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WO2013052263A2 - Antifungal compounds - Google Patents

Antifungal compounds Download PDF

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Publication number
WO2013052263A2
WO2013052263A2 PCT/US2012/055683 US2012055683W WO2013052263A2 WO 2013052263 A2 WO2013052263 A2 WO 2013052263A2 US 2012055683 W US2012055683 W US 2012055683W WO 2013052263 A2 WO2013052263 A2 WO 2013052263A2
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WO
WIPO (PCT)
Prior art keywords
compound
species
fungicide
antifungal
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2012/055683
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French (fr)
Other versions
WO2013052263A3 (en
Inventor
Son T. Nguyen
Xiaoyuan DING
John D. Williams
Timothy J. Opperman
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Microbiotix Inc
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Microbiotix Inc
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Publication of WO2013052263A2 publication Critical patent/WO2013052263A2/en
Publication of WO2013052263A3 publication Critical patent/WO2013052263A3/en
Anticipated expiration legal-status Critical
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Classifications

    • 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
    • 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
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic rings
    • 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
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • 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
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
    • 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
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines

Definitions

  • This invention is in the field of antifungal compounds.
  • the invention provides organic compounds that inhibit growth of fungal cells.
  • Fungal pathogens continue to pose a serious threat to public health and agriculture.
  • One aspect of this resurgence appears to be the result of prior widespread, and largely effective, therapeutic and prophylactic use of fungicides, which, unfortunately, over time has also selected for resistant strains of various fungal pathogens.
  • Of particular concern to the public health has been the emergence and proliferation of a wide variety fungal species responsible for a variety of severe, even fatal, diseases and fungal infections in humans, non-human animals, and plant populations throughout the world. Strains of such fungi species have also developed resistant to respective fungicide and antifungal agents.
  • prominent fungal pathogens include, but are not limited to, species of Candida, such as C. albicans, C. parapsilosis, C. tropicalis, C. krusei, C. glabrata, and C.
  • species of Aspergillus such as A. fumgatus, A. niger, and A. flavus
  • species of Aspergillus such as A. fumgatus, A. niger, and A. flavus
  • species of Aspergillus such as A. fumgatus, A. niger, and A. flavus
  • species of Aspergillus such as A. fumgatus, A. niger, and A. flavus
  • Cryptococcus such as C. neoformans, C. laurentii, C. albidus, and C. gatti; species of Histoplasma, such as H. capsulatum; and species of Pneumocystis, such as P. jiroveci.
  • Fungal pathogens are of particular concern for immunocompromised individuals, such as patients of acquired
  • AIDS immunodeficiency syndrome
  • radiation therapy radiation therapy
  • chemotherapy chemotherapy
  • Fungicides are compounds, of natural or synthetic origin, which act to protect plants against damage caused by fungi, including oomycetes.
  • Current methods of agriculture rely heavily on the use of fungicides. In fact, some crops cannot be grown usefully without the use of fungicides.
  • Using fungicides allows a grower to increase the yield of the crop and consequently, increase the value of the crop.
  • Numerous fungicidal agents have been developed; however, the treatment of fungal infestations and infections continues to be a major problem. Losses of crops due to fungal diseases (e.g., rice blast disease caused by the plant-pathogenic fungus Magnaporthe grisea, also known as rice blast fungus) or food spoilage can have a large impact on human food supplies and local economies.
  • fungal diseases e.g., rice blast disease caused by the plant-pathogenic fungus Magnaporthe grisea, also known as rice blast fungus
  • food spoilage can have a large impact on human food supplies and local
  • rice blast disease is widely distributed (85 countries) and can be very destructive when environmental conditions are favorable, with yield loss estimates from 1-50% around the world (Scardaci, S.C., et al. "Rice Blast: A New Diseases in California", University of California-Davis: Agronomy Fact Sheet Series (1997)
  • the invention addresses the above problem by providing methods of inhibiting growth of or killing cells of one or more species of fungi by administering one or more antifungal compounds described herein.
  • An antifungal compound of the invention inhibits growth of or kills cells of one or more fungi species the compound is brought into contact with the fungal cells.
  • Compounds of the invention are particularly useful in methods and compositions to inhibit growth of or kill cells of pathogenic fungi species (including opportunistic pathogenic species).
  • a fungicide and/or antifungal compound described herein may be used to inhibit growth of or kill cells of a pathogenic microbial species by administration to an individual (human or other mammal), plant, or foodstuff that is susceptible to infection by or has been infected with cells of the fungal species.
  • a fungicide and/or antifungal compound of the invention may also be applied to or incorporated into a liquid, solid, or semi-solid composition that is susceptible to or is already contaminated with cells of one or more pathogenic microbial species.
  • a method for inhibiting growth of or killing cells of one or more species of fungi comprising contacting the fungi with a compound disclosed herein.
  • a fungicide and/or antifungal compound useful in the methods of the invention herein has the structure:
  • n 1 or 2;
  • X 1 is N or NR 8 ;
  • X 3 and X 5 are each independently NH, NR 8 , S, O, or S0 2 ,
  • L is a direct bond or a linker which is ⁇ ⁇ where Z is an optionally substituted aryl, heteroaryl, carboxamide (-CONH- or -NHCO-), or alkyl radical;
  • L is a linker which is a direct bond or is ⁇ ⁇ where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, carboxamide (-CONH- or -NHCO-), aryl, or heteroaryl radical; and
  • R 1 , R 2 , R 3 , R 4 , R 6 and R 7 are each independently hydrogen, halo, amino, amidino, guanidino, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, amino, alkylamino, acylamino, amido, sulfonamido, mercapto, alkylthio, arylthio, hydroxamate, thioacyl, alkylsulfonyl, or aminosulfonyl; and R 8 is hydrogen, OH, a halogen, or an optionally substituted alkyl; or pharmaceutically acceptable salts thereof.
  • a fungicide and/or antifungal compound of the invention has a structure
  • the compounds described herein are useful as fungicides and antifungal agents and may be used to treat fungal infections. Accordingly, an individual, plant, crop, or foodstuff infected with or exposed to fungal infection, may be treated by administering to the individual, plant, crop, or foodstuff in need thereof an effective amount of a compound according to the invention, e.g., administering one or more of the compounds of formula (I) described above.
  • the present invention also provides antifungal uses of pharmaceutical compositions containing one or more of the antifungal compounds disclosed herein and a pharmaceutically acceptable carrier or excipient.
  • the use of one or more of the antifungal compounds in the preparation of a medicament for combating fungal infection is contemplated.
  • antifungal compounds as disclosed herein have many non-pharmaceutical or agricultural uses, such as on surfaces (objects, countertops, floors, teeth, etc.) or added to solutions or mixtures (cleaning solutions, detergents, dentifrices, etc.), to inhibit fungal growth or eliminate infectious agents.
  • An antifungal compound or combination of compounds described herein may be used as a supporting or adjunctive therapy for the treatment of fungal infection in an individual (human or other animal).
  • administration of an antifungal compound as described herein to inhibit the growth of microbes in or on an individual may be sufficient to permit the individual's own immune system to effectively clear or kill infecting or contaminating fungi from the tissue of the individual.
  • an antifungal compound described herein may be administered to an individual in conjunction (i.e., in a mixture, sequentially, or simultaneously) with an antibacterial agent, such as an antibiotic, an antibody, or
  • immunostimulatory agent to provide inhibition of microbial growth.
  • composition comprising an antifungal compound or a combination of antifungal compounds described herein may also comprise a second agent (second active ingredient, second active agent) that possesses a desired therapeutic or prophylactic activity other than that of the antifungal compound.
  • a second agent second active ingredient, second active agent
  • Such a second active agent may include, but is not limited to, an antibiotic, an antibody, an antiviral agent, an anticancer agent, an analgesic (e.g., a nonsteroidal anti-inflammatory drug (NSAID), acetaminophen, an opioid, a COX-2 inhibitor), an immunostimulatory agent (e.g., a cytokine), a hormone (natural or synthetic), a central nervous system (CNS) stimulant, an antiemetic agent, an anti-histamine, an erythropoietin, a complement stimulating agent, a sedative, a muscle relaxant agent, an anesthetic agent, an anticonvulsive agent, an antidepressant, an antipsychotic agent, and combinations thereof.
  • an antibiotic e.g., an antibody, an antiviral agent, an anticancer agent, an analgesic (e.g., a nonsteroidal anti-inflammatory drug (NSAID), acetaminophen, an opioid, a COX-2
  • compositions comprising an anti- fungal compound described herein may be formulated for administration to an individual (human or other animal) by any of a variety of routes including, but not limited to, intravenous, intramuscular, subcutaneous, intra-arterial, parenteral, intraperitoneal, sublingual (under the tongue), buccal (cheek), oral (for swallowing), topical (epidermis), transdermal (absorption through skin and lower dermal layers to underlying vasculature), nasal (nasal mucosa), intrapulmonary (lungs), intrauterine, vaginal, intracervical, rectal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrarenal, nasojejunal, and intraduodenal.
  • routes including, but not limited to, intravenous, intramuscular, subcutaneous, intra-arterial, parenteral, intraperitoneal, sublingual (under the tongue), buccal (cheek), oral (for swallowing), topical (epider
  • the invention provides pharmaceutically acceptable salts of the fungicide and/or antifungal compounds described herein, solvated forms of the fungicide and/or antifungal compounds described herein, multimeric forms of the fungicide and/or antifungal compounds described herein, and prodrugs of the compounds described herein.
  • the invention is based on a discovery of a class of organic compounds, which when brought into contact of cells of one or more fungal species inhibit growth of or kill the cells of the one or more fungal species.
  • Compounds of the invention are thus referred to as "fungicide and/or antifungal" compounds.
  • Fungicide and/or antifungal compounds described herein are particularly useful in compositions and methods to kill or inhibit growth of cells of one or more pathogenic (including opportunistic pathogenic) fungi.
  • Fungicide and/or antifungal compounds described herein may be used in compositions and methods to treat an individual (human or other mammal), plant, crop, or foodstuff that is infected with, at risk of infection by, or suspected of being infected with a fungal species.
  • Fungicide and/or antifungal compounds described herein may also be used to treat or disinfect a liquid, solid, or semi-solid composition that is contaminated with or susceptible to contamination by cells of a fungal species.
  • Halo or "halogen” means fluorine, chlorine, bromine, or iodine.
  • Alkyl means a straight or branched chain monovalent or a divalent radical of saturated and/or unsaturated carbon atoms.
  • alkyl radical include, but are not limited to, methyl (abbreviated “Me”), ethyl (“Et”), propyl (“Pr”), isopropyl (“zPr”), butyl ("Bu”), isobutyl ("; ' Bu”), sec-butyl (sBu), ieri-butyl (iBu), and the like.
  • An alkyl group may be unsubstituted or substituted by one or more suitable substituents found herein.
  • Haloalkyl means an alkyl radical that is substituted with one or more identical or different halogen atoms, e.g., -CH 2 C1, -CF 3 , -CH 2 CF 3 , -CH 2 CC1 3 , and the like.
  • alkenyl means a straight-chain, branched, or cyclic hydrocarbon radical that has from 2 to 8 carbon atoms (C 2 - C 8 ) and at least one double bond, e.g., ethenyl, 3-buten-l-yl, 3-hexen-l-yl, cyclopent-l-en-3-yl, and the like.
  • An alkenyl group may be unsubstituted or substituted by one or more suitable substituents found herein.
  • Alkynyl means a straight-chain or branched hydrocarbon radical that has from 2 to 8 carbon atoms (C 2 - C 8 ) and at least one triple bond, e.g., ethynyl, 3-butyn-l-yl, 2-butyn-l-yl, 3-pentyn-l-yl, and the like.
  • An alkynyl group may be unsubstituted or substituted with one or more suitable substituents found herein.
  • Cycloalkyl means a non-aromatic monovalent or divalent monocyclic or polycyclic radical that has 3 to 12 carbon atoms (C 3 - Ci 2 ), e.g., cyclopentyl, cyclohexyl, decalinyl, and the like.
  • a cycloalkyl radical may be unsubstituted or may be substituted with one or more suitable substituents found herein.
  • a cycloalkyl radical may also be fused to one or more aryl groups, heteroaryl groups, or heterocycloalkyl groups, which themselves may be unsubstituted or may be substituted with one or more suitable substituents found herein.
  • Heterocycloalkyl means a non-aromatic monovalent or divalent, monocyclic or polycyclic radical that has 2 to 12 carbon atoms (C 2 - Ci 2 ) and 1 to 5 heteroatoms selected from nitrogen (N), oxygen (O), or sulfur (S), e.g., pyrrolodinyl, tetrahydropyranyl, morpholinyl, piperazinyl, oxiranyl, and the like.
  • a hetercycloalkyl radical may be unsubstituted or may be substituted with one or more suitable substituents found herein.
  • a heterocycloalkyl radical may also be fused to one or more aryl groups, heteroaryl groups, or heterocycloalkyl groups, which themselves may be unsubstituted or substituted with one or more suitable substituents found herein.
  • Aryl (abbreviated “Ar”) means an aromatic monovalent or divalent monocyclic or polycyclic radical comprising between 6 and 18 carbon ring members, e.g., phenyl, biphenyl, naphthyl, phenanthryl, and the like.
  • An aryl radical may be unsubstituted or substituted with one or more of the suitable substituents found herein.
  • An aryl radical may also be fused to one or more heteroaryl groups or heterocycloalkyl groups, which themselves may be unsubstituted or substituted with one or more suitable substituents found herein.
  • Heteroaryl (abbreviated “HAr”) means an aromatic monovalent or divalent monocyclic or polycyclic radical comprising between 2 and 18 carbon ring members and at least 1 heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), e.g., pyridyl, pyrazinyl, pyridizinyl, pyrimidinyl, furanyl, thienyl, triazolyl, quinolinyl, imidazolinyl, benzimidazolinyl, indolyl, and the like.
  • a heteroaryl radical may be unsubstituted or may be substituted with one or more of the suitable substituents found herein.
  • a heteroaryl radical may also be fused to one or more aryl groups, heteroaryl groups, or heterocycloalkyl groups, which themselves may be unsubstituted or may be substituted with one or more suitable substituents found herein.
  • Haldroxy means the radical -OH.
  • Alkoxy means the radical -OR, wherein R is an alkyl or cycloalkyl group.
  • Aryloxy means the radical -OAr, wherein Ar is an aryl group.
  • Heteroaryloxy means the radical -O(HAr), where HAr is a heteroaryl group
  • Acyl means a -C(0)R radical, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, e.g. acetyl, benzoyl, and the like.
  • Carboxy means the radical -C(0)OH.
  • Alkoxycarbonyl means a -C(0)OR radical where R is alkyl, alkenyl, alkynyl, or cycloalkyl.
  • Aryloxycarbonyl means a -C(0)OR radical where R is aryl or heteroaryl.
  • Amino means the radical -NH 2 .
  • substituted amino means the radical -NRR', wherein R and R' are, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
  • Acylamino means the radical -NHC(0)R, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, e.g., acetyl, benzoyl, acetylamino, benzoylamino, and the like.
  • Amido means the radical -C(0)NRR', wherein R and R' are, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
  • Sulfonylamino means the radical -NHS0 2 R, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
  • Amidino means the radical -C(NR)NR'R", wherein R, R', and R" are, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, and wherein R, R', and R" may form heterocycloalkyl rings, e.g. carboxamido, imidazolinyl, tetrahydropyrimidinyl.
  • “Guanidino” means the radical -NHC(NR)NR'R", wherein R, R', and R" are, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, and wherein R, R', and R" may form heterocycloalkyl rings.
  • Alkylthio means the radical -SR, wherein R is an alkyl or cycloalkyl group.
  • Arylthio means the radical -SAr, wherein Ar is an aryl group.
  • “Hydroxamate” means the radical -C(0)NHOR, whereub R is an alkyl or cycloalkyl group.
  • Thioacyl means a -C(S)R radical, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
  • Alkylsulfonyl means the radical -S0 2 R, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
  • Aminosulfonyl means the radical -S0 2 NRR', wherein R and R' are, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
  • a “leaving group” (Lv) means any suitable group that will be displaced by a substitution reaction.
  • any conjugate base of a strong acid can act as a leaving group.
  • Suitable leaving groups include, but are not limited to, -F, - CI, -Br, alkyl chlorides, alkyl bromides, alkyl iodides, alkyl sulfonates, alkyl benzenesulfonates, alkyl p-toluene-sulfonates, alkyl methanesulfonates, triflate, and any groups having a bisulfate, methyl sulfate, or sulfonate ion.
  • a “protecting group” refers to a group that protects one or more inherent functional group from premature reaction. Suitable protecting groups may be routinely selected by those skilled in the art in light of the functionality and particular chemistry used to construct the compound. Examples of suitable protecting groups are described, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 3d edition, John Wiley and Sons, New York, N.Y. (1999).
  • suitable organic moiety means any organic moiety recognizable, such as by routine testing, to those skilled in the art as not adversely affecting the fungicide and/or antifungal activity of compounds described herein.
  • suitable organic moieties include, but are not limited to, hydroxyl groups, alkyl groups, oxo groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxyl groups, carboxyl groups, amino groups, substituted amino groups, disubstituted amino groups, carbamoyl groups, arylthio groups, heteroarylthio groups, and the like.
  • substituted substituent or "suitable substituent” means any suitable substituent that may be recognized or selected, such as through routine testing, by those skilled in the art.
  • pyrazolyl pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); nitro; thiol; thioether, O-lower alkyl (alkoxyl); O-aryl (aryloxy), aryl; aryl-lower alkyl; C0 2 CH 3 ; CONH 2 ; OCH 2 CONH 2 ; NH 2 ; S0 2 NH 2 ; OCHF 2 ; CF 3 ; OCF 3 ; and the like.
  • Such moieties may also be optionally substituted by a fused-ring structure or bridge, for example OCH 2 -0. All of these substituents may optionally be further substituted with a substituent selected from groups such as hydroxyl groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxyl groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxyl groups, amino groups, substitued amino groups, disubstitued amino groups, carbamoyl groups, aryloxyl groups, heteroaryloxyl groups, arylthio groups, heteroarylthio groups, and the like.
  • solvated forms of a fungicide and/or antifungal compound described herein includes solvated forms of the compound.
  • solvated forms of a fungicide and/or antifungal compound of the invention include, but are not limited to, the fungicide and/or antifungal compound in combination with a solvent selected from water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, and acetone.
  • Some of the compounds of the present invention may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, or mixtures of enantiomers, diastereomers, or both when they contain one or more stereogenic centers as designated by R or S according to the Cahn- Ingold-Prelog rules whether the absolute or relative configuration is known. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.
  • Some of the compounds in the present invention may exist as geometric isomers as the result of containing a stereogenic double bond. In such cases, they may exist either as pure or mixtures of cis or trans geometric isomers or (E) and (Z) designated forms according to the Cahn-Ingold-Prelog rules and include compounds that adopt a double bond configuration as a result of electronic derealization.
  • an optically pure compound having one or more chiral centers is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
  • the compounds of the present invention may be used in a form that is at least 90% optically pure, that is, a form that comprises at least 90% of a single isomer (80% enantiomeric excess (e.e.) or diastereomeric excess (d.e.), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
  • fungicide and/or antifungal compounds of the invention include active tautomeric and stereoisomeric forms of the compounds of the present invention, which may be readily obtained using techniques known in the art.
  • optically active (R) and (S) isomers may be prepared via a stereospecific synthesis, e.g., using chiral synthons and chiral reagents, or racemic mixtures may be resolved using conventional techniques.
  • a compound of the present invention is a base
  • the desired salt of the compound may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid or with an organic acid along with appropriate counter ion.
  • Inorganic acids that may be used to form salts of compounds of the invention include, but art not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • Organic acids that may be used to form salts of compounds of the invention include, but are not limited to, acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyrvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid (such as glucuronic acid or galacturonic acid), an alpha-hydroxy acid (such as citric acid or tartaric acid), an amino acid (such as aspartic acid or glutamic acid), an aromatic acid (such as benzoic acid or cinnamic acid), and a sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid).
  • acetic acid maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyrvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid (such as glucur
  • a compound of the present invention is an acid
  • the desired salt form may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base and appropriate counter ion(s).
  • bases that may be used to form salts of compounds of the invention include, but are not limited to, amines (primary, secondary or tertiary), an alkali metal hydroxide, and an alkaline earth metal hydroxide.
  • suitable salts of compounds of the invention include, but are not limited to, organic salts derived from basic amino acids (such as lysine and arginine, ammonia, primary, secondary, and tertiary amines) and from cyclic amines (such as piperidine, morpholine and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • organic salts derived from basic amino acids such as lysine and arginine, ammonia, primary, secondary, and tertiary amines
  • cyclic amines such as piperidine, morpholine and piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium such as sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • Salts of fungicide and/or antifungal compounds of the invention include pharmaceutically acceptable salts of the compound.
  • pharmaceutically acceptable salts of the compound as understood and used herein, is meant those salts of any fungicide and/or antifungal compound of the invention derived from an inorganic or organic acid or base recognized in the art as compatible for pharmaceutical compositions.
  • pharmaceutically acceptable salts of the fungicide and/or antifungal compounds described herein are not limited to only pharmaceutical uses.
  • acids for pharmaceutically acceptable salts of fungicide and/or antifungal compounds of the invention include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, hydroxymaleic acid, malonic acid, glutamic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, 2-acetoxybenzoic acid, acetic acid, phenylacetic acid, propionic acid, glycolic acid, stearic acid, tartaric acid, acetic acid, methanesulfonic acid, formic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, ethane- disulfonic acid, and sulfanilic acid
  • Salts of other acids may not be pharmaceutically acceptable, but may find use in a variety of compositions and methods that are used to provide the benefit of the fungicide and/or antifungal activity of a compound of the invention to a solution, semi-solid, or solid composition that is not a pharmaceutical composition.
  • Salts derived from appropriate bases include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium and NR4+ (where R is a Ci .4 alkyl) salts, and the like.
  • multimer refers to multivalent or multimeric forms of fungicide and/or antifungal compounds of the invention. Such “multimers” may be made by linking or placing multiple copies of an active (i.e., possessing fungicide and/or antifungal activity) compound described herein in close proximity to each other, e.g., using a scaffolding provided by a carrier moiety. Multimers of various dimensions (i.e., bearing varying numbers of copies of an active compound) may be tested to arrive at a multimer of optimum size with respect to binding site interactions. Provision of such multivalent forms of active compounds with optimal spacing between the binding site moieties may enhance binding site interactions. See, e.g., Lee et al., Biochem., 23: 4255 (1984).
  • a suitable carrier moiety or linker units may be used to control the multivalency and spacing by selection of a suitable carrier moiety or linker units.
  • Useful moieties include molecular supports comprising a multiplicity of functional groups that can be reacted with functional groups associated with the active compounds of the invention.
  • a variety of carrier moieties may be used to build highly active multimers including, but not limited to, proteins such as bovine serum albumin (BSA); peptides such as pentapeptides, decapeptides, pentadecapeptides, and the like; and non-biological compounds selected for their beneficial effects on absorbability, transport, or persistence within or on a target microbial cell.
  • Functional groups on the carrier moiety such as amino, sulfhydryl, hydroxyl, and substituted amino groups, may be selected to obtain stable linkages to the compounds of the invention, optimal spacing between the immobilized compounds, and optimal biological properties.
  • pharmaceutically acceptable any compound or mixture that is not biologically, chemically, or in any other way, incompatible with body chemistry and metabolism and also does not adversely affect the desired, effective fungicide and/or antifungal activity of a compound of the invention or any other component of a composition comprising an fungicide and/or antifungal compound described herein that may be administered to an individual to effectively kill or inhibit growth of cells of a microbial pathogen infecting an individual.
  • oral refers to a route or mode for administering an effective amount of an fungicide and/or antifungal compound described herein, or composition thereof, to an individual anywhere along the alimentary canal of the individual.
  • enteral refers to a route or mode for administering an effective amount of an fungicide and/or antifungal compound described herein, or composition thereof, to an individual anywhere along the alimentary canal of the individual.
  • enteral routes of administration include, without, limitation, from the mouth, e.g., swallowing a solid (e.g., pill, tablet, capsule) or liquid (e.g., syrup, elixir) composition; nasojejunal or gastrostomy tubes (into the stomach); intraduodenal
  • enteral routes of administration may be employed in the invention.
  • enteral routes of administration may be employed in the invention.
  • enteral formulations are the same as “enteral” formulations and broadly encompass formulations that may be swallowed from the mouth as well as those that permit administration of an fungicide and/or antifungal compound of the invention anywhere along the alimentary canal.
  • sub-lingual (absorption under the tongue) and buccal (absorption through the inner cheek) administration of a anit-microbial compound of the invention may also be considered oral routes of administration.
  • parenteral and “parenterally” refer to routes or modes of administration of an fungicide and/or antifungal compound of the invention, or composition thereof, to an individual other than along the alimentary canal.
  • parenteral routes of administration include, without limitation, intravenous (i.v.), intramuscular (i.m.), intra-arterial (i.a.), intraperitoneal (i.p.), subcutaneous (s.c), transdermal (absorption through the skin or dermal layer), nasal or pulmonary (e.g., via inhalation or nebulization, for absorption through the respiratory mucosa or lungs), intraarticular (i.a.), direct injections or infusions into body cavities or organs, as well as by implantation of any of a variety of devices into the body that permit active or passive release into the body of an individual of an fungicide and/or antifungal compound described herein.
  • a “pharmaceutically acceptable prodrug” is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a salt of such compound, or a compound that is biologically active with respect to an intended pharmacodynamic effect.
  • a “pharmaceutically active metabolite” means a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med. Chem., 40: 2011-2016 (1997); Shan et al., /. Pharm. Set, 86(7):765-767 (1997); Bagshawe, Drug Dev.
  • fungicide and/or antifungal compound of the invention is present in a solid form
  • the compound and salts thereof may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified structural formulas.
  • a "patient” and “individual” are synonymous, unless noted otherwise, and mean any mammal, including without limitation, a human, who receives or may be a candidate to receive an fungicide and/or antifungal compound described herein or composition thereof.
  • a "patient” may or may not present a recognizable symptom of a microbial disease, but merely be at risk for infection by cells of a pathogenic microbial species that may cause a disease, e.g., due to exposure to a source of cells of the microbial pathogen.
  • an "effective amount” is intended to mean that amount of a compound that is sufficient to reduce, prevent or inhibit fungal growth as compared with a negative control.
  • a "therapeutically effective amount" of a fungicide and/or antifungal compound of the present invention, or of a prodrug, an active metabolite, or a salt thereof, is a quantity sufficient to, when administered to an individual to kill or inhibit growth of cells of a microbial pathogen.
  • a "therapeutically effective amount" of a compound of the present invention is an amount which prevents, inhibits, suppresses, or reduces a given clinical condition or disease symptom in an individual as known and understood by a skilled healthcare provider or as compared to a control, such as an individual that is not infected with a microbial pathogen.
  • a therapeutically effective amount of a compound of the present invention may be readily determined by one of ordinary skill by routine methods known in the art.
  • Therapy and “therapeutic” as understood and used herein refer to treatment of a patient for a microbial infection or disease due to the microbial infection. For convenience, the terms are also understood to encompass prophylactic or precautionary use or administration of a compound of the invention.
  • Such precautionary or prophylactic use is exemplified by administration of an antibiotic to an immunocompromised or immunodeficient patient to protect the patient from an infection; to a patient suspected, but not proven, of having a microbial infection; or to a patient that is susceptible to contracting a disease caused by infection of cells of a pathogenic species, for example, at open wounds; by contact with water, food, body fluids, corpses, or carcasses contaminated with cells of a pathoogenic microbial species; or by contact with infected individuals or body fluids of infected individuals containing cells of a pathogenic microbial species.
  • treatment will refer to any use of the fungicide and/or antifungal compound calculated or intended to arrest or inhibit the growth of or kill cells of a fungal species.
  • treating an individual may be carried out after any diagnosis indicating possible fungal, i.e., whether an infection by a particular microbe has been confirmed or whether the possibility of infection is only suspected, for example, after exposure to the microbe or to another individual infected by the microbe.
  • composition or method described herein as “comprising” one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method.
  • any composition or method described as “comprising” (or which "comprises") one or more named elements or steps also describes the corresponding, more limited composition or method “consisting essentially of” (or which "consists essentially of") the same named elements or steps, meaning that the composition or method includes the named essential elements or steps and may also include additional elements or steps that do not materially affect the basic and novel characteristic(s) of the composition or method.
  • composition or method described herein as “comprising” or “consisting essentially of” one or more named elements or steps also describes the corresponding, more limited, and closed-ended composition or method “consisting of” (or “consists of”) the named elements or steps to the exclusion of any other unnamed element or step.
  • known or disclosed equivalents of any named essential element or step may be substituted for that element or step.
  • An fungicide and/or antifungal compound of the invention has the following structure:
  • n 1 or 2;
  • X 1 is N or NR 8 ;
  • X 3 and X 5 are each independently NH, NR 8 , S, O, or S0 2 ,
  • L is a direct bond or a linker which is ⁇ ⁇ where Z is an optionally substituted aryl, heteroaryl, carboxamide (-CONH- or -NHCO-), or alkyl radical;
  • L is a linker which is a direct bond or is ⁇ ⁇ where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, carboxamide (-CONH- or -NHCO-), aryl, or heteroaryl radical; and
  • R 1 , R 2 , R 3 , R 4 , R 6 and R 7 are each independently hydrogen, halo, amino, amidino, guanidino, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, amino, alkylamino, acylamino, amido, sulfonamido, mercapto, alkylthio, arylthio, hydroxamate, thioacyl, alkylsulfonyl, or aminosulfonyl; and
  • R 8 is hydrogen, OH, a halogen, or an optionally substituted alkyl; or pharmaceutically acceptable salts thereof.
  • fungicide and/or antifungal compounds of the invention have a structure:
  • 2,5-bis(4-cyano-2-nitrostyryl)furan (390 mg, 0.95 mmol) was suspended in triethyl phosphite (15 mL) and heated to gentle reflux over a 170 °C oil bath for 16 hours. The excess phosphite was removed under vacuum, and the resulting dark residue was adsorbed onto silica gel (100 mL) by evaporation from CH 2 C1 2 . The product was eluted from the silica gel with 8: 1 acetone:EtOAc until no more product was obtained.
  • 2,5-bis(4-cyano-2-nitrostyryl)thiophene (1.76 g, 4.1 mmol) was suspended in triethyl phosphite (50 mL) and heated to gentle reflux over a 170 °C oil bath for 16 hours. The excess phosphite was removed under vacuum, and the resulting dark residue was adsorbed onto silica gel (200 mL) by evaporation from CH 2 C1 2 . The product was placed onto additional clean silica gel (100 mL), and eluted from the silica gel with 4: 1 acetone :EtO Ac until no more product was obtained.
  • the resulting brown mixture was brought to reflux in a preheated oil bath and stirred for 3 h. After cooling, the dark brown mostly homogeneous solution was extracted with EtOAc over Na 2 C0 3 solution (5% aq). The combined organic solution was washed with water (50 mL) and brine (30 mL), dried over MgS0 4 , filtered and evaporated to a fourth of the original volume. The solid that formed was collected by filtration, washed with 20% EtOAc in Hexanes (100 mL) and ether (100 mL) to yield 0.99 g of a cream-colored solid.
  • 2,5-Bis(A L Boc-6-cyanoindol-2-yl)pyridine (220 mg, 0.39 mmol) is heated (dry) to 200 °C in a small flask for 30 min. The remaining solid is collected to provide 141 mg (100%) of 2,5-bis(6-cyanoindol- 2-yl)pyridine as a yellow powder.
  • reaction mixture was heated at 120°C for 3 hours and poured to 10 mL of brine and the yellow precipitates were filtered, and dried to give crude product, which was purified by reverse phase C18 column chromatography (H 2 O/0.1% CH 3 COOH: Acetonitrile/0.1 CH 3 COOH) to provide desired 2,5-bis[6-(3,4,5,6-tetrahydropyrimidin- 2-yl)benzofuran-2-yl]thiophene acetic acid salt (MBX 1885; 68 mg, 26%) as yellow solid.
  • MBX 1885 2,5-bis[6-(3,4,5,6-tetrahydropyrimidin- 2-yl)benzofuran-2-yl]thiophene acetic acid salt
  • reaction mixture was heated at 120°C for 3 hours and poured to 5 mL of brine, and the yellow precipitates were filtered, and dried to provide crude product, which was purified by reverse phase CI 8 column chromatography (H 2 O/0.1% CH 3 COOH: Acetonitrile/0.1%CH 3 COOH) to give desired product 6-(4,5- dihydroimidazol-2-yl)-2- ⁇ 5-[6-(4,5-dihydro-imidazol-2-yl)benzofuran-2-yl]thiophen-2-yl ⁇ indole acetic acid salt (MBX 1887) (60 mg, 55%) as yellow solid.
  • MBX 1887 6-(4,5- dihydroimidazol-2-yl)-2- ⁇ 5-[6-(4,5-dihydro-imidazol-2-yl)benzofuran-2-yl]thiophen-2-yl ⁇ indole acetic acid salt (MBX 1887) (60 mg, 55%) as
  • 6-(3,4,5,6 etrahydropyrimidin-2-yl)-2- ⁇ 5 6-(3,4,5,6 etrahydropyrimidin-2-yl)benzofuran-2 ⁇ yl]thiophen-2-yl ⁇ indole acetic acid salt (MBX 1914) 6-cyano-2-[5-(6-cyanobenzofuran-2-yl)thiophene-2-yl]indole (158 mg, 0.43 mmol) was treated with 1,3-diaminopropane (2.5 mL) and P 2 Ss (60 mg, 0.3 mmol) for 3 hours at 120-130 °C in sealed tube. Water was added. The precipitate was filtered and dissolved by methanol and acetic acid.
  • 6-(5-hydroxy-3,4,5,6-tetrahydropyrimidin-2-yl)-2- ⁇ 5-[6-(5-hydroxy-3,4,5,6- tetrahydropyrimidin-2-yl)benzofuran-2-yl]thiophen-2-yl ⁇ indole acetic acid salt (MBX 1991)
  • 6-cyano-2-[5-(6-cyanobenzofuran-2-yl)thiophene-2-yl]indole 95 mg, 0.26 mmol
  • phosphorous pentasulfide 65 mg, 0.29 mmol
  • the vial was sealed and heated to 130 °C on a shaker block. After 4 hours, the mixture was allowed to cool to room temperature. Water (10 mL) was added slowly, and the viscous suspension that formed was filtered through celite. The retained on celite was loaded on a CI 8 chromatography column. The column was eluted with MeCN in water (from 0% to 90% of MeCN over 1 h, 30 mL/min) [solvents contain 0.1% acetic acid] to provide the product as a yellow-green powder after removal of solvents under vacuum, 116 mg, 90 % yield.
  • 6-(3,4,5,6 etrahydropyrimidin-2-yl)-2- ⁇ 5 2-(3,4,5,6-tetrahydropyrimidin-2-yl)benzofuran-6- yl]thiophene-2-yl ⁇ indole acetic acid salt (MBX 2015) A 10 mL sealed tube was charged with 6-cyano-2-[5-(2-cyanobenzofuran-6-yl)thiophene-2-yl] indole (65 mg, 0.14 mmol), P 2 Ss (31 mg, 0.07 mmol) and 1,3-diaminopropane (2.0 mL).
  • Compounds of the invention possess fungicide and/or antifungal activity, which means that the compounds kill or inhibit growth of cells of one or more species or strains of a fungi pathogen when the compounds are brought into contact with such cells. Accordingly, the compounds described herein are useful in compositions and methods for treating a human, animal, insect, plant, crop, or foodstuff which has been infected with a fungi or pathogenic fungi species, is at risk of infection by a fungi species, or is suspected of having been infected with a fungi species.
  • Compounds described herein may also be used in compositions and methods to kill or inhibit growth of cells of one or more fungi species in solutions, semi-solids, and solid compositions that are or are not susceptible to contamination by cells of fungi species and particularly pathogenic fungi species.
  • fungi species and strains that are known etiological agents for various diseases that can occur once an infection has become established in or on the body of individual.
  • a fungus species may be an opportunistic fungal pathogen, i.e., cause a disease only under certain conditions.
  • cells of an opportunistic pathogenic fungi species may not normally be pathogenic or only mildly pathogenic in the case of a healthy individual whose immune system can effectively identify the invading fungal cells and mount an effective response to inactivate and/or otherwise remove the cells from the individual's body.
  • cells of the same fungus species may be able to establish an infection resulting in significant pathology in an individual whose immune system has been weakened or otherwise suppressed.
  • Weakened or compromised immune systems may result from a variety conditions including, but not limited to, prior (primary) illness, cancer of the immune system, exposure to toxins, exposure to radiation, exposure to chemotherapy drugs, and use of immunosuppressive drugs.
  • Such individuals include, without limitation, patients of acquired immunodeficiency syndrome (AIDS), cancer patients undergoing radiation therapy, cancer patients receiving immunosuppressive chemotherapy drugs, and also individuals who take drugs designed to inhibit or suppress the activity of one or more cytokines, for example to treat diseases associated with an overactive cytokine(s), such as rheumatoid arthritis, psoriasis, and Crohn's disease.
  • AIDS acquired immunodeficiency syndrome
  • cancer patients undergoing radiation therapy cancer patients receiving immunosuppressive chemotherapy drugs
  • drugs designed to inhibit or suppress the activity of one or more cytokines for example to treat diseases associated with an overactive cytokine(s), such as rheumatoid arthritis, psoriasis, and Crohn's disease.
  • Fungicide and/or antifungal compounds described herein may be used to kill or inhibit growth of cells of one more species of fungi.
  • prominent fungal pathogens include, but are not limited to, species of Candida, such as C. albicans, C. parapsilosis, C. tropicalis, C. krusei, C. glabrata, and C. guillermondii; species of Aspergillus, such as A. fumgatus, A. niger, and A. flavus; species Cryptococcus, such as C. neoformans, C. laurentii, C. albidus, and C. gatti; species of
  • Histoplasma such as H. capsulation
  • species of Pneumocystis such as P. jiroveci, Claviceps purpurea, and Magnaporthe grisea.
  • Fungal pathogens are of particular concern for immunocompromised or immunosuppressed individuals.
  • Fungicide and/or antifungal compounds described herein may be formulated for
  • Fungicide and/or antifungal compounds described herein include compounds that may exhibit fungicidal and/or antifungal activity against multiple species and strains of fungi.
  • compounds described herein may also be effective at killing or inhibiting growth of cells of multiple pathogenic fungal species and also non-pathogenic fungal cells. Such broad spectrum fungicide and/or antifungal activity may be desirable in both
  • a compound that can kill or inhibit growth of cells of multiple pathogenic fungal organisms may provide new treatments for a variety of diseases, including those for which drug resistance by the etiological agent is a growing problem. Killing or inhibiting growth of non-pathogenic fungal cells is a common activity in agriculture and in preserving foodstuffs. Accordingly, persons skilled in this art understand that in view of the benefit provided to the medical field of a compound that kills or inhibits growth of cells of one or more fungal pathogens, any side-effect of also killing or inhibiting growth of non-pathogenic cells should be tolerable and acceptable for approval by regulatory agencies for use of the compound for treating a particular disease.
  • fungicide and/or antifungal compound described herein to kill or inhibit growth of cells of pathogenic and/or non-pathogenic species is also desirable in situations where growth of any fungal cells may interfere with proper operation, safety, efficiency, or appearance of a composition.
  • compositions for which it is desirable to inhibit growth of pathogenic and/or non-pathogenic fungal cells are exemplified by, but not limited to plants, crops, catheters, lock solutions, pumps (including cardiopulmonary bypass pumps, implantable patient pumps, non-implantable (exterior) patient pumps (e.g., for drug or hormone delivery), and industrial pumps), dialysis equipment, water pipes, plumbing fixtures, fuel lines, air ducts, gas lines (including air lines, oxygen lines, respirators), cosmetic products (including cosmetic skin products, cosmetic hair products), foods, eye products (eye drops, contact lenses, implantable lenses), ear products (e.g., ear drops), oral products (e.g., mouthwashes, tooth pastes, dental appliances), nasal products (e.g., nose drops, nose gels, nose swabs), vaginal care products, medical and veterinarian clothing (e.g., face masks, caps, gowns, gloves, footwear, gloves, aprons), gas masks, adhesives, soaps, detergents, and paints.
  • fungicide and/or antifungal compound described herein to kill or inhibit cells of one or more microbial pathogens does not preclude use of the compound to kill or inhibit growth of cells of pathogenic and non-pathogenic microbial organisms.
  • killing or inhibiting growth of cells of a fungal species comprises bringing a fungicide and/or antifungal compound described herein into contact with the cells of the fungal species.
  • a compound described herein may be formulated in a pharmaceutical composition (including veterinarian) composition for administration to an individual or formulated to provide fungicide and/or antifungal activity to an inanimate liquid, semi-solid, or solid composition that is susceptible or has already been contacted with (i.e., contaminated with) cells of a fungal species.
  • an fungicide and/or antifungal compound described herein is in contact with a solid, semi-solid, or liquid composition prior to contamination with cells of a fungal species, however, an fungicide and/or antifungal compound described herein may also be brought into contact with a solid, semi-solid, or liquid composition that is already contaminated with cells of a fungal species to kill or inhibit growth of the cells already present on or in the composition.
  • a fungicide and/or antifungal compound described herein may be incorporated into any of a variety of compositions to provide the benefit of killing or inhibiting growth of cells of a pathogenic microbial species or strain to the particular composition or to a surface to which the composition may be applied.
  • compositions comprising an fungicide and/or antifungal compound described herein include, but are not limited to, solutions, suspensions, dry mixtures, ointments, creams, gels, jellies, lotions, pastes, tooth pastes, petroleum products, porous membranes, porous filters, microparticles, microspheres, liposomes, micelles, lipid bilayers, resin particles, plastics, paints, glues, adhesives, cellulose products, textiles (fiber, yarn, or cloth), and nanoparticles.
  • An fungicide and/or antifungal compound described herein may also be formulated by standard methods for delivery to a surface in an aerosol of fine solid particles or liquid droplets mixed with a gas.
  • a fungicide and/or antifungal compound described herein may be brought into contact with a solid surface composed of or comprising any of a variety of materials that are capable of retaining and/or transmitting viable cells of one or more fungal species that may be present on the solid surface.
  • Such materials include, but are not limited to, enamel, plastic, glass, silicon, rubber, metal, stone, cement, nylon, cellulose, polymeric resin (including various cellulose and agarose resins), calcium phosphate (for example, as in, but not limited to, hydroxyapatite and bone), calcium carbonate (for example, as in, but not limited to, mollusk shells and mother-of-pearl), keratin (for example, as in, but not limited to, skin, hair, fur, wool, nails, claws, hooves, scales, beaks, and feathers), collagen (for example, as in, but not limited to, animal hides, tendons, and ligaments), chitin (for example, as in, but not limited to, exoskeletons and fungal cell walls), and combinations thereof.
  • the compound may be applied to a solid surface by any of a variety methods available in the art for applying an organic compound to a particular surface.
  • Such methods include methods of "treating” a surface, wherein it is understood that the terms “treat”, “treating”, and “treatment” in this context of combining a compound with a surface is distinct from the a medical treatment of an individual for disease.
  • Such methods of treating a surface with an fungicide and/or antifungal compound described herein include, but are not limited to, coating a surface with the compound, immersing the surface in the compound, impregnating the surface with the compound, absorbing the compound into the surface, adsorbing the compound to the surface, and covalently conjugating the compound to the surface.
  • compositions of the invention may be in any of a variety of forms particularly suited for the intended mode of providing the benefit of the fungicide and/or antifungal activity of a compound described herein to a solid composition, to a semi-solid composition, or to liquid composition.
  • a carrier is any compound that provides a medium for using fungicide and/or antifungal compound described herein.
  • a carrier may be liquid, solid, or semi-solid. To retain its utility, it will be necessary that the carrier (and any other component of a composition) does not significantly neutralize, inhibit, or block the fungicide and/or antifungal inhibitory activity of a compound of the invention included in the composition.
  • a suitable carrier for use in the compositions described herein includes, but is not limited to, an organic solvent, an aqueous buffer, water, emulsifying agent, and a solid dispersing agent. Solutions and suspensions comprising a fungicide and/or antifungal compound described herein may also be prepared using an appropriate organic solvent or emulsifying agent.
  • a preferred organic solvent is dimethyl sulfoxide (DMSO).
  • DMSO-based solutions comprising an antimicrobial compound described herein are particularly useful in providing required concentrations of the compound in various compositions, assays (including growth assays), and procedures.
  • Other organic solvents may also be used including, but not limited to, an alcohol, N-methylpyrrolidone (NMP), and ⁇ , ⁇ -dimethylacetamide (DMA).
  • NMP N-methylpyrrolidone
  • DMA ⁇ , ⁇ -dimethylacetamide
  • ethanol is more preferred than isopropanol, which is more preferred than butanol or an aryl alcohol, which are more preferred than methanol.
  • conventional solid carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • a composition comprising a fungicide and/or antifungal compound described herein may also comprise a dispersing agent.
  • the dispersing agent may be employed to disperse the fungicide and/or antifungal compound more uniformly in a composition and/or to enhance dispersion of the composition containing an antifungal compound described herein over a surface to which the composition is applied.
  • a dispersing agent may be a solid or liquid. Solid dispersing agents may include, without limitation, talc, starch, cellulose, metal oxide (e.g., zinc oxide, titanium oxide), graphite, and combinations thereof.
  • a preferred dispersing agent for liquid compositions is a surfactant, which may be an anionic, cationic, amphoteric, or nonionic surfactant.
  • a surfactant is employed at the lowest concentration that provides optimal dispersion of the fungicide and/or antifungal compound throughout the composition or optimal dispersion of the composition containing on a surface.
  • Preferred anionic surfactants useful in the compositions and methods described herein include, without limitation, linear alkyl benzene sulfonic acid; alkyl sulfate; polyoxyethylene alkyl ether sulfate having 1 to 10 moles of ethylene oxide; polyoxyethylene alkyl ether carboxylic acid having 1 to 10 moles ethylene oxide; polyoxyethylene alkyl amide ether carboxylic or fatty acid having 1 to 10 moles ethylene oxide; and potassium, sodium, magnesium, or alkanolamine salts thereof.
  • the alkyl and fatty groups in an anionic surfactant are, independently, 8 to 22 carbon atoms, and more preferably 10 to 18 carbon atoms.
  • a nonionic surfactant useful in the compositions and methods described herein is a nonionic polyoxyethylene ether, including, but not limited to, a polyoxyethylene alkyl ether having an alkyl chain containing 8 to 22 carbon atoms, more preferably 10 to 18 carbon atoms, and having 1 to 30 moles, and more preferably 4 to 20 moles, of ethylene oxide; a polyoxyethylene oxypropylene alkyl ether having 1 to 30 moles, and more preferably 1 to 20 moles, of ethylene oxide, and having 1 to 10 moles, more preferably 1 to 5 moles, of propylene oxide; a fatty acid alkanol amide containing 8 to 22 carbon atoms, and more preferably 10 to 18 carbon atoms to which 1 to 3 moles of ethylene oxide or propylene oxide may be added; and an alkyl polyglucoside having an alkyl chain containing 8 to 22 carbon atoms, and more preferably 10 to 18 carbon atoms, and preferably having 1
  • nonionic surfactant useful in compositions and methods described herein is t-octylphen-oxypolyethoxyethanol (e.g., brand name TRITON® X-100 non-ionic surfactant, Sigma- Aldrich, St. Louis, Missouri, US).
  • t-octylphen-oxypolyethoxyethanol e.g., brand name TRITON® X-100 non-ionic surfactant, Sigma- Aldrich, St. Louis, Missouri, US.
  • Another nonionic surfactant useful in the compositions and methods described herein may be an ester between a fatty acid containing 8 to 22 carbon atoms, and preferably 10 to 18 carbon atoms, and a polyvalent alcohol having a hydrocarbon group containing 2 to 10 carbon atoms and 2 to 8 hydroxy groups. More preferably, the ester is a glycerin fatty acid ester, a polyglycerin fatty acid ester, a sorbitan fatty acid ester, a sucrose fatty acid ester, or a propylene glycol fatty acid ester.
  • Amphoteric surfactants that may find use in the compositions and methods described herein include, without limitation, those having an alkyl group containing 8 to 22 carbon atoms, such as alkyl amidopropyl-N,N-dimethyl acetate betaine (N-alkanoyl aminopropyl-N,N-dimethyl-N-carboxymethyl ammonium carbobetaine), alkyl amidopropyl-N,N-dimethyl-2-hydroxypropyl sulfobetaine (N- alkanoyl aminopropyl-N,N-dimethyl-N-(2-hydroxy-3-sulfopropyl) ammonium sulfobetaine), alkyl- ⁇ , ⁇ -dimethyl acetate betaine (N-alkyl-N,N-dimethyl-N-carboxymethyl ammonium carbobetaine), alkyl amidopropyl-N,N-dimethyl-2-propyl sulfobetaine (N-al
  • preferred species may include lauric acid amidopropyl-N,N-dimethyl acetate betaine (N-lauroyl aminopropyl-N,N-dimethyl-N-carboxymethyl ammonium carbobetaine), myristic acid amidopropyl- ⁇ , ⁇ -dimethyl acetate betaine (N-myristyloyl aminopropyl-N,N-dimethyl-N-carboxymethyl ammonium carbobetaine), cocamide amide propyl-N,N-dimethyl acetate betaine (N-coconut composition alkanoyl aminopropyl-N,N-dimethyl-N-carboxymethyl ammonium carbobetaine), lauryl- N,N-dimethyl-2-hydroxypropyl sulfobetaine (N-lauryl-N,N-dimethyl-N-(2-hydroxy-3 -sulfopropyl) ammonium sulfobetaine), lauric acid amidoprop
  • Cationic surfactants that may be used in compositions and methods described herein include, but are not limited to, a long-chain dialkyl dimethyl ammonium salt, long-chain monoalkyl monobenzyl dimethyl ammonium salt, and monoalkyl trimethyl ammonium salt having a long alkyl chain containing 6 to 24 carbon atoms, and preferably 6 to 18 carbon atoms, which may be interrupted therein with an amide or ester linkage.
  • the counterion of such cationic species is preferably a halogen ion, sulfate ion, or alkyl sulfate containing 1 to 3 carbon atoms.
  • the cationic surfactants of amine type useful in compositions and methods described herein include long-chain dialkyl monomethylamine salts having a long alkyl chain containing 8 to 24 carbon atoms, which optionally may be interrupted therein with an amide or ester linkage.
  • Preferred counterions of such species include hydrochlorides, sulfates, and phosphates thereof.
  • compositions of the invention comprise at least one fungicide and/or antifungal compound described herein and may be prepared in a unit-dosage form appropriate for a desired mode of administration.
  • the pharmaceutical formulations of the present invention may be administered for therapy (including for preventive therapy) by any suitable route including, but not limited to, oral, buccal, sublingual, rectal, mucosal (mucosa), nasal, topical, dermal, vaginal and parenteral (including, but not limited to, subcutaneous, intramuscular, intravenous, and intradermal).
  • a pharmaceutically acceptable carrier used in a pharmaceutical composition of the invention must be "acceptable" in the sense of being compatible with the other agents and ingredients of the composition and not prohibitively deleterious to the patient to whom the pharmaceutical composition is administered.
  • An fungicide and/or antifungal compound of the invention may be administered alone, but will generally be administered as pharmaceutical formulations suitable for administration.
  • compositions known in the art contemplated herein comprise a therapeutically effective amount of at least one compound of the present invention, and an inert, pharmaceutically or cosmetically acceptable carrier or diluent.
  • pharmaceutically acceptable carrier or a “cosmetically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical or cosmetic administration, respectively. Except insofar as any conventional media or agent is incompatible with an fungicide and/or antifungal compound of the invention, use thereof in the formulation is contemplated.
  • a preferred pharmaceutical composition comprises an effective amount of one or more fungicide and/or antifungal compounds described herein in combination with a pharmaceutically acceptable carrier, and, optionally, one or more other active agents, diluents, fillers, or excipients.
  • An excipient is a compound that improves or provides a desirable physical property to a composition.
  • An excipient useful in a composition described herein includes, but is not limited, an emulsifying agent, pH buffering agent, a dispersing agent, co-solvent, a gelling agent, and a drying agent.
  • a compound of the invention may be administered as the raw chemical, preferably the compound is present as an active ingredient in a pharmaceutical composition.
  • the invention thus further provides a pharmaceutical composition comprising an fungicide and/or antifungal compound described herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers therefor and, optionally, one or more other therapeutic or beneficial agents known in the art, such as, an antibiotic, another antifungal drug, an anti-protozoan drug, an anti-viral compound, an anti-cancer compound, a vitamin, a trace metal supplement, or an ion supplement to restore or maintain proper ionic balance in blood or other tissues.
  • Suitable therapeutic agents include, without limitation, penicillins and other beta lactamase inhibitors, carbapenems, cephalosporins, macrolides (including erythromycin and ketolides), sulfonamides, aminoglycosides, quinolones (such as fluoroquinolones), oxazolidinones, lipopeptides (such as daptomycin), tetracyclines, vancomycin, erythromycin, streptomycin, efflux pump inhibitors, lactoferrins, and cationic peptides.
  • Such agents may be administered to an individual in the same pharmaceutical composition comprising an fungicide and/or antifungal compound of this invention or in a separate composition.
  • a composition comprising a fungicide and/or antifungal compound of the invention may further comprise one or more antibiotics such as, but not limited to, penicillin,cephalosporin, cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, ampicillin, amoxicillin, bacampicillin, azlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, azithromycin, clarithromycin, clindamycin, erythromycin, lincomycin, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, quinolone, cinoxacin, nalidixic acid, fluoroquinolone, ciprofloxacin, enoxacin, grepafloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxaci
  • a composition comprising a fungicide and/or antifungal compound of the invention may further comprise one or more antifungal agents such as, but not limited to, amphotericin B, fluconazole, itraconazole, ketoconazole, potassium iodide, flucytosine, caspofungin acetate, nystatin, and the like.
  • antifungal agents such as, but not limited to, amphotericin B, fluconazole, itraconazole, ketoconazole, potassium iodide, flucytosine, caspofungin acetate, nystatin, and the like.
  • a composition comprising a fungicide and/or antifungal compound of the invention may further comprise one or more anti-protozoan agents such as, but not limited to chloroquine, doxycycline, mefloquine, metronidazole, eplornithine, furazolidone, hydroxychloroquine, iodoquinol, pentamidine, mebendazole, piperazine, halofan trine, primaquine, pyrimethamine sulfadoxine, doxycycline, clindamycin, quinine sulfate, quinidine gluconate, quinine dihydrochloride, hydroxychloroquine sulfate, proguanil, quinine, clindamycin, atovaquone, azithromycin, suramin, melarsoprol, eflornithine, nifurtimox, amphotericin B, sodium stibogluconate, pent
  • a composition comprising a fungicide and/or antifungal compound of the invention may further comprise one or more anti-proliferative agents such as, but not limited to, altretamine, amifostine, anastrozole, arsenic trioxide, bexarotene, bleomycin, busulfan, capecitabine, carboplatin, carmustine, celecoxib, chlorambucil, cisplatin, cisplatin-epinephrine gel, cladribine, liposomal cytarabine, daunorubicin (same as daunomycin), liposomal daunoribin, dexrazoxane, docetaxel, doxorubicin, liposomal doxorubicin, epirubicin, estramustine, etoposide phosphate, etoposide VP- 16, exemestane, fludarabine, fluorouracil 5-FU, fulvestrant, gemicitabine,
  • combination therapies may also include a compound of this invention.
  • combination therapies described herein are merely exemplary and are not meant to limit possibilities for other combination treatments or co-administration regimens.
  • compositions according to the invention include those suitable for administration to an individual by any medically acceptable route including, but not limited to, parenteral, subcutaneous, intramuscular, intravenous, auricular (ear), ocular, intra-articular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary (e.g., by inhalation or insufflation), intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, oral, rectal, buccal, sublingual, intranasal, and transdermal.
  • the pharmaceutical compositions may, where appropriate, be conveniently presented
  • compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of a compound of the invention in a powder or granule form, in a solution, in a suspension, or as an emulsion.
  • a compound of the invention may also be presented as a bolus, electuary, or paste.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
  • the compounds according to the invention may also be formulated for parenteral administration (e.g., by injection as a bolus or by continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion, 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.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water or pharmaceutically acceptable buffer, prior to use.
  • a suitable vehicle e.g., sterile, pyrogen-free water or pharmaceutically acceptable buffer
  • fungicide and/or antifungal compounds according to the invention may be formulated as ointments, creams, gels, jellies, or lotions.
  • a compound of the invention may also be incorporated into a transdermal patch.
  • Such transdermal patches may contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol, t-anethole, and the like.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base comprising one or more 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.
  • compositions suitable for topical administration of a fungicide and/or antifungal compound of the invention in the mouth include lozenges comprising the compound, optionally, in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • compositions suitable for rectal administration wherein the carrier is a solid are presented as unit dose suppositories.
  • suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of a compound of the invention with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or sprays containing in addition to a compound of the invention such carriers as are known in the art to be appropriate.
  • the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops.
  • Drops may be formulated with an aqueous or nonaqueous base also comprising one more dispersing agents, solubilizing agents, or suspending agents.
  • Liquid sprays may conveniently be delivered from pressurized packs.
  • the compounds according to the invention may conveniently be delivered from an insufflator, nebulizer, a pressurized pack, or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example, a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges, or, for example, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • a fungicide and/or antifungal compound of the invention may also be formulated into a pharmaceutical composition for treating an eye or ear infection.
  • Pharmaceutical compositions comprising a fungicide and/or antifungal compound of the invention for treating an eye or ear disease may be a liquid or lotion, which may be administered directly into or on the infected eye or ear.
  • Such compositions may be formulated in a manner similar to any of those known and used to administer an antibiotic to an eye or ear, such as compositions comprising fluoroquinolones (see, e.g., Am. Fam. Physician, 62: 1870-1876 (2000), and references cited therein).
  • compositions may be adapted to give a sustained or time- delayed release of compound of the invention using any of the sustained or time-delayed formats available in art.
  • each compound may be either the same as or differ from that when the compound is used alone.
  • Appropriate doses will be readily appreciated by those skilled in the art.
  • the ratio between a compound of the present invention and a second therapeutic compound for co-administration to a patient will be readily appreciated by those skilled in the art. For example, one may use a ratio in the range from about 1 : 1 to about 1 :50 (by weight) of fungicide and/or antifungal compound of the invention: second therapeutic compound or, vice versa, i.e., of the second compound: fungicide and/or antifungal compound of the invention.
  • the ranges of ratios that may be used in preparing a composition for coadministration of an fungicide and/or antifungal compound of the invention with a second therapeutic compound include, without limitation: about 1 : 1 to about 1 :30 (by weight), about 1 : 1 to about 1: 20 (by weight), about 1: 1 to about 1 : 15 (by weight), about 1: 1 to about 1: 10 (by weight), about 1: 1 to about 1 :5 (by weight), and about 1 : 1 to about 1:3 (by weight) of a fungicide and/or antifungal compound of the invention: second therapeutic compound, or vice versa. If yet a further therapeutic compound(s) is added, ratios are adjusted accordingly.
  • An fungicide and/or antifungal compound of the invention may be provided and packaged in any of a variety of forms as described above, including in a powder or lyophilized state for reconstitution with sterile water or buffer, in unit doses for convenient administration, with one or more pharmaceutically acceptable buffers or salts, and/or with instructions for using the packaged compound as an antifungal to treat an infection by a fungal pathogen.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD 5 o/ED 5 o.
  • Fungicide and/or antifungal compounds that exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells of an individual and, thereby, reduce untoward side effects.
  • Data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC5 0 (i.e., the concentration of the test fungicide and/or antifungal compound that achieves a half-maximal inhibition of microbial growth).
  • IC5 0 i.e., the concentration of the test fungicide and/or antifungal compound that achieves a half-maximal inhibition of microbial growth.
  • levels in plasma may be measured, for example, by high performance liquid chromatography.
  • MIC Minimum inhibitory concentrations
  • the data in Table 1 show the organic compounds of the present invention are effective in inhibiting growth of a range of fungal cells.
  • Consideration of the foregoing data defined a new group of compounds of related structure that are useful as antifungal compounds, and particularly, inhibit growth of fungal cells, and may have further potency and/or toxicity profiles that make them candidates for use as therapeutic agents.
  • the new family of antimicrobial compounds can be described by the Formula I:
  • n 1 or 2;
  • X 1 is N or NR 8 ;
  • X 3 and X 5 are each independently NH, NR 8 , S, O, or S0 2 ,
  • X 4 , and X 6 are each independently N or CR ,
  • L is a direct bond or a linker which is ⁇ ⁇ where Z is an optionally substituted aryl, heteroaryl, carboxamide (-CONH- or -NHCO-), or alkyl radical;
  • L is a linker which is a direct bond or is ⁇ ⁇ where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, carboxamide (-CONH- or -NHCO-), aryl, or heteroaryl radical; and
  • R 1 , R 2 , R 3 , R 4 , R 6 and R 7 are each independently hydrogen, halo, amino, amidino, guanidino, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, amino, alkylamino, acylamino, amido, sulfonamido, mercapto, alkylthio, arylthio, hydroxamate, thioacyl, alkylsulfonyl, or aminosulfonyl; and
  • R 8 is hydrogen, OH, a halogen, or an optionally substituted alkyl; larmaceutically acceptable salts thereof.
  • the compounds identified above are candidates for development as antifungal compounds, and particularly, compounds which inhibit growth of fungal cells.

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Abstract

The invention provides fungicide and/or antifungal organic compounds and compositions thereof that kill or inhibit growth of cells of one or more microbial pathogens.

Description

ANTIFUNGAL COMPOUNDS
Cross-Reference to Priority Applications
This application claims priority to US Provisional Appln. No. 61/535,805 filed September 16,
2011.
Statement of Federally Sponsored Research
The invention described herein was supported by SBIR grant numbers 1 R42 AI083032 and Research Project Cooperative Agreement 1 U01 AI082052 from the National Institutes of Health, as well as Contract No. HDTRA1-06-C-0042 from the Department of Defense. The United States Government has certain rights in the invention.
Field of the Invention
This invention is in the field of antifungal compounds. In particular, the invention provides organic compounds that inhibit growth of fungal cells.
Background of the Invention
Fungal pathogens continue to pose a serious threat to public health and agriculture. One aspect of this resurgence appears to be the result of prior widespread, and largely effective, therapeutic and prophylactic use of fungicides, which, unfortunately, over time has also selected for resistant strains of various fungal pathogens. Of particular concern to the public health has been the emergence and proliferation of a wide variety fungal species responsible for a variety of severe, even fatal, diseases and fungal infections in humans, non-human animals, and plant populations throughout the world. Strains of such fungi species have also developed resistant to respective fungicide and antifungal agents. For example, prominent fungal pathogens include, but are not limited to, species of Candida, such as C. albicans, C. parapsilosis, C. tropicalis, C. krusei, C. glabrata, and C.
guillermondii; species of Aspergillus, such as A. fumgatus, A. niger, and A. flavus; species
Cryptococcus, such as C. neoformans, C. laurentii, C. albidus, and C. gatti; species of Histoplasma, such as H. capsulatum; and species of Pneumocystis, such as P. jiroveci. Fungal pathogens are of particular concern for immunocompromised individuals, such as patients of acquired
immunodeficiency syndrome (AIDS), radiation therapy, and chemotherapy.
Fungicides are compounds, of natural or synthetic origin, which act to protect plants against damage caused by fungi, including oomycetes. Current methods of agriculture rely heavily on the use of fungicides. In fact, some crops cannot be grown usefully without the use of fungicides. Using fungicides allows a grower to increase the yield of the crop and consequently, increase the value of the crop. Numerous fungicidal agents have been developed; however, the treatment of fungal infestations and infections continues to be a major problem. Losses of crops due to fungal diseases (e.g., rice blast disease caused by the plant-pathogenic fungus Magnaporthe grisea, also known as rice blast fungus) or food spoilage can have a large impact on human food supplies and local economies. For example, rice blast disease is widely distributed (85 countries) and can be very destructive when environmental conditions are favorable, with yield loss estimates from 1-50% around the world (Scardaci, S.C., et al. "Rice Blast: A New Diseases in California", University of California-Davis: Agronomy Fact Sheet Series (1997)
(http://www.plantsciences.ucdavis.edu/uccerice/afs/agfs0297.htm).
The prevalence and persistence of fungal pathogens, diseases, and infestations throughout the world along with the increasing reports of fungicide and antifungal resistant strains attest to the urgent need for new fungicide and antifungal agents.
Summary of the Invention
The invention addresses the above problem by providing methods of inhibiting growth of or killing cells of one or more species of fungi by administering one or more antifungal compounds described herein. An antifungal compound of the invention inhibits growth of or kills cells of one or more fungi species the compound is brought into contact with the fungal cells. Compounds of the invention are particularly useful in methods and compositions to inhibit growth of or kill cells of pathogenic fungi species (including opportunistic pathogenic species). A fungicide and/or antifungal compound described herein may be used to inhibit growth of or kill cells of a pathogenic microbial species by administration to an individual (human or other mammal), plant, or foodstuff that is susceptible to infection by or has been infected with cells of the fungal species. A fungicide and/or antifungal compound of the invention may also be applied to or incorporated into a liquid, solid, or semi-solid composition that is susceptible to or is already contaminated with cells of one or more pathogenic microbial species.
In one embodiment of the invention, a method is presented for inhibiting growth of or killing cells of one or more species of fungi comprising contacting the fungi with a compound disclosed herein.
In an embodiment of the invention, a fungicide and/or antifungal compound useful in the methods of the invention herein has the structure:
is
Figure imgf000003_0001
or
Figure imgf000004_0001
wherein:
n is 1 or 2;
X1 is N or NR8;
X3 and X5 are each independently NH, NR8, S, O, or S02,
X2, X4, and X6, are
wherein, when Y is
Figure imgf000004_0002
L is a direct bond or a linker which is < < where Z is an optionally substituted aryl, heteroaryl, carboxamide (-CONH- or -NHCO-), or alkyl radical;
and
wherein, when Y is
Figure imgf000004_0003
L is a linker which is a direct bond or is < < where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, carboxamide (-CONH- or -NHCO-), aryl, or heteroaryl radical; and
R1, R2, R3, R4, R6 and R7 are each independently hydrogen, halo, amino, amidino, guanidino, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, amino, alkylamino, acylamino, amido, sulfonamido, mercapto, alkylthio, arylthio, hydroxamate, thioacyl, alkylsulfonyl, or aminosulfonyl; and R8 is hydrogen, OH, a halogen, or an optionally substituted alkyl; or pharmaceutically acceptable salts thereof. In still another embodiment, a fungicide and/or antifungal compound of the invention has a structure:
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0003
Figure imgf000006_0004
Figure imgf000006_0005
Figure imgf000006_0006
Figure imgf000007_0001
Figure imgf000007_0002
Figure imgf000007_0003
Figure imgf000007_0004
Figure imgf000007_0005
Figure imgf000007_0006
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0003
Figure imgf000008_0004
Figure imgf000008_0005
Figure imgf000008_0006
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000011_0002
10
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000012_0003
Figure imgf000012_0004
Figure imgf000012_0005
Figure imgf000012_0006
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
Figure imgf000013_0004
 2055683
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0003
Figure imgf000014_0004
Figure imgf000014_0005
Figure imgf000014_0006
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0003
Figure imgf000015_0004
Figure imgf000015_0005
Figure imgf000015_0006
Figure imgf000016_0001
The compounds described herein are useful as fungicides and antifungal agents and may be used to treat fungal infections. Accordingly, an individual, plant, crop, or foodstuff infected with or exposed to fungal infection, may be treated by administering to the individual, plant, crop, or foodstuff in need thereof an effective amount of a compound according to the invention, e.g., administering one or more of the compounds of formula (I) described above.
The present invention also provides antifungal uses of pharmaceutical compositions containing one or more of the antifungal compounds disclosed herein and a pharmaceutically acceptable carrier or excipient. The use of one or more of the antifungal compounds in the preparation of a medicament for combating fungal infection is contemplated. In addition, antifungal compounds as disclosed herein have many non-pharmaceutical or agricultural uses, such as on surfaces (objects, countertops, floors, teeth, etc.) or added to solutions or mixtures (cleaning solutions, detergents, dentifrices, etc.), to inhibit fungal growth or eliminate infectious agents.
An antifungal compound or combination of compounds described herein may be used as a supporting or adjunctive therapy for the treatment of fungal infection in an individual (human or other animal). In the case of an individual with a healthy immune system, administration of an antifungal compound as described herein to inhibit the growth of microbes in or on an individual may be sufficient to permit the individual's own immune system to effectively clear or kill infecting or contaminating fungi from the tissue of the individual. Alternatively, an antifungal compound described herein may be administered to an individual in conjunction (i.e., in a mixture, sequentially, or simultaneously) with an antibacterial agent, such as an antibiotic, an antibody, or
immunostimulatory agent, to provide inhibition of microbial growth.
In yet another embodiment, a composition comprising an antifungal compound or a combination of antifungal compounds described herein may also comprise a second agent (second active ingredient, second active agent) that possesses a desired therapeutic or prophylactic activity other than that of the antifungal compound. Such a second active agent may include, but is not limited to, an antibiotic, an antibody, an antiviral agent, an anticancer agent, an analgesic (e.g., a nonsteroidal anti-inflammatory drug (NSAID), acetaminophen, an opioid, a COX-2 inhibitor), an immunostimulatory agent (e.g., a cytokine), a hormone (natural or synthetic), a central nervous system (CNS) stimulant, an antiemetic agent, an anti-histamine, an erythropoietin, a complement stimulating agent, a sedative, a muscle relaxant agent, an anesthetic agent, an anticonvulsive agent, an antidepressant, an antipsychotic agent, and combinations thereof.
Compositions comprising an anti- fungal compound described herein may be formulated for administration to an individual (human or other animal) by any of a variety of routes including, but not limited to, intravenous, intramuscular, subcutaneous, intra-arterial, parenteral, intraperitoneal, sublingual (under the tongue), buccal (cheek), oral (for swallowing), topical (epidermis), transdermal (absorption through skin and lower dermal layers to underlying vasculature), nasal (nasal mucosa), intrapulmonary (lungs), intrauterine, vaginal, intracervical, rectal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrarenal, nasojejunal, and intraduodenal.
Additionally, the invention provides pharmaceutically acceptable salts of the fungicide and/or antifungal compounds described herein, solvated forms of the fungicide and/or antifungal compounds described herein, multimeric forms of the fungicide and/or antifungal compounds described herein, and prodrugs of the compounds described herein. Detailed Description of the Invention
The invention is based on a discovery of a class of organic compounds, which when brought into contact of cells of one or more fungal species inhibit growth of or kill the cells of the one or more fungal species. Compounds of the invention are thus referred to as "fungicide and/or antifungal" compounds. Fungicide and/or antifungal compounds described herein are particularly useful in compositions and methods to kill or inhibit growth of cells of one or more pathogenic (including opportunistic pathogenic) fungi. Fungicide and/or antifungal compounds described herein may be used in compositions and methods to treat an individual (human or other mammal), plant, crop, or foodstuff that is infected with, at risk of infection by, or suspected of being infected with a fungal species. Fungicide and/or antifungal compounds described herein may also be used to treat or disinfect a liquid, solid, or semi-solid composition that is contaminated with or susceptible to contamination by cells of a fungal species.
In order that the invention may be more clearly understood, the following terms and abbreviations are used as defined below.
Unless indicated otherwise, when the terms "about" and "approximately" are used in combination with an amount, number, or value, then that combination describes the recited amount, number, or value alone as well as the amount, number, or value plus or minus 10% of that amount, number, or value. By way of example, the phrases "about 40%" and "approximately 40%" disclose both "40%" and "from 36% to 44%, inclusive".
"Halo" or "halogen" means fluorine, chlorine, bromine, or iodine.
"Alkyl" means a straight or branched chain monovalent or a divalent radical of saturated and/or unsaturated carbon atoms. Examples of an "alkyl" radical include, but are not limited to, methyl (abbreviated "Me"), ethyl ("Et"), propyl ("Pr"), isopropyl ("zPr"), butyl ("Bu"), isobutyl (";'Bu"), sec-butyl (sBu), ieri-butyl (iBu), and the like. An alkyl group may be unsubstituted or substituted by one or more suitable substituents found herein.
"Haloalkyl" means an alkyl radical that is substituted with one or more identical or different halogen atoms, e.g., -CH2C1, -CF3, -CH2CF3, -CH2CC13, and the like.
"Alkenyl" means a straight-chain, branched, or cyclic hydrocarbon radical that has from 2 to 8 carbon atoms (C2 - C8) and at least one double bond, e.g., ethenyl, 3-buten-l-yl, 3-hexen-l-yl, cyclopent-l-en-3-yl, and the like. An alkenyl group may be unsubstituted or substituted by one or more suitable substituents found herein.
"Alkynyl" means a straight-chain or branched hydrocarbon radical that has from 2 to 8 carbon atoms (C2 - C8) and at least one triple bond, e.g., ethynyl, 3-butyn-l-yl, 2-butyn-l-yl, 3-pentyn-l-yl, and the like. An alkynyl group may be unsubstituted or substituted with one or more suitable substituents found herein.
"Cycloalkyl" means a non-aromatic monovalent or divalent monocyclic or polycyclic radical that has 3 to 12 carbon atoms (C3 - Ci2), e.g., cyclopentyl, cyclohexyl, decalinyl, and the like. A cycloalkyl radical may be unsubstituted or may be substituted with one or more suitable substituents found herein. A cycloalkyl radical may also be fused to one or more aryl groups, heteroaryl groups, or heterocycloalkyl groups, which themselves may be unsubstituted or may be substituted with one or more suitable substituents found herein.
"Heterocycloalkyl" means a non-aromatic monovalent or divalent, monocyclic or polycyclic radical that has 2 to 12 carbon atoms (C2 - Ci2) and 1 to 5 heteroatoms selected from nitrogen (N), oxygen (O), or sulfur (S), e.g., pyrrolodinyl, tetrahydropyranyl, morpholinyl, piperazinyl, oxiranyl, and the like. A hetercycloalkyl radical may be unsubstituted or may be substituted with one or more suitable substituents found herein. A heterocycloalkyl radical may also be fused to one or more aryl groups, heteroaryl groups, or heterocycloalkyl groups, which themselves may be unsubstituted or substituted with one or more suitable substituents found herein.
"Aryl" (abbreviated "Ar") means an aromatic monovalent or divalent monocyclic or polycyclic radical comprising between 6 and 18 carbon ring members, e.g., phenyl, biphenyl, naphthyl, phenanthryl, and the like. An aryl radical may be unsubstituted or substituted with one or more of the suitable substituents found herein. An aryl radical may also be fused to one or more heteroaryl groups or heterocycloalkyl groups, which themselves may be unsubstituted or substituted with one or more suitable substituents found herein.
"Heteroaryl" (abbreviated "HAr") means an aromatic monovalent or divalent monocyclic or polycyclic radical comprising between 2 and 18 carbon ring members and at least 1 heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), e.g., pyridyl, pyrazinyl, pyridizinyl, pyrimidinyl, furanyl, thienyl, triazolyl, quinolinyl, imidazolinyl, benzimidazolinyl, indolyl, and the like. A heteroaryl radical may be unsubstituted or may be substituted with one or more of the suitable substituents found herein. A heteroaryl radical may also be fused to one or more aryl groups, heteroaryl groups, or heterocycloalkyl groups, which themselves may be unsubstituted or may be substituted with one or more suitable substituents found herein.
"Hydroxy" means the radical -OH.
"Alkoxy" means the radical -OR, wherein R is an alkyl or cycloalkyl group.
"Aryloxy" means the radical -OAr, wherein Ar is an aryl group.
"Heteroaryloxy" means the radical -O(HAr), where HAr is a heteroaryl group
"Acyl" means a -C(0)R radical, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, e.g. acetyl, benzoyl, and the like.
"Carboxy" means the radical -C(0)OH.
"Alkoxycarbonyl" means a -C(0)OR radical where R is alkyl, alkenyl, alkynyl, or cycloalkyl.
"Aryloxycarbonyl" means a -C(0)OR radical where R is aryl or heteroaryl.
"Amino" means the radical -NH2.
"substituted amino" means the radical -NRR', wherein R and R' are, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
"Acylamino" means the radical -NHC(0)R, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, e.g., acetyl, benzoyl, acetylamino, benzoylamino, and the like.
"Amido" means the radical -C(0)NRR', wherein R and R' are, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
"Sulfonylamino" means the radical -NHS02R, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
"Amidino" means the radical -C(NR)NR'R", wherein R, R', and R" are, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, and wherein R, R', and R" may form heterocycloalkyl rings, e.g. carboxamido, imidazolinyl, tetrahydropyrimidinyl.
"Guanidino" means the radical -NHC(NR)NR'R", wherein R, R', and R" are, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, and wherein R, R', and R" may form heterocycloalkyl rings.
"Mercapto" means the radical -SH.
"Alkylthio" means the radical -SR, wherein R is an alkyl or cycloalkyl group.
"Arylthio" means the radical -SAr, wherein Ar is an aryl group.
"Hydroxamate" means the radical -C(0)NHOR, whereub R is an alkyl or cycloalkyl group.
"Thioacyl" means a -C(S)R radical, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
"Alkylsulfonyl" means the radical -S02R, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
"Aminosulfonyl" means the radical -S02NRR', wherein R and R' are, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. A "leaving group" (Lv) means any suitable group that will be displaced by a substitution reaction. One of ordinary skill in the art will know that any conjugate base of a strong acid can act as a leaving group. Illustrative examples of suitable leaving groups include, but are not limited to, -F, - CI, -Br, alkyl chlorides, alkyl bromides, alkyl iodides, alkyl sulfonates, alkyl benzenesulfonates, alkyl p-toluene-sulfonates, alkyl methanesulfonates, triflate, and any groups having a bisulfate, methyl sulfate, or sulfonate ion.
A "protecting group" refers to a group that protects one or more inherent functional group from premature reaction. Suitable protecting groups may be routinely selected by those skilled in the art in light of the functionality and particular chemistry used to construct the compound. Examples of suitable protecting groups are described, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 3d edition, John Wiley and Sons, New York, N.Y. (1999).
The term "suitable organic moiety" means any organic moiety recognizable, such as by routine testing, to those skilled in the art as not adversely affecting the fungicide and/or antifungal activity of compounds described herein. Illustrative examples of suitable organic moieties include, but are not limited to, hydroxyl groups, alkyl groups, oxo groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxyl groups, carboxyl groups, amino groups, substituted amino groups, disubstituted amino groups, carbamoyl groups, arylthio groups, heteroarylthio groups, and the like.
In general, the various moieties or functional groups for variables in the structural formulas of compounds of the invention may be "optionally substituted" by one or more suitable "substituents".
The term "substituent" or "suitable substituent" means any suitable substituent that may be recognized or selected, such as through routine testing, by those skilled in the art. Illustrative examples of useful substituents are those found in the exemplary compounds that described herein, as well as a halogen; Ci_6-alkyl; Ci_6-alkenyl; Ci_6-alkynyl; hydroxyl; Ci_6 alkoxyl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; carbonyl; aminocarbonyl; thiocarbonyl; sulfonyl; sulfonamine; sulfonamide; ketone; aldehyde; ester; oxygen (=0); haloalkyl (e.g., trifluoro methyl); carbocyclic cycloalkyl, which may be monocyclic or fused or non-fused polycyclic alkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or a heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl,
pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); nitro; thiol; thioether, O-lower alkyl (alkoxyl); O-aryl (aryloxy), aryl; aryl-lower alkyl; C02CH3; CONH2; OCH2CONH2; NH2; S02NH2; OCHF2; CF3; OCF3; and the like. Such moieties may also be optionally substituted by a fused-ring structure or bridge, for example OCH2-0. All of these substituents may optionally be further substituted with a substituent selected from groups such as hydroxyl groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxyl groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxyl groups, amino groups, substitued amino groups, disubstitued amino groups, carbamoyl groups, aryloxyl groups, heteroaryloxyl groups, arylthio groups, heteroarylthio groups, and the like.
The term "optionally substituted" is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the
specified substituents. As defined above, various groups may be unsubstituted or substituted (i.e., they are optionally substituted) unless indicated otherwise herein (e.g., by indicating that the specified group is unsubstituted).
It is understood that the structure of a fungicide and/or antifungal compound described herein includes solvated forms of the compound. Examples of solvated forms of a fungicide and/or antifungal compound of the invention include, but are not limited to, the fungicide and/or antifungal compound in combination with a solvent selected from water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, and acetone.
It is understood that while a compound of the general structural formulas herein may exhibit the phenomenon of tautomerism, the structural formulas within this specification expressly depict only one of the possible tautomeric forms. It is therefore to be understood that the structural formulas herein are
intended to represent any tautomeric form of the depicted compound and is not to be limited merely to a specific compound form depicted by the structural formulas.
It is also understood that the structural formulas are intended to represent any configurational form of the depicted compound and is not to be limited merely to a specific compound form depicted by the structural formulas.
Some of the compounds of the present invention may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, or mixtures of enantiomers, diastereomers, or both when they contain one or more stereogenic centers as designated by R or S according to the Cahn- Ingold-Prelog rules whether the absolute or relative configuration is known. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.
Some of the compounds in the present invention may exist as geometric isomers as the result of containing a stereogenic double bond. In such cases, they may exist either as pure or mixtures of cis or trans geometric isomers or (E) and (Z) designated forms according to the Cahn-Ingold-Prelog rules and include compounds that adopt a double bond configuration as a result of electronic derealization.
As generally understood by those skilled in the art, an optically pure compound having one or more chiral centers (i.e., one asymmetric atom producing unique tetrahedral configuration) is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. If the compounds of the present invention are made synthetically, they may be used in a form that is at least 90% optically pure, that is, a form that comprises at least 90% of a single isomer (80% enantiomeric excess (e.e.) or diastereomeric excess (d.e.), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
As noted above, fungicide and/or antifungal compounds of the invention include active tautomeric and stereoisomeric forms of the compounds of the present invention, which may be readily obtained using techniques known in the art. For example, optically active (R) and (S) isomers may be prepared via a stereospecific synthesis, e.g., using chiral synthons and chiral reagents, or racemic mixtures may be resolved using conventional techniques.
If a compound of the present invention is a base, the desired salt of the compound may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid or with an organic acid along with appropriate counter ion. Inorganic acids that may be used to form salts of compounds of the invention include, but art not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids that may be used to form salts of compounds of the invention include, but are not limited to, acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyrvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid (such as glucuronic acid or galacturonic acid), an alpha-hydroxy acid (such as citric acid or tartaric acid), an amino acid (such as aspartic acid or glutamic acid), an aromatic acid (such as benzoic acid or cinnamic acid), and a sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid).
If a compound of the present invention is an acid, then the desired salt form may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base and appropriate counter ion(s). Examples of bases that may be used to form salts of compounds of the invention include, but are not limited to, amines (primary, secondary or tertiary), an alkali metal hydroxide, and an alkaline earth metal hydroxide. Illustrative examples of suitable salts of compounds of the invention include, but are not limited to, organic salts derived from basic amino acids (such as lysine and arginine, ammonia, primary, secondary, and tertiary amines) and from cyclic amines (such as piperidine, morpholine and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
Salts of fungicide and/or antifungal compounds of the invention include pharmaceutically acceptable salts of the compound. By the term "pharmaceutically acceptable salts of the compound" as understood and used herein, is meant those salts of any fungicide and/or antifungal compound of the invention derived from an inorganic or organic acid or base recognized in the art as compatible for pharmaceutical compositions. For convenience, the terms "pharmaceutical" and "pharmaceutically acceptable" also are understood to encompass compounds acceptable for the practice of veterinary medicine as well. It is understood that pharmaceutically acceptable salts of the fungicide and/or antifungal compounds described herein are not limited to only pharmaceutical uses. Examples of suitable acids for pharmaceutically acceptable salts of fungicide and/or antifungal compounds of the invention include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, hydroxymaleic acid, malonic acid, glutamic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, 2-acetoxybenzoic acid, acetic acid, phenylacetic acid, propionic acid, glycolic acid, stearic acid, tartaric acid, acetic acid, methanesulfonic acid, formic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, ethane- disulfonic acid, and sulfanilic acid. Salts of other acids, such as oxalic acid or isethionic acid, may not be pharmaceutically acceptable, but may find use in a variety of compositions and methods that are used to provide the benefit of the fungicide and/or antifungal activity of a compound of the invention to a solution, semi-solid, or solid composition that is not a pharmaceutical composition. Salts derived from appropriate bases include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium and NR4+ (where R is a Ci .4 alkyl) salts, and the like.
Reference, hereinafter, to a compound according to the invention (or an equivalent term) is understood to include any and all corresponding salts, including pharmaceutically acceptable salts, thereof.
The term "multimer" refers to multivalent or multimeric forms of fungicide and/or antifungal compounds of the invention. Such "multimers" may be made by linking or placing multiple copies of an active (i.e., possessing fungicide and/or antifungal activity) compound described herein in close proximity to each other, e.g., using a scaffolding provided by a carrier moiety. Multimers of various dimensions (i.e., bearing varying numbers of copies of an active compound) may be tested to arrive at a multimer of optimum size with respect to binding site interactions. Provision of such multivalent forms of active compounds with optimal spacing between the binding site moieties may enhance binding site interactions. See, e.g., Lee et al., Biochem., 23: 4255 (1984). The artisan may control the multivalency and spacing by selection of a suitable carrier moiety or linker units. Useful moieties include molecular supports comprising a multiplicity of functional groups that can be reacted with functional groups associated with the active compounds of the invention. A variety of carrier moieties may be used to build highly active multimers including, but not limited to, proteins such as bovine serum albumin (BSA); peptides such as pentapeptides, decapeptides, pentadecapeptides, and the like; and non-biological compounds selected for their beneficial effects on absorbability, transport, or persistence within or on a target microbial cell. Functional groups on the carrier moiety, such as amino, sulfhydryl, hydroxyl, and substituted amino groups, may be selected to obtain stable linkages to the compounds of the invention, optimal spacing between the immobilized compounds, and optimal biological properties.
By "pharmaceutically acceptable" is meant any compound or mixture that is not biologically, chemically, or in any other way, incompatible with body chemistry and metabolism and also does not adversely affect the desired, effective fungicide and/or antifungal activity of a compound of the invention or any other component of a composition comprising an fungicide and/or antifungal compound described herein that may be administered to an individual to effectively kill or inhibit growth of cells of a microbial pathogen infecting an individual.
The terms "oral", "orally", enteral", "enterally", "non-parenteral", "non-parenterally", and the like, refer to a route or mode for administering an effective amount of an fungicide and/or antifungal compound described herein, or composition thereof, to an individual anywhere along the alimentary canal of the individual. Examples of such "enteral" routes of administration include, without, limitation, from the mouth, e.g., swallowing a solid (e.g., pill, tablet, capsule) or liquid (e.g., syrup, elixir) composition; nasojejunal or gastrostomy tubes (into the stomach); intraduodenal
administration; and rectal (e.g., using suppositories for release and absorption of a compound or composition in the lower intestinal tract of the alimentary canal). One or more enteral routes of administration may be employed in the invention. Thus, unless a particular type of "oral" formulation described herein is specified or indicated by the context, "oral" formulations are the same as "enteral" formulations and broadly encompass formulations that may be swallowed from the mouth as well as those that permit administration of an fungicide and/or antifungal compound of the invention anywhere along the alimentary canal. For the purposes of this discussion, sub-lingual (absorption under the tongue) and buccal (absorption through the inner cheek) administration of a anit-microbial compound of the invention may also be considered oral routes of administration.
The terms "parenteral" and "parenterally" refer to routes or modes of administration of an fungicide and/or antifungal compound of the invention, or composition thereof, to an individual other than along the alimentary canal. Examples of parenteral routes of administration include, without limitation, intravenous (i.v.), intramuscular (i.m.), intra-arterial (i.a.), intraperitoneal (i.p.), subcutaneous (s.c), transdermal (absorption through the skin or dermal layer), nasal or pulmonary (e.g., via inhalation or nebulization, for absorption through the respiratory mucosa or lungs), intraarticular (i.a.), direct injections or infusions into body cavities or organs, as well as by implantation of any of a variety of devices into the body that permit active or passive release into the body of an individual of an fungicide and/or antifungal compound described herein.
A "pharmaceutically acceptable prodrug" is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a salt of such compound, or a compound that is biologically active with respect to an intended pharmacodynamic effect. A "pharmaceutically active metabolite" means a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med. Chem., 40: 2011-2016 (1997); Shan et al., /. Pharm. Set, 86(7):765-767 (1997); Bagshawe, Drug Dev. Res., 34: 220-230 (1995); Bodor, Advances in Drug Res., 13: 224-331 (1984); Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).
In the case where a fungicide and/or antifungal compound of the invention is present in a solid form, it is understood by those skilled in the art that the compound and salts thereof may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified structural formulas.
The terms "patient" and "individual" are synonymous, unless noted otherwise, and mean any mammal, including without limitation, a human, who receives or may be a candidate to receive an fungicide and/or antifungal compound described herein or composition thereof. Thus, as used herein, a "patient" may or may not present a recognizable symptom of a microbial disease, but merely be at risk for infection by cells of a pathogenic microbial species that may cause a disease, e.g., due to exposure to a source of cells of the microbial pathogen.
As provided herein, an "effective amount" is intended to mean that amount of a compound that is sufficient to reduce, prevent or inhibit fungal growth as compared with a negative control. A "therapeutically effective amount" of a fungicide and/or antifungal compound of the present invention, or of a prodrug, an active metabolite, or a salt thereof, is a quantity sufficient to, when administered to an individual to kill or inhibit growth of cells of a microbial pathogen. Also, as used herein, a "therapeutically effective amount" of a compound of the present invention is an amount which prevents, inhibits, suppresses, or reduces a given clinical condition or disease symptom in an individual as known and understood by a skilled healthcare provider or as compared to a control, such as an individual that is not infected with a microbial pathogen. As defined herein, a therapeutically effective amount of a compound of the present invention may be readily determined by one of ordinary skill by routine methods known in the art.
"Therapy" and "therapeutic" as understood and used herein refer to treatment of a patient for a microbial infection or disease due to the microbial infection. For convenience, the terms are also understood to encompass prophylactic or precautionary use or administration of a compound of the invention. Such precautionary or prophylactic use is exemplified by administration of an antibiotic to an immunocompromised or immunodeficient patient to protect the patient from an infection; to a patient suspected, but not proven, of having a microbial infection; or to a patient that is susceptible to contracting a disease caused by infection of cells of a pathogenic species, for example, at open wounds; by contact with water, food, body fluids, corpses, or carcasses contaminated with cells of a pathoogenic microbial species; or by contact with infected individuals or body fluids of infected individuals containing cells of a pathogenic microbial species.
In the context of therapeutic use of the fungicide and/or antifungal compound compounds described herein, the terms "treatment", "to treat", or "treating" will refer to any use of the fungicide and/or antifungal compound calculated or intended to arrest or inhibit the growth of or kill cells of a fungal species. Thus, treating an individual may be carried out after any diagnosis indicating possible fungal, i.e., whether an infection by a particular microbe has been confirmed or whether the possibility of infection is only suspected, for example, after exposure to the microbe or to another individual infected by the microbe.
A composition or method described herein as "comprising" one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method. To avoid prolixity, it is also understood that any composition or method described as "comprising" (or which "comprises") one or more named elements or steps also describes the corresponding, more limited composition or method "consisting essentially of" (or which "consists essentially of") the same named elements or steps, meaning that the composition or method includes the named essential elements or steps and may also include additional elements or steps that do not materially affect the basic and novel characteristic(s) of the composition or method. It is also understood that any composition or method described herein as "comprising" or "consisting essentially of" one or more named elements or steps also describes the corresponding, more limited, and closed-ended composition or method "consisting of" (or "consists of") the named elements or steps to the exclusion of any other unnamed element or step. In any composition or method disclosed herein, known or disclosed equivalents of any named essential element or step may be substituted for that element or step.
It is also understood that an element or step "selected from the group consisting of" or otherwise recited in a list of elements or steps refers to one or more of the elements or steps in the list that follows, including combinations of any two or more of the listed elements or steps, unless otherwise stated.
The meaning of other terms will be understood by the context as understood by the skilled practitioner in the art, including the fields of organic chemistry, pharmacology, pharmaceuticals, and microbiology.
An fungicide and/or antifungal compound of the invention has the following structure:
Figure imgf000026_0001
where Y is
Figure imgf000027_0001
wherein:
n is 1 or 2;
X1 is N or NR8;
X3 and X5 are each independently NH, NR8, S, O, or S02,
X2, X4, and X6, are
wherein^ when Y is
Figure imgf000027_0002
L is a direct bond or a linker which is < < where Z is an optionally substituted aryl, heteroaryl, carboxamide (-CONH- or -NHCO-), or alkyl radical;
and
wherein., when Y is
Figure imgf000027_0003
L is a linker which is a direct bond or is < < where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, carboxamide (-CONH- or -NHCO-), aryl, or heteroaryl radical; and
R1, R2, R3, R4, R6 and R7 are each independently hydrogen, halo, amino, amidino, guanidino, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, amino, alkylamino, acylamino, amido, sulfonamido, mercapto, alkylthio, arylthio, hydroxamate, thioacyl, alkylsulfonyl, or aminosulfonyl; and
R8 is hydrogen, OH, a halogen, or an optionally substituted alkyl; or pharmaceutically acceptable salts thereof.
Additionally preferred fungicide and/or antifungal compounds of the invention have a structure:
Figure imgf000028_0001
Figure imgf000028_0002
Figure imgf000028_0003
Figure imgf000029_0001
Figure imgf000029_0002
Figure imgf000029_0003
Figure imgf000029_0004
Figure imgf000029_0005
Figure imgf000029_0006

Figure imgf000030_0001
Figure imgf000030_0002
Figure imgf000030_0003
Figure imgf000030_0004
Figure imgf000030_0005

Figure imgf000031_0001
Figure imgf000031_0002
Figure imgf000031_0003
Figure imgf000031_0004
Figure imgf000031_0005
Figure imgf000031_0006
30
Figure imgf000032_0001
Figure imgf000032_0002
Figure imgf000032_0003
Figure imgf000032_0004
Figure imgf000032_0005
31
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000033_0003
Figure imgf000033_0004
Figure imgf000033_0005
32
Figure imgf000034_0001
33
Figure imgf000035_0001
Figure imgf000035_0002
Figure imgf000035_0003
Figure imgf000035_0004
Figure imgf000035_0005
Figure imgf000036_0001
Figure imgf000036_0002
Figure imgf000036_0003
Figure imgf000036_0004

Figure imgf000037_0001
Figure imgf000037_0002
Figure imgf000037_0003
Figure imgf000037_0004
Figure imgf000037_0005
Figure imgf000037_0006

Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000038_0003
Figure imgf000038_0004
Figure imgf000038_0005
Figure imgf000038_0006
Figure imgf000039_0001
Figure imgf000039_0002
Synthesis of Compounds
Compounds described herein may be synthesized using established chemistries, and suitable synthesis schemes for the compounds include the following:
Synthesis of 2,5-bisr6-(4,5-dihydro-lj -imidazol-2-yl)indol-2-yl1furan trifluoroacetic acid salt (MBX 1195)
Figure imgf000039_0003
2,5-bis(4-cyano-2-nitrostyryl)furan
Furan-2,5-dicarboxaldehyde (197 mg, 1.6 mmol) and 4-cyano-2-nitrotoluene (600 mg, 3.7 mmol) were dissolved in sulfolane (1 mL) to which was added piperidine (200 μΐ^, 2.0 mmol). The mixture was heated to 150 °C in a sealed tube for 30 minutes, producing a dark suspension. The reaction was cooled, and MeOH (5 mL) was added, followed by Et20 (5 mL). The solids were filtered, rinsed with Et20, and dried to yield 417 mg (64%) of 2,5-bis(4-cyano-2-nitrostyryl)furan as a brown powder 'H-NMR (DMSO) δ 8.55 (s, 2H), 8.18 (q, 4H), 7.54 (d, 2H), 7.36 (d, 2H), 6.95 (s, 2H).
Figure imgf000039_0004
2,5-bis(6-cyanoindol-2-yl)furan
2,5-bis(4-cyano-2-nitrostyryl)furan (390 mg, 0.95 mmol) was suspended in triethyl phosphite (15 mL) and heated to gentle reflux over a 170 °C oil bath for 16 hours. The excess phosphite was removed under vacuum, and the resulting dark residue was adsorbed onto silica gel (100 mL) by evaporation from CH2C12. The product was eluted from the silica gel with 8: 1 acetone:EtOAc until no more product was obtained. The filtrate was evaporated, and the residue was recrystallized from boiling CH3CN/acetone to yield 121 mg (37%) of 2,5-bis(6-cyanoindol-2-yl)furan as an orange-brown solid. 'H-NMR (DMSO) δ 12.24 (s, 2H), 8.88 (s, 2H), 7.75 (d, 2H), 7.38 (d, 2H), 7.21 (s, 2h), 7.05 (s, 2H); mp >300 °C; Rf 0.43 (1: 1 hex:EtOAc).
Figure imgf000040_0001
2,5-bis[6-(4,5-dihydro-li7-imidazol-2-yl)indol-2-yl]furan trifluoroacetic acid salt (MBX 1195)
To a solution of 2,5-bis(6-cyanoindol-2-yl)furan (96 mg, 0.28 mmol) in ethylenediamine (2 mL) was added phosphorous pentasulfide (12 mg, 0.05 mmol). The mixture was heated in a sealed tube at 120 °C for 3 h, then cooled to room temperature and poured into water (50 mL). The resulting solid was rinsed with water (50 mL) and dried under vacuum. The solids thus obtained were complete dissolved in trifluoroacetic acid (2 mL) with gentle warming. The yellow solution was diluted with MeOH (2 mL), then poured into Et20 (20 mL). The resulting yellow precipitate was filtered and dried under vacuum to constant weight to provide 163 mg (95%) of 2,5-bis[6-(4,5-dihydro-l/i- imidazol-2-yl)indol-2-yl]furan trifluoroacetic acid salt (MBX 1195) as a yellow powder
¾-NMR (DMSO) δ 12. 43 (s, 2H), 10.43 (s, 4H), 8.06 (s, 2H), 7.82 (d, 2H), 7.59 (dd, 2H), 7.28 (s, 2H), 7.09 (d, 2H), 4.03 (s, 8H); mp dec >220 °C.
Synthesis of 2,5-bisr6-(4,5-dihvdro-lj -imidazol-2-yl)indol-2-yl1thiophene trifluoroacetic acid salt (MBX 1196) piperidine
NC 'NO, OHC CHO
Figure imgf000041_0001
2,5-bis(4-cyano-2-nitrostyr l)thiophene
Thiophene-2,5-dicarboxaldehyde (700 mg, 5.0 mmol) and 4-cyano-2-nitrotoluene (1.65 g, 5.0 mmol) were dissolved in sulfolane (2 mL) to which was added piperidine (250 pL, 2.5 mmol). The mixture was heated to 150 °C in a sealed tube for 30 minutes, producing a dark suspension. The reaction was cooled, and MeOH (50 mL) was added. The solids were triturated with 1: 1 MeOH:Et20 (50 mL), filtered, rinsed with Et20, and dried to yield 1.76 g (82%) of 2,5-bis(4-cyano-2-nitrostyryl)thiophene as a brown powder. Material is too insoluble for ^-NMR evaluation.
Figure imgf000041_0002
2,5-bis(6-cyanoindol-2-yl)thiophene
2,5-bis(4-cyano-2-nitrostyryl)thiophene (1.76 g, 4.1 mmol) was suspended in triethyl phosphite (50 mL) and heated to gentle reflux over a 170 °C oil bath for 16 hours. The excess phosphite was removed under vacuum, and the resulting dark residue was adsorbed onto silica gel (200 mL) by evaporation from CH2C12. The product was placed onto additional clean silica gel (100 mL), and eluted from the silica gel with 4: 1 acetone :EtO Ac until no more product was obtained. The filtrate was evaporated, and the residue was recrystallized from boiling CH3CN/acetone to yield 397 mg (26%) of 2,5-bis(6-cyanoindol-2-yl)thiophene as an orange -brown solid.
'H-NMR (DMSO) δ 12.28 (s, 2H), 7.84 (s, 2h), 7.71 (d, 2H), 7.70 (s, 2H), 7.36 (d, 2H), 6.93 (s, 2h); mp >300 °C; Rf 0.42 (1: 1 hex:EtOAc).
Figure imgf000041_0003
2,5-bis[6-(4,5-dihydro-l/ -imidazol-2-yl)indol-2-yl]thiophene trifluoroacetic acid salt (MBX 1195)
To a solution of 2,5-bis(6-cyanoindol-2-yl)thiophene (100 mg, 0.27 mmol) in ethylenediamine (2 mL) was added phosphorous pentasulfide (12 mg, 0.05 mmol). The mixture was heated in a sealed tube at 120 °C for 4 hours, then cooled to room temperature and poured into water (50 mL). The resulting solid was rinsed with water (50 mL) and dried under vacuum. The solids thus obtained were complete dissolved in trifluoroacetic acid (2.5 mL) with gentle warming. The yellow solution was diluted with MeOH (2.5 mL), then poured into Et20 (40 mL). The resulting yellow precipitate was filtered and dried under vacuum to constant weight to provide 173 mg (95%) of 2,5-bis[6-(4,5- dihydro-l/i-imidazol-2-yl)indol-2-yl]thiophene trifluoroacetic acid salt (MBX 1195) as a yellow- orange powder
'H-NMR (DMSO) δ 12.48 (s, 2H), 10.42 (s, 4H), 8.04 (s, 2H), 7.78 (d, 2H), 7.77 (s, 2H), 7.57 (d, 2H), 6.96 (s, 2H), 4.03 (s, 8H); mp >300 °C. Synthesis of 2,5-bisr6-(3,4,5,6-tetrahvdropyrimidin-2-yl)indol-2-yl1thiophene acetic acid salt
(MBX 1634)
Figure imgf000042_0001
2,5-bis[6-(3,4,5,6-tetrahydropyrimidin-2-yl)indol-2-yl]thiophene acetic acid salt (MBX 1634)
To a solution of 2,5-bis(6-cyanoindol-2-yl)thiophene (0.57 g, 1.6 mmol) in ethylenediamine (10 mL) was added phosphorous pentasulfide (120 mg, 0.6 mmol) and 2 drops of H20. The mixture was heated in a sealed tube at 120 °C for 2 hours, then cooled to room temperature and poured into water (200 mL), and refrigerated overnight. The resulting solids were filtered, rinsed with water (50 mL), and dried under vacuum. The solids thus obtained were dissolved in acetic acid (5 mL) with gentle warming, and remaining insoluble matter was removed by filtration through Celite. The yellow solution was diluted with MeOH (10 mL), then poured into Et20 (150 mL). The resulting yellow precipitate was filtered and dried under vacuum to constant weight to provide 0.38 g (34%) of 2,5- bis[6-(3,4,5,6-tetrahydropyrimidin-2-yl)indol-2-yl]thiophene acetic acid salt (MBX 1634) as a yellow- orange powder
¾-NMR (DMSO/D20) δ 7.89 (s, 2H), 7.77 (d, 4H), 7.34 (d, 2H), 6.90 (s, 2H), 3.51 (s, br, 8H), 1.98 (s, 4H), 1.77 (s, 12 H). Synthesis of 2,5-bisr6-(3,4,5,6-tetrahvdropyrimidin-2-yl)indol-2-yl1pyridine acetic acid salt
(MBX 1643)
Figure imgf000043_0001
N-Boc-6-cyano-2-(5-bromopyridin-2-yl)indole
To a suspension of Ar-Boc-6-cyano-indole-2-boronic acid (5.06 g, 17.67 mmol) in 10% EtOH/toluene (40 mL) in a round bottom flask fitted with a condenser was added Pd(PPh3)4 (510 mg, 0.44 mmol) under a slow stream of Ar. After stirring for a few minutes, a solution of 2-bromo-5-iodo pyridine (5.50 g, 19.44 mmol) in 10% EtOH/toluene (10 mL) was added, followed by a 2 M aqueous solution of Na2C03 (17.7 mL, 35.4 mmol). The resulting brown mixture was brought to reflux in a preheated oil bath and stirred for 3 h. After cooling, the dark brown mostly homogeneous solution was extracted with EtOAc over Na2C03 solution (5% aq). The combined organic solution was washed with water (50 mL) and brine (30 mL), dried over MgS04, filtered and evaporated to a fourth of the original volume. The solid that formed was collected by filtration, washed with 20% EtOAc in Hexanes (100 mL) and ether (100 mL) to yield 0.99 g of a cream-colored solid. The filtrate was evaporated, treated with di-i-butyl dicarbonate in pyridine at 60°C followed by acidic work-up, then subjected to column chromatography on silica gel (0-25% EtOAc/hexane) to yield 280 mg of additional crude product. The combined crude products were recrystallized from boiling
EtOAc/hexane to yield to yield 826 mg (12%) of Ar-Boc-6-cyano-2-(5-bromopyridin-2-yl)indole as a cream-colored solid.
¾-NMR (300 MHz, 6-DMSO): δ 8.58 (s, 1H), 8.49 (s, 1H), 7.96 (dd, 1H), 7.86 (d, 1H), 7.79 (d, 1H), 7.69 (dd, 1H), 7.03 (s, 1), 1.35 (s, 9H).
Figure imgf000043_0002
2,5-Bis(N-Boc-6-cyanoindol-2-yl)pyridine
A solution of Ar-Boc-6-cyano-2-(5-bromopyridin-2-yl)indole (401 mg, 1.0 mmol), N-Boc-6- cyanoindole-2-boronic acid (301 mg, 1.0 mmol), and Pd(PPh3)4 (15 mg) in 10% EtOH/toluene (12 mL) is sparged with argon gas for 10 minutes, then a 2.0 M aqueous solution of sodium carbonate (1.0 mL, 2.0 mmol) is added. The reaction is heated to 100 °C in a sealed tube for 1 hour, then cooled to room temperature and diluted with EtOAc (50 mL) and brine (50 mL). The organic layer is separated, dried over MgS04, filtered, and evaporated to yield an orange oil which is subjected to flash chromatography on silica gel with 2: 1 hex:EtOAc. Product-containing fractions were pooled and evaporated to yield a yellow solid that was recrystallized from boiling CH2Cl2 hexane to yield 228 mg (41 ) of 2,5-Bis(ALBoc-6-cyanoindol-2-yl)pyridine as a crystalline yellow solid.
'H-NMR (300 MHz, CDC13): δ 8.76 (d, 1H), 8.56 (s, 1H), 8.51 (s, 1H), 7.86 (dd, 1H), 7.70-7.61 (m, 3H), 7.56-7.51 (m, 2H), 6.88 (s, 1H), 6.74 (s, lh), 1.48 (s, 9H), 1.45 (s, 9H); mp >300 °C; Rf 0.17 (3: 1 hex:EOAc)
Figure imgf000044_0001
2,5-bis(6-cyanoindol-2-yl)pyridine
2,5-Bis(ALBoc-6-cyanoindol-2-yl)pyridine (220 mg, 0.39 mmol) is heated (dry) to 200 °C in a small flask for 30 min. The remaining solid is collected to provide 141 mg (100%) of 2,5-bis(6-cyanoindol- 2-yl)pyridine as a yellow powder.
'H-NMR (DMSO/D20) δ 12.36 (s, 1H), 12.32 (s, 1H), 9.26 (d, 1H), 8.43 (dd, 1H), 8.23 (d, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.79 (d, 1H), 7.77 (d, 1H), 7.41-7.33 (m, 4H); mp >300 °C; Rf 0.48 (5% MeOH/CHCl3).
Figure imgf000044_0002
2,5-bis[6-(3,4,5,6-tetrahydropyrimidin-2-yl)indol-2-yl]pyridine acetic acid salt (MBX 1643)
To a solution of 2,5-bis(6-cyanoindol-2-yl)pyridine (130 mg, 0.36 mmol) in 1,3-diaminopropane (10 mL) was added phosphorous pentasulfide (45 mg, 0.26 mmol) and 2 drops of H20. The mixture was heated in a sealed tube at 120 °C for 2 hours, then cooled to room temperature and poured into water (200 mL), and refrigerated overnight. The resulting solids were filtered, rinsed with water (50 mL), and dried under vacuum. The solids thus obtained were dissolved in boiling acetic acid (8 mL), then cooled to room temperature and filtered through Celite. The yellow solution was diluted with MeOH (4 mL), then poured into Et20 (100 mL). The resulting yellow precipitate was filtered and dried under vacuum to constant weight to provide 219 mg (85%) of 2,5-bis[6-(3,4,5,6-tetrahydropyrimidin- 2-yl)indol-2-yl]pyridine acetic acid salt (MBX 1643) as a bright yellow powder
'H-NMR (DMSO/D20) δ 9,26 (s, IH), 8.45 (d, IH), 8.22 (d, IH), 7.91 (d, 2H), 7.81 (t, 2H), 7.38-7.29 (m, 4H), 3.53 (s, br, 8H), 2.01 (s, br, 4H), 1.80 (s, 12H); mp dec >290 °C.
Synthesis of 2,5-bisr6-(3,4,5,6-tetrahvdropyrimidin-2-yl)benzofuran-2-yllthiophene acetic acid salt (MBX 1885)
Figure imgf000045_0001
2,5-bis[6-cyanobenzofuran-2-yl]thiophene
A 50 mL round-bottom flask was charged with Pd(Ph3P)4 (174 mg, 0.15 mmol), 6-cyanobenzofuran- 2-boronic acid pinacol ester (808 mg, 3.00 mmol) and Na2C03 (1.82 g, 17.10 mmol). The mixture was flushed with Argon for 2 min. DME (4.3 mL), water (8.6 mL), and 2,5-dibromothiophene (0.34 mL, 3.00 mmol) were added. The reaction mixture was refluxed for 6 hours and cooled to room temperature. The yellow solid was collected and dried under vacuum to provide 2,5-bis[6- cyanobenzofuran-2-yl]thiophene (122 mg, 22%).
¾ NMR (300 MHz, CDC13): 7.81 (s, 2H), 7.67 (d, 2H), 7.59 (s, 2H), 7.55 (dd, 2H), 7.02 (s, 2H); Rf: 0.14 (hexanes: EtOAc, 4: 1)
Figure imgf000045_0002
2,5-bis[6-(3,4,5,6-tetrahydropyrimidin-2-yl)benzofuran-2-yl]thiophene acetic acid salt (MBX 1885)
A 10 mL sealed tube was charged with 2,5-bis[6-cyanobenzofuran-2-yl]thiophene (157 mg, 0.43 mmol), P2S5 (98 mg, 0.22 mmol) and 1,3-diaminopropane (4.3 mL). The reaction mixture was heated at 120°C for 3 hours and poured to 10 mL of brine and the yellow precipitates were filtered, and dried to give crude product, which was purified by reverse phase C18 column chromatography (H2O/0.1% CH3COOH: Acetonitrile/0.1 CH3COOH) to provide desired 2,5-bis[6-(3,4,5,6-tetrahydropyrimidin- 2-yl)benzofuran-2-yl]thiophene acetic acid salt (MBX 1885; 68 mg, 26%) as yellow solid.
¾ NMR (300 MHz, DMSO-d6): 7.99 (s, 2H), 7.77-7.75 (m, 4H), 7.65 (d, 2H), 7.42 (s, 2H), 3.41 (t, 8H), 1.78-1.74 (m, 4H), 1.65 (s, 6H); LC-MS m/e 481.7 (M+l)+; m.p. >300 °C.
Synthesis of 6-(4,5-dihvdroimidazol-2-yl)-2-{5-r6-(4,5-dihvdro-imidazol-2-yl)benzofuran-2- yllthiophen-2-yl}indole acetic acid salt (MBX 1887)
Figure imgf000046_0001
2-bromo-5-(6-cyanobenzofuran-2-yl)thiophene
A 50 mL round-bottom flask was charged with Pd(Ph3P)4 (174 mg, 0.15 mmol), 6-cyanobenzofuran- 2-boronic acid pinacol ester (808 mg, 3.00 mmol) and Na2C03 (1.82 g, 17.10 mmol). The mixture was flushed with Argon for 2 minutes. DME (4.3 mL), water (8.6 mL), and 2,5-dibromothiophene (0.34 mL, 3.00 mmol) were added. The reaction mixture was refluxed for 6 hours and cooled to room temperature. The yellow solid was filtered and the filtrate was extracted with EtOAc (3x20 mL), dried over anhydrous Na2S04, filtered, concentrated and purified by column chromatography on silica gel (hexanes: ethyl acetate) to provide 2-bromo-5-(6-cyanobenzofuran-2-yl)thiophene (200 mg, 22%) as light yellow solid.
¾ NMR (300 MHz, CDC13): 7.77 (s, 1H), 7.63 (d, 1H), 7.52 (dd, 1H), 7.32 (d, 1H), 7.11 (d, 1H), 6.87 (s, 1H); Rf: 0.47 (hexanes: EtOAc, 4: 1)
Figure imgf000046_0002
6-cyano-2-[5-(6-cyanobenzofuran-2-yl)thiophene-2-yl]indole
A 50 mL round-bottom flask was charged with Pd(Ph3P)4 (38 mg, 0.033 mmol), 6-cyanoindole-2- boronic acid pinacol ester (226 mg, 0.79 mmol) and Na2C03 (398 mg, 3.75 mmol). The mixture was flushed with Argon for 2 minutes. DME (3.0 mL), water (6.0 mL) and bromide 2-bromo-5-(6- cyanobenzofuran-2-yl)thiophene (200 mg, 0.66 mmol) were added. The reaction mixture was heated at 85 °C for 24 hours and cooled to room temperature. The yellow solid was collected, re-dissolved in EtOAc (50 mL), washed with water (25 mL), dried over anhydrous Na2S04, filtered, concentrated and dried under vacuum to provide 6-cyano-2-[5-(6-cyanobenzofuran-2-yl)thiophene-2-yl] indole as yellow solid. The reaction filtrate was extracted with EtOAc (2 x 20 mL), dried over anhydrous Na2S04, filtered, concentrated and purified by column chromatography on silica gel (hexanes: ethyl acetate) to provide additional product. A total of 82 mg (34%) of 6-cyano-2-[5-(6-cyanobenzofuran- 2-yl)thiophene-2-yl]indole was thus obtained.
¾ NMR (300 MHz, CDC13): 8.58 (s, IH), 7.81 (s, IH), 7.72 (s, IH), 7.68-7.63 (m, 2H), 7.58 (d, IH), 7.54 (dd, IH), 7.40-7.36 (m, 2H), 6.98 (s, IH), 6.88 (s, IH); Rf: 0.61 (hexanes: EtOAc, 2: 1)
Figure imgf000047_0001
6-(4,5-dihydroimidazol-2-yl)-2-{5 6-(4,5-dihydro-imM
yljindole acetic acid salt (MBX 1887)
A 10 mL sealed tube was charged with 6-cyano-2-[5-(6-cyanobenzofuran-2-yl)thiophene-2-yl] indole (70 mg, 0.19 mmol), P2Ss (43 mg, 0.096 mmol) and ethylenediamine (2.0 mL). The reaction mixture was heated at 120°C for 3 hours and poured to 5 mL of brine, and the yellow precipitates were filtered, and dried to provide crude product, which was purified by reverse phase CI 8 column chromatography (H2O/0.1% CH3COOH: Acetonitrile/0.1%CH3COOH) to give desired product 6-(4,5- dihydroimidazol-2-yl)-2-{5-[6-(4,5-dihydro-imidazol-2-yl)benzofuran-2-yl]thiophen-2-yl }indole acetic acid salt (MBX 1887) (60 mg, 55%) as yellow solid.
¾ NMR (300 MHz, DMSO-d6): 8.04 (s, IH), 7.93 (s, IH), 7.83 (d, IH), 7.76-7.68 (m, 3H), 7.63-7.58 (m, 2H), 7.38 (s, IH), 6.91 (s, IH), 3.74 (s, 4H), 3.67 (s, 4H), 1.90 (s, 6H); LC-MS mJe 452.6 (M+l)+; m.p. 230 °C decomposed.
Synthesis of 6-(3,4,5,6-tetrahvdropyrimidin-2-yl)-2-{5-r6-(3,4,5,6-tetrahvdropyrimidin-2- yl)benzofuran-2-yllthiophen-2-yl}indole acetic acid salt (MBX 1914)
Figure imgf000047_0002
6-(3,4,5,6 etrahydropyrimidin-2-yl)-2-{5 6-(3,4,5,6 etrahydropyrimidin-2-yl)benzofuran-2^ yl]thiophen-2-yl}indole acetic acid salt (MBX 1914) 6-cyano-2-[5-(6-cyanobenzofuran-2-yl)thiophene-2-yl]indole (158 mg, 0.43 mmol) was treated with 1,3-diaminopropane (2.5 mL) and P2Ss (60 mg, 0.3 mmol) for 3 hours at 120-130 °C in sealed tube. Water was added. The precipitate was filtered and dissolved by methanol and acetic acid. The filtrate was concentrated and residue purified by C18-column chromatography. Elution with MeCN 0-50% in water with 0.1% acetic acid additive over 30 min provided 220 mg (85%) of 6-(3, 4,5,6- tetrahydropyrimidin-2-yl)-2-{5-[6-(3,4,5,6-tetrahydropyrimidin-2-yl)benzofuran-2-yl]thiophen-2- yljindole acetic acid salt (MBX 1914) as a yellow solid after lyophilization.
¾ NMR (MeOD): 7.88 (s, 1H), 7.77-7.74 (m, 2H), 7.70-7.63 (m, 2H), 7.56-7.53 (m, 2H), 7.29 (dd, 1H), 7.20 (s, 1H), 6.86 (s, 1H), 3.58 (t, 8H), 2.09 (quint, 4H), 1.84 (s, 6H). LCMS: 241 [M+2]/2. Synthesis of 6-(3,4,5,6-tetrahvdropyrimidin-2-yl)-2-{5-r6-(3,4,5,6-tetrahvdropyrimidin-2- yl)benzofuran-2-yl1pyridin-2-yl}indole acetic acid salt (MBX 1932)
Figure imgf000048_0001
N-Boc-6-cyano-2-[5-(6-cyanobenzofuran-2-yl)pyridin-2-yl]indole
To a mixture of Ar-Boc-6-cyano-2-(5-bromopyridin-2-yl)indole (100 mg, 0.25 mmol) and cyanobenzofuran-2-boronic acid pinacol ester (70 mg, 0.26 mmol), and Pd(PhP3)4 (29 mg) were added sequentially freshly distilled toluene (4 mL), freshly distilled ethanol (2 mL) and 2.0 M aqueous Na2C03 (2 mL). The mixture was stirred and heated to 70 °C. After 1 hour, and additional amount of cyanobenzofuran-2-boronic acid pinacol ester (63 mg, 23 mmol) was added and the reaction was continued for another hour. The mixture was allowed to cool to room temperature. The organic material was extracted with ether, washed with water, and dried over MgS04. The solvents were removed under reduced atmosphere, and the product was purified by silica gel column chromatography (50%-90% [DCM:EtOAc (2: 1)] in hexanes) to provide 85 mg (73%) of N-Boc-6- cyano-2-[5-(6-cyanobenzofuran-2-yl)pyridin-2-yl]indole as a pale yellow powder.
Rf. 0.17 (25% EtOAc in hexanes); 'H-NMR: (CDC13) 8.78 (d, 1H), 8.60 (s, 1H), 8.03 (d, 1H), 7.92- 7.88 (m, 2H), 7.76 (d, 1H), 7.67 (d, 1H), 7.58-7.53 (m, 3H), 6.76 (s, 1H), 1.45 (s, 9H)
Figure imgf000049_0001
MBX-1932
6-(3,4,5,6 etrahydropyrimidin-2-yl)-2-{5 6-(3,4,5,6 etrahydropyrimidin-2-yl)benzofuran-2- yl]pyridin-2-yl}indole acetic acid salt (MBX 1932)
To a mixture of Ar-Boc-6-cyano-2-[5-(6-cyanobenzofuran-2-yl)pyridin-2-yl]indole (170 mg, 0.37 mmol) and phosphorous pentasulfide (100 mg, 0.45 mmol) was added 1,3-diaminopropane (2.5 mL). The tube was sealed and placed in an oil bath preheated at 80 °C. The mixture was stirred well, the color of the suspension changed from orange to greenish brown. The temperature was raised to 130 °C and maintained as such for 3 h before cooling to rt. The solution was slowly added to water (10 mL). The yellow precipitate was filtered and rinsed with water. The crude solid product was purified by CI 8 column chromatography (43 g size). Elution: 0-50% MeCN in water over 30 min (30 mL/min) [solvents contain 0.1% acetic acid]. Product-containing fractions were pooled and evaporated to yield 170 mg (77%) of 6-(3,4,5,6-tetrahydropyrimidin-2-yl)-2-{5-[6-(3,4,5,6- tetrahydropyrimidin-2-yl)benzofuran-2-yl]pyridin-2-yl}indole acetic acid salt (MBX 1932) as yellow solid.
'H-NMR (MeOD): 9.08 (s, 1H), 8.16 (d, 1H), 7.85 (d, 2H), 7.72 (d, 2H). 7.62 (d, 1H), 7.44 (d, 1H), 7.21 (s, 1H), 6.97 (s, 1H), 3.48 (bs, 8H), 1.98 (bs, 4H), 1.82 (s, 6H); LCMS: 238.6 (M+2)/2 Synthesis of 6-(5-methyl-3,4,5,6-tetrahvdropyrimidin-2-yl)-2-{5-r6-(5-methyl-3,4,5,6- tetrahvdropyrimidin-2-yl)benzofuran-2-yl1pyridin-2-yl}indole acetic acid salt (MBX 1935)
Figure imgf000049_0002
MBX-1935
6-(5-methyl ,4,5,6 etrahydropyrimidin-2-yl)-2-{5 6-(5-methyl-3,4,5,6 etrahydropyrimidin-2- yl)benzofuran-2-yl]pyridin-2-yl}indole acetic acid salt (MBX 1935)
To a mixture of Ar-Boc-6-cyano-2-[5-(6-cyanobenzofuran-2-yl)pyridin-2-yl]indole (85 mg, 0.18 mmol) and phosphorous pentasulfide (65 mg, 0.29 mmol) was added 2-methyl- 1,3-diaminopropane (0.5 mL) and diphenyl ether (2 mL). The tube was sealed and placed in an oil bath preheated at 125 °C. The mixture was stirred well for 3 hours. Upon cooling to room temperature (rt), the mixture solidified, and water (10 mL) was slowly added. The suspension was thoroughly mixed. The yellow precipitate was filtered and rinsed with water, then ether. The crude solid product was purified by CI 8 column chromatography. Elution: 5 -50 MeCN in water over 25 min (30 mL/min) [solvents contain 0.1% acetic acid] to provide 33 mg (26%) of 6-(5-methyl-3,4,5,6-tetrahydropyrimidin-2-yl)-2- {5-[6-(5-methyl-3,4,5,6-tetrahydropyrimidin-2-yl)benzofuran-2-yl]pyridin-2-yl}indole acetic acid salt (MBX 1935) as a yellow solid.
'H-NMR (MeOD): 9.01 (s, IH), 8.28 (d, IH), 7.97-7.87 (m, 3H), 7.79 (d, IH), 7.69 (d, IH), 7.55-7.48 (m, 2H), 7.28 (d, IH), 7.06 (s, IH), 4.64-3.58 (m, 4H), 3.17-3.10 (m, 4H), 2.15-2.09 (m, 2H), 1.83 (s, 9H, AcOH), 1.13-1.06 (m, 6H); LCMS: 252.7 (M+2)/2.
Synthesis of 6-(5-hvdroxy-3,4,5,6-tetrahvdropyrimidin-2-yl)-2-{4-r2-(5-hvdroxy-3,4,5,6- tetrahvdropyrimidin-2-yl)benzofuran-2-yl1pyrid-2-yl}indole acetic acid salt (MBX 1967)
Figure imgf000051_0001
MBX-1967
6-(5-hydroxy-3,4,5,6-tetrahydropyrimidin-2-yl)-2-{4-[2-(5-hydroxy-3,4,5,6- tetrahydropyrimidin-2-yl)benzofuran-2-yl]pyrid-2-yl}indole acetic acid salt (MBX 1967)
To a mixture of Ar-Boc-6-cyano-2-[5-(6-cyanobenzofuran-2-yl)pyridin-2-yl]indole (60 mg, 0.13 mmol) and phosphorous pentasulfide (60 mg, 0.27 mmol) was added 2-hydroxy-l,3-diaminopropane (1 mL). The tube was sealed and placed in an oil bath preheated at 80 °C. The temperature was raised to 130 °C, then stirred for 3.5 hours and allowed to cool to room temperature. Water (10 mL) was added slowly, and the suspension that formed was loaded on a C18 column. The column was eluted with 30% MeCN in water over 1 h (30 mL/min) [solvents contain 0.1% acetic acid] to provide 64 mg (72%) of 6-(5-hydroxy-3,4,5,6-tetrahydropyrimidin-2-yl)-2-{4-[2-(5-hydroxy-3,4,5,6- tetrahydropyrimidin-2-yl)benzofuran-2-yl]pyrid-2-yl}indole acetic acid salt (MBX 1967) as a yellow solid.
¾-NMR (MeOD) 9.19 (d, IH), 8.42 (dd, IH), 8.16 (d, IH), 8.04 (s, IH), 7.94 (d, IH), 7.89 (s, IH), 7.81 (d, IH), 7.69 (s, IH), 7.66 (dd, IH), 7.39 (dd, IH), 7.22 (s, IH), 4.43 (m, 2H), 3.70 (dt, 4H), 3.57 (dt, 4H), 1.93 (s, 9H, AcOH); MS: 254.7 (M+2)/2.
Synthesis of 6-(5-hvdroxy-3,4,5,6-tetrahvdropyrimidin-2-yl)-2-{5-r6-(5-hydroxy-3,4,5,6- tetrahvdropyrimidin-2-yl)benzofuran-2-yllthiophen-2-yl}indole acetic acid salt (MBX 1991)
Figure imgf000051_0002
6-(5-hydroxy-3,4,5,6-tetrahydropyrimidin-2-yl)-2-{5-[6-(5-hydroxy-3,4,5,6- tetrahydropyrimidin-2-yl)benzofuran-2-yl]thiophen-2-yl}indole acetic acid salt (MBX 1991) To a mixture of 6-cyano-2-[5-(6-cyanobenzofuran-2-yl)thiophene-2-yl]indole (95 mg, 0.26 mmol) 9and phosphorous pentasulfide (65 mg, 0.29 mmol) was added 2-hydroxy-l,3-diaminopropane (1.5 mL). The vial was sealed and heated to 130 °C on a shaker block. After 4 hours, the mixture was allowed to cool to room temperature. Water (10 mL) was added slowly, and the viscous suspension that formed was filtered through celite. The retained on celite was loaded on a CI 8 chromatography column. The column was eluted with MeCN in water (from 0% to 90% of MeCN over 1 h, 30 mL/min) [solvents contain 0.1% acetic acid] to provide the product as a yellow-green powder after removal of solvents under vacuum, 116 mg, 90 % yield.
H NMR (MeOD:DMSO, 3: 1) 8.15 (s, 1H), 7.90-7.85 (m, 2H), 7.81-7.75 (m, 2H), 7.69-7.65 (m, 2H), 7.42 (d, 1H), 7.33 (s, 1H), 6.99 (s, 1H), 4.44 (pent, 2H), 3.64 (dd, 8H), 1.90 (s, 6H, AcOH)
MS: 257.1 (M+2)/2
Synthesis of 6-(3,4,5,6-tetrahvdropyrimidin-2-yl)-2-{5-r2-(3,4,5,6-tetrahvdropyrimidin-2- yl)benzofuran-6-yllpyridin-2-yl}indole acetic acid salt (MBX 2014)
Figure imgf000052_0001
2-cyanobenzofuran-6-boronic acid pinacol ester
To a 50 mL round bottom flask was added 2-cyano-6-bromobenzofuran (498 mg, 2.243 mmol), bis(pinacolato)diboron (683 mg, 2.691 mmol), PdCl2(dppf) CH2Cl2 (110 mg, 0.134 mmol), potassium acetate (660 mg, 6.729 mmol) and 1,4-dioxane (11.0 mL). The yellow mixture was heated at 80 °C for 5 hours and cooled to room temperature. EtOAC (15 mL) was added to the dark reaction mixture and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 x 25 mL), the combined organic layers were dried over anhydrous Na2S04, filtered and concentrated by rotary evaporator to yellow residue, which was purified by column chromatography on silica gel (hexanes: ethyl acetate) to provide desired product 15 (419 mg, 69%) as white solid.
¾ NMR (300 MHz, CDC13): 8.00 (s, 1H), 7.79 (d, 1H), 7.68 (d, 1H), 7.46 (s, 1H), 1.37 (s, 12H); Rf: 0.35 (hexanes: EtOAc, 10: 1)
Figure imgf000053_0001
6-cyano-2-[5-(2-cyanobenzofuran-6-yl)pyridin-2-yl]indole
A 50 mL round bottom flask was charged with Pd(Ph3P)4 (57 mg, 0.05 mmol), 2-cyanobenzofuran-6- boronic acid pinacol ester (200 mg, 0.74 mmol) and Na2C03 (299 mg, 2.8 mmol). The mixture was flushed with Argon for 2 minutes, then DME (3.3 mL), water (3.3 mL), and Ar-Boc-6-cyano-2-(5- bromopyridin-2-yl)indole (197 mg, 0.495 mmol) were added. The reaction mixture was heated at 78 °C for 3.5 hours and then cooled to room temperature. The yellow solid was filtered, washed with EtOAc and water, dried under vacuum to provide one batch of desired product as yellow solid (64 mg). The filtrate was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, concentrated and purified by column chromatography on silica gel (hexanes: ethyl acetate). The material thus obtained was combined with the previous batch to provide 195 mg (86%) of 6-cyano-2-[5-(2-cyanobenzofuran-6-yl)pyridin-2-yl]indole as a yellow powder. ¾ NMR (300 MHz, DMSO-d6): 9.18 (d, 1H), 8.41-8.37 (m, 2H), 8.29 (s, 1H), 8.19 (s, 1H), 8.02 (d, 1H), 7.94-7.89 (m, 3H), 7.71 (dd, 1H), 7.22 (s, 1H), 1.32 (s, 9H); Rf: 0.54 (hexanes: EtOAc, 3:2) [
Figure imgf000053_0002
6-(3,4,5,6 etrahydropyrimidin-2-yl)-2-{5 2-(3,4,5,6 etrahydropyrimidin-2-yl)benzofuran-6- yl]pyridin-2-yl}indole acetic acid salt (MBX 2014)
A 10 mL sealed tube was charged with 6-cyano-2-[5-(2-cyanobenzofuran-6-yl)pyridin-2-yl] indole (60 mg, 0.13 mmol), P2Ss (29 mg, 0.065 mmol) and 1,3-diaminopropane (1.9 mL). The reaction mixture was heated at 120 °C for 3 hours (h) and poured to 10 mL of brine and the yellow precipitates were filtered, and dried to give crude product, which was purified by reverse phase CI 8 column chromatography (H2O/0.1% CH3COOH: Acetonitrile/0.1%CH3COOH) to provide desired 55 mg, (79%) of 6-(3,4,5,6-tetrahydropyrimidin-2-yl)-2-{5-[2-(3,4,5,6-tetrahydropyrimidin-2-yl)benzofuran- 6-yl]pyridin-2-yl}indole acetic acid salt (MBX 2014) as yellow solid. ¾ NMR (300 MHz, DMSO-d6): 12.51 (s, IH), 9.09 (s, IH), 8.35 (dd, IH), 8.25 (d, IH), 8.08 (s, IH), 7.91-7.88 (m, 2H), 7.81 (d, 2H), 7.54 (s, IH), 7.38-7.34 (m, 2H), 3.54-3.50 (m, 8H), 2.10-1.90 (m, 2H), 1.88 (s, 3H), 1.85-1.75 (m, 2H); LC-MS mJe 475.6 (M+l)+; m.p. 217-278 °C.
Synthesis of 6-(3,4,5,6-tetrahvdropyrimidin-2-yl)-2-{5-r2-(3,4,5,6-tetrahvdropyrimidin-2- yl)benzofuran-6-yllthiophene-2-yl}indole acetic acid salt (MBX 2015)
Figure imgf000054_0001
6-cyano-2-[5-(2-cyanobenzofuran-6-yl)thiophene-2-yl]indole
A 50 mL round bottom flask was charged with Pd(Ph3P)4 (57 mg, 0.05 mmol), 2-cyanobenzofuran-6- boronic acid pinacol ester (200 mg, 0.743 mmol) and Na2C03 (299 mg, 2.8 mmol). The mixture was flushed with Argon for 2 min , then DME (3.3 mL), water (3.3 mL), and Ar-Boc-6-cyano-2-(5- bromothiophene-2-yl)indole (200 mg, 0.495 mmol) were added. The reaction mixture was heated at 78 °C for 2.5 hours and cooled to room temperature. The yellow solid was filtered, washed with EtOAc and water, the dried under vacuum to provide 159 mg of desired product. The filtrate was extracted with EtOAc (3 x 25 mL). The combined organic layers were combined, dried over anhydrous Na2S04, filtered, concentrated and purified by column chromatography on silica gel (hexanes: ethyl acetate). The resulting material was combined with the previous batch to 222 mg (69%) of 6-cyano-2-[5-(2-cyanobenzofuran-6-yl)thiophene-2-yl]indole as yellow solid.
¾ NMR (300 MHz, DMSO-d6): 8.43 (s, IH), 8.15-8.14 (m, 2H), 7.92 (d, IH), 7.86 (d, IH), 7.80-7.77 (m, 2H), 7.71 (d, IH), 7.41 (d, IH), 7.09 (s, IH), 1.44 (s, 9H); Rf: 0.40 (hexanes: EtOAc, 4: 1)
Figure imgf000054_0002
6-(3,4,5,6 etrahydropyrimidin-2-yl)-2-{5 2-(3,4,5,6-tetrahydropyrimidin-2-yl)benzofuran-6- yl]thiophene-2-yl}indole acetic acid salt (MBX 2015) A 10 mL sealed tube was charged with 6-cyano-2-[5-(2-cyanobenzofuran-6-yl)thiophene-2-yl] indole (65 mg, 0.14 mmol), P2Ss (31 mg, 0.07 mmol) and 1,3-diaminopropane (2.0 mL). The reaction mixture was heated at 120 °C for 3 hours and poured to 10 mL of brine and the yellow precipitates were filtered, and dried to give crude product, which was purified by reverse phase C18 column chromatography (H2O/0.1% CH3COOH: Acetonitrile/0.1 CH3COOH) to provide 81 mg (100%) of 6-(3,4,5,6-tetrahydropyrimidin-2-yl)-2-{5-[2-(3,4,5,6-tetrahydropyrimidin-2-yl)benzofuran-6- yl]thiophene-2-yl} indole acetic acid salt (MBX 2015) as yellow solid.
¾ NMR (300 MHz, DMSO-d6): 12.49 (s, IH), 7.93 (s, IH), 7.85-7.68 (m, 6H), 7.57 (s, IH), 7.37 (dd, IH), 6.90 (s, IH), 3.60-3.40 (m, 8H), 2.01- 1.99 (m, 2H), 1.90 (s, 3H), 1.90-1.70 (m, 2H); LC-MS m/e 480.6 (M+l)+; m.p. 212-253 °C.
Synthesis of 6-(4-methyl-4,5-dihvdro j -imidazol-2-yl)-2-{5-r2-(5-methyl-4,5-dihvdro-lj - imidazol-2-yl)benzofuran-6-yllpyridin-2-yl}indole acetic acid salt diasteriomer 1 (MBX 2041) and 6-(4-methyl-4,5-dihvdro-lg-imidazol-2-yl)^
yl)benzofuran-6-yllpyridin-2-yl}indole acetic acid salt diasteriomer 2 (MBX 2042)
Figure imgf000055_0001
6-(4-methyl-4,5-dihydro i7-imidazol-2-yl)-2-{5 2-(5-methyl-4,5-dihydro-li7-imidazol-2 yl)benzofuran-6-yl]pyridin-2-yl}indole acetic acid salt diasteriomer 1 (MBX 2041) and 6-(4- methyl-4,5-dihydro i7-imidazol-2-yl)-2-{5-[2-(5-methyl-4,5-dihydro-li/-imidazol-2- yl)benzofuran-6-yl]pyridin-2-yl}indole acetic acid salt diasteriomer 2 (MBX 2042)
A 10 mL sealed tube was charged with 6-cyano-2-[5-(2-cyanobenzofuran-6-yl)pyridin-2-yl] indole (61 mg, 0.13 mmol), P2Ss (30 mg, 0.066 mmol) and 1,2-diaminopropane (1.9 mL). The reaction mixture was heated to 120°C in oil bath and turned into a clear green solution. It was stirred at the same temperature for 3 hours, poured to 10 mL of brine and the yellow precipitates were filtered, and dried under vacuum to give crude product, which was purified by reverse phase CI 8 column chromatography (H2O/0.1% CH3COOH: Acetonitrile/0.1 CH3COOH) to provide MBX2041 (37 mg,
47%) and MBX2042 (15 mg, 19%) as yellow solids.
MBX2041:
¾ NMR (300 MHz, DMSO-d6): 9.07 (s, IH), 8.31 (d, IH), 8.20 (d, IH), 8.10 (d, 2H), 7.89 (d, IH), 7.79-7.72 (m, 2H), 7.58 (d, IH), 7.45 (s, IH), 7.33 (s, IH), 4.34-4.26 (m, IH), 4.09-3.96 (m, 3H), 3.47 (dd, IH), 3.25 (dd, IH), 1.86 (s, 6H), 1.32 (d, 3H), 1.20 (d, 3H); ); LC-MS mJe 475.6 (M+l)+; m.p. 243-284 °C.
MBX2042:
¾ NMR (300 MHz, DMSO-d6): 9.08 (s, IH), 8.33 (dd, IH), 8.19 (d, IH), 8.12 (s, IH), 8.02 (s, IH), 7.90 (d, IH), 7.80 (dd, IH), 7.69 (d, IH), 7.56 (dd, IH), 7.43 (s, IH), 7.31 (s, IH), 4.21-4.13 (m, IH), 4.11-4.00 (m, IH), 3.93-3.30 (m, 4H), 1.88 (s, 6H), 1.28 (d, 3H), 1.21 (d, 3H); LC-MS mJe 475.6 (M+l)+; m.p. 186-292 °C.
Synthesis of 6-(4-methyl-4,5-dihvdro-lj -imidazol-2-yl)-2-{5-r2-(4-methyl-4,5-dihvdro-lj - imidazol-2-yl)benzofuran-6-yllthiophen-2-yl}indole acetic acid salt (MBX 2073)
Figure imgf000056_0001
6-(4-methyl-4,5-dihydro i7-imidazol-2-yl)-2-{5 2-(4-methyl-4,5-dihydro-li7-imi
yl)benzofuran-6-yl]thiophen-2-yl}indole acetic acid salt (MBX 2073)
A 10 mL sealed tube was charged with 6-cyano-2-[5-(2-cyanobenzofuran-6-yl)thiophene-2-yl] indole (75 mg, 0.16 mmol), P2S5 (36 mg, 0.08 mmol) and 1,2-diaminopropane (2.0 mL). The reaction mixture was heated to 120 °C in oil bath and turned into a clear green solution. It was stirred at the same temperature for 3 h, poured to 10 mL of brine and the yellow precipitates were filtered, and dried under vacuum to give crude product, which was purified by reverse phase C 18 column chromatography (H2O/0.2% CH3COOH: Acetonitrile/0.2%CH3COOH) to provide desired product MBX2073 (47 mg, 54%) as yellow solid.
¾ NMR (300 MHz, DMSO-d6): 12.46 (s, IH), 8.05 (s, IH), 7.97 (s, IH), 7.82-7.58 (m, 6H), 7.42 (s, IH), 6.89 (s, IH), 4.48-4.42 (m, IH), 4.06-3.99 (m, 2H), 3.50-3.44 (m, 2H), 3.26-3.19 (m, IH), 1.89 (s, 3H), 1.35 (d, 3H), 1.21 (d, 3H); LC-MS m/e 480.5 (M+l)+; m.p. 178-283 °C. Synthesis of 6-(5-fluoro-3,4,5,6-tetrahvdropyrimidin-2-yl)-2-{5-r6-(5-fluoro-3,4,5,6- tetrahvdropyrimidin-2-yl)benzofuran-2-yl1thiophen-2-yl}indole trifluoroacetic acid salt (MBX 2089)
Figure imgf000057_0001
6-(5-fluoro ,4,5,6 etrahydropyrimidin-2-yl)-2-{5 6-(5-fluoro ,4,5,6 etrahydropyrimidin-2- yl)benzofuran-2-yl]thiophen-2-yl}indole trifluoroacetic acid salt (MBX 2089)
A mixture of 6-cyano-2-[5-(2-cyanobenzofuran-6-yl)thiophene-2-yl]indole (50 mg, 0.11 mmol), phosphorous pentasulfide (30 mg, 0.14 mmol), and 2-fluoro-l,3-diaminopropane (2 mL) in a sealed tube was stirred and heated in an oil bath to 130 °C for 5 hours. The mixture was allowed to cool to room temperature, then ethanol (3 mL) was added. The suspension was mixed thoroughly and filtered. The solid was dissolved in DMSO (2 mL) containing 10% TFA and purified by HPLC. The column was eluted with MeCN in water (from 20% to 100% of MeCN over 10 min, 20 mL/min)
[solvents contain 0.1% TFA] to provide 48 mg (60%) of 6-(5-fluoro-3,4,5,6-tetrahydropyrimidin-2- yl)-2-{5-[6-(5-fluoro-3,4,5,6-tetrahydropyrimidin-2-yl)benzofuran-2-yl]thiophen-2-yl}indole trifluoroacetic acid salt (MBX 2089) as a yellow, waxy solid (60% yield).
(DMSO-d6): 12.43 (bs, 1H), 10.21 (bs, 2H), 10.05 (bs, 2H), 8.14 (s, 1H), 7.92 (d, 1H), 7.87 (d, 1H), 7.80-7.77 (m, 3H), 7.67 (dd, 1H), 7.52 (s, 1H), 7.38 (dd, 1H), 7.05 (d, 1H), 5.57 (m, 1H), 5.41 (m, 1H), 3.84 (m, 4H), 3.82-3.62 (m, 4H); LCMS: 516.4 (M+l).
Synthesis of 6-(5-fluoro-3,4,5,6-tetrahvdropyrimidin-2-yl)-2-{4-r6-(5-fluoro-3,4,5,6- tetrahvdropyrimidin-2-yl)benzofuran-2-yl1pyridin-2-yl}indole trifluoroacetic acid salt (MBX 2102A)
Figure imgf000057_0002
6-(5-fluoro ,4,5,6 etrahydropyrimidin-2-yl)-2-{^
yl)benzofuran-2-yl]pyridin-2-yl}indole trifluoroacetic acid salt (MBX 2102A)
A mixture of 6-cyano-2-[5-(2-cyanobenzofuran-6-yl)pyridin-2-yl]indole (50 mg, 0.11 mmol), phosphorous pentasulfide (30 mg, 0.14 mmol), and 2-fluoro-l,3-diaminopropane (0.3 mL) in a sealed tube was stirred and heated in an oil bath to 130 °C for 6.5 hours. The mixture was allowed to cool to room temperature, then ethanol (3 mL) was added. T he suspension was mixed thoroughly and filtered. The solid was dissolved in DMSO (2 mL) containing 10% TFA and purified by HPLC. The column was eluted with MeCN in water (from 20% to 100% of MeCN over 10 min, 20 mL/min) [solvents contain 0.1% TFA] to provide 29 mg (36%) of 6-(5-fluoro-3,4,5,6-tetrahydropyrimidin-2- yl)-2-{4-[6-(5-fluoro-3,4,5,6-tetrahydropyrimidin-2-yl)benzofuran-2-yl]pyridin-2-yl}indole trifluoroacetic acid salt (MBX 2102A) as an orange-colored solid.
'H-NMR (DMSO-d6): 12.60 (bs, IH), 10.36 (bs, 2H), 10.17 (bs, 2H), 9.42 (d, IH), 8.59 (dd, IH), 8.26 (d, IH), 8.23 (s, IH), 8.08 (d, IH), 7.94-7.90 (m, 3H), 7.77 (dd, IH), 7.47 (dd, IH), 7.43 (d, IH), 5.64 (m, IH), 5.49 (m, IH), 3.91 (bd, 4H), 3.90-3.60 (m, 4H); LCMS: 511.4 (M+l).
Synthesis of 6-(4,5-dihvdroimidazol-2-yl)-2-{5-r6-(4,5-dihydro-imidazol-2-yl)benzofuran-2- yllthiophen-2-yliindole (MBX 2145)
Figure imgf000058_0001
6-(4,5-dihydroimidazol-2-yl)-2-{5 6-(4,5-dihydro-imidazol-2-yl)benzofuran-2-yl]thiophen-2- yljindole (MBX 2145)
In a 10 mL sealable tube equipped with a stirring bar, the dinitrile 6-cyano-2-[5-(2-cyanobenzofuran- 6-yl)thiophene-2-yl]indole (85 mg, 0.18 mmol), phosphorous pentasulfide (50 mg, 0.22 mmol) and ethylenediamine (2 mL) were added. The tube was sealed and put in an oil bath preheated at 130 °C. The solid dissolved upon heating and the mixture was stirred at 130 °C for 4 hours before being cooled to approximately 40 °C. Water (5mL) was added, and the orange colored suspension was filtered through a fritted funnel to collect the orange-brown solid. The solid was rinsed with 20 mL of water and dried in high vacuum overnight to provide 90 mg (109%) of 6-(4,5-dihydroimidazol-2-yl)- 2-{5-[6-(4,5-dihydro-imidazol-2-yl)benzofuran-2-yl]thiophen-2-yl}indole (MBX 2145) as an orange- brown solid. (DMSO): 11.96 (bs, 1H), 8.08 (s, 1H), 7.87 (s, 1H), 7.81 (d, 1H), 7.74 (d, 1H), 7.69-7.66 (m, 2H), 7.55 (s, 1H), 7.35 (s, 1H), 6.87 (s, 1H), 3.64 (m, 8H); MS: 452.0 (M+l)
Uses and Compositions
Compounds of the invention possess fungicide and/or antifungal activity, which means that the compounds kill or inhibit growth of cells of one or more species or strains of a fungi pathogen when the compounds are brought into contact with such cells. Accordingly, the compounds described herein are useful in compositions and methods for treating a human, animal, insect, plant, crop, or foodstuff which has been infected with a fungi or pathogenic fungi species, is at risk of infection by a fungi species, or is suspected of having been infected with a fungi species. Compounds described herein may also be used in compositions and methods to kill or inhibit growth of cells of one or more fungi species in solutions, semi-solids, and solid compositions that are or are not susceptible to contamination by cells of fungi species and particularly pathogenic fungi species.
There are a variety of pathogenic fungi species and strains that are known etiological agents for various diseases that can occur once an infection has become established in or on the body of individual. In some cases, a fungus species may be an opportunistic fungal pathogen, i.e., cause a disease only under certain conditions. For example, cells of an opportunistic pathogenic fungi species may not normally be pathogenic or only mildly pathogenic in the case of a healthy individual whose immune system can effectively identify the invading fungal cells and mount an effective response to inactivate and/or otherwise remove the cells from the individual's body. However, cells of the same fungus species may be able to establish an infection resulting in significant pathology in an individual whose immune system has been weakened or otherwise suppressed. Weakened or compromised immune systems may result from a variety conditions including, but not limited to, prior (primary) illness, cancer of the immune system, exposure to toxins, exposure to radiation, exposure to chemotherapy drugs, and use of immunosuppressive drugs. Such individuals include, without limitation, patients of acquired immunodeficiency syndrome (AIDS), cancer patients undergoing radiation therapy, cancer patients receiving immunosuppressive chemotherapy drugs, and also individuals who take drugs designed to inhibit or suppress the activity of one or more cytokines, for example to treat diseases associated with an overactive cytokine(s), such as rheumatoid arthritis, psoriasis, and Crohn's disease.
Fungicide and/or antifungal compounds described herein may be used to kill or inhibit growth of cells of one more species of fungi. Examples of prominent fungal pathogens include, but are not limited to, species of Candida, such as C. albicans, C. parapsilosis, C. tropicalis, C. krusei, C. glabrata, and C. guillermondii; species of Aspergillus, such as A. fumgatus, A. niger, and A. flavus; species Cryptococcus, such as C. neoformans, C. laurentii, C. albidus, and C. gatti; species of
Histoplasma, such as H. capsulation; and species of Pneumocystis, such as P. jiroveci, Claviceps purpurea, and Magnaporthe grisea. Fungal pathogens are of particular concern for immunocompromised or immunosuppressed individuals.
Fungicide and/or antifungal compounds described herein may be formulated for
pharmaceutical and non-pharmaceutical uses. Fungicide and/or antifungal compounds described herein include compounds that may exhibit fungicidal and/or antifungal activity against multiple species and strains of fungi. In addition, compounds described herein may also be effective at killing or inhibiting growth of cells of multiple pathogenic fungal species and also non-pathogenic fungal cells. Such broad spectrum fungicide and/or antifungal activity may be desirable in both
pharmaceutical and non-pharmaceutical uses. In pharmaceutical uses, a compound that can kill or inhibit growth of cells of multiple pathogenic fungal organisms may provide new treatments for a variety of diseases, including those for which drug resistance by the etiological agent is a growing problem. Killing or inhibiting growth of non-pathogenic fungal cells is a common activity in agriculture and in preserving foodstuffs. Accordingly, persons skilled in this art understand that in view of the benefit provided to the medical field of a compound that kills or inhibits growth of cells of one or more fungal pathogens, any side-effect of also killing or inhibiting growth of non-pathogenic cells should be tolerable and acceptable for approval by regulatory agencies for use of the compound for treating a particular disease.
Use of a fungicide and/or antifungal compound described herein to kill or inhibit growth of cells of pathogenic and/or non-pathogenic species is also desirable in situations where growth of any fungal cells may interfere with proper operation, safety, efficiency, or appearance of a composition. Compositions for which it is desirable to inhibit growth of pathogenic and/or non-pathogenic fungal cells are exemplified by, but not limited to plants, crops, catheters, lock solutions, pumps (including cardiopulmonary bypass pumps, implantable patient pumps, non-implantable (exterior) patient pumps (e.g., for drug or hormone delivery), and industrial pumps), dialysis equipment, water pipes, plumbing fixtures, fuel lines, air ducts, gas lines (including air lines, oxygen lines, respirators), cosmetic products (including cosmetic skin products, cosmetic hair products), foods, eye products (eye drops, contact lenses, implantable lenses), ear products (e.g., ear drops), oral products (e.g., mouthwashes, tooth pastes, dental appliances), nasal products (e.g., nose drops, nose gels, nose swabs), vaginal care products, medical and veterinarian clothing (e.g., face masks, caps, gowns, gloves, footwear, gloves, aprons), gas masks, adhesives, soaps, detergents, and paints. Accordingly, in the discussion herein, it is understood that use of an fungicide and/or antifungal compound described herein to kill or inhibit cells of one or more microbial pathogens does not preclude use of the compound to kill or inhibit growth of cells of pathogenic and non-pathogenic microbial organisms.
In a method according to the invention, killing or inhibiting growth of cells of a fungal species comprises bringing a fungicide and/or antifungal compound described herein into contact with the cells of the fungal species. A compound described herein may be formulated in a pharmaceutical composition (including veterinarian) composition for administration to an individual or formulated to provide fungicide and/or antifungal activity to an inanimate liquid, semi-solid, or solid composition that is susceptible or has already been contacted with (i.e., contaminated with) cells of a fungal species. Preferably, an fungicide and/or antifungal compound described herein is in contact with a solid, semi-solid, or liquid composition prior to contamination with cells of a fungal species, however, an fungicide and/or antifungal compound described herein may also be brought into contact with a solid, semi-solid, or liquid composition that is already contaminated with cells of a fungal species to kill or inhibit growth of the cells already present on or in the composition. A fungicide and/or antifungal compound described herein may be incorporated into any of a variety of compositions to provide the benefit of killing or inhibiting growth of cells of a pathogenic microbial species or strain to the particular composition or to a surface to which the composition may be applied. Compositions comprising an fungicide and/or antifungal compound described herein include, but are not limited to, solutions, suspensions, dry mixtures, ointments, creams, gels, jellies, lotions, pastes, tooth pastes, petroleum products, porous membranes, porous filters, microparticles, microspheres, liposomes, micelles, lipid bilayers, resin particles, plastics, paints, glues, adhesives, cellulose products, textiles (fiber, yarn, or cloth), and nanoparticles. An fungicide and/or antifungal compound described herein may also be formulated by standard methods for delivery to a surface in an aerosol of fine solid particles or liquid droplets mixed with a gas.
A fungicide and/or antifungal compound described herein may be brought into contact with a solid surface composed of or comprising any of a variety of materials that are capable of retaining and/or transmitting viable cells of one or more fungal species that may be present on the solid surface. Such materials include, but are not limited to, enamel, plastic, glass, silicon, rubber, metal, stone, cement, nylon, cellulose, polymeric resin (including various cellulose and agarose resins), calcium phosphate (for example, as in, but not limited to, hydroxyapatite and bone), calcium carbonate (for example, as in, but not limited to, mollusk shells and mother-of-pearl), keratin (for example, as in, but not limited to, skin, hair, fur, wool, nails, claws, hooves, scales, beaks, and feathers), collagen (for example, as in, but not limited to, animal hides, tendons, and ligaments), chitin (for example, as in, but not limited to, exoskeletons and fungal cell walls), and combinations thereof. The compound may be applied to a solid surface by any of a variety methods available in the art for applying an organic compound to a particular surface. Such methods include methods of "treating" a surface, wherein it is understood that the terms "treat", "treating", and "treatment" in this context of combining a compound with a surface is distinct from the a medical treatment of an individual for disease. Such methods of treating a surface with an fungicide and/or antifungal compound described herein include, but are not limited to, coating a surface with the compound, immersing the surface in the compound, impregnating the surface with the compound, absorbing the compound into the surface, adsorbing the compound to the surface, and covalently conjugating the compound to the surface. The skilled practitioner is able to determine which method is optimally suited for combining ("treating") a particular surface with a particular fungicide and/or antifungal compound described herein. While in theory a fungicide and/or antifungal compound described herein may be used as the isolated compound alone (raw compound), it is more likely that the compound will be employed in a composition with at least one other compound. Compositions of the invention may be in any of a variety of forms particularly suited for the intended mode of providing the benefit of the fungicide and/or antifungal activity of a compound described herein to a solid composition, to a semi-solid composition, or to liquid composition.
A carrier is any compound that provides a medium for using fungicide and/or antifungal compound described herein. A carrier may be liquid, solid, or semi-solid. To retain its utility, it will be necessary that the carrier (and any other component of a composition) does not significantly neutralize, inhibit, or block the fungicide and/or antifungal inhibitory activity of a compound of the invention included in the composition. A suitable carrier for use in the compositions described herein includes, but is not limited to, an organic solvent, an aqueous buffer, water, emulsifying agent, and a solid dispersing agent. Solutions and suspensions comprising a fungicide and/or antifungal compound described herein may also be prepared using an appropriate organic solvent or emulsifying agent. A preferred organic solvent is dimethyl sulfoxide (DMSO). DMSO-based solutions comprising an antimicrobial compound described herein are particularly useful in providing required concentrations of the compound in various compositions, assays (including growth assays), and procedures. Other organic solvents may also be used including, but not limited to, an alcohol, N-methylpyrrolidone (NMP), and Ν,Ν-dimethylacetamide (DMA). For most in vitro purposes, DMSO is more preferred. As a general guide for using an alcohol as a solvent for a compound described herein, ethanol is more preferred than isopropanol, which is more preferred than butanol or an aryl alcohol, which are more preferred than methanol.
For solid compositions, conventional solid carriers are preferred and include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
A composition comprising a fungicide and/or antifungal compound described herein may also comprise a dispersing agent. The dispersing agent may be employed to disperse the fungicide and/or antifungal compound more uniformly in a composition and/or to enhance dispersion of the composition containing an antifungal compound described herein over a surface to which the composition is applied. A dispersing agent may be a solid or liquid. Solid dispersing agents may include, without limitation, talc, starch, cellulose, metal oxide (e.g., zinc oxide, titanium oxide), graphite, and combinations thereof. A preferred dispersing agent for liquid compositions is a surfactant, which may be an anionic, cationic, amphoteric, or nonionic surfactant. See, for example, US Patent No. 6,921,745. Preferably, a surfactant is employed at the lowest concentration that provides optimal dispersion of the fungicide and/or antifungal compound throughout the composition or optimal dispersion of the composition containing on a surface. Preferred anionic surfactants useful in the compositions and methods described herein include, without limitation, linear alkyl benzene sulfonic acid; alkyl sulfate; polyoxyethylene alkyl ether sulfate having 1 to 10 moles of ethylene oxide; polyoxyethylene alkyl ether carboxylic acid having 1 to 10 moles ethylene oxide; polyoxyethylene alkyl amide ether carboxylic or fatty acid having 1 to 10 moles ethylene oxide; and potassium, sodium, magnesium, or alkanolamine salts thereof. Preferably, the alkyl and fatty groups in an anionic surfactant are, independently, 8 to 22 carbon atoms, and more preferably 10 to 18 carbon atoms.
Preferably, a nonionic surfactant useful in the compositions and methods described herein is a nonionic polyoxyethylene ether, including, but not limited to, a polyoxyethylene alkyl ether having an alkyl chain containing 8 to 22 carbon atoms, more preferably 10 to 18 carbon atoms, and having 1 to 30 moles, and more preferably 4 to 20 moles, of ethylene oxide; a polyoxyethylene oxypropylene alkyl ether having 1 to 30 moles, and more preferably 1 to 20 moles, of ethylene oxide, and having 1 to 10 moles, more preferably 1 to 5 moles, of propylene oxide; a fatty acid alkanol amide containing 8 to 22 carbon atoms, and more preferably 10 to 18 carbon atoms to which 1 to 3 moles of ethylene oxide or propylene oxide may be added; and an alkyl polyglucoside having an alkyl chain containing 8 to 22 carbon atoms, and more preferably 10 to 18 carbon atoms, and preferably having 1 to 10 sugars, and more preferably 1 to 2 sugars, condensed therein. A preferred species of nonionic surfactant useful in compositions and methods described herein is t-octylphen-oxypolyethoxyethanol (e.g., brand name TRITON® X-100 non-ionic surfactant, Sigma- Aldrich, St. Louis, Missouri, US).
Another nonionic surfactant useful in the compositions and methods described herein may be an ester between a fatty acid containing 8 to 22 carbon atoms, and preferably 10 to 18 carbon atoms, and a polyvalent alcohol having a hydrocarbon group containing 2 to 10 carbon atoms and 2 to 8 hydroxy groups. More preferably, the ester is a glycerin fatty acid ester, a polyglycerin fatty acid ester, a sorbitan fatty acid ester, a sucrose fatty acid ester, or a propylene glycol fatty acid ester.
Amphoteric surfactants that may find use in the compositions and methods described herein include, without limitation, those having an alkyl group containing 8 to 22 carbon atoms, such as alkyl amidopropyl-N,N-dimethyl acetate betaine (N-alkanoyl aminopropyl-N,N-dimethyl-N-carboxymethyl ammonium carbobetaine), alkyl amidopropyl-N,N-dimethyl-2-hydroxypropyl sulfobetaine (N- alkanoyl aminopropyl-N,N-dimethyl-N-(2-hydroxy-3-sulfopropyl) ammonium sulfobetaine), alkyl- Ν,Ν-dimethyl acetate betaine (N-alkyl-N,N-dimethyl-N-carboxymethyl ammonium carbobetaine), alkyl amidopropyl-N,N-dimethyl-2-propyl sulfobetaine (N-alkanoyl aminopropyl-N,N-dimethyl-N- (2-sulfopropyl) ammonium sulfobetaine), lauryl-N,N-dimethyl-hydroxypropyl sulfobetaine (N-lauryl- N,N-dimethyl-N-(2-hydroxy-3-sulfopropyl) ammonium sulfobetaine), and alkyl amine oxide. Among these, preferred species may include lauric acid amidopropyl-N,N-dimethyl acetate betaine (N-lauroyl aminopropyl-N,N-dimethyl-N-carboxymethyl ammonium carbobetaine), myristic acid amidopropyl- Ν,Ν-dimethyl acetate betaine (N-myristyloyl aminopropyl-N,N-dimethyl-N-carboxymethyl ammonium carbobetaine), cocamide amide propyl-N,N-dimethyl acetate betaine (N-coconut composition alkanoyl aminopropyl-N,N-dimethyl-N-carboxymethyl ammonium carbobetaine), lauryl- N,N-dimethyl-2-hydroxypropyl sulfobetaine (N-lauryl-N,N-dimethyl-N-(2-hydroxy-3 -sulfopropyl) ammonium sulfobetaine), lauric acid amide propyl-N,N-dimethyl-23-hydroxypropyl betaine (N- lauroyl aminopropyl-N,N-dimethyl-N-(2-hydroxy-3-sulfopropyl) ammonium sulfobetaine), and an alkyl amine oxide having two alkyl groups containing 2 or less carbon atoms and one long-chain alkyl group containing 8 to 22 carbon atoms, which optionally may have an amide linkage.
Cationic surfactants that may be used in compositions and methods described herein include, but are not limited to, a long-chain dialkyl dimethyl ammonium salt, long-chain monoalkyl monobenzyl dimethyl ammonium salt, and monoalkyl trimethyl ammonium salt having a long alkyl chain containing 6 to 24 carbon atoms, and preferably 6 to 18 carbon atoms, which may be interrupted therein with an amide or ester linkage. The counterion of such cationic species is preferably a halogen ion, sulfate ion, or alkyl sulfate containing 1 to 3 carbon atoms. The cationic surfactants of amine type useful in compositions and methods described herein include long-chain dialkyl monomethylamine salts having a long alkyl chain containing 8 to 24 carbon atoms, which optionally may be interrupted therein with an amide or ester linkage. Preferred counterions of such species include hydrochlorides, sulfates, and phosphates thereof.
Pharmaceutical compositions of the invention comprise at least one fungicide and/or antifungal compound described herein and may be prepared in a unit-dosage form appropriate for a desired mode of administration. The pharmaceutical formulations of the present invention may be administered for therapy (including for preventive therapy) by any suitable route including, but not limited to, oral, buccal, sublingual, rectal, mucosal (mucosa), nasal, topical, dermal, vaginal and parenteral (including, but not limited to, subcutaneous, intramuscular, intravenous, and intradermal). It will be appreciated that the preferred route will vary with the condition and age of the individual receiving the pharmaceutical composition, the nature of the condition to be treated, and the chosen fungicide and/or antifungal compound of the present invention. A pharmaceutically acceptable carrier used in a pharmaceutical composition of the invention must be "acceptable" in the sense of being compatible with the other agents and ingredients of the composition and not prohibitively deleterious to the patient to whom the pharmaceutical composition is administered.
An fungicide and/or antifungal compound of the invention may be administered alone, but will generally be administered as pharmaceutical formulations suitable for administration.
Pharmaceutical formulations known in the art contemplated herein. Pharmaceutical formulations of this invention comprise a therapeutically effective amount of at least one compound of the present invention, and an inert, pharmaceutically or cosmetically acceptable carrier or diluent. As used herein the language "pharmaceutically acceptable carrier" or a "cosmetically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical or cosmetic administration, respectively. Except insofar as any conventional media or agent is incompatible with an fungicide and/or antifungal compound of the invention, use thereof in the formulation is contemplated.
Descriptions of suitable pharmaceutically acceptable carriers, formulations, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington's Pharmaceutical Sciences, 17th ed., (Mack Publishing Company, Easton, Pennsylvania, 1985), which is incorporated herein by reference.
A preferred pharmaceutical composition comprises an effective amount of one or more fungicide and/or antifungal compounds described herein in combination with a pharmaceutically acceptable carrier, and, optionally, one or more other active agents, diluents, fillers, or excipients. An excipient is a compound that improves or provides a desirable physical property to a composition. An excipient useful in a composition described herein includes, but is not limited, an emulsifying agent, pH buffering agent, a dispersing agent, co-solvent, a gelling agent, and a drying agent.
While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical, preferably the compound is present as an active ingredient in a pharmaceutical composition. The invention thus further provides a pharmaceutical composition comprising an fungicide and/or antifungal compound described herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers therefor and, optionally, one or more other therapeutic or beneficial agents known in the art, such as, an antibiotic, another antifungal drug, an anti-protozoan drug, an anti-viral compound, an anti-cancer compound, a vitamin, a trace metal supplement, or an ion supplement to restore or maintain proper ionic balance in blood or other tissues. Other examples of suitable therapeutic agents that may be used in combination with fungicide and/or antifungal compounds of this invention include, without limitation, penicillins and other beta lactamase inhibitors, carbapenems, cephalosporins, macrolides (including erythromycin and ketolides), sulfonamides, aminoglycosides, quinolones (such as fluoroquinolones), oxazolidinones, lipopeptides (such as daptomycin), tetracyclines, vancomycin, erythromycin, streptomycin, efflux pump inhibitors, lactoferrins, and cationic peptides. Such agents may be administered to an individual in the same pharmaceutical composition comprising an fungicide and/or antifungal compound of this invention or in a separate composition.
A composition comprising a fungicide and/or antifungal compound of the invention may further comprise one or more antibiotics such as, but not limited to, penicillin,cephalosporin, cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, ampicillin, amoxicillin, bacampicillin, azlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, azithromycin, clarithromycin, clindamycin, erythromycin, lincomycin, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, quinolone, cinoxacin, nalidixic acid, fluoroquinolone, ciprofloxacin, enoxacin, grepafloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, sulfonamide, trimethoprim-sulfamethoxazole, co-amoxyclav, cephalothin, cefuroxime, ceftriaxone, vancomycin, gentamicin, amikacin, metronidazole, chloramphenicol, nitrofurantoin, co-trimoxazole, rifampicin, isoniazid, pyrazinamide, kirromycin, thiostrepton, micrococcin, fusidic acid, thiolactomycin, fosmidomycin, and the like.
A composition comprising a fungicide and/or antifungal compound of the invention may further comprise one or more antifungal agents such as, but not limited to, amphotericin B, fluconazole, itraconazole, ketoconazole, potassium iodide, flucytosine, caspofungin acetate, nystatin, and the like.
A composition comprising a fungicide and/or antifungal compound of the invention may further comprise one or more anti-protozoan agents such as, but not limited to chloroquine, doxycycline, mefloquine, metronidazole, eplornithine, furazolidone, hydroxychloroquine, iodoquinol, pentamidine, mebendazole, piperazine, halofan trine, primaquine, pyrimethamine sulfadoxine, doxycycline, clindamycin, quinine sulfate, quinidine gluconate, quinine dihydrochloride, hydroxychloroquine sulfate, proguanil, quinine, clindamycin, atovaquone, azithromycin, suramin, melarsoprol, eflornithine, nifurtimox, amphotericin B, sodium stibogluconate, pentamidine isethionate, trimethoprim- sulfamethoxazole, pyrimethamine, sulfadiazine, and the like.
A composition comprising a fungicide and/or antifungal compound of the invention may further comprise one or more anti-proliferative agents such as, but not limited to, altretamine, amifostine, anastrozole, arsenic trioxide, bexarotene, bleomycin, busulfan, capecitabine, carboplatin, carmustine, celecoxib, chlorambucil, cisplatin, cisplatin-epinephrine gel, cladribine, liposomal cytarabine, daunorubicin (same as daunomycin), liposomal daunoribin, dexrazoxane, docetaxel, doxorubicin, liposomal doxorubicin, epirubicin, estramustine, etoposide phosphate, etoposide VP- 16, exemestane, fludarabine, fluorouracil 5-FU, fulvestrant, gemicitabine, gemtuzumab-ozogamicin, goserelin acetate, hydroxyurea, idarubicin, ifosfamide, imatinib mesylate, irinotecan, letrozole, leucovorin, levamisole, melphalan L-PAM, mesna, methotrexate, methoxsalen, mitomycin C, mitoxantrone, paclitaxel, pamidronate, pegademase, pentostain, porfimer sodium, streptozocin, talc, tamoxifen, temozolamide, teniposide VM-26, topotecan, toremifene, tretinoin, ATRA, valrubicin, vinorelbine, zoledronate, steroids, and the like.
Additional combination therapies may also include a compound of this invention. Clearly, the combination therapies described herein are merely exemplary and are not meant to limit possibilities for other combination treatments or co-administration regimens.
Pharmaceutical compositions according to the invention include those suitable for administration to an individual by any medically acceptable route including, but not limited to, parenteral, subcutaneous, intramuscular, intravenous, auricular (ear), ocular, intra-articular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary (e.g., by inhalation or insufflation), intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, oral, rectal, buccal, sublingual, intranasal, and transdermal. The pharmaceutical compositions may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmaceutical compositions.
Pharmaceutical compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of a compound of the invention in a powder or granule form, in a solution, in a suspension, or as an emulsion. A compound of the invention may also be presented as a bolus, electuary, or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
The compounds according to the invention may also be formulated for parenteral administration (e.g., by injection as a bolus or by continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion, 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. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water or pharmaceutically acceptable buffer, prior to use.
For topical administration to the epidermis, fungicide and/or antifungal compounds according to the invention may be formulated as ointments, creams, gels, jellies, or lotions. A compound of the invention may also be incorporated into a transdermal patch. Such transdermal patches may contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol, t-anethole, and the like. Ointments and creams may, for example, be formulated with an aqueous or oily base comprising one or more 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.
Compositions suitable for topical administration of a fungicide and/or antifungal compound of the invention in the mouth include lozenges comprising the compound, optionally, in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Pharmaceutical compositions suitable for rectal administration wherein the carrier is a solid are presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of a compound of the invention with the softened or melted carrier(s) followed by chilling and shaping in molds.
Pharmaceutical compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or sprays containing in addition to a compound of the invention such carriers as are known in the art to be appropriate.
For intra-nasal administration the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops. Drops may be formulated with an aqueous or nonaqueous base also comprising one more dispersing agents, solubilizing agents, or suspending agents. Liquid sprays may conveniently be delivered from pressurized packs.
For administration by inhalation, the compounds according to the invention may conveniently be delivered from an insufflator, nebulizer, a pressurized pack, or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example, a powder mix of a compound of the invention and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges, or, for example, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
A fungicide and/or antifungal compound of the invention may also be formulated into a pharmaceutical composition for treating an eye or ear infection. Pharmaceutical compositions comprising a fungicide and/or antifungal compound of the invention for treating an eye or ear disease may be a liquid or lotion, which may be administered directly into or on the infected eye or ear. Such compositions may be formulated in a manner similar to any of those known and used to administer an antibiotic to an eye or ear, such as compositions comprising fluoroquinolones (see, e.g., Am. Fam. Physician, 62: 1870-1876 (2000), and references cited therein).
When desired, the above described compositions may be adapted to give a sustained or time- delayed release of compound of the invention using any of the sustained or time-delayed formats available in art.
When a compound of the invention or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic compound, the dose of each compound may be either the same as or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. The ratio between a compound of the present invention and a second therapeutic compound for co-administration to a patient will be readily appreciated by those skilled in the art. For example, one may use a ratio in the range from about 1 : 1 to about 1 :50 (by weight) of fungicide and/or antifungal compound of the invention: second therapeutic compound or, vice versa, i.e., of the second compound: fungicide and/or antifungal compound of the invention. In additional embodiments, the ranges of ratios that may be used in preparing a composition for coadministration of an fungicide and/or antifungal compound of the invention with a second therapeutic compound include, without limitation: about 1 : 1 to about 1 :30 (by weight), about 1 : 1 to about 1: 20 (by weight), about 1: 1 to about 1 : 15 (by weight), about 1: 1 to about 1: 10 (by weight), about 1: 1 to about 1 :5 (by weight), and about 1 : 1 to about 1:3 (by weight) of a fungicide and/or antifungal compound of the invention: second therapeutic compound, or vice versa. If yet a further therapeutic compound(s) is added, ratios are adjusted accordingly.
An fungicide and/or antifungal compound of the invention may be provided and packaged in any of a variety of forms as described above, including in a powder or lyophilized state for reconstitution with sterile water or buffer, in unit doses for convenient administration, with one or more pharmaceutically acceptable buffers or salts, and/or with instructions for using the packaged compound as an antifungal to treat an infection by a fungal pathogen.
Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD5o/ED5o. Fungicide and/or antifungal compounds that exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells of an individual and, thereby, reduce untoward side effects.
Data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in a method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test fungicide and/or antifungal compound that achieves a half-maximal inhibition of microbial growth). Such information can be used to more accurately determine useful doses for humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.
The following examples are provided to illustrate various embodiments of the present invention and shall not be considered as limiting in scope.
Examples Example 1. Determination of minimum inhibitory concentration (MIC) of select compounds
The following compounds were synthesized using the established chemistries described herein and were tested for in vitro inhibition of a panel of fungi using the broth microdilution method in accordance with Clinical Laboratory Standards Institute guidelines (See, as an example, Clinical and Laboratory Standards Institute Approved Standard M27-A2— Seventh Edition, Clinical and Laboratory Standards Institute, Wayne, PA (2006)). Minimum inhibitory concentrations (MIC) values were determined for Candida albicans, Candida krusei, Saccharomyces cerevesiae, Cryptococcus neoformans Cnl8 Serotype C.
The results are shown in Table 1 below.
Table 1.
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
The data in Table 1 show the organic compounds of the present invention are effective in inhibiting growth of a range of fungal cells. Consideration of the foregoing data defined a new group of compounds of related structure that are useful as antifungal compounds, and particularly, inhibit growth of fungal cells, and may have further potency and/or toxicity profiles that make them candidates for use as therapeutic agents. The new family of antimicrobial compounds can be described by the Formula I:
Figure imgf000081_0002
Figure imgf000082_0001
wherein:
n is 1 or 2;
X1 is N or NR8;
X3 and X5 are each independently NH, NR8, S, O, or S02,
2, X4, and X6, are each independently N or CR ,
Figure imgf000082_0002
wherein^ when Y is
L is a direct bond or a linker which is < < where Z is an optionally substituted aryl, heteroaryl, carboxamide (-CONH- or -NHCO-), or alkyl radical;
and
wherein., when Y is
Figure imgf000082_0003
L is a linker which is a direct bond or is < < where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, carboxamide (-CONH- or -NHCO-), aryl, or heteroaryl radical; and
R1, R2, R3, R4, R6 and R7 are each independently hydrogen, halo, amino, amidino, guanidino, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, amino, alkylamino, acylamino, amido, sulfonamido, mercapto, alkylthio, arylthio, hydroxamate, thioacyl, alkylsulfonyl, or aminosulfonyl; and
R8 is hydrogen, OH, a halogen, or an optionally substituted alkyl; larmaceutically acceptable salts thereof. The compounds identified above are candidates for development as antifungal compounds, and particularly, compounds which inhibit growth of fungal cells.
All publications, patent applications, patents, and other documents cited herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Obvious variations to the disclosed compounds and alternative embodiments of the invention will be apparent to those skilled in the art in view of the foregoing disclosure. All such obvious variants and alternatives are considered to be within the scope of the invention as described herein.

Claims

1. A method of inhibiting or reducing growth of fungi of at least one fungal strain, said method comprising contacting a fungus with an effective amount of at least one antifungal compound having the following structure:
where Y is
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000085_0002
Figure imgf000085_0003
Figure imgf000085_0004
Figure imgf000085_0005
Figure imgf000085_0006
X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, X13, X14, X16, X17, and X18 are each independently C or N,
L is a linker which is a direct bond or is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, carboxamide (-CONH- or -NHCO-), aryl, or heteroaryl radical; and
R1 to R17 are each independently hydrogen, halo, amino, amidino, guanidino, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, amino, substituted amino, acylamino, amido, sulfonamido, mercapto, alkylthio, arylthio, hydroxamate, thioacyl, alkylsulfonyl, or aminosulfonyl; and
R18 is hydrogen, an alkyl, or acyl radical;
or pharmaceutical salts thereof.
2. The method of Claim 1, wherein said at least one antifungal compound fungicide and/or antifungal compound having the structure:
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000087_0002
Figure imgf000087_0004
Figure imgf000087_0005
Figure imgf000087_0006
86
Figure imgf000088_0001
Figure imgf000088_0002
Figure imgf000088_0003
Figure imgf000088_0004
Figure imgf000088_0005
87
Figure imgf000089_0001
Figure imgf000089_0002
Figure imgf000089_0003
Figure imgf000089_0004
Figure imgf000089_0005
Figure imgf000089_0006
88
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000090_0003
Figure imgf000090_0004
Figure imgf000090_0005
89
Figure imgf000091_0001
Figure imgf000091_0002
Figure imgf000091_0003
Figure imgf000091_0004
Figure imgf000091_0005
Figure imgf000091_0006
90
Figure imgf000092_0001
Figure imgf000092_0002
Figure imgf000092_0003
Figure imgf000092_0004
Figure imgf000092_0005
Figure imgf000092_0006
91
Figure imgf000093_0001
Figure imgf000093_0002
Figure imgf000093_0003
Figure imgf000093_0004
Figure imgf000093_0005
Figure imgf000093_0006
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000094_0003
Figure imgf000094_0004
Figure imgf000094_0005
Figure imgf000094_0006
93
Figure imgf000095_0001
Figure imgf000095_0002
Figure imgf000095_0003
Figure imgf000095_0004
Figure imgf000095_0005
Figure imgf000095_0006
94
Figure imgf000096_0001
Figure imgf000096_0002
Figure imgf000096_0003
Figure imgf000096_0004
Figure imgf000096_0005
Figure imgf000096_0006
Figure imgf000097_0001
Figure imgf000097_0002
Figure imgf000097_0003
3. The method according to any of the preceding claims, wherein said at least one fungal strain is selected from the group consisting of species of: Candida, Aspergillus, Cryptococcus, Histoplasma, and Pneumocystis.
4. The method according to Claim 3, wherein said species of Candida is selected from the group consisting of C. albicans, C. parapsilosis, C. tropicalis, C. krusei, C. glabrata, and C. guillermondii.
5. The method according to Claim 3, wherein said species of Aspergillus is selected from the group consisting of A. fumgatus, A. niger, and A. flavus^
6. The method according to Claim 3, wherein said species of Cryptococcus is selected from the group consisting of C. neoformans, C. laurentii, C. albidus, and C. gatti.
1. The method according to Claim 3, wherein said species of Histoplasma is H. capsulatum.
8. The method according to Claim 3, wherein said species of Pneumocystis is P. jiroveci.
9. The method according to Claim 3, wherein said species is selected from the group consisting of:
Candida albicans, Candida krusei, Saccharomyces cerevesiae, and Cryptococcus neoformans Cnl8 Serotype C.
10. The method according to any of the preceding claims, wherein said method inhibits or reduces growth of fungi of at least two or more fungal strains.
11. The method according to any of the preceding claims, wherein said fungi is present in an individual, plant, crop, or foodstuff.
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