CN101316811A

CN101316811A - Puleganic amides as insect repellants

Info

Publication number: CN101316811A
Application number: CNA2006800443291A
Authority: CN
Inventors: M·夏尔多内
Original assignee: EI Du Pont de Nemours and Co
Current assignee: EIDP Inc
Priority date: 2005-09-30
Filing date: 2006-09-29
Publication date: 2008-12-03

Abstract

The present invention provides substituted puleganic amides and compositions thereof, which are both useful as a topical treatment for skin, such as a repellant for insects and arthropods.

Description

Puleganic amides as insect repellent

The application requires the U.S. Provisional Patent Application number 60/722 of on September 30th, 2006 application, the U.S. Provisional Patent Application of on September 30th, 663 and 2006 application number 60/722,806 rights and interests, these two patent applications all are attached to this paper by reference and partly are used for all purposes.

Technical field

Puleganic amides that the present invention relates to replace (puleganic amide) and composition thereof.The purposes of described compound and composition comprises the Local treatment that is used for skin, for example as insect or arthropodan repellent.

Background of invention

Insect repellent is used as globally reduces the measure that the people contacts with insect vector, thereby makes the incidence of vector-borne disease propagation and the general discomfort relevant with sting drop to minimum.

In the topical insect repellents of commercial usefulness, famous and the most widely used activeconstituents is synthetic benzamide derivatives N, N-DEET (DEET).Yet DEET has some to make us feeling less-than-ideal characteristic, for example the greasy feeling on the not good and skin of smell.

Have been found that the raw material that can derive from nepeta oil is the substitute of insect repellent DEET, for example Schizonepetolactone is [referring to Eisner, Science (1964) 146:1318-1320] and dihydro nepetalactone (referring to Hallahan, WO 03/79786 and US 03/225,290).Yet however, still need to provide low-cost and effective insect repellent, particularly can be from the insect repellent of natural origin acquisition.

Summary of the invention

In one embodiment, the invention provides generally by the represented replacement Puleganic amides of following formula I schematic construction:

R wherein ¹And R ²Independently be selected from separately:

a)H、CH ₃、C ₂H ₅；

B) C ₃-C ₂₀Straight chain, side chain or cyclic alkane base or alkylene;

C) contain and be selected from O, N and the heteroatomic C of S ₃-C ₂₀Straight chain, side chain or cyclic alkane base or alkylene;

D) C that does not replace or replace ₆-C ₂₀Aryl, wherein substituting group is selected from C ₁-C ₁₂Straight chain, side chain or cyclic alkane base or alkylene; With

E) contain the C that is selected from O, N and heteroatomic not replacement of S or replacement ₆-C ₂₀Aryl,

Wherein substituting group is selected from C ₁-C ₁₂Straight chain, side chain or cyclic alkane base or alkylene; Precondition is R ¹And R ²Be not hydrogen simultaneously; And precondition is R ¹And R ²Can choose wantonly and form cycloalkyl, bicyclic alkyl, cycloalkenyl group or bicycloenyl together, unless formed Puleganic amides is N-methyl-N-phenyl Puleganic amides.

In another embodiment, the present invention relates to comprise formula I compound compositions.Said composition also can comprise one or more following compositions except that comprising formula I compound: carrier, makeup auxiliary material or pharmaceutical excipient and other insect/arthropod repellent be dihydro nepetalactone for example.

In another embodiment, the present invention relates to repel insects and/or arthropodan method, this method comprises is exposed in above-mentioned formula I compound or its composition insect and/or arthropods.

In other another embodiment, the present invention relates to prepare skin, animal skin, hair, feather or the fur or other the surperficial method for compositions that can be applicable to people or performing animal, this method comprises generally mixes in (a) carrier and makeup auxiliary material or the pharmaceutical excipient one or both by compound shown in the above-mentioned formula I mutually with (b).

The accompanying drawing summary

Fig. 1 and Fig. 2 are illustrated in the external landing experimental technique of the present invention, and the compound that the present invention limits is compared with specified contrast, Aedes aegypti (Aedes aegypti) is thrust the test result of behavior effect.X-coordinate represent the time (minute), ordinate zou is represented the average number of falls of mosquito.

Detailed Description Of The Invention

Although Puleganic amides can be made into the nepetalactone derivative, before unprecedented about Puleganic amides and derivative thereof are for the report of repel insects and/or arthropodan purposes. Cause This present invention relates to Puleganic amides, Puleganic amides composition and relates to Puleganic amides and combination Thing is processed the purposes of (for example insect and arthropodan repellant) as local skin.

Term Pu Le used herein acid (Puleganic acid) is 2-isopropyl-5-methyl cyclopentane formic acid, generally uses following formula I V representation:

Available nepetalactone is that the raw material preparation is applicable to that the present invention is as the Pu Le acid of intermediate. Chaste tree The mustard lactone, general representation by Formula Il:

Can be by obtaining in schizonepeta plant (for example schizonepeta (Nepeta the Cataria)) essential oil. The schizonepeta leaves of plants is Preferred raw material sources are purified because have a large amount of nepetalactones and be easy to. Can be by steaming Steam distillation herbaceous plant raw material obtains the essential oil of schizonepeta plant, a kind of main isomery of nepetalactone Body, namely anti-, suitable-nepetalactone (seeing formula IIa) can adopt benzinum-hexane, passed through by catnip oil The crystallisation purifying comes out.

Except anti-, outside suitable-nepetalactone (IIa), the another kind of main isomers of nepetalactone is suitable, and is anti--nepetalactone (seeing formula IIb), it has (S)-configuration on 7-carbon (press the illustrated numbering of following formula II, namely on the cyclopenta ring with the carbon of methyl):

When nepetalactone hydrogenation, it is sour and dihydro nepetalactone (" DHN ") that it produces Pu Le Mixture. DHN is generally by Formula Il I representation, can single diastereomer or with non-The combination of enantiomer exists:

The structure of 9S-dihydro nepetalactone stereoisomer is as follows.

(1S, 5S, 9S, 6R)-5,9-dimethyl-3-oxa-(1S, 9S, 5R, 6R)-5,9-dimethyl-3-oxa-

Two rings [4.3.0]-ninth of the ten Heavenly Stems-2-ketone two rings [4.3.0]-ninth of the ten Heavenly Stems-2-ketone

(1S, 5S, 9S, 6S)-5,9-dimethyl-3-oxa-(1S, 9S, 6S, 5R)-5,9-dimethyl-3-oxa-

(9S, 5S, 1R, 6R)-5,9-dimethyl-3-oxa-(9S, 1R, 5R, 6R)-5,9-dimethyl-3-oxa-

(9S, 6S, 1R, 5S)-5,9-dimethyl-3-oxa-(9S, 6S, 1R, 5R)-5,9-dimethyl-3-oxa-

Wherein generally can represent by the flow process of following reaction I by the reaction of Schizonepetolactone hydrogenation formation Pu Le acid:

Schizonepetolactone hydrogenation can be carried out in the presence of catalyzer, and catalyzer promptly influences speed of reaction but do not influence molecular balance and the material of chemical transformation does not take place in reaction.In a preferred embodiment, adopt the load type metal hydrogenation catalyst.This hydrogenation appropriate catalyst, carrier and reaction conditions are referring to Manzer, and US 03/225,290[2003 December 4 (this patent all is attached to this paper by reference and partly is used for all purposes)], particularly wherein 33-130 paragraph and table 1 thereof.The exemplary catalysts of the Pu Le acid of acquisition high yield is drawn together the catalyzer based on platinum and iridium.For example, Manzer shows and can obtain to make anti-that suitable-Schizonepetolactone (IIa) is reduced into the catalyzer and the condition of dihydro nepetalactone (IIIa) and Pu Le acid (IVa), as by as shown in the flow process of reacting (II):

Reaction (II)

By supercarbonate liquid/liquid extraction method (liquid/liquid bicarbonate extraction), acidifying then can obtain product mixtures from Schizonepetolactone hydrogenation, can obtain Pu Le acid after purified again.The suitable organic solvent of this extraction process comprises methylene dichloride and chloroform.

Puleganic amides of the present invention can derive from as single stereoisomers or as the Pu Le acid diastereomer of steric isomer combination.Because Schizonepetolactone can exist by naturally occurring independent three-dimensional chemical isomer (discrete stereochemical isomer), so the Pu Le acid that obtains from Schizonepetolactone hydrogenation also can exist by diastereomer, for example generally by the steric isomer shown in following formula I Va～IVd:

Except the stereoisomerism of Pu Le acid shown in last figure IVa～IVd external, Pu Le acid has the S configuration (by the illustrated numbering of formula IV on its 5-carbon, be the carbon that has methyl on the cyclopentyl ring), the steric isomer that has the Pu Le acid of R configuration on 5-carbon also can be used as intermediate of the present invention, thus the intermediate preparation Puleganic amides.For example, and the Puleganic amides that obtains from Pu Le acid steric isomer IVa (1S, 2R, 5S)-and 2-sec.-propyl-5-methylcyclopentane methane amide, be instead, formed in suitable-Schizonepetolactone (IIa) hydrogenation.

The method that is converted into carboxylic acid amides by carboxylic acid is well-known, referring to for example Comprehensive Organic Transformations, and Richard C.Larock, VCHPublishers, Inc., NY, 1989, the 972-976 pages or leaves.Can pass through the solution of acid chloride and the amine reaction formation Puleganic amides (formula Ia) of Pu Le acid by Pu Le acid (formula IVa), shown in reaction (III):

Reaction (III)

Used amine also can contain three-dimensional generation center (stereogenic centers) and chirality, for example is used as the pipecoline of racemic modification among the embodiment 2, is exactly the combination of (2S)-methyl-piperidines and (2R)-methyl-piperidines enantiomorph.In reaction (III) described couling process, use this amine to obtain diastereoisomeric Puleganic amides.

Puleganic amides can come out by supercarbonate liquid/liquid extraction method purifying from middle reactant Pu Le acid.Evaporating solvent behind the separation organic layer obtains rough Puleganic amides product.Available fast silica gel chromatogram method is further purified, referring to W.C.Still etc., Rapid ChromatographicTechnique for Preparative Separations with Moderate Resolution, J.Org.Chemistry (1978), 43 (14): 2923-2925.

The acid amides of known Pu Le acid has two kinds: Puleganic amides (acid amides of 2-sec.-propyl-5-methyl-cyclopentane-carboxylic acid) [Wallach, Terpenes and Ethereal Oils, CXI.I., Carvenolideand Pulegenolide (terpene and perfume oil, CXI.I., sylvestrene acid amides and pulegene acid amides), Justus Liebigs Ann.Chem. (1913) 392:49-59]; And N-methyl-N-phenyl Puleganic amides [Curran, J.Org.Chem. (1991) 56:4335-4337; And Curran, Tetrahedron (1994) 50:7343-7366].

Be applicable to that Puleganic amides compound of the present invention generally can be represented by following structural formula I:

Formula I

R wherein ¹And R ²Independently be selected from separately:

1)H、CH ₃、C ₂H ₅；

2) C ₃-C ₂₀, preferred C ₃-C ₁₂Straight chain, side chain or cyclic alkane base or alkylene;

3) contain and be selected from O, N and the heteroatomic C of S ₃-C ₂₀, preferred C ₃-C ₁₂Straight chain, side chain or cyclic alkane base or alkylene;

4) C that does not replace or replace ₆-C ₂₀Aryl, the preferred C that does not replace or replace ₆-C ₁₂Aryl, wherein substituting group is selected from C ₁-C ₁₂Straight chain, side chain or cyclic alkane base or alkylene; With

5) contain the C that is selected from O, N and heteroatomic not replacement of S or replacement ₆-C ₂₀, preferred C ₆-C ₁₂Aryl, wherein substituting group is selected from C ₁-C ₁₂Straight chain, side chain or cyclic alkane base or alkylene;

Precondition is R ¹And R ²Be not hydrogen simultaneously; Precondition is R ¹And R ²Can choose wantonly and form cycloalkyl, bicyclic alkyl, cycloalkenyl group or bicycloenyl together, unless formed Puleganic amides is N-methyl-N-phenyl Puleganic amides.

In a preferred embodiment, replacement Puleganic amides of the present invention is selected from N, N-diethyl-(1S,, 2R, 5S)-2-sec.-propyl-5-methylcyclopentane methane amide or [(±)-pipecoline base]-(1S, 2R, 5S)-2-sec.-propyl-5-methylcyclopentane-methane amide.

As mentioned above, Schizonepetolactone, dihydro nepetalactone, Pu Le acid and Puleganic amides all can the diastereomer form exist.Therefore, unless opposite explanation is arranged, otherwise when mentioning the title of compound, for example " Puleganic amides ", " Pu Le acid ", " Schizonepetolactone " or " dihydro nepetalactone ", when perhaps mentioning structure not clear and definite on the stereochemistry, all be interpreted as comprising any combination of any and/or all steric isomers of mentioning its any single stereoisomers and/or these compounds.Therefore, can form the mixture of steric isomer, wherein with respect to total mixture, the molar content or the mass content of the mixture of any independent steric isomer or any subclass can be variable.

The present invention relates to aforesaid Puleganic amides, comprise the purposes of composition and the Puleganic amides and the composition thereof of Puleganic amides.Goods of the present invention and composition thereof all can be used for multiple purpose, and goods of the present invention comprise above-mentioned Puleganic amides compound and can be by composition, preparation and other raw material of these compound of the present invention.These purposes for example comprise various insects of repellent or the arthropodan activeconstituents as significant quantity, as aromatic compound itself or as the composition of flavor compositions, perhaps as the local skin processing.

For example, goods of the present invention can be applied on skin, animal skin, hair, fur, feather or other surface of the Mammals (for example people or performing animal) as insect or arthropodan host by local mode.For example, these lived hosts that live can be used as the insect foods acceptable source of hematophagous bug and arthropods (for example stinging fly, trombiculid, flea, mosquito, tick and lice).

Goods of the present invention also can be applicable to or mix in insect or the arthropodan no life host, it comprises food source for example (for example plant or the farm crop of growth or results), or the protective articles of suitable habitat (for example buildings or structure) or other type (for example protective articles that can be made by fabric or textiles).The abiotic host of this class can comprise tower, cellar, bin, magazine (hopper), box and the bag of product (such as grain) that for example store away grain, and may be to insect (for example flour or beans beetle or weevil) attractive habitat or food source.Can be by goods of the present invention being applied in container or article or leading on any point of this container or article, thus these insects driven away with these goods.

Goods of the present invention are as aromatic compound itself or as the composition of flavor compositions, also can be applicable to people's skin and/or hair and give pleasant smell or fragrance; Goods of the present invention also can be by with Clean Living articles for use, the washing article of coughing, hair conditioner, toning agent (toner), lotion, propellant, sprays or be used for the form of other type makeup of user individual, be applied to people's skin and/or hair, handle as local skin.

The repellent material is driven insect or arthropods away from its preferred host (no matter whether life is arranged), and these hosts are not accepted by insect or arthropods.Most of repellents are not active poisonous substances, but the host of ideal insect/arthropod or the condition relevant with these hosts are become have no attraction or be not suitable for.Usually, repellent is the goods that can be applied topically to around host or the host, perhaps can mix among the host with stop insect/arthropod near or rest near the three-dimensional space that the host exists.Under any situation, the effect of repellent all is to make insect/arthropod keep off the host, perhaps in the host, evict out of insect/arthropod, thereby make " biting " frequency reduce to minimum, perhaps make insect/arthropod cause that the amount of no life host infringement reduces to minimum lived host.Repellent can be the form of gas (sense of smell), liquid or solid (sense of taste).

For total effectiveness of repellent is that an important performance is a surfactivity, because many repellents contain polarity and nonpolar two districts in its structure.Second performance is volatility.Repellent forms the unusual compound of a class; wherein activeconstituents evaporates near host surface, host or host; help very much it to render a service, as by protecting lived host not bitten or protect no life host to be without prejudice to be measured.

The one side of repellent material effect is the degree of material concentration in surface or the surrounding space, and wherein applied repellent is enough to repel insects or arthropods, particularly flying insect.Repellent concentration level required in the space mainly comes self-evaporatint n., but vaporator rate is subjected to any absorption to enter surface, impermeable surface and passes the influence of surface velocity, therefore also almost always repellent from the undesirable mode of surface losses.Need to consider to enter the repellent loss on skin or other lived host surface equally by absorption, the same from the loss on the no life host surface of being made by synthetic materials with repellent, wherein the repellent material can produce untoward reaction with other chemical that is present in this similar face.The repellent material is by the concentration loss of physical action (for example dilution or absorption), or the concentration loss who passes through chemical action (for example reaction), under repellent crawling insect/arthropodan situation, be unfavorable equally, because just in time lip-deep concentration is important factor.

Therefore, selecting as aspect the material of insect/arthropod repellent active, material inherent volatility usually is an important consideration.Yet, when needs attempt to increase active persistence, do not reduce again simultaneously and when preferably increasing volatility, have the multiple choices strategy.For example, active substance can be prepared persistence to be increased in its applied surface or therefrom to come out with polymkeric substance and inert fraction.Yet the active substance in the preparation has been diluted in the existence of inert fraction in the preparation, and active substance loses from unfavorable rapid evaporation, therefore, to such an extent as to must have invalid risk to carry out balance to the active substance of using very little.Perhaps, activeconstituents can be included in the speed of losing from surface or article with control in the microcapsule; Can use in surface or article the slowly precursor molecule of disintegration, with the rate of release of control activeconstituents; Perhaps can use synergistic agent from composition prepared, to be evaporated with continuous stimulating activity material.

The release that is applied to lived host's skin or other surperficial activeconstituents can realize by for example sub-micron encapsulate capsule (sub-micron encapsulation), wherein activeconstituents is sealed or is encapsulated in the skin-nourishing albumen.Can use this albumen by for example concentration of about 20% (weight).The application of repellent comprises many protein capsules that are suspended in water based lotion or the spraying water.With skin contact after, the protein capsule begins fragmentation, discharges the active substance of being sealed.This process is constant, because after each trickle capsule exhausts, is replaced by the capsule of new surface in contact continuously and discharges its activeconstituents.This process can be lasted in once using and be reached 24 hours.Because protein sticks on the skin very effectively, the very anti-perspiration of these preparations (anti-because of perspiration dispose) and diluted by the water in other source.

A unique advantage of goods of the present invention is that they are feature with high relatively volatility all, make their suitable being used for obtain required high-caliber activity component concentration around above-mentioned lived host or abiotic host surface, surface or surface.In these goods one or more can be used for this purpose as active substance or active ingredient in composition, these goods mix mutually with carrier in the composition, this carrier is suitable for the form with for example liquid preparation, aerosol, gelifying agent, aerogel, foam or powder (for example ejection-type powder (sprayable powder) or toilet powder shui), and dried or wet is applied to the surface with composition.Suitable carriers comprises multiple commercially available organic and inorganic liquid, solid or semi-solid carrier or is used to prepare any of carrier formulation of multiple makeup.When preparation is applied to people's skin or other surperficial composition, importantly select skin acceptable carrier.Be applicable to that carrier of the present invention can comprise water, alcohol, siloxanes, Vaseline, lanolin; Perhaps can comprise organic liquid carrier for example liquid aliphatic hydrocarbon (for example pentane, hexane, heptane, nonane, decane and analogue thereof) or liquid aromatic hydrocarbon.

The example of the liquid hydrocarbon that other is useful comprises the oil that coal distillation and all kinds and other petroleum chemistry raw material distillation of level are produced, and comprises the kerosene that is obtained by the oil fractional distillation.Suitable oil comprises the oil (for example so-called light and middle spray oils is made up of the middle runnings of petroleum distillation, only is slightly volatilizable) that is commonly referred to as agricultural spray oils.This class oil generally is purified, only contains a spot of unsaturated compound.And this class oil generally is paraffin oil, so used water and emulsifying agent emulsification, be diluted to lower concentration after, as sprays.The image-stone wax oil is the same, can use the oil slick that obtains from the kraft cooking of wood pulp equally.Other organic liquid carrier can comprise liquid terpene hydro carbons and terpene alcohols, for example α-Pai Xi, kautschin, terpinol etc.

Other suitable carriers comprises siloxanes, Vaseline, lanolin, liquid hydrocarbon, agricultural spraying oils, paraffin oil, oil slick class, liquid terpene hydro carbons and terpene alcohols, aliphatic series and aromatic alcohols, ester class, aldehydes, ketone, mineral oil, higher alcohols, fine organic and solid inorganic material.Except that the aforesaid liquid hydrocarbon, carrier can contain emulsifying agent commonly used, and emulsifying agent can be used to make activeconstituents to be scattered in the water, and dilute with water is used for end-use.Other liquid vehicle can comprise organic solvent for example aliphatic series and aromatic alcohols, ester class, aldehydes and ketone.The aliphatic series MHA comprises methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol and the trimethyl carbinol.Suitable alcohols comprises dibasic alcohol (for example ethylene glycol and propylene glycol) and pinanol.Suitable polyhydroxy-alcohol comprises glycerine, arabitol, tetrahydroxybutane, sorbyl alcohol etc.At last, suitable cycloalcohol comprises cyclopentanol and hexalin.

Aromatics and aliphatic ester class, aldehydes and ketone commonly used can be used as carrier, and common and above-mentioned pure coupling.Other liquid vehicle comprises the higher relatively petroleum products of boiling point for example mineral oil and higher alcohols (for example hexadecanol).In addition, commonly used or so-called " stablizer " (for example tertiary butyl sulfinyl Methyl disulfide is for carbonic ether) can with one or more carrier couplings that are used for by the composition of the present invention's preparation, perhaps as wherein component.

Have the multiple clay of band gap layered structure and aspect chemical constitution, degree of crystallinity and layered morphology the synthetic inorganic material of similar this clay, be applicable to as carrier of the present invention.Suitable clays with band gap layered structure comprises terre verte, kaolin, white mica, vermiculite, phlogopite, xanthophyllite and chrysotile and composition thereof.Be preferably smectic clays and kaolin clay.Smectic clays comprises montmorillonite, beidellite, nontronite, talcum powder, hectorite, sauconite etc.Kaolin clay comprises kaolinite, deckite, nakrite, antigorite (antigorite) etc.Montmorillonite more preferably.Average particle size range is 0.5～50 micron.

The required character of insect/arthropod repellent composition (especially for lived host's skin or other surperficial repellant compositions) comprises that toxicity is low, water-fast soaking or anti-perspiration loss, little or the odorlessness of smell or be at least pleasant smell, be easy to use, and form the tack-free surface film of doing fast.Composition with these character can be by with a certain amount of composition and skin, animal skin, hair, fur, feather or other surperficial contact of effectively driving away insect/arthropod from the host surface, processing grow insect/arthropod performing animal (for example grow flea dog, grow the poultry of lice or grow horn fly or the ox of tick) or unavoidably be exposed to people in the insect/arthropod.

The repellant compositions of significant quantity is applied in surface (host's that for example lives skin, animal skin, hair, fur or the feather that attacked by insect/arthropod, the perhaps handle of plant or farm crop, stem, leaf or flower), can finish by the following method: composition is dispersed in the air, perhaps composition is dispersed into liquid mist, perhaps incorporate in the dust, this will make composition fall on the required host surface.Also may need to prepare repellant compositions, be used for Sprayable by goods of the present invention are mixed mutually with fugitive solvent.Such composition can be aerosol, spraying fluid or ejection-type powder composition, is suitable for by pressurized gas or mechanical pump spraying activeconstituents being distributed in the atmosphere.Equally, with form (for example being easy crushed solid) wet or that do liquid/semi-solid/solid repellent directly being spread to the host surface is the process useful that the host surface is contacted with the repellent of significant quantity.

In addition, also may in composition, goods of the present invention be mixed mutually with one or more other known compound with insect repellant, to reach synergism.Suitable insect repellant immunomodulator compounds comprises Schizonepetolactone to can be used for this coupling purpose, Nepetalactams, dihydro nepetalactone and derivative thereof, Dihydronepetalactamsand and derivative thereof, dibenzoyl, peruscabin, 2,3,4, two (but-2-ene) tetrahydrofurfurals of 5-, the butoxy polypropylene glycol, the N-acetanilide butyl, 6,6-dimethyl-5,6-dihydro-1, pyrokomane-2-n-buty formate, Polycizer W 260, dibutyl phthalate, dibutyl succinate, N, a N-diethyl-toluamide, dime-thyl cisbi-(dimethyl carbate), dimethyl phthalate, 2-ethyl-2-butyl-1, ammediol, 2-ethyl-1, the 3-hexylene glycol, pyridinedicarboxylic acid di-n-propyl ester (di-normal-propylisocinchomeronate), the 2-phenylcyclohexanol, to methane-3,8-two pure and mild N, N-diethyl succinamic acid n-propyl.

Except that one or more goods of the present invention, insect/arthropod repellent composition also can comprise the activeconstituents of one or more essential oils and/or essential oil.Essential oil comprises the volatile oil that obtains and have plant scent and other plant ins and outs from plant of any kind.The example of useful essential oil comprises: Semen Armeniacae Amarum oil, olium anisi, basil oil, oreodaphene, the Gorgon euryale caraway oil, Oils, Elettaria cardamomum, Cedrus deoclar (Roxb.) G. Don oil, Oils, Apium graveolens, chamomile oil, Oleum Cinnamomi, pamorusa oil, clove(bud)oil, Fructus Coriandri oil, cumin oil, oleum anethi, Oil of Eucalyptus, Sweet fennel oil, ginger oil, grapefruit oil, lemon oil, sour lime oil, spearmint oil, Parsley seed oil, Fructus Piperis peppermint oil, pepper oil, rose oil, Oleum Menthae Rotundifoliae (menthol), sweet orange oil, thyme oil, turmeric oil and wintergreen oil.The example that is dissolved in the activeconstituents of essential oil has: geranial, wintergreen oil, salicylic ether, propyl salicylate, geraniol, safrole He limonene.

But the insect of goods repellent of the present invention and arthropods comprise any member of multiple invertebrates, it is characterized in that body is divided into head, chest and abdomen, three pairs of foots (leg) are arranged, and the adult state (the insect state of non-adult comprises larva and pupa) of common (but not always) two pairs of membranaceous wings.Therefore, this definition comprise multiple biting insects (for example ant, honeybee, trombiculid, flea, mosquito, tick, wasp), sting fly [for example buffalo gnat, bluebottle, tatukira, horn fly (Haematobia irritans (haematobiairritans))], eat into wooden insect (for example termite), harmful insect (for example housefly, cockroach, lice, blattaria, wood louse) and household insect (for example flour and beans beetle, dirt mite, moth, moth, weevil).

In another embodiment, goods of the present invention can be used as the active substance in spices or the flavor compositions, are applied to human or animal's skin or hair giving its pleasant fragrance or fragrance with local mode, Gulong perfume or the perfume used as people or pet.Perhaps, obtain pleasant fragrance or fragrance by using the goods of the present invention as the insect/arthropod repellent, wherein these goods have the dual nature of giving repellent and pleasant fragrance or fragrance simultaneously.

In another embodiment, relate to the product of other functional purpose, the repellency of its insect/arthropod and/or fragrance will be improved because of the existence of goods of the present invention.Other products comprises for example Clean Living articles for use, the washing article of coughing, lotion, propellant, toning agent or last toner, bath gels, foam articles for use (for example shaving foam), makeup, deodorant, shampoo, pomade/hair conditioner, personal soap composition (for example hand soaps and bath soap), other personal care amendment or alleviating medicine, sanitising agent (for example washing composition and solvent) and air freshener and deodovization agent.Can following form make this series products: for example with spraying fluid, aerosol, foaming agent, ointment, ointment, gelifying agent, paste, pulvis or frangible solid preparation.Therefore, the manufacture method of this series products can comprise mixes goods of the present invention mutually with suitable carriers or other inert fraction, to help sending by described physical form, for example is easy to the liquid vehicle of spraying; The propellent that is used for aerosol or foaming agent; The adhesive carrier that is used for ointment, ointment, gelifying agent or paste; Perhaps be used for pulvis or dried solid carrier of frangible solid or semi-solid carrier.

Any the said products also can contain other therapeutic or cosmetic active adjuvants or added ingredients, because this is common in personal-care supplies industry.The example of these compositions comprises mycocide, sun-screening agent, opalizer, VITAMIN, tanning agent, plant milk extract, antiphlogiston, antioxidant, free-radical scavengers, retinoids, alpha-hydroxy acid, antiseptic-germicide, microbiotic, antibacterial agent, antihistaminic; Auxiliary material is thickening material, buffer reagent, sequestrant, sanitas, jelling agent, stablizer, tensio-active agent, tenderizer, tinting material, aloe, wax and penetration enhancer for example; And their any two or more mixture.

Goods of the present invention can mix wherein to produce the insect/arthropod repellent action or to give the no life host who improves fragrance and comprise article or manufacture, for example for example tent, tarpaulin, knapsack or mosquito net, candle, paper, paint, ink, woodwork (for example furniture), plastics and other polymkeric substance etc. of textiles and fibre product, clothing, sanitary product, carpet, linen, outdoor goods or military supplies.

Can pass through any known same procedure of cosmetic industry, goods of the present invention are mixed with composition or mix composition be used for lived host, for example dilute, mixing, thickening, emulsification, bottling and pressurization.Can mix or through production later steps (for example spraying or dipping) at production period, goods of the present invention are mixed in the article as no life host.

Goods of the present invention can mix with other component in composition mutually, for example a certain amount of carrier that is effective to specific purpose (for example insect/arthropod repellent, spices or other skin condition product) of other component.The content of Puleganic amides of the present invention in the composition generally will be no more than about 80% based on the finished product weight by weight, yet, can use higher content in some applications, this content is not restrictive.More preferably the content of suitable Puleganic amides be account for composition or article gross weight at least about 0.001% (weight), preferred about 0.01% to about 50% (weight); More preferably from about 0.01% to about 20% (weight).Concrete composition will depend on set purposes.

About other composition, raw material and the method for using Puleganic amides referring to US2003/062,357, US 2003/079,786, US 2003/191,047 and US 2006/148,842, described each patent all is attached to this paper by reference and partly is used for all purposes.

The present invention will be further described in following specific embodiments, but be not limited to this.

Embodiment

Universal method

The implication of used abbreviation is as follows: " ml " represents milliliter, and " μ l " represents microlitre, and " g " represents gram, " mg " represents milligram, " kPa " expression kPa, " MP " represents fusing point, " NMR " represents nucleus magnetic resonance, " HPLC-MS " represents high performance liquid chromatography-mass spectroscopy, " GCMS " represents gas chromatography-mass spectrography, " ℃ " expression degree centigrade, " RT " represents room temperature (about 25 ℃), " hr " expression hour, " ATP " represents adenosine triphosphate.

Except that anhydrous tetrahydro furan (THF), all inorganic salt and organic solvent all available from VWR Scientific (West Chester, PA).All (Milwaukee WI) and by accepted method uses all used among the embodiment other reagent available from Sigma-Al drich Chemical.(derive from Micro Essential Laboratory, Inc. (Brooklyn, NY)) measures pH with the pHydrion test paper.The Puleganic amides product is with silica gel column chromatography purifying (is elutriant with ethyl acetate/hexane); Product behind purifying NMR spectral characterization.The NMR spectrum is available from Bruker DRXAdvance (500MHz ¹H, 125MHz ¹³C; Bruker Biospin Corp., Billerica MA), uses available from Cambridge Isotope Laboratories Inc. (Andover, deuterate solvent MA).

About contrast and test repellents synthetic respond and operate all in the standard laboratory stink cupboard, in the standard laboratory glassware, carry out.

Instead, the purifying of suitable-Schizonepetolactone:

Nepeta oil (60g) (the Berj é that will contain about 75% anti-, suitable-Schizonepetolactone (IIa); Bloomfield, NJ; Lot number 22941) packs in the 500ml round-bottomed flask, under stirring at room, handle with sherwood oil (200ml).When being cooled to 0 ℃, drag is separated out and be deposited in to white solid from solution.White solid is used petroleum ether after filtering, is cooled to 0 ℃ of final vacuum drying.The white solid product of gained (30g, yield 50%) with NMR analyze be defined as anti-, suitable-Schizonepetolactone, fusing point be 27-29 ℃ (MP 27.5-29 ℃, referring to Sakan etc., Tetrahedron Lett.1965,4097-4101).

Synthesizing of Pu Le acid:

(1S, 2R, 5S)-2-sec.-propyl-5-methylcyclopentane formic acid (Pu Le acid, formula IV) synthetic as follows:

Will be anti-, suitable-Schizonepetolactone (30.0g) is dissolved in 95% ethanol/5% Virahol (300ml), and (catalyzer 6.0g) is packed in the Fisher-Porter bottle together with 5%Pt/C.With hydrogen backfill twice, under 30 pounds/square inch (206.9kPa), charge into hydrogen then after the evacuated tube.After at room temperature stirring 19 hours, will manage emptying, content is removed catalyzer through diatomite filtration.Removal of solvent under reduced pressure is distributed the gained resistates between hexane (100ml) and saturated sodium bicarbonate solution (150ml).Water layer is acidified to pH=1.0 with concentrated hydrochloric acid.Mixture extracts three times with methylene dichloride (50ml) then, and the organic layer of merging is through anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains Pu Le acid (21.0g, yield 68%, transparent oily matter).The NMR of products therefrom analyzes and Pu Le acid, and promptly shown in the formula III (1S, 2R, 5S)-the structure unanimity of 2-sec.-propyl-5-methylcyclopentane formic acid.

Embodiment 1

N, the N-diethyl-(1S, 2R, 5S)-2-sec.-propyl-5-methylcyclopentane methane amide

Under nitrogen atmosphere, in the 100ml round-bottomed flask, Pu Le acid (III) (1.0g) is dissolved in methylene dichloride (10ml) and be cooled to 0 ℃ with ice bath.(0.82ml) is added in the solution with triethylamine, by syringe thionyl chloride (0.43ml) slowly.Under nitrogen atmosphere, in independent 100ml round-bottomed flask, be added to diethylamine (0.73ml) in the methylene dichloride (5ml) and be cooled to 0 ℃.Under nitrogen atmosphere, 0 ℃, the Pu Le acid-triethylamine-thionyl chloride solution in first flask is added drop-wise in the diethylamine solution by sleeve pipe.After adding is finished, gained solution was stirred 30 minutes down at 0 ℃, be warming up to room temperature then.After 30 minutes, reaction soln is concentrated in rotatory evaporator (rotoevaporator), the gained resistates is distributed between methylene dichloride (25ml) and 10% citric acid solution (25ml).Each layer separates by separatory funnel, and water layer extracts with methylene dichloride (25ml) again.The dichloromethane layer that merges is with saturated solution of sodium bicarbonate (30ml) washing, through anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains N, N-diethyl-Puleganic amides (0.95g, yield 79%, light yellow oil).The NMR of gained high-purity product and GCMS analyze and N shown in the structural representation Ia, the N-diethyl-(1S, 2R, 5S)-the structure unanimity of 2-sec.-propyl-5-methylcyclopentane methane amide.

Embodiment 2

[(±)-pipecoline base]-(1S, 2R, 5S)-2-sec.-propyl-5-methylcyclopentane-methane amide

Adopt embodiment 1 described same procedure, replace diethylamine, obtain (±)-pipecoline base-Puleganic amides (1.32g, yield 86%, transparent oily matter) with racemize pipecoline (0.70ml).By resulting rough reaction product is dissolved in methylene dichloride (6ml), use saturated aqueous sodium carbonate (10ml) to carry out liquid-liquid extraction again, carry out the purifying of rough reaction product.Isolating organic layer except that desolvating, obtains pure N-hexyl-Puleganic amides (381mg, yield 26%, white solid) with rotatory evaporator through anhydrous sodium sulfate drying.The NMR of products therefrom and GCMS analysis and [(±)-pipecoline base]-(1S, 2R, 5S)-2-sec.-propyl-5-methylcyclopentane-methane amide unanimity.

Embodiment 3

In external landing experiment, the product of embodiment 1 and embodiment 2 is estimated at the insect repellant of Aedes aegypti.In the method, test cabinet has 5 holes, and each Kong Douyong Baudruche (animal intestine) film covers.Each hole is full of ox blood and is heated to 37 ℃, and ox blood contains Trisodium Citrate (preventing to condense) and ATP (72mg ATP disodium salt/26ml blood).With volume is that the Virahol (IPA) that 25 μ l contain a kind of laboratory sample or contrast is added on each film.Making concentration is the IPA solution of 1.0% (weight/volume).Negative control is purified IPA, and positive control is the DEET solution of 1.0% (weight/volume).

After 5 minutes, the female Aedes aegypti of about 250 4 ages in days is introduced test cabinet.In 20 minutes, thrust the number of times that each handles film by 2 minutes interval record mosquito.The result of diethyl Puleganic amides (Ia) and 2-methyl-piperidines Puleganic amides (Ib) sees Fig. 1 and Fig. 2 respectively; The mean number of 5 repeated experiments of each data representation.

Embodiment 4

Adopt embodiment 1 described same procedure, replace diethylamine, obtain N-methyl-Puleganic amides (1.07g, yield 82%, oily matter) with methylamine (2.95ml, the THF solution of 2M).There is Pu Le acid in the NMR analysis revealed of rough reaction product.Rough reaction product silica gel chromatography purifying obtains pure N-methyl-Puleganic amides (204mg, yield 19%, white solid).The GCMS of purified product, HPLC-MS and NMR analyze with the N-methyl of structural representation (as implied above)-(1S, 2R, 5S)-2-sec.-propyl-5-methylcyclopentane-methane amide unanimity (MP measured value=133 ℃).

Embodiment 5

Adopt embodiment 1 described same procedure, replace diethylamine, obtain propyl group Puleganic amides (1.24g, yield 89%, oily matter) with propylamine (0.5ml).There is Pu Le acid in the NMR analysis revealed of rough reaction product.Rough reaction product silica gel chromatography purifying obtains pure n-propyl-Puleganic amides (265mg, yield 21%, white solid).The GCMS of purified product, HPLC-MS and NMR analyze with the N-propyl group of structural representation (as implied above)-(1S, 2R, 5S)-2-sec.-propyl-5-methylcyclopentane-methane amide unanimity (MP measured value=110 ℃).

Embodiment 6

Adopt embodiment 1 described same procedure, replace diethylamine, obtain N-hexyl-Puleganic amides (1.49g, yield 83%, oily matter) with hexylamine (0.8ml).There is Pu Le acid in the NMR analysis revealed of rough reaction product.The rough reaction product of gained is dissolved in methylene dichloride (6ml), uses saturated aqueous sodium carbonate (10ml) to carry out liquid-liquid extraction again, carry out the purifying of rough reaction product.Isolating organic layer removes with rotatory evaporator behind anhydrous sodium sulfate drying and desolvates, and obtains pure N-hexyl-Puleganic amides (485mg, yield 33%, white solid).The GCMS of purified product, HPLC-MS and NMR analyze with the N-hexyl of structural representation (as implied above)-(1S, 2R, 5S)-2-sec.-propyl-5-methylcyclopentane-methane amide unanimity (MP measured value=50.5 ℃).

Embodiment 7

Adopt embodiment 1 described same procedure, replace diethylamine, obtain N-benzyl-Puleganic amides (1.52g, yield 87%, oily matter) with benzylamine (0.64ml).There is Pu Le acid in the NMR analysis revealed of rough reaction product.Rough reaction product silica gel chromatography purifying obtains pure N-benzyl-Puleganic amides (550mg, yield 36%, white solid).The GCMS of purified product, HPLC-MS and NMR analyze with the N-benzyl of structural representation (as implied above)-(1S, 2R, 5S)-2-sec.-propyl-5-methylcyclopentane-methane amide unanimity (MP measured value=114 ℃).

Embodiment 8

Adopt embodiment 1 described same procedure, replace diethylamine, obtain N-allyl group-Puleganic amides (1.23g, yield 85%, oily matter) with allylamine (0.34ml).There is Pu Le acid in the NMR analysis revealed of rough reaction product.Rough reaction product silica gel chromatography purifying obtains pure N-allyl group-Puleganic amides (310mg, yield 25%, white solid).The GCMS of purified product, HPLC-MS and NMR analyze with the N-allyl group of structural representation (as implied above)-(1S, 2R, 5S)-2-sec.-propyl-5-methylcyclopentane-methane amide unanimity (MP measured value=89.5 ℃).

Claims

1. one kind generally by the represented compound of the structure of following formula I:

Formula I

R wherein ¹And R ²Independently be selected from separately:

a)H、CH ₃、C ₂H ₅；

B) C ₃-C ₂₀Straight chain, side chain or cyclic alkane base or alkylene;

2. the compound of claim 1, wherein R ¹And R ²Independently be selected from separately:

1) C ₃-C ₁₂Straight chain, side chain or cyclic alkane base or alkylene;

2) contain and be selected from O, N and the heteroatomic C of S ₃-C ₁₂Straight chain, side chain or cyclic alkane base or alkylene;

3) C that does not replace or replace ₆-C ₁₂Aryl, wherein substituting group is selected from C ₁-C ₁₂Straight chain, side chain or cyclic alkane base or alkylene; With

4) contain the C that is selected from O, N and heteroatomic not replacement of S or replacement ₆-C ₁₂Aryl,

Wherein substituting group is selected from C ₁-C ₁₂Straight chain, side chain or cyclic alkane base or alkylene; R wherein ¹And R ²Can choose wantonly and form cycloalkyl, bicyclic alkyl, cycloalkenyl group or bicycloenyl together; Precondition is that formed Puleganic amides is not N-methyl-N-phenyl Puleganic amides.

3. the compound of claim 1, described compound is N, the N-diethyl-(1S, 2R, 5S)-2-sec.-propyl-5-methylcyclopentane methane amide or [(±)-pipecoline base]-(1S, 2R, 5S)-2-sec.-propyl-5-methylcyclopentane-methane amide.

4. the compound of claim 1, described compound is the single stereoisomers of formula I compound, or the combination of the steric isomer of formula I compound.

5. the compound of claim 1, described compound have at its cyclopentyl endless belt on the carbon of methyl and have the S configuration.

6. composition of matter, described composition comprise in (a) carrier and makeup auxiliary material or the pharmaceutical excipient one or both and (b) generally by the represented compound of the structure of following formula I:

Formula I

R wherein ¹And R ²Independently be selected from separately:

a)H、CH ₃、C ₂H ₅；

B) C ₃-C ₂₀Straight chain, side chain or cyclic alkane base or alkylene;

7. the composition of claim 6, its Chinese style I compound is the single stereoisomers of described compound, or the mixture of described compound steric isomer.

8. the composition of claim 6, its Chinese style I compound have at its cyclopentyl endless belt on the carbon of methyl and have the S configuration.

9. the composition of claim 6, described composition also comprises dihydro nepetalactone.

10. the composition of claim 6, described composition also comprises essential oil.

11. the composition of claim 6, wherein auxiliary material comprises that any one or more is selected from following composition: mycocide, sun-screening agent, opalizer, VITAMIN, tanning agent, plant milk extract, antiphlogiston, antioxidant, free-radical scavengers, retinoids, alpha-hydroxy acid, antiseptic-germicide, microbiotic, antibacterial agent, antihistaminic, thickening material, buffer reagent, sequestrant, sanitas, jelling agent, stablizer, tensio-active agent, tenderizer, tinting material, aloe, wax and penetration enhancer.

12. comprising, the composition of claim 6, described composition account for the formula I compound of composition total weight about 0.001% to about 80% weight.

13. the composition of claim 6, the form of described composition are spraying fluid, aerosol, foaming agent, ointment, ointment, gelifying agent, paste, pulvis or frangible solid preparation.

14. a repel insects or arthropodan method, this method comprise insect or arthropods are exposed to generally by in the represented compound of the structure of following formula I:

Formula I

R wherein ¹And R ²Independently be selected from separately:

a)H、CH ₃、C ₂H ₅；

B) C ₃-C ₂₀Straight chain, side chain or cyclic alkane base or alkylene;

15. the method for claim 14, its Chinese style I compound is the single stereoisomers of described compound, or the mixture of described compound steric isomer.

16. the method for claim 14, its Chinese style I compound have at its cyclopentyl endless belt on the carbon of methyl and have the S configuration.

17. the method for claim 14, this method comprise insect or arthropods are exposed in the composition, described composition comprises and accounts for the formula I compound of composition total weight about 0.001% to about 80% weight.

18. the method for claim 17, wherein said composition comprise in carrier or makeup auxiliary material or the pharmaceutical excipient one or both.

19. the method for claim 17, wherein said composition also comprises dihydro nepetalactone.

20. the method for claim 17, wherein said composition also comprises essential oil.

21. the method for claim 17, wherein said composition comprises the auxiliary material that is selected from following any one or more composition: mycocide, sun-screening agent, opalizer, VITAMIN, tanning agent, plant milk extract, antiphlogiston, antioxidant, free-radical scavengers, retinoids, alpha-hydroxy acid, antiseptic-germicide, microbiotic, antibacterial agent, antihistaminic, thickening material, buffer reagent, sequestrant, sanitas, jelling agent, stablizer, tensio-active agent, tenderizer, tinting material, aloe, wax and penetration enhancer.

22. the method for claim 14, this method comprise hematophagous bug or arthropods are exposed in the described compound.

23. the method for claim 17, this method comprise hematophagous bug or arthropods are exposed in the described composition.

Be selected from the insect or the arthropods that sting fly, trombiculid, flea, mosquito, tick and lice and be exposed in the described compound 24. the method for claim 14, this method comprise making.

Be selected from the insect or the arthropods that sting fly, trombiculid, flea, mosquito, tick and lice and be exposed in the described composition 25. the method for claim 17, this method comprise making.

26. the method for claim 14, this method comprise described compound is applied on insect or arthropodan host's skin, animal skin, hair, feather or the fur or other surface.

27. the method for claim 17, this method comprise described composition is applied on insect or arthropodan host's skin, animal skin, hair, feather or the fur or other surface.

28. one kind prepares skin, animal skin, hair, feather or fur or other the surperficial method for compositions that can be applicable to people or performing animal, this method comprises generally mixes in (a) carrier and makeup auxiliary material or the pharmaceutical excipient one or both by the represented compound of following formula I structure mutually with (b):

Formula I

R wherein ¹And R ²Independently be selected from separately:

a)H、CH ₃、C ₂H ₅；

B) C ₃-C ₂₀Straight chain, side chain or cyclic alkane base or alkylene;

29. the method for claim 28, its Chinese style I compound is the single stereoisomers of described compound, or the mixture of described compound steric isomer.

30. the method for claim 28, its Chinese style I compound have at its cyclopentyl endless belt on the carbon of methyl and have the S configuration.

31. the method for claim 28, this method also comprises the step by the Schizonepetolactone preparation I compound.

32. the method for claim 28, wherein said composition also comprises dihydro nepetalactone.

33. the method for claim 28, wherein said composition also comprises the auxiliary material that is selected from following any one or more composition: mycocide, sun-screening agent, opalizer, VITAMIN, tanning agent, plant milk extract, antiphlogiston, antioxidant, free-radical scavengers, retinoids, alpha-hydroxy acid, antiseptic-germicide, microbiotic, antibacterial agent, antihistaminic, thickening material, buffer reagent, sequestrant, sanitas, jelling agent, stablizer, tensio-active agent, tenderizer, tinting material, aloe, wax and penetration enhancer.

34. comprising, the method for claim 28, wherein said composition account for the formula I compound of composition total weight about 0.001% to about 80% weight.

35. the method for claim 28, this method also comprise the step of the composition of preparation spraying fluid, aerosol, foaming agent, ointment, ointment, gelifying agent, paste, pulvis or frangible solid preparation form.