CN101090890A

CN101090890A - Dihydronepetalactams and n-substituted derivatives thereof

Info

Publication number: CN101090890A
Application number: CNA2005800451185A
Authority: CN
Inventors: M·A·夏尔多恩; A·Y·廖
Original assignee: EI Du Pont de Nemours and Co
Current assignee: EIDP Inc
Priority date: 2004-12-29
Filing date: 2005-12-29
Publication date: 2007-12-19

Abstract

Dihydronepetalactams and N-substituted derivatives thereof are prepared by alkylation of metallated lactams. Dihydronepetalactams and N-substituted derivatives thereof have utility as insect repellents.

Description

Dihydronepetalactamsand and N-substitutive derivative thereof

The rights and interests of the U.S. Provisional Application that the application requires to submit on December 29th, 2004 U.S. Provisional Application is submitted to number on December 29th, 60/640,129 and 2004 number 60/640,130, the two is attached to herein by comprehensive quoting in full.

Technical field

The present invention relates to Dihydronepetalactamsand and N-substitutive derivative thereof, it is useful insect and arthropods repellent.

Background

Thereby insect repellent is widely used as minimizing people-worm vector contact in the world and makes the incidence of vector-borne disease propagation and follow the general malaise of insect bite to drop to minimum measure.Know the most in the topical insect repellents commodity and most popular activeconstituents is synthetic benzene derivative N, N-diethylbenzene methane amide (DEET).

Schizonepetolactone (I schematically shows with general formula I), as the main ingredient of Nepeta excretory essential oil and the activeconstituents in the Catnip, known it is a kind of to the effective natural repellent of various insects [Eisner, T., Science (1964) 146:1318-1320].

United States Patent (USP) 6,524 discloses Schizonepetolactone and independent suitable in 605, anti-(Z, E) and anti-, along (E, Z) isomer is to the repellency of Groton bug.

Dihydro nepetalactone (DHN) (I schematically shows with formula) is a kind of chemical substance of some insect excretory, has known to have the insect repellant activity.

Jefson etc. [J.Chemical Ecology (1983) 9:159-180] have described the repellent effect of microgroove MonomoriumMayr (Monomorium destructor) kind ant excretory DHN.Than more recently, Hallahan (WO 2003/079786) has been found that DHN is more favourable insect repellent than DEET.

But still need continue to obtain wide as far as possible various insects repellent, and have been found that Dihydronepetalactamsand and its derivative are useful insect and arthropods repellents.

Summary of the invention

In one embodiment, the present invention relates to the compound that general formula (IV) schematically shows:

Wherein R is alkyl, (2) thiazolinyl, (3) alkynyl or (4) aryl of (1) non-methyl.

Another embodiment of the present invention for comprise (a) carrier and (b) above the compound compositions of general formula I V, wherein R is H, alkyl, thiazolinyl, alkynyl or aryl.

Another embodiment of the present invention is repel insects or arthropodan method, and described method is that insect or arthropods are exposed in the compound of top general formula I V, and wherein R is H, alkyl, thiazolinyl, alkynyl or aryl.

The compound that another embodiment of the present invention is top general formula I V makes it away from the purposes among people, animal or the non-animal host expulsion insect and/or arthropods, and wherein R is H, alkyl, thiazolinyl, alkynyl or aryl.

Another embodiment of the present invention is the article that added the compound of top general formula I V, and wherein R is H, alkyl, thiazolinyl, alkynyl or aryl.

Another embodiment of the present invention is for producing the method for insect repellant compositions or insect repellent goods, described method realizes that by joining the article from the compound formation composition of top general formula I V or with the compound of top general formula I V wherein R is H, alkyl, thiazolinyl, alkynyl or aryl.

Another embodiment of the present invention for produce to be administered to skin composition or the method for fragrance product, described method is to join the article from the compound formation composition of top general formula I V or with the compound of top general formula I V, and wherein R is H, alkyl, thiazolinyl, alkynyl or aryl.Composition to skin to be administered can have fragrance or other treatment character.

The accompanying drawing summary

Fig. 1-10 has provided with specifying control group and has compared, and specifies Dihydronepetalactamsand or its derivative compound and/or its to be combined in the test-results of in the external Gupta case landing testing method as herein described Aedes aegypti (Aedes aegypti) being surveyed the influence of behavior.X-coordinate is represented the time (unit: minute), and ordinate zou is represented the mean number that mosquito is landed.

Describe in detail

The present invention relates to based on C₂-C ₂₀The new compound of N-substituted-dihydro Nepetalactams, described compound can be used as insect repellent. The present invention also relates to Dihydronepetalactamsand and N-substituted-dihydro Nepetalactams and composition thereof, they also can be used as insect repellent.

The invention provides can be by the new compound of formula IV structural representation ground expression,

Wherein R is alkyl, (2) thiazolinyl, (3) alkynyl or (4) aryl of (1) non-methyl. Term " alkane " refers to that general formula is C_nH _2n+2Saturated hydrocarbons. Term " alkene " refers to contain the unsaturated hydrocarbons of the two keys of one or more C=C, and term " alkynes " refers to contain the unsaturated hydrocarbons of one or more carbon-to-carbon triple bonds. Alkene or alkynes require minimum two carbon atoms. Cyclic compound requires minimum three carbon atoms. Term " aromatics " refers to the compound that benzene is similar to benzene with chemical behavior.

Although in principle to the type of the alkyl, thiazolinyl, alkynyl or the aryl that can be used as the R group in the enforcement of the present invention without limits, but should consider the substituent size of R from reality, make it have a practical use industrial. May need in addition to avoid in the R substituting group, introducing the functional group of high activity to avoid side reaction to take place.

The R of preferred formula (IV) is (1) C₂-C ₂₀Alkyl, (2) C₂-C ₂₀Thiazolinyl, (3) C₃-C ₂₀Alkynyl or (4) C₆-C ₂₀Aryl. More preferably the R of formula (IV) is selected from (1) C₂H ₅；(2)C ₃-C ₂₀Straight chain, side chain or cyclic alkyl or thiazolinyl; (3) comprise the heteroatomic C that is selected from O, N and S₃- C ₂₀Straight chain, side chain or cyclic alkyl or thiazolinyl; (4) C that does not replace or replace₆-C ₂₀It is optional by the C of Cl, Br or F replacement that aryl, wherein said substituting group are selected from (a)₁-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (b) be selected from the halogen of Cl, Br and F; (5) comprise the heteroatomic C that does not replace or replace that is selected from O, N and S₆-C ₂₀It is optional by the C of Cl, Br or F replacement that aryl, wherein said substituting group are selected from (a)₁-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (b) be selected from the halogen of Cl, Br and F.

In another embodiment, R is selected from (1) C₂H ₅、(2)C ₃-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (3) comprise the heteroatomic C that is selected from O, N and S₃-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl. In another more particular embodiment, R can be the phenyl that does not replace or replace, and it is optional by the C of Cl, Br or F replacement that wherein said substituting group is selected from (a)₁-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (b) be selected from the halogen of Cl, Br and F. The example of the alkyl that is replaced by F is CF₃。

Particularly preferred R comprises ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, n-pentyl, n-hexyl, cyclohexyl, n-octyl, tri-methyl-amyl, ring octyl group, pi-allyl, propargyl, phenyl, aminomethyl phenyl, ethylphenyl, n-pro-pyl phenyl, n-butylphenyl, tert-butyl-phenyl, rubigan and to bromophenyl.

The represented compound of formula IV can pass through the Nepetalactams alkylation, hydrogenation prepares or prepares by the Dihydronepetalactamsand alkylation then. Nepetalactams can prepare from nepetalactone. The nepetalactone twin nuclei can formula IIa-IId shown in any existence in four kinds of stereoisomeric forms in any ratio.

Suitable, anti-, suitable, along anti-, anti-

IIa IIb IIc IId

The Schizonepetolactone that extracts in schizonepeta (Catnip) leaf essential oil is preferred raw material source, and reason is that Schizonepetolactone exists in a large number therein and is easy to therefrom purify.This provides a desirable approach for prepare compound of the present invention from natural product.Fractionation as described herein, has found it is purification Schizonepetolactone and the effective ways that separate some steric isomers from each other from essential oil.Chromatographic separation also suits.

Only first three listed Schizonepetolactone steric isomer is present in the essential oil of Nepeta cateria plant.Suitable, anti--Schizonepetolactone be can be from Nepeta cateria plant isolating main isomer, because of its availability, so the most useful.It is anti-that the other plant kind has been identified what be rich in its essential oil, suitable-and suitable, suitable-Schizonepetolactone isomer.

Lactan is the nitrogen analogue of cyclic ester or lactone, and lactan (particularly N-substituted lactams) is more stable to hydrolysis than its lactone counterpart usually.Eisenbraun etc. [J.Org.Chem. (1988) 53:3968-3972] have introduced the synthetic of Nepetalactams.By this method, Schizonepetolactone (formula II) is converted into Nepetalactams (formula III) (seeing reaction I) in the presence of anhydrous ammonia.

Reaction I

Subsequently, Nepetalactams is converted into Dihydronepetalactamsand by hydrogenization in the presence of the Pd/C catalyzer.

Eisenbraun etc. (the same) have synthesized methyl substituted Nepetalactams (IIIa) with Schizonepetolactone and methylamine, shown in reaction II.

Reaction II

N-methyl Nepetalactams (IIIa) then in the presence of the Pd/C catalyzer hydrogenation obtain N-methyl Dihydronepetalactamsand.

Eisenbraun etc. (the same) are used for the optional method of synthetic N-methyl Dihydronepetalactamsand and relate to KOH, tertiary butyl bromination ammonium and methyl iodide and make the Dihydronepetalactamsand alkylation.

Therefore, Nepetalactams can make suitable by the method for describing by (the same) such as Eisenbraun, and anti--Schizonepetolactone (formula II) and anhydrous ammonia contact preparation are shown in reaction III.

Reaction III

Preferred use is suitable, and anti--Schizonepetolactone is as starting raw material.Also available anti-, suitable-Schizonepetolactone, but being configured as of gained N-replacement Nepetalactams product is suitable, anti-configuration, reason is that the end of the bridge carbon three-dimensional chemical configuration epimerization adjacent with carbonyl is suitable, anti-configuration.

N-substituted-dihydro Nepetalactams obtains Dihydronepetalactamsand, then the azanylization of lactan is synthesized by Nepetalactams hydrogenation, or by the Nepetalactams alkylation, make N-replace Nepetalactams hydrogenation then to synthesize, respectively shown in following reaction IV and V.

The hydrogenation of Nepetalactams can be implemented in the presence of suitable reactive metal hydrogenation catalyst.The general acceptable solvent of hydrogenation, catalyzer, device and program can be at Augustine, Heterogeneous Catalysis for the Synthetic Chemist, and Marcel Decker, NewYork, N.Y. finds in (1996).Hydrogenation can be undertaken by (the same) such as Eisenbraun is described, wherein handles N-methyl-3,4-Dihydronepetalactamsand with hydrogen in the presence of the 10%Pd/C catalyzer.Hydrogenation also can be undertaken by disclosed hydrogenant method at Schizonepetolactone among the WO 2003/084946, and this patent is attached to herein by comprehensive the quoting of full text.The hydrogenant proper method is also seen and is set forth in for example United States Patent (USP) 6,664,402,6,673,946 and 6,686,310.

N-substituted-dihydro Nepetalactams can be as shown in reaction IV by Dihydronepetalactamsand (formula V) and proper metal hydride reaction formation Dihydronepetalactamsand salt, make Dihydronepetalactamsand salt and suitable alkylating agent contact formation N-substituted-dihydro Nepetalactams (formula IV) then to form.

Reaction IV

Perhaps, N-substituted-dihydro Nepetalactams can be as shown in reaction V forms by the alkylation of Nepetalactams, the hydrogenation that replaces Nepetalactams by N-then.Catalyzer

Reaction V

Dihydronepetalactamsand carries out under the temperature of about 0 ℃-Yue room temperature (about 25 ℃) to the conversion of N-substituted-dihydro Nepetalactams.Equally, Schizonepetolactone carries out under the temperature of about 0 ℃-Yue room temperature to the conversion of N-substituted-dihydro Nepetalactams.

Use metal hydride to generate the amide metal salt of Dihydronepetalactamsand.Suitable metal hydride includes but not limited to potassium hydride KH and sodium hydride.Reactive very strong metal hydride such as its reactivity of lithium aluminum hydride (carbonyl on its reducible lactan) may be so preferred too by force and not.

The alkylating alkylating agent of N-that is applicable to Dihydronepetalactamsand salt comprises muriate, bromide, iodide, vitriol, mesylate, tosylate and the trifluoromethyl sulfonic acid of alkyl, thiazolinyl, alkynyl or aryl.Preferably with alkyl, thiazolinyl, alkynyl or aryl iodide as alkylating agent.

Preferred alkylating agent also comprises alkyl, thiazolinyl or aryl, and it is selected from (1) C ₂H ₅(2) C ₃-C ₂₀Straight chain, side chain or cyclic alkyl or thiazolinyl; (3) comprise the heteroatomic C that is selected from O, N and S ₃-C ₂₀Straight chain, side chain or cyclic alkyl or thiazolinyl; (4) C that does not replace or replace ₆-C ₂₀It is optional by the C of Cl, Br or F replacement that aryl, wherein said substituting group are selected from (a) ₁-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (b) be selected from the halogen of Cl, Br and F; (5) comprise the heteroatomic C that does not replace or replace that is selected from O, N and S ₆-C ₂₀It is optional by the C of Cl, Br or F replacement that aryl, wherein said substituting group are selected from (a) ₁-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (b) be selected from the halogen of Cl, Br and F.

In another embodiment, preferred alkylating agent comprises alkyl and thiazolinyl, and it is selected from (1) C ₂H ₅(2) C ₃-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl; (3) comprise the heteroatomic C that is selected from O, N and S ₃-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl.In another embodiment, preferred aryl groups is the phenyl that does not replace or replace, and it is optional by the C of Cl, Br or F replacement that wherein said substituting group is selected from (a) ₁-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (b) be selected from the halogen of Cl, Br and F.

The solvent that uses in the N-alkylated reaction must be anhydrous, can be any suitable anhydrous solvent, as tetrahydrofuran (THF) (THF), ether, dimethoxy-ethyl ether or dioxane.

Alkylated reaction is by adding the in addition quencher of about 10% aqueous solution of sodium bisulfite, and reaction mixture is with dichloromethane extraction and use anhydrous sodium sulfate drying.Obtain N-after the removal of solvent under reduced pressure and replace the Nepetalactams crude product, its available ethyl acetate/hexane is passed through purification by silica gel column chromatography as elutriant.Fraction is monitored by tlc (TLC) as elutriant with 25% ethyl acetate/hexane.Still, Kahn and Mitra[J.Org.Chem. (1978) 43:2923-2925] this standard technique is described.

The fraction that contains N-substituted-dihydro Nepetalactams that obtains by column chromatography can merge and removal of solvent under reduced pressure to obtain purified N-substituted-dihydro Nepetalactams product.This product can be used ¹H and ¹³C NMR method is analyzed to identify structure.

N-aryl Dihydronepetalactamsand also can be by Chan[Tetrahedron Letters (1996) 37:9013-9016] described method is by making Dihydronepetalactamsand and suitable triaryl bismuth alkane (the formula VI among the reaction VI) at Cu (OAc) ₂Exist reaction down to form N-aryl Dihydronepetalactamsand (the formula VII among the reaction VI) with triethylamine and prepare

Reaction III

Wherein Ar is the defined aryl that does not replace or replace among the top formula IV.

In view of structure I Ia-IId as implied above, described herein compound can be considered to have steric isomerism, and it can be enantiomerism and diastereo-isomerism.Unless point out the steric isomer that certain is specific specially, otherwise the discussion here all is interpreted as referring to all possible isomer, no matter and its structure is to illustrate or as specific steric isomer (at this moment, other steric isomers also are possible) is shown with fuzzy form on the stereochemistry of formula IV.

Compound of the present invention is included as the compound of single stereoisomers and is the compound of stereoisomer mixture.Can form composition from the mixture of compound of the present invention, wherein aforesaid R is different in all cpds that forms composition.

Dihydronepetalactamsand, N-methyl Dihydronepetalactamsand and the described compound of formula IV are the compound that can be used for multiple purpose, as coming repellent various insects or arthropods with significant quantity as actives or as the aromatic compound in the essence combination or as the local nursing agent of skin.For example, these compounds can local mode be administered on human or animal host's skin, skin, hair, fur or the feather with repel insects or arthropods, or are administered on non-animal host such as growing plants or the crops to give insect or arthropods repellency or pleasant smell or fragrance with local mode.Non-animal host also can comprise any goods that are subjected to insect infestations, as buildings, furniture etc.Usually, these article are considered to desirable food source of insect or the desirable site of insect.

Repellent or repellant compositions refer to insect or arthropods from its preferred host or compound or the composition driven away from the goods that are fit to insect.Most of known repellents are not active toxic agent, but food source by making insect/arthropod or living condition become not attractive or make it unhappyly prevent that it from causing damage to human body, animals and plants and/or goods.Usually, repellent for can locally apply to maybe can be added on the host in the article that are subject to insect influence with stop insect/arthropod near or stop compound or composition in the three-dimensional space at nigh host or article place.In both cases, the effect of repellent all be order about insect/arthropod make its away from or repel (1) host (thereby will reduce to minimum) or (2) article (thereby the protection article are avoided insect pest) to " sting and bite " frequency of host.Repellent can be gas (sense of smell), liquid or solid (sense of taste) form.

A character very important to the comprehensive validity of repellent is surfactivity, because many repellents contain polarity and nonpolar district simultaneously in its structure.Second character is volatility.Repellent is the unusual compound of a class, and activeconstituents is necessary from host's skin surface or from the evaporation of insect repellant article for validity, and validity can be avoided stinging and bitten or protect article to avoid impaired measuring with the protection host.

With regard to the repellent of the insect/arthropod on locally applying to host's skin, skin, hair, feather or fur, an aspect of repellent usefulness be to use repellent the surface directly in the space concentration of repellent reached and be enough to repel insects/arthropodan degree.The main self-evaporatint n. of the repellent concentration level that needs in the space obtains, but vaporator rate is absorbed the influence of skin into or other surperficial speed, therefore, penetrate into and pass the surface almost always repellent from undesirable mode of surface losses.Also must do similarly to consider to article that contain repellent or the article that wherein added repellent, because in the three-dimensional space around the article self, need to reach minimum repellent concentration to obtain the desired protection level.

When selecting to be used as the material of insect/arthropod repellent activity thing, intrinsic volatility is an important consideration item.But, can take multiple strategy when not reducing and preferably increase volatile purpose when required for attempting to increase the actives persistence.For example, can be with actives and polymkeric substance and inert fraction allotment to be increased on the surface of using it or the persistence in article.But the existence of inert fraction is the actives in the diluted formulations in the prescription, so must be not enough to very little average out between effective risk in the loss that causes because of undesirable rapid evaporation with because of the actives of using.Perhaps, activeconstituents can be contained in the speed of losing from surface or article with control in the microcapsule; The available precursors molecule is controlled (it slowly decomposes from the teeth outwards or in the article) rate of release of activeconstituents; Or available synergist constantly encourages actives to evaporate from composition.

The release of activeconstituents can realize that in the submicron capsule, activeconstituents encapsulated (holding) resembles air and is captured in the air bag by for example submicron capsule in skin nourishes protein.Protein can about 20% concentration use.A kind of application of repellent contain many these be suspended in water-based emulsion or spraying water-based in the protein capsule.After skin contact, the protein capsule begins to decompose and discharges actives in being encapsulated in.Depleted and then replaced by new contact skin and the capsule that discharges its activeconstituents along with each microcapsule, this process continues always.For once using sustainable 24 hours of this process.Because protein is attached on the skin very effectively, the very water of sweat proof (being swept away) and other sources so these are filled a prescription by sweat.

A unique advantage of Dihydronepetalactamsand, N-methyl Dihydronepetalactamsand and the described compound of formula IV is that it all has such feature, promptly its relative volatility make that it is suitable for being used for making on surface as mentioned above or the article, top and obtain the desirable high level of activity concentration on every side.In these Dihydronepetalactamsand compounds one or more are generally used for as the purposes such as actives in the composition, in described composition, described compound be suitable for that composition is administered to any lip-deep carrier with the form of for example liquid, aerosol, gel, aerogel, foam or powder (as dusting or apply powder) with wet method or dry method and mix.Suitable carrier comprises any in multiple organic and inorganic liquid, solid or the semi-solid carrier commodity or can be used for preparing the carrier formulation of skin or insect repellent product.At preparation skin products or local when using insect repellent, preferably select acceptable carrier on the dermatology.For example described carrier can comprise perhaps many other carrier component that are widely known by the people of water, ethanol, silicone, vaseline, lanolin.The example of organic liquid carrier comprises liquid aliphatic hydrocarbon (as pentane, hexane, heptane, nonane, decane and its analogue) and liquid aromatic hydrocarbons.

The example of other liquid hydrocarbons comprises the oil that the distillation of the distillation of coal and the various rank petrochemical materials of all kinds produces, and comprises the kerosene that obtains by petroleum fractionating.Other oil be oils comprise be commonly called agricultural spray oil (as so-called low sticking and in sticking spray oil, form by the middle runnings in the petroleum distillation, only hazing) those.The normal process of oil like this is highly purified and can only contain micro-unsaturated compound.In addition, such oil is generally paraffin oil and correspondingly used water and emulsifying agent emulsification, uses as spray through being diluted to low concentration.The same with paraffin oil, the Yatall MA that is obtained from vitriol boiling wood pulp can use in a similar manner.Other organic liquid carriers can comprise liquid terpene hydrocarbon and terpenol, as α-Pai Xi, kautschin, terpinol etc.

Other carriers comprise the organic and solid inorganic material of silicone, vaseline, lanolin, liquid hydrocarbon, agricultural spray oil, paraffin oil, Yatall MA, liquid terpene hydrocarbon and terpenol, aliphatic series and aromatic alcohol, ester, aldehyde, ketone, mineral oil, higher alcohols, fine dispersion.Except that above-mentioned liquid hydrocarbon, described carrier also can contain conventional emulsifying agent, emulsifying agent can be used to make the Nepetalactams compound to be dispersed in the water and dilute with water to realize terminal applies.Other liquid vehicle can comprise that organic solvent is as aliphatic series and aromatic alcohol, ester, aldehyde and ketone.Aliphatic monohydric alcohol comprises methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol and the trimethyl carbinol.Suitable alcohol comprises glycol (as ethylene glycol and propylene glycol) and tetramethyl ethylene ketone.Suitable polyvalent alcohol comprises glycerine, arabitol, erythritol, Sorbitol Powder etc.At last, Shi Yi cycloalcohol comprises cyclopentanol and hexalin.

Conventional aromatics and aliphatic ester, aldehyde and ketone can be used as carrier, and are used in combination with above-mentioned alcohol sometimes.Other liquid vehicle comprises the petroleum products of higher, as mineral oil and higher alcohols (as hexadecanol).In addition, conventional or so-called " stablizer " (as tertiary butyl sulfinyl Methyl disulfide for carbonic ether) can be used in combination or use as its component with one or more carriers that are used for by the made composition of the present invention.

Many clays with band gap laminate structure reach at synthetic inorganic material similar to such clay aspect chemical constitution, crystallinity and the lamellar morphologies and are suitable for as carrier with in the present invention.Suitable clay with band gap laminate structure comprises terre verte, kaolin, white mica, vermiculite, phlogopite, xanthophyllite and chrysotile and composition thereof.Preferred smectic clays and kaolinton.Smectic clays comprises montmorillonite, beidellite, nontronite, saponite, hectorite, sauconite etc.Kaolinton comprises kaolinite, deckite, nakrite, antigorite etc.Montmorillonite most preferably.Median size is in the 0.5-50 micrometer range.

The desirable properties that insect and/or arthropods are had the topical compositions of repellency or article comprises hypotoxicity, anti-water logging or the loss of perspiring, smell is little or odorlessness or have at least pleasant smell, be easy to use and can on host's skin or other surfaces, form fast dried no maxxaedium film.For obtaining these character, local prescription with repellent or repellency article should be able to make the animal that is subjected to insect and/or arthropod infestation (as the cow and people of poultry, band horn fly or the tick of the dog of band flea, the band louse) human or animal of available repellent (comprising its composition) by making skin, skin, hair, fur or feather contact and can be handled for people or animal host's repel insects or arthropodan significant quantity repellent.

The repellant compositions of significant quantity using on the surface that is subjected to insect infestations (as skin, skin, hair, fur, feather or plant or surface, crops) can disperse or be added in powder or the dirt to realize that this can make repellent fall on the host surface of expectation with the liquid mist by repellent being dispersed in the air or with repellent.Ideal also has by preparing repellent in conjunction with the Dihydronepetalactamsand compound, forms to have the composition of property carrier that easily looses, thereby uses with the spray form.Such composition can be to be suitable for spraying by pressurized gas or mechanical pump but active compound is distributed to the airborne aerosol jetting liquid powder composition that maybe can dust.Equally, liquid/semi-solid/solid repellent is the effective ways that the host surface is contacted with the repellent of significant quantity with wet type or dry type (but as with crushed solid) directly sprawling on the host.

In addition, ideal also has in composition in conjunction with one or more described herein active compounds and one or more known other compounds with insect repellant, to obtain the issuable synergistic effect of such combination.The known suitable compound with insect repellant that reaches this purpose includes but not limited to dihydro nepetalactone, dibenzoyl, peruscabin, 2,3:4, two (the 2-butylene-1 of 5-, 4-two bases) tetrahydrofurfural, 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, benzamide between the N-diethyl, dime-thyl cisbi-, dimethyl phthalate, 2-ethyl-2-butyl-1, ammediol, 2-ethyl-1, the 3-hexylene glycol, 2,5-dinicotinic acid di-n-propyl ester, the 2-phenylcyclohexanol, to menthane-3,8-two pure and mild N, N-diethyl succinamic acid n-propyl.

Remove described one or more active ingredient beyond the region of objective existences herein, insect repellant compositions also can contain the activeconstituents of one or more essential oils and/or essential oil." essential oil " is defined as the ethereal oil of any classification that obtains from the plant with smell and other plant characteristic.The example of useful essential oil comprises: Semen Armeniacae Amarum oil, olium anisi, basil oil, oreodaphene, caraway oil, Oils, Elettaria cardamomum, Cedrus deoclar (Roxb.) G. Don oil, Oils, Apium graveolens, chamomile oil, Oleum Cinnamomi, pamorusa oil, Syzygium aromaticum stem oil, Fructus Coriandri oil, cumin oil, oleum anethi, eucalyptus oil, Sweet fennel oil, ginger oil, grapefruit oil, lemon oil, lime oil, spearmint oil, Parsley seed oil, spearmint oil, pepper oil, rose oil, Oleum Menthae Rotundifoliae (menthol), sweet orange oil, thyme oil, turmeric oil and wintergreen oil.The example of the activeconstituents in the essential oil is: geranial, wintergreen oil, salicylic ether, propyl salicylate, geraniol, safrole and limonene.

Can be comprised a big any member who organizes invertebrates by the insect of compound of the present invention and/or composition repellent and arthropods, invertebrates is characterised in that in its adult form (non-adult form comprises larva and pupa) its health can be divided into head, chest, abdomen, three pairs of legs and common (but not always) two pairs of film wings.Therefore this definition comprises multiple thorn sting insect (as ant, honeybee, trombiculid, flea, mosquito, tick, wasp), thorn sting fly [as black fly, blow fly, tatukira, horn fly (Haematobia irritans)], wood-boring insect (as termite), insect (as housefly, cockroach, louse, non-Lian, wood louse) and house insect (as flour beetle and Epilachna spp, dust tick, moth, moth, weevil).

May need the host of repel insects to comprise any plant or animal (comprising the people) that is subjected to insect infestations.Usually, the host is considered to desirable food source of insect or the desirable site of insect.For example, humans and animals serves as the food source host for food blood insect and arthropods (as thorn sting fly, trombiculid, flea, mosquito, tick and louse).

In another embodiment, the Dihydronepetalactamsand compound can be used as aromatic compound or uses as the actives in the fragrance composition, and be administered on human or animal's skin or the hair giving the fragrance of pleasant, as be used in the skin emulsion and be used for people or pet essence with local mode.

Particularly because described compound has the fragrance of pleasant, and in another embodiment of the present invention, one or more Dihydronepetalactamsand compounds are formulated into composition, as product at other main purposes.The fragrance of these products and/or insect repellant can be strengthened by active compound of the present invention or composition existence therein.Such product includes but not limited to Gu Longshui, emulsion, spray, white cream, gel, ointment, shower and shower gels, froth product (as shaving foam), cosmetics, reodorant, shampoo, pomade/rinseing agent and body soap composition (as hand soap and shower/shower soap).Described compound can simply be added in such product certainly to give the fragrance of pleasant.Any adding approach of implementing in this area is all satisfactory.

A corresponding aspects of multiple product discussed above is another optional embodiment of the present invention, and it is for providing or join the method for producing theme composition, local skin nursing agent or goods in composition, skin-care agent or the goods by the mixture with one or more Dihydronepetalactamsand compounds or its steric isomer with composition.Such product and aforesaid method and process explanation Dihydronepetalactamsand as aromatic compound or spices or in fragrance composition or prescription or in the part with in the skin-care agent or the purposes in goods.For example, when producing theme composition, but but composition can be prepared as jetting liquid, aerosol, foam, white cream, ointment, gel, paste, powder or crushed solid.Therefore production technique under such situation can comprise mixed active thing and suitable carrier or other inert fractions promoting the conveying with described material form, but as the liquid vehicle that is easy to spray, is used for aerosol or foamy propelling agent, is used for the adhesive carrier of white cream, ointment, gel or paste or is used for powder or the doing or semi-solid carrier of crushed solid.

Contain one or more above-mentioned active compounds and preparation and also can contain other typical treatment or cosmetic activity auxiliary agent or ancillary components in personal care industries with composition as insect/arthropod repellent, aromatic props, skin-care agent or other personal care products.The example comprises mycocide, sun-screening agent, resistance solarization agent, vitamin b6 usp, suntan, plant milk extract, antiphlogistic, oxidation inhibitor, free-radical scavengers, retinoids, alpha hydroxy acid, sterilizing agent, microbiotic, antiseptic-germicide, antihistaminic agent; Auxiliary agent such as thickening material, buffer reagent, sequestrant, sanitas, jelling agent, stablizer, surface-active substance, softener, tinting material, aloe, wax and penetration enhancers; And the two or many persons' mixture arbitrarily.

In another embodiment of the present invention, the Dihydronepetalactamsand compound is added in the article to produce repel insects/arthropods effect.The article that are encompassed in the present embodiment scope comprise goods, and described goods comprise textiles such as clothes, outdoor or military equipment such as mosquito net; Natural product such as timber; Or be subject to the leaf of the plant of attack of insect.

In another embodiment of the invention, the Dihydronepetalactamsand compound is added in the article producing the fragrance of pleasant, or the Nepetalactams compound is applied to body surface to give its smell.Concrete method of application depends on the surface of being discussed and will give the necessary required concentration of odor intensity.The article that are encompassed in these embodiment scopes comprise goods, and described goods comprise textiles, air freshener, candle, various dulcet article, fiber, plate, paper, paint, ink, clay, timber, furniture (as being used for garden and deck), carpet, sanitary product, plastics, polymkeric substance etc.

The Dihydronepetalactamsand compound can be effective to the amount of specific end use (as insect/arthropod repellent, aromatic props or other skin-care agents) to be mixed with other components such as carrier in composition.The amount of contained active compound is no more than about 80% weight of the finished product weight usually in the composition, but can adopt higher amount in some applications, and should measure unrestricted.More preferably the sufficient quantity of described compound be whole composition or article at least about 0.001% weight, preferred about 0.01% to about 20% weight.Specific composition will depend on the purposes of expection.

Use the additive method of Dihydronepetalactamsand to be disclosed in US 2003/062,357, US2003/079,786 and US 2003/191,047 in, these patents all are attached to herein in full.

Following particular has been done further description to the present invention, but scope of the present invention is not limited thereto.

Embodiment

Universal program

All all carry out in the laboratory glassware of standard in the laboratory fume hood of standard with the synthetic relevant reaction and the operation of contrast and test repellents.Mainly by suitable, the Schizonepetolactone (II) that anti--steric isomer is formed (from Nepeta cataria, can obtain from the vapor distillation of Berj é (Bloomfield NJ) has bought) by commodity Catnip oil.All inorganic salt and the organic solvent except that anhydrous THF all from VWR Scientific (West Chester, PA).Every other reagent used among the embodiment is all from Sigma-Aldrich Chemical (Milwaukee, WI) not treated direct use.The mensuration of pH Laboratory from MicroEssential, (Brooklyn, pH test paper NY) carries out Inc..The lactan product passes through purification by silica gel column chromatography with ethyl acetate/hexane as elutriant; Purified product characterizes with the NMR spectrography.NMR spectrogram Laboratories from Cambridge Isotope, (Andover, deuterate solvent MA) is at Bruker DRX Advance (500MHz for Inc. ¹H, 125MHz ¹³C; Bruker Biospin Corp., Billerica obtains on MA).

The implication of used abbreviation is as follows: " mL " represents milliliter, and " μ L " represents microlitre, and " g " represents gram, " mg " represents milligram, and " psi " represents pound per square inch, and " MP " represents fusing point, " NMR " represents nucleus magnetic resonance, " ℃ " expression degree centigrade, " ATP " represents Triphosaden.

Synthesizing of three (4-chloro-phenyl-) bismuth alkane (used triaryl bismuth alkane among the reaction VI):

In the solution that in the 4-chloro-phenyl-magnesium bromide/diethyl ether solution of 100mL 1M of cooling in ice bath, dropwise adds 10.51g Trichlorobismuthine/50mL tetrahydrofuran (THF) under the nitrogen so that temperature remain on below 5 ℃.Allow reaction be warming up to room temperature and restir 1 hour.The 50mL saturated aqueous ammonium chloride quencher reaction that adds 5 ℃.Remove by filter in the reaction system solid and with the extracted with diethyl ether of 200mL.Merging filtrate is with the saturated aqueous ammonium chloride solution washing of 100mL.Ammonium chloride solution 200mL extracted with diethyl ether, combined ether solution, and with the saturated aqueous ammonium chloride washed twice of 75mL.Ethereal solution obtains thick solid with anhydrous magnesium sulfate drying and vacuum concentration, and thick solid is with the hexane extraction of some parts of heat.Merge hexane extract (400mL) and vacuum concentration, obtain being three (4-chloro-phenyl-) bismuth alkane (13.94g, productive rate 62%, m.p.100 ℃) of yellow solid.The NMR of product analyzes consistent with the result of three (4-chloro-phenyl-) bismuth alkane.

Synthesizing of three (4-bromophenyl) bismuth alkane (used triaryl bismuth alkane among the reaction VI):

In under the nitrogen to the 320mL 4-bromophenyl magnesium bromide/diethyl ether solution of cooling in ice bath (by making 54.9g 1, the preparation of 4-dibromobenzene and 5.63g reactive magnesium) solution that dropwise adds 23.6g Trichlorobismuthine/120mL tetrahydrofuran (THF) in, added in 1 hour, temperature is remained on below 7 ℃.Allow reaction be warming up to room temperature and restir 1 hour.The 60mL saturated aqueous ammonium chloride quencher reaction that adds 5 ℃.Remove by filter in the reaction system solid and with the extracted with diethyl ether of 150mL.The extracted with diethyl ether of water layer usefulness 100mL three times.Combined ether solution with the washing of the saturated aqueous ammonium chloride of 150mL, obtains thick solid with anhydrous magnesium sulfate drying and vacuum concentration, and thick solid is with the hexane extraction of some parts of heat.Merge hexane extract (700mL) and vacuum concentration, obtain being three (4-bromophenyl) bismuth alkane (17.5g, productive rate 35%, m.p.112 ℃) of yellow solid.The NMR of product analyzes consistent with the result of three (4-bromophenyl) bismuth alkane.

Program described in the embodiment 1-15 is used for synthesizing the compound shown in the table 1, and structure number refers to the Dihydronepetalactamsand derivative that designated R-group is replaced in the described compound.

Table 1 N-substituted-dihydro Nepetalactams

R	Structure number
R	Structure number	H	V
Methyl	IVa	H	V
Methyl	IVa	Ethyl	IVb
N-propyl	IVc	Ethyl	IVb
N-propyl	IVc	Normal-butyl	IVd
N-pentyl	IVe	Normal-butyl	IVd
N-pentyl	IVe	N-hexyl	IVf
N-octyl	IVg	N-hexyl	IVf
N-octyl	IVg	Sec.-propyl	IVh
Allyl group	IVi	Sec.-propyl	IVh
Allyl group	IVi	Propargyl	IVj
Phenyl	VIIa	Propargyl	IVj
Phenyl	VIIa	Rubigan	VIIb
To bromophenyl	VIIc	Rubigan	VIIb

Embodiment 1

Nepetalactams (II)

(4aS, 7S, 7aR)-4,7-dimethyl-2,4a, 5,6,7,7a-six hydrogen-1H-cyclopenta [c] pyridine-1-ketone

From suitable, anti--Schizonepetolactone prepares Nepetalactams by the method for (the same) such as Eisenbraun.100g is suitable, anti--Schizonepetolactone/250mL methylene dichloride is sealed in pressure-regulator together with the stirring rod that has applied Teflon  in 1 liter the reactor.Container charges into ammonia to 103.4kPa through three vacuum exhausts with after charging into gaseous ammonia.Solution is depressed stirring three days in room temperature and constant ammonia.The emptying container is also used nitrogen purging.Solution is transferred in the round-bottomed flask of 500mL and removal of solvent under reduced pressure, obtained yellow thick slurry (109.49g).Thick Nepetalactams obtains light yellow crystalline solid through the vacuum distilling purifying.This solid recrystallization in hexane obtains pure Nepetalactams (89.60g, productive rate 88%), observed MP=94-96 ℃ (document MP=95-96 ℃).

Embodiment 2

Dihydronepetalactamsand (V)

(4S, 4aR, 7S, 7aR)-4,7-dimethyl octahydro-1H-cyclopenta [c] pyridine-1-ketone

The ethanol of 10g Nepetalactams/20mL 95% is used the Pd/SrCO of 0.25g 2% in the pressure reactor of 100mL ₃Handle.Container seals with pressure-regulator, through seven vacuum exhausts with to charge into hydrogen to pressure after charging into hydrogen be 103.4kPa, and stirs three days under room temperature and constant hydrogen pressure.The emptying container is also used nitrogen purging.Make mixture pass through the Celite Celite pad then and filter, and with the other alcohol flushing of 50mL.Remove from filtrate and desolvate, obtain being clarification buttery 10.24g Dihydronepetalactamsand, it leaves standstill after fixing is the low melting point solid.The NMR of products therefrom analyzes consistent with the described Dihydronepetalactamsand structure of structural formula V.

Embodiment 3

N-methyl-Dihydronepetalactamsand (IVa)

(4S, 4aR, 7S, 7aR)-2,4,7-trimethylammonium octahydro-1H-cyclopenta [c] pyridine-1-ketone

1.0g Dihydronepetalactamsand IV/30mL THF handles in room temperature with under stirring with 2.15g methyl iodide, 0.85g potassium hydroxide and 0.39g Tetrabutyl amonium bromide in the round-bottomed flask of 100mL.After three days, removal of solvent under reduced pressure from reaction system.In the gained residue, add entry (50mL) and use 25mL dichloromethane extraction aqueous mixture three times.Merge organic layer, use anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains N-methyl-Dihydronepetalactamsand IVa (productive rate 63%) that 0.69g is yellow oily.Product passes through purification by silica gel column chromatography with ethyl acetate/hexane as elutriant.Described N-methyl-the Dihydronepetalactamsand structure is consistent with structural formula IVa in the NMR analysis of products therefrom.

Embodiment 4

N-ethyl-Dihydronepetalactamsand (IVb)

(4S, 4aR, 7S, 7aR)-and 2-ethyl-4,7-dimethyl octahydro-1H-cyclopenta [c] pyridine-1-ketone

250mL three neck round-bottomed flask cool to room temperature after under nitrogen gas stream, will drying; Add the solution of 1.68g Dihydronepetalactamsand (V)/anhydrous THF of 30mL and be cooled to 0 ℃ with transfer pipet with ice bath.In addition, with the 10mL hexane with the potassium hydride KH of 0.80g 30%-mineral oil suspension washing three times to remove mineral oil.0 ℃ and stir under the gained white solid be divided into aliquot be added in the reaction soln, have gas to generate.Add finish after, reaction mixture was stirred 30 minutes, handle with the 1.2mL iodoethane, stirred 30 minutes down at 0 ℃ then.Reaction is risen to room temperature, kept 30 minutes, the aqueous solution of sodium bisulfite that adds 30mL 10% then reacts with quencher.Mixture 20mL dichloromethane extraction three times merge organic moiety and also use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains being the crude product of yellow oily, this crude product with ethyl acetate/hexane as elutriant by purification by silica gel column chromatography, obtain purified product (0.75g, productive rate 38%).Described N-ethyl-the Dihydronepetalactamsand structure is consistent with structural formula IVb in the NMR analysis.

Embodiment 5

N-propyl group-Dihydronepetalactamsand (IVc)

(4S, 4aR, 7S, 7aR)-and 2-n-propyl-4,7-dimethyl octahydro-1H-cyclopenta [c] pyridine-1-ketone

250mL three neck round-bottomed flask cool to room temperature after under nitrogen gas stream, will drying; Add the solution of 1.12g Dihydronepetalactamsand (V)/anhydrous THF of 30mL and be cooled to 0 ℃ with transfer pipet with ice bath.In addition, with the 10mL hexane with the potassium hydride KH of 0.90g 30%-mineral oil suspension washing three times to remove mineral oil.0 ℃ and stir under the gained white solid be divided into aliquot be added in the reaction soln, have gas to generate.Add finish after, reaction mixture was stirred 30 minutes, handle with the 1.46mL iodopropane, stirred 30 minutes down at 0 ℃ then.Reaction is risen to room temperature, kept 30 minutes, the aqueous solution of sodium bisulfite that adds 30mL 10% then reacts with quencher.Mixture 20mL dichloromethane extraction three times merge organic moiety and also use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains being the crude product of yellow oily, this crude product with ethyl acetate/hexane as elutriant by purification by silica gel column chromatography, obtain purified product (1.41g, productive rate 67%).Described N-propyl group-the Dihydronepetalactamsand structure is consistent with structural formula IVc in the NMR analysis.

Embodiment 6

N-butyl-Dihydronepetalactamsand (IVd)

(4S, 4aR, 7S, 7aR)-and 2-normal-butyl-4,7-dimethyl octahydro-1H-cyclopenta [c] pyridine-1-ketone

250mL three neck round-bottomed flask cool to room temperature after under nitrogen gas stream, will drying; Add the solution of 1.12g Dihydronepetalactamsand (V)/anhydrous THF of 30mL and be cooled to 0 ℃ with transfer pipet with ice bath.In addition, with the 10mL hexane with the potassium hydride KH of 0.80g 30%-mineral oil suspension washing three times to remove mineral oil.0 ℃ and stir under the gained white solid be divided into aliquot be added in the reaction soln, have gas to generate.Add finish after, reaction mixture was stirred 30 minutes, handle with the 1.67mL butyl iodide, stirred 30 minutes down at 0 ℃ then.Reaction is risen to room temperature, kept 30 minutes, add the aqueous solution of sodium bisulfite quencher reaction of 30mL 10% then.Mixture 20mL dichloromethane extraction three times merge organic moiety and also use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains being the crude product of yellow oily, this crude product with ethyl acetate/hexane as elutriant by purification by silica gel column chromatography, obtain purified product (0.89g, productive rate 60%).Described N-butyl-the Dihydronepetalactamsand structure is consistent with structural formula IVd in the NMR analysis.

Embodiment 7

N-amyl group-Dihydronepetalactamsand (IVe)

(4S, 4aR, 7S, 7aR)-and 2-n-pentyl-4,7-dimethyl octahydro-1H-cyclopenta [c] pyridine-1-ketone

250mL three neck round-bottomed flask cool to room temperature after under nitrogen gas stream, will drying; In flask, add the solution of 4.65g Nepetalactams (II)/anhydrous THF of 100mL with transfer pipet, use the nitrogen purging flask simultaneously, and under nitrogen, be cooled to 0 ℃ with ice bath.In addition, with the 30mL hexane with the potassium hydride KH of 6.05g 30%-mineral oil suspension washing three times to remove mineral oil.0 ℃ and stir under the gained white solid be divided into aliquot be added in the reaction soln, have gas to generate.Add finish after, reaction mixture was stirred 30 minutes, handle with the 5.93mL iodopentane, stirred 30 minutes down at 0 ℃ then.Reaction is risen to room temperature, kept 30 minutes, add the saturated aqueous solution of sodium bisulfite quencher reaction of 50mL then.Mixture is with 30mL dichloromethane extraction three times, merges organic moiety and with 10% sodium bisulfite drying.Removal of solvent under reduced pressure obtains being brown buttery crude product (7.2g), and this crude product passes through purification by silica gel column chromatography with ethyl acetate/hexane as elutriant, obtains purified product (4.4g, productive rate 67%).The NMR of purified product analyzes consistent with N-amyl group-Nepetalactams.

2.4g the ethanol of N-amyl group-Nepetalactams/100mL 95% is used the Pd/SrCO of 0.70g 2% in the pressure reactor of 250mL ₃Handle.Container seals with pressure-regulator, through three vacuum exhausts with to charge into hydrogen to pressure after charging into hydrogen be 103.4kPa, and stirs under room temperature and constant hydrogen pressure and spends the night.The emptying container is also used nitrogen purging.Make mixture pass through the Celite Celite pad then and filter, and with the other alcohol flushing of 50mL.Removal of solvent under reduced pressure obtains being the crude product of yellow oily, this crude product with ethyl acetate/hexane as elutriant by purification by silica gel column chromatography, obtain purified product (1.5g, productive rate 62%).Described N-amyl group-the Dihydronepetalactamsand structure is consistent with structural formula IVe in the NMR analysis.

Embodiment 8

N-hexyl-Dihydronepetalactamsand (IVf)

(4S, 4aR, 7S, 7aR)-and 2-n-hexyl-4,7-dimethyl octahydro-1H-cyclopenta [c] pyridine-1-ketone

250mL three neck round-bottomed flask cool to room temperature after under nitrogen gas stream, will drying; In flask, add the solution of 4.65g Nepetalactams (II)/anhydrous THF of 100mL with transfer pipet, use the nitrogen purging flask simultaneously, and under nitrogen, be cooled to 0 ℃ with ice bath.In addition, with the 30mL hexane with the potassium hydride KH of 6.0g 30%-mineral oil suspension washing three times to remove mineral oil.0 ℃ and stir under the gained white solid be divided into aliquot be added in the reaction soln, have gas to generate.Add finish after, reaction mixture was stirred 30 minutes, handle with the 6.7mL iodohexane, stirred 30 minutes down at 0 ℃ then.Reaction is risen to room temperature, kept 30 minutes, add the aqueous solution of sodium bisulfite quencher reaction of 30mL 10% then.Mixture 30mL dichloromethane extraction three times merge organic moiety and also use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains being brown buttery crude product (5.46g), and this crude product passes through purification by silica gel column chromatography with ethyl acetate/hexane as elutriant, obtains purified product (3.2g, productive rate 46%).The NMR of purified product analyzes consistent with N-hexyl-Nepetalactams.

1.5g the ethanol of N-hexyl-Nepetalactams/100mL 95% is used the Pd/SrCO of 0.70g 2% in the pressure reactor of 250mL ₃Handle.Container seals with pressure-regulator, through three vacuum exhausts with to charge into hydrogen to pressure after charging into hydrogen be 103.4kPa, and stirs under room temperature and constant hydrogen pressure and spends the night.The emptying container is also used nitrogen purging.Make mixture pass through the Celite Celite pad then and filter, and with the other alcohol flushing of 50mL.Removal of solvent under reduced pressure obtains being the crude product of yellow oily, this crude product with ethyl acetate/hexane as elutriant by purification by silica gel column chromatography, obtain purified product (1.35g, productive rate 89%).Described N-hexyl-the Dihydronepetalactamsand structure is consistent with structural formula IVf in the NMR analysis.

Embodiment 9

N-octyl group-Dihydronepetalactamsand (IVg)

(4S, 4aR, 7S, 7aR)-and 2-n-octyl-4,7-dimethyl octahydro-1H-cyclopenta [c] pyridine-1-ketone

250mL three neck round-bottomed flask cool to room temperature after under nitrogen gas stream, will drying; In flask, add the solution of 4.65g Nepetalactams (II)/anhydrous THF of 30mL with transfer pipet, use the nitrogen purging flask simultaneously, and under nitrogen, be cooled to 0 ℃ with ice bath.In addition, with the 30mL hexane with the potassium hydride KH of 6.0g 30%-mineral oil suspension washing three times to remove mineral oil.0 ℃ and stir under the gained white solid be divided into aliquot be added in the reaction soln, have gas to generate.Add finish after, reaction mixture was stirred 30 minutes, handle with the 8.2mL iodo-octane, stirred 30 minutes down at 0 ℃ then.Reaction is risen to room temperature, kept 30 minutes, add the aqueous solution of sodium bisulfite quencher reaction of 30mL 10% then.Mixture 30mL dichloromethane extraction three times merge organic moiety and also use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains being brown buttery crude product (5.36g), and this crude product passes through purification by silica gel column chromatography with ethyl acetate/hexane as elutriant, obtains purified product (4.26g, productive rate 53%).The NMR of purified product analyzes consistent with N-octyl group-Nepetalactams.

2.4g the ethanol of N-octyl group-Nepetalactams/100mL 95% is used the Pd/SrCO of 0.70g 2% in the pressure reactor of 250mL ₃Handle.Container seals with pressure-regulator, through three vacuum exhausts with to charge into hydrogen to pressure after charging into hydrogen be 103.4kPa, and stirs under room temperature and constant hydrogen pressure and spends the night.The emptying container is also used nitrogen purging.Make mixture pass through the Celite Celite pad then and filter, and with the other alcohol flushing of 50mL.Removal of solvent under reduced pressure obtains being the crude product of yellow oily, this crude product with ethyl acetate/hexane as elutriant by purification by silica gel column chromatography, obtain purified product (1.7g, productive rate 68%).Described N-octyl group-the Dihydronepetalactamsand structure is consistent with structural formula IVg in the NMR analysis.

Embodiment 10

N-sec.-propyl-Dihydronepetalactamsand (IVh)

(4S, 4aR, 7S, 7aR)-and 2-sec.-propyl-4,7-dimethyl octahydro-1H-cyclopenta [c] pyridine-1-ketone

250mL three neck round-bottomed flask cool to room temperature after under nitrogen gas stream, will drying; Add the solution of 3.0g Nepetalactams (II)/anhydrous THF of 50mL and be cooled to 0 ℃ with transfer pipet with ice bath.In addition, with the 10mL hexane with the potassium hydride KH of 4.0g 30%-mineral oil suspension washing three times to remove mineral oil.0 ℃ and stir under the gained white solid be divided into aliquot be added in the reaction soln, have gas to generate.Add finish after, reaction mixture was stirred 30 minutes, handle with the 5.0g 2-iodopropane, stirred 30 minutes down at 0 ℃ then.Reaction system is risen to room temperature, kept 30 minutes, add the aqueous solution of sodium bisulfite quencher reaction of 30mL 10% then.Mixture 20mL dichloromethane extraction three times merge organic moiety and also use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains being the crude product of yellow oily, this crude product with ethyl acetate/hexane as elutriant by purification by silica gel column chromatography, obtain purified product (3.0g, productive rate 85%).NMR analyzes consistent with N-sec.-propyl-Nepetalactams.

2.4g the ethanol of N-sec.-propyl-Nepetalactams/100mL 95% is used the Pd/SrCO of 0.70g 2% in the pressure reactor of 250mL ₃Handle.Container seals with pressure-regulator, through three vacuum exhausts with to charge into hydrogen to pressure after charging into hydrogen be 103.4kPa, and stirs under room temperature and constant hydrogen pressure and spends the night.The emptying container is also used nitrogen purging.Make mixture pass through the Celite Celite pad then and filter, and with the other alcohol flushing of 50mL.Removal of solvent under reduced pressure obtains being the crude product of yellow oily, this crude product with ethyl acetate/hexane as elutriant by purification by silica gel column chromatography, obtain purified product (0.96g, productive rate 40%).Described N-sec.-propyl-the Dihydronepetalactamsand structure is consistent with structural formula IVh in the NMR analysis.

Embodiment 11

N-allyl group-Dihydronepetalactamsand (IVi)

(4S, 4aR, 7S, 7aR)-and 2-allyl group-4,7-dimethyl octahydro-1H-cyclopenta [c] pyridine-1-ketone

250mL three neck round-bottomed flask cool to room temperature after under nitrogen gas stream, will drying; Add the solution of 0.93g Dihydronepetalactamsand (V)/anhydrous THF of 20mL and be cooled to 0 ℃ with transfer pipet with ice bath.In addition, with the 10mL hexane with the potassium hydride KH of 1.9g 30%-mineral oil suspension washing three times to remove mineral oil.0 ℃ and stir under the gained white solid be divided into aliquot be added in the reaction soln, have gas to generate.Add finish after, reaction mixture was stirred 30 minutes, handle with the 1.52mL allyl iodide, stirred 30 minutes down at 0 ℃ then.Reaction system is risen to room temperature, kept 30 minutes, add the aqueous solution of sodium bisulfite quencher reaction of 30mL 10% then.Mixture 20mL dichloromethane extraction three times merge organic moiety and also use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains being the crude product of yellow oily, this crude product with ethyl acetate/hexane as elutriant by purification by silica gel column chromatography, obtain purified product (0.503g, productive rate 43%).Described N-allyl group-the Dihydronepetalactamsand structure is consistent with structural formula IVi in the NMR analysis.

Embodiment 12

N-propargyl-Dihydronepetalactamsand (IVj)

(4S, 4aR, 7S, 7aR)-and 2-propargyl-4,7-dimethyl octahydro-1H-cyclopenta [c] pyridine-1-ketone

250mL three neck round-bottomed flask cool to room temperature after under nitrogen gas stream, will drying; Add the solution of 1.00g Dihydronepetalactamsand (V)/anhydrous THF of 30mL and be cooled to 0 ℃ with transfer pipet with ice bath.In addition, with the 10mL hexane with the potassium hydride KH of 1.2g 30%-mineral oil suspension washing three times to remove mineral oil.0 ℃ and stir under the gained white solid be divided into aliquot be added in the reaction soln, have gas to generate.Add finish after, reaction mixture was stirred 30 minutes, handle with the 1.07mL propargyl bromide, stirred 30 minutes down at 0 ℃ then.Reaction is risen to room temperature, kept 30 minutes, add the saturated 10% aqueous solution of sodium bisulfite quencher reaction of 30mL then.Mixture 20mL dichloromethane extraction three times merge organic moiety and also use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains being the crude product of yellow oily, this crude product with ethyl acetate/hexane as elutriant by purification by silica gel column chromatography, obtain purified product (0.64g, productive rate 52%).Described N-propargyl-the Dihydronepetalactamsand structure is consistent with structural formula IVj in the NMR analysis.

Embodiment 13

Phenyl Nepetalactams (VIIa)

(4S, 4aR, 7S, 7aR)-4,7-dimethyl-2-phenyl octahydro-1H-cyclopenta [c] pyridine-1-ketone

0.25g Dihydronepetalactamsand (V), 1.31g triphenyl bismuth alkane, 0.27g Glacial acetic acid copper (II) and the slurry of 0.41mL triethylamine in the 10mL methylene dichloride were stirred 24 hours under room temperature.Removal of solvent under reduced pressure obtains crude product mixture, and this crude product mixture is passed through purification by silica gel column chromatography, the solid purified product that obtains being white in color (0.23g, productive rate 63%) with ethyl acetate/hexane as elutriant.Described N-phenyl-the Dihydronepetalactamsand structure is consistent with structural formula VIIa in the NMR analysis.

Embodiment 14

Rubigan Nepetalactams (VIIb)

(4S, 4aR, 7S, 7aR)-and 2-(4-chloro-phenyl-)-4,7-dimethyl octahydro-1H-cyclopenta [c] pyridine-1-ketone

0.15g Nepetalactams (V), 0.98g three (4-chloro-phenyl-) bismuth alkane, 0.16g Glacial acetic acid copper (II) and the slurry of 0.25mL triethylamine in the 15mL methylene dichloride were stirred 24 hours under room temperature.Removal of solvent under reduced pressure obtains crude product mixture, and this crude product mixture is passed through purification by silica gel column chromatography with ethyl acetate/hexane as elutriant, obtains being the purified product (0.16g, productive rate 64%) of pale solid.Described N-4-chloro-phenyl--the Dihydronepetalactamsand structure is consistent with structural formula VIIb in the NMR analysis of purified product.

Embodiment 15

To bromophenyl Nepetalactams (VIIc)

(4S, 4aR, 7S, 7aR)-and 2-(4-bromophenyl)-4,7-dimethyl octahydro-1H-cyclopenta [c] pyridine-1-ketone

0.15g Nepetalactams (II), 1.22g three (4-bromophenyl) bismuth alkane, 0.16g Glacial acetic acid copper (II) and the slurry of 0.25mL triethylamine in the 15mL methylene dichloride were stirred 24 hours under room temperature.Removal of solvent under reduced pressure obtains crude product mixture, and this crude product mixture is passed through purification by silica gel column chromatography with ethyl acetate/hexane as elutriant, obtains being the crude product (0.08g) of colorless oil.Amplify 4 times of reaction repeated with identical program.This crude product mixture and the crude product that obtains from the first round are merged, pass through purification by silica gel column chromatography as elutriant, obtain being the purified product (0.16g, overall yield 11%) of colorless oil with ethyl acetate/hexane.Described N-4-bromophenyl-the Dihydronepetalactamsand structure is consistent with structural formula VIIc in the NMR analysis of purified product.

Assess the repellency of the product of embodiment 1-15 with external Gupta case landing method of testing (Gupta box landing assay) to Aedes aegypti.In this method, case contains 5 holes, respectively is coated with Baudruche (animal intestine) film.Be filled with the ox blood that contains Trisodium Citrate (to stop grumeleuse) and ATP (every 26ml blood 72mg ATP disodium salt) in each hole and be heated to 37 ℃.To contain a kind of sample or in the same old way 25 μ L Virahols (IPA) will be applied on each film.The concentration of Dihydronepetalactamsand product is 1% (weight/volume) among the IPA.The negative control sample is pure IPA, and the positive control sample is 1% (weight/volume) solution of DEET.

In the female Aedes aegypti leading-in box with about 250 4 day ages after 5 minutes.Spy the quantity of the mosquito of film in following 20 minutes with every kind of situations of timed intervals of 2 minutes record.The result about the compound of embodiment 1-12 who obtains like this depicts (being labeled as embodiment 16-25) in Fig. 1-10, wherein each data is the mean value of five repeated experiments.

Available following formula is determined the average repellency of % of repellent under the given repellent test solution concentration from these data:

Average repellency=the C-T/C of % * 100

The landing sum on the C=IPA control wells wherein, the landing sum on the T=testing liquid hole.Provided the % average repellency of compound under 1% (weight/volume) concentration of embodiment 1-15 in the table 2, wherein R refers to the substituting group on the Dihydronepetalactamsand.

Embodiment 16

The repellency of Fig. 1 IVa and V and DEET is (under 1% weight/volume) relatively

Embodiment 17

The repellency of Fig. 2 IVb and DEET is (under 1% weight/volume) relatively

Embodiment 18

The repellency of Fig. 3 IVc and DEET is (under 1% weight/volume) relatively

Embodiment 19

The repellency of Fig. 4 IVd and DEET is (under 1% weight/volume) relatively

Embodiment 20

The repellency of Fig. 5 IVe and DEET is (under 1% weight/volume) relatively

Embodiment 21

The repellency of Fig. 6 IVf and DEET is (under 1% weight/volume) relatively

Embodiment 22

The repellency of Fig. 7 IVg and DEET is (under 1% weight/volume) relatively

Embodiment 23

The repellency of Fig. 8 IVh and DEET is (under 1% weight/volume) relatively

Embodiment 24

The repellency of Fig. 9 IVi and DEET is (under 1% weight/volume) relatively

Embodiment 25

The repellency of Figure 10 IVj and DEET is (under 1% weight/volume) relatively

Table 2

N-substituted-dihydro Nepetalactams:

The average repellency of % under 1% (weight/volume) concentration

R	Structure number	The average repellency of %
R	Structure number	The average repellency of %	H Methylethyl n-pro-pyl normal-butyl n-pentyl n-hexyl n-octyl isopropyl pi-allyl propargyl phenyl rubigan is to bromophenyl	V IVa IVb IVc IVd IVe IVf IVg IVh IVi IVj VIIa VIIb VIIc	69.6 39.6 96.8 87.9 86.3 100 99.8 98.3 69.4 90.6 88.1 59.1 81.5 54.1

Claims

1. the compound that schematically shows of following formula:

Wherein R comprises the alkyl, (b) thiazolinyl, (c) alkynyl of (a) non-methyl or (d) aryl.

2. the compound of claim 1, wherein R comprises (a) C ₂-C ₂₀Alkyl, (b) C ₂-C ₂₀Thiazolinyl, (c) C ₃-C ₂₀Alkynyl or (d) C ₆-C ₂₀Aryl.

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

(a)C ₂H ₅，

(b) C ₃-C ₂₀Straight chain, side chain or cyclic alkyl or thiazolinyl,

(c) comprise the heteroatomic C that is selected from O, N and S ₃-C ₂₀Straight chain, side chain or cyclic alkyl or thiazolinyl,

(d) C that does not replace or replace ₆-C ₂₀It is optional by the C of Cl, Br or F replacement that aryl, wherein said substituting group are selected from (i) ₁-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (ii) be selected from Cl, Br and F halogen and

(e) comprise the heteroatomic C that does not replace or replace that is selected from O, N and S ₆-C ₂₀It is optional by the C of Cl, Br or F replacement that aryl, wherein said substituting group are selected from (i) ₁-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (ii) be selected from the halogen of Cl, Br and F.

4. the compound of claim 1, wherein R is selected from (a) C ₂H ₅, (b) C ₃-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (c) comprise the heteroatomic C that is selected from O, N and S ₃-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl.

5. the compound of claim 1, wherein R is the phenyl that does not replace or replace, wherein said substituting group is selected from (a) optional C that is replaced by Cl, Br or F ₁-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (b) be selected from the halogen of Cl, Br and F.

6. the compound of claim 1, described compound is the single stereoisomers of simplification compound, or is the stereoisomer mixture of simplification compound.

7. composition, described composition comprise (a) carrier and (b) compound represented of following general formula:

Wherein R is H, alkyl, thiazolinyl, alkynyl or aryl.

8. the composition of claim 7, wherein R is (a) H, (b) C ₁-C ₂₀Alkyl, (c) C ₂-C ₂₀Thiazolinyl, (d) C ₃-C ₂₀Alkynyl or (e) C ₆-C ₂₀Aryl.

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

(a)CH ₃、C ₂H ₅，

(b) C ₃-C ₂₀Straight chain, side chain or cyclic alkyl or thiazolinyl,

10. the composition of claim 7, wherein R is selected from (a) CH ₃, (b) C ₂H ₅, (c) C ₃-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (d) comprise the heteroatomic C that is selected from O, N and S ₃-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl.

11. the composition of claim 7, wherein R is the phenyl that does not replace or replace, and it is optional by the C of Cl, Br or F replacement that wherein said substituting group is selected from (a) ₁-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (b) be selected from the halogen of Cl, Br and F.

12. the composition of claim 7, it is the single stereoisomers of simplification compound, or is the stereoisomer mixture of simplification compound.

13. the composition of claim 7, described composition also comprises and is selected from dihydro nepetalactone, dibenzoyl, peruscabin, 2,3:4, two (the 2-butylene-1 of 5-, 4-two bases) tetrahydrofurfural, 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, benzamide between the N-diethyl, dime-thyl cisbi-, dimethyl phthalate, 2-ethyl-2-butyl-1, ammediol, 2-ethyl-1, the 3-hexylene glycol, 2,5-dinicotinic acid di-n-propyl ester, the 2-phenylcyclohexanol, to menthane-3,8-two pure and mild N, the repellent of N-diethyl succinamic acid n-propyl.

14. the composition of claim 14, wherein said composition also comprises essential oil.

15. the composition of claim 14, wherein said essential oil are selected from following any one or more: Semen Armeniacae Amarum oil, olium anisi, basil oil, oreodaphene, caraway oil, Oils, Elettaria cardamomum, Cedrus deoclar (Roxb.) G. Don oil, Oils, Apium graveolens, chamomile oil, Oleum Cinnamomi, pamorusa oil, Syzygium aromaticum stem oil, Fructus Coriandri oil, cumin oil, oleum anethi, eucalyptus oil, Sweet fennel oil, ginger oil, grapefruit oil, lemon oil, lime oil, spearmint oil, Parsley seed oil, spearmint oil, pepper oil, rose oil, Oleum Menthae Rotundifoliae (menthol), sweet orange oil, thyme oil, turmeric oil and wintergreen oil.

16. the composition of claim 17, described composition also comprises any one or more in the following auxiliary agent: agent, vitamin b6 usp, suntan, plant milk extract, antiphlogistic, oxidation inhibitor, free-radical scavengers, retinoids, alpha hydroxy acid, sterilizing agent, microbiotic, antiseptic-germicide, antihistaminic agent are shone in mycocide, sun-screening agent, resistance.

17. the composition of claim 7, described composition packet content account for the described compound of about 0.001%-about 80% of composition total weight.

18. the composition of claim 7, but but described composition is the form of jetting liquid, aerosol, foam, white cream, ointment, gel, paste, powder or crushed solid.

19. a repel insects or arthropodan method, described method comprise insect or arthropods are exposed in the compound that following general formula represents:

Wherein R is H, alkyl, thiazolinyl, alkynyl or aryl.

20. the method for claim 19, wherein R is (a) H, (b) C ₁-C ₂₀Alkyl, (c) C ₂-C ₂₀Thiazolinyl, (d) C ₃-C ₂₀Alkynyl or (e) C ₆-C ₂₀Aryl.

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

(a)CH ₃、C ₂H ₅，

(b) C ₃-C ₂₀Straight chain, side chain or cyclic alkyl or thiazolinyl,

22. the method for claim 19, wherein R is selected from (a) CH ₃, (b) C ₂H ₅, (c) C ₃-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (d) comprise the heteroatomic C that is selected from O, N and S ₃-C ₁₁Straight chain, side chain or cyclic alkyl or thiazolinyl.

23. the method for claim 19, wherein R is the phenyl that does not replace or replace, and it is optional by the C of Cl, Br or F replacement that wherein said substituting group is selected from (a) ₁-C ₁₂Straight chain, side chain or cyclic alkyl or thiazolinyl and (b) be selected from the halogen of Cl, Br and F.

24. the method for claim 19, wherein said compound are the single stereoisomers of simplification compound, or are the stereoisomer mixture of simplification compound.

25. the method for claim 19, described method comprise insect or arthropods are exposed in the described compound compositions of about 80% weight of about 0.001%-that packet content accounts for composition total weight.

26. the method for claim 19, described method comprise food blood insect or arthropods are exposed in the described compound.

Be selected from sting insect or the arthropods of fly, trombiculid, flea, mosquito, tick and louse of thorn and be exposed in the described compound 27. the method for claim 19, described method comprise making.

28. the method for claim 19, described method comprise described compound administration on insect or arthropodan human or animal host's skin, skin, hair, feather or fur.