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WO1996016014A1 - Biocomposes actifs - Google Patents

Biocomposes actifs Download PDF

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Publication number
WO1996016014A1
WO1996016014A1 PCT/DK1995/000461 DK9500461W WO9616014A1 WO 1996016014 A1 WO1996016014 A1 WO 1996016014A1 DK 9500461 W DK9500461 W DK 9500461W WO 9616014 A1 WO9616014 A1 WO 9616014A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbon atoms
compound
straight
branched chain
alkyl
Prior art date
Application number
PCT/DK1995/000461
Other languages
English (en)
Inventor
Jens Breinholt
Anders Ohmann
Brigitte Rømer RASSING
Georg W. Jensen
Inge MØLLER
Original Assignee
Novo Nordisk A/S
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU39239/95A priority Critical patent/AU3923995A/en
Publication of WO1996016014A1 publication Critical patent/WO1996016014A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • 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
    • A01N35/06—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 keto or thioketo groups as part of a ring, e.g. cyclohexanone, quinone; Derivatives thereof, e.g. ketals
    • 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
    • A01N49/00—Biocides, pest repellants or attractants, or plant growth regulators, containing compounds containing the group, wherein m+n>=1, both X together may also mean —Y— or a direct carbon-to-carbon bond, and the carbon atoms marked with an asterisk are not part of any ring system other than that which may be formed by the atoms X, the carbon atoms in square brackets being part of any acyclic or cyclic structure, or the group, wherein A means a carbon atom or Y, n>=0, and not more than one of these carbon atoms being a member of the same ring system, e.g. juvenile insect hormones or mimics thereof
    • 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
    • A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
    • A01N63/30—Microbial fungi; Substances produced thereby or obtained therefrom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P29/00—Preparation of compounds containing a naphthacene ring system, e.g. tetracycline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi

Definitions

  • the invention relates to biologically active compounds of te- tracyclic structures, related to the tetracyclines, methods for their production, and microorganisms capable of synthe ⁇ sizing such compounds.
  • the compounds of this invention are tetracyclic structures, related to the tetracyclines.
  • the invention further relates to fungicidal compositions com ⁇ prising said compounds and methods of controlling fungi by the use of such compositions.
  • Synthetic chemical fungicides, pesticides, acaricides, pre ⁇ servatives etc. have been used for decades, in various fields, such as medicine, agriculture, forestry, horticul ⁇ ture, food industry etc.
  • synthetic chemical fungicides, pesticides, acaricides, pre ⁇ servatives etc. have been used for decades, in various fields, such as medicine, agriculture, forestry, horticul ⁇ ture, food industry etc.
  • bioactive agents such as microbes and icrobial metabolites, useful for controlling diseases and pests in valuable crops, has been a growing area of research during the last decade.
  • microorganisms are capable of producing metabolites associated with interesting biological activiti ⁇ es.
  • tetracyclines One group of compounds exhibiting biological activities are the tetracyclines.
  • the tetracyclines are important drugs used extensively in treating bacterial infections in humans and animals. O96/16014 PC-7DK95.00461
  • the linear arrangement of four six-membered rings is a struc ⁇ tural feature common to the tetracyclines isolated from Strep- tomyces spp..
  • Viridicatumtoxin exhibits acute toxicity when administered to laboratory animals (Hutchinson et al., Toxicol. Appl. Pharm. ,
  • hypomyces The genus Hypomyces is known to produce metabolites of indus- trial interest. However these are not of tetracyclic struc ⁇ ture.
  • alkaloids produced from the strain Hypomyces aurantius IFO 7773, as described in JP-A-5-9140892 (TAKADA CHEMICALS) .
  • JP-A-5-9102396 (ENDO A) concerns a metabolite ML- 236B prepared by culturing Hypomyces chrysospermu ⁇ , which exhibits inhibitory effect on cholesterol synthesis.
  • the present inventors have surprisingly succeeded in isolat- ing and characterizing novel biologically active compounds from a fungus of the genus Hypomyces .
  • R is hydrogen, -COR,, straight or branched chain alkyl with 1-10 carbon atoms, straight or branched chain alkenyl with 2- 10 carbon atoms, straight or branched chain alkynyl with 2-10 carbon atoms, benzyl or aryl, optionally mono- or plurisub- stituted with alkyl with 1-10 carbon atoms, hydroxy, alkoxy, halogen, amino or a nitro group, in which
  • R ⁇ is straight or branched chain alkyl with 1-10 carbon atoms, straight or branched chain alkenyl with 2-10 carbon atoms, straight or branched chain alkynyl with 2-10 carbon atoms, aryl, optionally mono- or plurisubstituted with alkyl with 1-10 carbon atoms, hydroxy, alkoxy, halogen, amino or a nitro group,
  • R 2 is hydrogen, -COR,, straight or branched chain alkyl with 1-10 carbon atoms, straight or branched chain alkenyl with 2- 10 carbon atoms, straight or branched chain alkynyl with 2-10 carbon atoms, benzyl or aryl, optionally mono- or plurisub ⁇ stituted with alkyl with 1-10 carbon atoms, hydroxy, alkoxy, halogen, amino or a nitro group,
  • R 3 is hydrogen, -COR,, straight or branched chain alkyl with 1-10 carbon atoms, straight or branched chain alkenyl with 2- 10 carbon atoms, straight or branched chain alkynyl with 2-10 carbon atoms, benzyl or aryl, optionally mono- or plurisub ⁇ stituted with alkyl with 1-10 carbon atoms, hydroxy, alkoxy, halogen, amino or a nitro group,
  • R 4 is hydrogen, -COR,, straight or branched chain alkyl with 1-10 carbon atoms, straight or branched chain alkenyl with 2- 10 carbon atoms, straight or branched chain alkynyl with 2-10 carbon atoms, benzyl or aryl, optionally mono- or plurisub ⁇ stituted with alkyl with 1-10 carbon atoms, hydroxy, alkoxy, halogen, amino or a nitro group, and
  • R 5 is hydrogen, -COR,, straight or branched chain alkyl with 1-10 carbon atoms, straight or branched chain alkenyl with 2- 10 carbon atoms, straight or branched chain alkynyl with 2-10 carbon atoms, benzyl or aryl, optionally mono- or plurisub ⁇ stituted with alkyl with 1-10 carbon atoms, hydroxy, alkoxy, halogen, amino or a nitro group,
  • R 2 is hydrogen and R 4 is methyl, R 3 is 3-methyl-2-butenyl, R 5 is hydrogen, resulting in compounds with the formula:
  • the invention in another aspect, relates to a method of pre- paring said compound comprising a) cultivating a microorganism capable of producing said compound in or on a suitable nutrient medium and under suit ⁇ able conditions, and b) recovering the compound from the biomass and/or the cul ⁇ ture medium.
  • the method further compri ⁇ ses the step of c) chemically modifying the compound obtained in step b) .
  • said microorganism is a fungus of the genus Hypomyces , preferably of the species Hypomyces aurantius , especially of the strain Hypomyces au- rantius (CBS No. 654.93) or a mutant thereof capable of pro ⁇ ducing a compound of the invention.
  • a third object of the invention is to provide a fungicidal composition comprising, as an active ingredient, said com- pound alone or in combination with one or more other fungi ⁇ cidal or pesticidal agents and/or growth regulators.
  • Also contemplated according to the invention is a method of controlling fungi at a locus infested or liable to be in- fested therewith, which comprises applying to said locus said compound or said composition of the invention.
  • the invention relates to the use of the novel com ⁇ pounds as a fungicide, preservative and/or additive for co - bating plant diseases, especially fungal attack or control fungi in timber, wood, cosmetics, paints, growth media, feeds and foods.
  • the invention relates to an isolated pure culture of the microorganism Hypomyces aurantius A03892 (CBS No. 654.93) or a mutant thereof capable of producing a compound of the invention.
  • Figure 1 shows the Infrared spectrum (IR spectrum) of com ⁇ pound with the formula lb.
  • R is hydrogen, -COR,, straight or branched chain alkyl with 1-10 carbon atoms, straight or branched chain alkenyl with 2- 10 carbon atoms, straight or branched chain alkynyl with 2-10 carbon atoms, benzyl or aryl, optionally mono- or plurisub ⁇ stituted with alkyl with 1-10 carbon atoms, hydroxy, alkoxy, halogen, amino or a nitro group, in which
  • R is straight or branched chain alkyl with 1-10 carbon atoms, straight or branched chain alkenyl with 2-10 carbon atoms, straight or branched chain alkynyl with 2-10 carbon atoms, aryl, optionally mono- or plurisubstituted with alkyl with 1-10 carbon atoms, hydroxy, alkoxy, halogen, amino or a nitro group
  • R 2 is hydrogen, -COR, straight or branched chain alkyl with 1-10 carbon atoms, straight or branched chain alkenyl with 2- 10 carbon atoms, straight or branched chain alkynyl with 2-10 carbon atoms, benzyl or aryl, optionally mono- or plurisub- stituted with alkyl with 1-10 carbon atoms, hydroxy, alkoxy, halogen, amino or a nitro group
  • R 2 is hydrogen, -COR, straight or branched chain alkyl with 1-10 carbon atoms, straight or branche
  • R 3 is hydrogen, -COR,, straight or branched chain alkyl with 1-10 carbon atoms, straight or branched chain alkenyl with 2- 10 carbon atoms, straight or branched chain alkynyl with 2-10 carbon atoms, benzyl or aryl, optionally mono- or plurisub ⁇ stituted with alkyl with 1-10 carbon atoms, hydroxy, alkoxy, halogen, amino or a nitro group,
  • R 4 is hydrogen, -COR,, straight or branched chain alkyl with 1-10 carbon atoms, straight or branched chain alkenyl with 2- 10 carbon atoms, straight or branched chain alkynyl with 2-10 carbon atoms, benzyl or aryl, optionally mono- or plurisub ⁇ stituted with alkyl with 1-10 carbon atoms, hydroxy, alkoxy, halogen, amino or a nitro group, and
  • R 5 is hydrogen, -COR,, straight or branched chain alkyl with 1-10 carbon atoms, straight or branched chain alkenyl with 2- 10 carbon atoms, straight or branched chain alkynyl with 2-10 carbon atoms, benzyl or aryl, optionally mono- or plurisub ⁇ stituted with alkyl with 1-10 carbon atoms, hydroxy, alkoxy, halogen, amino or a nitro group.
  • alkyl with 1-10 carbon atoms is intended to include methyl, ethyl, propyl, butyl, pentyl, hexyl etc. straight, branched or cyclic where appropriate.
  • alkenyl with 2-10 carbon atoms is intended to in ⁇ clude ethenyl, propenyl, butenyl, pentenyl, hexenyl etc. straight, branched or cyclic where appropriate. Also polyenyl (dienyl, trienyl etc.) is intended to be included in the O 96/16014 PC--7DK95/00461
  • alkynyl with 2-10 carbon atoms is intended to in ⁇ clude ethynyl, propynyl, butynyl pentynyl, hexynyl etc. straight, branched or cyclic where appropriate. Also polyynyl (diynyl, triynyl etc.) is intended to be included in the term.
  • aryl is intended to include aromatic radicals like phenyl, naphtyl, phenantryl etc. and hetero aromatic radicals like furanyl, thiophenyl, pyridinyl, imidazolyl, oxazolyl etc.
  • halogen covers fluorine, chlorine, bromine and iodine.
  • R 2 and R 5 is hydrogen or hydroxy.
  • R is hydrogen or a straight or branch ⁇ ed chain alkyl with 1-10 carbon atoms.
  • R 2 is hydrogen
  • R 3 is 3- methyl-2-butenyl
  • R, is methyl
  • R s is hydrogen
  • Another object of the invention is to provide for a method of preparing compound having the formula I, comprising a) cultivating a microorganism capable of producing said compound in or on a suitable nutrient medium and under suit ⁇ able conditions, and b) recovering the compound from the biomass and/or the cul ⁇ ture medium. Also contemplated according to the invention are methods which further comprise a step c) of chemically modifying the compound obtained in step b) .
  • said microorganism is a fungus, pre ⁇ ferably of the genus Hypomyces , especially of the species Hypomyces aurantius, in particular the strain thereof ident ⁇ ified by the deposition number CBS No. 654.93, or a mutant thereof capable of producing a compound of the invention.
  • hypomyces aurantius A03892 (CBS No. 654.93) has been deposited under conditions that assure that access to the isolated fungus will be available during the pendency of this patent application to one deter ⁇ mined by the commissioner of Patents and Trademarks to be entitled thereto under 37 C.F.R. S 1.14 and 35 U.S.C ⁇ 122.
  • the deposit represents a substantially pure culture of the isolated fungus.
  • the deposit is available as required by foreign patent laws in countries wherein counterparts of the subject application, or its progeny are filed. However, it should be understood that the availability of a deposit does not constitute a license to practice the subject invention in derogation of patent rights granted by governmental action.
  • a suitable nutrient medium is one which comprises the micro- and macronutrients required to obtain a satisfactory growth of the microorganism in question and at the same time give rise to a production of the compound of the invention when subjected to suitable cultivation conditions.
  • a suitable nutrient medium contain sources of car ⁇ bon and nitrogen assimilable by the microorganism and normal ⁇ ly a low level of inorganic salts.
  • the nutrient medium may contain traces of metals and other components ne ⁇ cessary for the growth of the microorganisms and the produc- tion of the desired compound.
  • Such other components may be in sufficient concentrations in the complex sources of carbon and nitrogen, typically used as nutrient sources, but can, of course, be added separately to the medium if desired.
  • the conditions under which the microorganism is cultivated may be chosen so as to optimize the production of secondary metabolites therefrom.
  • the optimization of the production of secondary metabolites may be performed by methods known in the art, such as methods based on batch fermentation, fed- batch fermentation or continuous fermentation.
  • the compound produced may be contained in the bio ass or may alternatively be excreted into the culture medium, fully or partially, depending on the microorganism in question.
  • the compound is normally contained in the biomass, such as in or on the mycelium, the spores, and the like.
  • the recovery of the compound of the invention from the bio ⁇ mass and/or culture medium produced in accordance with step a) above may be performed by any suitable technique useful for the microorganism in question.
  • the recovery comprises harvesting the mycelium, e.g. by filtration and/or centrifugation, and subsequently isolating the compound the- refrom.
  • Suitable methods for isolating the compound includes extraction using a suitable solvent such as polar solvents like methanol, ethanol, ethyl acetate, or acetone, and solid phase extraction using a hydrophobic resin, an example of which is XAD-8 (Rohm and Haas Co.). Further purification may be accomplished by chromatography and/or crystallisation.
  • modification may be achieved by feeding suitable precursors to the medium in which the microorganism producing the compound is cultured to obtain production of the deriva ⁇ tive.
  • derivatives may be produced by chemical synthesis using the natural metabolite as a lead structure. The compounds produced by such modifications may either belong to the group of compounds having the general formula I or may be different from these compounds.
  • compounds of the invention hav ⁇ ing formula I may be prepared by the general method outlined above, i.e. from a microorganism capable of producing such compound
  • -some compounds of the invention may advantageously be prepared from the compound I using a synthetic process.
  • appropriate acylating reagents such as acid halides, acid anhydrides or activated esters, optio ⁇ nally under influence of a basic catalyst (pyridine, other amines etc.).
  • Ether derivatives of compound la yielding com- pounds of formula I may be prepared by treating la (wherein R-H) , dissolved in a suitable solvent, with an appropriate alkylating reagents, such as diazo compounds or with appro ⁇ priate alkyl halides and alike, under influence of a catalyst (potassium carbonate, silver oxide etc.).
  • an appropriate alkylating reagents such as diazo compounds or with appro ⁇ priate alkyl halides and alike, under influence of a catalyst (potassium carbonate, silver oxide etc.).
  • the oxygen substitution pattern of lb indicates that the tetracyclic core is constructed by folding and cyclization of a linear decaketide (10 acetate units) , with C13-C14 being the starting unit.
  • derivatives where R 4 varies may be obtained by directed biosynthesis, i.e. forcing the producing microorganism to build in other starter units than acetate by feeding to the growth media appropriate substances acceptable for the enzyme system involved i the biosynthesis.
  • Stereogenic centers of lb may independently be of R- or S configuration.
  • Compounds of formula I carrying substitutents at C7 and C9 may be prepared from compounds of formula la by nucleophilic substitution using standard methods.
  • compounds, according to the invention may be produced entirely by well known chemical synthetic processes using available starting materials, e.g. other tetracyclic compounds.
  • Still another object of the invention is to provide a fungi- cidal composition
  • a fungi- cidal composition comprising, as an active ingredient, said novel compound with the formula I.
  • said fungicidal composition comprises said compound in an amount of from 0.001 ⁇ g/ml to 100 mg/ml.
  • the active ingredient may be a fun- gus of a species belonging to the genus Hypomyces capable of producing said novel compound, preferably of the species Hy ⁇ pomyces aurantius, especially a strain of the Hypomyces au ⁇ rantius (CBS No. 654.93) or a mutant thereof capable of pro- ducing said compound of the invention.
  • Fungicidal compositions according to the invention exhibit ⁇ ing fungicidal and antibacterial active, having compounds of the invention as its active ingredient, may for agronomical and/or horticultural applications be formulated by mixing the active principle with suitable inert and compatible carriers or diluents to obtain a composition of the type generally used in agricultural compositions, examples of which are fur ⁇ ther discussed below.
  • the diluent or carrier in the composition of the invention may be a solid or a liquid conventionally used for the pur ⁇ pose.
  • solid carriers bentonite diatomaceous earth, apati ⁇ te gypsum, talc, pyrophyllite, vermiculite, ground shells, and clay may be mentioned.
  • a surface-active agent may be associated with the diluent or carrier.
  • the surface-active agent may, for instance, be a dispersing agent, an emulsifying agent or a wetting agent, examples of which are anionic compounds such as a carboxy- late, for example a metal carboxylate of a long chain fatty acid; an N-acylsarcosinate; mono- or di-esters of phosphoric acid with fatty alcohol ethoxylates or salts of such esters; fatty alcohol sulphates such as sodium dodecyl sulphate, sodium octadecyl sulphate or sodium cetyl sulphate; ethoxy- lated fatty alcohol sulphates; ethoxylated alkylphenol sul ⁇ phates; lignin sulphonates; petroleum sulphonates; alkyl aryl sulphonates such as alkyl-benzene
  • butyl-naphthalene sulphonate salts of sulphonated naphthalene-formaldehyde condensates; salts of sulphonated phenol-formaldehyde condensates; or more complex sulphonates such as the amide sulphonates, e.g. the sulphonated condensation product of oleic acid and N-methyl taurine or the dialkyl sulphosuccinates, e.g. the sodium sul ⁇ phonate of dioctyl succinate.
  • amide sulphonates e.g. the sulphonated condensation product of oleic acid and N-methyl taurine or the dialkyl sulphosuccinates, e.g. the sodium sul ⁇ phonate of dioctyl succinate.
  • Non-ionic agents include conden ⁇ sation products of fatty acid esters, fatty alcohols, fatty acid amides or fatty-alkyl- of alkenyl-substituted phenols with ethylene oxide, fatty esters of polyhydric alcohol ethers, e.g. sorbitan fatty acid esters, condensation prod ⁇ ucts of such esters with ethylene oxide, e.g.
  • polyoxyethylene sorbitan fatty acid esters block copolymers of ethylene oxide and propylene oxide, acetylenic glycols such as 2,4,7,9-tetraethyl-5-decyn-4,7-diol, or ethoxylated acetyle- nic glycols.
  • Examples of a cationic surface-active agent include, for in ⁇ stance, an aliphatic mono-, di-, or polyamine as an acetate, naphthenate or oleate; an oxygen-containing amine such as an amine oxide or polyoxyethylene alkylamine; an amide-linked amine prepared by the condensation of a carboxylic acid with a di- or polyamine; or a quaternary ammonium salt.
  • composition of the invention can be in any form known in the art for the formulation of agrochemicals, for example, an emulsifiable concentrate, a concentrated emulsion, a multiple emulsion, an aqueous emulsion, a solution, a dispersion, a suspension concentrate, a release formulation (including a slow release formulation) , a seed dressing, a granular formu- lation, a water soluble powder, a wettable powder, a dusting powder, a dispersible powder, an alginate, a xanthan gum and/or an aerosol.
  • it can be in a suitable form for direct application or as a concentrate or primary composition which requires dilution with a suitable quantity of water or other diluent before application.
  • An emulsifiable concentrate comprises the active ingredient dissolved in a water-immiscible solvent which is formed into an emulsion with water in the presence of an emulsifying agent.
  • Another suitable concentrate is a flowable suspension concentrate which is formed by grinding the active ingredient with water or other liquid, a wetting agent and a suspending agent.
  • a dusting powder comprises the active ingredient intimately mixed and ground with a solid pulverulent diluent, for example, kaolin.
  • a granular solid comprises the active ingre- dominant diluents to those which may be employed in dusting powders, but the mixture is granulated by known methods. Alternatively it comprises the active ingredi ⁇ ent absorbed or adsorbed on a pre-granular diluent for exam ⁇ ple, Fuller's earth, attapulgite or limestone grit.
  • Wettable powders, granules or grains usually comprise the active ingredient in admixture with a suitable surfactant and an inert powder diluent such as china clay.
  • composition of the invention in addition to said fungicidally active compounds of the invention may also con ⁇ tain other active ingredients such as biocides, e.g. fungi ⁇ cides, pesticides, herbicides, insecticides, nematocides or acaricides, or plant nutrients or fertilizers.
  • EBIs ergosterol bio ⁇ synthesis inhibitors
  • These are generally imidazole or triazole derivatives and examples include those known by the common names prochloraz, triadimefon, propiconazole, di- clobutrazol, triadiminol, flusilazole, flutriafol, myclobuta- nil, penconazole, quinconazole, imazalil and diniconazole.
  • non azole EBis include nuari ol, fenari ol, fen- propimorph, tridemorph, fenpropidine and dimethomorph.
  • Dithiocarbamates e.g. thira , maneb, zineb and mancozeb;
  • Phatalimides e.g. captan, folpet and captafol
  • Carboxines e.g. carboxin and oxycarboxin
  • Benzimidazoles e.g. benomyl, carbendazim and fuberidazole; Carbamates, e.g. prothiocarb and propamocarb;
  • Isoxazoles e.g. hymexazol
  • Cyanoacetamides e.g. cymoxanil
  • Ethylphosphonates e.g. fosetylaluminium
  • Phenylamides e.g. furalaxyl, metalaxyl, benalaxyl, ofurace, cyprofuram and oxandixyl;
  • Dicarboximides e.g. procymidone, iprodione and vinclozolin;
  • Organophosphorous fungicides e.g. pyrazophos, tria iphos, ditalimfos and tolcofosmethyl;
  • Aromatic hydrocarbon fungicides e.g. quintozene, dichloren, and diphenyl;
  • Dinitroanilies e.g. fluazinam.
  • concentration of the active compounds of the invention described herein in the compositions of the invention may vary within a wide range depending on the type of formulation and the field of application.
  • the active compound should normally be present in an amount from 0.001 ⁇ g/ml to 100 mg/ l, such as 0.1 ⁇ g/ml to 5 mg/ml.
  • concentration of the biologically active compounds of the invention in the compositions of the present invention when used alone or in combination with a conventional fungicide, as applied to plants is preferably within the range from about 0.001 to about 30 per cent by weight, especially 0.01 to 3.0 per cent by weight, although it may vary more widely and be, for instance, within the range from about 5 to about 95 per cent by weight of the composition.
  • the concentration of the other fungicidally active ingredient in the mixed composition of the present invention, as applied to plants is preferably within the range of 0.001 to 50 per cent by weight, especially 0.01 to 10 per cent by weight, al ⁇ though it can vary widely and can be, for example, from 5 to 80 per cent by weight of the composition.
  • the invention also relates to the use of these active ingre ⁇ washers alone or in combination with one or more other fungi ⁇ cidal or pesticidal agents and/or growth regulators for con- trolling fungi in agriculture, forestry, horticulture etc.
  • the invention relates to a method of con ⁇ trolling fungi and bacteria at a locus infested or liable to be infested therewith, which comprises applying to said locus a compound or a composition of the invention as defined above.
  • said compound or composi ⁇ tion is applied to a locus selected from the group consisting of plants, timber, wood, cosmetics, feeds and foods.
  • fungal genera and species which has been found to be sensitive to compounds of the invention are fungi of the genera Pyt iu ⁇ r, especially Pythium ultimum, or Aphanomyces , especially Aphanomyces euteiches , or Phytophthora , especially Phytophthora cryptogea , or Colletotrichum, especially Colle- totrichum graminicola , or Gaeu annomyces , especially Gaeuman- nomyces graminis , or Pyricularia , especially Pyricularia ory- zae, or Sclerotium, especially Sclerotium rolfsii , or Alter- naria, especially Alternaria alternata .
  • the composition may for agronomical or horticul ⁇ tural uses be applied to a region to be treated either direct ⁇ ly to the soil as a pre-emergence treatment or to the foliage or fruits of the plants as a pre- and/or post-emergence treatment.
  • the treat- ⁇ o ment may be postponed until seeds or fruits appear on the plants, wherein fungi are to be controlled.
  • composition according to the invention may also comprise compounds which contributes to various functions, such as protection of the fungicidal properties of the active compo ⁇ nents from sun, or UV damage.
  • UV protectants are lignins or lignin derivatives, which are readily available by-product of the pulp and paper industry, alone or combined with sugar alco ⁇ hols as described in the pending US patent application no. 254017.000 (Entotech, Inc.).
  • Suitable lignins comprise lignin sulfulfonate and salts thereof (e.g. Na, K, Ca, and Mg salts), oxylignins and salts thereof, lignin liquors, Kraft lignins and derivatives 30 thereof and low and high lignins.
  • an "effective amount" of lignin refers to an amount which when combined with an effective amount of sugar alcohol, under normal sun conditions, increases the UV protection of 35 the composition at least 25%, and preferably at least 50%, relative to the protection provided by lignin alone in the same composition.
  • the amount of lignin in the composition is at least 2% w/w, up to about 95% w/w, and preferably at least about 5% w/w, most preferably at least about 15% w/w, up to about 50% w/w.
  • the sugar alcohols have the formula CH 2 OH(CHOH) n CH 2 OH, wherein n is an integer from 2 to 5.
  • sugar alcohols useful for this purpose are sorbitol, mannitol and xylitol.
  • an "effective amount" of a sugar alcohol is that amount, which in combination with a given amount of lignin, will en- hance the UV protective properties of lignin at least 25%, and preferably at least 50%, relative to lignin alone in the same, composition.
  • a preferred concentration of the sugar al ⁇ cohol in the composition is at least 4% w/w, up to about 95% w/w, and preferably at least about 10% w/w, up to about 35% w/w.
  • the formulation contai ⁇ ning a fungicide or a pesticide must first be deposited di ⁇ rectly on the plants to be treated, and then must adhere to and remain active on the surface to which it is applied.
  • the UV protecting components may be sup ⁇ plemented with other components.
  • composition according to the invention may fur- ther advantageously comprise at least one agent which is capable of enhancing deposition (hereinafter, "deposition agent") of the composition, i.e., a component which will assist in keeping it from drifting from the target area as it is being applied (e.g. as it is sprayed from a plane) , or from being blown away from the plant once it has been deposi ⁇ ted.
  • deposition agent a component which has sufficient density to prevent random dispersal.
  • Any animal or vegetable protein is suitable for this purpose, in dry or in liquid form.
  • useful sources of pro ⁇ tein which can be conveniently and economically added to the formulation are soy protein, potato protein, soy flour, pota ⁇ to flour, fish meal, bone meal, yeast extract, blood meal and the like .
  • protein is not the only material which can be used in this manner.
  • Alternative deposition agents include modi- fied cellulose (e.g. carboxymethyIcellulose) , botanicals (e.g. grain flours, ground plant parts) , natural earths (talc, vermiticulite, diatomaceous earth) , natural clays (e.g. attapulgite, bentonite, kaolinite, montmorillonite) , or synthetic (e.g. Laponite) .
  • the deposition agent preferably constitutes at least about 1% w/w up to about 50% w/w, more preferably at least 2% w/w up to about 20% w/w.
  • Retention of the composition can be aided by inclusion of an adherent component.
  • an adherent component one or more polyhydric alco ⁇ hols are added to the composition.
  • This component can serve a number of functions. First, it functions as an adherent which permits the composition to stick to the plant surface. In ad- dition, these components serve as a humectant, to attract moisture to the composition in situ . Such components also can be useful in preventing freezing of the composition, thereby protecting the activity of the fungicidal component.
  • the alcohol component can be chosen from one or more of the following: ethylene glycol, propylene glycol, dipropylene glycol, glycerol, butylene glycols, pentylene glycols, hexy- lene glycols; the sugar alcohol component may also contribute to this function, but it is desirable to add a second poly- hydric alcohol to the composition.
  • the second poly ⁇ hydric alcohol component of the composition if present, should comprise from about 1 to about 20% w/w of the total composition.
  • the active preparation or the compositions of the invention can be applied directly to the plant by, for example, spray ⁇ ing or dusting either at the time when the fungus has begun to appear on the plant or before the appearance of fungus as a protective measure. In both such cases the preferred mode of application is by foliar spraying.
  • the spray or dust can conveniently contain a pre-or post-emergence herbicide if this is thought necessary.
  • a suitable rate of application is from 0.001 to 50 kg per hectare of active com ⁇ pound, preferably from 0.05 to 5 kg per hectare of active compound.
  • the active preparation of the invention alone or in combination with a conventional biocide can also be applied to seeds or other habitats.
  • the preparation can be applied directly to the soil before, at or after drilling so that the presence of active ingredient in the soil can control the growth of fungi which may attack seeds.
  • compositions may be applied in amounts corresponding to from about 1 g to about 50 kg biologically active compound per hectare.
  • the active preparation alone or in a mixture with the conventional biocide can be applied in any manner which allows it to be intimately mixed with the soil such as by spraying, by broadcasting a solid form of granules, or by applying the active ingredient at the same time as drilling by inserting it in the same drill as the seeds.
  • a suitable application rate is within the range of from 0.01 to 50 kg of active compound per hectare, more pre ⁇ ferably from 0.05 to 5 kg of active compound per hectare.
  • the active compounds of the invention may be used for controlling fungi in mammals, including humans; for the preservation of cosmetics; for the preservation for wood by adding said compounds to wood preservation and/or impreg ⁇ nation compositions; for the preservation of food or feed by adding the compounds directly to the food or feed or to the containers in which it is present; and for the preservation of cosmetics.
  • the active compounds of the invention may be useful as a fungicide and preservant in paints - both to prevent growth in the paint during storage, and growth on the painted object such as the plastered surface of a house - and as an additive to growth media, e.g. for cultivation of cer ⁇ tain bacteria or yeast.
  • a final aspect of the invention is to provide an isolated pure culture of the microorganism Hypomyces aurantius A03892 (CBS No. 654.93) or a mutant thereof capable of producing a compound of the invention.
  • PD agar P_otato ⁇ extrose agar (Difco) Tween® 80: Merck Art. 822187
  • PCS medium 1 % Pharmamedia (Traders Protein, Southern Cotton Oil Company, Tennessee, USA), 0.5 % spray dried corn steep liquet (Solulys® A ST, Roquette Freres, France) and 3 % glucose. The pH was adjusted to 7 before the substrate was autoclaved at 121°C for 40 minutes.
  • a culture of the strain can be grown on Potato Dextrose agar (Difco) slants (12 ml/slant), autoclaved at 121°C for 40 min ⁇ utes.
  • PD agar Potato Dextrose agar
  • a slant culture grown on PD agar for 16 days ' at 26 ⁇ C was mixed with 10 ml of sterile water containing 0.1 % Tween® 80 and inoculated into 500 ml Erlenmeyer flasks containing 100 ml PCS medium using tap water. After inoculation, the flasks were incubated at 26°C and shaken at 150 rpm for 12 days.
  • the obtained compound was found to have the following physical and spectroscopic properties:
  • Fungicidal activity Agar diffusion assay The compound has been found to have an in vitro inhibitory effect on the growth of fungi belonging to the classes Oomycetes , Basidiomycetes and As corny ce t e ⁇ .
  • Anamorph fungus Alternaria alternata
  • test organisms were em ⁇ bedded in agar media. Small wells were punched in the agar and 15 ⁇ l sample was applied to the wells. Inhibition zones were scored after incubation at 26°C. Table 2 show the activ ⁇ ity observed when applying a 1000 ppm (1 mg/ml) solution of the compound lb in EtOH. Table 2
  • Vitis vinifera Vine, var. Ugni Blanc
  • Vine plants (5 weeks old) were sprayed to run off (6.5 ml/plant) with the liquid solution containing the active com ⁇ pound with the formula la (see the section "MATERIALS AND METHODS") - 5 repetitions per treatment - using a robot atom- izer.
  • the plants were kept for ventilation 24 hours (16 hours light, approximately 20°C) in the cabinet of the robot. They were then inoculated with a spore suspension (seven days old) containing 1*10 5 spores/ml. The inoculation was carried out with a handhold atomizer (Wagner, Pico Bel) using approxima- tely 3.5 ml/plant.
  • the plants were then incubated in a plexi glass box to keep a high humidity (>95%RH) .
  • the box was plac ⁇ ed in a climate chamber at the following conditions: 16 hours light, approximately 10.000 lux, 20°C and 8 hours darkness. The assessment was done 9 days after starting incubation.
  • the compound lb (125 ppm ai) gave 90-95% control to downy mildew (Plasmopara viticola) on vine.
  • JP-A-5-9140892 (TAKADA CHEMICALS)

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Abstract

L'invention concerne de nouveaux composés biologiquement actifs de formule générale (I). Elle porte également sur un procédé de préparation desdits nouveaux composés, sur une composition fongicide comprenant, comme principe actif, les nouveaux composés, sur l'utilisation desdits composés et sur un procédé de lutte contre les champignons sur un locus infesté ou susceptible d'être infesté par ceux-ci. L'invention concerne également une culture pure isolée du micro-organisme Hypomyces aurantius A03892 (CBS No. 654 93) ou à un mutant de celui-ci, capable de produire lesdits composés.
PCT/DK1995/000461 1994-11-22 1995-11-21 Biocomposes actifs WO1996016014A1 (fr)

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AU39239/95A AU3923995A (en) 1994-11-22 1995-11-21 Active bio-compounds

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DK132894 1994-11-22

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2712517A (en) * 1954-03-03 1955-07-05 Bristol Lab Inc Production of tetracycline and substituted tetracyclines
EP0436474A1 (fr) * 1989-11-13 1991-07-10 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Fluoro-naphtacènediones, leurs dérivés glycosilés et procédé pour leur fabrication

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2712517A (en) * 1954-03-03 1955-07-05 Bristol Lab Inc Production of tetracycline and substituted tetracyclines
EP0436474A1 (fr) * 1989-11-13 1991-07-10 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Fluoro-naphtacènediones, leurs dérivés glycosilés et procédé pour leur fabrication

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN, Vol. 8, No. 218, C-245; & JP,A,59 102 396, (AKIRA ENDOU), 13 June 1984. *
PATENT ABSTRACTS OF JAPAN, Vol. 8, No. 266, C-255; & JP,A,59 140 892, (TAKEDA YAKUHIN KOGYO K.K.), 13 August 1984. *
STN INTERNATIONAL, File Biosis, Biosis Accession No. 79:135023, SIDOROVA I.I. et al., "Biologically Active Substances of Mycophilic Fungi of the Genus Hypomyces"; & MIKOL. FITOPATOL., 11(4), 1977, (RECD 1978), 315-320. *
STN INTERNATIONAL, File Biosis, Biosis Accession No. 84:293838, KELLOCK L. et al., "Antagonism by Hypomyces Aurantius 1. Toxins and Hyphal Interactions"; & TRANS. BR. MYCOL. SOC., 82(2), 1984, 327-334. *
STN INTERNATIONAL, File Biosis, Biosis Accession No. 84:293839, KELLOCK L. et al., "Antagonism by Hypomyces Aurantius 2. Ultrastructure Studies of Hyphal Disruption"; & TRANS. BR. MYCOL. SOC., 82(2), 1984, 335-338. *
STN INTERNATIONAL, File CAPLUS, CAPLUS Accession No. 1980:194340, ZHLOBA N.M. et al., "Antibiotic and Hydrolytic Activity of Some Species of Mycophilic Fungi"; & VESTN. MOSK. UNIV., SER. 16: BIOL., (1980), (1), 64-8. *

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