HK1115872A - Nepetalactams and n-substituted derivatives thereof - Google Patents

Description

Nepetalactams and N-substituted derivatives thereof

This application claims the benefit of U.S. provisional application No. 60/639,945 filed on month 12, 29, 2004 and U.S. provisional application No. 60/639,951 filed on month 12, 29, 2004, both of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to nepetalactams and N-substituted derivatives thereof, which are useful insect and arthropod repellents.

Background

Insect repellents are widely used worldwide as a means of reducing human-insect vector contact and thereby minimizing the incidence of vector-borne disease transmission and the general discomfort associated with insect bites. The most well known and widely used active ingredient in the commercial field of topical insect repellents is the synthetic benzene derivative, N-Diethylbenzamide (DEET).

Nepetalactone, schematically represented by formula I, as a major component of essential oils secreted by plants of the genus nepeta and as an active ingredient in catnip, has been known to be a natural repellent effective against a wide variety of insects [ Eisner, t., Science (1964) 146: 1318-1320].

Repellency to german cockroach by nepetalactone, as well as the cis, trans (Z, E) and trans, cis (E, Z) isomers alone, is disclosed in U.S. patent 6,524,605.

There is a continuing need to obtain as broad a variety of insect repellents as possible and nepetalactams and derivatives thereof have been found to be useful insect and arthropod repellents.

Summary of The Invention

In one embodiment, the invention relates to a compound represented schematically by formula III:

wherein R is (a) a non-methyl alkyl group, (b) an alkenyl group, (c) an alkynyl group, or (d) an aryl group.

Another embodiment of the invention is a composition comprising (a) a carrier and (b) a compound of formula IV above, wherein R is H, alkyl, alkenyl, alkynyl, or aryl.

Yet another embodiment of this invention is a method of repelling an insect or arthropod by exposing the insect or arthropod to a compound of formula III above, wherein R is H, alkyl, alkenyl, alkynyl, or aryl.

Yet another embodiment of the present invention is the use of a compound of formula III above, wherein R is H, alkyl, alkenyl, alkynyl or aryl, for repelling insects and/or arthropods from human, animal or non-animal hosts.

Yet another embodiment of the invention is an article incorporating a compound of formula III above, wherein R is H, alkyl, alkenyl, alkynyl, or aryl.

Yet another embodiment of the invention is a method of producing an insect repellent composition or insect repellent article by forming a composition from or adding to an article a compound of formula III above, wherein R is H, alkyl, alkenyl, alkynyl, or aryl.

Yet another embodiment of the present invention is a method of producing a composition or fragrance article to be applied to the skin by forming a composition from or adding to the article a compound of formula III above, wherein R is H, alkyl, alkenyl, alkynyl or aryl. The composition to be applied to the skin may have fragrance or other therapeutic properties.

Brief Description of Drawings

Figures 1-12 show the results of experiments on the effect of a given nepetalactam or derivative compound thereof and/or combination thereof on the detection behavior of Aedes aegypti (Aedes aegypti) in the in vitro Gupta box landing test method described below, compared to a given control group. The abscissa represents time (unit: minute), and the ordinate represents the average number of landings of mosquitoes.

Detailed Description

The invention relates to a catalyst based on C₂-C₂₀Novel compounds of N-substituted nepetalactams, which are useful as insect repellents. The invention also relates to nepetalactams and N-substituted nepetalactams, and compositions thereof, which are also useful as insect repellents.

Lactams are nitrogen analogs of cyclic esters or lactones, and lactams, particularly N-substituted lactams, are generally more stable to hydrolysis than their corresponding lactones. Nepetalactam (formula II) and methyl-substituted nepetalactam derivatives (formula IIIa)

Has been identified by Eisenbraun et al [ J.org.chem. (1988) 53: 3968-3972] in the presence of a catalyst. Nepetalactones are treated with anhydrous ammonium salts to synthesize nepetalactams. Methyl-substituted nepetalactams are synthesized with nepetalactone and methylamine, or by alkylation of nepetalactams.

The present invention provides compounds that can be represented schematically by formula III,

wherein R is (1) a non-methyl alkyl group, (2) an alkenyl group, (3) an alkynyl group or (4) an aryl group. The term "alkane" refers to a compound of formula C_nH_2n+2Is a saturated hydrocarbon of (1). The term "alkene" refers to an unsaturated hydrocarbon containing one or more C ═ C double bonds, and the term "alkyne" refers to an unsaturated hydrocarbon containing one or more carbon-carbon triple bonds. Alkenes or alkynes require a minimum of two carbon atoms. The cyclic compounds require a minimum of three carbon atoms. The term "aromatic" refers to benzene and compounds that behave chemically similarly to benzene.

Although there is in principle no limitation on the type of alkyl, alkenyl, alkynyl or aryl groups that may be used as R groups in the practice of the invention, the size of the R substituents should be considered practical to make them commercially practical. It may furthermore be desirable to avoid the introduction of highly reactive functional groups in the R substituents to avoid side reactions.

Preferably, R of the formula (III) is (1) C₂-C₂₀Alkyl group, (2) C₂-C₂₀Alkenyl, (3) C₃-C₂₀Alkynyl or (4) C₆-C₂₀And (4) an aryl group.

More preferably, R of formula (III) is selected from:

(1)C₂H₅；

(2)C₃-C₂₀or C₃-C₁₂A linear, branched or cyclic alkyl or alkenyl group;

(3) c comprising a heteroatom selected from O, N and S₃-C₂₀Or C₃-C₁₂A linear, branched or cyclic alkyl or alkenyl group;

(4) unsubstituted or substituted C₆-C₂₀Or C₆-C₁₂Aryl, wherein the substituents are selected from (a) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (b) a halogen selected from Cl, Br and F; and

(5) unsubstituted or substituted C comprising a heteroatom selected from O, N and S₆-C₂₀Or C₆-C₁₂Aryl, wherein the substituents are selected from (a) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (b) a halogen selected from Cl, Br and F.

In a more specific embodiment, R is selected from (1) C₂H₅、(2)C₃-C₁₂And (3) C containing a heteroatom selected from the group consisting of O, N and S₃-C₁₂A linear, branched or cyclic alkyl or alkenyl group.

In another more particular embodiment, R is unsubstituted or substituted phenyl, wherein the substituents are selected from (a) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (b) a halogen selected from Cl, Br and F. An example of an alkyl group substituted by F is CF₃。

Particularly preferred R groups include ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, cyclohexyl, n-octyl, trimethylpentyl, cyclooctyl, allyl, propargyl, phenyl, methylphenyl, ethylphenyl, n-propylphenyl, n-butylphenyl, tert-butylphenyl, p-chlorophenyl and p-bromophenyl.

The compound represented by formula III is prepared by alkylation of nepetalactam. N-substituted nepetalactams can also be prepared by reacting nepetalactones with amines as described in the process by Eisenbraun et al (supra) for preparing N-methyl nepetalactams, but this reaction can result in a mixture of amines requiring additional purification steps to obtain the desired product.

Cis, trans, cis, trans

a b c d

Nepetalactams can be prepared from nepetalactone. The nepetalactone bicyclic structure can exist in any one of four stereoisomeric forms represented by structural formulae Ia-Id:

nepetalactone, extracted from essential oils of the plant leaves of catmint (catmint), is a preferred source of raw material because nepetalactone is present in large quantities therein and is readily purified therefrom. This provides an ideal route for the preparation of the compounds of the invention from natural products. Fractional distillation, as described herein, has been found to be an effective method for purifying nepetalactones from essential oils and separating several stereoisomers from each other. Chromatographic separation is also suitable.

Only the first three listed nepetalactone stereoisomers are present in essential oils of the plant Nepeta america. Cis, trans-nepetalactone is the major isomer that can be isolated from the plant Nepeta cateria and is most useful due to its availability. Other plant species have been identified as being rich in trans, cis and cis, cis nepetalactone isomers in essential oils.

Nepetalactams can be prepared by contacting nepetalactone (formula I) with anhydrous ammonia as shown in reaction I, by the method described by Eisenbraun et al, supra:

reaction I

The N-substituted nepetalactams can be prepared by the following method: the nepetalactams (formula II) are reacted with a suitable metal hydride to form a nepetalactam salt, which is subsequently contacted with a suitable alkylating agent to form an N-substituted nepetalactam (formula III in reaction II).

Reaction II

A metal hydride is used to form the amide metal salt of nepetalactam. Suitable metal hydrides include, but are not limited to, potassium hydride and sodium hydride. Very reactive metal hydrides such as lithium aluminum hydride, which can reduce the carbonyl on the lactam, may be too reactive to be preferred.

Suitable alkylating agents for the N-alkylation of nepetalactam salts include chlorides, bromides, iodides, sulfates, methanesulfonates, tosylates and triflates of alkyl, alkenyl, alkynyl or aryl groups. Alkyl, alkenyl, alkynyl or aryl iodides are preferably used as alkylating agents. Preferred alkylating agents comprise an alkyl, alkenyl or aryl group selected from (1) C₂H₅；(2)C₃-C₂₀A linear, branched or cyclic alkyl or alkenyl group; (3) c comprising a heteroatom selected from O, N and S₃-C₂₀A linear, branched or cyclic alkyl or alkenyl group; (4) unsubstituted or substituted C₆-C₂₀Aryl, wherein the substituents are selected from (a) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (b) a halogen selected from Cl, Br and F; and (5) unsubstituted or substituted C containing a heteroatom selected from O, N and S₆-C₂₀Aryl, wherein the substituents are selected from (a) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (b) a halogen selected from Cl, Br and F.

In another embodiment, preferred alkylating agents comprise alkyl and alkenyl groups selected from (1) C₂H₅；(2)C₃-C₁₂A linear, branched or cyclic alkyl or alkenyl group; (3) c comprising a heteroatom selected from O, N and S₃-C₁₂A linear, branched or cyclic alkyl or alkenyl group. In another embodiment, preferred aryl groups are unsubstituted or substituted phenyl, wherein the substituents are selected from (a) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (b) a halogen selected from Cl, Br and F.

The solvent used in the N-alkylation reaction must be anhydrous and may be any suitable anhydrous solvent such as Tetrahydrofuran (THF), diethyl ether, dimethoxyethyl ether or dioxane.

The conversion of nepetalactam to N-substituted nepetalactam occurs at a temperature of from about 0 ℃ to about room temperature (about 25 ℃).

The alkylation reaction was quenched by the addition of about 10% aqueous sodium bisulfite solution and the reaction mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave the crude N-substituted nepetalactam product, which was purified by column chromatography on silica gel using ethyl acetate/hexane as the eluent. Fractions were monitored by Thin Layer Chromatography (TLC) using 25% ethyl acetate/hexane as eluent. Still, Kahn and Mitra [ j.org.chem. (1978) 43: 2923-.

The N-substituted nepetalactam-containing fractions obtained by column chromatography can be combined and the solvent removed under reduced pressure to give the N-substituted nepetalactam product. The product can be used¹H and¹³the CNMR method was analyzed to identify the structure.

N-aryl nepetalactams may also be as Chan [ Tetrahedron Letters (199)6)37：9013-9016]The process is carried out by reacting nepetalactam (formula II) with the appropriate triarylbisalane (formula IV in reaction III) in Cu (OAc)₂And triethylamine to form N-aryl nepetalactams (formula V in reaction III)

Reaction III

Wherein Ar is an unsubstituted or substituted aryl group as defined above in formula III.

In view of the structures Ia-Id as shown above, the compounds described herein may be considered to have stereoisomerism, which may be enantiomeric or diastereomeric. Unless a particular stereoisomer is specifically indicated, the discussion herein should be understood to refer to all possible isomers, whether the structure is shown in stereochemically obscured form in formula III or as a particular stereoisomer (in which case other stereoisomers are also possible).

The compounds of the present invention include compounds that are single stereoisomers as well as compounds that are mixtures of stereoisomers. Compositions may be formed from mixtures of compounds of the present invention, wherein R, as described above, differs among the various compounds forming the composition.

Nepetalactams, N-methyl nepetalactams, and the compounds described by formula III are all compounds useful for a variety of purposes, such as use as an active in an effective amount to repel a variety of insects or arthropods, or as a fragrance compound in a fragrance composition, or as a topical care agent for skin. For example, these compounds may be applied topically to the skin, hide, hair, fur or feathers of a human or animal host to repel insects or arthropods, or topically to a non-animal host such as growing plants or crops to impart repellency or a pleasant odor or fragrance to insects or arthropods. Non-animal hosts may also include any article of manufacture infested with insects, such as buildings, furniture, and the like. Typically, these items are considered to be a desirable food source for the insect or a desirable habitat for the insect.

A repellent or repellent composition refers to a compound or composition that repels an insect or arthropod from its preferred host or from an article of manufacture suitable for the insect. Most known repellents are not active toxicants at all, but rather prevent damage to humans, animals and plants and/or articles by rendering the food source or living conditions of the insect/arthropod unattractive or unpleasant. Generally, a repellent is a compound or composition that can be topically applied to a host or can be added to an insect-susceptible item to prevent the insect/arthropod from approaching or staying within the three-dimensional space of a nearby host or item. In both cases, the action of the repellent is to drive the insect/arthropod away from or repel (1) the host (thereby minimizing the frequency of "biting" into the host), or (2) the item (thereby protecting the item from pests). The repellent may be in gaseous (olfactory), liquid or solid (gustatory) form.

One property that is important to the overall effectiveness of a repellent is surface activity, since many repellents contain both polar and non-polar regions in their structure. The second property is volatility. Repellents are an unusual class of compounds, and evaporation of an active ingredient from the skin surface of a host or from an insect repellent is essential for effectiveness, which can be measured by protecting the host from biting or by protecting the article from damage.

In the case of insect/arthropod repellents which are topically applied to the skin, hide, hair, feathers or fur of a host, one aspect of the efficacy of the repellent is that the concentration of the repellent in the space immediately above the surface to which it is applied is sufficient to repel the insects/arthropods. The desired concentration level of repellent in the space is obtained primarily from evaporation, but the rate of evaporation is affected by the rate of absorption into the skin or other surface, and thus, penetration into and through a surface is almost always an undesirable way of losing repellent from the surface. Similar considerations must be made for items containing a repellent or items to which a repellent has been added, since a minimum concentration of repellent needs to be achieved in the three-dimensional space around the item itself to achieve the desired level of protection.

Inherent volatility is an important consideration in selecting materials for use as insect/arthropod repellant actives. However, when needed for the purpose of attempting to increase the persistence of an active without decreasing and preferably increasing volatility, various strategies can be taken. For example, the active may be formulated with a polymer and inert ingredients to increase the persistence on the surface to which it is applied or within the article. The presence of inert ingredients in the formulation dilutes the actives in the formulation and must be balanced against the risk of loss due to undesirable rapid evaporation and the risk of applying too little active to be effective. Alternatively, the active ingredient may be contained in microcapsules to control the rate of loss from the surface or article; the release rate of the active ingredient can be controlled with precursor molecules that slowly decompose on the surface or within the article; or a synergist may be used to continually encourage evaporation of the active from the composition.

The release of the active ingredient can be achieved, for example, by sub-micron capsules in which the active ingredient is encapsulated (surrounded) within skin nourishing proteins, as if the air were trapped within air pockets. The protein may be used at a concentration of about 20%. One application of repellents contains many of these protein capsules suspended in an aqueous emulsion or water for spraying. Upon contact with the skin, the protein capsules begin to break down releasing the encapsulated actives. This process continues as each microcapsule is depleted and then replaced by a new capsule that contacts the skin and releases its active ingredient. This process may last for 24 hours for one application. Because proteins adhere very effectively to the skin, these formulations are very resistant to sweat (being washed down by sweat) and other sources of water.

One particular advantage of nepetalactams, N-methyl nepetalactams, and the compounds described by formula III, is that each possess characteristics in which their relative volatility makes them suitable for use in achieving the desired high levels of active concentration on, above, and around a surface or article as described above. One or more of these nepetalactam compounds are typically used for such purposes as the active in a composition in which the compound is mixed with a carrier suitable for wet or dry application of the composition to any surface, for example in the form of a liquid, aerosol, gel, aerogel, foam or powder (e.g. dustable or dusting powder). Suitable carriers include any of a variety of organic and inorganic liquid, solid or semi-solid carrier commodities or carrier formulations useful in formulating skin or insect repellent products. In formulating a skin product or a topical insect repellent, a dermatologically acceptable carrier is preferably selected. For example, the carrier may comprise water, ethanol, silicone, petrolatum, lanolin, or many other well known carrier components. Examples of organic liquid carriers include liquid aliphatic hydrocarbons (e.g., pentane, hexane, heptane, nonane, decane, and the like) and liquid aromatic hydrocarbons.

Examples of other liquid hydrocarbons include oils produced by the distillation of coal and the distillation of various types of various grades of petrochemical feedstocks, including mineral oils obtained by the fractionation of petroleum. Other petroleum-based oils include those commonly referred to as agricultural spray oils (e.g., so-called low and medium viscosity spray oils, consisting of middle distillates in petroleum distillation, which are only mildly volatile). Such oils are often highly refined and may contain only trace amounts of unsaturated compounds. Furthermore, such oils are usually paraffinic oils and accordingly can be emulsified with water and emulsifiers, diluted to lower concentrations and used as sprays. As with paraffin oil, tall oil obtained from sulfate cooking of wood pulp can be used in a similar manner. Other organic liquid carriers may include liquid terpene hydrocarbons and terpene alcohols such as alpha pinene, dipentene, terpineol, and the like.

Other carriers include silicones, petrolatum, lanolin, liquid hydrocarbons, agricultural spray oils, paraffin oils, tall oils, liquid terpene hydrocarbons and terpene alcohols, aliphatic and aromatic alcohols, esters, aldehydes, ketones, mineral oils, higher alcohols, finely divided organic and inorganic solid materials. In addition to the above-mentioned liquid hydrocarbons, the carrier may also contain conventional emulsifiers which may be used to disperse and dilute the nepetalactam compound in water for end use. Additional liquid carriers can include organic solvents such as aliphatic and aromatic alcohols, esters, aldehydes, and ketones. Aliphatic monohydric alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol and tert-butanol. Suitable alcohols include glycols (e.g., ethylene glycol and propylene glycol) and pinacols. Suitable polyols include glycerol, arabitol, erythritol, sorbitol, and the like. Finally, suitable cyclic alcohols include cyclopentanol and cyclohexanol.

Conventional aromatic and aliphatic esters, aldehydes and ketones can be used as supports and sometimes in combination with the alcohols mentioned above. Additional liquid carriers include higher boiling petroleum products such as mineral oil and higher alcohols (e.g., cetyl alcohol). In addition, conventional or so-called "stabilizers" (e.g., tert-butylsulfinyldimethyldithiocararbonate) may be used in combination with or as a component of one or more of the carriers used in the compositions prepared according to the present invention.

Many clays having a lamellar structure with interstices and synthetic inorganic materials similar to such clays in chemical composition, crystallinity and lamellar morphology are suitable for use as supports in the present invention. Suitable clays having an interstitial layered structure include smectite, kaolin, muscovite, vermiculite, phlogopite, chloromagnite and chrysotile and mixtures thereof. Smectite clays and kaolin clays are preferred. Smectite clays include montmorillonite, beidellite, nontronite, saponite, hectorite, sauconite, and the like. The kaolinite clay includes kaolinite, deckite, nacrite, antigorite, etc. Montmorillonite is most preferred. The average particle size is in the range of 0.5-50 microns.

Desirable properties of a topical composition or article that is repellent to insects and/or arthropods include low toxicity, resistance to water immersion or loss of perspiration, low or no odor or at least pleasant odor, ease of application, and the ability to rapidly form a dry, non-tacky surface film on the skin or other surface of the host. To achieve these properties, the topical repellent or repellent article is formulated such that animals infested with insects and/or arthropods (e.g., flea-bearing dogs, lice-bearing poultry, horn or tick-bearing cows and humans) can be treated with the repellent (including compositions thereof) by contacting the skin, hair, fur or feathers of such human or animal with an effective amount of the repellent to repel insects or arthropods from the human or animal host.

Application of an effective amount of the repellent composition to a surface (e.g., skin, bark, hair, fur, feathers, or plant or crop surface) infested by insects can be accomplished by dispersing the repellent in air or by dispersing or adding the repellent as a liquid mist to powder or dust, which will cause the repellent to fall onto the desired host surface. It is also desirable to formulate the repellent by combining nepetalactam compounds to form a composition with a fugitive carrier to be applied as a spray. Such compositions may be aerosol, sprayable liquid or sprayable powder compositions suitable for dispersing the active compound in air by means of compressed gas or mechanical pump spraying. Likewise, direct spreading of a liquid/semi-solid/solid repellent onto a host in either a wet or dry (e.g., as a breakable solid) manner is an effective method of contacting a surface of the host with an effective amount of the repellent.

In addition, it may be desirable to combine one or more of the active compounds described herein with one or more other compounds known to be insect repellent in a composition to obtain a synergistic effect that such a combination may produce. Suitable compounds known to achieve this goal with insect repellency include, but are not limited to, dihydronepetalactone, benzil, benzyl benzoate, 2, 3: 4, 5-bis (2-butene-1, 4-diyl) tetrahydrofurfural, butoxypropylene glycol, N-butylacetanilide, 6-dimethyl-5, 6-dihydro-1, 4-pyrone-2-carboxylic acid N-butyl ester, dibutyl adipate, dibutyl phthalate, di-N-butyl succinate, N, n-diethylisophthalamide, dimethyl carboxanoate, dimethyl phthalate, 2-ethyl-2-butyl-1, 3-propanediol, 2-ethyl-1, 3-hexanediol, di-N-propyl 2, 5-pyridinedicarboxylate, 2-phenylcyclohexanol, p-menthane-3, 8-diol and N, N-diethylsuccinamic acid N-propyl ester.

The insect repellent composition may also contain one or more essential oils and/or active ingredients of essential oils in addition to one or more of the active compounds described herein. "essential oils" are defined as any class of volatile oils obtained from plants having odor and other plant characteristics. Examples of useful essential oils include: bitter almond oil, fennel oil, basil oil, bay oil, caraway oil, cardamom oil, cedar oil, celery oil, chamomile oil, cinnamon oil, citronella oil, clove oil, coriander oil, cumin oil, dill oil, eucalyptus oil, fennel oil, ginger oil, grapefruit oil, lemon oil, lime oil, peppermint oil, parsley oil, peppermint oil, pepper oil, rose oil, spearmint oil (menthol), sweet orange oil, thyme oil, turmeric oil and wintergreen oil. Examples of active ingredients in essential oils are: citronellal, methyl salicylate, ethyl salicylate, propyl salicylate, citronellol, safrole and limonene.

Insects and arthropods which may be repelled by the compounds and/or compositions of the present invention may include any member of a large group of invertebrates characterized by their adult state (non-adult state including larvae and pupae) whose bodies may be divided into head, chest, abdomen, three pairs of legs, and usually (but not always) two pairs of membranous wings. This definition thus includes a variety of stinging insects (such as ants, bees, chiggers, fleas, mosquitoes, ticks, wasps), stinging flies [ such as black flies, green flies, stable flies, horn flies (blood-disturbing flies) ], piercing insects (such as termites), pests (such as house flies, cockroaches, lice, non-cockroaches, wood lice) and household pests (such as flour weevils and bean beetles, dust ticks, moths, silverfish, weevils).

Hosts that may be in need of insect repellency include any plant or animal (including humans) infested by insects. Generally, the host is considered to be a desirable food source for the insect or a desirable habitat for the insect. For example, humans and animals serve as food source hosts for blood-feeding insects and arthropods (such as stinging flies, chiggers, fleas, mosquitoes, ticks, and lice).

In another embodiment, the nepetalactam compounds may be used as fragrance compounds or as actives in fragrance compositions and applied to human or animal skin or hair in a topical manner to impart a pleasant fragrance, such as in skin lotions and in human or pet fragrances.

In particular, because the compounds are pleasant fragrant, in another embodiment of the invention, one or more nepetalactam compounds are formulated as a composition for use as a product for another primary purpose. The aroma and/or insect repellency of these products may be enhanced by the presence therein of the active compounds or compositions of the present invention. Such products include, but are not limited to, colognes, lotions, sprays, creams, gels, ointments, bath and shower gels, foam products (such as shave foams), cosmetics, deodorants, shampoos, pomades/rinses, and body soap compositions (such as hand soaps and bath/shower soaps). The compounds may of course be simply added to such products to impart a pleasant aroma. Any route of addition practiced in the art is satisfactory.

One corresponding aspect of the various products discussed above is another alternative embodiment of the present invention, which is a method of producing the subject compositions, topical skin care agents or articles by providing in a composition, or adding to a composition, skin care agent or article, one or more nepetalactam compounds, or mixtures of stereoisomers thereof. Such products and the above-described methods and processes illustrate the use of nepetalactams as fragrance compounds or perfumes, or in fragrance compositions or formulations, or in topical skin care agents, or in articles of manufacture. For example, in producing the subject compositions, the compositions can be prepared as a sprayable liquid, aerosol, foam, cream, ointment, gel, paste, powder, or breakable solid. The manufacturing process in such cases may thus comprise mixing the active with a suitable carrier or other inert ingredient to facilitate delivery in the form of the substance, such as a liquid carrier for easy spraying, a propellant for aerosols or foams, a viscous carrier for creams, ointments, gels or pastes, or a dry or semi-solid carrier for powders or breakable solids.

Compositions containing one or more of the above active compounds and prepared to act as insect/arthropod repellents, fragrance products, skin care agents, or other personal care products may also contain other therapeutic or cosmetic co-agents or adjunct ingredients typical in the personal care industry. Examples thereof include fungicides, sunscreens, sun-screening agents, vitamins, tanning agents, plant extracts, anti-inflammatory agents, antioxidants, radical scavengers, retinoids, alpha-hydroxy acids, disinfectants, antibiotics, antibacterial agents, antihistamines; adjuvants such as thickening agents, buffers, chelating agents, preservatives, gelling agents, stabilizers, surfactants, emollients, colorants, aloe vera, waxes and penetration enhancers; and mixtures of any two or more thereof.

In yet another embodiment of the present invention, a nepetalactam compound is added to an article to produce an insect/arthropod repellant effect. Articles encompassed within the scope of this embodiment include articles including textiles such as clothing, outdoor or military equipment such as mosquito nets; natural products such as wood; or leaves of plants susceptible to attack by insects.

In another embodiment of the invention, a nepetalactam compound is added to an article to produce a pleasing fragrance, or a nepetalactam compound is applied to the surface of an object to impart an odor thereto. The particular mode of application depends on the surface in question and the concentration required to impart the necessary odor intensity. Articles contemplated within the scope of these embodiments include articles including textiles, air fresheners, candles, various scented articles, fibers, boards, paper, paint, ink, clay, wood, furniture (e.g., for patios and decks), carpeting, sanitary goods, plastics, polymers, and the like.

The nepetalactam compound may be mixed in the composition with other components, such as a carrier, in an amount effective for a particular use (such as an insect/arthropod repellent, fragrance product, or other skin care agent). The amount of active compound contained in the composition will generally not exceed about 80% by weight of the final product, although higher amounts may be used in certain applications and are not limited. More preferably, the compound is present in an amount of at least about 0.001%, preferably from about 0.01% to about 20%, by weight of the composition or article. The particular composition will depend on the intended use.

Other methods of using nepetalactams are disclosed in US 2003/062,357, US2003/079,786, and US 2003/191,047, all of which are incorporated herein in their entirety.

The invention is further described in the following specific embodiments, but the scope of the invention is not limited thereto.

Examples

General procedure

All reactions and manipulations related to the synthesis of control and test repellents were performed in standard laboratory fume hoods in standard laboratory glassware. Nepetalactone (I), which consists predominantly of the cis, trans-stereoisomer, is obtained by steam distillation of commercial catmint oil (from Nepeta cataria, commercially available from Berj (Bloomfield, NJ)). All inorganic salts and organic solvents except anhydrous THF were from VWR Scientific (West Chester, PA). All other reagents used in the examples were obtained from Sigma-Aldrich Chemical (Milwaukee, Wis.) and used without treatment. The determination of pH was performed using pH paper from MicroEssential Laboratory, Inc (Brooklyn, NY). The lactam product was purified by column chromatography on silica gel using ethyl acetate/hexane as eluent; the purified product was characterized by NMR spectroscopy. NMR spectra were obtained using a deuterated solvent from Cambridge Isotrope Laboratories, Inc. (Andover, MA) in Bruker DRX Advance (500 MHz)¹H，125MHz¹³C; bruker Biospin Corp., Billerica, MA).

The abbreviations used have the following meanings: "mL" means milliliters, "μ L" means microliters, "g" means grams, "mg" means milligrams, "kpa" means kilopascals, "MP" means melting point, "NMR" means nuclear magnetic resonance, "° C" means degrees Celsius, and "ATP" means adenosine triphosphate.

Synthesis of tris (4-chlorophenyl) bismuthane (triarylbismuthane used in reaction III):

to 100mL of a 1M solution of 4-chlorophenylmagnesium bromide in ether cooled in an ice bath was added dropwise a solution of 10.51g of bismuth trichloride in 50mL of tetrahydrofuran under nitrogen to keep the temperature below 5 ℃. The reaction was allowed to warm to room temperature and stirred for an additional 1 hour. The reaction was quenched by the addition of 50mL of saturated aqueous ammonium chloride at 5 ℃. The solid in the reaction system was removed by filtration and extracted with 200mL of diethyl ether. The filtrates were combined and washed with 100mL of saturated aqueous ammonium chloride solution. The ammonium chloride solution was extracted with 200mL of ether, the ether solutions were combined and washed twice with 75mL of saturated aqueous ammonium chloride solution. The ether solution was dried over anhydrous magnesium sulfate and concentrated in vacuo to give a crude solid, which was extracted with several portions of hot hexane. The hexane extracts (400mL) were combined and concentrated in vacuo to give tris (4-chlorophenyl) bismuthane (13.94g, 62% yield, m.p.100 ℃) as a yellow solid. NMR analysis of the product was consistent with that of tris (4-chlorophenyl) bismuthane.

Synthesis of tris (4-bromophenyl) bismuthane (triarylbismuthane used in reaction III):

to 320mL of a 4-bromophenyl magnesium bromide/ether solution (prepared by reacting 54.9g of 1, 4-dibromobenzene with 5.63g of magnesium) in an ice bath was added a solution of 23.6g of bismuth trichloride in 120mL of tetrahydrofuran dropwise under nitrogen, over 1 hour, maintaining the temperature below 7 ℃. The reaction was allowed to warm to room temperature and stirred for an additional 1 hour. The reaction was quenched by addition of 60mL of saturated aqueous ammonium chloride at 5 ℃. The solid in the reaction system was removed by filtration and extracted with 150mL of diethyl ether. The aqueous layer was extracted three times with 100mL of diethyl ether. The combined ether solutions were washed with 150mL of saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a crude solid, which was extracted with several portions of hot hexanes. The hexane extracts (700mL) were combined and concentrated in vacuo to give tris (4-bromophenyl) bisalane (17.5g, 35% yield, m.p.112 ℃) as a yellow solid. NMR analysis of the product was consistent with that of tris (4-bromophenyl) bismuthane.

The procedures described in examples 1-15 were used to synthesize the various compounds shown in Table 1, where R refers to a substituent on the nepetalactam.

TABLE 1N-substituted nepetalactams

R	Structural formula numbering
		H	II
Methyl radical	IIIa
		Ethyl radical	IIIb
N-propyl radical	IIIc
		N-butyl	IIId
N-pentyl group	IIIe
		N-hexyl radical	IIIf
N-octyl radical	IIIg
		Cyclohexyl radical	IIIh
Isopropyl group	IIIi
		Allyl radical	IIIj
Propargyl group	IIIk
		Phenyl radical	Va
Para-chloroPhenyl radical	Vb
		Para-bromophenyl radical	Vc

Example 1

Schizonepeta lactam (II)

(4aS, 7S, 7aR) -4, 7-dimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ] pyridin-1-one

Nepetalactams are prepared from cis, trans-nepetalactones by the method of Eisenbraun et al (supra). 100g of cis, trans-nepetalactone/250 mL of methylene chloride was sealed in a 1-liter reaction vessel with a pressure regulator along with a Teflon  coated stir bar. The container is evacuated and filled with gaseous ammonia three times and then with ammonia to 103.4 kPa. The solution was stirred at room temperature under constant ammonia pressure for three days. The vessel was vented and purged with nitrogen. The solution was transferred to a 500mL round bottom flask and the solvent was removed under reduced pressure to give a yellow thick syrup (109.49 g). The crude nepetalactam was purified by vacuum distillation to give a pale yellow crystalline solid. The solid was recrystallized from hexane to give pure nepetalactam (89.60g, 88% yield), observed MP ═ 94-96 ℃ (MP ═ 95-96 ℃ in the literature).

Example 2

N-methyl-nepetalactam (IIIa)

(4aS, 7S, 7aR) -2, 4, 7-trimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ] pyridine-

1-ketones

N-methyl-nepetalactams are prepared from cis, trans-nepetalactones by the method of Eisenbraun et al (supra). 3.3g of nepetalactam (structure II) in 100mL of THF was treated with 7.1g of methyl iodide, 2.8g of potassium hydroxide, and 1.28g of tetrabutylammonium bromide in a 500mL round bottom flask with stirring at room temperature. After 3 days, the solvent was removed from the reaction under reduced pressure. To the resulting residue was added water (150mL) and the aqueous mixture was treated 3 times with 50mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give N-methyl-nepetalactam (IIIa) as a pale yellow oil (2.7g, 75% yield). The product was purified by column chromatography on silica gel using ethyl acetate/hexane as eluent. The NMR analysis of the resulting product was consistent with the structure of N-methyl-nepetalactam represented by structural formula IIIa.

Example 3

N-Ethyl-nepetalactam (IIIb)

(4aS, 7S, 7aR) -2-Ethyl-4, 7-dimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ]

Pyridin-1-ones

An oven dried 250mL three-necked round bottom flask was cooled to room temperature under a nitrogen flow and a solution of 1.66g of nepetalactam (II) in 30mL of dry THF was pipetted into the flask while the flask was purged with nitrogen. In addition, 0.80g of 30% potassium hydride-mineral oil suspension was washed 3 times with 10mL of hexane to remove mineral oil. The obtained white solid was added to the reaction solution in small amounts with stirring at 0 ℃ with evolution of gas. After the addition was complete, the reaction mixture was stirred for 30 minutes, treated with 1.2mL of iodoethane, and then stirred at 0 ℃ for 30 minutes. The reaction was then allowed to warm to room temperature for 30 minutes, after which the reaction was quenched by the addition of 30mL of 10% aqueous sodium bicarbonate. The mixture was extracted 3 times with 20mL of dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the crude product as a brown oil. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane as an eluent to give a purified product (1.02g, 53% yield). NMR analysis of the purified product was consistent with the structure of N-ethyl-nepetalactam represented by structural formula IIIb.

Example 4

N-propyl-nepetalactam (IIIc)

(4aS, 7S, 7aR) -2-n-propyl-4, 7-dimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta

[c] Pyridin-1-ones

An oven dried 250mL three-necked round bottom flask was cooled to room temperature under a nitrogen flow and a solution of 1.12g of nepetalactam (II) in 30mL of dry THF was pipetted into the flask while the flask was purged with nitrogen. Additionally, 0.90g of 30% potassium hydride-mineral oil suspension was washed 3 times with 10mL of hexane to remove mineral oil. The obtained white solid was added to the reaction solution in small amounts with stirring at 0 ℃ with evolution of gas. After the addition was complete, the reaction mixture was stirred for 30 minutes, treated with 1.46mL iodopropane, and then stirred at 0 ℃ for 30 minutes. The reaction was then allowed to warm to room temperature for 30 minutes, after which the reaction was quenched by the addition of 30mL of 10% aqueous sodium bicarbonate. The mixture was extracted 3 times with 20mL of dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the crude product as a brown oil. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane as an eluent to give a purified product (1.42g, 69% yield). NMR analysis of the purified product was consistent with the structure of N-propyl-nepetalactam represented by structural formula IIIc.

Example 5

N-butyl-nepetalactam (IIId)

(4aS, 7S, 7aR) -2-n-butyl-4, 7-dimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ] pyridin-1-one

An oven dried 250mL three-necked round bottom flask was cooled to room temperature under a nitrogen flow and a solution of 1.12g of nepetalactam (II) in 30mL of dry THF was pipetted into the flask while the flask was purged with nitrogen. Additionally, 0.80g of 30% potassium hydride-mineral oil suspension was washed 3 times with 10mL of hexane to remove mineral oil. The obtained white solid was added to the reaction solution in small amounts with stirring at 0 ℃ with evolution of gas. After the addition was complete, the reaction mixture was stirred for 30 minutes, treated with 1.67mL of iodobutane, and then stirred at 0 ℃ for 30 minutes. The reaction was then allowed to warm to room temperature for 30 minutes, after which the reaction was quenched by the addition of 30mL of 10% aqueous sodium bicarbonate. The mixture was extracted 3 times with 20mL of dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the crude product as a brown oil. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane as an eluent to give a purified product (1.54g, yield 100%). NMR analysis of the purified product was consistent with the structure of N-butyl-nepetalactam represented by structural formula IIId.

Example 6

N-pentyl-nepetalactam (IIIe)

(4aS, 7S, 7aR) -2-n-pentyl-4, 7-dimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ] pyridin-1-one

An oven dried 250mL three-necked round bottom flask was cooled to room temperature under a nitrogen flow and a solution of 4.65g of nepetalactam (II) in 100mL of dry THF was pipetted into the flask while the flask was purged with nitrogen. In addition, 6.05g of 30% potassium hydride-mineral oil suspension was washed 3 times with 30mL of hexane to remove mineral oil. The obtained white solid was added to the reaction solution in small amounts with stirring at 0 ℃ with evolution of gas. After the addition was complete, the reaction mixture was stirred for 30 minutes, treated with 5.93mL of iodopentane, and then stirred at 0 ℃ for 30 minutes. The reaction was then warmed to room temperature and held for 30 minutes and quenched by the addition of 50mL of 10% aqueous sodium bicarbonate. The mixture was extracted 3 times with 30mL dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the crude product as a brown oil (7.2 g). The crude product was purified by silica gel column chromatography using ethyl acetate/hexane as an eluent to give a purified product (4.4g, yield 67%). NMR analysis of the purified product was consistent with the structure represented by N-pentyl-nepetalactam, represented by structural formula IIIe.

Example 7

N-hexyl-nepetalactam (IIIf)

(4aS, 7S, 7aR) -2-n-hexyl-4, 7-dimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ] pyridin-1-one

An oven-dried 250mL three-necked round bottom flask was cooled to room temperature under a nitrogen flow, and a solution of 4.65g of nepetalactam (II) in 100mL of anhydrous THF was added to the flask with a pipette while purging the flask with nitrogen. In addition, 6.0g of 30% potassium hydride-mineral oil suspension was washed 3 times with 30mL of hexane to remove mineral oil. The obtained white solid was added to the reaction solution in small amounts with stirring at 0 ℃ with evolution of gas. After the addition was complete, the reaction mixture was stirred for 30 minutes, treated with 6.7mL of iodohexane, and then stirred at 0 ℃ for 30 minutes. The reaction was then allowed to warm to room temperature for 30 minutes, after which the reaction was quenched by the addition of 30mL of 10% aqueous sodium bicarbonate. The mixture was extracted 3 times with 30mL dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the crude product as a brown oil (5.46 g). The crude product was purified by silica gel column chromatography using ethyl acetate/hexane as an eluent to give a purified product (3.2g, yield 46%). NMR analysis of the purified product was consistent with the structure of N-hexyl-nepetalactam represented by structural formula IIIf.

Example 8

N-octyl-nepetalactam (IIIg)

(4aS, 7S, 7aR) -2-N-octyl-4, 7-dimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ] pyridin-1-one

The oven dried 250mL three neck round bottom flask was cooled to room temperature under a nitrogen flow, and while purging the flask with nitrogen, a solution of 4.65g of nepetalactam (II) in 30mL of dry THF was pipetted into the flask, followed by cooling the solution to 0 ℃ in an ice bath under a nitrogen atmosphere. In addition, 6.0g of 30% potassium hydride-mineral oil suspension was washed 3 times with 30mL of hexane to remove mineral oil. The obtained white solid was added to the reaction solution in small amounts with stirring at 0 ℃ with evolution of gas. After the addition was complete, the reaction mixture was stirred for 30 minutes, treated with 8.2mL iodooctane, and then stirred at 0 ℃ for 30 minutes. The reaction was then allowed to warm to room temperature for 30 minutes, after which the reaction was quenched by the addition of 30mL of 10% aqueous sodium bicarbonate. The mixture was extracted 3 times with 30mL dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the crude product as a brown oil (5.36 g). The crude product was purified by silica gel column chromatography using ethyl acetate/hexane as an eluent to give a purified product (4.26g, 53% yield). NMR analysis of the purified product was consistent with the structure of N-octyl-nepetalactam represented by structural formula IIIg.

Example 9

N-cyclohexyl-nepetalactam (IIIh)

(4aS, 7S, 7aR) -2-cyclohexyl-4, 7-dimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ] pyridin-1-one

The oven dried 250mL three neck round bottom flask was cooled to room temperature under a nitrogen flow, and while purging the flask with nitrogen, a solution of 4.65g of nepetalactam (II) in 100mL of dry THF was pipetted into the flask, followed by cooling the solution to 0 ℃ in an ice bath under a nitrogen atmosphere. In addition, 6.0g of 30% potassium hydride-mineral oil suspension was washed 3 times with 30mL of hexane to remove mineral oil. The obtained white solid was added to the reaction solution in small amounts with stirring at 0 ℃ with evolution of gas. After the addition was complete, the reaction mixture was stirred for 30 minutes, treated with 5.87mL of cyclohexyl iodide, and then stirred at 0 ℃ for 30 minutes. The reaction was then allowed to warm to room temperature for 30 minutes, after which the reaction was quenched by the addition of 30mL of 10% aqueous sodium bicarbonate. The mixture was extracted 3 times with 30mL dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the crude product as a brown oil. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane as an eluent to give a purified product (0.17g, yield 2.4%). NMR analysis of the purified product was consistent with the structure of N-cyclohexyl-nepetalactam represented by structural formula IIIh.

Example 10

N-isopropyl-nepetalactam (IIIi)

(4aS, 7S, 7aR) -2-isopropyl-4, 7-dimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ] pyridin-1-one

The oven dried 250mL three neck round bottom flask was cooled to room temperature under a nitrogen flow, and while purging the flask with nitrogen, a solution of 3.0g of nepetalactam (II) in 50mL of dry THF was pipetted into the flask, followed by cooling the solution to 0 ℃ in an ice bath under a nitrogen atmosphere. Additionally, 4.0g of 30% potassium hydride-mineral oil suspension was washed 3 times with 50mL of hexane to remove mineral oil. The obtained white solid was added to the reaction solution in small amounts with stirring at 0 ℃ with evolution of gas. After the addition was complete, the reaction mixture was stirred for 30 minutes, treated with 5.0g of 2-iodopropane and subsequently stirred for 30 minutes at 0 ℃. The reaction was then allowed to warm to room temperature for 30 minutes, after which the reaction was quenched by the addition of 30mL of 10% aqueous sodium bicarbonate. The mixture was extracted 3 times with 30mL dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the crude product as a brown oil. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane as an eluent to give a purified product (3.20g, yield 85%). NMR analysis of the purified product was consistent with the structure of N-isopropyl-nepetalactam, represented by structural formula IIIi.

Example 11

N-allyl-nepetalactam (IIIj)

(4aS, 7S, 7aR) -2-allyl-4, 7-dimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ] pyridin-1-one

The oven dried 250mL three neck round bottom flask was cooled to room temperature under a nitrogen flow, and while purging the flask with nitrogen, a solution of 0.936g of nepetalactam (II) in 20mL of dry THF was pipetted into the flask, followed by cooling the solution to 0 ℃ in an ice bath under a nitrogen atmosphere. Additionally, 1.9g of 30% potassium hydride-mineral oil suspension was washed 3 times with 30mL of hexane to remove mineral oil. The obtained white solid was added to the reaction solution in small amounts with stirring at 0 ℃ with evolution of gas. After the addition was complete, the reaction mixture was stirred for 30 minutes, treated with 1.52g of allyl iodide and subsequently stirred for 30 minutes at 0 ℃. The reaction was then allowed to warm to room temperature for 30 minutes, after which the reaction was quenched by the addition of 30mL of 10% aqueous sodium bicarbonate. The mixture was extracted 3 times with 30mL dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the crude product as a light brown oil. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane as an eluent to give a purified product (2.04g, yield 35%). NMR analysis of the purified product was consistent with the structure of N-allyl-nepetalactam represented by structural formula IIIj.

Example 12

N-propargyl-nepetalactam (IIIk)

(4aS, 7S, 7aR) -2-propargyl-4, 7-dimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ] pyridin-1-one

The oven dried 250mL three neck round bottom flask was cooled to room temperature under a nitrogen flow, and while purging the flask with nitrogen, a solution of 1.0g of nepetalactam (II) in 30mL of dry THF was pipetted into the flask, followed by cooling the solution to 0 ℃ in an ice bath under a nitrogen atmosphere. Additionally, 1.2g of 30% potassium hydride-mineral oil suspension was washed 3 times with 30mL of hexane to remove mineral oil. The obtained white solid was added to the reaction solution in small amounts with stirring at 0 ℃ with evolution of gas. After the addition was complete, the reaction mixture was stirred for 30 minutes, treated with 1.07 propargyl bromide, and then stirred for 30 minutes at 0 ℃. The reaction was then allowed to warm to room temperature for 30 minutes, after which the reaction was quenched by the addition of 30mL of 10% aqueous sodium bicarbonate. The mixture was extracted 3 times with 30mL dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the crude product as a brown oil (5.36 g). The crude product was purified by silica gel column chromatography using ethyl acetate/hexane as an eluent to give a purified product (0.92g, yield 75%). NMR analysis of the purified product was consistent with the structure of N-propargyl-nepetalactam represented by structural formula IIIk.

Example 13

N-Phenylnepetalactams (Va)

(4aS, 7S, 7aR) -4, 7-dimethyl-2-phenyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ] pyridin-1-one

A slurry of 0.30g of nepetalactam (II), 1.60g of triphenylbismuthyl, 0.33g of anhydrous copper (II) acetate and 0.51mL of triethylamine in 10mL of dichloromethane was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure to give a crude reaction mixture. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane as an eluent to give the purified product as a colorless oil (0.26g, yield 60%). NMR analysis of the purified product was consistent with the structure of N-phenyl-nepetalactam represented by structural formula Va.

Example 14

P-chlorophenyl Schizonepeta lactam (Vb)

(4aS, 7S, 7aR) -2- (4-chlorophenyl) -4, 7-dimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ] pyridin-1-one

A slurry of 0.20g of nepetalactam (II), 1.32g of tris (4-chlorophenyl) bismuthane, 0.22g of anhydrous copper (II) acetate, 0.34mL of triethylamine in 25mL of dichloromethane was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure to give a crude reaction mixture. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane as an eluent to give the purified product as a pale yellow oil (0.21g, yield 63%). NMR analysis of the purified product was consistent with the structure of N-4-chlorophenyl-nepetalactam represented by structural formula Vb.

Example 15

P-bromophenyl nepetalactam (Vc)

(4aS, 7S, 7aR) -2- (4-bromophenyl) -4, 7-dimethyl-2, 4a, 5, 6, 7, 7 a-hexahydro-1H-cyclopenta [ c ] pyridin-1-one

A slurry of 0.20g of nepetalactam (II), 1.64g of tris (4-bromophenyl) bisalane, 0.22g of anhydrous copper (II) acetate, 0.34mL of triethylamine in 15mL of dichloromethane was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure to give a crude reaction mixture. The crude product was purified by column chromatography on silica gel using ethyl acetate/hexane as eluent to give the purified product as a pale yellow oil (0.30g, 77% yield). NMR analysis of the purified product was consistent with the structure of N-4-bromophenyl-nepetalactam represented by structural formula Vc.

The repellency of the products of examples 1-15 to Aedes aegypti mosquitoes was evaluated by the in vitro Gupta Box landing test (Gupta box landing assay). In this method, the chamber contains 5 wells, each covered with Baudruche (animal intestine) membrane. Each well was filled with bovine blood containing sodium citrate (to prevent clotting) and ATP (72 mg ATP disodium salt per 26ml of blood) and heated to 37 ℃. 25 μ L of isopropyl alcohol (IPA) containing one sample or control was applied to each membrane. The concentration in IPA was 1% (w/v). The negative control was pure IPA and the positive control was a 1% (w/v) solution of DEET.

Approximately 250 female aedes aegypti mosquitoes (4 days old) were introduced into the chamber after 5 minutes. The number of mosquitoes probing the membrane was recorded at 2 minute intervals in each case for 20 minutes. The results thus obtained for the compounds of examples 1 to 12 are depicted in figures 1 to 12 (labeled as examples 16 to 27), wherein each data is the average of five replicates.

The% average repellency of the repellent at a given repellent test solution concentration can be determined from these data using the following equation:

% average repellency ═ C-T/Cx 100

Where C is the total number of landings on IPA control wells and T is the total number of landings on test solution wells. The% average repellency at a concentration of 1% (w/v) for the compounds of examples 1-15 is given in table 2, where R refers to the substituent on the nepetalactam.

Example 16

FIG. 1II comparison of repellency to DEET

Example 17

FIG. 2 repellency comparison of IIIa to DEET

Example 18

FIG. 3 repellency comparison of IIIb to DEET

Example 19

FIG. 4 repellency comparison of IIIc to DEET

Example 20

FIG. 5 repellency comparison of IIId with DEET

Example 21

FIG. 6 repellency comparison of IIIe to DEET

Example 22

FIG. 7 repellency comparison of IIIf with DEET

Example 23

FIG. 8 repellency comparison of IIIg to DEET

Example 24

FIG. 9 repellency comparison of IIIh with DEET

Example 25

FIG. 10 repellency comparison of IIIi with DEET

Example 26

FIG. 11 repellency comparison of IIIj with DEET

Example 27

FIG. 12 repellency comparison of IIIk with DEET

Table 2N-substituted nepetalactams: % average repellency (1.0% weight/volume)

Compound (I)	R	% average repellency
			IIIIIaIIIbIIIcIIIdIIIeIIIfIIIgIIIhIIIiIIIjIIIkVaVbVc	Hmethyl already n-propyl n-butyl n-pentyl n-hexyl n-octyl cyclohexyl isopropyl allyl propargylphenyl p-chlorophenyl p-bromophenyl	66.094.897.999.897.397.597 293.298.994.778.195.693.175.341.5

Claims (28)

1. A compound represented schematically by the formula:

wherein R comprises (a) a non-methyl alkyl, (b) an alkenyl, (c) an alkynyl, or (d) an aryl.

2. The compound of claim 1, wherein R comprises (a) C₂-C₂₀Alkyl group, (b) C₂-C₂₀Alkenyl, (C) C₃-C₂₀Alkynyl or (d) C₆-C₂₀And (4) an aryl group.

3. The compound of claim 1, wherein R comprises one of:

(a)C₂H₅，

(b)C₃-C₂₀a linear, branched or cyclic alkyl or alkenyl group,

(c) c comprising a heteroatom selected from O, N and S₃-C₂₀A linear, branched or cyclic alkyl or alkenyl group,

(d) unsubstituted or substituted C₆-C₂₀Aryl, wherein the substituents are selected from (i) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (ii) a halogen selected from Cl, Br and F, and

(e) unsubstituted or substituted C comprising a heteroatom selected from O, N and S₆-C₂₀Aryl, wherein the substituents are selected from (i) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (ii) a halogen selected from Cl, Br and F.

4. The compound of claim 1, wherein R is selected from (a) C₂H₅、(b)C₃-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (C) C comprising a heteroatom selected from O, N and S₃-C₁₂A linear, branched or cyclic alkyl or alkenyl group.

5. The compound of claim 1, wherein R is unsubstituted or substituted phenyl, wherein the substituent is selected from the group consisting of (a) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (b) a halogen selected from Cl, Br and F.

6. The compound of claim 1 which is a single stereoisomer of a single compound, or a mixture of stereoisomers of a single compound.

7. A composition comprising (a) a carrier and (b) a compound represented by the general formula:

wherein R is H, alkyl, alkenyl, alkynyl or aryl.

8. The composition of claim 7 wherein R is (a) H, (b) C₁-C₂₀Alkyl group, (C) C₂-C₂₀Alkenyl, (d) C₃-C₂₀Alkynyl or (e) C₆-C₂₀And (4) an aryl group.

9. The composition of claim 7, wherein R is selected from the group consisting of:

(a)CH₃、C₂H₅，

(b)C₃-C₂₀a linear, branched or cyclic alkyl or alkenyl group,

(c) c comprising a heteroatom selected from O, N and S₃-C₂₀A linear, branched or cyclic alkyl or alkenyl group,

(d) unsubstituted or substituted C₆-C₂₀Aryl, wherein the substituents are selected from (i) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (ii) a halogen selected from Cl, Br and F, and

(e) unsubstituted or substituted C comprising a heteroatom selected from O, N and S₆-C₂₀Aryl, wherein the substituents are selected from (i) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (ii) a halogen selected from Cl, Br and F.

10. The composition of claim 7 wherein R is selected from (a) CH₃、(b)C₂H₅、(c)C₃-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (d) comprises a group selected from O, N andc of a hetero atom of S₃-C₁₂A linear, branched or cyclic alkyl or alkenyl group.

11. The composition of claim 7 wherein R is unsubstituted or substituted phenyl wherein said substituents are selected from the group consisting of (a) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (b) a halogen selected from Cl, Br and F.

12. The composition of claim 7 which is a single stereoisomer of a single compound, or a mixture of stereoisomers of a single compound.

13. The composition of claim 7 further comprising a compound selected from the group consisting of dihydronepetalactones, dibenzoyl, benzyl benzoate, 2, 3: 4, 5-bis (2-butene-1, 4-diyl) tetrahydrofurfural, butoxypropylene glycol, N-butylacetanilide, 6-dimethyl-5, 6-dihydro-1, 4-pyrone-2-carboxylic acid N-butyl ester, dibutyl adipate, dibutyl phthalate, di-N-butyl succinate, N, repellents of N-diethylisophthalamide, dimethyl carboxanoate, dimethyl phthalate, 2-ethyl-2-butyl-1, 3-propanediol, 2-ethyl-1, 3-hexanediol, di-N-propyl 2, 5-pyridinedicarboxylate, 2-phenylcyclohexanol, p-menthane-3, 8-diol and N, N-diethylsuccinamic acid N-propyl ester.

14. The composition of claim 7, wherein the composition further comprises an essential oil.

15. The composition of claim 14, wherein the essential oil is selected from any one or more of: bitter almond oil, fennel oil, basil oil, bay oil, caraway oil, cardamom oil, cedar oil, celery oil, chamomile oil, cinnamon oil, citronella oil, clove oil, coriander oil, cumin oil, dill oil, eucalyptus oil, fennel oil, ginger oil, grapefruit oil, lemon oil, lime oil, peppermint oil, parsley oil, peppermint oil, pepper oil, rose oil, spearmint oil (menthol), sweet orange oil, thyme oil, turmeric oil and wintergreen oil.

16. The composition of claim 7, further comprising any one or more of the following adjuvants: fungicides, sunscreens, vitamins, tanning agents, plant extracts, anti-inflammatory agents, antioxidants, free radical scavengers, retinoids, alpha hydroxy acids, disinfectants, antibiotics, antibacterial agents and antihistamines.

17. The composition of claim 7 comprising said compound in an amount of from about 0.001% to about 80% by weight of the total composition.

18. The composition of claim 7 in the form of a sprayable liquid, an aerosol, a foam, a cream, an ointment, a gel, a paste, a powder, or a breakable solid.

19. A method of repelling an insect or arthropod comprising exposing the insect or arthropod to a compound represented by the general formula:

wherein R is H, alkyl, alkenyl, alkynyl or aryl.

20. The method of claim 19, wherein R is (a) H, (b) C₁-C₂₀Alkyl group, (C) C₂-C₂₀Alkenyl, (d) C₃-C₂₀Alkynyl or (e) C₆-C₂₀And (4) an aryl group.

21. The compound of claim 19, wherein R is selected from:

(a)CH₃、C₂H₅，

(b)C₃-C₂₀straight chain,A branched or cyclic alkyl or alkenyl group,

(c) c comprising a heteroatom selected from O, N and S₃-C₂₀A linear, branched or cyclic alkyl or alkenyl group,

(d) unsubstituted or substituted C₆-C₂₀Aryl, wherein the substituents are selected from (i) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (ii) a halogen selected from Cl, Br and F, and

(e) unsubstituted or substituted C comprising a heteroatom selected from O, N and S₆-C₂₀Aryl, wherein the substituents are selected from (i) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (ii) a halogen selected from Cl, Br and F.

22. The method of claim 19, wherein R is selected from (a) CH₃、(b)C₂H₅、(c)C₃-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (d) C containing a heteroatom selected from O, N and S₃-C₁₂A linear, branched or cyclic alkyl or alkenyl group.

23. The method of claim 19, wherein R is unsubstituted or substituted phenyl, wherein the substituents are selected from the group consisting of (a) C optionally substituted with Cl, Br or F₁-C₁₂A linear, branched or cyclic alkyl or alkenyl group and (b) a halogen selected from Cl, Br and F.

24. The method of claim 19, wherein the compound is a single stereoisomer of a single compound, or is a mixture of stereoisomers of a single compound.

25. The method of claim 19 comprising exposing the insect or arthropod to a composition comprising the compound in an amount of from about 0.001% to about 80% by weight, based on the total weight of the composition.

26. The method of claim 19 comprising exposing a blood-feeding insect or arthropod to the compound.

27. The method of claim 19 comprising exposing an insect or arthropod selected from the group consisting of stinging flies, chiggers, fleas, mosquitoes, ticks, and lice to said compound.

28. The method of claim 19 comprising applying the compound to the skin, hide, hair, feathers or fur of a human or animal host of an insect or arthropod.