WO2010055474A2 - Composés antiviraux et compositions antivirales - Google Patents

Composés antiviraux et compositions antivirales Download PDF

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Publication number
WO2010055474A2
WO2010055474A2 PCT/IB2009/055016 IB2009055016W WO2010055474A2 WO 2010055474 A2 WO2010055474 A2 WO 2010055474A2 IB 2009055016 W IB2009055016 W IB 2009055016W WO 2010055474 A2 WO2010055474 A2 WO 2010055474A2
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Prior art keywords
compound
formula
composition
group
infection
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PCT/IB2009/055016
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English (en)
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WO2010055474A3 (fr
Inventor
Gary Gellerman
Oded Yarden
Alex Aizikovich
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Ariel-University Research And Development Company Ltd.
Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.
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Publication of WO2010055474A2 publication Critical patent/WO2010055474A2/fr
Publication of WO2010055474A3 publication Critical patent/WO2010055474A3/fr

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/18—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, directly attached to a heterocyclic or cycloaliphatic ring
    • 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
    • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
    • A01N35/04—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical containing aldehyde or keto groups, or thio analogues thereof, directly attached to an aromatic ring system, e.g. acetophenone; Derivatives thereof, e.g. acetals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
    • A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
    • A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
    • A23L3/3463—Organic compounds; Microorganisms; Enzymes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
    • A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
    • A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
    • A23L3/3463—Organic compounds; Microorganisms; Enzymes
    • A23L3/3526—Organic compounds containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to the field of antimicrobial compounds and compositions and especially anti-fungal and anti-oomycete compounds and compositions.
  • microbes cause infections that exact a high toll in terms of pathogenesis in humans, non-human animals and plants as well as in terms of direct economic damage to animals and animal products, plants and plant products and industrial products.
  • fungi including yeasts and molds
  • oomycetes There are many different types of microbes that cause such infection including fungi (including yeasts and molds) and oomycetes.
  • Fungi is a kingdom of eukaryotic organisms. Many species of fungi are known, about 400 of which are pathogenic to man, animals or plants. Some fungi cause damage to surfaces, e.g. mildew on walls.
  • fungi are multicellular. Such fungi germinate from spores and grow as filaments termed hyphae. As the hyphae grow, they branch repeatedly. Hyphae from individual fungal cells interconnect with hyphae from other cells, forming one larger structure termed the mycelium. There is some disagreement as how to classify fungi, althouh one approach is to divide fungi (including molds) into phyla based on characteristics of the reproductive organs. Yeasts are unicellular, with individual cells being spheroid or elongated, and reproduce by dividing in a fashion similar to animal cells. However, some yeasts, such as Candida, can grow in hyphal form and also produce strucutres known as chlamydospores.
  • Oomycetes are a class of eukaryotic organisms of the phylum heterozziphyta popularly known as water molds, which superficially resemble Fungi. Some species of Oomycetes are plant or animal pathogens, the main pathogenic species being Phytophthora, Pythium, and downy mildew.
  • Phytophthora infestans which causes potato blight
  • Phytophthora sojae which causes stem and root rot of soybean
  • Phytophthora alni which causes alder root rot
  • Phytophthora cactorum which causes rhodendron root rot affecting rhodendrons and azaleas
  • Phytophthora capsi which affects Cucurbitacea fruits, such as cucumbers and squash
  • Phytophthora cinnamomi which causes cinnamon root rot affecting woody ornamentals including arborvitae, azalea, Chamaecyparis, dogwood, forsythia, Fraser fir, hemlock, Japanese holly, juniper, Pieris, rhodendron, Taxus, white pine, American chestnut and Australian Jarrah
  • Phytophthora fragariae which causes red root rot affecting strawberries
  • Phytophthora kernoviae a path
  • Pythium species are known, many of which are plant pathogens. Some species of Pythium kill seedlings in greenhouses by damping off. For example, Pythium aphanidermatum is an aggressive pathogen that causes damping off, root and stem rots, and blights, especially in greenhouses. Economic damage is primarily in greenhouses, beets, peppers, cucurbits, beans, broccoli, chrysanthemums, begonia, pansy, cotton and grasses. Pythium aphanidermatum infection is usually treated by soil drenches of fungicide compositions both prophylactically and curatively, by irrigation or by foliar spray (both air and ground). Pythium aphanidermatum is considered a re-emerging disease due to strains developing resistance to previously known treatments (e.g., mefenoxam). Pythium insidiosum is known to infect mammals.
  • antimicrobial compounds for treatment of fungal infections and oomycete infections.
  • anti-fungal compounds include polyene antifungals, imidazole, triazole and thiazole antifungals, allylamines, echinocandines, and others.
  • fungicides are extensively used to prevent and curb the progression of plant diseases that have severe adverse effects on crop yields and quality.
  • the prolonged and repeated use of many fungicides has resulted in the proliferation of plant pathogen isolates that are resistant to the fungicides employed. Therefore, identifying new classes of antifungal compounds based on structures not previously used in combating plant diseases may assist in the control of plant pathogens that are tolerant or resistant to known compounds.
  • an antimicrobial composition comprising at least one compound selected from the group consisting of a compound of Formula I:
  • Z is chosen from the group consisting of O and S; n is an integer from 0 to 20; each X is independently selected from the group consisting of H and F; each of R 1 , R 2 R 3 and R 4 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, amino and -NR 5 R 6 , or, alternatively, two of R 2 , R 3 and R 4 form a five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring; and
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or, alternatively R 5 and R 6 form a five- or six- member aromatic, heteroaromatic, alicyclic or heteroalicyclic ring.
  • a method of treating an infection by microbes comprising administering an effective amount of the compositions described above.
  • the compound of Formula I is selected from the group consisting of compounds having the Formulae NP-25, NP- 18a, NP-5, NP- 17, NP-6, NP-IO, NP- 19a, AG-5, AG-2 and AG-4.
  • the compound of Formula II comprises NP- 18b.
  • the microbes are selected from the group consisting of fungi and oomycetes.
  • the fungi are members of a phylum selected from the group consisting of Chytridiomycota; Blastocladiomycota; Neocallimastigomycota; Zygomycota; Glomeromycota; Ascomycota; Basidiomycota; and Deuteromycota.
  • the fungi are selected from the group consisting of yeast and mold.
  • the mold is a member of a phylum selected from the group consisting of Zygomycota, Deuteromycota, and Ascomycota.
  • the Ascomycota is selected from the group consisting of Aspergillus, Sclerotinia, Botrytis, Penicillum, Neurospora, Alternaria; Verticillium and Candida. In some embodiments, the Aspergillus is selected from the group consisting of
  • the Sclerotinia is selected from the group consisting of Sclerotinia sclerotiorum, Sclerotinia trifoliorum and Sclerotinia minor.
  • the Sclerotinia sclerotiorum comprises sclerotiorum and the compound of Formula I comprises AG-5.
  • the Botrytis is selected from the group consisting of Botrytis cinerea, Botrytis convolute, Botrytis polyblastis, Botrytis allii and Botrytis fabae. In some embodiments, the Botrytis comprises Botrytis cinerea, and the compound of
  • Formula I is selected from the group consisting of NP- 19a, NP- 18a and AG-5.
  • the Penicillum is selected from the group consisting of Penicillium chrysogenum, Penicillium citrinum, Penicillium janthinellum, Penicillium marneffei, Penicillium purpurogenum, Penicillium expansum, Penicillium funiculosum and Penicillium digitatum.
  • the Penicillium comprises Penicillium digitatum, and the compound of Formula I or Formula II is selected from the group consisting of NP- 19a, NP-18a and NP-IO.
  • the Neurospora comprises Neurospora crassa
  • the compound of Formula I or Formula II is selected from the group consisting of NP-6, NP- 19a, NP- 18b, NP- 18a, AG-5 and AG-4.
  • the Alternaria comprises Alternaria alternaria
  • the compound of Formula I comprises NP- 18a.
  • the Verticillium comprises Verticillium dahlia.
  • the Candida comprises Candida albicans.
  • the Basidiomycota comprises Rhizoctonia solani and the compound of Formula I is selected from the group consisting of NP-6 and NP- 18a.
  • the oomycete is selected from the group consisting of
  • the Phytophthora is selected from the group consisting of Phytophthora infestans; Phytophthora sojae; Phytophthora alni; Phytophthora cactorum; Phytophthora capsi; Phytophthora cinnamomi;
  • the Pythium is selected from the group consisting of Pythium aphanidermatum and Pythium insidiosum. In some embodiments, the Pythium comprises Pythium aphanidermatum and the composition comprises at least one selected from the group consisting of a compound of Formula AG-5,
  • the composition comprises a sprayable composition.
  • the composition comprises a liquid carrier. According to an aspect of some embodiments of the invention, there is also provided a use of a composition described above for prevention or delay of development of an infection by microbes in a food stuff.
  • the foodstuff is selected from the group consisting of a fruit, vegetables and a grain.
  • the composition is applied to the foodstuff post-harvest.
  • a composition described above is a medicament for human use.
  • the compositions is for the treatment of a condition selected from the group consisting of diaper rash, an infection of the mouth, a genital infection, a nail infection, tinea pedis, tinea crutis; tinea capitis; finger tinea unguium; tinea corporis; tinea barbae and Aspergilliosis.
  • a composition described above is a medicament for veterinary use. In some embodiments, the composition is used as a medicament for veterinary medicine.
  • a composition described above is configured for use in agriculture. In some embodiments, the composition is used in agriculture. In some embodiments, a composition described above is configured for use in animal husbandry. In some embodiments, the composition is used in animal husbandry.
  • a composition described above is configured for use in treating plants or plant matter.
  • the composition is used for treating plant or plant matter.
  • the plants or plant matter comprises living plants, seeds, harvested fruit and grain.
  • a composition described above is configured for use in treating soil.
  • the composition is used for treating soil.
  • the composition is applied to soil during soil irrigation
  • the composition described above is a topical composition.
  • the composition is topically applied.
  • the composition is configured for application to a surface selected from the group consisting of a surface of an animal, a surface of a plant, a soil surface and a surface of an inanimate object.
  • the surface of an animal is selected from the group consisting of skin, keratinous surface and mucous membrane.
  • the surface of a plant is selected from the group consisting of a surface of a leaf, a surface of a stalk, a surface of a fruit and a surface of a seed.
  • the composition comprises a form selected from the group consisting of a cream, a spray, an ointment, a lotion, a solution, a suspension, a spray, a wash, a paint and a lacquer.
  • the composition is configured for use with edible products. In some embodiments, the composition is used by applying to an edible product.
  • the composition is applied to a wrapping for an edible product, such as a food wrapping, a food container, or a food additive.
  • a wrapping for an edible product such as a food wrapping, a food container, or a food additive.
  • composition comprising a compound selected from the group consisting of NP- 18b and NP-100 for the treatment of an infection by Penicillium digitatum.
  • composition comprising a compound selected from the group consisting of NP- 19a, NP- 18a, and AG-5 for the treatment of an infection by Botrytis cinerea.
  • composition comprising a compound selected from the group consisting of NP- 18b, NP-19a, NP-IO and AG-5, for the treatment of an infection by Pythium aphanidermatum.
  • composition comprising a compound selected from the group consisting of NP-6, NP- 19a, NP-18b, NP- 18a, NP-10, AG-5 and AG-4, for the treatment of an infection by Neurospora crassa.
  • a composition comprising NP- 18a for the treatment of an infection by Alternaria alternate.
  • a composition comprising a compound selected from the group consisting of NP-6 and NP- 18a for the treatment of an infection by Rhizoctonia solani.
  • a composition described above further comprises an additional agent for the treatment of infection by microbes.
  • an amount of the compound selected from the group consisting of a compound of Formula I and a compound of Formula II, esters thereof, and salts thereof alone, and the amount of the additional antifungal agent alone is insufficient to achieve the antifungal effect achieved by the administration of the combination of the two or more ingredients.
  • the compound of Formula I is (Z)-3-amino-4,4,4-trifluoro-l-
  • Some embodiments of the present invention have at least one beneficial effect in treating microbial infections on plant and animal (including human) species.
  • Beneficial effects include effects such as curing a microbial infection, preventing a microbial infection (i.e., prophylaxis), treating symptoms of a microbial infection, curing symptoms of a microbial infection, ameliorating symptoms of a microbial infection, treating effects of a microbial infection, ameliorating effects of a microbial infection, and preventing results of a microbial infection.
  • FIG. IA shows the chemical structure of compounds of Formula I
  • FIG. IB shows the chemical structure of compound NP-25
  • FIG. 1C shows the chemical structure of compounds of Formula II
  • FIG. ID shows the chemical structure of compound NP- 18b
  • FIG. 2 shows the synthetic route taken to prepare compounds of the invention
  • FIG. 3A and 3B are bar charts showing the plant toxicity of tested compounds on Arabidopsis plant
  • FIGS. 4 and 5 are bar charts showing the in vitro antimicrobial efficacy of tested compounds
  • FIGS. 6A-6D show the in vitro antimicrobial efficacy of compounds NP- 18a, NP- 18b and AG-5 against Botrytis cinerea and Sclerotinia sclerotiorum in Petri dishes;
  • FIG. 6E is a bar chart summarizing the results shown in FIGS. 6A-6D;
  • FIG. 7 is a bar chart showing the effect of compounds NP- 18a, NP- 18b, AG-5, NP-6 and NP-25 on radial growth of Sclerotina sclerotiorum and Botrytis cinerea; and
  • FIG. 8 is a table showing the in vitro antimicrobial efficacy of tested compounds on Candida albicans, Aspergillus fumigates, and Aspergillus niger.
  • Some embodiments of the present invention provide for compounds, antimicrobial compositions, methods and uses that relate to treatment of infections by microbes, such as fungi and oomycetes. Specifically, some embodiments relate to (Z) ⁇ -trifluroalkyl aminovinyl ketones and thioketones, that in some instances have antimicrobial activity.
  • the compounds of the present invention are compounds of Formula I (see Figure IA and below), Formula II (see Figure 1C and below), esters thereof or salts thereof, or combinations thereof.
  • an antimicrobial composition comprising at least one of the compounds from the group of compounds consisting of a compound of Formula I, esters thereof, salts thereof, a compound of Formula II, esters thereof, and salts thereof.
  • a method of treating an infection by microbes comprising applying or administering an effective amount of a composition as described above.
  • a use of at least one compound selected from the group consisting of a compound of Formula I and a compound of Formula II, esters thereof, and salts thereof for the treatment of an infection by microbes there is provided a use of at least one compound selected from the group consisting of a compound of Formula I and a compound of Formula II, esters thereof or salts thereof, in the manufacture of an antimicrobial composition for the treatment of an infection by microbes.
  • microbe by microbe is meant a fungus (including a yeast or a mold) and by antimicrobial is meant antifungal. In some embodiments, by microbe is meant an oomycete and by antimicrobial is meant anti-oomycete.
  • the present invention relates to compounds having Formula I:
  • Z is chosen from the group consisting of O and S; n is an integer from 0 to 20; each X is independently selected from the group consisting of H and F (each of the between 1 and 42 Xs is independently selected from the group consisting of H and F); each of R 1 , R 2 R 3 and R 4 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, amino and -NR 5 R 6 , or, alternatively, two of R 2 , R 3 and R 4 form a five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring; and
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or, alternatively R 5 and R 6 form a five- or six- member aromatic, heteroaromatic, alicyclic or heteroalicyclic ring; and salts and esters thereof.
  • At least one of R 2 , R 3 and R 4 is in an ortho or para position relative to the functional group bearing Z.
  • at least one of R 2 , R 3 and R 4 is an electron donating group, for example is selected from the group consisting of alkyl, hydroxyalkyl, cycloalkyl, halo, hydroxy, alkoxy, aryloxy, amino and -NR 7 R 8 , where R 7 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or, alternatively R 7 and R 8 form a five- or six-member aromatic, heteroaromatic, alicyclic or heteroalicyclic ring. Exemplary compounds of Formula I prepared and tested are shown in Figure IB.
  • the present invention relates to compounds having Formula II: z
  • compositions comprising compounds of Formula I and/or Formula II are used for treating an infection by microbes, especially microbes such as fungi and oomycetes.
  • microbes especially microbes such as fungi and oomycetes.
  • the present invention provides various different types of compositions.
  • some embodiments of the present invention provide for compounds, antimicrobial compositions, methods and uses that relate to treatment of infections by microbes.
  • the infections are infections by fungi, such as yeasts or molds.
  • the fungi may comprise one or more members of the phyla Chytridiomycota; Blastocladiomycota; Neocallimastigomycota; Zygomycota; Glomeromycota; Ascomycota; Basidiomycota or Deuteromycota.
  • the Ascomycota may comprise, for example, Aspergillus, including Aspergillus fumigatus and Aspergillus niger; Sclerotinia, such as Sclerotinia sclerotiorum, Sclerotinia sclerotiorum, Sclerotinia trifoliorum and Sclerotinia minor; Botrytis, such as Botrytis cinerea, Botrytis convolute, Botrytis polyblastis, Botrytis allii and Botrytis fabae; Penicillum, including Penicillium chrysogenum, Penicillium citrinum, Penicillum italicum, Penicillium janthinellum, Penicillium marneffei, Penicillium purpurogenum, Penicillium expansum, Penicillium funiculosum and Penicillium digitatum; Neurospora, including Neurospora crassa; Alternaria, including Altemaria altemata,
  • the Basidiomycota may comprise, for example, Agaricomycotina (including Rhizoctonia, such as Rhizoctonia solani), Ustilaginomycotina, Pucciniomycotina, Wallemiomycetes and Entorrhizomycetes.
  • the infections are infections by oomycetes.
  • the oomycetes may comprise one or more members of the group consisting of Phytophthora (such as, for example, Phytophthora infestans; Phytophthora sojae; Phytophthora alni; Phytophthora cactorum; Phytophthora capsi; Phytophthora cinnamomi; Phytophthora fragariae; Phytophthora kernoviae; Phytophthor palmivora; Phytophthora ramorum; or Phytophthora quercind), Pythium (such as, for example, Pythium aphanidermatum or Pythium insidiosum), and downy mildew.
  • Phytophthora such as, for example, Phytophthora infestans; Phytophthora sojae; Phytophthora alni; Phytophthora cactorum; Phytophthora capsi; Phytoph
  • the present invention is applied to the field of pharmaceuticals, both human and non-human (veterinary medicine) to treat microbial infections.
  • the composition of the present invention is applied to the treatment of an infection of humans involving fungi or yeast.
  • the infection may occur, for example, at the site of an injury, in mucous membranes, the sinuses or the lungs.
  • the infection may be caused by a species of the yeast Candidia, such as Candida albicans, and may comprise diaper rash, infection of the mouth, genital infection in women, or nail infection.
  • the composition of the present invention is applied to the treatment of fungal infection of humans such as Athlete's foot (tinea pedis); jock itch (tinea crutis); scalp and hair infections (tinea capitis); finger or toenail infection (tinea unguium); ringworm of the body (tinea corporis); and barber's itch (tinea barbae).
  • fungal infection of humans such as Athlete's foot (tinea pedis); jock itch (tinea crutis); scalp and hair infections (tinea capitis); finger or toenail infection (tinea unguium); ringworm of the body (tinea corporis); and barber's itch (tinea barbae).
  • composition of the present invention is applied to the treatment of a systemic fungal infection of mammals, including humans, such as
  • Aspergillosis caused by Aspergillus fumigatus or other Aspergillus species; an infection caused by Alternaria alternate, such as upper respiratory infections, particularly in AIDS patients; or an infection caused by Pythium insidiosum in humans, dogs, cattle and horses.
  • the present invention is applied to the field of agriculture, both of animal husbandry and of plants. In some such embodiments, the present invention is applied prophylactically, for example to prevent or delay the onset of mold.
  • the present invention is applied for use in treating plants or plant matter.
  • Such embodiments include, but are not limited to, treating living plants, treating seeds, treating harvested fruit, grain and other plant products.
  • the microbe is a fungus of the phylum Ascomycota, such as Aspergillus, including Aspergillus niger;
  • Sclerotinia such as Sclerotinia sclerotiorum, Sclerotinia trifoliorum and Sclerotinia minor
  • Botrytis such as Botrytis cinerea, Botrytis convolute, Botrytis polyblastis, Botrytis allii and
  • Penicillum such as Penicillium chrysogenum, Penicillium citrinum
  • Penicillum italicum Penicillium janthinellum, Penicillium marneffei, Penicillium purpurogenum, Penicillium expansum, Penicillium funiculosum and Penicillium digitatum;
  • Verticillium including Verticillium dahlia, Verticillium albo-atrum, and Verticillium lecanii.
  • a plant in which an Aspergillus niger infection occurs may comprise, for example, a grape, an onion or a peanut.
  • a plant in which a Sclerotinia sclerotiorum infection occurs may comprise, for example, cabbage, common bean, citrus, celery, coriander, melon, squash, soybean, tomato, lettuce, and cucumber.
  • a plant in which a Botrytis cinerea infection occurs may comprise, for example, asparagus, bean, beet, carrot, celery, chicory, crucifers, cucurbits, eggplant, endive, grape, lettuce, onion, pepper, potato, raspberry, rhubarb, rutabaga, shallot, strawberry, tomato, turnip; or an ornamental plant such as ornamental plants including: anemone, begonia, calendula, chrysanthemum, dahlia, dogwood, fuchsia, geranium, hawthorn, heather, hydrangea, marigold, pansy, periwinkle, petunia, rose, snapdragon, sunflower, sweet pea, violet, and zinnia.
  • a plant in which a Penicillium digitatum infection occurs may comprise, for example, a citrus fruit.
  • the present invention is applied for preventing formation of mold on baked goods, such as bread, for example formation of molds similar to the mold such as Neurospora, such as Neurospora crassa.
  • the present invention is applied for use in treating soil.
  • Such embodiments include but are not limited to treating agricultural land during soil irrigation, prior to sowing, prior to sprouting or when the plants have already emerged.
  • the present invention is applied for use in treating edible products.
  • Such embodiments include but are not limited to wrappings for food products such as cheese and fruit, a bread additive, a jam additive or a tomato product (e.g., tomato juice and paste) additive.
  • the present invention is applied to other fields, for example in the field of surface treatments for the formulation of paint compositions (such as for prevention of growth of Alternaria alternata on paint surfaces), lacquers or anti-mold and mildew compositions.
  • compositions of the present invention may comprise, in addition to the antimicrobial agents, an approved carrier or a diluent that does not cause significant damage to an organism and does not abrogate the biological activity and properties of the administered antimicrobial agent.
  • compositions of the present invention may comprise, in addition to the compounds of Formula I and/or Formula II, an additional antifungal agent.
  • the additional antifungal agent may comprise any antifungal agent known in the art, such as polyene antifungals; imidazole, triazole and thiazole antifungals; allylamines; echinocandins; and others.
  • polyene antifungals examples include natamycin, rimocidin, filipin, nystatin, amphotericin B, and candicin.
  • imidazoles include miconazole, ketocanazole, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole,
  • triazoles examples include fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, and terconazole.
  • thiazoles examples include abafungin.
  • allylamines examples include terbinafine, amorolfine, natifine, and butenafine.
  • echinocandins examples include anidulafungin, caspofungin and micafungin.
  • antifungal agents examples include ciclopirox, tolnaftate, undecylenic acid, flucytosine, griseofluvin, haloprogin and sodium bicarbonate.
  • the additional antifungal agent may comprise a natural product having antifungal activity, such as, for example, allicin, tea tree oil, citronella, iodine, lemon grass, olive leaf, orange oil, palmarosa oil, patchouli, lemon myrtle, neem seed oil, coconut oil, zinc or selenium.
  • a natural product having antifungal activity such as, for example, allicin, tea tree oil, citronella, iodine, lemon grass, olive leaf, orange oil, palmarosa oil, patchouli, lemon myrtle, neem seed oil, coconut oil, zinc or selenium.
  • Formula II, esters thereof or salts thereof, and the additional antifungal agent are present in a single composition.
  • the compound of Formula I and/or the compound of Formula II, esters thereof or salts thereof, and the additional antifungal agent may be administered sequentially or simultaneously in separate dosage forms.
  • a combination of the compound of Formula I and/or the compound of Formula II, esters thereof or salts thereof, and the additional antifungal agent may produce a synergistic effect, such that the effect of the combination is greater than the effect of the compound of Formula I and/or the compound of Formula II, esters thereof or salts thereof alone, and of the additional antifungal agent alone.
  • composition comprising a combination of a compound of Formula I and/or a compound of Formula II, esters thereof or salts thereof, and an additional antifungal agent, wherein the amount of the compound of Formula I and/or the compound of Formula II, esters thereof or salts thereof, and the amount of the additional antifungal agent alone is insufficient to achieve the therapeutic effect achieved by the administration of the combination of the two or more ingredients.
  • a composition of the invention especially a composition comprising a compound of Formula AG-5 and/or NP- 18b is used to treat a microbial infection of plants, especially to treat an Oomycete infection, especially of Pythium, especially Pythium aphanidermatum.
  • a sprayable composition comprising a liquid carrier and an effective concentration of AG-5 and/or NP- 18b, is applied as a foliar spray on affected plants.
  • a composition comprising a liquid carrier and an effective concentration of AG-5 and/or NP- 18b is applied to soil as a soil wash or during plant irrigation.
  • Penicillium is a genus of molds that attacks stored foodstuffs, including cooled food stuffs. Exceptionally vulnerable are fruit such as citrus fruit, bread and cereal products and meats. Stored grains, including feed grains, are susceptible to Penicillium infection which leads to the production of mycotoxins that may damage mammals consuming the grain.
  • Penicillium has several species. Examples include Penicillium chrysogenum, Penicillium citrinum, Penicillum italicum, Penicillium janthinellum,
  • Penicillium marnejfei Penicillium purpurogenum, Penicillium expansum, Penicillium funiculosum and Penicillium digitatum.
  • Penicillium digitatum is a common mold found on post-harvest citrus and grain, and recognized by the appearance of green brush-like fruiting structures.
  • a composition of the invention especially a composition comprising a compound of Formula NP- 18a is used to treat a microbial infection of food stuffs, especially to prevent and/or delay development of a Penicillium infection, especially of Penicillium digitatum, especially for harvested fruit such as citrus and other fruits or grain for animal feed.
  • a sprayable composition comprising a liquid carrier (and in some embodiments additional inert materials) and an effective concentration of NP- 18a, is sprayed on the harvested fruit.
  • the harvested fruit is washed, for example in a bath, with a composition comprising a liquid carrier and an effective amount of NP- 18a.
  • a composition of the invention especially a composition comprising a compound of Formula AG-5 and/or NP- 18b is used to treat or prevent growth of mold on baked goods, such as bread, for example formation of molds similar to Neurospora such as Neurospora crassa.
  • composition comprises at least one compound having Formula I or
  • a carrier is formulated in accordance with the desired use of the composition.
  • One skilled in the relevant art for which a given composition is to be used is able to formulate a desired composition.
  • compositions of the present invention are generally formulated to be topical compositions, whether to be applied to a surface of an animal (e.g., skin, mucous membranes), a surface of a plant (e.g., leaves, stalks, fruit, seeds), soil or surfaces such as walls and other inanimate surfaces.
  • Typical topical compositions include creams, sprays, ointments, lotions, solutions, suspensions, sprays, foams, washes, paints and lacquers.
  • one skilled in the art of polymer technology is able to integrate the compounds described herein into a food wrapping, a paint, a lacquer, generally by mixing an effective amount of the composition into a known non-polymerized precursor.
  • a suitable carrier e.g. of paper, cardboard or plastic.
  • the carrier includes an adhesive or polymerizing component that assists in maintaining the applied compound associated with the wrapping or container.
  • the carrier includes volatile components that, subsequent to application and evaporation of the volatile components, leave the compounds associated with the wrapping or container.
  • an applied compound is absorbed into a wrapper or container.
  • a wrapper or container For example, one skilled in the art of food technology is able to integrate the compounds described herin into food stuffs, for example adding a compound to dough prior to baking in bread and baked goods; adding a compound to a meat mixture during the preparation of a processed meat product (sausage); adding a compound to a fluid edible product such as jam, a syrup or a tomato product.
  • compositions useful in agriculture useful for administering to plants and useful for treating plant products such as adding compounds to growth media for tissue culture and hydroponics; soil washes and treatments; as additives to irrigation water; as aerial and terrestrial sprays suitable for sprouts, trunks, branches, stems, leaves and fruit and as baths, washes and sprays for harvested fruit, vegetables and grains.
  • Mass spectra were measured in the positive mode using a quadrupole mass spectrometer equipped with an electrospray ionization source and cross-flow inlet. Unless otherwise stated, chemicals and materials were obtained from Sigma-Aldrich
  • NP- 18b was commercially available and obtained from Sigma- Aldrich (St. Louis, MO, USA).
  • NP- 18a, NP-5, NP-17, NP-6, NP-IO, NP- 19a, AG-5, AG-2, AG-4, NP-25 were synthesized using standard methods and commercially available materials substantially as depicted in Figure 2 and detailed hereinbelow where compound 2 was trifluoroacetamide (prepared from ammonia and trifluoroethyl ester) and compound 3 was trifluoroacetonitrile, excepting NP-25 where compound 2 was pentafluoropropionamide (prepared from ammonia and pentafluoropropyl ester) and compound 3 was pentafluoropropiononitrile.
  • NP-17 1 HNMR ( ⁇ , ppm, CDCl 3 ): 6.19 (s, IH), 7.58 (m, 3H), 7.99 (m, 4H), 8.40 (s, IH).
  • AG-2 was prepared from 3 and 4-cyanoacetophenone (1 g, 6.9 mmol) following the second general procedure. Purification by column chromatography on silica gel using n- hexane-EtOAc (8:2) as eluent, yielded 1.44 g AG-2 (87 % yield) as a colorless oil.
  • NP-18a was prepared from 3 and 4-hydroxyacetophenone (1 g, 7.4 mmol) following the second general procedure.
  • NP-19a was prepared from 3 and 4-BOC-amino acetophenone (1 g, 4.3 mmol) following the
  • NP-5 was prepared from 3 and 3-trifluoromethyl acetonapthone (I g, 4.29 mmol) following the second general procedure. Purification by column chromatography on silica gel using n- hexane-EtOAc (8:2) as eluent yielded 1.02 NP-5 (84 % yield) as a colorless oil.
  • NP-6 was prepared from 3 and 3-bromoacetophenone (1 g, 5.0 mmol) following the second general procedure. Purification by column chromatography on silica gel using n- hexane-EtOAc (8:2) as eluent yielded 1.32g NP-6 (89 % yield) as a colorless oil: iw (KBr): 1675, 1640, 1410.
  • NP-25 was prepared from gaseous 2,2,3,3, 3-pentafluoropropanenitrile (prepared from commercial CF 3 CF 2 CONH 2 in the same manner as for 3) and 4-chlrobutyrophenone (1 g, 6.9 mmol) following the second general procedure.
  • Phytotoxicity Phytotoxicity of the compounds was tested by placing seeds of Arabidopsis on water agar containing the test compounds (using a stock solution prepared as described above).
  • Germination rates and radicle length were measured and compared to those of seeds germinating on dishes lacking the test compounds.
  • Figure 3A shows the effect of the tested compounds on germination of Arabidopsis seeds.
  • Figure 3B shows the effect of the compounds on the growth of Arabidopsis leaves.
  • ⁇ Solatium lycopersicum L. leaves (maintained on moist filter paper placed in Petri dishes) to the various compounds.
  • the test compounds were administered, by drop- wise topical application (10 or lOO ⁇ l per leaflet). The appearance of necrosis in the vicinity of the droplet administration point within 7 days was considered as a phytotoxic response. The compounds were found to have no significant phytotoxic effect.
  • the fungi Sclerotinia sclerotiorum (isolate 1980; 12), Botrytis cinerea (isolate BcI16; 13), Penicillium digitatum (14) Altemaria alternata and Rhizoctonia solani (both from the fungal collection of the Dept. of Plant Pathology and Microbiology) and Neurospora crassa (strain 74-OR23-1A, The Fungal Genetics Stock Center; 75) were used during this study.
  • the oomycete Pythium aphanidermatum (from the Dept. of Plant Pathology and Microbiology, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel) was also used as a test organism. Strains were cultured on potato dextrose agar (PDA, Difco Laboratories, Detroit, MI), unless otherwise stated.
  • Sclerotinia sclerotiorum and Botrytis cinerea are necrotrophic phytopathogenic filamentous ascomycetes known to attack more than 400 and 200 plant species, respectively (1-7). Diseases caused in economically important plants by these fungi occur worldwide, cause considerable damage, have proven difficult to control (culturally or chemically) and host resistance to these fungi is inadequate. Annual losses of crops from diseases caused by
  • S. sclerotiorum and B. cinerea are in the multimillion dollar range.
  • their ubiquitous prevalence along with the intensive use of fungicides for their control has resulted in repeated appearance of fungicide-resistant strains (8-11).
  • NP- 18a, NP- 18b and AG-5 The in vitro antimicrobial activity of NP- 18a, NP- 18b and AG-5 was tested at a concentration of 10 ⁇ M and 100 ⁇ M for antifungal activity towards Botrytis cinerea and Sclerotinia sclerotiorum.
  • NP-5, NP-6, NP-IO, NP-17, NP-18b, NP- 19a, AG-4 and AG-5 was further tested for antifungal activity against the fungi Candida albicans (a yeast), Aspergillus fumigatus (a mold) and Aspergillus niger (a mold), using the minimum
  • a commercially available composition comprising fluconzole is diluted 10, 100 and 20 1000-fold. To each of eleven samples at each dilution are added 5 ⁇ M of one of the compounds having a Formula I or II (NP- 18b, AG-2, AG-4, AG-5, NP-18a, NP- 19a, NP-17,
  • each of the thirty-three thus-obtained compositions is compared to that of the commerically- available composition alone at 10, 100 and 1000-fold 25 dilution against Blastomyces dermatitidis, Candida spp., Coccidioides immitis, Cryptococcus neoformans, Epidermophyton spp., Histoplasma capsulatum, Microsporum spp. and
  • compositions comprising fluconazole together with compounds having Formula I and Formula II have a synergistic antimicrobial effect, such that the effect is achieved at concentrations of each component which would be insufficient alone to produce the effect.
  • a commercially available composition comprising amphotericin B is diluted 10, 100 and 1000-fold. To each of eleven samples at each dilution are added 5 ⁇ M of one of the compounds having a Formula I or II (NP- 18b, AG-2, AG-4, AG-5, NP-18a, NP- 19a, NP-17, NP-5, NP-6, NP-IO or NP-25).
  • each of the thirty-three thus-obtained compositions is compared to that of the commerically- available composition at 10, 100 and 1000-fold dilution against Candida spp. and Cryptococcus neoformans.
  • each of the composition is further compared to that of 10 and 100 ⁇ M compositions of the compounds of Formula I or II alone.
  • compositions comprising amphotericin B together with compounds having Formula I and Formula II have a synergistic antimicrobial effect, such that the effect is achieved at concentrations of each component which would be insufficient alone to produce the effect.

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Abstract

La présente invention concerne des composés antiviraux et compositions antivirales, l'utilisation de tels composés et de telles compositions pour le traitement d’une infection microbienne, et des méthodes de traitement d’une infection microbienne, notamment d’infections par des champignons et des oomycètes.
PCT/IB2009/055016 2008-11-13 2009-11-11 Composés antiviraux et compositions antivirales WO2010055474A2 (fr)

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WO2020182318A1 (fr) 2019-03-12 2020-09-17 Symrise Ag Mélange antimicrobien

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2774481A1 (fr) * 2013-03-08 2014-09-10 Symrise AG Compositions antimicrobielles
WO2014135650A1 (fr) * 2013-03-08 2014-09-12 Symrise Ag Compositions antimicrobiennes
CN105025712A (zh) * 2013-03-08 2015-11-04 西姆莱斯股份公司 抗微生物组合物
KR20150127223A (ko) * 2013-03-08 2015-11-16 시므라이즈 아게 항균 조성물
KR101888233B1 (ko) * 2013-03-08 2018-08-13 시므라이즈 아게 항균 조성물
US10638755B2 (en) 2013-03-08 2020-05-05 Symrise Ag Antimicrobial compositions
WO2016003673A1 (fr) * 2014-07-03 2016-01-07 Coorstek Fluorochemicals, Inc. Fluoration de cétones alpha-haloalkyles
US9643907B2 (en) 2014-07-03 2017-05-09 Coorstek Fluorochemicals, Inc. Fluoronation of alpha-haloalkyl ketones
CN109112069A (zh) * 2017-06-23 2019-01-01 沈阳药科大学 一种生防内生真菌及其应用
WO2020182318A1 (fr) 2019-03-12 2020-09-17 Symrise Ag Mélange antimicrobien

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