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WO2012047762A2 - Agents antifongiques - Google Patents

Agents antifongiques Download PDF

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Publication number
WO2012047762A2
WO2012047762A2 PCT/US2011/054371 US2011054371W WO2012047762A2 WO 2012047762 A2 WO2012047762 A2 WO 2012047762A2 US 2011054371 W US2011054371 W US 2011054371W WO 2012047762 A2 WO2012047762 A2 WO 2012047762A2
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moiety
active
moieties
active moiety
compound
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WO2012047762A3 (fr
Inventor
Flórián TÓTH
Jr. Ronald Alan Aungst
Atchyuta Rama Chandra Murty Bulusu
Robert Webb
Mitchell Mutz
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Amplyx Pharmaceuticals Inc
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Amplyx Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/552—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being an antibiotic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • Nosocomial infections i.e., infections resulting from treatment in a hospital or other medical care facililty
  • nosocomial fungal infections of Candida albicans or Aspergillus fumigatus have become significant health concerns, as the scope and efficacy of antifungal agents to treat such infections is sub- optimal.
  • Microbial infections were ranked as the fourth leading cause of death worldwide in 2008 according to the World Health Organization.
  • Fungal infections represent a significant challenge due to the limited armamentarium available to treat diseases caused by fungi and low success rates of treatment.
  • Candida albicans is the fourth-ranked cause of nosocomial infections with a 50% mortality rate among patients who suffer from systemic infections.
  • the estimated cost of treating invasive fungal infections is over $2.6 billion annually in the United States alone.
  • Sales of antifungal drugs represent an increasingly large market with 2008 sales of over $1.1 billion combined for the leading triazole antifungals, voriconazole and fluconazole.
  • One reason for the increase in market size is the rise in numbers of immunocompromised patients, who are more subject to fungal infections than healthy individuals.
  • treatment of immunocompromised patients is often complicated by toxicities associated with antifungals.
  • the present disclosure provides compounds that address one or more of the abovementioned drawbacks.
  • the present disclosure provides compounds useful as antifungal agents.
  • a compound comprising a first active moiety having antifungal activity and selected from triazole moieties, imidazole moieties, and echinocandin moieties, a second active moiety, and a linking moiety.
  • the first and second active moieties are covalently bonded to the linker moiety.
  • the invention also provides pharmaceutically acceptable salts, prodrugs, and metabolites of such compounds.
  • a compound comprising first and second active moieties and a linker moiety, wherein the first active moiety is capable of binding to a first enzyme, and wherein the second active moiety is capable of binding to a second enzyme, and wherein the two active moieties are each covalently attached to the linker moiety.
  • a compound comprising first and second active moieties and a linker moiety, wherein the first active moiety is capable of binding to a protein, and wherein the second active moiety is capable of binding to an enzyme, and wherein the two active moieties are each covalently attached to the linker moiety.
  • A is a first active moiety
  • L is a linking moiety
  • U is a second active moiety.
  • the first and second active moieties are not linked covalently, and such embodiments can, for example, be represented by formula (I) wherein L is absent entirely.
  • a and U are administered together, such as in a liposome.
  • the invention provides a pharmaceutical formulation comprising a compound selected from those described herein and a pharmaceutically acceptable carrier.
  • the disclosure provides a method for treating a patient with an antifungal compound comprising administering an effective amount of a compound selected from those described herein.
  • a substituent includes a single substituent as well as two or more substituents, and the like.
  • the terms “may,” “optional,” “optionally,” or “may optionally” mean that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.
  • the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group (i.e., a mono-radical) typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, w-propyl, isopropyl, w-butyl, isobutyl, i-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like.
  • alkyl groups herein may contain 1 to about 18 carbon atoms, and such groups may contain 1 to about 12 carbon atoms.
  • lower alkyl intends an alkyl group of 1 to 6 carbon atoms.
  • heteroatom-containing alkyl and “heteroalkyl” refer to an alkyl substituent in which at least one carbon atom is replaced with a heteroatom, as described in further detail infra. If not otherwise indicated, the terms “alkyl” and “lower alkyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl or lower alkyl, respectively.
  • alkenyl refers to a linear, branched or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, w-propenyl, isopropenyl, w-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like.
  • alkenyl groups herein may contain 2 to about 18 carbon atoms, and for example may contain 2 to 12 carbon atoms.
  • lower alkenyl intends an alkenyl group of 2 to 6 carbon atoms.
  • substituted alkenyl refers to alkenyl substituted with one or more substituent groups
  • heteroatom-containing alkenyl and “heteroalkenyl” refer to alkenyl in which at least one carbon atom is replaced with a heteroatom.
  • alkenyl and “lower alkenyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkenyl and lower alkenyl, respectively.
  • alkynyl refers to a linear or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n- propynyl, and the like. Generally, although again not necessarily, alkynyl groups herein may contain 2 to about 18 carbon atoms, and such groups may further contain 2 to 12 carbon atoms. The term “lower alkynyl” intends an alkynyl group of 2 to 6 carbon atoms.
  • substituted alkynyl refers to alkynyl substituted with one or more substituent groups
  • heteroatom-containing alkynyl and “heteroalkynyl” refer to alkynyl in which at least one carbon atom is replaced with a heteroatom.
  • alkynyl and “lower alkynyl” include linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl and lower alkynyl, respectively.
  • alkoxy intends an alkyl group bound through a single, terminal ether linkage; that is, an "alkoxy” group may be represented as -O-alkyl where alkyl is as defined above.
  • a "lower alkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, w-propoxy, isopropoxy, t- butyloxy, etc.
  • Substituents identified as "C1-C6 alkoxy” or “lower alkoxy” herein may, for example, may contain 1 to 3 carbon atoms, and as a further example, such substituents may contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).
  • aryl refers to an aromatic substituent generally, although not necessarily, containing 5 to 30 carbon atoms and containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety).
  • Aryl groups may, for example, contain 5 to 20 carbon atoms, and as a further example, aryl groups may contain 5 to 12 carbon atoms.
  • aryl groups may contain one aromatic ring or two or more fused or linked aromatic rings (i.e., biaryl, aryl-substituted aryl, etc.).
  • aryl refers to an aryl moiety substituted with one or more substituent groups
  • heteroatom-containing aryl and “heteroaryl” refer to aryl substituent, in which at least one carbon atom is replaced with a heteroatom, as will be described in further detail infra. If not otherwise indicated, the term “aryl” includes unsubstituted, substituted, and/or heteroatom- containing aromatic substituents.
  • aralkyl refers to an alkyl group with an aryl substituent
  • alkaryl refers to an aryl group with an alkyl substituent, wherein “alkyl” and “aryl” are as defined above.
  • aralkyl and alkaryl groups herein contain 6 to 30 carbon atoms.
  • Aralkyl and alkaryl groups may, for example, contain 6 to 20 carbon atoms, and as a further example, such groups may contain 6 to 12 carbon atoms.
  • alkylene refers to a di-radical alkyl group. Unless otherwise indicated, such groups include saturated hydrocarbon chains containing from 1 to 24 carbon atoms, which may be substituted or unsubstituted, may contain one or more alicyclic groups, and may be heteroatom-containing. "Lower alkylene” refers to alkylene linkages containing from 1 to 6 carbon atoms. Examples include, methylene (— CH 2 — ), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), 2-methylpropylene (-CH 2 -CH(CH 3 )- CH 2 --), hexylene (-(CH 2 ) 6 ⁇ ) and the like.
  • alkarylene as used herein refer to di-radical alkenyl, alkynyl, aryl, aralkyl, and alkaryl groups, respectively.
  • amino is used herein to refer to the group -NZ Z 2 wherein Z 1 and
  • Z are hydrogen or nonhydrogen substituents, with nonhydrogen substituents including, for example, alkyl, aryl, alkenyl, aralkyl, and substituted and/or heteroatom-containing variants thereof.
  • halo and halogen are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.
  • heteroatom-containing as in a “heteroatom-containing alkyl group”
  • heteroalkyl also termed a “heteroalkyl” group
  • a heteroatom-containing aryl group also termed a “heteroaryl” group
  • heteroaryl refers to a molecule, linkage or substituent in which one or more carbon atoms are replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or sulfur.
  • heteroalkyl refers to an alkyl substituent that is heteroatom-containing
  • heterocyclic refers to a cyclic substituent that is heteroatom-containing
  • heteroaryl and “heteroaromatic” respectively refer to “aryl” and “aromatic” substituents that are heteroatom-containing, and the like.
  • heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyl, N-alkylated amino alkyl, and the like.
  • heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, furyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, etc.
  • heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuranyl, etc.
  • Hydrocarbyl refers to univalent hydrocarbyl radicals containing 1 to about
  • Substituted hydrocarbyl refers to hydrocarbyl substituted with one or more substituent groups
  • heteroatom-containing hydrocarbyl refers to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom.
  • hydrocarbyl is to be interpreted as including substituted and/or heteroatom- containing hydrocarbyl moieties.
  • substituted aryl and the like, as alluded to in some of the aforementioned definitions, is meant that in the hydrocarbyl, alkyl, aryl, or other moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents.
  • substituents include, without limitation: functional groups such as halo, hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl (including C 2 -C 24 alkylcarbonyl (-CO-alkyl) and C 6 -C 20 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C 2 -C 24 alkoxycarbonyl (-(CO)-O-alkyl), C 6 -C 20 aryloxycarbonyl (-(CO)- O-aryl), halocarbonyl (-CO)-X where X is halo), C 2 -C 24 alkylcarbonato (-O-(CO)-O-alkyl), C 6 -C 20 arylcarbonato (-O-(CO)-O-aryl), carboxy
  • the aforementioned functional groups may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbyl moieties such as those specifically enumerated above.
  • the above- mentioned hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties such as those specifically enumerated.
  • linking or "linker” as in “linking group,” “linker moiety,” etc., is meant a bivalent radical moiety.
  • linking groups include alkylene, alkenylene, alkynylene, arylene, alkarylene, aralkylene, and linking moieties containing functional groups including, without limitation: amido (-NH-CO-), urethane (i.e., carbamate, -0-CO-NH-), -NH-CO-NH-, imido (-CO-NH-CO-) , epoxy (-0-), epithio (-S-), epidioxy (-0-0-), carbonyldioxy (-O-CO-O-), alkyldioxy (-0-( ⁇ 3 ⁇ 4) ⁇ -0-), epoxyimino (-0- ⁇ -), epimino (-NH-), carbonyl (-CO-), etc., as well as substituted versions thereof (e.g., -NR-CO-, -O-CO
  • substituted appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group.
  • substituted alkyl and aryl is to be interpreted as “substituted alkyl and substituted aryl.”
  • reference to an atom is meant to include isotopes of that atom.
  • reference to H is meant to include 1 H, 2 H (i.e., D) and 3 H (i.e., T)
  • reference to C is meant to include 12 C and all isotopes of carbon (such as 13 C).
  • treating and “treatment” as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage.
  • the terms include prophylactic use of active agents.
  • Preventing a disorder or unwanted physiological event in a patient refers specifically to the prevention of the occurrence of symptoms and/or their underlying cause, wherein the patient may or may not exhibit heightened susceptibility to the disorder or event.
  • an effective amount of a therapeutic agent is meant a nontoxic but sufficient amount of a beneficial agent to provide a desirable effect.
  • an "effective amount" of a beneficial refers to an amount covering both therapeutically effective amounts and prophylactically effective amounts.
  • a “therapeutically effective amount” of an active agent refers to an amount that is effective to achieve a desirable therapeutic result
  • a “prophylactically effective amount” of an active agent refers to an amount that is effective to prevent or lessen the severity of an unwanted physiological condition.
  • a “pharmaceutically acceptable” component is meant a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation of the disclosure and administered to a patient as described herein without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained.
  • pharmaceutically acceptable is used to refer to an excipient, it is generally implied that the component has met the required standards of toxicologic al and
  • “pharmacologically active” derivative or analog refers to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
  • controlled release refers to a formulation, dosage form, or region thereof from which release of a beneficial agent is not immediate, i.e., with a "controlled release” dosage form, administration does not result in immediate release of the beneficial agent in an absorption pool.
  • controlled release includes sustained release and delayed release formulations.
  • sustained release (synonymous with “extended release”) is used in its conventional sense to refer to a formulation, dosage form, or region thereof that provides for gradual release of a beneficial agent over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of the agent over an extended time period.
  • naturally occurring refers to a compound or composition that occurs in nature, regardless of whether the compound or composition has been isolated from a natural source or chemically synthesized.
  • non-immunosuppressive refers to moieties, compounds, and/or formulations that, when administered to a patient according to the disclosure provided herein (i.e., using the compounds, dosages, methods of administration, etc. disclosed herein), do not substantially inhibit one or more aspects of the patient's immune system.
  • a non-immunosuppressive compound would be one with an IC 50 towards lymphocyte growth of greater than about 500 fold the IC 50 of FK-506.
  • the disclosure provides compounds capable of dual binding - i.e., specifically binding both fungal calcineurin and an additional antifungal target to yield a more efficacious, fungicidal drug.
  • the dual binding is accomplished using non-immunosuppressive ligands that inhibit fungal calcineurin but not human calcineurin.
  • the additional antifungal target examples include thimidylate synthase (targeted, for example, by flucytosine), DNA (targeted, for example, by flucytosine), ⁇ glucan synthase (targeted, for example, by echinocandins), squalene monooxygenase (targeted, for example, by terfinabine), ergosterol (targeted, for example, by amphotericin B), lanosterol 14 a-demethylase (targeted, for example, by triazoles), microtubules (targeted, for example, by griseofulvin). Additionally, the additional antifungal target may include blocking of the Gl/S phase initiation of the cell cycle and HSP90 which mediates fungal resistance to triazoles, such as by the hydroxypyridone class of antifungal agents.
  • the disclosure provides compounds having three components: a first active moiety, a second active moiety, and a linker moiety that links the first active moiety with the second active moiety.
  • the three components are typically linked via covalent bonds.
  • the first active moiety is selected from triazoles such as ketoconazole, posaconazole, fluconazole, voriconazole, and derivatives and analogs thereof.
  • the first active moiety is selected from echinocardins (naturally- occurring, synthetic, or semi- synthetic) such as micafungin, anidulafungin, and caspofungin. Any of the aforementioned moieties may be used as the first active moiety, although it will be appreciated that one or more of the atoms (typically, although not necessarily, hydrogen atoms) in each of these moieties will be replaced to accommodate one or more covalent linkages of the first active moiety to the linking moiety.
  • ketoconazole when the first active moiety is said herein to be "ketoconazole,” it will be appreciated that the moiety is in fact a ketoconazole moiety having an atom replaced with a covalent bond to the linking moiety.
  • analogs of the above mentioned example triazole compounds are within the scope of the invention.
  • fluconazole contains a lH-l,2,4-triazole ring, but analogs having a lH-l,2,3-triazole ring are also embodiments of the invention.
  • the first active moiety is selected from imidazoles or triazoles such as clotrimazole, miconazole, econazole, butoconazole, omoconazole, oxiconazole, terconazole, itraconazole, ravuconazole, flutrimazole, and derivatives and analogs thereof.
  • the first active moiety is selected from aminocandin, echinocandin B (ECB), echinocandin C, aculeacin ⁇ , mulundocandin, sporiofungin A, pneumocandin Ao, WF11899A, pneumocandin Bo, analogues of echinocandin B, such as cilofungin, analogues of WF11899A, and analogues of pneumocandin Bo.
  • ECB echinocandin B
  • echinocandin C echinocandin C
  • aculeacin ⁇ mulundocandin
  • sporiofungin A pneumocandin Ao
  • WF11899A pneumocandin Bo
  • analogues of echinocandin B such as cilofungin, analogues of WF11899A, and analogues of pneumocandin Bo.
  • the first active moiety has the structure of any one of
  • nl is an integer from 0 to 6, and the star represents the point of attachment to the linking moiety. It will be appreciated that alternative sites for attachment of the linking moiety are within the scope of the invention in addition to those shown above in A1-A7.
  • nl is 1, 2, 3, 4, or 5. In preferred embodiments, n is 4.
  • the second active moiety has the structure of any one of
  • p represents in integer in the range of 0-2;
  • L 1 , L 2 , and L 3 are selected from a bond, a heteroatom, C 1 -C 24 alkylene, C 1 -C 24 heteroalkylene, C 5 -C 24 arylene, C 5 -C 24 heteroarylene, and combinations thereof, any of which may be substituted or unsubstituted;
  • R U1 and R U2 are selected from Q-C24 hydrocarbyl, substituted Q-C24 hydrocarbyl, heteroatom-containing Q-C24 hydrocarbyl, and substituted heteroatom- containing Q-C24 hydrocarbyl;
  • R U3 is selected from H and OH; and [00058] the stars represents the point of attachment to the linking moiety.
  • L 1 is a bond, -0-, or is selected from CrC 12 alkylene
  • L 1 is methylene, ethylene, or propylene.
  • L 1 is 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, or
  • X 1 and X 3 are independently selected from -O- and -NH-, and n is an integer from 1 to 3.
  • X 1 is -0-
  • X 3 is -NH-
  • n is 2.
  • L 2 is selected from a bond and C 1 -C 12 alkylene, and comprises from 0 to 3 heteroatoms and from 0 to 3 substituents.
  • L is
  • L 3 is -O- or is selected from CrC 12 alkylene, C 5 -C 12 arylene, and C 1 -C 24 alkylarylene and comprises from 0 to 3 heteroatoms and from 0 to 3 substituents.
  • L is
  • the stars represent the attachment points to the linking moiety of the compounds of the invention (i.e., the stars are the same as those shown in U1-U6), and the wavy lines represent the attachment points to the remaining portions of the second active moiety.
  • the stars and wavy lines may be reversed, such that the groups identified above for L 1 , L2 , and L 3 may be incorporated in either direction into the compounds of the invention.
  • R U1 is selected from C 1 -C 12 alkyl, C 5 -C 12 aryl, C 5 -C 12 alkaryl, and C 5 -C 12 aralkyl, and comprises from 0 to 3 heteroatoms and from 0 to 3 substituents.
  • R U1 is -(CH 2 ) n -Ar 1 , wherein n is an integer from 1 to 3 and Ar 1 is an aryl group that may be substituted or unsubstituted and may have one or more
  • n is 2 and Ar 1 is pyridinyl or substituted phenyl.
  • Ar 1 is
  • R U2 is selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 5 -
  • the second active moiety may be selected from derivatives and analogs of any one of U1-U6.
  • derivatives include those having protected functional groups.
  • one or more of the hydroxyl groups may be protected by a hydroxyl protecting group.
  • R may be -OP, wherein P is a protecting group such as alkyl, silyl ester, etc.
  • Other derivatives and analogs include U4 wherein R is hexenenitrile, pentenenitrile, etc.
  • the second active moiety comprises a pipecolyl ester moiety.
  • the second active moiety may be
  • R U4 and R u5 are hydrocarbyl groups (e.g., alkyl, alkenyl, aryl, etc.) that may contain one or more substituents and one or more heteroatoms, provided that one of R U4 and R u5 contains a linkage to the linking groups (and therefore the first active moieties) described herein.
  • R U4 and R u5 are linked to form a cycle.
  • the second active moiety is FK506 or a derivative thereof.
  • the second active moiety is non-immunosuppressive as a stand-alone moiety (e.g., a compound having the structure of any one of U1-U6, wherein the star is replaced with a chemical moiety such as a hydrogen atom) and/or as a moiety conjugated according to the invention.
  • a non- immunosuppressive compound containing a second active moiety as described herein would be one with an IC 50 towards lymphocyte growth of greater than 0.5 ⁇ , or greater than 1.0 ⁇ , or greater than 5 ⁇ .
  • the linking moiety is any moiety that is capable of covalently linking the first and second active moieties, and does not interfere with the pharmacological activity of the first active moiety, the second active moiety, or the compound as a whole.
  • the linking moiety may be a bond, although, typically, the linking moiety is a bi-radical moiety that may be substituted or unsubstituted and/or may have one or more heteroatoms. Examples of linking moieties are mentioned supra.
  • the linking moiety may be selected from a bond, C 1 -C 24 hydrocarbylene, substituted C 1 -C 24 hydrocarbylene, heteroatom-containing C 1 -C 24 hydrocarbylene, and substituted heteroatom-containing C 1 -C 24 hydrocarbylene.
  • the linking moiety may be selected from C 1 -C 24 alkylene, C 2 -C 24 alkenylene, C 2 -C 24 alkynylene, C5-C 24 arylene, and combinations thereof (such as, for example, C6-C 24 arylalkylene, etc.), any of which may contain one or more (e.g., 2, 3, or 4) heteroatoms and/or may be unsubstituted or substituted with one or more (e.g., 2, 3, or 4) substituents.
  • the linking moiety is a C8-C 24 arylene that comprises two or more fused aryl rings.
  • the linking moiety is a C7-C 24 alkylene that comprises two or more fused cycloalkyl rings. In some embodiments, the linking moiety comprises a combination of aryl and alkyl rings, either fused or separated by another moiety.
  • linking moieties include alkylene linkers, arylenes, amides, amines, carbonyls, ureas, carbamates, sulfoxides, sulfonamides, ethers, and combinations such as amide/urea combinations, amide/amide combinations, sulfoxide/ether combinations, amide/ether combinations, amine/ether combinations, amide/amine
  • linkers may include unsaturated or saturated segments.
  • linking moieties include the structures shown below.
  • R, R 2 , and R 3 are selected from H, hydrocarbyl, and functional groups, and the stars represent attachment points to the first and second active moieties.
  • “m” and “n” represent integers that are independently selected. These integers may, for example, have the value 0, 1, 2, etc.
  • the compounds of the invention can be represented by the formula (I)
  • A is the first active moiety
  • L is a linking moiety
  • U is the second active moiety.
  • a number of example compounds according to formula (I) are shown in the Examples provided below.
  • the first and second active moieties are not covalently linked to one another.
  • Such embodiments may, for example, be represented by formula (I) wherein L is absent entirely.
  • a and U are administered together and may be physically associated (i.e., close in space) to one another such as when encapsulated within a liposome.
  • the compounds of the invention are bifunctional molecules - i.e., compounds having two moieties that are biologically active.
  • one active moiety may capable of binding to calcineurin.
  • the active moiety is capable of binding fungal calcineurin but not human calcineurin.
  • one active moiety is capable of binding to fungal HSP90.
  • the second active moiety may be an antifungal biomoiety.
  • Some preferred examples are compounds that target lanosterol 14oc-demethylase, calcineurin, and the enzyme ⁇ (1,3)- ⁇ - Glucan synthase.
  • the compounds of the invention may be prepared according to the Examples provided herein infra, wherein such procedures may be supplemented with synthetic techniques known in the art.
  • the compounds are prepared using a bismuth coupling reagent.
  • Scheme 1 provides a generalized linking reaction for the compounds of the invention.
  • R' is generally a group having an aromatic ring and an alkynyl group
  • A represents the first active moiety (and A'-OH represents the precursor reactant that provides the first active moiety)
  • B represents the second active moiety (and B'-OH represents the precursor reactant that provides the first active moiety)
  • N 3 is an azide group
  • L represents the linker moiety that results from the coupling reaction.
  • suitable R' groups include
  • n is an integer in the range of 0 to 6
  • R is hydrocarbyl (including substituted, unsubstituted, heteroatom containing, and substituted heteroatom-containing hydrocarbyl) or hydrogen
  • X is selected from -CH-, and -N-
  • Y is selected from -CH 2 -, -0-, -NH-, and -S-.
  • the first and second active moieties are non-covalently associated with each other.
  • there may be non-covalent bonding interactions between the two active moieties such as hydrogen bonding, Van der Waals bonding, and/or ionic bonding.
  • minimal or no such non-covalently bonding interactions are present, or such interactions are disrupted by the presence of salts, solvents, etc.
  • the first and second active moieties are not covalently attached to one another, but are together encapsulated within a liposome or a similar structure. In such embodiments, the first and second active moieties are co-administered via the liposome.
  • the structures shown herein for such moieties will be adjusted accordingly.
  • the stars will represent a chemical moiety (rather than a connection to the linker moiety).
  • the chemical moiety will typically be selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing substituted hydrocarbyl, functional groups, and protecting groups.
  • the star represents H.
  • the star represents an amine protecting group or a hydroxyl protecting group, respectively.
  • U5 the star represents any of the groups defined herein for R .
  • first and second active moieties may be co-administered in any ratio that is appropriate for optimal dosing.
  • Such ratios will typically be between 1:1 (i.e., equal molar parts of each active moiety) and 1:10 4 , or between 1:1 and 1:1000, or between 1:1 and 1:100, or between 1:1 and 1:10, or between 1:1 and 1:5, or between 1:1 and 1:2.
  • preferred ratios are between 1:1 and 1:100, or between 1:1 and 1:10.
  • a compound of the disclosure may be administered in the form of a salt, ester, amide, prodrug, active metabolite, analog, or the like, provided that the salt, ester, amide, prodrug, active metabolite or analog is pharmaceutically acceptable and pharmacologically active in the present context.
  • Salts, esters, amides, prodrugs, active metabolites, analogs, and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J.
  • any of the compounds described herein may be in the form of a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt may be prepared from any pharmaceutically acceptable organic acid or base, any pharmaceutically acceptable inorganic acid or base, or combinations thereof. The acid or base used to prepare the salt may be naturally occurring.
  • Suitable organic acids for preparing acid addition salts include, e.g., CrC 6 alkyl and C 6 -Ci2 aryl carboxylic acids, di-carboxylic acids, and tri-carboxylic acids such as acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, glycolic acid, citric acid, pyruvic acid, oxalic acid, malic acid, malonic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, phthalic acid, and terephthalic acid, and aryl and alkyl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid, and the like.
  • Suitable inorganic acids for preparing acid addition salts include, e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and the like.
  • An acid addition salt may be reconverted to the free base by treatment with a suitable base.
  • Suitable organic bases for preparing basic addition salts include, e.g., primary, secondary and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, N,N- dibenzylethylenediamine, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, glucamine, glucosamine, histidine, and polyamine resins, cyclic amines such as caffeine, N- ethylmorpholine, N-ethylpiperidine, and purine, and salts of amines such as betaine, choline, and procaine, and the like.
  • primary, secondary and tertiary amines such as trimethylamine, triethylamine, tripropylamine, N,N- dibenzylethylenediamine, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, glucamine, glucosamine, histidine, and polyamine resins, cyclic
  • Suitable inorganic bases for preparing basic addition salts include, e.g., salts derived from sodium, potassium, ammonium, calcium, ferric, ferrous, aluminum, lithium, magnesium, or zinc such as sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, and potassium carbonate, and the like.
  • a basic addition salt may be reconverted to the free acid by treatment with a suitable acid.
  • esters involves transformation of a carboxylic acid group via a conventional esterification reaction involving nucleophilic attack of an RCT moiety at the carbonyl carbon. Esterification may also be carried out by reaction of a hydroxyl group with an esterification reagent such as an acid chloride. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures. Amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine. Prodrugs and active metabolites may also be prepared using techniques known to those skilled in the art or described in the pertinent literature. Prodrugs are typically prepared by covalent attachment of a moiety that results in a compound that is therapeutically inactive until modified by an individual's metabolic system.
  • active agents may be prepared using standard techniques known to those skilled in the art of synthetic organic chemistry, or may be deduced by reference to the pertinent literature.
  • chiral active agents may be in isomerically pure form, or they may be administered as a racemic mixture of isomers.
  • any of the compounds of the disclosure may be the active agent in a formulation as described herein.
  • Formulations containing the compounds of the disclosure may include 1, 2, 3 or more of the compounds described herein, and may also include one or more additional active agents such as analgesics and other antibiotics.
  • the amount of active agent in the formulation typically ranges from about
  • the amount of active agent may range from about 0.05 wt% to about 50 wt%, or from about 0.1 wt% to about 25 wt%.
  • the amount of active agent in the formulation may be measured so as to achieve a desired dose.
  • Formulations containing the compounds of the disclosure may be presented in unit dose form or in multi-dose containers with an optional preservative to increase shelf life.
  • compositions of the disclosure may be administered to the patient by any appropriate method.
  • both systemic and localized methods of administration are acceptable.
  • selection of a method of administration will be influenced by a number of factors, such as the condition being treated, frequency of administration, dosage level, and the wants and needs of the patient. For example, certain methods may be better suited for rapid delivery of high doses of active agent, while other methods may be better suited for slow, steady delivery of active agent.
  • methods of administration that are suitable for delivery of the compounds of the disclosure include parental and transmembrane absorption (including delivery via the digestive and respiratory tracts). Formulations suitable for delivery via these methods are well known in the art.
  • formulations containing the compounds of the disclosure may be administered parenterally, such as via intravenous, subcutaneous, intraperitoneal, or intramuscular injection, using bolus injection and/or continuous infusion.
  • parenteral administration employs liquid formulations.
  • compositions may also be administered via the digestive tract, including orally and rectally.
  • formulations that are appropriate for administration via the digestive tract include tablets, capsules, pastilles, chewing gum, aqueous solutions, and suppositories.
  • formulations may also be administered via transmucosal administration.
  • Transmucosal delivery includes delivery via the oral (including buccal and sublingual), nasal, vaginal, and rectal mucosal membranes.
  • Formulations suitable for transmucosal deliver are well known in the art and include tablets, chewing gums, mouthwashes, lozenges, suppositories, gels, creams, liquids, and pastes.
  • the formulations may also be administered transdermally.
  • Transdermal delivery may be accomplished using, for example, topically applied creams, liquids, pastes, gels and the like as well as what is often referred to as transdermal "patches.”
  • formulations may also be administered via the respiratory tract.
  • Pulmonary delivery may be accomplished via oral or nasal inhalation, using aerosols, dry powders, liquid formulations, or the like. Aerosol inhalers and imitation cigarettes are examples of pulmonary dosage forms.
  • Liquid formulations include solutions, suspensions, and emulsions.
  • solutions may be aqueous solutions of the active agent and may include one or more of propylene glycol, polyethylene glycol, and the like.
  • Aqueous suspensions can be made by dispersing the finely divided active agent in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • formulations of solid form which are intended to be converted, shortly before use, to liquid form.
  • Tablets and lozenges may comprise, for example, a flavored base such as compressed lactose, sucrose and acacia or tragacanth and an effective amount of an active agent.
  • Pastilles generally comprise the active agent in an inert base such as gelatin and glycerine or sucrose and acacia.
  • Mouthwashes generally comprise the active agent in a suitable liquid carrier.
  • the chemical compound according to the disclosure may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Transdermal patches typically comprise: (1) a impermeable backing layer which may be made up of any of a wide variety of plastics or resins, e.g. aluminized polyester or polyester alone or other impermeable films; and (2) a reservoir layer comprising, for example, a compound of the disclosure in combination with mineral oil, polyisobutylene, and alcohols gelled with USP hydroxymethylcellulose.
  • the reservoir layer may comprise acrylic -based polymer adhesives with resinous crosslinking agents which provide for diffusion of the active agent from the reservoir layer to the surface of the skin.
  • the transdermal patch may also have a delivery rate-controlling membrane such as a microporous polypropylene disposed between the reservoir and the skin. Ethylene- vinyl acetate copolymers and other microporous membranes may also be used.
  • an adhesive layer is provided which may comprise an adhesive formulation such as mineral oil and polyisobutylene combined with the active agent.
  • transdermal delivery systems may also involve incorporation of highly lipid soluble carrier compounds such as dimethyl sulfoxide (DMSO), to facilitate penetration of the skin.
  • DMSO dimethyl sulfoxide
  • Other carrier compounds include lanolin and glycerin.
  • Rectal or vaginal suppositories comprise, for example, an active agent in combination with glycerin, glycerol monopalmitate, glycerol, monostearate, hydrogenated palm kernel oil and fatty acids.
  • an active agent in combination with glycerin, glycerol monopalmitate, glycerol, monostearate, hydrogenated palm kernel oil and fatty acids.
  • Another example of a suppository formulation includes ascorbyl palmitate, silicon dioxide, white wax, and cocoa butter in combination with an effective amount of an active agent.
  • Nasal spray formulations may comprise a solution of active agent in physiologic saline or other pharmaceutically suitable carder liquids.
  • Nasal spray compression pumps are also well known in the art and can be calibrated to deliver a predetermined dose of the solution.
  • Aerosol formulations suitable for pulmonary administration include, for example, formulations wherein the active agent is provided in a pressurized pack with a suitable propellant.
  • suitable propellants include chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gases.
  • CFCs chlorofluorocarbons
  • the aerosol may also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • Dry powder suitable for pulmonary administration include, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • Unit doses for dry powder formulations may be, for example, in the form of capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • additives e.g., components that improve drug delivery, shelf-life, patient acceptance, etc.
  • Suitable additives include acids,
  • antioxidants antimicrobials, buffers, colorants, crystal growth inhibitors, defoaming agents, diluents, emollients, fillers, flavorings, gelling agents, fragrances, lubricants, propellants, thickeners, salts, solvents, surfactants, other chemical stabilizers, or mixtures thereof.
  • the amount of active agent in formulations that contain the compounds of the disclosure may be calculated to achieve a specific dose (i.e., unit weight of active agent per unit weight of patient) of active agent.
  • the treatment regimen may be designed to sustain a predetermined systemic level of active agent.
  • formulations and treatment regimen may be designed to provide an amount of active agent that ranges from about 0.001 mg/kg/day to about 100 mg/kg/day for an adult.
  • the amount of active agent may range from about 0.1 mg/kg/day to about 50 mg/kg/day, about O.lmg/kg/day to about 25 mg/kg/day, or about lmg/kg/day to about 10 mg/kg/day.
  • dosages may vary depending on a variety of factors, including method and frequency of administration, and physical characteristics of the patient.
  • the compounds of the disclosure may be prepared using standard procedures that are known to those skilled in the art of synthetic organic chemistry and used for the preparation of analogous compounds. Appropriate synthetic procedures may be found, for example, in J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 5th Edition (New York: Wiley-Interscience, 2001). Syntheses of
  • the invention further includes an improved method for preparation of the compounds of the invention.
  • the inventive methods include forming a carbamate or carbonate on either the first active moiety or the second active moiety with a carbamate- or carbonate-forming reagent.
  • the carbamate or carbonate thus formed is able to react with a nucleophile present on the other moiety (i.e., the first moiety if the carbamate or carbonate is formed on the second moiety, or the second moiety if the carbamate or carbonate is formed on the first moiety).
  • the carbamate or carbonate is formed on a first hydroxyl group of the first or second active moiety, wherein the moiety may have one or more additional hydroxyl groups that are unreactive (relative to the first hydroxyl group) with the carbamate- or carbonate- forming reagent.
  • the carbamate or carbonate is formed at the C-32 position of FK-506 or a derivative thereof (FK-506 numbering shown below) without the need to protect the other hydroxyl groups (i.e., at C-24, C-10, and, when present, C-18).
  • the compounds find utility in treating infections by
  • the disclosure provides a method for treating an infected patient, the method comprising administering to the patient an effective amount of any of the compounds disclosed herein.
  • the disclosure also provides a method for preventing infection, the method comprising administering an effective amount of any of the compounds disclosed herein.
  • the disclosure also provides a method for treating a patient suffering from an infection, the method comprising administering an effective amount of any of the compounds disclosed herein to a patient in need thereof.
  • the disclosure also provides a method for inhibiting the spread of an infection, the method comprising contacting a cell infected with a microorganism with an effective amount of any of the compounds disclosed herein.
  • the disclosure also provides a method for inhibiting the spread of an infection, the method comprising contacting a tissue infected with a microorganism (wherein the infection is either within the cells of the tissue, in the intercellular matrix of the tissue, or both) with an effective amount of any of the compounds disclosed herein.
  • the compound may be administered in a composition comprising one or more active agents and one or more additives.
  • the compounds and compositions of the invention are suitable for treating fungal infections.
  • the compounds inhibit fungal calcineurin.
  • the compounds of the invention are useful in treating fungal infections.
  • the compounds are useful in treating fungal infections wherein the fungal infection is of a fungus from the genus Candida, Aspergillus, or Cryptococcus.
  • the compounds are useful in treating infections of C. albicans, A. fumigatus, C. neoformans, C. glabrata, C. krusei, or C. gattii.
  • linker Lla can be replaced with the following linker Lib, with a corresponding change in the final product (i.e., PL2, shown below prior to removal of the silyl group):
  • Ascomycin (2, 2.0 g, 2.53 mmol) was dissolved in a mixture of AcOH (32 mL) and water (32 mL) and Se0 2 (420 mg, 3.79 mmol) was added to it. The reaction mixture was stirred at rt for 24 h. An additional amount of Se0 2 (420 mg, 3.79 mmol) was added to the reaction mixture and stirring continued for 24 h. After completion of the reaction (TLC: 3% methanol in chlorofom), the reaction mixture was diluted with EtOAc (100 mL) and the pH was adjusted to 7 by saturated Na 2 C0 3 . The phases were separated and the aqueous phase was extracted with EtOAc (3x50 mL).

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Abstract

La présente invention concerne des composés et des compositions utiles comme antifongiques, ainsi que des procédés d'utilisation et de préparation de tels composés et de compositions contenant de tels composés. Dans certains modes de réalisation, les composés sont bifonctionnels, et comprennent deux groupements actifs connectés par le biais d'un groupement de liaison. Les composés selon l'invention sont utiles pour traiter des infections par des micro-organismes.
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