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WO2005034626A1 - Compositions insectifuges comprenant du dihydronepetalactone - Google Patents

Compositions insectifuges comprenant du dihydronepetalactone Download PDF

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Publication number
WO2005034626A1
WO2005034626A1 PCT/US2003/029344 US0329344W WO2005034626A1 WO 2005034626 A1 WO2005034626 A1 WO 2005034626A1 US 0329344 W US0329344 W US 0329344W WO 2005034626 A1 WO2005034626 A1 WO 2005034626A1
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WO
WIPO (PCT)
Prior art keywords
dihydronepetalactone
composition
insects
dhn
repellent
Prior art date
Application number
PCT/US2003/029344
Other languages
English (en)
Inventor
David L. Hallahan
Leo E. Manzer
Original Assignee
E.I. Du Pont De Nemours And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by E.I. Du Pont De Nemours And Company filed Critical E.I. Du Pont De Nemours And Company
Priority to CN200810129703.9A priority Critical patent/CN101396020B/zh
Priority to CNA038270951A priority patent/CN1838881A/zh
Priority to AU2003270748A priority patent/AU2003270748A1/en
Priority to EP03752458A priority patent/EP1681925A4/fr
Priority to PCT/US2003/029344 priority patent/WO2005034626A1/fr
Priority to CA2538363A priority patent/CA2538363C/fr
Priority to BRPI0318501-0A priority patent/BR0318501A/pt
Priority to JP2005509534A priority patent/JP2007521240A/ja
Publication of WO2005034626A1 publication Critical patent/WO2005034626A1/fr
Priority to IL173903A priority patent/IL173903A0/en

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Classifications

    • 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
    • A01N43/14—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 six-membered rings
    • A01N43/16—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 six-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/02—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings containing insect repellants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings

Definitions

  • the present invention relates to the field of insect repellency, and the use of dihydronepetalactone stereoisomers generally as repellent materials.
  • Repellent substances generally cause insects to be driven away from, or to reject, otherwise insect-acceptable food sources or habitats. At least 85% of insect repellent sales in the United States are for insect repellents containing ⁇ , ⁇ /-diethyl-m-toluamide (DEET) as their primary active ingredient. Further, Consumer Reports tests indicated that products with the highest concentration of DEET lasted the longest against mosquitoes. Although an effective repellent, DEET possesses an unpleasant odor and imparts a greasy feeling to the skin. Furthermore, although it has recently been re-registered for use in the U.S.
  • DEET ⁇ , ⁇ /-diethyl-m-toluamide
  • DEET dissolves or mars many plastics and painted surfaces; and 4) DEET may plasticize some inert ingredients typically used in topical formulations which leads to lower user acceptability.
  • DEET-free products with repellent activity are finding favor with consumers.
  • demand for compositions containing natural products is increasing.
  • New candidate repellents should possess a desirable balance of properties, and will preferably reach or exceed the positive properties of DEET, and/or not suffer from its negative properties (Hollon, T. (2003) The Principle June 16 2003, 25-26).
  • Potential substitutes for DEET should desirably then exhibit a combination of excellent repellency, high residual activity and low toxicity to humans (or pets) and the environment.
  • repellent compounds that can be obtained from, or synthesized from, natural plant materials and that are pleasant to use. Any candidate to replace DEET should exhibit repellency to a wide variety of insects considered noxious by humans, including, but not limited to, biting insects, wood-boring insects, noxious insects, household pests, and the like.
  • Citronella oil known for its general repellence towards insects, is obtained from the graminaceous plants Cymbopogon winterianus and C. nardus.
  • plants used as sources of fragrant chemicals include Melissa officinalis (Melissa), Perilla frutescens (Perilla), Posostemon cablin (Patchouli) and various Lavandula spp. (Lavender). All of these examples of plants yielding oils of value are members of the Labiatae (Lamiaceae) family. Plants of the genus Nepeta (catmints) are also members of this family, and produce an essential oil that is a minor item of commerce. This oil is very rich in a class of monoterpenoid compounds known as iridoids [Inouye, H. Iridoids.
  • U.S. Patent 4,663,346 discloses insect repellants with compositions containing bicyclic iridoid lactones (e.g., iridomyrmecin). Further, U.S. Patent 4,869,896 discloses use of these bicyclic iridoid lactone compositions in potentiated insect repellent mixtures with DEET.
  • U.S. Patent 6,524,605 discloses insect repellents comprising nepetalactones derived from the catmint plant N. cataria, and the differential efficacy of nepetalactone stereoisomers as insect repellents.
  • compositions containing dihydronepetalactones are known to provide insecticidal effects.
  • DBN dihydronepetalactones
  • a study of the composition of the secretion from anal glands of the ant Iridomyrmex nitidus showed that isodihydronepetalactone was present in appreciable amounts, together with isoiridomyrmecin (Cavill, G.W.K., and D.V. Clark. (1967) J. Insect Physiol. 13:131-135). Isoiridomyrmecin was known at the time to possess good 'knockdown' insecticidal activity.
  • Cavill et al. (1982) discloses the presence of dihydronepetalactones in the insect repellent secretion of an ant but the compound iridodial is said to be the principal repellent constituent.
  • One embodiment of this invention is an insect repellent composition of matter that is or includes a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula:
  • Another embodiment of this invention is a composition of matter that repels insects when applied to a human, animal or inanimate host that includes a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula set forth above.
  • a further embodiment of this invention is a composition of matter that repels one or more insects selected from the group consisting of bees, black flies, chiggers, fleas, green head flies, mosquitoes, stable flies, ticks, wasps, wood-boring insects, houseflies, cockroaches, lice, roaches, wood lice, flour and bean beetles, dust mites, moths, silverfish, and weevils, that includes a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula set forth above.
  • Yet another embodiment of this invention is a composition of matter that has a mean complete protection time that is statistically indistinguishable from that of ⁇ /,/V-diethyl-m-toluamide that includes a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula set forth above.
  • Yet another embodiment of this invention is an insect repellent composition of matter that includes, in an amount of about 0.001% to about 80% by weight, a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula set forth above.
  • Yet another embodiment of this invention is a process for fabricating an insect repellent composition or an insect repellent article of manufacture by providing as the composition or article, or incorporating into the composition or article, a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula set forth above.
  • Yet another embodiment of this invention is a method of imparting, augmenting or enhancing the insect repellent effect of an article, by incorporating into the article a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula set forth above.
  • Yet another embodiment of this invention is a method of repelling insects from a human, animal or inanimate host by exposing the insects to a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula set forth above.
  • the insects repelled may be, for example, one or more of mosquitoes, stable flies and ticks.
  • Yet another embodiment of this invention is the use of a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula above to repel insects from a human, animal or inanimate host.
  • the insects repelled may be, for example, one or more of mosquitoes, stable flies and ticks.
  • Yet another embodiment of this invention is a process for the production of a dihydronepetalactone of formula (XVI) by hydrogenating a nepetalactone of formula (XV) according to the following scheme:
  • DHN dihydronepetalactones perform well as a new class of effective insect repellent compounds without the disadvantageous properties characteristic of prior-art compositions.
  • DHN When used as an insect repellent, DHN prevents damage to plants and animals, including humans, orto articles of manufacture, by making insect food sources or living conditions unattractive or offensive.
  • Figure 1 shows the chemical structures of the naturally-occurring iridoid (methylcyclopentanoid) nepetalactones.
  • Figure 2 shows the total ion chromatograms from combined gas chromatography/mass spectrometry (GC-MS) analysis of a distilled nepetalactone-enriched fraction from commercially-available catmint oil (A), together with that of the material produced from this fraction by hydrogenation (B).
  • Figure 3 shows the mass spectra of the major constituents of the nepetalactone-enriched fraction (A) and the hydrogenated material (B) identified by GC-MS analysis in Fig. 2.
  • GC-MS gas chromatography/mass spectrometry
  • Figure 4 shows the ⁇ C NMR analysis performed on a distilled nepetalactone-enriched fraction of commercially-available catmint oil.
  • Figure 5 shows the ⁇ 3 C NMR spectrum obtained from analysis of the dihydronepetalactones produced by hydrogenation of a distilled nepetalactone-enriched fraction of commercially-available catmint oil
  • Figure 6 shows the distribution of probing density with time, during tests of various repellents against female Aedes aegypti mosquitoes in an in vitro repellency test.
  • Figure 7 shows the 13 C NMR analysis of trans, c/s-nepetalactone.
  • Figure 8 shows the 13 C NMR analysis of dihydronepetalactones derived from hydrogenation of frar?s,c/s-nepetalactone.
  • Figure 9 shows the distribution of probing density with time, during tests of dihydronepetalactones derived from hydrogenation of trans,cis- nepetalactone against female Aedes aegypti mosquitoes in an in vitro repellency test.
  • Figure 10 shows the distribution of landing density with time, during tests of various repellents against stable flies (Stomoxys calcitrans) in an in vitro repellency test.
  • Figure 11 shows the distribution of probing density with time, during tests of various repellents against female anopheles mosquitoes (Anopheles albimanus) in an in vitro repellency test.
  • Dihydronepetalactones are known as minor constituents of the essential oils of several labiate plants of the genus Nepeta (Regnier, F.E., et al. (1967) Phytochemistry 6: 1281 -1289; DePooter, H.L., et al. (1988) Flavour and Fragrance Journal 3:155-159; Handjieva, N.V. and S.S. Popov (1996) J. Essential Oil Res. 8:639-643). Dihydronepetalactones are defined by Formula 1 :
  • dihydronepetalactone will be understood to encompass any and all dihydronepetalactone stereoisomers and mixtures thereof, unless a particular isomer or mixture is specified.
  • dihydronepetalactone is prepared from a naturally occurring source of nepetalactone some variation in molar concentration of stereoisomers is expected. Preparation from a naturally occurring source is, however, a preferred method of preparation.
  • Regnier et al, op.cit. discloses the preparation of DHN from nepetalactone by the catalyzed hydrogenation of nepetalactone isolated from the essential oils of plants of the genus Nepeta (catmints).
  • One preferred and convenient method for synthesis of dihydronepetalactone is thus by hydrogenation of nepetalactone obtained in relatively pure form from the essential oils isolated by various means from plants of the genus Nepeta (catmints). Catalysts such as platinum oxide and palladium supported on strontium carbonate give dihydronepalactone in 24-90% yields (Regnier et al. op.cit).
  • Catalysts such as platinum oxide and palladium supported on strontium carbonate give dihydronepalactone in 24-90% yields (Regnier et al. op.cit).
  • a particularly preferred method is described in U.S. Application SN 10/405,444, filed April 2, 2003, which is incorporated in its entirety as a part hereof for all purposes.
  • Methods for isolation of essential oils are well known in the art, and examples of methodology for oil extraction include (but are not limited to) steam distillation, organic solvent extraction, microwave-assisted organic solvent extraction, supercritical fluid extraction, mechanical extraction and enfleurage (initial cold extraction into fats followed by organic solvent extraction).
  • DHN prepared from oil derived from any Nepeta species will necessarily be a mixture of stereoisomers thereof, the constitution of that mixture depending upon the particular species of Nepeta from which it is derived.
  • four chiral centers are present within the methylcyclopentanoid backbone of the nepetalactone at carbons 4, 4a, 7 and 7a as shown: 05 0
  • a total of eight pairs of dihydronepetalactone enantiomers are possible after hydrogenation of nepetalactone.
  • the naturally occurring stereoisomers described thus far are (9S)- dihydronepetalactones.
  • Preferred repellent materials in accordance with the present invention include a mixture of any or all of the possible stereoisomers of dihydronepetalactone. More preferred repellent materials include a mixture of (9S)-dihydronepetalactones. Most preferred are (9S)-dihydronepetalactone stereoisomers derived from (7S)- nepetalactones.
  • the predominant stereoisomers produced by N. cataria (cis,trans and trans,cis-) are preferred.
  • the resulting mixture of isomer products may be separated by a conventional method (e.g., preparative liquid chromatography) to yield each highly purified pair of dihydronepetalactone diastereomers. This permits the use of various different diastereomers as are found to be most effective against particular insects.
  • nepetalactone isomer It is preferable to isolate a specific nepetalactone isomer from a plant to convert to its corresponding pair of diastereomers by hydrogenation.
  • intra-species variation is also known to exist. Plants of a given species may produce oils with different compositions depending on the conditions of their growth or growth stage at harvest. In fact variation in oil composition independent of growth conditions or growth stage at harvest has been found in Nepeta racemosa, (Clark, L.J., et al. op.cit). Plants of a single species exhibiting different oil compositions are termed chemotypes.
  • Nepeta racemosa chemotypes exhibiting marked differences in the proportion of different nepetalactone stereoisomers exist.
  • the preferred process for producing specific dihydronepetalactone enantiomers is hydrogenation of an oil from a Nepeta chemotype known to contain specific nepetalactone stereoisomers.
  • An insect as repelled by the composition of this invention includes any member of a large group of invertebrate animals characterized, in the adult state (non-adult insect states include larva and pupa), by division of the body into head, thorax, and abdomen, three pairs of legs, and, often (but not always) two pairs of membranous wings.
  • This definition therefore includes but is not limited to a variety of biting insects (e.g., ants, bees, black flies, chiggers, fleas, green head flies, mosquitoes, stable flies, ticks, wasps), wood-boring insects (e.g., termites), noxious insects (e.g., houseflies, cockroaches, lice, roaches, wood lice), and household pests (e.g., flour and bean beetles, dust mites, moths, silverfish, weevils).
  • biting insects e.g., ants, bees, black flies, chiggers, fleas, green head flies, mosquitoes, stable flies, ticks, wasps
  • wood-boring insects e.g., termites
  • noxious insects e.g., houseflies, cockroaches, lice, roaches, wood lice
  • household pests e.g.,
  • the DHN compositions of the present invention are effective insect repellents against a wide spectra of common insect pests, such as those mentinoed above and also including biting insects, wood-boring insects, noxious insects, and household pests, most particularly mosquitoes, stable flies, and ticks such as deer ticks.
  • the DHN compositions of this invention are effective to repel any one or more of the members of the group consisting of bees, black flies, chiggers, fleas, green head flies, mosquitoes, stable flies, ticks, wasps, wood-boring insects, houseflies, cockroaches, lice, roaches, wood lice, flour and bean beetles, dust mites, moths, silverfish, and weevils.
  • the insects repelled may also, however, be one or more those that are selected from a subgroup of the foregoing formed by omitting any one or more members from the whole group as set forth in the list in the first sentence of this paragraph.
  • the repelled insect(s) may in such instance not only be those selected from any subgroup of any size that may be formed from the whole group as set forth in the list above, but may exclude the members that have been omitted from the whole group to form the subgroup.
  • the subgroup formed by omitting various members from the whole group in the list above may, moreover, be an individual member of the whole group such that the repelled insect excludes all other members of the whole group.
  • a host is any plant or animal affected by insects.
  • hosts are considered to be insect-acceptable food sources or insect-acceptable habitats.
  • Hosts can be animals (including without limitation pets and/or other domesticated animals), humans, plants or a so-called "insect susceptible article", encompassing any inanimate article which is affected by insects. This may include buildings, furniture, and the like.
  • DHN is incorporated into a host such as an insect susceptible article to produce an insect repellent article for the purpose either of deterring insects from landing on the article, or from occupying the air surrounding the article.
  • Contemplated in this embodiment are those instances in which an article may already exhibit some degree of insect repellency prior to treatment with a DHN composition of the invention. In such instances it is contemplated that the insect repellency of the article will be enhanced by the application of the DHN composition of the invention.
  • An insect repellent is any compound or composition which deters insects from a host. It will be appreciated that such usage makes no distinction among compounds that have highly ephemeral effects as compared to those that exhibit long term beneficial effects, and/or those that require very high surface concentrations before there is an observable effect on insect behavior.
  • the term "insect repellent” thus indicates a compound or composition conferring on a host protection from insects when compared to no treatment at all. "Protection” desirably results in a statistically significant reduction in numbers of insects, and may, for example, be usefully determined by measuring mean complete protection time ("CPT”) in tests in which insect behavior toward treated animals, including humans, and treated inanimate surfaces is observed.
  • CPT mean complete protection time
  • Mean CPT refers to the mean length of time over repetitions of tests in which the time before the first landing, probing or biting (in the case of a biting insect) or crawling (in the case of a crawling insect such as a tick or chigger) on a treated surface is observed [see e.g. US EPA Office of Prevention, Pesticides and Toxic Substances product performance test guidelines OPPTS 810.3700; and Fradin, M.S., Day, J.F. (2002) New England Journal of Medicine 347, 13-18].
  • the insect repellent composition hereof has a mean CPT that is statistically indistinguishable from that of DEET.
  • test conditions including amounts of active ingredients
  • the test conditions must of course be identical, or, if not identical, must differ only in ways that do not prevent utilization of the results for the purposes of documenting the existence of the condition described.
  • DHN compared favorably in performance with DEET.
  • DHN is advantageously prepared from naturally occurring nepetalactone derived from plants whereas DEET, and many other insect repellents, are not prepared from natural sources - an important consumer consideration when choosing an effective repellent. Preparation from natural sources also offers the potential for low production costs.
  • DHN provides a considerable improvement over the odor of DEET while exhibiting effective insect repellency.
  • the DHN compounds and compositions of this invention possess a pleasant fragrance.
  • the fragrance notes of the DHN materials make them useful in imparting, altering, augmenting or enhancing the overall olfactory component of an insect repellent composition or article, for example, by utilizing or moderating the olfactory reaction contributed by one or more other ingredients in the composition.
  • the DHN compositions of the invention may be utilized to either mask or modify the odor contributed by other ingredients in the formulation of the final repellent composition or article, and/or to enhance consumer appeal of a product by imparting a characteristic perfume or aroma.
  • DHN insect repellent
  • Many compounds known in the art to exhibit insect repellency do so, however, only in relatively concentrated form. See, for example, McGovern et al in U.S. 4,416, 881 , which discloses the use of repellent concentrations of 6.25-25%.
  • concentrations of DEET much below 1% require repeated application to achieve an effective surface concentration, yet concentrations above 30% result in excessive surface concentration, which is both wasteful and conducive to the production of undesirable side effects.
  • a further advantage of this invention is consequently that DHN not only provides effective insect repellency at concentrations similar to those employed for DEET, DHN may be employed at concentrations up to and including neat DHN (i.e. the composition hereof may, if desired, contain 100% by weight DHN).
  • the property of effective repellency in DHN provides many options for economical utilization of the DHN active ingredient over a wide range of levels of concentration.
  • DHN is incorporated in effective amounts into a composition suitable for application to a host plant or animal, preferably to human skin.
  • Suitable compositions include DHN and a vehicle, preferably alcohol such as iso-propyl alcohol, a lotion such as numerous skin creams such as are known in the art, or a silicaceous clay.
  • the DHN is present in the insect repellent composition of the invention at a concentration of about 0.1 % to 30% by weight, preferably about 0.5% to 20% by weight, and most preferably about 1 % to 15% by weight.
  • the evaporation rate of the active ingredient from the host's skin or the treated article must be sufficiently high to provide a vapor density which has the desired effect on the target insects.
  • a balance must be struck between evaporation rate and the desired duration of the insect repellent effect - too high an evaporation rate will deplete the insect repellent on the surface causing a loss in efficacy.
  • Numerous extrinsic factors affect the evaporation rate, such as the ambient temperature, the temperature of the treated surface, and the presence or absence of air movement.
  • the composition of this invention has a skin surface evaporation rate of at least a minimum effective evaporation rate, and preferably has a skin surface evaporation rate of at least a minimum effective evaporation rate for at least five hours.
  • penetration into and through the skin is an undesirable mode of loss of compound from the skin surface.
  • insect repellents are known to be absorbed into human skin, making potential toxicity a concern on the one hand, and clearly removing the absorbed amount of repellent from insect repellent activity. Similar considerations must be made for insect repellent articles. While DHN provides effective insect repellency under typical conditions of use, it may under some circumstances be desirable to reduce the rate of evaporation thereof.
  • a variety of strategies may be employed to reduce the evaporation rate of DHN if so desired.
  • one method is to combine the DHN with a polymer or other inert ingredient, forcing the DHN to migrate through the mixture to the surface thereof before it can evaporate.
  • the active ingredient is micro- encapsulated to control rates of loss from the host's skin surface or insect repellent article.
  • a precursor molecule may be prepared, which slowly disintegrates on the skin surface or insect repellent article to release the active ingredient.
  • release of the active ingredient may be, for example, by sub-micron encapsulation, in which the active ingredient is encapsulated (surrounded) within a skin nourishing protein just the way air is captured within a balloon.
  • the protein may be used at, for example, a 20% concentration.
  • An application of repellent contains many of these protein capsules that are suspended in either a water-based lotion, or water for spray application. After contact with skin the protein capsules begin to breakdown releasing the encapsulated dihydronepetalactone. The process continues as each microscopic capsule is depleted then replaced in succession by a new capsule that contacts the skin and releases its active ingredient. The process may take up to 24 hours for one application.
  • a variety of carriers or diluents for the above-disclosed dihydronepetalactones can be used.
  • the carrier allows the formulation to be adjusted to an effective concentration of repellant molecules.
  • the repellant molecules are mixed in a dermatologically acceptable carrier.
  • the carrier may further provide water repellency, prevent skin irritation, and/or soothe and condition skin.
  • Factors to consider when selecting a carrier(s) for any formulation of insect repellent include commercial availability, cost, repellency, evaporation rate, odor, and stability. Some carriers can themselves have repellent properties.
  • the carrier moreover, should preferably also be one that will not be harmful to the environment.
  • Suitable for the present invention are one or more commercially available organic and inorganic liquid, solid, or semi- solid carriers or carrier formuiations known in the art for formulating insect repellent products.
  • the carrier may include silicone, petrolatum, or lanolin.
  • organic liquid carriers include liquid aliphatic hydrocarbons (e.g., pentane, hexane, heptane, nonane, decane and their analogs) and liquid aromatic hydrocarbons.
  • other liquid hydrocarbons include oils produced by the distillation of coal and the distillation of various types and grades of petrochemical stocks, including kerosene oils that are obtained by fractional distillation of petroleum.
  • Other petroleum oils include those generally referred to as agricultural spray oils (e.g., the so-called light and medium spray oils, consisting of middle fractions in the distillation of petroleum and which are only slightly volatile). Such oils are usually highly refined and may contain only minute amounts of unsaturated compounds. Such oils, moreover, are generally paraffin oils and accordingly can be emulsified with water and an emulsifier, diluted to lower concentrations, and used as sprays. Tall oils, obtained from sulfate digestion of wood pulp, like the paraffin oils, can similarly be used.
  • Other organic liquid carriers can include liquid terpene hydrocarbons and terpene alcohols such as alpha-pinene, dipentene, terpineol, and the like.
  • carrier examples include aliphatic and aromatic alcohols, esters, aldehydes, ketones, mineral oil, higher alcohols, finely divided organic and inorganic solid materials.
  • the carrier can contain conventional emulsifying agents which can be used for causing the dihydronepetalactone compounds to be dispersed in, and diluted with, water for end-use application.
  • Aliphatic monohydric alcohols include methyl, ethyl, normal-propyl, isopropyl, normal-butyl, sec-butyl, and tert-butyl alcohols.
  • Suitable alcohols include glycols (such as ethylene and propylene glycol) and pinacols.
  • Suitable polyhydroxy alcohols include glycerol, arabitol, erythritol, sorbitol, and the like.
  • suitable cyclic alcohols include cyclopentyl and cyclohexyl alcohols.
  • stabilizers e.g., tert-butyl sulfinyl dimethyl dithiocarbonate
  • tert-butyl sulfinyl dimethyl dithiocarbonate can be used in conjunction with, or as a component of, the carrier or carriers comprising the compositions of the present invention.
  • Solid carriers that can be used in the compositions of the present invention include finely divided organic and inorganic solid materials.
  • Suitable finely divided solid inorganic carriers include siliceous minerals such as synthetic and natural clay, bentonite, attapulgite, fuller's earth, diatomaceous earth, kaolin, mica, talc, finely divided quartz, and the like, as well as synthetically prepared siliceous materials, such as silica aerogels and precipitated and fume silicas.
  • Examples of finely divided solid organic materials include cellulose, sawdust, synthetic organic polymers, and the like.
  • semi-solid or colloidal carriers examples include waxy solids, gels (such as petroleum jelly), lanolin, and the like, and mixtures of well-known liquid and solid substances which can provide semi-solid carrier products, for providing effective repellency within the scope of the instant invention.
  • Insect repellent compositions of the present invention containing the dihydronepetalactones may also contain adjuvants known in the art of personal care product formulations, such as thickeners, buffering agents, chelating agents, preservatives, fragrances, antioxidants, gelling agents, stabilizers, surfactants, emolients, coloring agents, aloe vera, waxes, other penetration enhancers and mixtures thereof, and therapeutically or cosmetically active agents.
  • adjuvants known in the art of personal care product formulations, such as thickeners, buffering agents, chelating agents, preservatives, fragrances, antioxidants, gelling agents, stabilizers, surfactants, emolients, coloring agents, aloe vera, waxes, other penetration enhancers and mixtures thereof, and therapeutically or cosmetically active agents.
  • Therapeutically or cosmetically active ingredients useful in the compositions of the invention include fungicides, sunscreening agents, sunblocking agents, vitamins, tanning agents, plant extracts, anti- inflammatory agents, anti-oxidants, radical scavenging agents, retinoids, alpha-hydroxy acids, emollients, antiseptics, antibiotics, antibacterial agents or antihistamines, and may be present in an amount effective for achieving the therapeutic or cosmetic result desired.
  • composition of this invention may also be blended with a non-dihydronepetalactone insect repellent, such as those included in the consisting of: benzil, benzyl benzoate, 2,3,4,5-bis(butyl-2-ene) tetrahydrofurfural, butoxypolypropylene glycol, N-butylacetanilide, normal- butyl-6,6-dimethyl-5,6-dihydro-1 ,4-pyrone-2-carboxylate, dibutyl adipate, dibutyl phthalate, di-normal-butyl succinate, N,N-diethyl-meta-toluamide, dimethyl carbate, dimethyl phthalate, 2-ethyl-2-butyl-1,3-propanediol, 2- ethyl-1 ,3-hexanediol, di-normal-propyl isocinchomeronate, 2- phenylcyclohexanol, p-
  • the DHN composition of the invention may include any number of the above recited adjuvants in order to meet the requirements of any particular application. The specific proportions of each ingredient will similarly be dictated by the requirements of the application. However, the compositions of the invention should preferably comprise at least about 0.001 % by weight DHN, or about 0.001% to about 80% by weight DHN, or about 0.01% to about 30% by weight of DHN, or about ⁇ .1% to about 30% by weight of DHN, preferably about 0.5% to about 20% by weight, most preferably about 1 % to about 15% by weight. In general, the composition of the repellent should contain sufficient amounts of active insect repellant material to be efficacious in repelling the insect from the host over a prolonged period of time (preferably, for a period of at least several hours).
  • Dihydronepetalactones may be utilized in the present invention in the form of individual diastereomers or a mixture of various diastereomers, or combined with other insect repellents.
  • DHN may be employed at any concentration level suitable for the particular need, including neat.
  • the amount of DHN in an insect repellent composition or repellent article in accordance with the present invention will generally not exceed about 80% by weight.
  • compositions of the invention may be formulated and packaged so as to deliver the product in a variety of forms including as a solution, suspension, cream, ointment, gel, film or spray, depending on the preferred method of use.
  • the carrier may be an aerosol composition adapted to disperse the dihydronepetalactone into the atmosphere by means of a compressed gas.
  • Desirable properties of a topical insect repellent article include low toxicity, resistance to loss by water immersion or sweating, low or no odor or at least a pleasant odor, ease of application, and rapid formation of a dry tack-free surface film on the host's skin.
  • the formulation for a topical insect repellent article should permit insect-infested animals (e.g., dogs with fleas, poultry with lice, cows with ticks, and humans) to be treated with an insect repellent composition of the present invention by contacting the skin, fur or feathers of such an animal with an effective amount of the repellent article for repelling the insect from the animal host.
  • insect-infested animals e.g., dogs with fleas, poultry with lice, cows with ticks, and humans
  • an insect repellent composition of the present invention by contacting the skin, fur or feathers of such an animal with an effective amount of the repellent article for repelling the insect from the animal host.
  • dispersing the article into the air or dispersing the composition as a liquid mist or fine dust will permit the repellent composition to fall on the desired host surfaces.
  • directly spreading of liquid/semi-solid/solid repellent article on the host is an effective method of contacting the surface of the host with an effective amount of the repellent composition.
  • a further embodiment of the present invention is the incorporation of DHN into products which are not primarily associated with insect repellency in order to provide an effective degree of repellency thereto.
  • products which are not primarily associated with insect repellency in order to provide an effective degree of repellency thereto.
  • foam products e.g., shaving foams
  • makeup, deodorants shampoo, hair lacquers/hair rinses
  • personal soap compositions e.g., hand soaps and bath/shower soaps.
  • Further contemplated in the present invention are those embodiments wherein DHN provides effective insect repellency in a variety of articles that are susceptible to attack by insects by incorporation therein.
  • the articles are outdoors, but need not be.
  • the articles contemplated are included, but not limited to, air fresheners, candles, various scented articles, fibers, sheets, textile goods, paper, paint, ink, clay, wood, furniture (e.g., for patios and decks), carpets, sanitary goods, plastics, polymers, and the like.
  • the dihydronepetalactone is combined with a polymer to provide moldability, reduction of evaporation rate, and controlled release.
  • a polymer may be biodegradeable Suitable polymers include but are not limited to high density polyethylene, low density polyethylene, biodegradable thermoplastic polyurethanes, biodegradable ethylene polymers, and poly(epsilon caprolactone) homopolymers and compositions containing the same, as disclosed for example in U.S. 4,496,467, U.S. 4,469,613 and U.S. 4,548,764.
  • Preferred biodegradeable polymers include DuPont Biomax® biodegradeable polyester and poly-L-lactide.
  • This invention also involves a process for manufacturing DHN in which a palladium catalyst is used.
  • catalyst refers to a substance that affects the rate of a chemical reaction (but not the reaction equilibrium) and emerges from the process chemically unchanged.
  • the process for the production of a dihydronepetalactone of formula (XVI) involves hydrogenating a nepetalactone of formula (XV) according to the following scheme:
  • promoter is a compound that is added to enhance the physical or chemical function of a catalyst.
  • a chemical promoter generally augments the activity of a catalyst and may be incorporated into the catalyst during any step in the chemical processing of the catalyst constituent.
  • the chemical promoter generally enhances the physical or chemical function of the catalyst agent, but can also be added to retard undesirable side reactions.
  • a "metal promoter” refers to a metallic compound that is added to enhance the physical or chemical function of a catalyst. Hydrogenation of nepetalactone is effected in the presence of a suitable active metal hydrogenation catalyst.
  • the metal catalyst used in the process of this invention may be used as a supported or as an unsupported catalyst.
  • a supported catalyst is one in which the active catalyst agent is deposited on a support material by spraying, soaking or physical mixing, followed by drying, calcination, and if necessary, activation through methods such as reduction or oxidation.
  • Materials frequently used as support are porous solids with high total surface areas (external and internal) which can provide high concentrations of active sites per unit weight of catalyst.
  • the catalyst support may enhance the function of the catalyst agent; and supported catalysts are generally preferred because the active metal catalyst is used more efficiently.
  • a catalyst which is not supported on a catalyst support material is an unsupported catalyst.
  • the catalyst support can be any solid, inert substance including, but not limited to, oxides such as silica, alumina, titania, calcium carbonate, barium sulfate, and carbons.
  • the catalyst support can be in the form of powder, granules, pellets, or the like.
  • a preferred support material of the present invention is selected from the group consisting of carbon, alumina, silica, silica-alumina, titania, titania-alumina, titania-silica, barium, calcium, compounds thereof and combinations thereof.
  • Suitable supports include carbon, Si ⁇ 2, CaCO3, BaSO4 and AI2O3.
  • supported catalytic metals may have the same supporting material or different supporting materials.
  • a more preferred support is carbon.
  • Further preferred supports are those, particularly carbon, that have a surface area greater than 100-200 m ⁇ /g. Further preferred supports are those, particularly carbon, that have a surface area of at least 300 m 2 /g.
  • Carbons which may be used in this invention include those sold under the following trademarks: Bameby & SutcliffeTM, DarcoTM, NucharTM, Columbia JXNTM, Columbia LCKTM, Calgon PCBTM, Calgon BPLTM, WestvacoTM, NoritTM and Barnaby Cheny NBTM.
  • the carbon can also be commercially available carbon such as Calsicat C, Sibunit C, or Calgon C (commercially available under the registered trademark Centaur®).
  • Preferred combinations of catalytic metal and support system include palladium on carbon such as in ESCAT#142 catalyst (Englehart). While the weight percent of catalyst on the support is not critical, it will be appreciated that the higher the weight percent of metal, the faster the reaction.
  • a preferred content range of the metal in a supported catalyst is from about 0.1 wt% to about 20 wt% of the whole of the supported catalyst (catalyst weight plus the support weight).
  • a more preferred catalytic metal content range is from about 1 wt% to about 10 wt% by weight of the whole of the supported catalyst.
  • a further preferred catalytic metal content range is from about 3 wt% to about 7 wt% by weight of the whole of the supported catalyst.
  • a metal promoter may be used with the catalytic metal in the method of the present invention.
  • Suitable metal promoters include: 1) those elements from groups 1 and 2 of the periodic table; 2) tin, copper, gold, silver, and combinations thereof; and 3) combinations of group 8 metals of the periodic table in lesser amounts.
  • Temperature, solvent, catalyst, pressure and mixing rate are all parameters that affect the hydrogenation. The relationships among these parameters may be adjusted to effect the desired conversion, reaction rate, and selectivity in the reaction of the process.
  • the preferred temperature is from about 25°C to 250°C, more preferably from about 50°C to about 150°C, and most preferred from about 50°C to 100°C.
  • the hydrogen pressure is preferably about 0.1 to about 20 MPa, more preferably about 0.3 to 10 MPa, and most preferably about 0.3 to 4 MPa.
  • the reaction may be performed neat or in the presence of a solvent.
  • Useful solvents include those known in the art of hydrogenation such as hydrocarbons, ethers, and alcohols. Alcohols are most preferred, particularly lower alkanols such as methanol, ethanol, propanol, butanol, and pentanol.
  • selectivites in the range of at least 70% are attainable where selectivites of at least 85% are typical.
  • Selectivity is the weight percent of the converted material that is dihydronepetalactone where the converted material is the portion of the starting material that participates in the hydrogenation reaction.
  • the process of the present invention may be carried out in batch, sequential batch (i.e. a series of batch reactors) or in continuous mode in any of the equipment customarily employed for continuous processes (see, for example, ⁇ .S. Fogler, Elementary Chemical Reaction Engineering, Prentice-Hall, Inc., NJ, USA).
  • the condensate water formed as the product of the reaction is removed by separation methods customarily employed for such separations.
  • the resulting mixture of dihydronepetalactone isomer products may be separated by a conventional method, such as for example, by distillation, by crystallization, or by preparative liquid chromatography to yield each highly purified pair of dihydronepetalactone enantiomers. Chiral chromatography may be employed to separate enantiomers.
  • w/v refers to the weight in grams of the active ingredient per 100 mL of solution.
  • nepetalactone fraction was prepared by fractional distillation of the as-received oil (21 pot; 12in. x 1 in. packed column with 0.24" SS packing; variable reflux head; ca. 2mm Hg, with fractions collected between 80°C and 99°C).
  • Figure 2A presents the GC-MS total ion chromatogram of the nepetalactone-enriched fraction prepared by fractional distillation of the commercial sample of Nepeta cataria essential oil. The conditions employed were: column HP5-MS, 25m x 0.2mm; oven 120°C, 2 min, 15°C/min, 210°C, 5 min.; He @ 1 ml/min. Peaks with m/z 166 are nepetalactones; the unlabelled peaks correspond to minor sesquiterpenoid contaminants.
  • nepetalactones were present in the following proportions: 80.2 mol% c/s,-ra/7S-nepetalactone, 17.7 mol% trans, c/s-nepetalactone and 2.1 mol% c/s,c/s-nepetalactone.
  • GC-MS analysis of this purified fraction indicated that it consisted predominantly of these nepetalactones (m/z 166), accompanied by trace amounts of the sesquiterpenoids caryophyllene and humulene (data not shown).
  • dihydronepetalactone of Formula 2 (9S,5S,1 f?,6R) ⁇ 5,9-dimethyl-3- oxabicyclo[4.3.0]nonan-2-one).
  • the distance between the methyl group (i) and proton (d) is longer than the distance between the methyl group (j) and the proton (e>, an observation consistent with the cis-trans stereochemical configuration.
  • the DHN prepared in accordance with Example 2 (designated "mDHN") was evaluated for its repellent effects against female Aedes aegypti mosquitoes.
  • Mosquitoes began probing the untreated control well within 4.6 min. Dihydronepetalactones at 5% concentration was found to discourage mosquito "first probing" for approximately 19 min, compared to 12 min for DEET (at 1 % w/v). Lower concentrations of dihydronepetalactones (1 % and 2.5% w/v) were found to inhibit first probing for an average of 8 and 9.3 min, respectively.
  • Nepetalactone was purified from the concentrated extract by silica gel chromatography in hexane/ethyl acetate (9:1 ) followed by preparative thin-layer chromatography on silica using the same solvent mixture. After removal of the solvent and re-dissolving in hexane, the trans, c/s-nepetalactone was crystallized on dry ice. GC-MS and NMR ( 1 H and 13 C) analysis confirmed the identity of the crystalline material as trans, c/s-nepetalactone. The 13 C chemical shifts (Fig. 7), compared to the chemical shifts of Table 1 , are shown in Table 5.
  • Table 7 presents the effect of DHN concentration with respect to the amount of time taken before the female A. aegypti mosquitoes first probed each membrane. Table 7 Effect of Dihydronepetalactone Concentraton on Mean Time to "First probe"
  • DHN 8.4 (1.16) Dihydronepetalactone at 1% concentration was found to discourage mosquito "first probing" for approximately 16 min. DEET at the same concentration, exhibited a mean time to first probe of 14.8 min. Lower concentrations of dihydronepetalactone (0.5% and 0.2% w/v) were found to inhibit first probing for an average of 9.6 and 8.4 min, respectively.
  • T the mean number of mosquitoes probing a treated well for that replicate at time t x
  • DHN derived from hydrogenation of frat7S,c/s-nepetalactone (consisting principally of 1 S,9S,5r?,6R-5,9-dimethyl-3- oxabicyclo[4.3.0]nonan-2-one; Formula 4), designated "Experimental
  • Example 3 Sample #1" and the mixture of dihydronepetalactones prepared according to Example 2 (designated Experimental Sample #2; mDHN) , were tested for repellency against Stomoxys calcitrans, essentially as described in Example 3.
  • the DHN used here differed from that prepared in Example 4 in that it was derived from hydrogenation (using a Pd/SrCO catalyst) of trans, c/s-nepetalactone crystallized from commercial oil (Berje, NJ).
  • an additional positive control compound was included, namely p-menthane-3,8-diol (PMD), obtained from Takasago International Corp. (USA), Rockleigh, NJ.
  • PMD p-menthane-3,8-diol
  • the experimental design is summarized in Table 10, and all data presented is an average of five replicate experiments. Table 10 Experimental Design Applied for Repellency Testing against Stable Flies Purpose Compound Concentration
  • 1% mDHN 49.8 mDHN, DEET and DHN performed statistically equally well, providing 43.2 to 55.5% repellency, and were statistically better than PMD, which gave only 4.7% repellency when compared to IPA.
  • DHN derived from hydrogenation of trans, c/s-nepetalactone (consisting principally of 1 S,9S,5R,6R-5,9-dimethyl-3- oxabicyclo[4.3.0]nonan-2-one; Formula 4) designated "Experimental Sample #1 ", and the mixture of dihydronepetalactones prepared according to Example 2 (designated as "Experimental Sample #2”; mDHN) were tested for repellency against one hundred unfed adult female A. albimanus, essentially as described in Example 3.
  • the DHN used here differed from that prepared in Example 4 in that it was derived from hydrogenation (using a Pd/SrCO 3 catalyst) of trans, c/s-nepetalactone crystallized from commercial oil (Berje, Bloomfield, NJ). PMD was again included as a further control.
  • the experimental design is summarized in Table 13, and all data presented is the average of five replicate experiments.
  • mDHN was statistically superior to DEET and provided 46.1% repellency.
  • DHN while statistically equal to mDHN, was also statistically equal to DEET and provided 32.9% repellency.
  • DEET and PMD which provided 13.3% and 11.5% repellency respectively, were statistically equal in efficacy.
  • DHN derived from hydrogenation of trans, c/s-nepetalactone (consisting principally of 1 S,9S,5R,6R-5,9-dimethyl-3-oxabicyclo[4.3.0]nonan-2-one; Formula 4) prepared as in Example 7, and the mixture of dihydronepetalactones prepared according to Example 2 were tested for repellency against /. Scapularis, with DEET included in the test as a positive control. A volume of 25 ⁇ l of each compound (30% (w/v) in isopropanol) was applied within 4cm diameter circles drawn on the left forearms of six male human volunteers.
  • a qualified tick which quested at or crawled onto the treated area within 60s was recorded as having not been repelled.
  • a qualified tick which did not quest or ceased questing within 60s an/or retreated from the treated area was recorded as repelled.
  • Example 7 (consisting principally of 1S,9S,5R,6R-5,9-dimethyl-3- oxabicyclo[4.3.0]nonan-2-one; Formula 4), prepared as in Example 7, and the mixture of dihydronepetalactones prepared according to Example 2, were tested for repellency against A. albimanus, with DEET included in the test as a positive control, using adult human volunteers.
  • Test cages (2 x 2 x 2 feet) with two sleeved entry ports on each of two opposite sides were used, with a hand rest in the center. The sides and top were screened and the base was equipped with a mirror to facilitate observations.
  • a volume of 1.0ml of each compound (either 5% or 10% (w/v) in isopropanol) was applied to 250cm 2 areas on the forearms of six male human volunteers, the remainder of the limbs having been made inaccessible to insects.
  • Each volunteer had different repellents applied individually onto each forearm. After allowing the applied repellents to dry for 30min, the forearms were placed into the test cage for 5min periods at 30min intervals, and the number of mosquitoes probing or biting during each exposure period recorded. Breakdown of repellency was recorded for each repellent on each volunteer.
  • Breakdown was defined as the time at which the first confirmed bite occurred; the first confirmed bite was defined as a bite which was followed by a second bite either within the same or the next exposure period.
  • the data is presented in Table 17 as mean complete protection time. The data indicates that both DHN and mDHN conferred complete protection from bites for significant periods of time (eg., at 10% (w/v) for 3.5 and 5 hours, respectively), and comparable to that afforded by DEET at the same concentration.

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Abstract

Le dihydronépétalactone, un constituant naturel mineur de l'huile essentielle de l'herbe à chats (espèces Nepeta) notamment Nepeta cataria, a été identifié comme un composé insectifuge efficace. La synthèse du dihydronépétalactone peut être obtenue par hydrogénation du népétalactone, le constituant principal des huiles essentielles de l'herbe à chats. Ce composé, qui possède également des propriétés aromatisantes, peut être utilisé commercialement pour ses propriétés insectifuges.
PCT/US2003/029344 2003-09-18 2003-09-18 Compositions insectifuges comprenant du dihydronepetalactone WO2005034626A1 (fr)

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AU2003270748A AU2003270748A1 (en) 2003-09-18 2003-09-18 Insect repellent compositions comprising dihydronepetalactone
EP03752458A EP1681925A4 (fr) 2003-09-18 2003-09-18 Compositions insectifuges comprenant du dihydronepetalactone
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JOURNAL OF CHEMICAL ECOLOGY, vol. 9, no. 1, 1983, pages 159 - 180, XP002977049 *
See also references of EP1681925A4 *

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CA2538363A1 (fr) 2005-04-21
CN1838881A (zh) 2006-09-27
EP1681925A4 (fr) 2008-07-02
EP1681925A1 (fr) 2006-07-26
CN101396020B (zh) 2014-10-29
AU2003270748A1 (en) 2005-04-27
AU2003270748A2 (en) 2005-04-27
CN101396020A (zh) 2009-04-01
JP2007521240A (ja) 2007-08-02
IL173903A0 (en) 2006-07-05
CA2538363C (fr) 2012-01-10
BR0318501A (pt) 2006-09-12

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