100 of inoculum. Test compounds are reconstituted with 1.0 mL of 5% dextrose.
  • Each animal in the treatment group is given a single 200 intraperitoneal (ip) injection of reconstituted test compound 2 hours post-infection. Doses are calculated in terms of mg of compound/kg of body weight.
  • ip intraperitoneal
  • three animals per experimental condition are sacrificed by C0 2 asphyxiation.
  • the kidneys from each animal are removed and homogenized.
  • the homogenate is diluted serially 10-fold with 9% saline and plated on SDA.
  • the plates are incubated for 24 hours at 35 °C and inspected for CFU viable counts. The lower limit of detection for this technique is 100 CFU/mL. All results are expressed as the mean logio CFU per kidney for three animals.
  • mice All studies are approved by the Animal Research Committee of the William S. Middleton Memorial VA Hospital (Madison, WI). Uninfected Swiss ICR mice are used for assessment of infusion toxicity. Groups of five mice are treated with single intravenous doses of test compound (reconstituted with 1.0 mL of 5% dextrose), or sterile pyrogen- free 0.85% NaCl administered via the lateral tail vein over 30 seconds. Dose levels studies included 0.5, 1, 2, 4, 8, 16, 32, and 64 mg/kg. Following administration mice are observed continuously for one hour and then every 6 hours up to 24 hours for signs of distress or death.

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Abstract

L'invention concerne des dérivés d'urée d'antibiotiques macrolides polyéniques, autres que l'amphotéricine B, comprenant une sous-structure contenant de l'urée représenté par la formule dans laquelle R représente hydrogène, alkyle, aryle, aralkyle, hétéroaryle, hétéroaralkyle, aminoalkyle ou -(CH2)n-COOH ; et n vaut 1, 2, 3, 4, 5 ou 6. L'invention concerne également des compositions pharmaceutiques comprenant les dérivés d'urée, des méthodes d'utilisation des dérivés d'urée pour inhiber la croissance d'une levure ou d'un champignon, et des méthodes de traitement d'une infection fongique ou d'une infection à levure. Dans divers modes de réalisation, l'antibiotique macrolide polyénique est choisi dans le groupe constitué par l'amphotéricine A, l'arénomycine B, la candicidine D, la candidine, la candidoïne, CE -108, l'étruscomycine, l'eurocidine D, l'eurocidine E, FR-008-VI, HA-2-91, l'hamycine A, la lévorine AO, la lévorine A3, la mycoheptine, la natamycine (pimaricine), la nystatine Al, la nystatine A2, la nystatine A3, la partricine A, la polyfongine B, la rimocidine, la tétramycine A, la tétramycine B, la tétrine A, la tétrine B, la tétrine C, la trichomycine A, la trichomycine B, la vacidine A, YS-822A, 3874 HI, 3874 H2, 3874 H3 et 67-121-A.
PCT/US2015/049647 2014-09-12 2015-09-11 Dérivés d'urée d'antibiotiques macrolides polyéniques WO2016040779A1 (fr)

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