WO2006004433A2 - Substituted pyrrolidine compounds, compositions and methods for controlling plant pests - Google Patents

Substituted pyrrolidine compounds, compositions and methods for controlling plant pests Download PDF

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WO2006004433A2
WO2006004433A2 PCT/NZ2005/000147 NZ2005000147W WO2006004433A2 WO 2006004433 A2 WO2006004433 A2 WO 2006004433A2 NZ 2005000147 W NZ2005000147 W NZ 2005000147W WO 2006004433 A2 WO2006004433 A2 WO 2006004433A2
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Prior art keywords
imino
carbonyl
methylenepyrrolidine
compound
alanine
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PCT/NZ2005/000147
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French (fr)
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WO2006004433A3 (en
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Robin Edward Mitchell
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The Horticulture And Food Research Institute Of New Zealand Limited
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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
    • A01N43/36—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Environmental Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Dentistry (AREA)
  • Plant Pathology (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to novel 2-imino-3-methylenepyrrolidine compounds, compositions of same and methods of their use. The compounds are particularly useful in the treatment or prevention of Erwinia amylovora, which causes the plant disease fire blight.

Description

COMPOUNDS, COMPOSITIONS AND METHODS FOR CONTROLLING
PLANT PESTS
FIELD OF THE INVENTION
The present invention relates to novel antibiotic compounds, compositions and methods of their use. In particular, the invention relates to substituted pyrrolidine compounds that are useful in the treatment or prevention of bacterial infection, especially Erwinia amylovora infection.
BACKGROUND OF THE INVENTION
Fire blight disease, caused by the bacterium Erwinia amylovora is the most devastating bacterial disease affecting pome fruits worldwide. Erwinia amylovora grows readily utilising sugars and acids as food sources. It can affect all parts of the tree, including blossoms and fruit, twigs and leaves, trunk and root stock. An affected tree may die within a few months of infection, or may survive with reduced yield for a few years.
Serious outbreaks can cause significant economic loss from the death or necessary removal of infected trees. Fire blight disease has eliminated commercial pear production in the eastern United States, where the industry was once centred, and continues to cause serious economic damage to western pear production and apple production throughout the US.
Fire blight has been reported in 40 countries around the world. It has spread frbrn its original site in the Hudson Valley of New York State, USA across the North American continent and to the Pacific Rim, Europe and the Middle East during the past 200 years.
There are limited options (biological, chemical and orchard management) for the control of fire blight. In the past, the preferred means of chemical control has been to spray with streptomycin, a medical antibiotic. However, because of the potential for cross- resistance the agricultural use of streptomycin is undesirable and may be prohibited in _
many countries. In addition, increasing resistance to streptomycin is decreasing its effectiveness in controlling fire blight.
It would be desirable to provide an improved or alternative antibiotic compound and method of its use or to at least provide the public with a useful choice.
SUMMARY OF THE INVENTION
Accordingly, in a broadest aspect the present invention provides a compound of Formula I:
Figure imgf000003_0001
or an agriculturally acceptable salt thereof, wherein
R1 is selected from
(a) hydrogen,
(b) (C1-C10) alkyl,
(c) (C2-C10) alkenyl, (d) (C2-C10) alkynyl,
(e) (C3- C8) cycloalkyl,
(f) aryl,
(g) amino,
(h) (C1-C10) alkoxy, (i) (C1-C10) alkanoyl,
G) hydroxy,
(k) nitro or nitroso, (1) cyano, or
(m) halogen, wherein each of (b) to (i) are optionally substituted with one or more of
(C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C8) cycloalkyl, aryl, amino, (Ci-C1O) alkoxy, (C1-C10) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy; or
R1 is selected from the group comprising an amino acid, a di- or tri-peptide, an oligopeptide, a polypeptide or an ester thereof.
In one embodiment R1 is selected from
(a) hydrogen,
(b) (C1-C10) alkyl,
(c) (C2-C10) alkenyl,
(d) (C2-C10) alkynyl, (e) (C3- C8) cycloalkyl, or
(f) aryl, wherein each of (b) to (f) are optionally substituted with one or more of (C1 -Ci0) alkyl, (C2-C1O) alkenyl, (C2-C10) alkynyl, (C3-C8) cycloalkyl, aryl, amino, (C1-CiO) alkoxy, (C1-C10) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment R1 is selected from
(b) (C1-Ci0) alkyl,
(c) (C2-C10) alkenyl,
(d) (C2-C10) alkynyl, or (e) (C3- C8) cycloalkyl, wherein each of (b) to (e) are optionally substituted with one or more of (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C8) cycloalkyl, aryl, amino, (Ci-Ci0) alkoxy, (C1-C1O) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment R1 is selected from (h) (C1-C10) alkoxy, (i) (Ci-C10) alkanoyl, - -
G) hydroxy,
(k) nitro or nitroso,
(1) cyano, or
(m) halogen, wherein each of (h) and (i) are optionally substituted with one or more of (C1-Ci0) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C8) cycloalkyl, aryl, amino, (C1-Ci0) alkoxy, (C1-C10) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment R1 is amino. In one embodiment R1 is amino optionally substituted with one or more of (Ci-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C8) cycloalkyl, aryl, (Ci-C10) alkoxy, (C1-C10) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment R1 is amino optionally substituted with one or more of (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C8) cycloalkyl or aryl.
In one embodiment R1 is amino optionally substituted with one or more of (Ci-C10) alkoxy, (C1-C10) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In another aspect the invention provides a compound of formula I wherein R1 is selected from the group comprising an amino acid, a di- or tri-peptide, an oligopeptide, a polypeptide or an agriculturally acceptable salt or ester thereof.
In one embodiment the compound of formula (I) is of the L-configuration at the 5- position of the pyrrolidine ring.
In one embodiment the amino acid is an L-amino acid.
In one embodiment the di- or tri-peptide, oligopeptide or polypeptide comprises L- amino acids. _
In one embodiment the amino acid is selected from the group comprising glycine, alanine, β-alanine, valine, leucine, isoleucine, alloisoleucine, phenylalanine, proline, serine, homoserine, threonine, allothreonine, glutamic acid, methionine, asparagine, aspartic acid, glutamine, histidine, lysine, arginine, tyrosine and tryptophan.
In one embodiment the amino acid is selected from the group comprising glycine, L- alanine, β-alanine, L-valine, L-leucine, L-isoleucine, L-alloisoleucine, L-phenylalanine, L-proline, L-serine, L-homoserine, L-threonine, L-allothreonine, L-glutamic acid, L- methionine, L-asparagine, L-aspartic acid, L-glutamine, L-histidine, L-lysine, L- arginine, L-tyrosine and L-tryptophan.
In one embodiment the amino acid is selected from the group comprising glycine, L- alanine, β-alanine, L-valine, L-leucine, L-phenylalanine, L-proline, and L-threonine.
In one embodiment the di-peptide comprises amino acids selected from the group comprising glycine, alanine, β-alanine, valine, leucine, isoleucine, alloisoleucine, phenylalanine, proline, serine, homoserine, threonine, allothreonine, glutamic acid, methionine, asparagine, aspartic acid, glutamine, histidine, lysine, arginine, tyrosine and tryptophan.
In one embodiment the di-peptide comprises amino acids selected from the group comprising glycine, L-alanine, β-alanine, L-valine, L-leucine, L-isoleucine, L- alloisoleucine, L-phenylalanine, L-proline, L-serine, L-homoserine, L-threonine, L- allothreonme, L-glutamic acid, L-methionine, L-asparagine, L-aspartic acid, L- glutamine, L-histidine, L-lysine, L-arginine, L-tyrosine and L-tryptophan.
Preferred di-peptides comprise L-valine, L-alanine or L-threonine coupled to a second L-amino acid. In one embodiment, the di-peptide comprises L-alanyl-L-valine, L-valyl- L-alanine, L-valyl-L-threonine, L-threonyl-L-valine, L-alanyl-L-threonine and L- threonyl-L-alanine. Particularly preferred dipeptides are L-valyl-L-alanine and L- alanyl-L- valine. _ _
In another aspect the invention provides a compound of Formula IA:
Figure imgf000007_0001
or an agriculturally acceptable salt thereof, wherein
R2 is hydrogen or (C1-C10) alkyl optionally substituted with one or more of (C1- C1O) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C3-Cs) cycloalkyl, aryl, amino, (C1-C1O) alkoxy, (C1-C10) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment the compound of formula (IA) is of the L-configuration at the 5- position of the pyrrolidine ring.
In one embodiment R2 comprises (C1-4) alkyl, optionally substituted with one or more of amino, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment R2 is selected from -H, -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CO2H and -CH2CH2CO2H.
In another aspect, the invention provides a compound of Formula IB: - -
Figure imgf000008_0001
or an agriculturally acceptable salt thereof, wherein
each R2 is independently selected from hydrogen or (Ci-C1O) alkyl optionally substituted with one or more Of (Ci-C1O) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C3 to Cg) cycloalkyl, aryl, amino, (Ci-Ci0) alkoxy, (Ci-Cio) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment the compound of formula (IB) is of the L-configuration at the 5- position of the pyrrolidine ring.
In one embodiment R comprises (Cj-4) alkyl, optionally substituted with one or more of ammo, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment R2 is selected from -H, -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CO2H and -CH2CH2CO2H.
In one embodiment, the compound is selected from the group comprising:
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-glycine), 2-imino-3 -methylenepyrrolidine-5 -L-(carbonyl-L- alanine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-β-alanine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L- valine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-leucine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-phenylalanine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-isoleucine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-alloisoleucine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-proline), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-serine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-homoserine),
2-imino-3 -methylenepyrrolidine-5 -L-(carbonyl-L-threonine), 2-imino-3 -methylenepyrrolidine-5 -L-(carbonyl-L-allothreonine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-glutamic acid), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-methionine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-asparagine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-aspartic acid), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-glutamine), 2-imino-3 -methylenepyrrolidine-5 -L-(carbonyl-L-histidine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-lysine), 2-immo-3-methylenepyrrolidine-5-L-(carbonyl-L-arginine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-tyrosine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-typtophan), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-valyl-L-alanine) 2-imino-3 -methylenepyrrolidine-5 -L-(carbonyl-L-alanyl-L- valine) , 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-valyl-L-threonine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-threonyl-L-valine), 2-immo-3-methylenepyrrolidine-5-L-(carbonyl-L-alanyl-L-threonine), and 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-threonyl-L-alanine).
embodiment, the compound is selected from the group comprising:
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-glycine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-alanine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-β-alanine)5
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L- valine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-leucine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-phenylalanine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-proline), 2-imino-3 -methylenepyrrolidine-5-L-(carbonyl-L-threonine), and 2-imino-3-methylenepyrτolidine-5-L-(carbonyl-L-valyl-L-alanine).
In another aspect, the invention provides an antibiotic composition comprising a compound of the invention or an agriculturally acceptable salt thereof and an agriculturally acceptable carrier.
In one embodiment, the composition further comprises one or more of a second antibiotic, a nutrient, a pesticide, an insecticide or a fungicide.
In still another embodiment the composition is formulated as a powder, as granules, a paste, a liquid including a sprayable liquid or an aerosol. Preferably, a composition of the invention is formulated as a sprayable liquid.
In another aspect the invention provides a method of treating or preventing a bacterial infection comprising administering a compound of the invention or an agriculturally acceptable salt thereof or a composition of the invention to a subject in need thereof.
In one embodiment the bacterial infection is an Erwinia amylovora infection.
In another aspect the invention provides a method of treating or preventing an Erwinia amylovora infection comprising administering a compound of the invention or an agriculturally acceptable salt thereof or composition of the invention to a subject in need thereof.
In one embodiment the subject comprises a plant. Preferably, the plant comprises a species that is susceptible to bacterial infection, in particular infection by Erwinia amylovora. Preferred plants include crop plants. Preferred crop plants include pome trees. _ _
In one embodiment the compound of the invention or an agriculturally acceptable salt thereof or composition of the invention is applied to the site of infection.
In another embodiment the subject comprises plant material including seeds, cuttings, root stock, scions or harvested crops such as fruit.
In another embodiment the subject comprises any surface that may contact harvested fruit, including harvesting equipment, packaging equipment and packaging material.
In another aspect the invention provides a use of a compound of the invention or an agriculturally acceptable salt thereof or a composition of the invention in the manufacture of a formulation for the treatment or prevention of a bacterial infection. In one embodiment the infection is an Erwinia amylovora infection.
The entire disclosures of all applications, patents and publications, cited above and below, if any, are hereby incorporated by reference.
DETAILED DESCRIPTION
The present inventor has discovered that compounds of Formulae I, IA and IB (collectively referred to as Formula I), or agriculturally acceptable salts thereof are useful in the treatment or prevention of bacterial infection, particularly Erwinia amylovora infection.
Accordingly, the present invention provides a compound of Formula I:
Figure imgf000011_0001
(I) _
or an agriculturally acceptable salt thereof, wherein
R1 is selected from
(a) hydrogen, (b) (C1-C10) alkyl,
(c) (C2-C10) alkenyl,
(d) (C2-C10) alkynyl,
(e) (C3-C8) cycloalkyl,
(f) aryl, (g) amino,
(h) (C1-C10) alkoxy,
(i) (C1-C10) alkanoyl,
Q) hydroxy,
(k) nitro or nitroso, (1) cyano, or
(m) halogen, wherein each of (b) to (i) are optionally substituted with one or more of
(Ci-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C3-C8) cycloalkyl, aryl, amino, (C1-C10) alkoxy, (C1-C10) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy; or
R1 is selected from the group comprising an amino acid, a di- or tri-peptide, an oligopeptide, a polypeptide, or an ester thereof.
In one embodiment R1 is selected from (a) hydrogen,
(b) (C1-C10) alkyl,
(C) (C2-C10) alkenyl,
(d) (C2-C10) alkynyl,
(e) (C3- C8) cycloalkyl, or (f) aryl, _
wherein each of (b) to (f) are optionally substituted with one or more of (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C8) cycloalkyl, aryl, amino, (C1-C10) alkoxy, (C1-C10) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment R1 is selected from
(b) (C1-C10) alkyl,
(c) (C2-C10) alkenyl,
(d) (C2-C10) alkynyl, or
(e) (C3- C8) cycloalkyl, wherein each of (b) to (e) are optionally substituted with one or more of (C1-C10) alkyl, (C2-C1O) alkenyl, (C2-C10) alkynyl, (C3-Cs) cycloalkyl, aryl, amino, (C1-C10) alkoxy, (C1-C1O) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment R1 is selected from (h) (C1-C10) alkoxy,
(i) (Ci-C10) alkanoyl,
Q) hydroxy,
(k) nitro or nitroso,
(1) cyano, or (m) halogen, wherein each of (h) and (i) are optionally substituted with one or more Of (Ci-C10) alkyl, (C2-C1O) alkenyl, (C2-C10) alkynyl, (C3-C8) cycloalkyl, aryl, amino, (C1-C10) alkoxy, (C1-C10) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment R1 is amino. In one embodiment R1 is amino optionally substituted with one or more of (Ci-Ci0) alkyl, (C2-C10) alkenyl, (C2-Ci0) alkynyl, (C3-C8) cycloalkyl, aryl, (C1-C10) alkoxy, (Ci-C10) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
hi one embodiment R1 is amino optionally substituted with one or more of (C1-CiO) alkyl, (C2-Ci0) alkenyl, (C2-Ci0) alkynyl, (C3-C8) cycloalkyl or aryl. ^
In one embodiment R1 is amino optionally substituted with one or more of (C1-C10) alkoxy, (C1-C10) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In another aspect the invention provides a compound of Formula (I) wherein R1 is selected from the group comprising an amino acid, a di- or tri-peptide, an oligopeptide, a polypeptide or an agriculturally acceptable salt or ester thereof.
In one embodiment the compound of formula (I) is of the L-configuration at the 5- position of the pyrrolidine ring. In one embodiment, the amino acid is an L-amino acid. In one embodiment, the di- or tri-peptide, oligopeptide or polypeptide comprises L- amino acids.
In one embodiment the amino acid is selected from the group comprising glycine, alanine, β-alanine, valine, leucine, isoleucine, alloisoleucine, L-phenylalanine, proline, serine, homoserine, threonine, allothreonine, glutamic acid, methionine, asparagine, aspartic acid, glutamine, histidine, lysine, arginine, tyrosine and tryptophan.
In one embodiment the amino acid is selected from the group comprising glycine, L- alanine, β-alanine, L-valine, L-leucine, L-isoleucine, L-alloisoleucine, L-phenylalanine, L-proline, L-serine, L-homoserine, L-threonine, L-allothreonine, L-glutamic acid, L- methionine, L-asparagine, L-aspartic acid, L-glutamine, L-histidine, L-lysine, L- arginine, L-tyrosine and L-tryptophan.
In one embodiment the amino acid is selected from the group comprising glycine, L- alanine, β-alanine, L-valine, L-leucine, L-phenylalanine, L-proline, and L-threonine.
" In one embodiment the di-peptide comprises amino acids selected from the group comprising glycine, alanine, β-alanine, valine, leucine, isoleucine, alloisoleucine, phenylalanine, proline, serine, homoserine, threonine, allothreonine, glutamic acid, methionine, asparagine, aspartic acid, glutamine, histidine, lysine, arginine, tyrosine and tryptophan. In one embodiment the di-peptide comprises amino acids selected from the group comprising glycine, L-alanine, β-alanine, L-valine, L-leucine, L-isoleucine, L- alloisoleucine, L-phenylalanine, L-proline, L-serine, L-homoserine, L-threonine, L- allothreonine, L-glutamic acid, L-methionine, L-asparagine, L-aspartic acid, L- glutamine, L-histidine, L-lysine, L-arginine, L-tyrosine and L-tryptophan.
Preferred di-peptides comprise L-valine, L-alanine or L-threonine coupled to a second L-amino acid. In one embodiment the di-peptide comprises L-alanyl-L-valine, L-valyl- L-alanine, L-valyl-L-threonine and L-threonyl-L-valine, L-alanyl-L-threonine and L- threonyl-L-alanine. Particularly preferred dipeptides are L-valyl-L-alanine and L- alanyl-L- valine.
Compounds of Formula I may exist in a number of isomeric forms. All isomeric forms are encompassed within the scope of the present invention. In one embodiment L- isomers are preferred.
Compounds of the invention may be prepared according to the general methodology described in Example 1 below. It is to be understood that a skilled worker will be able, without undue experimentation and with regard to that skill and this disclosure, to select appropriate reagents and conditions to modify this methodology to produce compounds of Formula I.
Those of skill in the art will also appreciate that other synthetic routes may be used to synthesise the compounds of the invention. In addition, it will be appreciated by those of skill in the art that, in the course of preparing the compounds of the invention, the functional groups of intermediate compounds may need to be protected by protecting groups. Functional groups which it is desirable to protect include, but are not limited to hydroxyl, amino and carboxylic acid. Protecting groups may be added and removed in accordance with techniques that are well known to those skilled in the art. The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by J.W.F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 2nd Ed, T. W. Greene and P.G.M Wutz, Wiley-Interscience (1991). _
As used herein the term "alkyl" includes straight or branched chain saturated hydrocarbon groups. Preferably, an alkyl group comprises (C1-CiO) alkyl, (C1-C8) alkyl, (C1-C6) alkyl, (Ci-C4) alkyl, propyl, ethyl or methyl.
As used herein the terms "alkenyl" and "alkynyl" include straight or branched chain groups having at least one double or triple bond, respectively. Preferably, an alkenyl group comprises (C2-C10) alkenyl, (C2-C8) alkenyl, (C2-C6) alkenyl, (C2-C4) alkenyl, propenyl or ethenyl. Preferably, an alkynyl group comprises (C2-C10) alkynyl, (C2-C8) alkynyl, (C2-C6) alkynyl, (C2-C4) alkynyl, propynyl, or ethynyl.
As used herein the term "cycloalkyl" includes single or multiple cyclic or heterocyclic rings which are fused together or covalently linke; and may be saturated or unsaturated. Preferably, a cycloalkyl group comprises (C3-C8) cycloalkyl, (C3-C6) cycloalkyl, cyclopentyl, cyclobutyl or cyclopropyl. In one embodiment the term "heterocyclic" includes rings having at least one heteroatom selected from nitrogen, oxygen and sulphur.
As used herein the term "aryl" is intended to include single or multiple aromatic rings which are fused together or covalently linked and includes aryl groups containing one or more heteroatoms. In one embodiment the term "heteroatom" includes nitrogen, oxygen and sulphur.
As used herein the term "amino" is intended to include amino, alkylamino and dialkylarnino.
As used herein the term "amino acid" is intended to include α, β and γ-amino acids.
As used- herein the term "alkoxy" is intended to include alkyl-O-, alkenyl-O-, cycloalkyl-O- and alkynyl-O-. Preferably, an alkoxy group comprises (Ci-C10) alkoxy, (Ci-C8) alkoxy, (Ci-C6) alkoxy, (Ci-C4) alkoxy, propoxy, ethoxy or methoxy.
As used herein the term "alkanoyl" is intended to include alkyl-C(O)-, alkenyl-C(O)-, cycloalkyl-C(O)- and alkynyl-C(O)-. Preferably, an alkoxy group comprises (C1-Ci0) _ ^ _
alkanoyl, (C1-C8) alkanoyl, (C1-C6) alkanoyl, (C1-C4) alkanoyl, propanoyl, ethanoyl or methanoyl.
As used herein the term "halogen" is intended to mean fluoro, chloro, bromo and iodo.
As used herein the term "antibiotic" is intended to include any substance that is able to kill or inhibit the growth of a microorganism. Useful antibiotics may be produced by a microorganism or by a synthetic or semi synthetic process.
As used herein the term "agriculturally acceptable salt" is intended to include salts of any carboxylic acid group present in the compound of the invention and acid addition salts of any amino or substituted amino groups that may be present in a compound of the invention. Examples of acceptable salts of a carboxylic acid group include aluminium salts, alkali metal salts (e.g. sodium, lithium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts), and ammonium salts. Suitable acid addition salts include for example hydrochlorides, sulphates, hydrogen sulphates, acetates and phosphates. Other agriculturally acceptable salts will be apparent to those skilled in the art.
As used herein the term "agriculturally acceptable carrier" is intended to include any material that facilitates application of a compound or composition of the invention to the intended subject, which may for example be a plant, plant material or equipment, or that facilitates storage, transport or handling. Carriers used in compositions for application to plants and plant material are preferably non-phytotoxic or only mildly phytotoxic. A suitable carrier may be a solid, liquid or gas depending on the desired formulation. Examples of solid carriers include but are not limited to fillers such as kaolin, bentonite, dolomite, calcium carbonate, talc, powdered magnesia, Fuller's earth, gypsum, diatomaceous earth and China clay, water; alcohols, particularly butanol or glycol, as well as their ethers or esters, particularly methylglycol acetate; ketones, particularly acetone, cyclohexanone, methylethyl ketone, methylisobutylketone, or isophorone; petroleum fractions such as paraffmic or aromatic hydrocarbons, particularly xylenes or alkyl naphthalenes; mineral or vegetable oils; aliphatic _ _
chlorinated hydrocarbons, particularly trichloroethane or methylene chloride; aromatic chlorinated hydrocarbons, particularly chlorobenzenes; water-soluble or strongly polar solvents such as dimethylformamide, dimethyl sulfoxide, or iV-methylpyrrolidone; liquefied gases; or the like or a mixture thereof. A carrier which provides for slow or delayed release of a compound of the invention may also be included in a composition of the invention. It is to be understood that a skilled worker will be able, without undue experimentation, with regard to that skill and this disclosure, to select a suitable carrier for the desired mode of application, storage, transport or handling.
As used herein, the term "subject" is intended to include any target surface to which a compound or composition of the invention may be applied, for example a plant, plant material including seeds, cuttings, root stock, scions or harvested crops such as fruit, or any surface that may contact harvested fruit including harvesting equipment, packaging equipment and packaging material.
As used herein, the term "comprising" means "consisting at least in part of; that is to say when interpreting statements in this specification and claims which include that term, the features prefaced by that term in each statement all need to be present but other features can also be present.
It is intended that reference to a range of numbers disclosed herein (for example, 1 to 10) also incorporates reference to all rational numbers within that range (for example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of rational numbers within that range (for example, 2 to 8, 1.5 to 5.5 and 3.1 to 4.7) and, therefore, all sub-ranges of all ranges expressly disclosed herein are hereby expressly disclosed. These are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner.
In another aspect, the invention provides a compound of Formula IA: _ _
Figure imgf000019_0001
or an agriculturally acceptable salt thereof, wherein
R2 is hydrogen or (C1-C10) alkyl optionally substituted with one or more of (C1-
C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C3-C8) cycloalkyl, aryl, amino, (C1-C10) alkoxy, (C1-C10) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment, the compound of formula (IA) is of the L- configuration at the 5- position of the pyrrolidine ring.
In one embodiment, R2 comprises (C1-4) alkyl, optionally substituted with one or more of amino, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment, R2 is selected from the group comprising -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CO2H and -CH2CH2CO2H.
In another aspect, the invention provides a compound of Formula IB:
Figure imgf000019_0002
_ _
or an agriculturally acceptable salt thereof, wherein
each R2 is independently selected from hydrogen or (C1-C10) alkyl optionally substituted with one or more of (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C3-C8) cycloalkyl, aryl, amino, (C1-C10) alkoxy, (C1-Ci0) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment, the compound of formula (IA) is of the L- configuration at the 5- position of the pyrrolidine ring.
In one embodiment, R2 comprises (C1-4) alkyl, optionally substituted with one or more of amino, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
In one embodiment, R2 is selected from the group comprising -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CO2H and -CH2CH2CO2H.
In one embodiment, the compound is selected from the group comprising:
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-glycine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-alanine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-β-alanine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-valine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-leucine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-phenylalanine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-isoleucine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-alloisoleucine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-proline),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-serine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-homoserine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-threonine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-threonine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-allothreonine), _
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-glutamic acid), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-methionine), 2-imino-3-niethylenepyrrolidine-5-L-(carbonyl-L-asparagine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-aspartic acid), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-glutamine)5
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-histidine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-lysine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-arginine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-tyrosine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-typtophan), and
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-valyl-L-alanine) 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-alanyl-L-valine)5 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-valyl-L-threonine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-threonyl-L-valine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-alanyl-L-threonme), and
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-threonyl-L-alanine).
In another embodiment the compound is selected from the group comprising: 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-glycine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-alanine),
2-imino-3 -methylenepyrrolidine-5 -L-(carbonyl-β -alanine), 2-imino-3 -methylenepyrrolidine-5 -L-(carbonyl-L- valine) , 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-leucine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-phenylalanine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-proline),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-threonine), and 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-valyl-L-alanine).
Compounds of formula (I) can conveniently be prepared using the methodology outlined in Example 1. In the synthesis shown, the starting material is L-pyro glutamic acid. This is available commercially, for example from Sigma- Aldrich (3050 Spruce St, _ _
St. Louis, MO 63103). Pyroglutamic acid is converted to the convenient intermediate compound 2-oxo-3-methylenepyrrolidine-5-carboxylic acid as shown in formula (II)
Figure imgf000022_0001
Compounds of formula (I) may be synthesised by reacting different moieties with the reactive carboxylic acid functionality of 2-oxo-3-methylenepyrrolidine-5-carboxylic acid (formula (H)). Amino acids, peptides and polypeptides are conveniently reacted using standard peptide coupling technology. For example, see "Principles of Peptide Synthesis", 1993 M. Bodanszky, editor, Springer Verlag, New York.
The reaction generally proceeds using the carboxyl protected amino acid, peptide or polypeptide. If necessary, side chain functionalities can also be protected. For example, threonine protected as the methyl ester and O-acetate was reacted with 2-oxo- 3-methylenepyrrolidine-5-carboxylic acid to produce the threonine analogue 2-imino-3- methylenepyrrolidine-5-L-(carbonyl-L-threonine) as shown in Example 3.
Functional groups other than amino acids, peptides and polypeptides may also be reacted with the carboxylic acid functionality using conventional organic chemistry techniques. See for example, "Advanced Organic Chemistry", 1992, J. March, John Wiley & Sons.
Following addition of the R1 functionality to 2-oxo-3-methylenepyrrolidine-5- carboxylic acid, the 2-carboxy functionality is converted to an imine. In Example 1 this is performed in two stages using first trimethyloxonium tetrafluoroborate, then methanol/ammonium chloride solution, however any other method known in the art maybe used. _ _
In a final step the carboxyl protecting group (and other protecting groups present) can be removed from the amino acid, peptide or polypeptide. However, in some embodiments the compound of formula (I) comprises the carboxyl-protected amino acid, peptide or polypeptide. Preferably, the amino acid, di- or tri-peptide, oligopeptide or polypeptide is protected as an ester such as an alkyl or aryl ester, in particular a methyl, ethyl or benzyl ester.
It is to be understood that the compounds of the invention can also be made from other starting materials, utilising different synthetic pathways.
In another aspect the invention provides an antibiotic composition comprising a compound of the invention or an agriculturally acceptable salt thereof and an agriculturally acceptable carrier.
In another aspect the invention provides a method of treating or preventing a bacterial infection comprising administering a compound of the invention or an agriculturally acceptable salt thereof or composition of the invention to a subject in need thereof.
In one embodiment the bacterial infection is an Erwinia amylovora infection.
In one embodiment the compound of the invention or an agriculturally acceptable salt thereof or composition of the invention is applied to the site of infection.
In one embodiment the subject comprises a plant. Preferred plants include crop plants. Preferred crop plants include pome trees. Preferred pome trees are apple and pear trees.
Apple trees refer to the genus trees Malus and include, for example, dessert apple and crabapple type varieties. The invention may be practiced on a variety of dessert apple trees including but not limited to Arkansas Black, Baldwin, Beacon, Ben Davis, Braeburn, Burgundy, Cortland, Delicious, Red Delicious, Empire, Fuji, Gala, Royal Gala, Golden Delicious, Granny Smith, Gravenstein, Grimes Golden, Idared, Jerseymac, Jonafree, Jonagold, Jonamac, Jonathan, Liberty, Lodi, Macoun, Mclntosh, Molly's Delicicious, Monroe, Mutsu, Niagara, Nittany, Nothern Spy, Northewestern Greening, Paulared, Priam, Prima, Priscilla, Qunite, Redfree, R. I. Greening, Rome Beauty, Sir Prize, Spartan, Stayman, Summer Rambo, Twenty Ounce, Tydeman Early, Wayne, Wealthy, Winesap, Winter Banana, Yellow Newton, Yellow Transparent, York Imperial, Sciros, Scifresh, Cox's Orange, Elstar and Cripps Pink.
The invention may also be practiced on a variety of crabapple trees such as Adirondack, Ames White, Bob White, Centennial, Centurion, Dolgo, Florence, Harvest Gold, Hyslop, Marshall Slender, Naragansett, Omiston Roy, Pink Perfection, Profusion, Red Splendor, Silver Moon, Snowdrift, Spring Snow, Transcendent, White Candle, White Cascade, Whitney, and Winter cold.
Pear trees refer to the genus trees Pyrus and include, for example, dessert pear, asian pear, low chilling pear, and ornamental pear varieties. The invention may be practiced on such variety of dessert pear trees as Aurora, Ayers, Bartlett, Beurre Bosc, Beurre d' Anjou, Beurre Hardy, California, Cascade, Clapp's Favorite, Dawn, DeVoe, Douglas, Doyeene du Cornice, Duchesse d'Angouleme, Earlibrite, Flemish Beauty, Forelle, Garber, Gorham, Harrow Delight, Harvest Queen, Highland, Honeysweet, Lincoln, Luscious, Magness, Maxine, Monterey, Moonglow, Packham's Triumph, Rogue Red, Seckel, Sierra, Spartlett, Starkrimson, Tyson, Winter Cole, Winter Nelis, and Worden Seckel.
The invention may also be practiced on such varieties of asian pear trees as Ar-riang one, Chojuro Imamura aki, Hosui, Ichiban nashi, Ikusankichi, Ishilwase, Kikusui, Kosui, Kumoi, Meigetsu, Nitaka, Nijissekiki, Seigyoku, Seuri, Shinko, Shinseiki, Shinsui, Singo, Tsu Li, and Ya Li.
The invention may also be practiced on such varieties of low chilling pear such as Baldwin, Carnes, Flordahome, Hood, Kieffer, Le Conte, Orient, Pineapple, and Tenn.
The invention may also be practiced on such varieties of ornamental pear as Autumn Blaze, Bradford, Capital, Chanticleer and Whitehouse. The invention may further be practiced on plants susceptible to fireblight infection such as those belonging to the genera: Cotoneaster, Crataegys, Cydonia, Photinia, Pyracantha, and Sorbus.
The compounds or compositions of the invention can be applied to a subject in a number of ways, for example, they can be applied, formulated or unformulated, directly to plant parts such as roots, leaves, cuttings, flowers, stems, fruits and/or the foliage of a tree, or to seeds or other propagative material, or to other medium in which the trees are growing or are to be planted, or they can be sprayed on, dusted on, or applied as a cream or paste formulation, or they can be applied as slow release granules.
In another aspect, the invention provides a use of a compound of the invention or an agriculturally acceptable salt thereof or a composition of the invention in the manufacture of an antibiotic.
In another aspect, the invention provides a use of a compound of the invention or an agriculturally acceptable salt thereof or a composition of the invention in the manufacture of a formulation for the treatment or prevention of bacterial infection.
In one embodiment the bacterial infection is an Erwinia amylovora infection.
In one embodiment an agriculturally acceptable carrier can be solid or liquid. Carriers useful herein include any substance typically used to formulate agricultural composition.
In one embodiment the agriculturally acceptable carrier maybe selected from the group comprising fillers, solvents, excipients, surfactants, suspending agents, speaders/stickers (adhesives), antifoaming agents, dispersants, wetting agents, drift reducing agents, auxiliaries, adjuvants or a mixture thereof.
Compositions of the invention may be formulated as, for example, concentrates, solutions, sprays, aerosols, immersion baths, dips, emulsions, wettable powders, soluble powders, suspension concentrates, dusts, granules, water dispersible granules, microcapsules, pastes, gels and other formulation types by well-established procedures.
These procedures include mixing and/or milling of the active ingredients with agriculturally acceptable carrier substances, such as fillers, solvents, excipients, surfactants, suspending agents, speaders/stickers (adhesives), antifoaming agents, dispersants, wetting agents, drift reducing agents, auxiliaries and adjuvants.
In one embodiment solid carriers include but are not limited to mineral earths such as silicic acids, silica gels, silicates, talc, kaolin, attapulgus clay, limestone, lime, chalk, bole, loess, clay, dolomite, diatomaceous earth, aluminas calcium sulfate, magnesium sulfate, magnesium oxide, ground plastics, fertilizers such as ammonium sulfate, ammonium phosphate, ammonium nitrate, and ureas, and vegetable products such as grain meals, bark meal, wood meal, and nutshell meal, cellulosic powders and the like. As solid carriers for granules the following are suitable: crushed or fractionated natural rocks such as calcite, marble, pumice, sepiolite and dolomite; synthetic granules of inorganic or organic meals; granules of organic material such as sawdust, coconut shells, corn cobs, corn husks or tobacco stalks; kieselguhr, tricalcium phosphate, powdered cork, or absorbent carbon black; water soluble polymers, resins, waxes; or solid fertilizers. Such solid compositions may, if desired, contain one or more compatible wetting, dispersing, emulsifying or coloring agents which, when solid, may also serve as a diluent.
In one embodiment the carrier may also be liquid, for example, water; alcohols, particularly butanol or glycol, as well as their ethers or esters, particularly methylglycol acetate; ketones, particularly acetone, cyclohexanone, methylethyl ketone, methylisobutylketone, or isophorone; petroleum fractions such as paraffinic or aromatic hydrocarbons, particularly xylenes or alkyl naphthalenes; mineral or vegetable oils; aliphatic chlorinated hydrocarbons, particularly trichloroethane or methylene chloride; aromatic chlorinated hydrocarbons, particularly chlorobenzenes; water-soluble or strongly polar solvents such as dimethylformamide, dimethyl sulfoxide, or N- methylpyrrolidone; liquefied gases; or the like or a mixture thereof. - ZO -
In one embodiment surfactants include nonionic surfactants, anionic surfactants, cationic surfactants and/or amphoteric surfactants and promote the ability of aggregates to remain in solution during spraying.
Spreaders/stickers promote the ability of the compositions of the invention to adhere to plant surfaces. Examples of surfactants, spreaders/stickers include but are not limited to Tween and Triton (Rhom and Hass Company), Fortune®, Pulse, C. Daxoil, Codacide oil®, D-C talc, Supamet Oil, Bond®, Penetrant, Glowelt® and Freeway, alkali metal, alkaline earth metal and ammonium salts of aromatic sulfonic acids, e.g., ligninsulfonic acid, phenolsulfonic acid, naphthalenesulfonic acid and dibutylnaphthalenesulfonic acid, and of fatty acids, alkyl and alkylaryl sulfonates, and alkyl, lauryl ether and fatty alcohol sulfates, and salts of sulfated hexadecanols, heptadecanols, and octadecanols, salts of fatty alcohol glycol ethers, condensation products of sulfonated naphthalene and naphthalene derivatives with formaldehyde, condensation products of naphthalene or naphthalenesulfonic acids with phenol and formaldehyde, polyoxyethylene octylphenol ethers, ethoxylated isooctylphenol, ethoxylated octylphenol and ethoxylated nonylphenol, alkylphenol polyglycol ethers, tributylphenyl polyglycol ethers, alkylaryl polyether alcohols, isotridecyl alcohol, fatty alcohol ethylene oxide condensates, ethoxylated castor oil, polyoxyethylene alkyl ethers, ethoxylated polyoxypropylene, lauryl alcohol polyglycol ether acetal, sorbitol esters, lignin-sulfite waste liquors and methyl cellulose.
Wetting agents reduce surface tension of water in the composition and thus increase the surface area over which a given amount of the composition may be applied. Examples of wetting agents include but are not limited to salts of polyacrylic acids, salts of lignosulfonic acids, salts of phenolsulfonic or naphthalenesulfonic acids, polycondensates of ethylene oxide with fatty alcohols or fatty acids or fatty esters or fatty amines, substituted phenols (particularly alkylphenols or arylphenols), salts of sulfosuccinic acid esters, taurine derivatives (particularly alkyltaurates), phosphoric esters of alcohols or of polycondensates of ethylene oxide with phenols, esters of fatty acids with polyols, or sulfate, sulfonate or phosphate functional derivatives of the above compounds. _
In one embodiment the compositions of the invention may be formulated to comprise at least about 0.001 to 95% by weight of one or more compounds of the invention, preferably 0.001 to 90% by weight, more preferably 0.001 to 85% by weight, more preferably 0.001 to 75% by weight, more preferably 0.001 to 75% by weight, more preferable 0.001 to 70% by weight, more preferably 0.001 to 65% by weight, more preferably 0.001 to 60% by weight, more preferably 0.001 to 55% by weight, more preferably 0.001 to 50% by weight, more preferably 0.001 to 45% by weight, more preferably 0.001 to 40% by weight, more preferably 0.001 to 35% by weight, more preferably 0.001 to 30% by weight, more preferably 0.001 to 25% by weight, more preferably 0.001 to 20% by weight, more preferably 0.001 to 15% by weight, more preferably 0.001 to 10% by weight, more preferably 0.005 to 10% by weight, more preferably 0.01 to 10% by weight, more preferably 0.1 to 10% by weight, more preferably 0.5 to 10% by weight, more preferably 1.0 to 10% by weight more preferably 2 to 8% by weight, more preferably 4 to 6% by weight and useful ranges may be selected between any of the foregoing values, for example, 10 to 20% by weight.
Preferably, the rate of application is such that the amount of compound applied is sufficient to significantly reduce the number of infected branch shoots and/or to decrease the average canker length.
In one embodiment the rate of application of a compound or composition of the invention may be in the range of about 0.00001 to 50 kg per hectare, more preferably 0.0005 kg to 50 kg per hectare, more preferably 0.0005 to 40 kg per hectare, more preferably 0.0005 to 30 kg per hectare, more preferably 0.001 to 30 kg per hectare, more preferably 0.001 to 25 kg per hectare, more preferably 0.005 to 25 kg per hectare, more preferably 0.005 to 20 kg per hectare, more preferably 0.01 to 20 kg per hectare, more preferably 0.01 to 15 kg per hectare, more preferably 0.05 to 15 kg per hectare, more preferably 0.05 to 10 kg per hectare, more preferably 0.1 to 10 kg per hectare, more preferably 0.1 to 5 kg per hectare, more preferably 1 to 5 kg per hectare and useful ranges may be selected between any of the foregoing values, for example, 0.5 to 1 kg per hectare. In one embodiment the preferred method of applying the compound or composition of the invention is to spray a dilute or concentrated solution by handgun or commercial airblast.
When actually applying a compound or composition of the invention as a spray, in one embodiment it is diluted with water at a concentration in the range of about 1 ppm or up, preferably 1 to 1000 ppm, more preferably 1 to 500 ppm, more preferably 1 to 300 ppm, more preferably 10 to 300 ppm, more preferably 10 to 200 ppm, more preferably 20 to 200 ppm, more preferably 20 to 150 ppm, more preferably 30 to 150 pm, more preferably 30 to 100 ppm, more preferably 40 to 100 ppm and useful ranges may be selected between any of the foregoing values, for example, 10 to 20 ppm.
Predictive models, particularly Maryblyt™, may be used to help identify potential infection periods and improve the timing of antibiotic treatments, as well as avoid unnecessary treatments .
The compounds and compositions of the invention may be applied to a plant at any appropriate stage of the growth of the plant. Generally, it is suggested that plants be treated for fireblight prior to or during blossoming. Application of the compounds and compositions of the invention may be used in conjunction with pruning and other techniques for preventing or controlling fireblight. It is to be understood that a person of ordinary skill in the art will be able, without undue experimentation, having regard to that skill and this disclosure, to determine the appropriate timing of treatment. In one embodiment, a composition of the invention may be formulated to include additional active ingredients including fertilisers, nutrients, antibiotics, pesticides, insecticides or fungicides. It is to be understood that a skilled worker will be able, without undue experimentation, with regard to that skill and this disclosure, -to prepare a suitable composition for the desired mode of application, storage, transport or handling.
The compounds and compositions of the present invention may be used alone or in combination with one or more other agricultural agents, including pesticides, insecticides, acaracides, fungicides, bactericides, herbicides, antibiotics, antimicrobials, _
nemacides, rodenticides, entomopathogens, phermones, attractants, plant growth regulators, insect growth regulators, chemosterilants, microbial pest control agents, repellents, viruses, phagostimulents, plant nutrients and biological controls. When used in combination with other agricultural agents the administration of the two agents may be simultaneous or sequential. Specific examples of these agricultural agents are known to those skilled in the art, and many are readily commercially available.
Examples of plant nutrients include but are not limited to nitrogen, magnesium, calcium, boron, potassium, copper, iron, phosphorus, manganese, molybdenum, cobalt, boron, copper, silicon, selenium, nickel, aluminum, chromium and zinc.
Examples of antibiotics that may be used in combination with the compounds and compositions of the invention include, but are not limited to oxytetracyline, streptomycin and copper spray.
Examples of fungicides that may be used in combination with the compounds and compositions of the invention include, but are not limited to the following classes of fungicides: carboxamides, benzimidazoles, triazoles, hydroxypyridines, dicarboxamides, phenylamides, thiadiazoles, carbamates, cyano-oximes, cinnamic acid derivatives, morpholines, imidazoles, β-methoxy acrylates and pyridines/pyrimidines.
Examples of pesticides that may be used in combination with the compounds and compositions of the invention include, but are not limited to azoxystrobin, bitertanol, carboxin, Cu2O, cymoxanil, cyproconazole, cyprodinil, dichlofluamid, difenoconazole, diniconazole, epoxiconazole, fenpiclonil, fludioxonil, fluquiconazole, flusilazole, flutriafol, furalaxyl, guazatin, hexaconazole, hymexazol, imazalil, imibenconazole, ipconazole, kresoxim-methyl, mancozeb, metalaxyl, R-metalaxyl, metconazole, oxadixyl, pefurazoate, penconazole, pencycuron, prochloraz, propiconazole, pyroquilone, SSF-109, spiroxamin, tebuconazole, thiabendazole, tolifluamid, triazoxide, triadimefon, triadimenol, triflumizole, triticonazole and uniconazole. _
Examples of biological controls that may be used in combination with the compounds and compositions of the invention include, but are not limited to Blight Ban™, a biological control formulation using the bacterium Pseudomonas fluorescens A-506 and formulations including Pantoea agglomorans PlOc.
As will be apparent to one of skill in the art, the amount and/or concentration of a compound or composition of the invention required for a particular application may vary depending on several factors such as (1) the nature of the subject, (2) the physiological condition of the subject, (3) the type and level of infestation, (4) the type of composition used, (5) the type of wound on the subject, and (6) environmental factors such as temperature and humidity. It should be understood that a person of ordinary skill in the art will be able, without undue experimentation, having regard to that skill and this disclosure, to determine an effective amount of a composition of this invention for a given application.
The efficacy of compounds and compositions of the invention may be confirmed using an assay system such as that described in Examples 3 and 4 below.
Efficacy of the compounds and compositions of the invention may also be confirmed using field trial assay systems. For example, confirmation of the ability of compounds and compositions of the invention to prevent bacterial growth may be obtained by applying a compound or composition of the invention to plant material and then inoculating with bacteria, Erwinia amylovora for example. Efficacy is confirmed by the absence of bacterial growth or less bacterial growth than an untreated control.
Confirmation of the ability of compounds and compositions of the invention to treat bacterial growth may be obtained by inoculating plant material with bacteria, Erwinia amylovora for example and then applying a compound or composition of the invention. Efficacy is confirmed by a reduction in the degree of bacterial growth or the disappearance of bacterial growth compared to an untreated control. ^
Various aspects of the invention will now be illustrated in non-limiting ways by reference to the following examples.
EXAMPLE 1
Compounds of Formula I may be prepared according to Scheme 1 shown below, as illustrated by the synthesis of 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-valine).
Scheme 1
Figure imgf000032_0001
The synthesis was carried out using the following steps:
1. L-Pyroglutamic acid, 5.16 g (0.04 mol), 1.2 ml (0.044 mol) of 70% perchloric acid and 80 ml of tert-butyl acetate were stirred overnight at ambient temp. The product was extracted into ether and remaining acidic material removed by washing the ether solution with aqueous bicarbonate.
2. tert-Butyl (2S)-pyroglutamate, 5.0 g (0.027 mol) was dissolved into 100 ml MeCN solvent and cooled to O0C. Then added DMAP (4- dimethylaminopyridine) 0.33 g (2.70 rnmol) followed by a solution of di-tert- butyl dicarbonate (8.85 g, 0.041 mol) in 30 ml MeCN. Stirring continued for 2 h at O0C and 12 h at ambient temperature, and the product was crystallised from Et2O-hexane. _
3. tert-Butyl (2S)-N-(tert-butoxycarbonyl)pyroglutamate, 4.1 g (14.4 mmol) was dissolved in 35 ml dimethoxymethane and Bredereck's reagent (tert- butoxybis(dimethylamino)methane), 3.75 g (21.55 mmol) was added. The reaction was heated under nitrogen at 75 °C for 16 h. Solvents were then removed under reduced pressure, and the product crystallised from Et2O- hexane.
4. tert-Butyl (2S)-N-(tert-butoxycarbonyl)-4-
(dimethylaminomethylene)pyroglutamate 5.0 g (14.7 mmol) was dissolved in 150 ml THF (tetrahydrofuran), cooled to -780C, and 22 ml (22 mmol) of a solution of 1 M DIBAL (diisobutylaluminium hydride) added dropwise during ca. 10 min. Stirring was continued for 2 h during warming to room temperature. The product solution was then quenched with saturated NH4Cl (ca. 25 ml), and stirred overnight. Solution (containing product) was decanted and the remaining slurry washed with EtOAc, and product recovered from the combined organic phases was crystallised from Et2O-hexane.
5. To tert-Butyl(2S)-N-(tert-butoxycarbonyl)-4-(methylene)pyroglutamate, 1.0 g (3.36 mmol) in 10 ml CH2Cl2 3.1 ml (40 mmol) of TFA (trifmoroacetic acid) was added and the mixture allowed to stand 18 h at ambient temperature. Solvent and excess TFA were evaporated and product solidified by addition of Et2O.
6. A slurry of 4-methylenepyroglutamate, 141.3 mg (1.0 mmol) in 4 ml MeCN was stirred and a solution of 211.3 mg (1.025 mmol) DCCD (1,3- dicyclohexylcarbodiimide) in 1.2 ml MeCN was added. After 30 min, a solution of L-valine methyl ester (as free base), 123 mg (1.05 mmol) in 1.2 ml MeCN was added and stirring continued for 3 h. The reaction was terminated by addition of 2 ml water, and product was obtained from filtrate after overnight storage (refrigerator), and purified chromatographically (LH20 Sephadex in 1 : 1 MeOH- water).
7. Trimethyloxonium tetrafiuoroborate (CH3)3O+BF4 ~), 92 mg (0.625 mmol), was stirred in 3 ml CH2Cl2 under nitrogen and a solution of 4- methylenepyroglutamyl-L- valine methy ester, 127.1 mg (0.5 mmol) in 1 ml CH2Cl2 was added. After 5 h the reaction was diluted into 40 ml CH2Cl2 and washed with 2x 5 ml of 1:1 1 M KHCO3/satd. NaCl. Product was recovered from the CH2Cl2 solution.
8. Product from step 7 was used directly - it was stirred and heated at 65°C under reflux conditions in 4 ml MeOH solution containing 160 mg solid NH4Cl for 20 h. The iminopyrrolidine product was obtained after chromatography on
LH20 Sephadex in 1:1 MeOH-water.
9. Hydrolysis to the carboxylic acid was in aqueous solution (containing methanol if required for solubility) with a small excess of 0.1 M NaOH solution. Reaction was monitored by HPLC and terminated by addition of 0.1 M HCl solution until a pH of 5.0 was attained.
All synthetic steps were monitored by isocratic HPLC on C- 18 a reversed phase silica column with eluting solvent of CH3CN-H2O-MeOH where the MeOH content was 5% and the other components varied to obtain product elution at 4.0-5.0 min. Purifications were all by column chromatography on LH20 Sephadex using 1:1 MeOH-H2O, and monitored by HPLC analysis.
The product 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-valine) was obtained as a crystalline residue following purification, m/z (FAB) 240.1343(MH+). C11H18N3O3 requires 240.1348.
EXAMPLE 2
The compounds listed below were also made using the synthetic scheme outlined in Example 1. In step 6 of the synthesis the appropriate amino acid or peptide was coupled to 2-oxo-3-methylenepyrrolidine-5-carboxylic acid in place of L-valine.
Figure imgf000034_0001
- -
Figure imgf000035_0001
-imino-3-methylenepyrroIidine-5-L-(carbonyl-L-proIine) - -
Figure imgf000036_0001
EXAMPLE 3
Antibiotic activity was determined on plates of HS (Hoitink & Sinden) medium with 2% agar added. Plates were overlaid with a mid-log phase culture of Erwinia amylovora mixed with an equal volume of 2% agar, then 10μl of test samples were added to 5mm diameter wells cut into the agar. Inhibition zones appeared after overnight incubation at 26°C.
lOμl samples of 0.42mM solutions of each of 2-imino-3-methylenepyrrolidine-5-L- (carbonyl-L-valine) and 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-threonine) were applied to 5mm diameter wells cut into agar plates overlaid with Erwinia amylovora and gave clear zones of growth inhibition with sharp boundaries after 15 hours. Zone diameters were 18-20mm from l.Oμg applications of each compound. - -
Samples of 10 μl of 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-threonine), containing 1 μg per application, were applied to wells cut in agar plates overlaid with a growing bacterial culture. These were incubated overnight and then record taken of the appearance of inhibition zones. The efficacy of 2-imino-3-methylenepyrrolidine-5-L- (carbonyl-L-threonine) was compared to two known antibiotics (kanamycin and streptomycin) and the results are shown in Table 1.
Table 1: Inhibition activity of 4 natural products against various bacteria
Name Number Host X Kan Strep
Erwinia amylovora ICMP 1501 apple + + +
Erwinia amylovora ICMP 1540 pear + + +
Erwinia amylovora ICMP 1508 apple + + +
Erwinia amylovora 99.05 pear + + +
Erwinia carotovora 35E cymbidium Nil + +
Erwinia carotovora 13188 calla Nil + +
Erwinia carotovora
ICMP 3467 potato Nil + + pv. atroseptica
Erwinia carotovora
ICMP 3915 onion Nil + + pv. carotovora
Erwinia chrysanthemi ICMP 6926 celery Nil, + +
Pseudomonas
ICMP 6714 tomato Nil + + corrugata
Pseudomonas
ICMP 9503 kiwifruit Nil (faint+) + + marginalis
Pseudomonas
E:l apricot Nil + Nil syringae pv. syringae
Pseudomonas
ICMP 3938 pumpkin Nil + + syringae pv. syringae
Pseudomonas
ICMP 7380 tomato Nil (faint+) + + syringae pv. tomato
Pseudomonas
ICMP 4358 tomato Nil + + syringae pv. tomato
Xanthomonas
2.14 nectarine Nil + + compestris pv. pruni
Notes to Table 1: X = (2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-threonine); + = fully clear inhibition zone; Nil = no inhibition; Nil (faint +) = only a weak/faint zone shows; Kan = kanamycin; Strep = streptomycin, ICMP = International Collection of Micro-organisms from Plants. EXAMPLE 4
The compounds 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-valine) and 2-imino-3 -methylenepyrrolidine-5-L-(carbonyl-L-threonine) were also tested for their effectiveness in the inhibition of Erwinia amylovora in liquid cultures compared with streptomycin. The results are shown in Table 2.
Table 2: Effect on Erwinia amylovora growth
I50 (μg/ml) I80 (μg/ml)
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L- valine) 0.24 0.40
2-imino-3 -methylenepyrrolidine-5 -L-(carbonyl-L-threonine) 0.95 1.1
Streptomycin 5.5 8.5
The Ix value is the concentration of compound that gives an x% reduction in bacterial growth relative to the control.
EXAMPLE 5
Compounds of the invention (as described in Examples 1 and 2) were tested for antibiotic activity against Erwinia amylovora using the method described in Example 3. The rating provided is the inverse of the dosage size (μg) that gave an inhibition zone equivalent to that of lμg of 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-valine).
This compound was shown in Example 4 to have an I50(μg/ml) value of 0.24 against Erwinia amylovora growth.
Table 3: Bioactivity Rating of Synthetic Iminopyrrolidines
Figure imgf000038_0001
- -
Figure imgf000039_0001
INDUSTRIAL APPLICATION
The compounds and compositions of the present invention have utility as agricultural antibiotics. They may be employed to treat or prevent Erwinia amylovora infections as discussed above.
The compounds and compositions of the present invention may be employed as powders, pastes, sprays or in any other form suitable for agricultural applications.
Those skilled in the art will understand that the above description is provided by way of illustration only and that the invention is not limited thereto.
REFERENCES
T. Kolasa and M. J. Miller, J. Org Chem. 1990, 55, 1711-1721;
R. A. August, J. A. Khan, C. M. Moody and D. W. Young. "Stereospecific synthesis of
(2S,4R)-[5,5,5-2H3]leucine", J. Chem. Soc, Perkin Trans. 1, 507-514, 1996;
T. J. Hagen, A. A. Bergmanis, S. W. Kramer et al., "2-Iminopyrrolidines as potent and selective inhibitors of human inducible nitric oxide synthase", J. Med. Chem. 41, 3675-
3683, 1998;
H. A. J. Hoitink & S. L. Sinden, Phytopathol. 1970, 60, 1236-1237.

Claims

- -WHAT WE CLAIM IS
1. A compound of Formula (I) :
Figure imgf000041_0001
or an agriculturally acceptable salt thereof, wherein
R1 is selected from
(a) hydrogen,
(b) (C1-C10) alkyl,
(c) (C1-C10) alkenyl,
(d) (C1-C10) alkynyl, (e) (C3-C8) cycloalkyl,
CO aryl,
(g) amino,
(h) (C1-C10) alkoxy,
(i) (C1-C10) alkanoyl, (j) hydroxy,
(k) nitro or nitroso,
(1) cyano, or
(m) halogen, wherein each of (b) to (i) are optionally substituted with one or more of (Ci-Cio)alkyl, (C1-C10)alkenyl, (C1-C10)alkynyl, (C3-C8)cycloalkyl, aryl, amino, (Q-C^alkoxy, (C1-C10)alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy; or - -
R1 is selected from the group comprising an amino acid, a di- or tri-peptide, an oligopeptide, a polypeptide or an ester thereof.
2. A compound of claim 1 wherein R1 is selected from an amino acid, a di- or tri- peptide, an oligopeptide, a polypeptide, or an ester thereof.
3. A compound of claim 1 or claim 2 wherein the amino acid is an L-amino acid or the di- or tri-peptide, oligopeptide or polypeptide comprises L-amino acids.
A compound of claim 3 wherein the amino acid, di- or tri-peptide, oligopeptide or polypeptide comprises amino acids selected from the group comprising glycine, L-alanine, β-alanine, L-valine, L-leucine, L-isoleucine, L-alloisoleucine, L- phenylalanine, L-proline, L-serine, L-homoserine, L-threonine, L-allothreonine5 L-glutamic acid, L-methionine, L-asparagine, L-aspartic acid, L-glutamine, L- histidine, L-lysine, L-arginine, L-tyrosine and L-tryptophan.
5. A compound of claim 3 wherein the di-peptide is selected from the group comprising L-alanyl-L-valine, L-valyl-L-alanine, L-valyl-L-threonine, L- threonyl-L-valine, L-alanyl-L-threonine, and L-threonyl-L-alanine.
6. A compound of Formula IA:
Figure imgf000042_0001
or an agriculturally acceptable salt thereof, wherein R2 is hydrogen or (C1-Ci0) alkyl optionally substituted with one or more of (Ci- Cio) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C3-C8) cycloalkyl, aryl, amino, (C1-C10) alkoxy, (C1-CiO) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
7. A compound of Formula IB :
Figure imgf000043_0001
or an agriculturally acceptable salt thereof, wherein each R is independently selected from hydrogen or (C1-C10) alkyl optionally substituted with one or more of (Ci-C10) alkyl, (C1-C10) alkenyl, (C1-Ci0) alkynyl, (C3-C8) cycloalkyl, aryl, amino, (Ci-Ci0) alkoxy, (C1-C10) alkanoyl, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
8. A compound of claim 6 or claim 7 wherein each R2 is independently selected from the group comprising (C1-4) alkyl, optionally substituted with one or more of amino, hydroxy, nitro, nitroso, cyano, halogen, thiol or carboxy.
9. A compound of claim 8 wherein each R is independently selected from the group comprising -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph,
-CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CO2H and -CH2CH2CO2H.
10. A compound of any one of the preceding claims which is of the L- configuration at the 5- position of the pyrrolidine ring.
11. A compound selected from the group comprising:
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-glycine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-alanine), 2-imino-3 -methylenepyrrolidine-5 -L-(carbonyl-β-alanine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L- valine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-leucine), 2-imino-3 -methylenepyrrolidine-5 -L-(carbonyl-L-phenylalanine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-isoleucine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-alloisoleucine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-proline),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-serine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-homoserine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-threonine), 2-imino-3 -methylenepyrrolidine- 5 -L-(carbonyl-L-allothreonine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-glutamic acid),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-methionine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-asparagine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-aspartic acid), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-glutamine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-histidine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-lysine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-arginme), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-tyrosine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-typtophan), 2-imino-3 -methylenepyrrolidine-5 -L-(carbonyl-L- valyl-L-alanine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-alanyl-L-valine), -2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-valyl-L-threonine)5 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-threonyl-L-valine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-alanyl-L-threonine), and 2-imino-3-methyleiiepyrrolidine-5-L-(carbonyl-L-threonyl-L-valine).
12. A compound selected from the group comprising: 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-glycine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-alanine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-β-alanine), 2-imino-3 -methylenepyrrolidine-S-L-Ccarbonyl-L- valine),
2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-leucine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-phenylalanine), 2-imino-3-methylenepyrrolidine-5-L-(carbonyl-L-proline), 2-imino-3 -methylenepyrrolidine-5-L-(carbonyl-L-threonine), and 2-imino-3-metb.ylenepyrrolidine-5-L-(carbonyl-L-valyl-L-alanine).
13. An antibiotic composition comprising a compound of any one of claims 1-12 or an agriculturally acceptable salt thereof and an agriculturally acceptable carrier.
14. A composition of claim 13 wherein the composition further comprises one or more of a second antibiotic, a pesticide, an insecticide or a fungicide.
15. A composition of claim 14 wherein the second antibiotic is selected from the group comprising streptomycin, oxytetracycline and copper spray or combinations thereof.
16. A composition of any one of claims 13 to 15 wherein the composition is formulated as a powder, as granules, a paste, a liquid, a sprayable liquid or an aerosol.
17. A method of treating or preventing a bacterial infection comprising administering a compound of any one of claims 1 to 12 or an agriculturally acceptable salt thereof or a composition of any one of claims 13 to 16 to a subject in need thereof.
18. A method of claim 17 wherein the bacterial infection is an Erwinia amylovora infection. - -
19. A method of treating or preventing an Erwinia amylovora infection comprising administering a compound of any one of claims 1 to 12 or an agriculturally acceptable salt thereof or a composition of any one of claims 13 to 16 to a subject in need thereof.
20. A use of a compound of any one of claims 1 to 12 or an agriculturally acceptable salt therefore or a composition of any one of claims 13 to 16 in the manufacture of a formulation for the treatment or prevention of bacterial infection.
21. A use of claim 20 wherein the bacterial infection is an Erwinia amylovora infection.
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MITCHELL R.E. AND TEH K.L.: 'Antibacterial iminopyrrolidines from Burkholderia plantarii, a bacterial pathogen of rice' ORG. BIOMOL. CHEM. vol. 3, no. 19, 07 November 2005, pages 3540 - 3543 *
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CN108651468B (en) * 2018-06-15 2020-12-29 西北农林科技大学 Pesticide composition containing L-pyroglutamic acid, soluble powder, soluble liquid and application

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