JP2007521240A - Insect repellent composition comprising dihydronepetalactone - Google Patents

Abstract

  By-natural components of the essential oils of catnip (Nepeta spp.) Such as dihydronepetalactone, nepeta cataria have been identified as effective insect repellent compounds. The synthesis of dihydronepetalactone may be achieved by hydrogenation of the main components of nepetalactone, a catnip essential oil. This compound, which also has fragrance, can be used commercially for its insect repellency.

Description

Cross-reference of related applications

  This application is a continuation-in-part of US patent application Ser. No. 10 / 392,455 filed May 19, 2003, which is incorporated in its entirety for all purposes.

  The present invention relates to the field of insect repellency, and generally to the use of dihydronepetalactone stereoisomers as repellants.

  Repellent substances generally cause insects to be repelled from or rejected from insect-acceptable dietary sources or habitats. At least 85% of insect repellent sales in the United States are for insect repellents containing N, N-diethyl-m-toluamide (DEET) as their primary active ingredient. In addition, Consumer Reports tests have shown that the highest concentration of DEET-containing products lasts the longest against mosquitoes. Although an effective repellent, DEET has an unpleasant odor and gives the skin a greasy feel. Furthermore, it was recently re-registered for use in the United States by the EPA (Environmental Protection Agency), but concerns have been raised regarding its safety, especially when applied to children (Non-Patent Document 1). Some studies have suggested that high concentrations of DEET can cause allergic or toxic reactions in some individuals. Other disadvantages associated with DEET are 1) it is a synthetic chemical, i.e. it is not derived from natural sources, 2) it exhibits a limited spectrum of activity--for example, black foot mites or Not as effective as desired against deer mites (2), 3) DEET dissolves or damages many plastics and painted surfaces, and 4) DEET is typically used in topical formulations Inactive ingredients may be plasticized, including that leading to lower user acceptance.

  As a result of the above limitations, products without repellent DEET-free products are finding consumer support. Specifically, the demand for compositions containing natural products is increasing. The new candidate repellent should have a desirable balance of properties and preferably will reach or exceed the positive properties of DEET and / or will not suffer from its negative properties (3). A potential replacement for DEET should also desirably exhibit a combination of excellent repellency, high residual activity and low toxicity to humans (or pets) and the environment. Furthermore, there is an increasing demand for repellent compounds that can be obtained from natural plant materials or synthesized from them and are easy to use. It should be repellent to a wide variety of insects that are considered harmful by humans, including but not limited to insects, wood worms, harmful insects, domestic pests, etc. that bite any candidate to replace DEET It is.

  Many plant species produce essential oils (aromatic oils) that are used as insect repellent and natural sources of aroma chemicals [4]. Citronella oil, known for its general repellency to insects, is the grass family Cymbopogon winterianus and C. elegans. Obtained from C. nardus. Examples of plants used as a source of fragrance chemicals include Melissa officinalis (Melissa), Perilla frutecens (Posilla), Posostemon cablin (Pachori) and various Labandula species ( Lavender). All of these examples of plants that produce valuable oil are members of the family Lamiaceae (Lamiaceae). The plant of the genus Nepeta (cat mint) is also a member of this family and produces the essential oil, a commercial by-product. This oil is very rich in monoterpenoid compounds known as iridoids [Non-Patent Document 5], more specifically methylcyclopentanoid nepetalactone [Non-Patent Document 6] and derivatives.

  It has long been known that iridoid monoterpenoids are effective repellents against various insect species (Non-Patent Document 7, Non-Patent Document 8, Non-Patent Document 9, and Non-Patent Document 10). Studies of repellency of catnip oil (primarily nepetalactone) have shown that it repells many insect species, but not many other species, in short-term exposure (11).

  U.S. Patent No. 6,057,031 discloses an insect repellent composition comprising a bicyclic iridoid lactone (e.g., iridomylmecin). In addition, US Pat. No. 6,057,096 discloses the use of these bicyclic iridoid lactone compositions in an enhanced insect repellent mixture with DEET. Patent Document 3 discloses a cut-nip plant N.I. Insect repellents comprising nepetalactone derived from N. cataria and the unique efficacy of nepetalactone stereoisomers as insect repellents are disclosed.

  Compositions containing dihydronepetalactone (DHN), a class of iridoid monoterpenoids derived from nepetalactone (shown in FIG. 1) are known to provide insecticidal effects. For example, a study of the composition of secretions from the anal gland of Iridomyrmex nitidus showed that isodihydronepetalactone was present in significant amounts with isoiridomirmesin (non-patented) Reference 12). It was known at that time that isoylidomilmesin had good “knockdown” insecticidal activity.

  Non-patent document 13 discloses the presence of dihydronepetalactone in ant insect repellent secretions, but the compound iridodiar is said to be the main repellent component.

  Non-Patent Document 14 discloses that dihydronepetalactone exhibits effective repellency in the gas phase against ants for 25 seconds. Longer time was not studied. After 25 seconds exposure to vapor from pure dihydronepetalactone, approximately 50-60% of the Monomorium destructor ants stopped feeding. No index was given for duration of repellent effect.

US Pat. No. 4,663,346 US Pat. No. 4,869,896 US Pat. No. 6,524,605 Briasaurus, G. (Brassoulis, G.), Narlio Glow, M.C. (Narrioglou, M.), hatches, tees. (Hatzis, T.), Human and Experimental Toxology, 20 (1) (2001), pp. 8-14 Shrek, Sea. E. (Schreck, CE), Fish, Dee. (Fish, D.) and McGovern, Tee. Pee. (McGovern, TP), Journal of the American Mosquito Control Association, 11 (1) (1995), pages 136-140. Holon, tea. (Hollon, T.), Scientist, (2003), June 16, 2003, pages 25-26. Hey, Earl. K. M. (Hay, RKM), Waterman, Pea. Gee. (Waterman, PG), Volatile Oil Crops: Their Biology, Chemistry and Production (Hay, Earl. K. M. , Sububoda, K. Pee. (Svoboda, K.P.), “Botany”, Longman Group UK Limited, 1993. Inoue, etch. (Inouye, H.), iridoid. Methods in Plant Biochemistry (Iridoids. Methods in Plant Biochemistry), 7 (1991), pages 99-143 Clark, L. Je. (Clark, L. J.) et al., The Plant Journal, 11 (1997), pages 1387-1393. Eisner, tea. (Eisner, T.), Science, 146 (1964), 1318-1320. Eisner, tea. Written by Science, 148 (1965), pages 966-968 Paterson, See. (Peterson, C.) and Coates, J. (Coats, J.), Pesticide Outlook, 12 (2001), pages 154-158. Paterson, See. , Abstract of American Chemical Society (Abstracts of Papers American Chemical Society), 222 (1-2) (2001), AGRO 73 Eisner, tea. Written by Science, 146 (1964), 1318-1320 Cavill, G. W. K. (Cavill, GWK) and Dee. Vui. By Clark Clark, J.C. Insect Physiol. 13 (1967), pages 131-135. Cavill et al., Tetrahedron, 38 (1982), pages 1931-1938 Jeffson, M. (Jefson, M.) et al., J. Chemical Ecology, 9 (1983), pages 159-180.

  One embodiment of the present invention is an insect repellent composition comprising dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula:

  Another embodiment of the present invention is a composition that repels insects when applied to a human, animal or inanimate host, and is represented by the above general formula, dihydronepetalactone, or dihydronepetalactone stereoisomer It is a composition containing the mixture of these.

  Further embodiments of the present invention include bees, gnats, tsutsugamushi, fleas, green head gills, mosquitoes, flies, mites, wasps, carnivorous insects, house flies, cockroaches, louses, cockroaches, kingworms, beech beetles and beetle mites A composition that repels one or more insects selected from the group consisting of moths, moths, lice, and weevil, which is represented by the above general formula, dihydronepetalactone, or dihydronepetalactone stereoisomerism A composition comprising a mixture of bodies.

  Yet another embodiment of the present invention is a composition having an average full protection time that is not statistically indistinguishable from that of N, N-diethyl-m-toluamide, which is represented by the above general formula Or a mixture of dihydronepetalactone stereoisomers.

  Yet another embodiment of the present invention is an insect repellent composition comprising dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula above, in an amount of about 0.001% to about 80% by weight. It is.

  Yet another embodiment of the present invention provides as a composition or article, or incorporates into the composition or product a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula above. A method for producing an insect repellent composition or an insect repellent product.

  Yet another embodiment of the present invention provides and increases 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 above. Or how to enhance.

  Yet another embodiment of the present invention repels insects from humans, animals or inanimate hosts by exposing the insects to dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula above. It is a method to do. The insects to be repelled may be, for example, one or more of mosquitoes, flies and ticks.

  Yet another embodiment of the present invention is the use of dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula above to repel insects from humans, animals or inanimate hosts. The insects to be repelled may be, for example, one or more of mosquitoes, flies and ticks.

Yet another embodiment of the present invention provides the following scheme in the presence of palladium supported on a catalyst support that is not SrCO _3.

Is a process for preparing dihydronepetalactone of formula (XVI) by hydrogenating nepetalactone of formula (XV) according to

  Applicants have found that dihydronepetalactone works well as a new class of effective insect repellent compounds without the disadvantageous properties inherent in prior art compositions. When used as an insect repellent, DHN can damage plants and animals, including humans, or products by preventing or disgusting insect food sources or living conditions. prevent.

  Nepetalactone is a compound having the general formula:

  Four asymmetric centers are present in the methylcyclopentanoid backbone of nepetalactone at carbons 4, 4a, 7 and 7a as shown above, and (7S) -nepetalactone is produced by several plants and insects .

  Dihydronepetalactone is known as a minor component of the essential oil of several Lamiaceae plants of the genus Nepeta (Regnier, FE et al., Phytchemistry, 6 (1967), 1281- 1289; Depotter, HL et al., Flavor and Fragrance Journal, 3 (1988), pp. 155-159; Handjeva, NV (Handijeva, NV) And S. S. Popov, J. Essential Oil Res., 8 (1996), pages 639-643. Dihydronepetalactone is represented by the formula 1

(Wherein 1, 5, 6 and 9 represent the four asymmetric centers of the molecule and the structure shown is intended to encompass all stereoisomers of dihydronepetalactone)
It is specified with. The structure of the dihydronepetalactone stereoisomer that may be derived from (7S) -nepetalactone is shown below.

  “Dihydronepetalactone” (DHN) will be understood to encompass any and all dihydronepetalactone stereoisomers and mixtures thereof, unless a particular isomer or mixture is specifically indicated. When dihydronepetalactone is produced from a natural source of nepetalactone, several variations in stereoisomeric molar concentrations are expected. However, production from natural sources is the preferred production method.

  Renier et al., Supra, disclose the production of DHN from nepetalactone by catalytic hydrogenation of nepetalactone isolated from the essential oil of plants of the genus Nepeta (Catnip). One preferred and convenient method of synthesis of dihydronepetalactone is thus by hydrogenation of nepetalactone obtained in relatively pure form from essential oils isolated from plants of the genus Nepeta (Catnip) by various methods. Catalysts such as palladium on platinum oxide and strontium carbonate give dihydronepetalactone in 24-90% yield (Renni et al., Supra). A particularly preferred method is described in US patent application Ser. No. 10 / 405,444, filed Apr. 2, 2003, which is incorporated by reference in its entirety for all purposes. Yes. Methods for isolating essential oils are well known in the art, and examples of methodologies for oil extraction include steam distillation, organic solvent extraction, microwave assisted organic solvent extraction, supercritical fluid extraction, mechanical extraction, and amperage ( Initial cold extraction to fat, followed by organic solvent extraction) (but not limited to).

  It is well known that essential oils isolated from different Nepeta species have different proportions of each naturally occurring stereoisomer of nepetalactone (Renie et al., Supra; Deputer et al., Supra); Handjeba et al., Non-patent literature cited above). Thus, DHN produced from an oil derived from any Nepeta species is necessarily a mixture of its stereoisomers, and the composition of the mixture will depend on the specific species of Nepeta from which it is derived. Let's go.

  As described herein above, four asymmetric centers are present in the methylcyclopentanoid skeleton of nepetalactone at carbons 4, 4a, 7 and 7a as shown.

  A total of 8 pairs of dihydronepetalactone enantiomers are possible after hydrogenation of nepetalactone. Of these, the naturally occurring stereoisomer described so far is (9S) -dihydronepetalactone. Preferred repellent materials according to the present invention include mixtures of any or all of the possible stereoisomers of dihydronepetalactone. A more preferred repellent includes a mixture of (9S) -dihydronepetalactone. Most preferred is the (9S) -dihydronepetalactone stereoisomer derived from (7S) -nepetalactone. This includes compounds commonly known as cis, trans-nepetalactone, cis, cis-nepetalactone, trans, cis-nepetalactone, and trans, trans-nepetalactone, as illustrated in FIG. N. The main stereoisomers produced by cataria (cis, trans and trans, cis) are preferred.

  When the hydrogenation reaction is complete, the resulting mixture of isomeric products is obtained by conventional methods (eg, preparative liquid chromatography) to yield each highly purified pair of dihydronepetalactone diastereomers. It may be separated. This allows the use of a variety of different diastereomers as it turns out to be most effective against a particular insect. It is preferred to isolate certain nepetalactone isomers from plants and convert them to their corresponding pairs of diastereomers by hydrogenation.

  In addition to variations in nepetalactone stereoisomer content between different nepeta species, it is known that intra-species variation also exists. Plants of a given species may produce different compositions of oil depending on their growth conditions or growth stage at harvest. Variations in oil composition were found in Nepeta racemosa (Clark, L. J. et al., Supra), which is actually independent of the growth conditions or growth stage at harvest. Single species of plants that exhibit different oil compositions are called chemotypes. Nepeta Reismosa has a chemotype that shows a marked difference in the proportion of different nepetalactone stereoisomers. Accordingly, a preferred method for producing a particular dihydronepetalactone enantiomer is the hydrogenation of an oil from a nepeta chemotype known to contain a particular nepetalactone stereoisomer.

  Insects such as those to be repelled by the composition of the invention include in the mature state (non-mature insect states include larvae and willow), head, chest and abdomen, three pairs of legs, and often ( It includes any member of a large population of invertebrates characterized by division of the body into two pairs of membranous wings, but not necessarily. This definition therefore includes various biting insects (eg, ants, bees, gnats, tsutsugamushi, fleas, green head gills, mosquitoes, flies, mites, wasps), wood carnivores (eg, termites), harmful insects (E.g., house flies, cockroaches, lice, cockroaches, bracken), and domestic pests (e.g., black beetle and bean beetle, dust mites, moths, lice, weevil). In one embodiment, for example, the DHN compositions of the present invention are as described above, and also sting insects, woodworms, harmful insects and domestic pests, most specifically mosquitoes, flies and deer mites. It is an effective insect repellent against a broad spectrum of common pests including ticks.

  In a further embodiment, the DHN composition of the present invention comprises bees, gnats, tsutsugamushi, fleas, green head gills, mosquitoes, flies, ticks, carps, carnivorous insects, house flies, cockroaches, lice, cockroaches, bracken And effective in repelling any one or more of the members of the group consisting of beetle, dust mite, moth, lice, and weevil. However, the repelled insects are also selected from the subgroups of the foregoing that are formed by deleting any one or more members from the whole group as described in the list of the first sentence of this paragraph. There may be one or more of the following. As a result, the repelled insects may only be selected from any subgroup of any size that may be formed from the whole group as described in the list above. Rather, members deleted from the entire group to form subgroups may be excluded. The subgroups formed by removing various members from the whole group in the list above are also individual members of the whole group so that the repelled insects exclude all other members of the whole group. There may be.

  A host is any plant or animal that is affected by an insect. Typically, the host is considered an insect-acceptable dietary source or insect-acceptable habitat. The host can be a so-called “insect-sensitive article”, including animals (including without limitation pets and / or other livestock), humans, plants, or any inanimate article affected by insects. Inanimate items may include buildings, furniture, and the like.

  In a further embodiment of the invention, the DHN produces an insect repellent article for the purpose of either preventing the insect from landing on the article or occupying the air surrounding the article. To be incorporated into a host such as an insect sensitive article. Those cases where the article may already exhibit some degree of insect repellency prior to treatment with the DHN composition of the present invention are contemplated in this embodiment. In such cases, it is believed that the insect repellency of the article will be enhanced by application of the DHN composition of the present invention.

  An insect repellent is any formulation or composition that prevents insects from the host. Such usage is useful for compounds that exhibit long-term beneficial effects and / or compounds that have a very short-lived effect compared to those that require a very high surface concentration before having an observable effect on insect behavior. It will be understood that no distinction is made.

  The term “insect repellent” thus refers to a formulation or composition that provides host protection from insects when compared to no treatment at all. “Protection” desirably results in a statistically significant reduction in the number of insects, for example, average complete protection in treated animals, including humans, and in tests where insect behavior is observed on treated inanimate surfaces It may be determined practically by measuring time (“CPT”). Average CPT is for the repetition of the test where the time before the first landing on the treated surface, probing or piercing (in the case of a stinging insect) or reputing (in the case of a repellant insect like a tick or tsutsugamushi) is observed Means the average length of time [e.g., US EPA Office of Prevention, Pesticides and Toxic Substances Product Performance Testing Guidelines OPPTS 810.3700; and Fragin, M.C. S. (Fradin, MS), Day, J. F. (Day, JF), New England Journal of Medicine, 347 (2002), pages 13-18]. In an exemplary embodiment of the invention, the insect repellent compositions herein have an average CPT that is not statistically distinguishable from that of DEET. For tests where this state of average CPT performance for each of the DHN composition and DEET is shown to be statistically indistinguishable, the test conditions used (including the amount of active ingredient) must of course be the same, Or, if they are not the same, they must differ only to the extent that they do not interfere with the use of the results for the purpose of recording the existence of the conditions described.

  As noted above, DHN was conveniently comparable to DEET in terms of performance. In addition, DHN is advantageously manufactured from naturally derived nepetalactones derived from plants, but DEET and many other insect repellents are not manufactured from natural sources-an important consumer when choosing an effective repellent Considerations. Manufacturing from natural sources also offers the potential for low production costs.

  It is a particularly surprising aspect of the present invention that DHN provides significant improvements over DEET odor while exhibiting effective insect repellency. The DHN formulations and compositions of the present invention have a pleasant fragrance. The fragrance characteristics of the DHN material provide the overall olfactory component of the insect repellent composition or article, for example, by utilizing or mitigating the olfactory response contributed by one or more other components in the composition Help them when changing, increasing or enhancing. Specifically, the DHN composition of the present invention is either for masking or mitigating odor contributed by other components in the final repellent composition or article formulation and / or features. It may be utilized to increase the consumer appeal of a product by imparting a typical aroma or fragrance.

  It will be appreciated that the effectiveness of DHN or any insect repellent depends on the surface concentration of the active ingredient on the host surface to which it is applied. However, many compounds known in the art to exhibit insect repellency are only in relatively concentrated form. See, for example, McGovern et al. In US Pat. No. 4,416,881, which discloses the use of a repellent concentration of 6.25-25%. In other situations representative of the technology, concentrations of DEET well below 1% require repeated application to achieve effective surface concentrations, and concentrations above 30% are wasteful. It is often found to result in excessive surface concentrations that both contribute to the generation of undesirable side effects. A further advantage of the present invention is therefore that not only does DHN provide effective insect repellent at concentrations similar to those used for DEET, but DHN is neat DHN (ie, the compositions herein are For example, may contain 100 wt% DHN) and may be used at concentrations including neat DHN. The effective repellency profile in DHN offers many options for the economic use of DHN active ingredients over a wide range of levels of concentration.

  In one embodiment of the invention, DHN is incorporated in an effective amount into a composition suitable for application to a host plant or animal, preferably to human skin. Suitable compositions include DHN and a medium, preferably an alcohol such as isopropyl alcohol, a lotion such as a number of skin creams as known in the art, or siliceous clay. Preferably, the DHN is an insect repellent composition of the present invention at a concentration of about 0.1 wt% to 30 wt%, preferably about 0.5 wt% to 20 wt%, most preferably about 1 wt% to 15 wt%. Present in.

  For insect repellents to be effective, the rate of evaporation of the active ingredient from the host skin or treated article must not be high enough to provide a vapor density that has the desired effect on the target insect. Don't be. However, a balance must be found between the evaporation rate and the desired duration of the insect repellent effect-too high an evaporation rate will drastically reduce the insect repellent on the surface and result in a loss of efficacy . Many extrinsic factors affect the evaporation rate, such as ambient temperature, the temperature of the treated surface, and the presence or absence of air movement. The composition of the present invention has a skin surface evaporation rate of at least the lowest effective evaporation rate, and preferably has a skin surface evaporation rate of at least the lowest effective evaporation rate for at least 5 hours.

  In most cases, penetration into and through the skin is an undesirable mode of compound loss from the skin surface. For example, it is known that insect repellents are absorbed into human skin while being concerned about potential toxicity and clearly removing the amount of repellent absorbed from insect repellent activity. Similar considerations must be made for insect repellent articles.

  Although DHN provides effective insect repellency under typical use conditions, lowering its evaporation rate may be desirable under some circumstances. Various strategies may be used to reduce the rate of DHN evaporation if so desired. For example, one method is to combine DHN with a polymer or other inert component and transfer DHN to its surface by the mixture before it can evaporate. However, it is selected if the result is a dilution of the concentration of DHN that can be applied to the skin surface of the host or present on the surface of the insect repellent article, thus reducing the overall efficacy of the formulation. Must be part of the evaporation strategy. Alternatively, the active ingredient is microencapsulated to control the rate of loss from the host's skin surface or insect repellent article. In yet another alternative, precursor molecules may be produced that slowly decompose on the skin surface or insect repellent article to release the active ingredient.

  For example, the release of the active ingredient may be, for example, by sub-micron encapsulation where the active ingredient is encapsulated (enclosed) in skin nourishing protein just as air is trapped in the balloon. The protein may be used, for example, at a 20% concentration. The repellent application contains many of these protein capsules suspended in either an aqueous lotion or water for spray application. After contact with the skin, the protein capsule begins to break and release the encapsulated dihydronepetalactone. The process continues as each fine capsule is used up and subsequently replaced by new capsules that contact the skin and release its active ingredient. This process may take up to 24 hours per application. Since protein attachment to the skin is very effective, these methods are very resistant to sweat (sweat) and water. When applied they are dry and comfortable without any stickiness. This system provides very effective protection, but it is only effective when used on the skin because clothing does not have the ability to release proteins. An alternative system uses a polymer to encapsulate the repellent, which slows premature evaporation, leaving more dihydronepetalactone available for later evaporation. This system can often extend the effectiveness of the repellent by 25% to 50% over comparable non-encapsulated products, but often feels greasy due to the presence of the polymer. In another alternative, a synergist is used to continue to promote evaporation of dihydronepetalactone in the composition.

  In the present invention, various carriers or diluents for the dihydronepetalactone disclosed above can be used. The carrier allows the formulation to be adjusted to an effective concentration of repellent molecules. When formulating topical insect repellents suitable for human or animal skin, preferably the repellent molecules are mixed in a dermatologically acceptable carrier. The carrier may further provide water repellency, prevent skin irritation, and / or relieve and condition the skin. Factors to consider when selecting a carrier for any formulation of insect repellent include commercial availability, cost, water repellency, evaporation rate, odor, and stability. Some carriers can themselves have repellency. Furthermore, the carrier should preferably also be one that is not harmful to the environment.

  One or more commercially available organic and inorganic liquid, solid, or semi-solid carriers or carrier formulations known in the art for formulating insect repellent products are suitable for the present invention. For example, the carrier may include silicone, petrolatum, or lanolin.

  Examples of organic liquid carriers include liquid aliphatic hydrocarbons (eg, pentane, hexane, heptane, nonane, decane and the like) and liquid aromatic hydrocarbons. Examples of other liquid hydrocarbons include oils produced by distillation of coal and various types and grades of petrochemical materials, including kerosene obtained by fractional distillation of petroleum. Other petroleum oils include what are commonly referred to as agricultural spray oils (eg, so-called light and medium spray oils, consisting of middle distillates from petroleum distillation, only slightly volatile, so called). . Such oils are usually highly refined and may only contain trace amounts of unsaturated compounds. Furthermore, such oils are generally paraffinic oils and can therefore be emulsified with water and emulsifiers, diluted to lower concentrations and used as sprays. Tall oil obtained from sulfate digestion of wood pulp, such as paraffin oil, can be used as well. Other organic liquid carriers can include liquid terpene hydrocarbons and terpene alcohols such as alpha-pinene, dipentene, terpineol, and the like.

  Other carriers include aliphatic and aromatic alcohols, esters, aldehydes, ketones, mineral oils, higher alcohols, finely divided organic and inorganic solid materials. In addition to the liquid hydrocarbons described above, the carrier can contain conventional emulsifiers that can be used to disperse and dilute the dihydronepetalactone compound in water for end use.

  Aliphatic monohydric alcohols include methyl, ethyl, normal-propyl, isopropyl, normal-butyl, sec-butyl, and tert-butyl alcohol. Suitable alcohols include glycols (such as ethylene and propylene glycol) and pinacol. Suitable polyhydric alcohols include glycerol, arabitol, erythritol, sorbitol and the like. Finally, suitable cyclic alcohols include cyclopentyl and cyclohexyl alcohol.

  In addition, conventional or so-called “stabilizers” (eg tert-butylsulfinyldimethyldithiocarbonate) can be used in conjunction with or as a component of the carrier comprising the composition of the 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 silica aerogels and synthetically produced siliceous materials such as precipitated and fused silica, as well as synthetic and natural clays, bentonite, attapulgite, fuller earth, diatomaceous earth, kaolin, mica , Siliceous minerals such as talc, finely divided quartz and the like. Examples of finely divided solid organic materials include cellulose, sawdust, and synthetic organic polymers. Examples of semi-solid or colloidal carriers provide waxy solids, gels (such as petrolatum), lanolin, and semi-solid carrier products to provide effective repellency within the scope of the present invention. Well known liquid and solid material mixtures.

  The insect repellent composition of the present invention containing dihydronepetalactone is also a thickener, buffer, chelating agent, preservative, fragrance, antioxidant, gelling agent, stabilizer, surfactant, emollient, colorant. , Aloe, waxes, other penetration enhancers and mixtures thereof, and adjuvants known in the art of personal care product formulation, such as therapeutically or cosmetically active agents.

  The therapeutically or cosmetically active ingredients useful in the compositions of the present invention are bactericides, sunscreens, sunscreens, vitamins, tanning agents, plant extracts, anti-inflammatory agents, antioxidants, radical scavengers Including agents, retinoids, alpha-hydroxy acids, emollients, antiseptics, antibiotics, antibacterials or antihistamines, which may be present in an amount effective to achieve the desired therapeutic or cosmetic result.

  The compositions of the present invention also include benzyl, benzyl benzoate, 2,3,4,5-bis (butyl-2-ene) tetrahydrofurfural, butoxypolypropylene glycol, N-butylacetanilide, 6,6-dimethyl-5, 6-dihydro-1,4-pyrone-2-carboxylate normal-butyl, dibutyl adipate, dibutyl phthalate, di-normal-butyl succinate, N, N-diethyl-meta-toluamide, dimethyl carbonate, dimethyl phthalate 2-ethyl-2-butyl-1,3-propanediol, 2-ethyl-1,3-hexanediol, di-normal-propyl isocincomeronate, 2-phenylcyclohexanol, p-menthane-3,8 Included in diols and normal-propyl N, N-diethylsuccinamate Or such, it is non-dihydronepetalactone insect repellent blended as the.

  The DHN composition of the present invention may include any number of the above adjuvants to meet any particular application requirement. The specific proportions of each component will be similarly determined by application requirements. However, the compositions of the present invention are preferably 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 DHN, or about. It should comprise 1% to about 30% by weight DHN, preferably about 0.5% to about 20% by weight, and most preferably about 1% to about 15% by weight. In general, the repellent composition should contain a sufficient amount of active insect repellent material to be effective in repelling insects from the host over an extended period of time (preferably at least several hours).

  Dihydronepetalactone may be utilized in the present invention in the form of individual diastereomers or mixtures of various diastereomers, or in combination with other insect repellents. DHN may be used at any concentration level suitable for specific needs, including neat. However, it is believed that the amount of DHN in the insect repellent composition or repellent article according to the present invention will generally not exceed about 80% by weight.

  Depending on the preferred method of use, the compositions of the present invention are formulated to deliver products in a variety of forms including those such as solutions, suspensions, creams, ointments, gels, films or sprays. And may be packaged. The carrier may be an aerosol composition configured to disperse dihydronepetalactone into the air using a compressed gas.

  Desirable properties of a topical insect repellent article include low toxicity, resistance to loss due to water immersion or sweating, low odor or no odor or at least a pleasant scent, ease of application, and a dry, non-sticky surface on the host skin Includes rapid film formation. To obtain these properties, formulations for topical insect repellent articles are obtained by contacting the skin, fur or feathers of such animals with an amount of repellent article effective to repel the insects from the animal host. Infected animals (eg flea dogs, lice poultry, tick cows, and humans) should be allowed to be treated with the insect repellent composition of the present invention. Thus, dispersing the article into the air or dispersing the composition as a liquid mist or fine dust will allow the repellent composition to fall on the desired host surface. Similarly, direct application of a liquid / semi-solid / solid repellent article onto a host is an effective method of contacting the host surface with an effective amount of the repellent composition.

  Particularly for the pleasant aroma associated with DHN, a further embodiment of the present invention is the incorporation of DHN into a product that is initially unrelated to insect repellency to give it an effective degree of repellency. Such products include colons, lotions, sprays, creams, gels, ointments, bath or shower gels, foamed products (eg, shaving foam), makeup, deodorants, shampoos, hair spray / hair rinses, and personal soap compositions (eg, Hand soap and bath / shower soap).

  Further contemplated by the present invention are those embodiments in which DHN provides effective insect repellency in various articles susceptible to attack by insects by incorporation therein. In an exemplary embodiment, the article is outdoors, but need not be. Among the possible articles are air cleaners, candles, various fragrances, textiles, sheets, textiles, paper, paint, ink, clay, wood, furniture (eg terraces and decks), carpets, sanitary goods, Examples include, but are not limited to plastics, polymers, and the like.

  In one embodiment, dihydronepetalactone is combined with a polymer to provide moldability, reduced evaporation rate, and controlled release. Such polymers may be biodegradable. Suitable polymers include high density as disclosed, for example, in U.S. Pat. Nos. 4,496,467, 4,469,613 and 4,548,764. Polyethylene, low density polyethylene, biodegradable thermoplastic polyurethane, biodegradable ethylene polymer, and poly (epsilon-caprolactone) homopolymer and compositions containing them include, but are not limited to. Preferred biodegradable polymers include DuPont Biomax® biodegradable polyester and poly-L-lactide.

  The present invention also includes a method for producing DHN in which a palladium catalyst is used. The term “catalyst” as used herein refers to a substance that affects the rate of a chemical reaction (but does not affect the reaction equilibrium) and that leaves the process without being chemically altered. means.

A process for the preparation of dihydronepetalactone of formula (XVI) comprises the following scheme in the presence of palladium supported on a catalyst support that is not SrCO ₃ :

Hydrogenating nepetalactone of formula (XV) according to

  The term “promoter” as used herein is a compound that is added to enhance the physical or chemical function of the catalyst. Chemical promoters generally increase the activity of the catalyst and may be incorporated into the catalyst during any step of chemical treatment of the catalyst components. Chemical promoters generally enhance the physical or chemical function of the catalyst agent, but can also be added to suppress unwanted side reactions. “Metal promoter” means a metal compound added to enhance the physical or chemical function of the catalyst.

  Hydrogenation of nepetalactone is accomplished in the presence of a suitable active metal hydrogenation catalyst. Solvents, catalysts, equipment, and procedures that are generally acceptable for hydrogenation are described by Augustine, “Heterogeneous Catalysis for the Synthetic Chemist”, New York, NY NY), Marcel Decker, 1996. Many hydrogenation catalysts including, but not limited to, those containing iridium, palladium, rhodium, nickel, ruthenium, platinum, rhenium, their compounds, combinations thereof, and supported versions thereof Is effective.

  The metal catalyst used in the process of the present invention may be used as a supported catalyst or as an unsupported catalyst. A supported catalyst is one in which an active catalyst agent has been deposited on the support material by spraying, dipping or physical mixing and subsequently activated by methods such as drying, calcination, and, if necessary, reduction or oxidation. Materials often used as supports are high total surface area (external and internal) porous solids that can provide a high concentration of active sites per unit weight of catalyst. The catalyst support may enhance the function of the catalyst agent, and the supported catalyst is generally preferred because the active metal catalyst is used more efficiently. A catalyst that is not supported on a catalyst support material is an unsupported catalyst.

The catalyst support can be any solid inert material including, but not limited to, oxides such as silica, alumina, titania, calcium carbonate, barium sulfate, and carbon. The catalyst support can be in the form of powder, granules, pellets, and the like. Preferred carrier materials of the present invention are selected from the group consisting of carbon, alumina, silica, silica-alumina, titania, titania-alumina, titania-silica, barium, calcium, compounds thereof, and combinations thereof. Suitable carriers include _carbon, it is SiO _2, CaCO 3, BaSO ₄ and _Al 2 _{O 3.} Furthermore, the supported catalytic metals may have the same support material or different support materials.

In one embodiment of the invention, the more preferred support is carbon. Further preferred supports are those with a surface area greater than 100-200 m ² / g, in particular carbon. Further preferred supports are those with a surface area of at least 300 m ² / g, in particular carbon.

Commercially available carbon that may be used in the present invention includes those sold under the following trademarks: Bameby & Sutcliffe ^™ , Darco ^™ , Nucher ( ^{Nuchar) TM,} Colombia (Columbia) ^{JXN TM,} Colombia ^{LCK TM,} Calgon (Calgon) ^{PCB TM,} Calgon ^{BPL TM,} Westvaco ^{(Westvaco) TM,} Norit ^{(Norit) TM} and Barnaby Cheney (Barnaby Cheny) ^{NB TM.} Carbon is also a commercially available carbon such as Calsicat C, Sibunit C, or Calgon C (commercially available under the registered Centaur®). Can be.

  A preferred combination of catalytic metal and support system includes palladium-carbon, such as with ESCAT # 142 catalyst (Engelhard).

  Although the weight percent of catalyst on the support is not critical, it will be understood that the higher the weight percent of the metal, the faster the reaction. A preferred content range for the metal in the supported catalyst is from about 0.1% to about 20% by weight of the total supported catalyst (catalyst weight plus support weight). A more preferred catalytic metal content range is from about 1% to about 10% by weight of the total supported catalyst. A further preferred catalytic metal content range is from about 3% to about 7% by weight of the total supported catalyst.

  Optionally, a metal promoter may be used with the catalytic metal in the process 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) the periodic table in lesser amounts A combination of Group 8 metals is included.

  Temperature, solvent, catalyst, pressure and mixing rate are all parameters that affect hydrogenation. The relationship between these parameters may be adjusted to achieve the desired conversion, reaction rate, and selectivity in the reaction of the present method.

  Within the framework of the present invention, preferred temperatures are from about 25 ° C to 250 ° C, more preferably from about 50 ° C to about 150 ° C, and most preferably 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 carried out neat or in the presence of a solvent. Useful solvents include those known in the hydrogenation art such as hydrocarbons, ethers, and alcohols. Most preferred are alcohols, especially lower alkanols such as methanol, ethanol, propanol, butanol, and pentanol. If the reaction is carried out according to a preferred embodiment, a selectivity in the range of at least 70% can be achieved, where a selectivity of at least 85% is typical. Selectivity is the weight percent of the conversion material that is dihydronepetalactone when the conversion material is part of the starting material involved in the hydrogenation reaction.

  The method of the present invention may be performed in batch, sequential batch (ie, a series of batch reactors), or in continuous mode with any of the equipment typically used for continuous processes (eg, Et S. Fogler). (See HS Fogler, “Elementary Chemical Reaction Engineering”, Prentice-Hall, Inc., NJ, USA). Condensate formed as a product of the reaction is removed by separation methods commonly used for such separations.

  When the hydrogenation reaction is complete, the resulting mixture of dihydronepetalactone isomer products is obtained, for example, by distillation, by crystallization, or by separation, to yield each highly purified pair of dihydronepetalactone enantiomers. They may be separated by conventional methods such as by liquid chromatography. Asymmetric chromatography may be used to separate the enantiomers.

  The present invention is further illustrated by the following specific embodiments, but is not limited thereto.

  In the following examples, the abbreviation “w / v” means the weight in grams of active ingredient per 100 mL of solution.

  Other abbreviations used are: "h" means hours, "min" means minutes, "sec" means seconds, "d" means days, "mL" means milliliter, "L" means liter, "m / z" means mass (m) to charge (z) ratio, "ppm" means parts per million, “Mole%” means the percentage expressed on a molar basis, “Hz” means Hertz (1 / second), and “psig” means pound gauge per square inch.

Example 1
Preparation of nepeta by fractional steam distillation of Nepeta cataria oil A commercially available sample of catnip oil prepared by steam distillation of herbaceous material from Catnip Nepeta cataria was obtained (Berge, Bloomfield, NJ, USA (Berje, Bloomfield, NJ, USA). As-received oil combination gas chromatography-mass spectrometry (GC-MS) showed that the major component was the nepetalactone stereoisomer (FIG. 1). However, as purchased, the oil is a highly contaminated natural product and it is desirable to refine the extract to purified nepetalactone. We fractionally distilled to remove foreign substances with higher and lower boiling points than nepetalactone.

  Thus prepared by fractional distillation of the oil as received nepetalactone fraction (2 L pot; 12 inch × 1 inch packed column with 0.24 inch SS packing; variable reflux head; about 2 mmHg; Collected at 0 ° C to 99 ° C). FIG. 2A shows a GC-MS total ion chromatogram of a fraction rich in nepetalactone prepared by fractional distillation of a commercial sample of nepeta cataria essential oil. The conditions used were column HP5-MS, 25 m × 0.2 mm; oven: 120 ° C., 2 min, 15 ° C./min, 210 ° C., 5 min; He: 1 mL / min. The peak at m / z 166 is nepetalactone; the unlabeled peak corresponds to a minor sesquiterpenoid foreign body.

FIG. 3A shows the mass spectrum of the main peak of FIG. 2A (6.03 minutes, nepetalactone). ¹ H and ¹³ C NMR analysis of the oil and refined material was also performed and shows ¹³ C data (FIG. 4). The ¹³ C chemical shifts for the four possible stereoisomers reported in the literature were compared with the spectra taken for the samples. Three stereoisomers were detected and the amount was quantified as approximately 170 ppm based on the carbonyl region. The chemical shifts for both the original oil and the enriched material are provided in Table 1. Each carbon atom of nepetalactone is identified as shown in FIG.

  This analysis shows that nepetalactone is present in the oil in the following proportions: 80.2 mol% cis, trans-nepetalactone, 17.7 mol% trans, cis-nepetalactone and 2.1 mol% cis, cis-nepetalactone. showed that. The data indicated that the proportion of nepetalactone in the purified material was 84.5 mol% cis, trans-nepetalactone, 14.3 mol% trans, cis-nepetalactone and 1.2 mol% cis, cis-nepetalactone. GC-MS analysis of this purified fraction shows that it consists mainly of these nepetalactones (m / z 166), accompanied by trace amounts of sesquiterpenoids caryophyllene and humulene (data not shown). Indicated.

Example 2
Production of dihydronepetalactone 107 g of a distilled nepetalactone fraction of catnip oil prepared as described in Example 1 was dissolved in ethanol (200 mL) and 12.7 g of 2% Pd / SrCO ₃ (Aldrich) as a catalyst. 41, 461-1) in a Fisher-Porter bottle. The tube was evacuated twice, again filled with _{H 2,} then the 30psig was charged with _{H 2.} After stirring at room temperature for 48 hours, the tube was degassed and the contents were filtered over Celite to remove the catalyst. The solvent was removed under reduced pressure, resulting in a clear oil.

  GC-MS analysis (column HP5-MS, 25 m × 0.2 mm; oven: 120 ° C., 2 min, 15 ° C./min, 210 ° C., 5 min; He: 1 mL / min) was performed on this material. The total ion chromatogram is shown in FIG. 2B. This analysis shows that the major component (65.43 area%; Rt 7.08 min) represents the dihydronepetalactone isomer with m / z 168, and the mass spectrum of this component is shown in FIG. 3B. This spectrum contains ions with m / z 113 characteristic of dihydronepetalactone (Jeffson, M. et al., Supra). Five additional peaks representing the remaining dihydronepetalactone diastereomers that may be derived from the three nepetalactones present in the starting material were also displayed in the chromatogram. These are Rt 5.41 min, 6.8 area%, m / z 168; Rt 5.93 min, 1.2 area%, m / z 168; Rt 6.52 min, 4.88 area%, m / z z 168; Rt 6.76 min, 13.8 area%, m / z 168 and Rt 7.13 min, 1.25 area%, m / z 168. No remaining nepetalactone was detected by GC-MS.

¹ H, ¹³ C and a series of 2D NMR analyzes were also performed. The carbonyl region of the ¹³ C NMR spectrum (FIG. 5) showed at least 5 spin systems, one of which was more than the other 4 (about 75%). Very little remaining nepetalactone was detected.

  Based on an analysis of the binding constants and intensities of the different NOE cross peaks observed, the stereochemistry of the main component of the material is dihydronepetalactone (9S, 5S, 1R, 6R) -5,9-dimethyl-3 of formula 2. -Oxabicyclo [4.3.0] nonan-2-one).

  The distance between the methyl group (i) and the proton (d) is longer than the distance between the methyl group (j) and the proton (e), and the observed value is consistent with the cis-trans stereochemical configuration.

The stereoisomer isodihydronepetalactone (9S, 5R, 1R, 6R) -5,9-dimethyl-3-oxabicyclo [4.3.0] nonan-2-one) (Formula 3) is a ¹³ C chemical shift. As well as 3.6%.

  Thus, GC-MS and NMR data indicate that hydrogenation of a mixture of nepetalactone stereoisomers resulted in the corresponding dihydronepetalactone diastereomers, as expected. The diastereomeric pair (formula 2 and formula 3) derived from cis, trans-nepetalactone (84.5 mol% of the starting material) was the main dihydronepetalactone in 78.6% of the mixture after hydrogenation. It was.

Example 3
Repellent Test of Dihydronepetalactone Mixture DHN produced according to Example 2 (referred to as “mDHN”) was evaluated for its repellent effect on female Aedes aegypti.

  Approximately 250 female Aedes aegypti were introduced into a chamber containing 5 containers, each covered by a Baudruche (animal intestine) membrane. The container was filled with bovine blood containing sodium citrate (to prevent clotting) and ATP (72 mg ATP disodium salt per 26 mL blood) and heated to 37 ° C. A volume of 25 μL of isopropyl alcohol containing one of the test specimens shown in Table 2 was applied to each membrane.

  After 5 minutes, 4-day-old female mosquitoes were added to the chamber. The number of mosquitoes that probe the membrane for each treatment was recorded over 20 minutes at 2-minute intervals. Each data represents the average of three replicate experiments.

  Table 3 shows the amount of time it took for female Aedes aegypti to probe each treated membrane for the first time. The number in parentheses is the standard error of the mean (SEM) for 3 iterations.

  The mosquito began to probe the untreated control container within 4.6 minutes. Dihydronepetalactone at 5% concentration was found to prevent mosquitoes from making the “first probe” for approximately 19 minutes compared to 12 minutes for DEET (at 1% w / v). Lower concentrations (1% and 2.5% w / v) of dihydronepetalactone blocked the first probe for an average of 8 and 9.3 minutes, respectively.

  Landing / probe density distribution by female Aedes aegypti on membranes treated with dihydronepetalactone was analyzed over time and is shown graphically in FIG. The total number of allowed probes on each membrane was measured during the course of the experiment and the results are summarized in Table 4. DHN at 5% concentration was found to almost eliminate the mosquito probe for 20 minutes and only one probe was recorded over the entire 20 minute test time, but DEET (1% w / v) averaged Allowed 4.55 mosquitoes to land. Again, lower concentrations of DHN (1% and 2.5% w / v) show repellency (compared to untreated controls) but lower than the positive control (DEET at 1% w / v) It was found to show repellency at the level.

  Again, the data show that significantly increased repellency relative to 1% DEET was finally observed at 5% (w / v), but dihydronepetalactone was repellant at all concentrations tested. .

Example 4
Production of dihydronepetalactone from trans, cis-nepetalactone A number of plants were grown from the seeds of Catnip nepeta racemosa (Chirtern Seeds, Cumbria, UK). Leaf pairs picked from individual plants were immersed in ethyl acetate, the solvent was removed after 2 hours, and the extracts were analyzed by gas chromatography. Plants that mainly produce trans, cis-nepetalactone in their oils were thus identified (Clark, L.J. et al., Supra) and grown to maturity. Leaf material from these plants was harvested, lyophilized, extracted into ethyl acetate, and the extract concentrated. The nepetalactone concentrated extract was purified by silica gel chromatography with 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-dissolution in hexane, trans, cis-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, cis-nepetalactone. ^{The 13} C chemical shift (FIG. 7) is shown in Table 5 in comparison with the chemical shift in Table 1.

Hydrogenation of the trans, cis-nepetalactone thus prepared was carried out at 50 ° C. in ethanol for 4 hours using ESCAT # 142 catalyst (Engelhard). GC-MS and NMR ( ¹ H and ¹³ C) confirmed that trans, cis-nepetalactone was quantitatively converted to the corresponding dihydronepetalactone stereoisomer, one in significant excess. NMR analysis of the main diastereomer: ¹ H NMR (500 MHz, CDCl ₃ ): δ 0.97 (d, 3H, J = 6.28 Hz), 0.98 (d, 3H, J = 6.94 Hz), 1 .24 (m, 2H), 1.74 (m, 1H), 1.77 (m, 2H), 1.99 (m, 2H), 2.12 (dd, 1H, J = 6.86 and 13) .2 Hz), 2.51 (m, 1 H), 3.78 (tr, 1 H, J = 11.1 Hz), 4.33 (dd, 1 H, J = 5.73 and 11.32 Hz); ¹³ C ( 500 MHz, CDCl ₃ ): δ 15.43, 18.09, 27.95, 30.81, 31.58, 35.70, 42.51, 51.40, 76.18, 172.03. ^{The 13} C NMR spectrum (FIG. 8) showed that this major diastereomer constituted about 93.7% of the product. Based on the observed coupling of methylene to lactone oxygen, stereomethine carbon with methyl group, methyl group itself and bridgehead methine, the diastereomers are probably of the formula (1S, 9S, 5R, 6R)- It is concluded that it is 5,9-dimethyl-3-oxabicyclo [4.3.0] nonan-2-one.

  The size of the coupling observed is consistent with the dihedral angle between protons on the vicinal carbon atom in the above structure according to the Karplus equation (Robert M. Silverstein, “Spectrophotometric Identification of Organic Compounds”, 4th edition, 1981, 208-2, by G. Clayton Bassler and Terence C. Morill. Page).

Example 5
Repellency test of dihydronepetalactone prepared by hydrogenation of trans, cis-nepetalactone Dihydronepetalactone prepared in Example 4, Formula 4, was tested for repellency against Aedes aegypti essentially as described in Example 3. . The experimental design is summarized in Table 6 and all data shown are from 5 replicate experiments.

  Table 7 shows the effect of DHN concentration on the amount of time taken by female Aedes aegypti before first probing each membrane.

  Dihydronepetalactone at a concentration of 1% was found to prevent mosquito “first probing” for approximately 16 minutes. The DEET at the same concentration showed an average time to the first probe of 14.8 minutes. Lower concentrations of dihydronepetalactone (0.5 and 0.2% w / v) were found to prevent initial probing on average 9.6 and 8.4 minutes, respectively.

  The distribution of probe density by female Aedes aegypti on membranes treated with dihydronepetalactone was analyzed over time as shown graphically in FIG. The total number of allowed probes on each membrane was measured during the course of the experiment and the results are summarized in Table 8. Although DHN at 1.0% concentration was found to completely eliminate mosquito probing for 10 minutes, DEET (1% w / v) allowed mosquitoes to begin probing by 6 minutes. Again, lower concentrations of dihydronepetalactone (0.5 and 0.2% w / v) show repellency (compared to untreated controls) but positive controls (at 1% w / v) It was found that repellency was exhibited at a level lower than (DEET).

Percent repellency is the following equation:% repellency = 100 − [(T / C) × 100]
(here,
The average number of mosquitoes probing the IPA control vessel by the average number C = time t _x of mosquitoes probing the treated vessel for the repeated at T = time t _x)
For each repellent treatment at each observation time.

  The resulting percentage was then inverse sine transformed and an ANOVA (Analysis of Variance) was performed using the repellency calculated from all five iterations. Multiple comparisons of mean values were made using the Student-Newman-Keuls test. The average arc sine value from ANOVA was then converted back to a percentage. The results are shown in Table 9.

  1% DHN was ranked first in terms of repellency and was not statistically distinguishable from 1% DEET.

Example 6
Dihydronepetalactone repellency test against sand flies (Stomoxys calcitrans) DHN (mainly 1S, 9S, derived from hydrogenation of trans, cis-nepetalactone) Mixture of 5R, 6R-5,9-dimethyl-3-oxabicyclo [4.3.0] nonan-2-one; formula 4) and dihydronepetalactone prepared according to Example 2 (Experimental sample # 2 MDHN) was tested for repellency against Stomokiss calcitrans essentially as described in Example 3. The DHN used here was prepared in Example 4 in that it was derived by hydrogenation of trans, cis-nepetalactone (using Pd / SrCO ₃ catalyst) crystallized from a commercial oil (Berge, NJ). It was different from what I did. In these experiments, an additional positive control compound, p-menthane-3.8-diol (PMD), obtained from Takasago International Corp. (USA), Rockleight, NJ. ) Included. The experimental design is summarized in Table 10, and all data shown is the average of 5 replicate experiments.

  In these tests, the exact time to "first landing" is that some landing occurred before the first exposure period of 2 minutes in 3 or more of the 5 iterations for each test variable. It could not be measured.

  The distribution of the landing density by the fly flies on the membrane treated with dihydronepetalactone was analyzed over time as shown graphically in FIG. The total number of landings allowed on each membrane during the course of the experiment is measured and the results are summarized in Table 11. Landing began upon exposure of the insect to the test container and appeared to peak after about 5 minutes and then gradually decreased with time. In general, the number of landings on membranes treated with 1% concentration of dihydronepetalactone is significantly less than that observed for untreated (IPA) membranes, as observed with DEET (1% w / v). It was equivalent. p-Mentane-3,8-diol (PMD) was less effective at preventing landing than either dihydronepetalactone or DEET throughout the course of the experiment and observed some initial repellency The compound became ineffective after 6 minutes. Again, this data shows that 1% dihydronepetalactone showed repellent activity equivalent to 1% DEET.

  Percent repellency and statistical analysis were performed as described in Example 5, and the results are shown in Table 12.

  mDHN, DEET and DHN perform statistically equally well, provide 43.2-55.5% repellency and are statistically better than PMD which gives only 4.7% repellency when compared to IPA Met.

Example 7
Dihydronepetalactone repellent test against anopheles (Anopheles albimanus) DHN (mainly 1S, 9S, 5R), derived from hydrogenation of trans, cis-nepetalactone, referred to as “Experimental Sample # 1” , 6R-5,9-dimethyl-3-oxabicyclo [4.3.0] nonan-2-one; formula 4) and a mixture of dihydronepetalactone prepared according to Example 2 (experimental sample # 2 and MDHN) was tested for repellency against 100 non-fed mature female Aedes abalone, essentially as described in Example 3. The DHN used here is that of Example 4 in that it was derived by hydrogenation of trans, cis-nepetalactone (using Pd / SrCO ₃ catalyst) crystallized from a commercial oil (Berge, Bloomfield, NJ). It was different from what was manufactured in. PMD was again included as an additional control. The experimental design is summarized in Table 13, and all data shown is the average of 5 replicate experiments.

  In these tests, the exact time to "first probing" is that some probing occurred before the first exposure period of 2 minutes in two or more of the five iterations for each test variable. It could not be measured. The distribution of the probe density by anopheles on the membrane treated with dihydronepetalactone was analyzed over time as shown graphically in FIG. Proving began upon exposure of the insect to the test container and then gradually increased over time. In general, the number of probes on membranes treated with 1% concentration of dihydronepetalactone was significantly lower than that observed for untreated (IPA) membranes throughout the experiment.

  The total number of allowed probes on each membrane was measured during the course of the experiment and the results are summarized in Table 14. The data shows that 1% dihydronepetalactone is A.I. It shows that it showed higher repellent activity compared to either DEET or PMD at the same concentration for albicans.

  Percent repellency and statistical analysis were performed as described in Example 5, and the results are shown in Table 15.

  mDHN was statistically superior to DEET and provided 46.1% repellency. DHN is statistically equivalent to mDHN, but is also statistically equivalent to DEET, providing 32.9% repellency. DEET and PMD, which provided 13.3% and 11.5% repellency, respectively, were statistically equivalent in terms of efficacy.

Example 8
Repellency of dihydronepetalactone against the deer mite, Ixodes scapularis, DHN (primarily 1S, 9S, 5R, 6R) prepared by hydrogenation of trans, cis-nepetalactone prepared as in Example 7. Consisting of -5,9-dimethyl-3-oxabicyclo [4.3.0] nonan-2-one; a mixture of formula 4) and dihydronepetalactone prepared according to Example 2, using DEET as a positive control Included in the test Tested for repellency against Scapularis.

  A 25 μL volume of each compound (30% (w / v) in isopropanol) was applied in a 4 cm diameter circle drawn on the left forearm of six male human volunteers. Each volunteer applied two repellents individually in two circles on this forearm, and a single 4 cm diameter circle drawn on the other arm served as a control for tick attraction. Left untreated. Non-feeding larvae raised in the laboratory of the deer mite, Ixodes scapularis, were brought within 1 mm of an untreated circle with a cotton swab (Q-tip (registered trademark)). If normal exploratory behavior was observed and / or if the insect went over the untreated area, it was considered eligible and then provided to the treated area. Eligible mites that searched for or went over the treatment area within 60 seconds were recorded as not repelled. Eligible ticks that did not search or stopped searching and / or retreated from the processing area within 60 seconds were recorded as being repelled. In addition, qualifying ticks that went over the treatment area but left within an additional 60 seconds were recorded as repelled.

  Each volunteer was provided with 5 eligible ticks in each treated circle approximately every hour. Exposure was continued until 3 from any group of 5 provided ticks were considered “attracted”. The first unrepelled tick was defined as the first attracted tick, followed by the second attracted tick within the same or next exposure period. The first identified attracting tick time was considered the time when complete repellency was “broken” for the volunteer.

  The data (Table 16) show that DEET provided an average full protection time of 124 minutes from the deer tick, Ixodes scapularis, but DHN was also valid for 109 minutes and mDHN (mixed diastereomers of DHN) for 85 minutes Indicates that there was. Thus, it is clear that both DHN and mDHN repel deer mites. ANOVA of protection time was performed, which showed that DHN, mDHN and DEET were not statistically distinguishable in terms of their repellency against these ticks.

Example 9
Repellency of dihydronepetalactone applied to human subjects against mosquito Anofeles albicans DHN (primarily 1S, 9S, 5R, 6R) prepared by hydrogenation of trans, cis-nepetalactone prepared as in Example 7. Consisting of -5,9-dimethyl-3-oxabicyclo [4.3.0] nonan-2-one; a mixture of formula 4) and dihydronepetalactone prepared according to Example 2 using an adult volunteer, DEET was included in the study as a positive control. Tested for repellency against albicans. A test cage (2 × 2 × 2 feet) with two sleeved inlets on each of two opposite sides was used with a hand rest in the center. The side and top surfaces were blocked, and the bottom was equipped with a mirror to facilitate observation. 200 mature female mosquitoes who had not previously received a blood diet and had been taken up with their normal diet of 10% sucrose for 24 hours prior to use were released into the test cage. Each volunteer was prequalified as an attractant by having 10 insect landings on their untreated forearm within 30 seconds of insertion into the cage.

A 1.0 mL volume of each compound (either 5% or 10% (w / v) in isopropanol) was placed on the forearm of 6 male human volunteers, making the rest of the arm inaccessible to insects. It was applied to a 250 cm ² area. Each volunteer applied different repellents individually on each forearm. After the applied repellent was allowed to dry for 30 minutes, the forearm was placed into the test cage at 30 minute intervals for 5 minutes and the number of mosquitoes probed or stabbed during each exposure period was recorded. Repellent cessation was recorded for each repellent on each volunteer. Decommissioning is defined as the first confirmed stab, and the first confirmed stab is defined as a stab followed by a second stab either within the same exposure period or within the next exposure period. did. The data is shown in Table 17 as the average complete protection time. The data show that both DHN and mDHN provide complete protection from stabbing for a significant period of time (eg, 10% (w / v) 3.5 hours and 5 hours, respectively) and are given by DEET at the same concentration. Indicates that they are comparable.

  Data was analyzed using ANOVA, which showed that 5% and 10% mDHN solutions were not statistically distinguishable from 5% and 10% DEET, respectively, in terms of efficacy. The 5% and 10% solutions of DHN provided less protection time, although statistically equal to the corresponding solution of mDHN.

The chemical structure of naturally derived iridoid (methylcyclopentanoid) nepetalactone is shown. Combined gas chromatography / mass spectrometry (GC) of a fraction (A) rich in nepetalactone distilled from commercially available catnip oil with that of material (B) produced from this fraction by hydrogenation -MS) shows the total ion chromatogram from the analysis. FIG. 2 shows mass spectra of main components of the fraction (A) rich in nepetalactone and the hydrogenated substance (B) identified by GC-MS analysis. Figure 8 shows ¹³ C NMR analysis performed on a distillate-rich fraction of commercially available catnip oil rich in nepetalactone. Figure 7 shows a ¹³ C NMR spectrum obtained from analysis of dihydronepetalactone produced by hydrogenation of a commercially available catnip oil distilled fraction rich in nepetalactone. Figure 3 shows the distribution of probe density over time during testing of various repellents against female Aedes aegypti in an in vitro repellent test. ¹³ C NMR analysis of trans, cis-nepetalactone is shown. Figure 7 shows ¹³ C NMR analysis of dihydronepetalactone derived by hydrogenation of trans, cis-nepetalactone. Figure 3 shows the distribution of probe density over time during testing of dihydronepetalactone induced by hydrogenation of trans, cis-nepetalactone against female Aedes aegypti in an in vitro repellency test. Figure 6 shows the distribution of landing density over time during testing of various repellents against a fly fly (Stomokis calcitrans) in an in vitro repellent test. Figure 2 shows the distribution of probe density over time during testing of various repellents against female anopheles (Anoferes albicans) in an in vitro repellent test.

Claims (25)

A composition that repels insects when applied to a human, animal or inanimate host, having the general formula

A composition comprising dihydronepetalactone or a mixture of dihydronepetalactone stereoisomers represented by:   The composition of claim 1, wherein the dihydronepetalactone stereoisomer is a (9S) -dihydronepetalactone stereoisomer derived from (7S) -nepetalactone.   The composition of claim 1 comprising 1S, 9S, 5R, 6R-5,9-dimethyl-3-oxabicyclo [4.3.0] nonan-2-one.   The composition of claim 1, comprising dihydronepetalactone in an amount of from about 0.001% to about 80% by weight of the total weight of the composition.   The composition of claim 1, comprising dihydronepetalactone in an amount of about 0.01% to about 30% by weight of the total weight of the composition.   2. A composition according to claim 1 comprising one or more members of the group consisting of adjuvants, carriers and insect repellent compounds which are not dihydronepetalactones.   Adjuvants are thickeners, buffers, chelating agents, preservatives, fragrances, antioxidants, gelling agents, stabilizers, surfactants, emollients, colorants, aloe, waxes, and therapeutically or cosmetically The composition of claim 6 selected from the group consisting of active ingredients.   Carrier is silicone, petrolatum, lanolin, liquid hydrocarbon, agricultural spray oil, paraffin oil, tall oil, liquid terpene hydrocarbon and terpene alcohol, aliphatic and aromatic alcohol, ester, aldehyde, ketone, mineral oil, higher alcohol, fine powder The composition of claim 6 selected from the group consisting of organic and inorganic solid materials.   7. The composition of claim 6, wherein the carrier comprises an aerosol composition adapted to disperse dihydronepetalactone into the atmosphere by compressed gas.   Non-hydronepetalactone insect repellents are benzyl, benzyl benzoate, 2,3,4,5-bis (butyl-2-ene) tetrahydrofurfural, butoxypolypropylene glycol, N-butylacetanilide, 6,6-dimethyl-5, 6-dihydro-1,4-pyrone-2-carboxylate normal-butyl, dibutyl adipate, dibutyl phthalate, di-normal-butyl succinate, N, N-diethyl-meta-toluamide, dimethyl carbonate, dimethyl phthalate 2-ethyl-2-butyl-1,3-propanediol, 2-ethyl-1,3-hexanediol, di-normal-propyl isocincomeronate, 2-phenylcyclohexanol, p-menthane-3,8 A group consisting of a diol and normal-propyl N, N-diethylsuccinamate The composition of claim 6 which is al selected.   A composition according to claim 1, which repels insects comprising stinging insects, wood worms, harmful insects and domestic pests.   A composition according to claim 1 which repels one or more of mosquitoes, flies and ticks.   A composition according to claim 1 in the form of a colon, lotion, spray, cream, gel, ointment, bath or shower gel, foamed product, make-up, deodorant, shampoo, hair spray or rinse or personal soap.   A composition according to claim 1 in the form of an insect repellent product.   15. An article according to claim 14, selected from the group consisting of air fresheners, candles, fragrances, fibers, sheets, cloth, paper, paint, inks, clay, wood, furniture, carpets, hygiene products, plastics, and polymers. . Bees, gnats, tsutsugamushi, fleas, green-headed gills, mosquitoes, horn flies, ticks, hornets, wood worms, house flies, cockroaches, lice, cockroaches, kingfishers, moss A composition for repelling one or more insects selected from the group consisting of:
General formula

A composition comprising dihydronepetalactone or a mixture of dihydronepetalactone stereoisomers represented by: A composition having an average complete protection time that is statistically indistinguishable from that of N, N-diethyl-m-toluamide

A composition comprising dihydronepetalactone or a mixture of dihydronepetalactone stereoisomers represented by: General formula

A method of repelling an insect from a human, animal or inanimate host comprising exposing the insect to dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by: General formula for repelling insects from humans, animals or inanimate hosts

Use of dihydronepetalactone or a mixture of dihydronepetalactone stereoisomers represented by: In the presence of palladium on a catalyst support that is not SrCO _{3 the} following scheme

A process for the preparation of dihydronepetalactone of formula (XVI) comprising hydrogenating nepetalactone of formula (XV) according to   21. The method of claim 20, wherein the catalyst support is selected from the group consisting of carbon, alumina, silica, silica-alumina, titania, titania-alumina, titania-silica, barium, calcium, compounds thereof, and combinations thereof. .   The process according to claim 20, wherein the catalyst support is carbon.   21. The method of claim 20, wherein the palladium content is about 0.1 to about 20%.   21. The process of claim 20, wherein the process is accomplished in the presence of a metal promoter.   21. The method of claim 20, wherein the process is conducted at a temperature of about 25 ° C to about 250 ° C and a pressure of about 0.1 MPa to about 20 MPa.

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