WO1997048279A1 - Agents with antifungal activity and methods of use thereof - Google Patents

Agents with antifungal activity and methods of use thereof Download PDF

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Publication number
WO1997048279A1
WO1997048279A1 PCT/IB1997/000750 IB9700750W WO9748279A1 WO 1997048279 A1 WO1997048279 A1 WO 1997048279A1 IB 9700750 W IB9700750 W IB 9700750W WO 9748279 A1 WO9748279 A1 WO 9748279A1
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group
alkyl
acid
compound
bound
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PCT/IB1997/000750
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French (fr)
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William A. Ayer
Yasuvuki Hiratsuka
Latchezar S. Trifonov
Priyotosh Chakravarty
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University Of Alberta
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Publication of WO1997048279A1 publication Critical patent/WO1997048279A1/en

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/08—Oxygen or sulfur directly attached to an aromatic ring system
    • A01N31/10—Pentachlorophenol
    • 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
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/02—Amines; Quaternary ammonium compounds
    • A01N33/12—Quaternary ammonium compounds
    • 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
    • A01N35/02—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 aliphatically bound aldehyde or keto groups, or thio analogues thereof; Derivatives thereof, e.g. acetals
    • 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
    • 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
    • A01N35/08—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 at least one of the bonds to hetero atoms is to nitrogen
    • A01N35/10—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 at least one of the bonds to hetero atoms is to nitrogen containing a carbon-to-nitrogen double bond
    • 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/02—Saturated carboxylic acids or thio analogues thereof; Derivatives 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/02—Saturated carboxylic acids or thio analogues thereof; Derivatives thereof
    • A01N37/04—Saturated carboxylic acids or thio analogues thereof; Derivatives thereof polybasic
    • 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/06—Unsaturated carboxylic acids or thio analogues thereof; Derivatives 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing carboxylic groups or thio analogues thereof, directly attached by the carbon atom to a cycloaliphatic ring; Derivatives 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/10—Aromatic or araliphatic carboxylic acids, or thio analogues thereof; Derivatives 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
    • A01N37/38—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids having at least one oxygen or sulfur atom attached to an aromatic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A01N37/46—N-acyl derivatives
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/08—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B27—WORKING OR PRESERVING WOOD OR SIMILAR MATERIAL; NAILING OR STAPLING MACHINES IN GENERAL
    • B27K—PROCESSES, APPARATUS OR SELECTION OF SUBSTANCES FOR IMPREGNATING, STAINING, DYEING, BLEACHING OF WOOD OR SIMILAR MATERIALS, OR TREATING OF WOOD OR SIMILAR MATERIALS WITH PERMEANT LIQUIDS, NOT OTHERWISE PROVIDED FOR; CHEMICAL OR PHYSICAL TREATMENT OF CORK, CANE, REED, STRAW OR SIMILAR MATERIALS
    • B27K3/00—Impregnating wood, e.g. impregnation pretreatment, for example puncturing; Wood impregnation aids not directly involved in the impregnation process
    • B27K3/34—Organic impregnating agents
    • B27K3/38—Aromatic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B27—WORKING OR PRESERVING WOOD OR SIMILAR MATERIAL; NAILING OR STAPLING MACHINES IN GENERAL
    • B27K—PROCESSES, APPARATUS OR SELECTION OF SUBSTANCES FOR IMPREGNATING, STAINING, DYEING, BLEACHING OF WOOD OR SIMILAR MATERIALS, OR TREATING OF WOOD OR SIMILAR MATERIALS WITH PERMEANT LIQUIDS, NOT OTHERWISE PROVIDED FOR; CHEMICAL OR PHYSICAL TREATMENT OF CORK, CANE, REED, STRAW OR SIMILAR MATERIALS
    • B27K3/00—Impregnating wood, e.g. impregnation pretreatment, for example puncturing; Wood impregnation aids not directly involved in the impregnation process
    • B27K3/34—Organic impregnating agents
    • B27K3/50—Mixtures of different organic impregnating agents

Definitions

  • This invention relates to compounds that have antifungal activity. These compounds reduce or inhibit the growth of fungi from a variety of genera and species.
  • Trembling aspen or aspen is an important source of pulp for the paper-making industry. Aspen is also used for making particle board and solid wood products. Decay and stain caused by several fungi have been identified as the two most important factors limiting the use of aspen (Hiratsuka et al. 1990, 1995). Recently, the present inventors reported on the inhibition of the growth of aspen decay and stain fungi using certain antagonistic fungi (Chakravarty and
  • similis inhibits the in vitro growth as well as aspen wood chip colonization by blue stain fungi.
  • the present invention is an extension of work reported on the antifungal activity of metabolites of Peniophora polygonia (Trifonov et al. 1992) and Sporormiella similis (Chakravarty et al. 1994) against aspen pathogens. Summary of the Invention
  • the inventors extracted a variety of compounds from decay fungus Peniophora polygonia and found that isobutyric and isovaleric acid were amongst the most active compounds. Following this lead, they tested 4- phenyl-3-butenoic acid - a structural analog of the above acids.
  • 4-phenyl- 3-butenoic acid is known as a potent mechanism-based inhibitor of peptidylglycine amidating monooxygenase (Bradbury et al. 1990; Rhodes and Honsinger 1993), as a modulator of the activity of ⁇ -glutamic acid transpeptidase (Thompson and Meister 1980), as well as an antibacterial compound (Khristov 1973).
  • the objective of this invention is to provide an antifungal composition and methods of use against a wide range of fungi.
  • the invention is directed to methods of reducing or inhibiting fungal growth by applying the compounds of the invention to a region to be treated.
  • the antifungal compositions of the invention can be used against a wide variety of fungi, and it is well within the skill of an ordinary worker in the art to screen particular fungi against which the compositions of the invention are effective.
  • the objective of part of this invention was to determine the activity of homologs and analogs of 4-phenyl-3-butenoic acid against P. tremul ⁇ e and two species of blue stain fungi, Ophiostoma piliferum (Fr.) H. and P. Sydow and O. crassivaginatum (H.D. Griffin) T.C. Harrington.
  • phomalone Ayer and Jimenez 1994
  • pentachlorophenol, copper 8-oxyquinolinate, Zn salt of 10-undecenoic acid, as well as lauric acid were included in this study.
  • the inventors have also found that tiglic acid and senecioic acids, minor metabolites of S. similis, significantly inhibited the growth of the blue stain fungus Ophiostoma piliferum, even at concentrations as low as 1 ⁇ g/ml.
  • the inventors therefore synthesized derivatives and analogs of these two leads to test their activity against the aspen decay fungus Phellinus tremulae and the aspen blue stain fungi Ophiostoma crassivaginatum and O. piliferum.
  • the presently-disclosed compounds include derivatives, homologs and analogs of tiglic acid, senecioic acid and 4-phenyl-3-butenoic acid which are effective antifungal compounds. These compounds can be used in antifungal compositions, and methods of reducing or inhibiting fungal growth.
  • the present invention is directed to an antifungal composition
  • an antifungal composition comprising at least one compound selected from the group consisting of:
  • R 1 is selected from the group consisting of (1) H, (2) C,-C, 5 alkyl, (3) a group
  • R 7 and R 8 are C,-C 15 alkyl or, together with the carbon atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a group Ar, wherein Ar is an aromatic ring;
  • R 2 through R 5 are each independently H or C,-C, s alkyl, or R 2 and R 3 together are a bond thus creating a double bond between the carbon atoms to which they are bound, or R 2 and R 3 together, and R 4 and R 5 together, are bonds thus creating a triple bond between the carbon atoms to which they are bound, or two of R 1 through R 5 , together with the carbon atoms to which they are bound, form part of a 3-8 membered carbocyclic ring, with the proviso that when R 2 through R 5 are each H, then R 1 is only
  • R 6 is selected from the group consisting of (1) H, (2) C r C, 5 alkyl, (3) phenyl, (4) a group N(CH 3 ) 2 (C, 0 H 2I ) 2 , (5) a group N(C,-C I5 alkyl) 4 , wherein the alkyl groups are the same or different, (6) NH m (X) 4 . m , wherein each X is independently selected from C,-C 13 alkyl and 2-hydroxyethyl, and m is 0-4, with the proviso that when R' is Ar, then R 6 is other than phenyl; n is 0-10 and n' is O or 1 ; and
  • R 9 is selected from the group consisting of H, OH and C,-C 15 alkyl
  • R 10 is H or OH
  • R 11 and R 12 are each independently H or C,-C 15 alkyl
  • Ar is selected from the group consisting of
  • each of the rings may have non-interfering substituents thereon.
  • the present invention also relates to a method of reducing or inhibiting fungal growth in a region to be treated, comprising applying to the region a fungal reducing- or inhibiting-effective amount of at least one compound selected from the group consisting of:
  • the present invention is directed to an antifungal composition
  • an antifungal composition comprising at least one compound selected from the group consisting of:
  • R 1 is selected from the group consisting of (1) H, (2) C,-C 15 alkyl, (3) a group
  • R 7 and R 8 are C t -C 15 alkyl or, together with the carbon atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a group Ar, wherein Ar is an aromatic ring;
  • R 2 through R 5 are each independently H or C,-C 15 alkyl, or R 2 and R 3 are a bond thus creating a double bond between the carbon atoms to which they are bound, or R 2 and R 3 and R 4 and R 5 are bonds thus creating a triple bond between the carbon atoms to which they are bound, or two of R 1 through R 5 , together with the carbon atoms to which they are bound, form part of a 3-8 membered carbocyclic ring, with the proviso that when R 2 through R 5 are each H, then R 1 is only Ar;
  • R 6 is selected from the group consisting of (1) H, (2) C,-C, 5 alkyl, (3) phenyl, (4) a group N(CH 3 ) 2 (C 10 H 21 ) 2 , (5) a group N(C,-C 15 alkyl) 4 , wherein the alkyl groups are the same or different, (6) NH m (X) 4 . m , wherein each X is independently selected from Q-C.j alkyl and 2-hydroxyethyl, and m is 0-4, with the proviso that when R' is Ar, then R 6 is other than phenyl; n is 0-10 and n' is 0 or 1; and
  • R 9 is selected from the group consisting of H, OH and C,-C 15 alkyl; R 10 is H or OH; and R" and R 12 are each independently H or C,-C 15 alkyl,
  • Ar is preferably selected from the group consisting of
  • each of the rings may have non-interfering substituents thereon.
  • Non- interfering substituents can include, for example, but are not limited to, lower alkyl groups, lower alkoxy groups, lower acyl groups, amino groups, hydroxyl groups, etc.
  • the term "lower” is understood as meaning 1-6 branched or unbranched carbon atoms. Usually, monocyclic rings may have 0-2 substituents, and bicyclic rings may have 0-4 substituents, but this number is not critical.
  • a first class is compounds of formula III
  • R 13 through R 15 are each independently H or C,-C 1S alkyl, or two of R 13 through R 15 , together with the carbon atoms to which they are bound, form a 3-8 membered carbocyclic ring; and R 6 is as defined above.
  • a second class of preferred compounds are compounds of formula IV
  • R 6 through R 8 and n are as defined above.
  • a third class of preferred compounds are compounds of formula V
  • R 16 is a group Ar, wherein Ar is as defined above;
  • R' 7 through R 20 are each H, or R' 7 and R' 8 are a bond thus creating a double bond between the carbon atoms to which they are bound, or
  • R 17 and R 18 and R 19 and R 20 are bonds thus creating a triple bond between the carbon atoms to which they are bound;
  • R 21 is selected from the group consisting of (1) H, (2) C,-C 15 alkyl, (3) a group N(CH 3 ) 2 (C 10 H 2 ,) 2 , (4) a group N(C,-C 15 alkyl) 4 , wherein the alkyl groups are the same or different, (5) NH- ⁇ CX) ⁇ , wherein each X is independently selected from C
  • the fourth class of preferred compounds are compounds of formula II
  • R 9 through R' 2 are as defined above.
  • the present invention is directed to a method of reducing or inhibiting fungal growth in a region to be treated, comprising applying to the region a fungal reducing- or inhibiting-effective amount of at least one compound selected from the group consisting of:
  • antifungal includes, but is not limited to, compounds that reduce, destroy or kill fungi (fungicidai) or inhibit the growth of fungi (fungistatic).
  • antifungal composition includes not only the compounds of the present invention in a conventional diluent and/or solvent, but also includes the compounds of the present invention in other carriers and/or final preparations, such as paints, stains, wood stains, cleaners, disinfectants, rinses and wood or lawn treatments.
  • wood as used herein includes, but is not limited to, trees, logs, woody plants, wood products, wood chips, processed wood, saw dust or items made completely or partially of wood.
  • wood treatment includes, but is not limited to, washes, rinses, stains, pigmented finishes, natural finishes, exterior finishes, interior finishes, furniture finishes, filling, washcoating, sealing, topcoating, cleaners, polishes or fire retardants.
  • Preferred treatment includes oil based or water based finishes.
  • region refers not only to the surface of the area to be treated, but also to areas underneath the surface, if the surface is permeable.
  • region applies not only to the surface of soil having plants thereon, but also to areas underneath the soil surface.
  • region includes the inner portion of wood below the surface of the wood.
  • region is also meant to include the surface of non-permeable substrates, such as bathroom tile or kitchen countertops, or non-permeable painted surfaces.
  • alkyl is a radical containing only carbon and hydrogen, and lacking double or triple bonds.
  • alkyl radicals contain 1 to 15 carbons and, unless stated otherwise, the alkyl radicals can be branched or unbranched.
  • the antifungal compositions of the present invention are effective against a variety of genera and species of fungi.
  • Preferred fungi against which the present compositions are effective include the genera Phellinus, Ophiostoma (Ceratocystis), Haematostereum and Marasmius.
  • Preferred species include P tremulae, P. pint, O. crassivaginatum, O. piliferum, O. clavigerum, O. ips, H. sanguinolentum and M. oreades.
  • Preferred woods to be treated include aspen and conifers.
  • This invention also includes the use of the present compounds in a method for the treatment of wood or wood products to reduce or inhibit decay and/or staining comprising applying to a region to be treated a fungal-decay and/or fungal-staining reducing- or inhibiting-effective amount of at least one compound selected from the group consisting of:
  • the compounds of the present invention can be used in paints, stains, wood stains, cleaners, disinfectants, rinses or other wood treatments.
  • the compounds can also be used for other plants besides woody plants and grasses. Although treatment for wood, grasses and other plants are preferred, the compounds of the present invention can also be used on non- wood surfaces as an active agent of cleaners, disinfectants or rinses, such as bathroom or kitchen cleaners, cleaners for non- wood (e.g., aluminum or vinyl) house siding or other cleaning products or disinfectants where reducing or inhibiting fungal growth is desired.
  • a method for reducing wood staining using one or more of the following compounds la, 2, 4a, 4b, 6a, 7, 8a, 8c, 8f, 9a, 9b, 13, 14, 20, 21a, 21d, 21e, 22, 24, 26b, 26c, 26d, 26f, 28, 31 and 32 .
  • An antifungal composition in accordance with the present invention preferably contains at least one of the following compounds: la, le, lf, 2, 4a, 4b, 6a, 6d, 7, 8a, 8c, 8f, 9a, 9b, 12, 13, 14, 15, 33, 34, 20, 21a, 21d, 21e, 22, 23a, 24, 25d, 26a, 26b, 26c, 26d, 26e, 26f, 26g, 28, 29, 31, 32 and 35.
  • An antifungal composition and method of use for reducing or inhibiting fungal growth preferably includes two or more compounds to increase the breadth of organisms inhibited or reduced, or to increase the potency of the compounds. It is particularly preferred to use at least one compound of the present invention, along with benzoic acid and/or salicylic acid. Preferred compositions in this regard are compositions containing benzoic acid and at least one of the following compounds of the invention: 8f, la, 13 and 14. It is preferred to apply the compounds in 50:50 ratios (benzoic acidxompound(s) of the invention). However, a range of 25:75 to 75:25 is suitable.
  • the present compounds are soluble in at least one of acetone, alcohol and water. These compounds can also be dissolved in a variety of other solutions or solvents.
  • the compounds can also be directly added to a final preparation (e.g., paint, stain, wood or lawn treatment, cleaner or disinfectant). If the antifungal compound will not readily dissolve in the final preparation, then the compound must be first dissolved in an appropriate organic solvent and then diluted, as known in the art. The appropriate solvent must dissolve the compound and be able to mix with the final preparation. A worker skilled in the art can readily determine the appropriate solvent without undue experimentation.
  • the desired amount of the antifungal compounds in the composition is between 1 and 50 times the amount which inhibited 95 to 100% of fungal growth (according to information from Tables 1 to 7, for example).
  • the concentration of the antifungal compounds in the composition is not critical. Normally, however, the concentration range will be from 0.1% to 50%, more preferred 1% to 30%. It is well within the ordinary skill of a worker in the art to determine suitable amounts and concentrations of the specific antifungal composition to be formulated, depending on the treatment strategy.
  • One or more of the present compounds can be applied to wood using a variety of methods including but not limited to using a brush treatment, dipping, seeping, diffusion, spraying, dusting, pressure processes or ground line treatment ' .
  • Formulations for other applications may include but are not limited to solutions, emulsions, suspensions, dusting powders, lyophilized solutions, liposome formulations or slow release formulations. These formulations can include a variety of additives including solvents, lipids, buffering chemicals, detergents, fertilizers or other nutrients. Preparation of specific formulations is well within the skill of an ordinary worker in the art, and will depend on the particular treatment strategy employed.
  • Table 6 shows the effect of selected compounds on the in vitro growth of fairy ring fungus Marasmius oreades.
  • Table 7 shows the effect of benzoic acid alone and in combination with selected compounds on the in vitro growth of M. oreades.
  • Two conifer decay fungi Phellinus pini (NOF 2231) and Haematostereum sanguinolentum (NOF 118) and two species of conifer blue stain fungi Ophiostoma clavigerum (NOF 838) and O. ips (NOF 684), isolated from conifers were also used in this study. These fungi were maintained at 5°C on 2% malt extract agar in McCartney bottles until used and are deposited in the fungal culture collection at the Northern
  • Marasmius oreades (NOF 2255) was obtained from a fairy ring and maintained on malt extract agar.
  • estersification (lb), substitution of the phenyl group (lc,d), replacement of the phenyl group by a naphthyl group (le,f), introduction of a triple bond (2) and an allenic group (3), reduction (4a,b), introduction of a cyclopropane ring (5), chain shortening (6, 7, 8), and chain elongation (9-12).
  • Two dicarboxylic acids (10, 11) were also included in the study.
  • hydroxycinnamic acids 6b and 6c, phenylpropynoic acid (7), and hydrocinnamic acid (8a) were considered as promising candidates because of their low toxicity and enzyme inhibitory activity (Hodgins 1971 , Kubata et al. 1974).
  • the methyl ester of 4-phenyl-3-butenoic acid was prepared by treatment of the acid with diazomethane.
  • the naphthyl analogs le and If (Table 1) were synthesized from 1- or 2-naphthyl acetaldehyde and malonic acid (Mentzer & Pillon, 1950).
  • the acetylenic acid 2 and the allene carboxylic acid 3 were synthesized according to Shevchenko et al. 1974, Mansfield and Whiting, 1956, and Maerkl 1961.
  • the saturated acids 4a, 8d, 8e, 11, and 12 were obtained by catalytic hydrogenation of the corresponding unsaturated acids la, 6e, 6f, 9b, and 10 over Pd/C at 1 atm.
  • the dicarboxylic acid 10 and the phenyl analog of sorbic acid 9b were synthesized following the method of Stuart et al. (1886).
  • the modifications of the lead compounds tiglic (20) and senecioic (21a) acids includes formation of metal and ammonium salts (21b-e), synthesis of esters (23b, 24), and amides (25), replacement of the OH group with substituted phenyl groups (seneciophenones, 26), removal of the methyl groups (acrylophenone 28 and its precursor 27, as well as the substituted acrylophenones 29 and 30), and replacement of the methyl groups by a cyclohexane ring (31, 32).
  • the Zn salt of senecioic acid was prepared by stirring a suspension of ZnO in a dilute solution of senecioic acid.
  • the ammonium salt 21d was prepared by treatment of 21a with 1 equivalent of diethanolamine, while for the preparation of the ammonium salt 21e, the sodium salt of senecioic acid was treated with didecyldimethylammonium bromide.
  • the ester 24 was obtained from phenol and 21a in the attempt to synthesize 26b (Bragole et al. 1960).
  • the amides 25a,b,c were obtained by treatment of senecioyl chloride with the corresponding amine, while 25d was prepared by acylation of anthranilic acid with senecioic anhydride (Kaufmann 1909).
  • Seneciophenone (26a), and its derivatives 26b, 26d, and 26e were synthesized by Friedel-Krafts reaction with benzene, anisole (afforded a mixture of 26b and 26c), toluene, or isopropylbenzene (Smith 1949).
  • MULTIWELLTM Tissue culture plates (1.8. cm * 1.5 cm, diameter x length, individual well; manufactured by Becton Dickinson Labware, NJ, U.S.A.).
  • MULTIWELLTM culture plates were prepared by adding 2 ml of sterilized carrot agar into each well. Twenty five ⁇ l of each of the compounds at 1, 10, 100, and 1000 ⁇ g/ml in acetone was added separately to the surface of the agar in each well. In the case of the controls, 25 ⁇ l acetone was added.
  • MULTIWELLTM plates were kept in a laminar flow hood for two minutes to allow the acetone to evaporate. Each agar well was then individually inoculated with 5 mm agar plugs of P. tremulae, O. crassivaginatum, and O. piliferum. The MULTIWELLTM plates were then wrapped with parafilm and incubated at 22°C in the dark. The colony diameter was measured and mycelia were observed under a microscope.
  • the same method was used to screen for inhibition of Marasmius oreades except the agar was malt extract agar.
  • each compound also may have antibacterial or other antimicrobial activity.
  • the breadth of each compound's activity can be determined using a similar assay. For testing other fungi, bacteria or other microbes the same procedure can be used, but the nutrient media used will be based on the nutrient requirements of the organism to be tested. Some examples include blood agar plates, nutrient agar or another media or agar selected based on the organism being screened. An individual skilled in the art would be familiar with which agar or media is suitable for a specific organism for this assay.
  • flasks were treated with 2 ml sterile distilled water and five sterile agar plugs without inoculum.
  • the flasks were kept in the incubator in the dark at 22°C and were shaken periodically to fragment the growing mycelia in the wood chips. After 60 days of incubation, wood chips were removed from flasks and photographed. The anatomical structures of the wood chips were also studied by fixing wood chips in formalin- acetic acid-ethanol (FAA). After ten days, the chips were rinsed with 50% ethanol, dehydrated through a n-butanol series under vacuum, and infiltered with PARAPLAST X-TRATM (Monoject Scientific, St. Louis, Missouri) under vacuum at 56°C.
  • FAA formalin- acetic acid-ethanol
  • Transverse and radial or tangential sections were made using a rotary microtome. The sections were then observed under a microscope. Data were subjected to analysis of variance. The individual means were compared using Scheffe's test for multiple comparison using SAS software (SAS institute Inc. 1990).
  • Table 3 summarizes the effects of some congeners of 4-phenyl-3-butenoic acid on colonization of aspen chips by P. tremulae, O. crassivaginatum and O. piliferum.
  • senecioic acid has an LD 50 intragastrically of 3130 mg/kg in rats (Chemical
  • senecioic acid inhibits Clostridium botulinum (Huhtanen et al, 1985).
  • Example 5 Activity against aspen decay and stain fungi A. Congeners of 4-phenyl -3-butenoic acid (Table 1)
  • P. tremulae is a serious pathogen causing extensive decay of aspen.
  • the metal salts 21b, 21c, benzophenone oxime (23a), its ester 23b, the senecioic acid amides 25a, 25b, 25c, the Mannich base 27, as well as compounds 29 and 30 were completely inactive at 1000 ⁇ g/ml.
  • the most active compounds reported in Table 2 include the acids 20, 21a, 31, and 32 (against all three fungi), and the p-substituted seneciophenones 26d and 26f (against the blue stain fungi O. crassivaginatum and O. piliferum), and 26b (against O. piliferum) which show efficacy superior to that of the commercial fungicides 22 and 23a.
  • the above compounds have a low mammalian toxicity (Gurova et al. 1985) which makes them good candidates for chemical protection of aspen wood.
  • Example 7 Activity against fairy ring fungus Marasmius oreades (Tables 6 and 7) Several of the compounds described in Tables 1 and 2 were also tested against the fairy ring fungus Marasmius oreades (Table 6). Of the compounds tested for their ability to inhibit the growth of Marasmius oreades the most potent inhibitors were structures la, 21a, 14, 13, 32, 8f, and 35. Structures 19 and 26d were also inhibitory but for this organism they were not as potent.
  • Hiratsuka Y., Gibbard, D.A., Bakowsky, O., Maier, G.B. 1990, Classification and measurement of aspen decay and stain in Alberta. Northern For. Cent., Can. For.,
  • Table 1 Reduction (%) of growth from control 1,2 of P. tremulae, O. crassivaginatum, and O. piliferum induced by congeners of 4-phenyl -3-butenoic ncid and related compounds.
  • Table 2 Inhibition of the growth* of P. tremulae, O. crassivaginatum, and 0. piliferum by derivatives of tiglic and senecioic acid.

Abstract

An antifungal composition is disclosed comprising at least one compound selected from the group consisting of: (a) at least one compound of formula (I), and (b) at least one compound of formula (II), or an alkali or alkali earth salt thereof, and a carrier or diluent therefor. Methods of reducing or inhibiting fungal growth, fungal wood decay and fungal wood stain are also disclosed, along with a method of reducing or inhibiting fairy rings. Paints, stains, cleaning products, disinfectants and wood or lawn treatments containing the compounds are also disclosed.

Description

AGENTS WITH ANTIFUNGAL ACTIVITY AND METHODS OF USE
THEREOF
This application claims priority from provisional application Serial No. 60/020,035, filed June 21 , 1996.
Background Of the Invention
This invention relates to compounds that have antifungal activity. These compounds reduce or inhibit the growth of fungi from a variety of genera and species.
Trembling aspen or aspen (Populus tremuloides Michx.) is an important source of pulp for the paper-making industry. Aspen is also used for making particle board and solid wood products. Decay and stain caused by several fungi have been identified as the two most important factors limiting the use of aspen (Hiratsuka et al. 1990, 1995). Recently, the present inventors reported on the inhibition of the growth of aspen decay and stain fungi using certain antagonistic fungi (Chakravarty and
Hiratsuka 1992, 1994; Chakravarty et al. 1994; Hutchison et al. 1994). The growth of aspen decay fungus Phellinus tremulae (Bond.) Bond, et Borisov was inhibited by metabolites of another decay fungus Peniophora polygonia (Pers.:Fr.) Bou. et Gal. (Trifonov et al. 1992). The antagonistic activity of the coprophilous fungus Sporormiella similis Khan and Cain, frequently found on aspen black gall, as well as the activity of its metabolites were also studied (Chakravarty et al. 1994). It was shown that S. similis inhibits the in vitro growth as well as aspen wood chip colonization by blue stain fungi. The present invention is an extension of work reported on the antifungal activity of metabolites of Peniophora polygonia (Trifonov et al. 1992) and Sporormiella similis (Chakravarty et al. 1994) against aspen pathogens. Summary of the Invention
The inventors extracted a variety of compounds from decay fungus Peniophora polygonia and found that isobutyric and isovaleric acid were amongst the most active compounds. Following this lead, they tested 4- phenyl-3-butenoic acid - a structural analog of the above acids. 4-phenyl- 3-butenoic acid is known as a potent mechanism-based inhibitor of peptidylglycine amidating monooxygenase (Bradbury et al. 1990; Rhodes and Honsinger 1993), as a modulator of the activity of γ-glutamic acid transpeptidase (Thompson and Meister 1980), as well as an antibacterial compound (Khristov 1973).
The objective of this invention is to provide an antifungal composition and methods of use against a wide range of fungi. Specifically, the invention is directed to methods of reducing or inhibiting fungal growth by applying the compounds of the invention to a region to be treated. The antifungal compositions of the invention can be used against a wide variety of fungi, and it is well within the skill of an ordinary worker in the art to screen particular fungi against which the compositions of the invention are effective.
The objective of part of this invention was to determine the activity of homologs and analogs of 4-phenyl-3-butenoic acid against P. tremulαe and two species of blue stain fungi, Ophiostoma piliferum (Fr.) H. and P. Sydow and O. crassivaginatum (H.D. Griffin) T.C. Harrington. For comparison purposes, phomalone (Ayer and Jimenez 1994), pentachlorophenol, copper 8-oxyquinolinate, Zn salt of 10-undecenoic acid, as well as lauric acid were included in this study.
The inventors have also found that tiglic acid and senecioic acids, minor metabolites of S. similis, significantly inhibited the growth of the blue stain fungus Ophiostoma piliferum, even at concentrations as low as 1 μg/ml. The inventors therefore synthesized derivatives and analogs of these two leads to test their activity against the aspen decay fungus Phellinus tremulae and the aspen blue stain fungi Ophiostoma crassivaginatum and O. piliferum.
Selected compounds from the derivatives, homologs and analogs of tiglic acid, senecioic acid and 4-phenyl-3-butenoic acid were also tested against the conifer decay fungi Phellinus pini and Haematostereum sanguinolentum and the conifer blue stain fungi Ophiostoma clavigerum and O. ips. Finally, select compounds were tested against the fairy ring fungus Marasmius oreades.
Thus, the presently-disclosed compounds include derivatives, homologs and analogs of tiglic acid, senecioic acid and 4-phenyl-3-butenoic acid which are effective antifungal compounds. These compounds can be used in antifungal compositions, and methods of reducing or inhibiting fungal growth.
More specifically, the present invention is directed to an antifungal composition comprising at least one compound selected from the group consisting of:
(a) at least one compound of formula I
Figure imgf000005_0001
wherein
R1 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3) a group
Figure imgf000005_0002
wherein R7 and R8 are C,-C15 alkyl or, together with the carbon atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-C,s alkyl, or R2 and R3 together are a bond thus creating a double bond between the carbon atoms to which they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating a triple bond between the carbon atoms to which they are bound, or two of R1 through R5, together with the carbon atoms to which they are bound, form part of a 3-8 membered carbocyclic ring, with the proviso that when R2 through R5 are each H, then R1 is only
Ar;
R6 is selected from the group consisting of (1) H, (2) CrC,5 alkyl, (3) phenyl, (4) a group N(CH3)2(C,0H2I)2, (5) a group N(C,-CI5 alkyl)4, wherein the alkyl groups are the same or different, (6) NHm(X)4.m , wherein each X is independently selected from C,-C13 alkyl and 2-hydroxyethyl, and m is 0-4, with the proviso that when R' is Ar, then R6 is other than phenyl; n is 0-10 and n' is O or 1 ; and
(b) at least one compound of formula II
Figure imgf000006_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C15 alkyl;
R10 is H or OH; and
R11 and R12 are each independently H or C,-C15 alkyl,
or an alkali or alkali earth salt thereof, and a carrier or diluent therefor.
It is preferred that Ar is selected from the group consisting of
Figure imgf000007_0001
wherein each of the rings may have non-interfering substituents thereon.
The present invention also relates to a method of reducing or inhibiting fungal growth in a region to be treated, comprising applying to the region a fungal reducing- or inhibiting-effective amount of at least one compound selected from the group consisting of:
(a) at least one compound of formula I, wherein formula I is as defined above; and
(b) at least one compound of formula II, wherein formula II is as defined above, or an alkali or alkali earth salt thereof. The more preferred embodiments of the present invention are disclosed in the Detailed Description of the Invention, as follows.
Description of the Preferred Embodiments
In a first aspect, the present invention is directed to an antifungal composition comprising at least one compound selected from the group consisting of:
(a) at least one compound of formula I
Figure imgf000008_0001
wherein
R1 is selected from the group consisting of (1) H, (2) C,-C15 alkyl, (3) a group
>
Figure imgf000008_0002
wherein R7 and R8 are Ct-C15 alkyl or, together with the carbon atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-C15 alkyl, or R2 and R3 are a bond thus creating a double bond between the carbon atoms to which they are bound, or R2 and R3 and R4 and R5 are bonds thus creating a triple bond between the carbon atoms to which they are bound, or two of R1 through R5, together with the carbon atoms to which they are bound, form part of a 3-8 membered carbocyclic ring, with the proviso that when R2 through R5 are each H, then R1 is only Ar;
R6 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3) phenyl, (4) a group N(CH3)2(C10H21)2, (5) a group N(C,-C15 alkyl)4, wherein the alkyl groups are the same or different, (6) NHm(X)4.m , wherein each X is independently selected from Q-C.j alkyl and 2-hydroxyethyl, and m is 0-4, with the proviso that when R' is Ar, then R6 is other than phenyl; n is 0-10 and n' is 0 or 1; and
(b) at least one compound of formula II
Figure imgf000009_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C15 alkyl; R10 is H or OH; and R" and R12 are each independently H or C,-C15 alkyl,
or an alkali or alkali earth salt thereof, and a carrier or diluent therefor.
Unless otherwise specified, Ar is preferably selected from the group consisting of
Figure imgf000010_0001
wherein each of the rings may have non-interfering substituents thereon. Non- interfering substituents can include, for example, but are not limited to, lower alkyl groups, lower alkoxy groups, lower acyl groups, amino groups, hydroxyl groups, etc. The term "lower" is understood as meaning 1-6 branched or unbranched carbon atoms. Usually, monocyclic rings may have 0-2 substituents, and bicyclic rings may have 0-4 substituents, but this number is not critical.
There are generally four classes of preferred compounds. A first class is compounds of formula III
=
Figure imgf000010_0002
wherein
R13 through R15 are each independently H or C,-C1S alkyl, or two of R13 through R15, together with the carbon atoms to which they are bound, form a 3-8 membered carbocyclic ring; and R6 is as defined above.
A second class of preferred compounds are compounds of formula IV
>
Figure imgf000011_0001
wherein
R6 through R8 and n are as defined above.
A third class of preferred compounds are compounds of formula V
Figure imgf000011_0002
wherein
R16 is a group Ar, wherein Ar is as defined above; R'7 through R20 are each H, or R'7 and R'8 are a bond thus creating a double bond between the carbon atoms to which they are bound, or R17 and R18 and R19 and R20 are bonds thus creating a triple bond between the carbon atoms to which they are bound; R21 is selected from the group consisting of (1) H, (2) C,-C15 alkyl, (3) a group N(CH3)2(C10H2,)2, (4) a group N(C,-C15 alkyl)4, wherein the alkyl groups are the same or different, (5) NH-πCX)^ , wherein each X is independently selected from C|-C!5 alkyl and 2-hydroxyethyl, and m is 0-4; and n is as defined above.
The fourth class of preferred compounds are compounds of formula II
Figure imgf000012_0001
wherein R9 through R'2 are as defined above.
In another aspect, the present invention is directed to a method of reducing or inhibiting fungal growth in a region to be treated, comprising applying to the region a fungal reducing- or inhibiting-effective amount of at least one compound selected from the group consisting of:
(a) at least one compound of formula I, wherein formula I is as defined above; and
(b) at least one compound of formula II, wherein formula II is as defined above, or an alkali or alkali earth salt thereof. The term "antifungal" as used herein includes, but is not limited to, compounds that reduce, destroy or kill fungi (fungicidai) or inhibit the growth of fungi (fungistatic). The term "antifungal composition" as used herein includes not only the compounds of the present invention in a conventional diluent and/or solvent, but also includes the compounds of the present invention in other carriers and/or final preparations, such as paints, stains, wood stains, cleaners, disinfectants, rinses and wood or lawn treatments.
The term "wood" as used herein includes, but is not limited to, trees, logs, woody plants, wood products, wood chips, processed wood, saw dust or items made completely or partially of wood.
The term "wood treatment" includes, but is not limited to, washes, rinses, stains, pigmented finishes, natural finishes, exterior finishes, interior finishes, furniture finishes, filling, washcoating, sealing, topcoating, cleaners, polishes or fire retardants. Preferred treatment includes oil based or water based finishes.
The term "region" refers not only to the surface of the area to be treated, but also to areas underneath the surface, if the surface is permeable. For example, the term "region" applies not only to the surface of soil having plants thereon, but also to areas underneath the soil surface. Similarly, the term "region" includes the inner portion of wood below the surface of the wood. However, the term "region" is also meant to include the surface of non-permeable substrates, such as bathroom tile or kitchen countertops, or non-permeable painted surfaces.
Herein, the term "alkyl" is a radical containing only carbon and hydrogen, and lacking double or triple bonds. In this invention, unless stated otherwise, alkyl radicals contain 1 to 15 carbons and, unless stated otherwise, the alkyl radicals can be branched or unbranched.
The antifungal compositions of the present invention are effective against a variety of genera and species of fungi. Preferred fungi against which the present compositions are effective include the genera Phellinus, Ophiostoma (Ceratocystis), Haematostereum and Marasmius. Preferred species include P tremulae, P. pint, O. crassivaginatum, O. piliferum, O. clavigerum, O. ips, H. sanguinolentum and M. oreades.
Preferred woods to be treated include aspen and conifers.
This invention also includes the use of the present compounds in a method for the treatment of wood or wood products to reduce or inhibit decay and/or staining comprising applying to a region to be treated a fungal-decay and/or fungal-staining reducing- or inhibiting-effective amount of at least one compound selected from the group consisting of:
(a) at least one compound of formula I, wherein formula I is as defined above; and
(b) at least one compound of formula II, wherein formula II is as defined above, or an alkali or alkali earth salt thereof.
This invention also includes the use of these compounds in a method of treating fairy rings comprising applying to a region to be treated a fairy-ring fungal reducing- or inhibiting-effective amount of at least one compound selected from the group consisting of:
(a) at least one compound of formula I, wherein formula I is as defined above; and
(b) at least one compound of formula II, wherein formula II is as defined above, or an alkali or alkali earth salt thereof. It is preferred to use these compounds to reduce or inhibit the growth of fairy rings on grassy regions (e.g., golf courses and other grassy lawns).
The compounds of the present invention can be used in paints, stains, wood stains, cleaners, disinfectants, rinses or other wood treatments. The compounds can also be used for other plants besides woody plants and grasses. Although treatment for wood, grasses and other plants are preferred, the compounds of the present invention can also be used on non- wood surfaces as an active agent of cleaners, disinfectants or rinses, such as bathroom or kitchen cleaners, cleaners for non- wood (e.g., aluminum or vinyl) house siding or other cleaning products or disinfectants where reducing or inhibiting fungal growth is desired.
With reference to the numerical listings of various compounds of the invention in Tables 1-7, the following compounds are prefeσed for the following uses:
• The use of one or more of the following compounds in a method for reduction or inhibition of fungal growth: la, le, lf, 2, 4a, 4b, 6a, 6d, 7, 8a, 8c, 8f, 9a, 9b, 13, 14, 15,20, 21a, 21d, 21e, 22, 24, 25d, 31, 32, 33, 34, 26a, 26b, 26c, 26d, 26e, 26f, 26g, 28, 29, 23a and 35. The use of at least one of the following compounds is especially preferred: la, 2, 4b, 7, 8f, 13, 14, 20, 21a, 26c, 26d, 26f, 28, 31 and 32.
• The use of one or more of the following compounds in a method for reducing decay and/or staining of wood: la, 2, 4b, 7, 8c, 8f, 13, 14, 33, 34, 20, 21a, 21e, 24, 26b, 26c, 26d, 26f, 28, 31 and 32.
• A method for reducing wood staining using one or more of the following compounds: la, 2, 4a, 4b, 6a, 7, 8a, 8c, 8f, 9a, 9b, 13, 14, 20, 21a, 21d, 21e, 22, 24, 26b, 26c, 26d, 26f, 28, 31 and 32 . A method for reducing wood decay using one or more of the following compounds: la, le, 2, 4b, 7, 8c, 8f, 13, 14, 15, 33, 34, 20, 21a, 21e, 24, 25d, 26c, 26d, 26f, 26g, 28, 31 and 32.
A method for reducing or inhibiting growth of fairy ring fungus growth using one or more of the following compounds: la, 8f, 13, 14, 21a, 26d, 32 and 35.
An antifungal composition in accordance with the present invention preferably contains at least one of the following compounds: la, le, lf, 2, 4a, 4b, 6a, 6d, 7, 8a, 8c, 8f, 9a, 9b, 12, 13, 14, 15, 33, 34, 20, 21a, 21d, 21e, 22, 23a, 24, 25d, 26a, 26b, 26c, 26d, 26e, 26f, 26g, 28, 29, 31, 32 and 35. More preferred are at least one of the following compounds: la, le, lf, 2, 4a, 4b, 7, 8c, 8f, 12, 13, 14, 20, 21a, 26b, 26c, 26d, 26f, 28, 31, 32, 33, and 34, and most preferred are at least one of the following compounds: la, 2, 4b, 7, 8c and 8f.
An antifungal composition and method of use for reducing or inhibiting fungal growth preferably includes two or more compounds to increase the breadth of organisms inhibited or reduced, or to increase the potency of the compounds. It is particularly preferred to use at least one compound of the present invention, along with benzoic acid and/or salicylic acid. Preferred compositions in this regard are compositions containing benzoic acid and at least one of the following compounds of the invention: 8f, la, 13 and 14. It is preferred to apply the compounds in 50:50 ratios (benzoic acidxompound(s) of the invention). However, a range of 25:75 to 75:25 is suitable.
Formulations
The present compounds are soluble in at least one of acetone, alcohol and water. These compounds can also be dissolved in a variety of other solutions or solvents. The compounds can also be directly added to a final preparation (e.g., paint, stain, wood or lawn treatment, cleaner or disinfectant). If the antifungal compound will not readily dissolve in the final preparation, then the compound must be first dissolved in an appropriate organic solvent and then diluted, as known in the art. The appropriate solvent must dissolve the compound and be able to mix with the final preparation. A worker skilled in the art can readily determine the appropriate solvent without undue experimentation. The desired amount of the antifungal compounds in the composition is between 1 and 50 times the amount which inhibited 95 to 100% of fungal growth (according to information from Tables 1 to 7, for example). The concentration of the antifungal compounds in the composition is not critical. Normally, however, the concentration range will be from 0.1% to 50%, more preferred 1% to 30%. It is well within the ordinary skill of a worker in the art to determine suitable amounts and concentrations of the specific antifungal composition to be formulated, depending on the treatment strategy.
One or more of the present compounds can be applied to wood using a variety of methods including but not limited to using a brush treatment, dipping, seeping, diffusion, spraying, dusting, pressure processes or ground line treatment'."
The basic formulations for wood treatments, cleaners and disinfectants are known to those skilled in the art.
Formulations for other applications may include but are not limited to solutions, emulsions, suspensions, dusting powders, lyophilized solutions, liposome formulations or slow release formulations. These formulations can include a variety of additives including solvents, lipids, buffering chemicals, detergents, fertilizers or other nutrients. Preparation of specific formulations is well within the skill of an ordinary worker in the art, and will depend on the particular treatment strategy employed.
Examples The effect of 38 homologs and analogs of 4-phenyl-3-butenoic acid against
Phellinus tremulae. Ophiostoma crassivaginatum. and O. piliferum was studied. These compounds showed varied inhibition of the in vitro growth and the wood chip colonization by these fungi (Table 1). Six of the compounds tested prevented the development of blue stain caused by O. crassivaginatum and O. piliferum in wood chips at concentrations of 10 μg/ml (Table 3).
The effect of derivatives and analogs of tiglic acid and senecioic acids, minor metabolites of S. similis, were also studied. Activity was tested against the aspen decay fungus Phellinus tremulae and the aspen blue stain fungi Ophiostoma crassivaginatum and 0. piliferum (Table 2).
The effect of selected compounds against the conifer decay fungi Phellinus pini and Haematostereum sanguinolentum and the conifer blue stain fungi Ophiostoma clavigerum and 0. ips were also studied (Tables 4 and 5).
Table 6 shows the effect of selected compounds on the in vitro growth of fairy ring fungus Marasmius oreades. Table 7 shows the effect of benzoic acid alone and in combination with selected compounds on the in vitro growth of M. oreades.
Example 1. Organisms
Phellinus tremulae (P. tremulae, NOF 1464 = UAMH 7005), an aspen decay fungus and two species of blue stain fungi, 0. crassivaginatum (NOF 1509 = Ceratocystiopsis crassivaginatά), and O. piliferum (NOF 1772) isolated from decayed and stained wood of P. tremuloides were used in this study. Two conifer decay fungi Phellinus pini (NOF 2231) and Haematostereum sanguinolentum (NOF 118) and two species of conifer blue stain fungi Ophiostoma clavigerum (NOF 838) and O. ips (NOF 684), isolated from conifers were also used in this study. These fungi were maintained at 5°C on 2% malt extract agar in McCartney bottles until used and are deposited in the fungal culture collection at the Northern
Forestry Centre. Canadian Forest Service. Edmonton, Alberta (NOF) under the listed accession numbers.
Marasmius oreades (NOF 2255) was obtained from a fairy ring and maintained on malt extract agar.
Example 2. Chemistry
The modifications of the structure of the lead-compound la included: esterification (lb), substitution of the phenyl group (lc,d), replacement of the phenyl group by a naphthyl group (le,f), introduction of a triple bond (2) and an allenic group (3), reduction (4a,b), introduction of a cyclopropane ring (5), chain shortening (6, 7, 8), and chain elongation (9-12). Two dicarboxylic acids (10, 11) were also included in the study. The hydroxycinnamic acids 6b and 6c, phenylpropynoic acid (7), and hydrocinnamic acid (8a) were considered as promising candidates because of their low toxicity and enzyme inhibitory activity (Hodgins 1971 , Kubata et al. 1974).
The methyl ester of 4-phenyl-3-butenoic acid was prepared by treatment of the acid with diazomethane. The naphthyl analogs le and If (Table 1) were synthesized from 1- or 2-naphthyl acetaldehyde and malonic acid (Mentzer & Pillon, 1950). The acetylenic acid 2 and the allene carboxylic acid 3 were synthesized according to Shevchenko et al. 1974, Mansfield and Whiting, 1956, and Maerkl 1961. The saturated acids 4a, 8d, 8e, 11, and 12 were obtained by catalytic hydrogenation of the corresponding unsaturated acids la, 6e, 6f, 9b, and 10 over Pd/C at 1 atm. The dicarboxylic acid 10 and the phenyl analog of sorbic acid 9b were synthesized following the method of Stuart et al. (1886).
The identity of the synthetic compounds was based on three independent criteria (usually m.p., proton NMR spectrum and IR spectrum).
Compounds la, 4b, 4c, 6a, 6b, 6c, 6d, 6e, 6f, 6g, 7, 8a, 8b, 8f, 9a, 13, 14,
16, 17, 18, 19, 33, 34, and 35 are commercially available and were purchased from Aldrich.
The modifications of the lead compounds tiglic (20) and senecioic (21a) acids includes formation of metal and ammonium salts (21b-e), synthesis of esters (23b, 24), and amides (25), replacement of the OH group with substituted phenyl groups (seneciophenones, 26), removal of the methyl groups (acrylophenone 28 and its precursor 27, as well as the substituted acrylophenones 29 and 30), and replacement of the methyl groups by a cyclohexane ring (31, 32).
Compounds 20, 21a, and 22 are commercially available and were purchased from Aldrich. The Zn salt of senecioic acid was prepared by stirring a suspension of ZnO in a dilute solution of senecioic acid. The ammonium salt 21d was prepared by treatment of 21a with 1 equivalent of diethanolamine, while for the preparation of the ammonium salt 21e, the sodium salt of senecioic acid was treated with didecyldimethylammonium bromide. Treatment of 23a (Nietzki et al. 1887) with senecioic anhydride afforded the diester 23b (Kehrmann, 1895). The ester 24 was obtained from phenol and 21a in the attempt to synthesize 26b (Bragole et al. 1960). The amides 25a,b,c were obtained by treatment of senecioyl chloride with the corresponding amine, while 25d was prepared by acylation of anthranilic acid with senecioic anhydride (Kaufmann 1909). Seneciophenone (26a), and its derivatives 26b, 26d, and 26e were synthesized by Friedel-Krafts reaction with benzene, anisole (afforded a mixture of 26b and 26c), toluene, or isopropylbenzene (Smith 1949). Compounds 26c and 26f were prepared following the procedures of Dev (1956) and Sowmithran (1985), respectively. Methylation of 26f with diazomethane afforded compound 26g. Compounds 27 and 28 were prepared as described (Mannich et al. 1922). Condensation of p- methylacetophenone with furfural or cinnamic aldehyde afforded compounds 29 (Kostanecki 1896) and 30 (Scholtz, 1903). 1 -Cyclohexene- 1 -carboxylic acid (31) was obtained by alkaline hydrolysis of the commercial methyl ester. The unsaturated acid 32 was prepared by Wittig reaction of cyclohexanone (G. Fodor, 1961 ) followed by alkaline hydrolysis of the ester.
The identity of all compounds was based on three criteria (usually m.p., 'H- nmr, and IR spectra).
The commercial wood preservatives 22 and 23a were also included in this study for comparison purposes.
Example 3. Improved synthesis of 4-phenyl-3-butynoic acid
Metallic lithium (0.77g, 0.11 M) was added to a mixture of dry benzene (15 ml) and hexamethylphosphoric triamide (HMPT) (45 ml) under nitrogen at room temperature and stirred until dissolved (approximately 2 h). A solution of phenylacetylene (10.2 g, 0.10M) in benzene (20 ml) was added dropwise and the mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0°C and a solution of ethylene oxide (5.72 g, 0.13 M) in dry benzene (15 ml) was added dropwise. After stirring for 24 hours at room temperature, the reaction mixture was quenched with ice and extracted with ether (3 * 150 ml). The ether extract was washed with water (3 * 150 ml), dried over sodium sulfate, filtered and the solvent removed under vacuum. The residue was passed through a short silica gel column with petroleum etheπether equals 1 :1 to give pure 4-phenyl- 3-butynol (7.2 g, 50%) as an oil. Η n.m.r. (CDCl3):7.45-7.38, (m,2H,aromatic), 7.33-7.25 (m, 3H, aromatic), 3.81 (t,J=6.5, 2H, H-C(l)), 2.80 (t, J=6.5, 2H, H- C(2)), 2.88 (br. s, 1H, OH).
A solution of CrO3 (2.67 g) in 8 ml of 30% H2SO4 was added dropwise to a solution of 4- phenyl-3-butynol (lg, 0.0068 M) in acetone (35 ml) at 0°C. The reaction mixture was stirred for 30 minutes at 0°C and for 4 hours at room temperature. Saturated solution of NaCl was added and the organic material was extracted with ether. The ether extract was dried over sodium sulfate, the solvent removed and the residue recrystallized from petroleum ether: benzene to give 4- phenyl-3-butynoic acid (0.3 g). The mother liquor was subjected to column chromatography with methylene chloride:ethanol equals 95:5 to provide additional amount of the acid (0.14g). Total yield 40%. M.p. 74.0-75.5°C (Mansfield and Whiting, 1956; m.p. 71°C). I.r. (CHC13): 3400-2600, 3051, 1690, 1428, 1087 cm'1. 'H n.m.r. (CDC13): 7.45 (dd, J=8.0, 2.0, 2H, arom.), 7.38-7.30 (m, 3H, arom.), 3.62 (s,2H, H-C(2)).
Example 4. Bioassay s A. Agar cultures.
To test the effect of the above compounds on the in vitro growth of P. tremulae, O. crassivaginatum, and O. piliferum, these fungi were grown on MULTIWELL™ Tissue culture plates (1.8. cm * 1.5 cm, diameter x length, individual well; manufactured by Becton Dickinson Labware, NJ, U.S.A.). MULTIWELL™ culture plates were prepared by adding 2 ml of sterilized carrot agar into each well. Twenty five μl of each of the compounds at 1, 10, 100, and 1000 μg/ml in acetone was added separately to the surface of the agar in each well. In the case of the controls, 25 μl acetone was added. All the MULTIWELL™ plates were kept in a laminar flow hood for two minutes to allow the acetone to evaporate. Each agar well was then individually inoculated with 5 mm agar plugs of P. tremulae, O. crassivaginatum, and O. piliferum. The MULTIWELL™ plates were then wrapped with parafilm and incubated at 22°C in the dark. The colony diameter was measured and mycelia were observed under a microscope.
The same method was used to screen for inhibition of Marasmius oreades except the agar was malt extract agar.
Many of these compounds also may have antibacterial or other antimicrobial activity. The breadth of each compound's activity can be determined using a similar assay. For testing other fungi, bacteria or other microbes the same procedure can be used, but the nutrient media used will be based on the nutrient requirements of the organism to be tested. Some examples include blood agar plates, nutrient agar or another media or agar selected based on the organism being screened. An individual skilled in the art would be familiar with which agar or media is suitable for a specific organism for this assay.
B. Aspen wood chips
Two hundred grams of aspen wood chips were soaked in water in each of seventy-six 250 ml flasks. After one hour excess of water was drained and the flasks were autoclaved for one hour at 121°C. When the wood chips were cooled, the flasks were treated separately with 5 ml of 1, 10, and 100 μg/ml of the most active compounds listed in Table 1, namely: la, 2, 4b, 7, 8c, and 8f, and then inoculated separately with P. tremulae, O. crassivaginatum, and O. piliferum. Four flasks were used for each treatment. In the case of the controls, flasks were treated with 2 ml sterile distilled water and five sterile agar plugs without inoculum. The flasks were kept in the incubator in the dark at 22°C and were shaken periodically to fragment the growing mycelia in the wood chips. After 60 days of incubation, wood chips were removed from flasks and photographed. The anatomical structures of the wood chips were also studied by fixing wood chips in formalin- acetic acid-ethanol (FAA). After ten days, the chips were rinsed with 50% ethanol, dehydrated through a n-butanol series under vacuum, and infiltered with PARAPLAST X-TRA™ (Monoject Scientific, St. Louis, Missouri) under vacuum at 56°C. Transverse and radial or tangential sections were made using a rotary microtome. The sections were then observed under a microscope. Data were subjected to analysis of variance. The individual means were compared using Scheffe's test for multiple comparison using SAS software (SAS institute Inc. 1990).
A visual assessment of colony growth can also be performed and used as an indicator of the potency of a compound. Table 3 summarizes the effects of some congeners of 4-phenyl-3-butenoic acid on colonization of aspen chips by P. tremulae, O. crassivaginatum and O. piliferum.
Toxicity
The toxicity of many of these compounds is relatively low, for example senecioic acid has an LD50 intragastrically of 3130 mg/kg in rats (Chemical
Abstracts 103, 33135w; Gurova, AL, Smolyar, N.Y., Drazhzhina, N.A., Gig. Tr. Prof. Zabol. 1985 et al, 1985) and tiglic acid has an LDfr (Amount of chemical ingested during the Food Reduction test which killed or did not kill more than 50% of the test mice) equal to 1 150 mg/kg/day (Chemical Abstracts 103:1655) or LD50 equals 111 mg/kg acute oral toxicity (Chemical abstracts 99:65537).
Other organisms
Some of these compounds have antibacterial activity or inhibit the growth of other microorganisms, for example, senecioic acid inhibits Clostridium botulinum (Huhtanen et al, 1985).
The same procedures described above can be used to test the activity of the present compounds against other microorganisms (including other fungi of interest) or other types of wood including hardwoods or softwoods, conifers or deciduous trees. Example 5. Activity against aspen decay and stain fungi A. Congeners of 4-phenyl -3-butenoic acid (Table 1)
Thirty eight compounds related to 4-phenyl-3-butenoic acid were tested against P. tremulae, O. crassivaginatum, and O. piliferum and varied inhibition of these fungi was observed. E-4-Phenyl-3-butenoic acid (la), E-4-(l-naphthyl)-3- butenoic acid (le), 4-phenyl-3-butynoic acid (2), 4-cyclohexylbutanoic acid (4b), phenylpropynoic acid (7), 3-cyclohexylpropanoic acid (8c), 3-(3-indolyl)propanoic acid (8f), cyclohexanecarboxylic acid (13), cyclohexy lacetic acid (14), pentachlorophenol (16), copper 8-oxyquinolinate (18), and the zinc salt of 10- undecenoic acid (19) completely inhibited the in vitro growth of P. tremulae at 100 and 1000 μg/ml (Table 1). Except for compounds le, 7, and 19, the other nine compounds were inhibitory to P. tremulae even at 1 μg/ml.
Compounds lf, 8a, and 15 showed inhibition of P. tremulae only at 1000 μg/ml, while the remaining 22 compounds were inactive.
For O. crassivaginatum, compounds 2, 4b, 8c, 8f, 14, 16, and 18 were highly toxic and showed an inhibitory effect even at 1 μg/ml. Compounds 7, 13, and 19 did not show any inhibitory effect against O. crassivaginatum at 1 μg/ml, however, at 10-1000 μg/ml the growth was significantly reduced. The acids la, le, 9a, and 9b showed inhibitory effect against O. crassivaginatum at 100-1000 μg/ml. The acids lf and 6d showed growth reduction by 25% and 18%, respectively, at 1000 μg/ml. The remaining 22 compounds did not show any inhibitory effect against O. crassivaginatum (Table 1).
For O. piliferum, compounds 2, 13, and 14, as well as compounds 16, 18, and 19 completely inhibited the in vitro growth at 10 μg/ml, while compounds la, 4a, 4b, 8a, and 8c were inhibitory at 1-1000 μg/ml. The acids le, 6a, 7, 8f, and sorbic acid (9a) inhibited the growth of O. piliferum at 100 to 1000 μg/ml. The remaining 22 compounds did not show any inhibition at 1-1000 μg/ml. Six of the most active compounds, namely la, 2, 4b, 7, 8c, and 8f, were chosen for treatment of aspen wood chips. The organic co-solvent used for these experiments was acetone. All six compounds prevented colonization of aspen by P. tremulae, O. crassivaginatum, and O. piliferum even at 10 μg/ml (Table 3).
P. tremulae is a serious pathogen causing extensive decay of aspen.
Previously, the inventors reported growth inhibition of P. tremulae by the metabolites of an antagonistic fungus Peniophora polygonia (Per.:Fr.) Boud. et Galzin (Trifonov et al. 1992). The reduction of growth and colonization of aspen wood chips by blue stain fungi (O. crassivaginatum and O. piliferum) was also observed when treated with metabolites of the antagonistic hypomyceteous fungi Lecythophora hoffmannii (van Beyma) W. Gams and McGinnis, Stachybotrys cylindrospora C.N.Jensen, and Sporormiella similis Khan and Cain (Hiratsuka et al. 1994, Chakravarty and Hiratsuka 1994, and Chakravarty et al. 1994).
Growth of P. tremulae, O. crassivaginatum, and O. piliferum is significantly reduced when these are treated with congeners of the enzyme inhibitor 4-phenyl-3-butenoic acid (la).
Of the compounds which retain the chain length of the lead compound la (group C4) the naphthyl analog le showed comparable activity against P. tremulae. 4-Cyclohexylbutanoic acid (4b), which is the product of complete reduction of la, showed the same activity against P. tremulae as la, and was also very active against the blue-stain fungi. The most active product in the C4 group of derivatives is 4-phenyl-3-butynoic acid (2), which inhibited the growth of all three fungi by approximately 50% at 1 μg/ml and by 100% at 10 μg/ml, thus proving to be a more active and more general fungicide than la. The methyl ester of la, the derivatives with para-bromo (lc) or methoxy (Id) substituents, as well as the cyclopropane analog 5 were completely inactive even at the highest concentration tested (Table 1). The chain shortening of la leading to group C3 was less effective. Only the acids with a triple bond (7), cyclohexy 1 (8c), or 3 -indolyl (8f) substituent exhibited activity comparable to that of la.
The chain elongation (group C5) proved to be least effective. Sorbic acid (9a) and its phenyl analog 9b showed only a weak inhibition of O. crassivaginatum and O. piliferum. Lauric acid (17), although known as fungicide (Byrde, 1969), showed no activity against the three fungi even at 1000 μg/ml. Cyclohexanecarboxylic acid (13) and especially cyclohexylacetic acid (14) were the most active of the compounds tested. The latter inhibited the growth of all three fungi by at least 50% at 1 μg/ml and is superior to pentachlorophenol against P. tremulae.
The activity of these congeners was compared with the activity of the known fungicides pentachlorophenol (16), copper 8-oxyquinolinate (18), and the zinc salt of 10-undecenoic acid (19). Several of the compounds tested showed activity similar to that of the commercial fungicides. The high toxicity and persistance of pentachlorophenol in the environment for a long period of time has resulted in its withdrawal from the market. The copper complex 18 and the zinc salt 19 have similar characteristics. Our results show that some of the congeners of the enzyme inhibitor la can be used to control P. tremulae, O. crassivaginatum, and O. piliferum since their efficacy is very similar to that of pentachlorophenol. These congeners are less toxic, do not contain heavy metals or covalently bound chlorine, and do not persist in the environment as does pentachlorophenol, which makes them good candidates for use as antifungal agents.
B. Derivatives of tiglic acid and senecioic acid (Table 2) Twenty seven compounds which are related to tiglic acid or senecioic acid were tested against P. tremulae, O. crassivaginatum, and O. piliferum. The growth of P. tremulae was completely inhibited by tiglic acid (20), and the cyclic analogs
31 and 32 at 10 μg/ml. Of the p-substituted seneciophenones the methyl derivative 26d showed the highest activity - complete inhibition at 100 μg/ml and 47% inhibition at 10 μg/ml. The remaining seneciophenones 26a,b,c,e,f and g, the ammonium salts 21d,e, the wood preservative 22, phenyl senecioate (24), p- methylacrylophenone (28), and compound 29 showed moderate activity at concentrations 1-1000 μg/ml, while the remaining compounds were inactive.
Tiglic acid (20), senecioic acid (21a), and their cyclohexy 1 analogs 31 and
32 were the most active compounds against O. crassivaginatum (complete inhibition at 10 μg/ml), followed by the quaternary ammonium salt 21e, the substituted seneciophenones 26d,f, and p-methylacrylophenone (28), which had the same efficacy at 100 μg/ml. Compounds 22, 24, 26c, 26e, and 29 were weakly active at 100-1000 μg/ml, while the remaining compounds were inactive.
For O. piliferum 100% inhibition was observed with the parent acids 20 and 21a, with the substituted seneciophenones 26b,c,f, as well as with compounds 31 and 32 at 10 μg/ml. For p-methylseneciophenone (26d) the inhibition concentration was 100 μg/ml, while compounds 21d, 21e, 22, 24, 26a, 26e, 26g, and 28 exhibited weaker activity at concentrations 1-1000 μg/ml. The metal salts 21b, 21c, benzophenone oxime (23a), its ester 23b, the senecioic acid amides 25a, 25b, 25c, the Mannich base 27, as well as compounds 29 and 30 were completely inactive at 1000 μg/ml.
The most active compounds reported in Table 2 include the acids 20, 21a, 31, and 32 (against all three fungi), and the p-substituted seneciophenones 26d and 26f (against the blue stain fungi O. crassivaginatum and O. piliferum), and 26b (against O. piliferum) which show efficacy superior to that of the commercial fungicides 22 and 23a. In addition the above compounds have a low mammalian toxicity (Gurova et al. 1985) which makes them good candidates for chemical protection of aspen wood.
Example 6. Activity against conifer decay and stain fungi (Tables 4 and
5)
Selected most active against aspen pathogens compounds showed varied inhibitory effect on the in vitro growth of two conifer decay fungi Haematostereum sanguinolentum and Phellinus pini. The most active compounds against H. sanguinolentum were la, 4b, 8c, 14, 20, 21a, 22, and 26b (Table 4). Complete inhibition at 100 μg/ml was observed for 8c, while la, 4b, 14, 20, 21a, 26b, and the commercial fungicide 22 showed 45-65% inhibition at this concentration. For P. pini only compounds 4b, 8c, 8f, 20, and 21a showed activity comparable to that of the commercial fungicide 18 (Table 4). These compounds were also inhibitory against two species of conifer blue stain fungi Ophiostoma clavigerum and O ips. For O. clavigerum the growth was completely arrested by compounds la, 14, 18, and 22 at 100 μg/ml, while 4b, 8c, 8f, 20, and 21a, showed 50-80% inhibition at the same concentration. For O. ips compounds la and 8c (100% inhibition at 100 μg/ml), as well as 4b, 14, 20, and 21a (25-75% inhibition at the same concentration) were superior to the commercial fungicides 18 and 22 (Table 5).
Example 7. Activity against fairy ring fungus Marasmius oreades (Tables 6 and 7) Several of the compounds described in Tables 1 and 2 were also tested against the fairy ring fungus Marasmius oreades (Table 6). Of the compounds tested for their ability to inhibit the growth of Marasmius oreades the most potent inhibitors were structures la, 21a, 14, 13, 32, 8f, and 35. Structures 19 and 26d were also inhibitory but for this organism they were not as potent.
Combinations of compounds were also tested for their ability to inhibit
Marasmius oreades (Table 7). The combinations of equal amounts of benzoic acid (35) with la, 21a, 13, 14 or 8f resulted in the inhibition of growth more than or equal to the inhibition of la, 21a, 13, 14 or 8f alone and significantly more inhibition than 35 alone. There was a potentiation observed when the compounds were combined.
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Rhodes, C.H., Honsinger, C, 1993, Structure-activity relationships among inhibitors of peptidylglycine amidating monooxygenase, Ann.N.Y.Acad.Sci., 686, 663-666.
Santi, D.V., Danenberg, P.V., 1971, Phenylalanyl transfer ribonucleic acid synthetase from E. coli. Analysis of the phenylalanine binding site. Biochemistry 10(25), 4813-4820.
Scholtz, M., Wiedemann, A., 1903, Synthese α,α'-substituirter Pyridine. Zur Constitution des Pyridins, Berichte, 36, 846-852.
Shevchenko, Z.A.; Zhuravleva, E.F., Dmitrieva, T.L., Alekseeva, E.M., Favorskaya, I.A., 1974, Primary, β-acetylenic alcohols. Z.Org.Chem. 10, 957- 959.
Smith, L.I., Engelhardt, V.A., 1949, Cyclopropanes. I. The reaction between nitrocyclopropyl ketones and alkali, J.Am.Chem.Soc, 71, 2671-2676. Sowmithran, D., Prasad, K.J., 1985, Aluminium chloride/phosphoryl chloride as an efficient acylating compound, Synthesis, 545-546.
Stuart, CM., Fellow, M.A., 1886, Action of cinnamic and salicylic aldehydes on malonic acid. J.Chem.Soc. 49, 365-367. Thompson, G.A., Meister, A., 1980, Modulation of γ-glutamyl transpeptidase activities by hippurate and related compounds. J.Biol.Chem. 255(5), 2109-2113. Trifonov, L.S., Chakravarty, P., Hiratsuka, Y., Ayer, W.A., 1992, Antifungal activity of metabolites of Peniophora polygonia against the aspen decay fungus Phellinus tremulae, Eur.J.For.Path. 22, 441-448. Wyss, O., Ludwig, B.J., Joiner, R.R., 1945, The fungistatic and fungicidal action of fatty acids and related compounds, Arch. Biochem., 7, 415-425.
Table 1: Reduction (%) of growth from control 1,2 of P. tremulae, O. crassivaginatum, and O. piliferum induced by congeners of 4-phenyl -3-butenoic ncid and related compounds.
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Table 2: Inhibition of the growth* of P. tremulae, O. crassivaginatum, and 0. piliferum by derivatives of tiglic and senecioic acid.
Figure imgf000037_0001
Figure imgf000038_0001
Table 3: Effect of congeners of 4-phenyI-3-butenoic acid on colonization of aspen wood chips by P. tremulae,
O. crassivaginatum, and O. piliferum.
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Table 6: Effect of compounds on the in vitro growth oϊ Marasmius oreades
Figure imgf000042_0001
1 Values are means of 10 replicates. Data analyzed by one-way ANOVA and Scheffe's test for multiple comparison after Arscine Transformation. Values in each row followed by the same letter do not differ significandy (P=0.05).
Table 7; Effect of Benzoic acid alone and in combination with other compounds on the in vitro growth of Marasmius oreades
Figure imgf000043_0001

Claims

We claim:
1. An antifungal composition comprising at least one compound selected
from the group consisting of:
(a) at least one compound of formula I
Figure imgf000044_0001
wherein
R1 is selected from the group consisting of (1) H, (2) CrC15 alkyl, (3)
a group
>
Figure imgf000044_0002
wherein R7 and R8 are C,-C15 alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring; R2 through R5 are each independently H or C,-CI5 alkyl, or R2 and R3
together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 dirough R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R1
is only Ar;
R6 is selected from the group consisting of (1) H, (2) C,-C15 alkyl, (3)
phenyl, (4) a group N(CH3)2(C1()H21)2, (5) a group N(C,-C15 alkyl)4, wherein the alkyl
groups are the same or different, (6) NHm(X)4.m , wherein each X is independently
selected from C]-C15 alkyl and 2-hydroxyethyl, and m is 0-4,
with the proviso that when R' is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1; and
(b) at least one compound of formula II
Figure imgf000045_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C15 alkyl;
R10 is H or OH; and
R" and R12 are each independently H or C,-C15 alkyl,
or an alkali or alkali earth salt thereof, and
a carrier or diluent therefor.
2. The antifungal composition of claim 1, wherein the at least one
compound is of formula III
Figure imgf000046_0001
wherein
R13 through R15 are each independently H or CrC15 alkyl, or two of R13
through R15, together with the carbon atoms to which they are bound, form a 3-8
membered carbocyclic ring; and R6 is as defined above.
3. The antifungal composition of claim 1, wherein the at least one
compound is of formula IV
Figure imgf000047_0001
wherein
R6 through R8 and n are as defined above.
4. The antifungal composition of claim 1, wherein the at least one
compound is of formula V
Figure imgf000047_0002
wherein
R16 is a group Ar, wherein Ar is as defined above; R17 through R20 are each H, or R17 and R18 together are a bond thus
creating a double bond between the carbon atoms to which they are bound, or R17 and
R18 together, and R19 and R20 together, are bonds thus creating a triple bond between
the carbon atoms to which they are bound;
R21 is selected from the group consisting of (1) H, (2) C,-C15 alkyl, (3)
a group N(CH3)2(C,0H21)2, (4) a group N(C,-C15 alkyl)4, wherein the alkyl groups are
the same or different, (5) NHfn(X)4.m , wherein each X is independently selected from
C|-C15 alkyl and 2-hydroxyethyl, and m is 0-4; and
n is as defined above.
5. The antifungal composition of claim 1, wherein the composition
comprises at least one compound of formula II, wherein R9 through R12 are as defined
above.
6. The antifungal composition of claim 1, wherein the composition
comprises at least one compound selected from the group consisting of:
E-4-phenyl-3-butenoic acid, E-4-(l-naphthyl)-3-butenoic acid, E-4-(2-naphthyl)-3-
butenoic acid, 4-phenyl-3-butynoic acid, 4-phenylbutanoic acid, 4-cyclohexyIbutanoic
acid, E-cinnamic acid, E-4-hydroxy-3-methoxycinnamic acid, phenylpropynoic acid, hydrocinnamic acid, 3-cyclohexylpropanoic acid, 3-(3-indolyl)propanoic acid, sorbic
acid, E,E-5-phenyl-2,4-pentadienoic acid, 5-phenylpentanoic acid,
cyclohexanecarboxylic acid, cyclohexylacetic acid, phomalone, isobutyric acid,
isovaleric acid, tiglic acid, senecioic acid, p-benzoquinone dioxime, phenyl senecioate, N-senecioylanthranilic acid, seneciophenone, p-hydroxyseneciophenone, p-
methoxyseneciophenone, p-methylseneciophenone, p-isopropylseneciophenone, 2,4-
dihydroxyseneciophenone, 2-hydroxy-4-methoxyseneciophenone, p-
methylacrylophenone, 3-(2-furyl)-4'-methylacrylophenone, cyclohexene- 1 -carboxylic
acid and cyclohexylideneacetic acid, or an alkali or alkali earth salt thereof.
7. The antifungal composition of claim 6, wherein the composition
comprises at least one compound selected from the group consisting of:
E-4-phenyl-3-butenoic acid, E-4-(l-naphthyl)-3-butenoic acid, E-4-(2-naphthyl)-3-
butenoic acid, 4-phenyI-3-butynoic acid, 4-phenylbutanoic acid, 4-cyclohexylbutanoic
acid, phenylpropynoic acid, 3-cyclohexylpropanoic acid, 3-(3-indolyl)propanoic acid,
5-phenylpentanoic acid, cyclohexanecarboxylic acid, cyclohexylacetic acid, isobutyric
acid, isovaleric acid, tiglic acid, senecioic acid, p-hydroxyseneciophenone, p-
methoxyseneciophenone, p-methylseneciophenone, 2,4-dihydroxyseneciophenone,
p-methylacrylophenone, cyclohexene- 1 -carboxylic acid and cyclohexylideneacetic
acid, or an alkali or alkali earth salt thereof.
8. The antifungal composition of claim 6, wherein the composition
comprises at least one compound selected from the group consisting of:
E-4-phenyl-3-butenoic acid, 4-phenyl-3-butynoic acid, 4-cyclohexylbutanoic acid,
phenylpropynoic acid, 3 -cyclohexy Ipropanoic acid and 3-(3-indolyl)propanoic acid,
or an alkali or alkali earth salt thereof.
9. The antifungal composition of claim 1, further comprising benzoic
acid.
10. The antifungal composition of claim 1, further comprising salicylic acid.
11. The antifungal composition of claim 6, further comprising benzoic acid.
12. The antifungal composition of claim 11, wherein the compound is
selected from the group consisting of E-4-phenyl-3-butenoic acid, 3-(3- indolyl)propanoic acid, cyclohexanecarboxylic acid and cyclohexylacetic acid, or an
alkali or alkali earth salt thereof.
13. The antifungal composition of claim 1, wherein the group Ar is
selected from the group consisting of
Figure imgf000050_0001
14. A method of reducing or inhibiting fungal growth in a region to be
treated, comprising applying to the region a fungal reducing- or inhibiting-effective
amount of at least one compound selected from the group consisting of:
(a) at least one compound of formula I
Figure imgf000051_0001
wherein
R1 is selected from the group consisting of (1) H, (2) C,-C15 alkyl, (3)
a group
>
Figure imgf000051_0002
wherein R7 and R8 are C,-Cl5 alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or CrC,5 alkyl, or R2 and R3
together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R1
is only Ar;
R6 is selected from the group consisting of (1) H, (2) C,-Cι5 alkyl, (3)
phenyl, (4) a group N(CH3)2(C|0H21)2, (5) a group N(C,-C,5 alkyl)4) wherein the alkyl
groups are the same or different, (6) NHmQC^π, , wherein each X is independently
selected from C,-C15 alkyl and 2-hydroxyethyl, and m is 0-4,
with the proviso that when R1 is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1; and
(b) at least one compound of formula II
Figure imgf000053_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C15 alkyl;
R'° is H or OH; and
R" and R12 are each independently H or C,-C15 alkyl,
or an alkali or alkali earth salt thereof.
15. The method of claim 14, wherein the at least one compound is of
formula III
>
Figure imgf000053_0002
wherein
R13 through R15 are each independentiy H or C,-C,5 alkyl, or two of R13
through R15, together with the carbon atoms to which they are bound, form a 3-8
membered carbocyclic ring; and
R6 is as defined above.
16. The method of claim 14, wherein the at least one compound is of
formula IV
Figure imgf000054_0001
wherein
R6 through R8 and n are as defined above.
17. The method of claim 14, wherein the at least one compound is of
formula V
Figure imgf000054_0002
wherein
R16 is a group Ar, wherein Ar is as defined above;
R17 through R20 are each H, or R17 and R18 together are a bond thus creating a double bond between the carbon atoms to which they are bound, or R17 and
R18 together, and R19 and R20 together, are bonds thus creating a triple bond between
the carbon atoms to which they are bound;
R21 is selected from the group consisting of (1) H, (2) C,-Cι5 alkyl, (3)
a group N(CH3)2(CI0H21)2, (4) a group N(C,-C15 alkyl)4, wherein the alkyl groups are
the same or different, (5) NHm(X)4.m , wherein each X is independently selected from
CrC|5 alkyl and 2-hydroxyethyl, and m is 0-4; and
n is as defined above.
18. The method of claim 14, wherein the at least one compound is of
formula II, wherein R9 through R12 are as defined above.
19. The method of claim 14, wherein the at least one compound is selected
from the group consisting of:
E-4-phenyl-3-butenoic acid, E-4-(l-naphthyl)-3-butenoic acid, E-4-(2-naphthyl)-3-
butenoic acid, 4-phenyl-3-butynoic acid, 4-phenylbutanoic acid, 4-cyclohexylbutanoic
acid, E-cinnamic acid, E-4-hydroxy-3-methoxycinnamic acid, phenylpropynoic acid,
hydrocinnamic acid, 3-cyclohexylpropanoic acid, 3-(3-indolyl)propanoic acid, sorbic
acid, E,E-5-phenyl-2,4-pentadienoic acid, cyclohexanecarboxylic acid,
cyclohexylacetic acid, phomalone, isobutyric acid, isovaleric acid, tiglic acid,
senecioic acid, phenyl senecioate, N-senecioylanthranilic acid, cyclohexene- 1-
carboxylic acid, cyclohexylideneacetic acid, seneciophenone, p-
hydroxyseneciophenone, p-methoxyseneciophenone, p-methylseneciophenone, p- isopropylseneciophenone, 2, 4-dihydroxy seneciophenone, 2-hydroxy-4-
memoxyseneciophenone,p-memylacrylophenone,3-(2--uryl)-4'-methylacrylophenone and p-benzoquinone dioxime, or an alkali or alkali earth salt thereof.
20. The method of claim 19, wherein the at least one compound is selected
from the group consisting of:
E-4-phenyl-3-butenoic acid, 4-phenyl-3-butynoic acid, 4-cyclohexylbutanoic acid,
phenylpropynoic acid, 3-(3-indolyl)propanoic acid, cyclohexanecarboxylic acid,
cyclohexylacetic acid, tiglic acid, senecioic acid, cyclohexene- 1 -carboxylic acid,
cyclohexylideneacetic acid, p-memoxyseneciophenone, p-methylseneciophenone, 2,4-
dihydroxyseneciophenone and p-methylacrylophenone, or an alkali or alkali earth salt
thereof.
21. The method of claim 14, further comprising contacting benzoic acid
with the region, wherein the at least one compound and the benzoic acid are present
in amounts to produce a fungal reducing- or inhibiting-effect.
22. The method of claim 21 , wherein the benzoic acid and the at least one
compound are co-applied.
23. The method of claim 14, wherein the region comprises a plant surface.
24. The method of claim 14, wherein the region comprises a wood surface.
25. The method of claim 14, wherein the region is a soil region having
plants thereon.
26. The method of claim 14, wherein the group Ar is selected from the
group consisting of
^
Figure imgf000057_0001
27. A method of reducing or inhibiting at least one of fungal wood decay
and fungal wood stain on a wood substrate, comprising applying to the wood substrate
at least one of a fungal-decay and fungal-stain reducing- or inhibiting-effective
0 amount of at least one compound selected from the group consisting of:
(a) at least one compound of formula I
Figure imgf000057_0002
wherein
R1 is selected from me group consisting of (1) H, (2) CrC15 alkyl, (3)
a group
>
Figure imgf000058_0001
wherein R7 and R8 are C,-C15 alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-CI5 alkyl, or R2 and R3
together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R1
is only Ar;
R6 is selected from the group consisting of (1) H, (2) Ct-C15 alkyl, (3)
phenyl, (4) a group N(CH3)2(C10H21)2, (5) a group N(C,-C15 alkyl)4, wherein the alkyl groups are the same or different, (6) NHm(X)4.m , wherein each X is independently selected from Cj-C^ alkyl and 2-hydroxyethyl, and m is 0-4,
with the proviso that when R1 is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1 ; and
(b) at least one compound of formula II
Figure imgf000059_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C15 alkyl;
R10 is H or OH; and
R11 and R12 are each independently H or C,-C15 alkyl,
or an alkali or alkali earth salt thereof.
28. The method of claim 27, wherein the at least one compound is of the
formula III
Figure imgf000060_0001
wherein
R13 through R15 are each independently H or C,-C15 alkyl, or two of R13
through R15, together with the carbon atoms to which they are bound, form a 3-8
membered carbocyclic ring; and
R6 is as defined above.
29. The method of claim 27, wherein the at least one compound is of
formula IV
Figure imgf000060_0002
wherein
R6 through R8 and n are as defined above.
30. The method of claim 27, wherein the at least one compound is of
formula V
Figure imgf000061_0001
wherein
R16 is a group Ar, wherein Ar is as defined above;
R17 through R20 are each H, or R17 and R18 together are a bond thus
creating a double bond between the carbon atoms to which they are bound, or R17 and
R18 together, and R19 and R20 together, are bonds thus creating a triple bond between
the carbon atoms to which they are bound;
R21 is selected from the group consisting of (1) H, (2) C,-C1S alkyl, (3)
a group N(CH3)2(C10H21)2, (4) a group N(C,-C15 alkyl)4, wherein the alkyl groups are
the same or different, (5) NH-nQCV,., , wherein each X is independently selected from
C,-C15 alkyl and 2-hydroxyethyl, and m is 0-4; and
n is as defined above.
31. The method of claim 27, wherein the at least one compound is of
formula II, wherein R9 through R12 are as defined above.
32. The method of claim 27, wherein the at least one compound is selected
from the group consisting of:
E-4-phenyl-3-butenoic acid, 4-phenyl-3-butynoic acid, 4-cyclohexylbutanoic acid,
phenylpropynoic acid, 3-cyclohexylpropanoic acid, 3-(3-indolyl)propanoic acid,
cyclohexanecarboxylic acid, cyclohexylacetic acid, isobutyric acid, isovaleric acid,
tiglic acid, senecioic acid, phenyl senecioate, p-hydroxyseneciophenone, p-
methoxyseneciophenone, p-methylseneciophenone, 2,4-dihydroxyseneciophenone, p-
methylacrylophenone, cyclohexene- 1 -carboxylic acid and cyclohexylideneacetic acid,
or an alkali or alkali earth salt thereof.
33. The method of claim 27, wherein the method is for reducing or
inhibiting fungal wood stain and the at least one compound is selected from the group
consisting of:
E-4-phenyl-3-butenoic acid, 4-pheny 1-3 -buty noic acid, 4-phenylbutanoic acid, 4-
cyclohexylbutanoic acid, E-cinnamic acid, phenylpropynoic acid, hydrocinnamic acid,
3-cyclohexylpropanoic acid, 3-(3-indolyl)propanoic acid, sorbic acid, E,E-5-phenyl-
2,4-pentadienoic acid, cyclohexanecarboxylic acid, cyclohexylacetic acid, tiglic acid,
senecioic acid, phenyl senecioate, p-hydroxyseneciophenone, p-
methoxyseneciophenone, p-methylseneciophenone, 2,4-dihydroxyseneciophenone, p-
methylacrylophenone, cyclohexene- 1 -carboxylic acid and cyclohexylideneacetic acid,
or an alkali or alkali earth salt thereof.
34. The method of claim 27, wherein the method is for reducing or inhibiting fungal wood decay and the at least one compound is selected from the
group consisting of:
E-4-phenyl-3-butenoic acid, E-4-(l-naphthyl)-3-butenoic acid, 4-pheπyI-3-butynoic
acid, 4-cyclohexylbutanoic acid, phenylpropynoic acid, 3-cyclohexylpropanoic acid,
3-(3-indolyl)propanoic acid, cyclohexanecarboxylic acid, cyclohexylacetic acid,
phomalone, isobutyric acid, isovaleric acid, tiglic acid, senecioic acid, phenyl
senecioate, N-senecioylanthranilic acid, p-methoxyseneciophenone, p-
methylseneciophenone, 2,4-dihydroxyseneciophenone, 2-hydroxy-4-
methoxyseneciophenone, p-methylacrylophenone, cyclohexene- 1 -carboxylic acid and
cyclohexylideneacetic acid, or an alkali or alkali earth salt thereof.
35. The method of claim 27, wherein the group Ar is selected from the
group consisting of
Figure imgf000063_0001
36. A method of reducing or inhibiting fairy rings in a region to be treated,
comprising applying to the region a fairy-ring fungal reducing- or inhibiting-effective
amount of at least one compound selected from the group consisting of: 79 PCΪ7IB97/00750
(a) at least one compound of formula I
Figure imgf000064_0001
wherein
R1 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3) a group
>
Figure imgf000064_0002
wherein R7 and R8 are C,-C15 alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-C|? alkyl, or R2 and R3 together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R1
is only Ar;
R6 is selected from the group consisting of (1) H, (2) C,-Cι5 alkyl, (3)
phenyl, (4) a group N(CH3)2(C10H21)2, (5) a group N(C,-C,5 alkyl)4, wherein the alkyl
groups are the same or different, (6) NHm(X)4.m , wherein each X is independently
selected from C,-C!5 alkyl and 2-hydroxyefhyl, and m is 0-4,
with the proviso that when R1 is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1 ; and
(b) at least one compound of formula II
Figure imgf000065_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C15 alkyl;
R10 is H or OH; and
R" and R12 are each independently H or C,-C,5 alkyl,
or an alkali or alkali earth salt thereof.
37. The method of claim 36, wherein the at least one compound is of the formula III
<
Figure imgf000066_0001
wherein
R13 through R15 are each independently H or CpCu alkyl, or two of R13
through R15, together with the carbon atoms to which they are bound, form a 3-8
membered carbocyclic ring; and
R6 is as defined above.
38. The method of claim 36, wherein the at least one compound is of
formula IV
Figure imgf000067_0001
wherein
R6 through R8 and n are as defined above.
39. The method of claim 36, wherein the at least one compound is of formula V
Figure imgf000067_0002
wherein
R16 is a group Ar, wherein Ar is as defined above;
R17 through R20 are each H, or R17 and R18 together are a bond thus
creating a double bond between the carbon atoms to which they are bound, or R17 and
R18 together, and R19 and R20 together, are bonds thus creating a triple bond between
the carbon atoms to which they are bound;
R21 is selected from the group consisting of (1) H, (2) C,-C15 alkyl, (3) a group N(CH3)2(C)0H21)2, (4) a group N(C,-C,5 alkyl)4, wherein the alkyl groups are the same or different, (5) NHmrø^ , wherein each X is independently selected from CrCl5 alkyl and 2-hydroxy ethyl, and m is 0-4; and
n is as defined above.
40. The method of claim 36, wherein the at least one compound is of
formula II, wherein R9 through R12 are as defined above.
41. The method of claim 36, wherein the at least one compound is selected from the group consisting of:
E-4-phenyl-3-butenoic acid, 3-(3-indolyl)propanoic acid, cyclohexanecarboxylic acid, cyclohexylacetic acid, senecioic acid, p-methylseneciophenone and cyclohexylideneacetic acid, or an alkali or alkali earth salt thereof.
42. The method of claim 36, further comprising contacting benzoic acid
with the region, wherein the at least one compound and the benzoic acid are present
in amounts to produce a fairy-ring fungal reducing- or inhibiting-effect.
43. The method of claim 42, wherein the benzoic acid and the at least one compound are co-applied.
44. The method of claim 36, wherein the group Ar is selected from the
group consisting of
Figure imgf000069_0001
45. A paint containing at least one compound selected from the group
consisting of:
5 (a) at least one compound of formula I
Figure imgf000069_0002
wherein
R1 is selected from the group consisting of (1) H, (2) C,-C15 alkyl, (3)
a group
>
Figure imgf000069_0003
wherein R7 and R8 are C,-C,5 alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-CI5 alkyl, or R2 and R3
together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R1
is only Ar;
R6 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3)
phenyl, (4) a group N(CH3)2(C10H2,)2, (5) a group N(CrC15 alkyl)4, wherein the alkyl
groups are the same or different, (6) NHmCX)^,,, , wherein each X is independently
selected from C,-C15 alkyl and 2-hydroxyethyl, and m is 0-4,
with the proviso that when R1 is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1 ; and
(b) at least one compound of formula II
Figure imgf000071_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C,5 alkyl;
R10 is H or OH; and
R11 and R12 are each independently H or C,-C15 alkyl,
or an alkali or alkali earth salt thereof.
46. A stain containing at least one compound selected from the group
consisting of:
(a) at least one compound of formula I
Figure imgf000071_0002
wherein
R1 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3)
a group
Figure imgf000072_0001
wherein R7 and R8 are CrC15 alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-C15 alkyl, or R2 and R3
together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R1
is only Ar;
R6 is selected from the group consisting of ( 1 ) H, (2) C,-C,j alkyl, (3)
phenyl, (4) a group N(CH3)2(C,oH2i)2, (5) a group N(C,-C,5 alkyl)4, wherein the alkyl
groups are the same or different, (6) NHm(X)4-m , wherein each X is independently selected from CrC,5 alkyl and 2-hydroxyethyl, and m is 0-4, with the proviso that when R1 is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is O or 1; and
(b) at least one compound of formula II
Figure imgf000073_0001
wherein
R9 is selected from the group consisting of H, OH and C,-CI5 alkyl;
R10 is H or OH; and
R" and R12 are each independently H or C,-C15 alkyl,
or an alkali or alkali earth salt thereof.
47. A cleaning product containing at least one compound selected from the
group consisting of:
(a) at least one compound of formula I
Figure imgf000074_0001
wherein
R1 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3)
a group
>
Figure imgf000074_0002
wherein R7 and R8 are C,-C15 alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-C15 alkyl, or R2 and R3 together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R1
is only Ar;
R6 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3)
phenyl, (4) a group N(CH3)2(C,oH21)2, (5) a group N(C,-C,5 alkyl)4, wherein the alkyl
groups are the same or different, (6) NHm(X)4.m , wherein each X is independently
selected from CrCif alkyl and 2-hydroxyethyl, and m is 0-4,
with the proviso that when R1 is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1; and
(b) at least one compound of formula II
Figure imgf000075_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C,5 alkyl;
R'° is H or OH; and
R" and R12 are each independently H or C,-Cι5 alkyl,
or an alkali or alkali earth salt thereof.
48. A disinfectant containing at least one compound selected from the
group consisting of:
(a) at least one compound of formula I
Figure imgf000076_0001
wherein
R1 is selected from the group consisting of (1) H, (2) C,-C15 alkyl, (3)
a group
Figure imgf000077_0001
wherein R7 and R8 are C,-C15 alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-C,5 alkyl, or R2 and R3
together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R1
is only Ar;
R6 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3)
phenyl, (4) a group N(CH3)2(C10H2,)2, (5) a group N(C,-C15 alkyl)4, wherein the alkyl
groups are the same or different, (6) NH^CX)^,,, , wherein each X is independently
selected from C,-C,5 alkyl and 2-hydroxyethyl, and m is 0-4,
with the proviso that when R1 is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1; and (b) at least one compound of formula II
Figure imgf000078_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C,5 alkyl;
R10 is H or OH; and
R" and R12 are each independently H or C,-C15 alkyl,
or an alkali or alkali earth salt thereof.
49. A wood or lawn treatment containing at least one compound selected
from the group consisting of:
(a) at least one compound of formula I
Figure imgf000079_0001
wherein
R1 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3) a group
>
Figure imgf000079_0002
wherein R7 and R8 are C,-C15 alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-C15 alkyl, or R2 and R3
together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R1 is only Ar;
R6 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3)
phenyl, (4) a group N(CH3)2(C10H2ι)2, (5) a group N(Cι-C15 alkyl)4, wherein the alkyl
groups are the same or different, (6) NHm(X)4.m , wherein each X is independently
selected from C,-C15 alkyl and 2-hydroxyethyl, and m is 0-4,
with the proviso that when R1 is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1; and
(b) at least one compound of formula II
Figure imgf000080_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C,5 alkyl;
R10 is H or OH; and R" and R12 are each independently H or C,-C,5 alkyl,
or an alkali or alkali earth salt thereof.
50. Use of at least one compound selected from the group consisting of:
(a) at least one compound of formula I
Figure imgf000081_0001
wherein
R1 is selected from the group consisting of (1) H, (2) C,-C15 alkyl, (3)
a group
>
Figure imgf000081_0002
wherein R7 and R8 are C,-C15 alkyl or, together with the carbon atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-C15 alkyl, or R2 and R3
together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R!
is only Ar;
R6 is selected from the group consisting of (1) H, (2) C,-C15 alkyl, (3)
phenyl, (4) a group N(CH3)2(CI0H21)2, (5) a group N(C,-C,5 alkyl)4, wherein the alkyl
groups are the same or different, (6) NHm(X)4.m , wherein each X is independently
selected from 0,-0,5 alkyl and 2-hydroxyethyl, and m is 0-4,
with the proviso that when R' is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1 ; and
(b) at least one compound of formula II
Figure imgf000083_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C15 alkyl;
R'° is H or OH; and
R" and R'2 are each independently H or C,-C,5 alkyl,
or an alkali or alkali earth salt thereof
as an active ingredient in the preparation of an antifungal composition.
51. Use of at least one compound selected from the group consisting of:
(a) at least one compound of formula I
Figure imgf000083_0002
wherein
R1 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3)
a group
Figure imgf000084_0001
wherein R7 and R8 are C,-C]5 alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-C,5 alkyl, or R2 and R3
together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R1
is only Ar;
R6 is selected from the group consisting of ( 1 ) H, (2) C , -C , 5 alkyl, (3)
phenyl, (4) a group Ni^H^C,^,^, (5) a group N(C,-C,5 alkyl)4, wherein the alkyl
groups are the same or different, (6) NHm(X)4.m , wherein each X is independently
selected from C,-C15 alkyl and 2-hydroxyethyl, and m is 0-4, with the proviso that when R! is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1 ; and
(b) at least one compound of formula II
Figure imgf000085_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C15 alkyl;
R10 is H or OH; and
R" and R12 are each independently H or C,-C15 alkyl,
or an alkali or alkali earth salt thereof
as an ingredient in the preparation of a paint.
52. Use of at least one compound selected from the group consisting of:
(a) at least one compound of formula I
Figure imgf000086_0001
wherein
R' is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3)
a group
>
Figure imgf000086_0002
wherein R7 and R8 are CrC,5 alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-C15 alkyl, or R2 and R3
together are a bond thus creating a double bond between the carbon atoms to which they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R1
is only Ar;
R6 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3)
phenyl, (4) a group N(CH3)2(C,0H21)2, (5) a group N(C,-C,5 alkyl)4, wherein the alkyl
groups are the same or different, (6) NHm(X)4.m , wherein each X is independently
selected from 0,-0,5 alkyl and 2-hydroxyethyl, and m is 0-4,
with the proviso that when R' is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1; and
(b) at least one compound of formula II
Figure imgf000087_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C,5 alkyl;
R10 is H or OH; and
R" and R12 are each independently H or C,-C,5 alkyl,
or an alkali or alkali earth salt thereof
s an ingredient in the preparation of a stain.
53. Use of at least one compound selected from the group consisting of:
(a) at least one compound of formula I
Figure imgf000088_0001
wherein
R1 is selected from the group consisting of (1) H, (2) CrC,5 alkyl, (3)
a group >
Figure imgf000089_0001
wherein R7 and R8 are C,-C„ alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or 0,-0,5 alkyl, or R2 and R3
together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of Rl through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R1
is only Ar;
R6 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3)
phenyl, (4) a group N(CH3)2(CI0H2,)2, (5) a group N(C,-C15 alkyl)4, wherein the alkyl
groups are the same or different, (6) NHmOvV,,, , wherein each X is independently
selected from CrC15 alkyl and 2-hydroxyethyl, and m is 0-4,
with the proviso that when R1 is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1; and
(b) at least one compound of formula II
Figure imgf000090_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C15 alkyl;
R10 is H or OH; and
R11 and R12 are each independently H or C,-C,5 alkyl,
or an alkali or alkali earth salt thereof
as an ingredient in the preparation of a cleaning product.
54. Use of at least one compound selected from the group consisting of:
(a) at least one compound of formula I
Figure imgf000090_0002
wherein
R1 is selected from the group consisting of (1) H, (2) C,-C,5 alkyl, (3)
a group
Figure imgf000091_0001
wherein R7 and R8 are C,-C15 alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a
group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-C,5 alkyl, or R2 and R3
together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R'
is only Ar;
R6 is selected from the group consisting of (1 ) H, (2) 0,-0,5 alkyl, (3) phenyl, (4) a group
Figure imgf000092_0001
(5) a group N(C,-C,5 alkyl)4, wherein the alkyl
groups are the same or different, (6) NHm(X)4.m , wherein each X is independently
selected from C,-C15 alkyl and 2-hydroxyethyl, and m is 0-4,
with the proviso that when R1 is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1; and
(b) at least one compound of formula II
Figure imgf000092_0002
wherein
R9 is selected from the group consisting of H, OH and C,-C,5 alkyl;
R10 is H or OH; and
Rn and R12 are each independently H or C,-C15 alkyl, or an alkali or alkali earth salt thereof
as an ingredient in the preparation of a disinfectant.
55. Use of at least one compound selected from the group consisting of:
(a) at least one compound of formula I
Figure imgf000093_0001
wherein
R1 is selected from the group consisting of (1) H, (2) C,-CI5 alkyl, (3)
a group
>
Figure imgf000093_0002
wherein R7 and R8 are C,-C15 alkyl or, together with the carbon
atoms to which they are bound, form a 3-8 membered carbocyclic ring, and (4) a group Ar, wherein Ar is an aromatic ring;
R2 through R5 are each independently H or C,-C,5 alkyl, or R2 and R3
together are a bond thus creating a double bond between the carbon atoms to which
they are bound, or R2 and R3 together, and R4 and R5 together, are bonds thus creating
a triple bond between the carbon atoms to which they are bound, or
two of R1 through R5, together with the carbon atoms to which they are
bound, form part of a 3-8 membered carbocyclic ring,
with the proviso that when R2 through R5 are each H, then R1
is only Ar; R6 is selected from the group consisting of (1 ) H, (2) C,-C,5 alkyl, (3)
phenyl, (4) a group N(CH3)2(C10H2,)2, (5) a group N(C,-C,5 alkyl)4, wherein the alkyl
groups are the same or different, (6) NHm(X)4-rn , wherein each X is independently
selected from C,-C15 alkyl and 2-hydroxyethyl, and m is 0-4,
with the proviso that when R1 is Ar, then R6 is other than
phenyl;
n is 0-10 and n' is 0 or 1 ; and
(b) at least one compound of formula II
Figure imgf000094_0001
wherein
R9 is selected from the group consisting of H, OH and C,-C,5 alkyl;
R10 is H or OH; and
R" and R12 are each independently H or C,-CI5 alkyl,
or an alkali or alkali earth salt thereof
as an ingredient in the preparation of a wood or lawn treatment.
PCT/IB1997/000750 1996-06-21 1997-06-20 Agents with antifungal activity and methods of use thereof WO1997048279A1 (en)

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