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WO1999004789A1 - Derives d'aurone substitues - Google Patents

Derives d'aurone substitues Download PDF

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Publication number
WO1999004789A1
WO1999004789A1 PCT/US1998/015388 US9815388W WO9904789A1 WO 1999004789 A1 WO1999004789 A1 WO 1999004789A1 US 9815388 W US9815388 W US 9815388W WO 9904789 A1 WO9904789 A1 WO 9904789A1
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WIPO (PCT)
Prior art keywords
alkyl
alkoxy
alkenyloxy
alkenyl
compound
Prior art date
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PCT/US1998/015388
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English (en)
Inventor
Wai-Lam Alex Chu
Flemming R. Jensen
Thomas B. Jensen
Birgitte SØKILDE
Alexandra SANTANA-SØRENSON
James B. Mcalpine
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Phytera Inc
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Phytera Inc
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Priority to AU85876/98A priority Critical patent/AU751213B2/en
Priority to CA002297753A priority patent/CA2297753A1/fr
Priority to JP2000503845A priority patent/JP2001510801A/ja
Priority to EP98937084A priority patent/EP1005338A4/fr
Priority to BR9811554-5A priority patent/BR9811554A/pt
Publication of WO1999004789A1 publication Critical patent/WO1999004789A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms

Definitions

  • the invention relates to methods of inhibiting microbial infections with substituted aurone derivatives.
  • Microbial infections such as fungal infections and bacterial infections, can contribute to and complicate many diseases, including meningitis, pulmonary diseases, and respiratory tract diseases.
  • Opportunistic infections have proliferated, particularly in immunocompromised patients, such as those with AIDS, those undergoing chemotherapy for cancer, and those undergoing therapy to prevent graft rejection following organ transplant surgery.
  • Fungal infections may be cutaneous, subcutaneous, or systemic.
  • Superficial mycoses include tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, pityriasis versicolor, oral thrush, and other candidoses such as vaginal, respiratory tract, biliary, eosophageal, and urinary tract candidoses.
  • Systemic mycoses include systemic and mucocutaneous candidosis, cryptococcosis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, and sporotrichosis.
  • Pathogenic organisms include dermatophytes (e.g., Microsporum canis and other M. spp.; and Trichophyton spp. such as T. rubrum, and T. mentagrophytes), yeasts (e.g., Candida albicans or C. tropicalis), Torulopsis glabrata, Epidermophyton floccosum, Malassezia furfur (Pityropsporon orbiculare, or P.
  • dermatophytes e.g., Microsporum canis and other M. spp.; and Trichophyton spp. such as T. rubrum, and T. mentagrophytes
  • yeasts e.g., Candida albicans or C. tropicalis
  • Torulopsis glabrata e.g., Candida albicans or C. tropicalis
  • Torulopsis glabrata e.g., Candida albicans or C. tropicalis
  • Torulopsis glabrata e.g., Candida albican
  • Cryptococcus neoformans Aspergillus fumigatus and other Aspergillus spp.
  • Zygomycetes e.g., Rhizopus, Mucor
  • Paracoccidioides brasiliensis Blastomyces dermatitidis, Histoplasma capuslatum, Coccidioides immitis, and Sporothrix schenckii.
  • the invention features a method for treating a microbial infection.
  • the method includes administering to a patient a pharmaceutical composition containing a compound selected from formula (IA):
  • each R is independently H, OH, Br, Cl, I, amino, thiol, nitro, C 1-4 alkoxy,
  • C,. 4 alkenyloxy, C 2 remedy 6 alkoxyalkyleneoxy, C M alkylthio, C 3 . 18 alkyl, or C 3 . 18 alkenyl; or two adjacent Rs, taken together, are a C 2- ⁇ 8 bivalent moiety containing at least one oxgen atom, substituted or disubstituted with A or B, or both, A being H, OH, Br, Cl, I, amino, or thiol, and B being H, C 0 alkyl, C 2 ., 8 alkenyl, or C 6 .
  • X is phenyl substituted with a substituent containing three rings and with two additional substituents independently selected from OH, alkoxy, and alkenyloxy, the remaining R cannot be prenyl;
  • X is C 4 . 10 alkyl, C 4 . 20 alkenyl, or a C 4 . 20 single, C 6 . 20 bridged, or C 6 .
  • the infection can be, for example, a fungal infection or
  • the invention features a compound selected from formulae (I)-(IV) below:
  • V is a bivalent C 2 . 18 moiety containing at least one oxygen atom and substituted with A, B, or both; each of W and W is independently selected from the values for A, cyano, nitro, C,. 4 alkoxy, C,. alkenyloxy, C 2 . 6 alkyloxyalkyleneoxy, C 2 . 7 carboxyalkyloxy, C 7 . 15 arylalkoxy, and C,. 4 alkylthio;
  • R a is H, C 3-lg alkyl, C 3 . lg alkenyl, C 5 . lg cyclohexenyl, or C 6 . 18 aryl; each of R b and R c is independently selected from H and C,. 4 alkyl;
  • X is substituted or unsubstituted C 3 . 15 alkyl, C 3 . 18 alkenyl, C 3 . l5 cycloalkyl, C 4 ., 5 cycloalkenyl, C 4 . 20 bicyclo[a.b.c]alkyl, C 5 . 20 bicyclo[a.b.c] alkenyl, C 8 . 20 tricyclo[a.b.c.d]alkyl, C 8 . 20 tricycloalkenyl, or C 2 .
  • heterobicyclo[a.b.c]alkyl or a combination thereof, where each of a, b, c, and d is independently 0 to 10 (e.g., 0 to 4, 0 to 6, or 1 to 7); and each of Y and Z is independently selected from O and S.
  • the invention also features synthetic methods suitable for combinatorial synthetic strategies for the production of diverse libraries of structurally related compounds.
  • Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
  • the invention features a method of inhibiting a microbial infection, wherein the compound of formula (IA) is selected from formulae (I)-(IV):
  • V is a bivalent C 2 . 18 moiety containing at least one oxygen atom and substituted with A, B, or both.
  • V can contain between 1 and 3 rings, e.g., 1 ring, 2 rings, or three rings.
  • V can be selected from the following five formulae:
  • Each of W and W is independently selected from the values for A, cyano, nitro, C alkoxy, C M alkenyloxy, C 2.6 alkyloxyalkyleneoxy, C 2 . 7 carboxyalkyloxy, C- 7 ., 5 arylalkoxy, and C,. 4 alkylthio.
  • R a is H, C 3 . Ig alkyl, C 3.I8 alkenyl, C 5 ., g cyclohexenyl, or C 6 . lg aryl.
  • R, is H, prop-2-enyl, cinnamyl, 2-methylprop-2-enyl, but-2-enyl, 3-methylbut-2-enyl, 3,7-dimethylocta-2,6-dienyl, (cyclohexenyl)methyl, 3,7,1 l-trimethyldodeca-2,6.10-trienyl, or benzyl.
  • 1 ⁇ is not prenyl or isoprenyl.
  • each of R b and R,. is independently selected from H and C,. 4 alkyl.
  • the compounds are of the formula Q-H 2 , where the two hydrogens are methylene hydrogens.
  • the compound has an IC 50 of less than 50 micrograms per milliliter against at least one pathogenic strain of Candida or Aspergillus.
  • the compound is of formula (III), where each of Y and
  • Z is independently selected from O and S, for example, formulae S01-S06 and S08-S19 of Scheme P-l.
  • Other embodiments include a compound where: W and W are selected from H, OH, methoxy, methoxymethyleneoxy, and carboxyr ⁇ ethoxy; where Y and Z are O, and at least one of W and W is OH; where X is a heterocyclic radical, e.g., a heteroaryl; where X is C 4 . 10 alkyl, C 4 . 20 alkenyl, or a C 4 . 20 single, C 6 . 20 bridged, or C 6 .
  • Examples of X include benzyl, 2,5-dimethoxyphenyl, 2,3-dimethyl-4-methoxyphenyl, 3-benzyloxyphenyl, 3-phenoxyphenyl,
  • X-l through X-10 have the formulae X-CHO.
  • the fungal infection can be: an infection of a Candida species, an infection of a fungus resistant to at least one azole antifungal agent (e.g., where the azole antifungal agent is fluconazole); or an infection of an Aspergillus species.
  • pathogen strains examples include C. albicans, C glabrata, C krusei, C tropicalis, C parapsilosis, A. fumigatus, and A. niger.
  • the invention also features aurone derivatives, such as those described in formulae (I)-(IV) in the Summary section.
  • aurone derivatives such as those described in formulae (I)-(IV) in the Summary section.
  • these compounds include those where X is C 3 . 15 alkyl, C 3 . 18 alkenyl, C 3 . 15 cycloalkyl, C 4 . 15 cycloalkenyl, C 5 _ 10 bicyclo[a.b.c]alkyl, C 5 . 10 bicyclo[a.b.c]alkenyl, C 8 . 20 tricyclo[a.b.c.d]alkyl, C 8 _ 20 tricycloalkenyl, C 3 .
  • each of W and W is independently selected from H, hydroxyl, methoxy, hydroxymethyl, and halomethyl; and where W and W are both hydroxyl; or a combination thereof.
  • the bridges can be ortho-fused or ortho- and peri-fused.
  • the bridge can be alkylene, azo, azimino, biimino, epidioxy, nitrilo, imino, furano, epoxythioxy, epithio, alkanoxy, epoxy, or alkanoxyalkano (e.g., methanoxymethano).
  • the invention also features additional novel compounds described in the above method of treatment.
  • enantiomers of disclosed compounds are separated.
  • the bridging olefmic bond between Q and X is sometimes preferably E (enthafen) and sometimes preferably Z (zusammen).
  • chiral centers may be (R) or (S).
  • Alkyls may be substituted or unsubstituted and may be straight, branched, or cyclic.
  • alkyl groups have between 1 and 10 carbon atoms, and more preferably have between 1 and 6 carbon atoms.
  • alkyls include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, t-pentyl, sec-pentyl, hexyl, cyclohexyl, isohexyl,
  • alkylene is a bivalent hydrocarbon, e.g., an alkyl group with an additional hydrogen removed, such as methylene, propylene, or 1 ,4-cyclohexylene.
  • Alkoxy groups are alkyl groups linked to the remainder of the molecule, e.g., a ring, by an oxygen. Alkoxy groups also include polyethers, such as methoxyethyloxy.
  • Alkenyls are alkyl groups with one or more unsaturated carbon-carbon bonds, such as cyclopentenyl, cyclopentadienyl, cyclohexadiene, but-2-enyl, 3,4-dimethylpent-3-enyl, allyl, vinyl, prenyl, isoprenyl, and norbornenyl.
  • alkenylenes include vinylene and propenylene.
  • alkynyl groups have one or more triple bonds, and may also include one or more double bonds.
  • Aryls include aromatic rings, substituted or unsubstituted, preferably having between 6 and 20 carbon atoms, and more preferably between 6 and 14 carbon atoms, exclusive of substitution on the ring.
  • aryls include phenyl, naphthyl, indenyl, pentalenyl, anthryl, azulyl, and biphenylyl.
  • Combinations include alkylaryls (e.g., tolyl, xylyl, mesityl, cumenyl, 2-ethyl-4 methylphenyl) and arylalkyls (e.g., benzyl, phenylethyl, ) or arylalkenyls, and divalent arylenes such as 1 ,4-phenylene.
  • alkylaryls e.g., tolyl, xylyl, mesityl, cumenyl, 2-ethyl-4 methylphenyl
  • arylalkyls e.g., benzyl, phenylethyl, ) or arylalkenyls
  • divalent arylenes such as 1 ,4-phenylene.
  • Haloalkyl includes any alkyl (or alkenyl or alkynyl) group where at least one hydrogen is replaced with a halogen (fluorine, chlorine, bromine, or iodine). Where more than one hydrogen is replaced (e.g., a dihaloalkyl or a hexahaloalkyl), the halogens are selected independently and may be on the same carbon atom or on different carbon atoms. Amino-substituted, nitro-substituted, or otherwise substituted alkyls (or alkenyls or alkynyl or aryls) are analogous to the above. Halomethyls include perchloromethyl, bromomethyl, and fluorochloromethy 1.
  • Heterocyclic radicals may be aromatic (heteroaryl) or nonaromatic, and substituted or unsubstituted. They have one, two or three rings which are single, fused, bridged rings, or polycyclic. They contain between 2 and 15 carbon atoms in the ring, i.e., exclusive of substitution. They can be linked to the rest of the molecule through a carbon atom or a heteroatom.
  • Heterocyclic radicals include thienyl, thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, quinuclidinyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, 4H-carbazolyl, carbazolyl, beta-
  • Substituted moieties have one, two, three, or more of the following independently selected substituting moieties (instead of a hydrogen): C,. 10 alkyl, C 2 . 10 alkenyl, C ]0 alkoxy, C 2 . 10 alkenyloxy, C,. 10 haloalkyl, Cj_ 10 haloalkoxy, aryl, aryloxy, hydroxy, nitro, chloro, fluoro, bromo, and iodo, thiol, cyano, and amino.
  • Substituting moieties also include combinations of the above with carbonyl (acyl), sulfonyl, thionyl (e.g., thioketone), and carboxyl, such as alkyloxycarbonyl, arylalkyloxy, (N,N-dialkylamino)alkoxy, arylsulfonyl, and carboxylic acids.
  • substituting moieties have between 1 and 6 carbon atoms, and more preferably have between 1 and 3 carbon atoms.
  • Examples of carbon-containing substituting moieties include chloromethyl, hydroxymethyl, bromoethyl, methoxy, and ethoxy.
  • an alkyl does not have an alkyl or haloalkyl substituent, although, for example, a cycloalkyl may have an alkyl or haloalkyl substituent.
  • the invention also encompasses compounds identical to any of the disclosed structures (e.g., formula (IV)), except that one or more conventional protecting groups are used, such as hydroxyl protecting groups, carboxylate protecting groups, and carbonyl protecting groups. Methods of adding and removing such protecting groups are well known in the art (see, for example, Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M. Wuts, 2nd ed., 1991, Chapters 2-5). For example, the following representative hydroxyl protecting groups are provided.
  • Methyl ethers include methoxymethyl; methylthiomethyl; t-butylthio- methyl; (phenyldimethyldiyl)methoxy-methyl; benzyloxymethyl; p-methoxybenzyl- oxymethyl; (4-methoxyphenoxy)methyl; guaiacolmethyl; t-butoxymethyl; 4- pentenyloxymethyl; siloxymethyl; 2-methoxyethoxym ethyl; 2,2,2-trichloro- ethoxymethyl; bis(2-chloroethoxy)methyl; 2-(trimethylsilyl)ethoxymethyl; tetrahydropyran-2-yl; 3-bromotetrahydropyran-2-yl; 1 -methoxycyclohexyl; 4- methoxy-tetrahydropyran-2-yl; 4-methoxytetrahydrothiopyran-2
  • Ethyl ethers include 1-ethoxy ethyl; l-(2-chloroethoxy)ethyl; 1 -methyl- 1- methoxyethyl; 1 -methyl- l-benzyloxy-2-fluoroethyl; 2,2,2-trichloroethyl; 2-trimethylsilylethyl; 2-(phenylselenyl)ethyl; t-butyl; allyl; p-chlorophenyl; p- methoxyphenyl; and 2,4-dinitrophenyl.
  • Benzyl ethers include benzyl; p-methoxybenzyl; 3,4-dimethoxybenzyl; o- nitrobenzyl; p-nitrobenzyl; p-halobenzyl; 2,6-dichlorobenzyl; p-cyanobenzyl; p-phenylbenzyl; 2- and 4-picolyl; 3-methyl-2-picolyl-N-oxido; diphenylmethyl; p,p'- dinitrobenzhydryl; 5-dibenzosuberyl; triphenylmethyl; ⁇ -naphthyldiphenylmethyl; p- methoxyphenyldiphenylmethyl; di(p-methoxyphenyl)phenylmethyl; tri(p- methoxyphenyl)methyl; 4-(4'-bromo-phenacyloxy)phenyldiphenylmethyl; 4,4',4"- tris(4,5-dichlorophthalimidophenyl)methyl;
  • Silyl ethers include trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; diethylisopropyl-silyl; dimethylthexylsilyl; t- butyldimethylsilyl; t-butyl-diphenylsilyl; tribenzylsilyl; tri-p-xylylsilyl; triphenyl- silyl; diphenylmethylsilyl; and t-butylmethoxyphenylsilyl.
  • Esters include formate; benzoylformate; acetate; chloroacetate; trichloroacetate; methoxyacetate; triphenylmethoxyacetate; phenoxyacetate; p- chlorophenoxyacetate; p-(phosphate)phenylacetate; 3-phenylproprionate; 4- oxopentanoate (levulinate); 4,4-(ethylenedithio)pentanoate; pivaloate; adamantoate; crotonate; 4-methoxycrotonate; benzoate; p-phenylbenzoate; and 2,4,6- trimethylbenzoate.
  • Carbonates include methyl carbonate; 9-fluorenyl-methylcarbonate; ethyl carbonate; 2,2,2-trichloroethyl carbonate; 2-(trimethylsilyl)ethyl carbonate; 2-(phenyl- sulfonyl)ethyl carbonate; 2-(triphenylphosphono)ethyl carbonate; isobutyl carbonate; vinyl carbonate; allyl carbonate; p-nitrophenyl carbonate; benzyl carbonate; p- methoxybenzyl carbonate; 3,4-dimethoxybenzyl carbonate; o-nitrobenzyl carbonate; p-nitrobenzyl carbonate; S-benzyl thiocarbonate; 4-ethoxy-l -naphthyl carbonate; and methyl dithiocarbonate.
  • Protecting groups with assisted cleavage include 2-iodobenzoate; 4-azidobutyrate; 4-nitro-4-methylpentanoate; o-(dibromomethyl)benzoate; 2-formylbenzenesulfonate; 2-(methylthiomethoxy)ethyl carbonate;
  • Miscellaneous esters include 2,6-dichloro-4-methylphenoxyacetate; 2,6- dichloro-4-( 1,1,3 ,3-tetramethyl-butyl)phenoxyacetate; 2,4-bis( 1 , 1 -dimethylpropyl)- phenoxy-acetate; chlorodiphenylacetate; isobutyrate; monosuccinoate; (E)-2-methyl- 2-butenoate (tigloate); o-(methoxycarbonyl)benzoate; p-benzoate; ⁇ -naphthoate; nitrate; alkyl N,N,N',N'-tetramethylphosphorodiamidate; N-phenylcarbamate; borate; dimethylphosphinothioyl; and 2,4-dinitrophenyl-sulfenate.
  • Sulfonates include methanesulfonate (mesylate); benzylsulfonate; and tosylate.
  • Cyclic acetals and ketals include methylene; ethylidene; 1-t- butylethylidene; 1-phenylethylidene; 4-methoxyphenylethylidene; 2,2,2- trichloroethylidene; acetonide (isopropylidene); cyclopentylidene; cyclohexylidene; cycloheptylidene; benzylidene; p-methoxybenzylidene; 2,4-dimethoxybenzylidene; 3,4-dimethoxybenzylidene; and 2-, 3-, or 4-nitrobenzylidene.
  • Cyclic ortho esters include methoxymethylene; ethoxymethylene; dimethoxymethylene; 1-methoxyethylidene; 1 -ethoxyethylidine; 1 ,2-dimethoxy- ethylidene; ⁇ -methoxybenzylidene; l-(N,N-dimethylamino)ethylidene derivative; ⁇ -(N,N-dimethylamino)benzylidene derivative; and 2-oxacyclo-pentylidene.
  • these cyclic ortho esters may react with non-adjacent hydroxyl moieties.
  • a bivalent organic moiety recited in the preceding paragraph or recited above for adjacent pairs of substituents may be selected for two nonadjacent substituents on the same molecule or for any two substituents on two separate molecules.
  • the two separate molecules can be the same or different, and are selected from compounds disclosed herein.
  • Silyl derivatives include di-t-butylsilylene group; 1, 3-(l, 1,3,3- tetraisopropyldisiloxanylidene) derivative; tetra-t-butoxydisiloxane- 1 ,3-diylidene derivative; cyclic carbonates; cyclic boronates; ethyl boronate; and phenyl boronate.
  • Preferred protecting groups for catechols include cyclic acetals and ketals such as methylene, acetonide, cyclohexylidene, and diphenylmethylene; and cyclic esters such as cyclic borate and cyclic carbonate.
  • the invention encompasses other C,_ 10 hydroxyl protecting groups not individually identified above which are pharmaceutically acceptable, and are optionally metabolized (e.g., cleaved or modified) to form one of the compounds disclosed herein.
  • the invention encompasses metabolic precursors of the disclosed compounds and metabolites of the disclosed compounds having antimicrobial activity.
  • the invention also encompasses amides, amine salts, and other organic salts of the disclosed compounds.
  • Amides may be formed by reacting a disclosed compound or activated derivative thereof with any naturally-occurring amino acid, an oligopeptide having up to 10 (e.g., 4, 3, or 2) residues, a peptidomimetic having a molecular weight less than 300, or any C,.
  • naturally occurring amino acid is meant to include the 20 common ⁇ -amino acids (Gly, Ala, Val, Leu, He, Ser, Thr, Asp, Asn, Lys, Glu, Gin, Arg, His, Phe, Cys, Trp, Tyr, Met and Pro), and other amino acids that are natural products, such as norleucine, ethylglycine, ornithine, methylbutenylmethylthreonine, and phenylglycine.
  • 20 common ⁇ -amino acids Gly, Ala, Val, Leu, He, Ser, Thr, Asp, Asn, Lys, Glu, Gin, Arg, His, Phe, Cys, Trp, Tyr, Met and Pro
  • other amino acids that are natural products such as norleucine, ethylglycine, ornithine, methylbutenylmethylthreonine, and phenylglycine.
  • Subjects or patients of the disclosed methods may be any living animal, plant, or plant product (e.g., grain or feed).
  • Animals include mammals, particularly humans. Animals also include domestic animals bred for food or as pets, such as horses, cows, sheep, poultry, fish, pigs, cats, dogs, and zoo animals. Plants include trees, crops, grasses, and flowering plants.
  • the aldehydes were divided into two sets or plates of 80 aldehydes. Each set was reacted with a given benzofuranone. Phenolic hydroxyl groups were protected, for example, as methoxymethyl ethers. In general, the alicyclic or aliphatic aldehydes were less reactive than the aromatic aldehydes and thus required more vigorous conditions, such as higher temperatures. Even so, yields were generally lower than the aromatic aldehydes. Portions of the adducts were screened for antimicrobial activity, and the remainder deprotected with trimethylsilyl chloride in methanol to yield the unprotected aurone, which was also screened for antimicrobial activity.
  • the dried sample was redissolved in 1 ml methanol and divided into 2 equal portions, one of which was dried and tested for antimicrobial activity.
  • To the second portion was added trimethylsilyl chloride (50 ⁇ l).
  • ethyl acetate (1 ml) and saturated sodium bicarbonate (500 ⁇ l) were added.
  • the organic layer was collected and dried.
  • the dried sample was tested for antimicrobial activity.
  • the compounds were tested for antimicrobial activity using, for example, methods described in WO 97/26873.
  • Some preferred anti-Candida compounds have polar substituents on the aldehyde portion of the aurone.
  • aurones including 3,5-di-t-butyl-4-hydroxyphenyl and 2,4-difluorophenyl (again derived from the aldehyde reagent) generally exhibited good inhibition.
  • Less polar substituents tend to improve inhibition of Aspergillus. Inhibition can be measured in terms of an IC 50 , an MIC, or a percent inhibition relative to control (absence of test compound) at a given concentration, such as 8 ⁇ g/ml or 12.5 ⁇ g/ml.
  • a percent inhibition of at least 30% at 8 ⁇ g/ml or 12.5 ⁇ g/ml is preferred (e.g., at least 40%, at least 50%, at least 65%, and least 70%, and at least 85%).
  • Preferred compounds of formula (II) exhibit a percent inhibition of at least 70%, including two as high as 87%.
  • W is OH
  • V is 3',4'-(l,l-dimethylpropyloxy) to form a dihydropyran series
  • X is selected from 3,4-dimethoxyphenyl, 4-t-butylphenyl, 2(prop-2-enyloxy)phenyl, 3-phenoxyphenyl, 3-ethoxy-4-hydroxyphenyl, 6-cyclohexenyl, and norborn-4-yl.
  • the inhibition values of 60 compounds are shown in Tables 1 through 3 on the next three pages.
  • Compounds described herein also have activity against bacteria.
  • the compounds shown in the table below were tested using assays known in the art and were found to have activity against Staphylococcus aureus.
  • compositions including one or more disclosed compounds are useful for inhibiting microbial infections, or combinations of infections.
  • the invention features a method for inhibiting a microbial infection in a subject, which method includes administering a pharmaceutically effective amount of such a composition.
  • One aspect is a method for inhibiting a fungal infection which is resistant or sensitive to known therapies, such as fluconazole or other azoles. Examples of fluconazole-resistant or fluconazole-sensitive strains include C. glabrata, C kefyr, and C. tropicalis.
  • a disclosed composition contains from about 0.1 to 90% by weight (such as about 0.1 to 20%, or about 0.5 to 10%) of active compound(s).
  • Disclosed compositions can be formulated as solids or liquids for oral administration, or as liquids or semi-solids (ointments, creams) for topical administration.
  • the compositions can also be formulated for administration by nebulization or inhalation, or administration by intravenous, intramuscular, or intraperitoneal injection.
  • Formulations for controlled release including implantable or biodegradable or biocompatible matrices, are also contemplated. Controlled release includes continuous and intermittent release. Methods of formulation, including pharmaceutical carriers, are well-known to those in the art.
  • the effective amount of active compound(s) used to practice the present invention for therapeutic or prophylactic treatment of conditions caused by or contributed to by a microbial infection varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount.
  • the target compound (8) was synthesized in the manner described for the synthesis of (5) using 3,4,5-trimethoxyaniline (2.5 g, 13.6 mmol), BC1 3 (1 M in CH 2 C1 2 , 13.6 ml), ZnCl 2 (2.04 g, 15 mmol), and chloroacetonitrile (1.03 ml, 16.3 mmol) in dry CH 2 C1 2 . Purification by column chromatography as described for (5) afforded (8) (1.06 g, 30%) as a cystalline product.
  • Example 4 4.5.6-Trimethoxy-3-indolinone (9)
  • Compound (9) was synthesized from (8) in the same manner as described for the synthesis of (6) using 2-amino-4,5,6-trimethoxy- -chloroacetophenone (1.05 g, 4.0 mmol), K 2 CO 3 (838 mg, 6.1 mmol), a little KI, and dry acetone (50 ml). Purification by column chromatography (eluent: CH 2 Cl 2 /MeOH: 9/1) afforded (9) (190 mg, 21%) as red crystals.
  • Example 9 4-Methoxy-3 -benzofuranone (2) and 6-methoxy-3-benzofuranone (3) These compounds were prepared from 3-methoxyphenol (1) (6 ml, 55 mmol), ZnCl 2 (8.2 g, 60 mmol), and chloroacetonitrile (4.2 g, 66 mmol) in dry ether (100 ml). Purification of the crude product by column chromatography (eluent:
  • Example 11 4.6-Bismethoxymethoxybenzofuranone thioketone This reaction was performed under nitrogen and anhydrous conditions. To a solution of the product of Example 12 (0.3 g, 1.35 mmol) dissolved in 15 ml dry toluene was added Lawesson's reagent (0.36 g, 0.9 mmol). The reaction was refluxed overnight until the ketone was consumed, by TLC. Chromatographic purification (3:1 dichloromethane: petroleum ether and 2% diisopropylethylamine; or 3:1 ethe ⁇ petroleum ether and 2% diisopropylethylamine) gave a slightly yellow clear oil. TLC showed a major and minor product.
  • test compound was tested against nine isolates in an eight-point dose response assay ranging from 50 ⁇ g/ml to 0.39 ⁇ g/ml. Aspergillus MIC's (minimum inhibitory concentrations) were scored visually after 48 and 72 hours at 37 °C. All
  • Candida MIC's were scored visually after a 24 hour incubation at 35 °C.
  • Amphotericin B (2.5 ⁇ g/ml) and 5-flucytosine (2.0 ⁇ g/ml) were standard controls for each antifungal assay. In each case, total inhibition was observed for all assays relative to amphotericin B and 5-flucytosine. The results are shown below in Table 4, MIC values in ⁇ g/ml after 72 hours. HFF toxicity was analyzed after a 24 hour incubation at 37°C (5% CO 2 ). MTS/PMS was added, and the sample absorbance was read at 450 nm. TABLE 4
  • Scheme P-l shows several compounds of the invention.

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Abstract

On décrit un procédé de traitement d'une infection microbienne. Le procédé consiste à administrer à un patient une composition pharmaceutique contenant un composé de formule (IA). Dans la formule (IA) chaque R représente indépendamment H, OH, Br, Cl, I, amino, thiol, nitro, alcoxy C1-4, alcényloxy C1-4, alcoxyalkylèneoxy C2-6, alkylthio C1-4, alkyle C3-18, ou alcényle C3-18; ou bien deux R adjacents forment ensemble une fraction bivalente C2-18 contenant au moins un atome d'oxygène, substituée ou disubstitué avec A ou B ou bien avec les deux, A représentant H, OH, Br, Cl, I, amino, ou thiol, et B représentant H, alkyle C1-10, alcényle C2-18, ou aryle C6-18; à condition qu'au moins deux R ne représentent pas H; et à la condition que lorsque chacun des deux R représentent OH, alcoxy C1-4, alcényloxy C1-4, ou alcoxyalkylèneoxy C2-6, et que X représente phényle substituté par deux subsituants indépendamment sélectionnés parmi OH, alcoxy, et alcényloxy, le R restant ne soit pas prényle; à condition que lorsque chacun des deux R représente OH, alcoxy C1-4, alcényloxy C1-4, ou alcoxyalkylèneoxy C2-6, et que X est phényle substitué par trois substituants indépendamment sélectionnés parmi OH, alcoxy, et alcényloxy, le R restant ne soit pas prényle; à condition que lorsque chacun des deux R représentent OH, alcoxy C1-4, alcényloxy C1-4 ou alcoxyalkylèneoxy C2-6, et que X représente phényle substitué par un substituant prényle et par deux substituants additionels indépendamment sélectionnés parmi OH, alcoxy, et alcényloxy, le R restant ne soit pas H ou OH; à condition également que lorsque chacun des deux R représentent OH, alcoxy C1-4, alcényloxy C1-4, ou alcoxyalkylèneoxy C2-6, et que X représente phényle substitué par un substituant contenant trois cycles et par deux substituants aditionnels indépendamment sélectionnés parmi OH, alcoxy et alcényloxy, le R restant ne puisse être prényle. X représente alkyle C4-10, alcényle C4-20 ou une fraction de cycle simple C4-20, ponté C6-20 ou fusioné C6-20 contenant cycloakyle, cycloalcényle, aryle, hétérocycle ouhétéroaryle, ou X est substitué par H, OH, Cl, Br, I, amino, cyano, alkyle, alcoxy, alcényle, ou alcényloxy; à condition que, si X représente une fraction hétéroaryle ou hétérocyclique dans laquelle deux R représentent chacun OH, et sont méta l'un par rapport à l'autre, alors le R restant représente H et est ortho par rapport à chacun des deux hydroxyles, et Y et Z représentent chacun O, et un atome de cycle de X est lié directement à l'atome de carbone sp2 adjacent à X, puis est substitué par H, OH, Cl, Br, I, amino, cyano, alkyl, alkoxy, alcényle, ou alcényloxy; et Y et Z sont chacun indépendamment sélectionés parmi O, S, et NH. Cette invention concerne un composé de formule (IA) ou un sel pharmaceutiquement acceptable ou un ester de ce dernier.
PCT/US1998/015388 1997-07-25 1998-07-24 Derives d'aurone substitues Ceased WO1999004789A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU85876/98A AU751213B2 (en) 1997-07-25 1998-07-24 Substituted aurone derivatives
CA002297753A CA2297753A1 (fr) 1997-07-25 1998-07-24 Derives d'aurone substitues
JP2000503845A JP2001510801A (ja) 1997-07-25 1998-07-24 置換アウロン誘導体
EP98937084A EP1005338A4 (fr) 1997-07-25 1998-07-24 Derives d'aurone substitues
BR9811554-5A BR9811554A (pt) 1997-07-25 1998-07-24 Derivados de aurona substituìdos

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US5374297P 1997-07-25 1997-07-25
US60/053,742 1997-07-25

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WO (1) WO1999004789A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1247796A3 (fr) * 2001-04-06 2003-10-01 MERCK PATENT GmbH Composés photopolymérisables
GB2386891A (en) * 2002-03-28 2003-10-01 Pantherix Ltd Antibacterial benzofuran-2H-3-ones
US6849203B2 (en) 2001-04-06 2005-02-01 Merck Patent Gesellschaft Mit Beschraenkter Haftung Photoisomerizable compounds
CN104529961A (zh) * 2014-12-29 2015-04-22 贺州学院 荸荠皮提取5-异戊烯基金鱼草素的方法
CN105646417A (zh) * 2016-03-31 2016-06-08 四川大学 一类4-羟基噢哢类化合物、其制备方法和用途
CN106632181A (zh) * 2016-09-30 2017-05-10 四川大学 噢哢曼尼希碱类化合物、其制备方法和用途
CN106632191A (zh) * 2016-09-30 2017-05-10 四川大学 高异黄酮曼尼希碱类化合物、其制备方法和用途
CN109824637A (zh) * 2019-03-13 2019-05-31 南阳师范学院 一种茚酮查尔酮氨基甲酸酯类化合物及其制备方法和用途
US10899727B2 (en) 2016-04-11 2021-01-26 Middle Tennessee State University Therapeutic aurones
WO2024146619A1 (fr) * 2023-01-06 2024-07-11 中国科学院上海药物研究所 Dérivé ou analogue d'aurone, son procédé de préparation, composition pharmaceutique à base de celui-ci et son utilisation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3716531A (en) * 1967-11-14 1973-02-13 Schering Ag 5-nitro-furfurylidene antimicrobic agents
US3975380A (en) * 1974-06-03 1976-08-17 Smithkline Corporation Substituted aurones
US4067993A (en) * 1975-09-24 1978-01-10 Riker Laboratories, Inc. Antimicrobial 2-nitro-3-phenylbenzofurancarboxylic acids
USRE32196E (en) * 1978-09-13 1986-07-01 Lilly Industries Limited Aurone derivatives
US4806660A (en) * 1987-11-06 1989-02-21 Pennwalt Corporation Aurone oxypropanolamines

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1935685A1 (de) * 1969-07-10 1971-01-14 Schering Ag Neue antimikrobiell wirksame Verbindungen
WO1997026873A1 (fr) * 1996-01-26 1997-07-31 Phytera, Inc. Derives d'aurone antimicrobiens

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3716531A (en) * 1967-11-14 1973-02-13 Schering Ag 5-nitro-furfurylidene antimicrobic agents
US3975380A (en) * 1974-06-03 1976-08-17 Smithkline Corporation Substituted aurones
US4067993A (en) * 1975-09-24 1978-01-10 Riker Laboratories, Inc. Antimicrobial 2-nitro-3-phenylbenzofurancarboxylic acids
USRE32196E (en) * 1978-09-13 1986-07-01 Lilly Industries Limited Aurone derivatives
US4806660A (en) * 1987-11-06 1989-02-21 Pennwalt Corporation Aurone oxypropanolamines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1005338A4 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6849203B2 (en) 2001-04-06 2005-02-01 Merck Patent Gesellschaft Mit Beschraenkter Haftung Photoisomerizable compounds
EP1247796A3 (fr) * 2001-04-06 2003-10-01 MERCK PATENT GmbH Composés photopolymérisables
GB2386891A (en) * 2002-03-28 2003-10-01 Pantherix Ltd Antibacterial benzofuran-2H-3-ones
CN104529961A (zh) * 2014-12-29 2015-04-22 贺州学院 荸荠皮提取5-异戊烯基金鱼草素的方法
CN105646417A (zh) * 2016-03-31 2016-06-08 四川大学 一类4-羟基噢哢类化合物、其制备方法和用途
US10899727B2 (en) 2016-04-11 2021-01-26 Middle Tennessee State University Therapeutic aurones
US11286245B2 (en) 2016-04-11 2022-03-29 Middle Tennessee State University Therapeutic aurones
CN106632191A (zh) * 2016-09-30 2017-05-10 四川大学 高异黄酮曼尼希碱类化合物、其制备方法和用途
CN106632181B (zh) * 2016-09-30 2019-03-19 四川大学 噢哢曼尼希碱类化合物、其制备方法和用途
CN106632191B (zh) * 2016-09-30 2018-10-30 四川大学 高异黄酮曼尼希碱类化合物、其制备方法和用途
CN106632181A (zh) * 2016-09-30 2017-05-10 四川大学 噢哢曼尼希碱类化合物、其制备方法和用途
CN109824637A (zh) * 2019-03-13 2019-05-31 南阳师范学院 一种茚酮查尔酮氨基甲酸酯类化合物及其制备方法和用途
WO2024146619A1 (fr) * 2023-01-06 2024-07-11 中国科学院上海药物研究所 Dérivé ou analogue d'aurone, son procédé de préparation, composition pharmaceutique à base de celui-ci et son utilisation

Also Published As

Publication number Publication date
AU8587698A (en) 1999-02-16
EP1005338A4 (fr) 2001-11-07
CA2297753A1 (fr) 1999-02-04
AU751213B2 (en) 2002-08-08
JP2001510801A (ja) 2001-08-07
EP1005338A1 (fr) 2000-06-07
BR9811554A (pt) 2000-09-12

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