CN101396020A

CN101396020A - Preparation method of composition containing dihydro nepetalactone

Info

Publication number: CN101396020A
Application number: CNA2008101297039A
Authority: CN
Inventors: D·L·哈拉汉; L·E·曼泽尔
Original assignee: EI Du Pont de Nemours and Co
Current assignee: EIDP Inc
Priority date: 2003-09-18
Filing date: 2003-09-18
Publication date: 2009-04-01
Anticipated expiration: 2023-09-18
Also published as: IL173903A0; BR0318501A; CN101396020B; AU2003270748A1; EP1681925A4; CN1838881A; CA2538363C; CA2538363A1; EP1681925A1; WO2005034626A1; JP2007521240A; AU2003270748A2

Abstract

The invention relates to dihydro-Nepetalactone, which is the secondary natural ingredient of catnip (Nepeta), for example Nepeta essential oil and has been confirmed as an effective vermicide compound. The dihydro-Nepetalactone can be synthesized by hydriding Nepetalactone (the main ingredient of catnip essential oil). Meanwhile, the compound with aromaticity can be commercially used due to the disinsectization performance.

Description

The preparation of compositions method that comprises dihydro nepetalactone

The application is to be on September 18th, 2003, denomination of invention the applying date be the dividing an application of the application for a patent for invention of the PCT/US2003/029344 of " insect repellent compositions that comprises dihydro nepetalactone ", the Chinese patent application of original application number is 03827095.1.

The application is the U.S. application SN10/392 of application on March 19th, 2003,455 part continuation application, and for various purposes, the full text of this application is incorporated herein by the part of this paper.

Technical field

The present invention relates to the pest repellant field, and the dihydro nepetalactone stereoisomer is as the extensive use of anthelmintic substance.

Background technology

Anthelmintic substance generally can expel insect or make insect to repel insect foods acceptable source or site originally.For pest repellant, at least 85% pest repellant of selling in the U.S. that is used for expelling parasite contains N, and N-diethyl-toluamide (DEET) is as their main active.In addition, the consumer report test shows that the product repelling effect duration of containing maximum concentration DEET is the longest.Though be effective pest repellant, DEET has bad smell and gives skin with greasy sensation.In addition, be registered in the U.S. and use though this compound obtains EPA once more, for its safety, especially degree of concern more and more higher (Briassoulis, the G. of the safety when being applied to children; Narlioglou, M.; Hatzis, T. (2001) Human ﹠amp; Experimental Toxicology, 20 (1), 8-14).Some researchs propose, and high concentration DEET may cause allergic reaction or toxic reaction in some individualities.Other shortcoming relevant with DEET comprises: 1) it is the synthetic chemistry goods, and promptly it can not obtain from natural origin; 2) it demonstrates limited activity profile-for example, and it is not effective chemicals (Schreck, C.E., Fish, the D.﹠amp that drives away the expectation of black leg worm or deer lice; McGovern, T.P. (1995), Journal of theAmerican Mosquito Control Association, 11 (1), 136-140); 3) DEET dissolves or damages the surface of multiple plastic products and japanning; With 4) DEET can plasticising some generally be used for the inert component of topical formulations, this causes user's acceptability lower.

Because above-mentioned limiting factor, has anthelmintic activity but the product that do not contain DEET is subjected to consumer's favor.Particularly, the needs to the composition that contains natural prodcuts progressively improve.New pest repellant to be selected should have desirable performance balance and preferably reach or surpass the positive performance of DEET, and/or do not have it negative performance (Hollon, T., (2003), The Scientist, on June 16th, 2003,25-26).Secondly, possible DEET substitute should eligibly demonstrate good anthelmintic activity, high residue is active and to human (perhaps pet) and the hypotoxic combination of environment.In addition, to can from natural plant raw material, obtain or can be by natural plant raw material synthetic and demand that use suitable vermifuge compound increase day by day.The candidate of any replacement DEET all should think that poisonous various insects demonstrates anthelmintic activity to the mankind, and insect includes but not limited to sting the people insect, bores wooden class insect, kissing bug and house insect or the like are arranged.

Many plant speciess produce essential oil (the aromatic oil) [Hay as the natural origin of pest repellant and aromatic chemical goods, R.K.M., Svoboda, K.P., Botany, in ' VolatileOil Crops:their biology, chemistry and production ' .Hay, R.K.M., Waterman, P.G. (work) .Longman Group UK Limited (1993)].Citronella oil, well-known because of its generally expeling to insect, derive from gramineous plants winter lemongrass (Cymbopogon winterianus) and nardgrass (C.nardus).The example that is used as the plant in aromatic chemical goods source comprises lemon balm (Melissa officinalis) (Melissa), Perilla frutescens (Perilla), Posostemon cablin (Pogostemon cablin) and multiple lavender (Lavandula).All these plant examples of producing valuable oil all belong to Labiatae (Lamiaceae) family.Nepeta (Catnip) plant also belongs to this section, and they are produced as commercial less important product purpose essential oil.This oil is rich in a class and is commonly referred to as [Inouye H.Iridoids in the monoterpenoid compound of iridoid, Methods in Plant Biochemistry, 7:99-143 (1991)], more specifically, be rich in methyl cyclopentane sample nepetalactone [Clark, L.J. wait the people, The Plant Journal, 11:1387-1393 (1997)] and derivative in.

For a long time, the iridoid monoterpenoid is to know the effective pest repellant of various insects species (Eisner, T., (1964), Science, 146:1318-1320; Eisner, T., (1965), Science, 148:966-968; Peterson, C. and Coats, J., (2001), Pesticide Outlook, 12:154-158; Peterson, people such as C., (2001), Abstractsof Papers American Chemical Society, 222 (1-2): AGR073).The anthelmintic activity of catnip oil (mainly being nepetalactone) studies show that after tanning by the sun by short-term, this catnip oil is the pest repellant to many insect species, but it is not pest repellant (Eisner, T., (1964) for many other species, Science, 146:1318-1320).

United States Patent (USP) 4,663,346 disclose the pest repellant with the composition that contains bicyclic ring alkene ether terpene lactones (for example iridomyrmecin).In addition, United States Patent (USP) 4,869,896 disclose these bicyclic ring alkene ether terpene lactones compositions are applied to contain in the synergy pest repellant mixture of DEET.United States Patent (USP) 6,524,605 disclose the pest repellant that comprises the nepetalactone that is obtained by Catnip plant schizonepeta, and the nepetalactone stereoisomer is renderd a service as the difference of pest repellant.

The known composition that contains dihydro nepetalactone (DHN) (the iridoid monoterpenoid (as shown in Figure 1) that a class is derived and obtained by nepetalactone) can provide insecticidal action.For example, the anal gland secretion component of the smelly uranotaenia ant of light stern rainbow studies show that the wherein quite a large amount of different dihydro nepetalactone of existence, also has different iridomyrmecin (Cavill simultaneously, G.W.K. and D.V.Clark., (1967), J.Insect Physiol., 13:131-135).At that time, known different iridomyrmecin had good ' fatal ' insecticidal activity.

(Tetrahedron 38:1931-1938) discloses in ant pest repellant secretion and has had dihydro nepetalactone, but it is said that the compound iridodial is main pest repellant component people such as Cavill (1982).

Jefson, (J.Chemical Ecology 9:159-180) discloses in vapor phase people such as M. (1983), and dihydro nepetalactone shows effective anti-repelling properties to ant in 25 seconds.The longer time is not studied.Be exposed to pure dihydro nepetalactone steam after 25 seconds, the single tame ant of about 50～60% destruction stops to search for food.About the duration of pest repellant effect, do not provide any indication.

Summary of the invention

A kind of embodiment of the present invention is the anthelmintic composition of material that comprises the mixture of dihydro nepetalactone shown in the following general formula or dihydro nepetalactone stereoisomer:

Another embodiment of the present invention is the composition that expels the material of insect when being applied to the mankind, animal or not having the life main body, and described material comprises the mixture of dihydro nepetalactone shown in the top general formula or dihydro nepetalactone stereoisomer.

Another embodiment of the present invention is a kind of composition that expels the material of one or more insects, insect is selected from honeybee, black fly, trombiculid, flea, bluebottle, mosquito, stable fly, tick, wasp, brill wood class insect, housefly, camphor cockroach, louse, cockroach, wood louse, meal beetle worm and beans beetle, dirt mite, moth, moth and weevil, and described material comprises dihydro nepetalactone shown in the top general formula or dihydro nepetalactone stereoisomer mixture.

Another embodiment of the present invention is a kind of composition of material; described material have on the statistics can not with N; the average guard time fully that a N-diethyl-toluamide is distinguished, this material comprises the mixture of dihydro nepetalactone shown in the top general formula or dihydro nepetalactone stereoisomer.

Another embodiment of the present invention is a kind of insect repellent compositions of material, and described material comprises the dihydro nepetalactone shown in about by weight top general formula of 0.001%～about 80% or the mixture of dihydro nepetalactone stereoisomer.

Another embodiment of the present invention is a kind of method of making insect repellent compositions or pest repellant goods, described method comprises: the mixture of dihydro nepetalactone shown in the top general formula or dihydro nepetalactone stereoisomer is formed composition or goods, perhaps dihydro nepetalactone shown in the top general formula or dihydro nepetalactone stereoisomer mixture are incorporated in composition or the goods.

Another embodiment of the present invention is a kind of method that gives, increases or strengthen the goods anthelminthic effect, and described method is incorporated in the goods by the mixture with dihydro nepetalactone shown in the top general formula or dihydro nepetalactone stereoisomer carries out.

Another embodiment of the present invention is a kind of method that insect is expelled the mankind, animal or do not have the life host, and described method is undertaken by the mixture that insect is exposed to dihydro nepetalactone shown in the top general formula or dihydro nepetalactone stereoisomer.By the insect that expelled can be, for example, one or more in mosquito, stable fly and the tick.

Another embodiment of the present invention is that the mixture of dihydro nepetalactone shown in the top general formula or dihydro nepetalactone stereoisomer expels the mankind, animal with insect or do not have life host's purposes.The insect that expels can be, for example, and one or more in mosquito, stable fly and the tick.

Another embodiment of the present invention is a kind of method that is used for production formula (XVI) dihydro nepetalactone, and described method is carried out according to following scheme, (is not SrCO being carried on catalyst carrier ₃) on palladium have down hydrogenation of formula (XV) nepetalactone and obtain product:

The applicant has been found that dihydro nepetalactone is fine as the new effective vermifuge compound effect of a class, and it does not have the unfavorable performance characteristic of composition in the prior art.When the pest repellant, DHN is by making insect food source or living environment insect is had no attraction or make it disagreeable, prevents that with this it is to plant and animal (comprising the mankind) or to the infringement of goods.

Description of drawings

Fig. 1 is the structure of (7S)-nepetalactone, the chemical constitution that has shown naturally occurring iridoid (methyl cyclopentane sample) nepetalactone, wherein upper left structure is (4aS, 7S, 7aR)-nepetalactone (cis, trans-nepetalactone), upper right structure is (4aR, 7S, 7aS)-nepetalactone (cis, cis-nepetalactone), the structure of lower-left is (4aS, 7S, 7aS)-nepetalactone (trans, cis-nepetalactone), and the structure of bottom right is (4aR, 7S, 7aR)-nepetalactone (trans, trans-nepetalactone).

Fig. 2 be before hydrogenation after (A) and the hydrogenation GC-MS of the Catnip oil of (B) fractionation analyze the total ion chromatogram that obtains, shown from commercially available Catnip oil behind distillation enrichment nepetalactone cut (A) and the material (B) that is obtained by hydrogenation by this cut carried out the total ion chromatogram that gas chromatography/mass spectrometry (GC-MS) coupling analysis obtains.

Fig. 3 analyzes nepetalactone (A) peak obtain and the mass spectrum at dihydro nepetalactone (B) peak from GC-MS, has shown the mass spectrogram of the key component of the cut (A) of the enrichment nepetalactone by GC-MS Analysis and Identification among Fig. 2 and hydrogenation material (B).

Fig. 4 is a nepetalactone in the Catnip oil of fractionation ¹³C NMR analyzes, and has shown the Catnip oil that will commercially availablely buy to be distilled cut behind the enrichment nepetalactone carries out ¹³C NMR analyzes.

Fig. 5 is a dihydro nepetalactone in the Catnip oil of hydrogenation ¹³C NMR analyzes, and has shown to be obtained by the dihydro nepetalactone analysis ¹³C NMR spectrum, wherein said dihydro nepetalactone are by the cut hydrogenation behind the commercially available Catnip oil distillation enrichment nepetalactone is obtained.

Fig. 6 sounds out Density Distribution to scheme (yellow-fever mosquito over time; The dihydro nepetalactone of deriving and obtaining by the mixture of hydrogenation of nepetalactone stereoisomer), shown in external anthelmintic activity test, female yellow-fever mosquito duration of test has been soundd out density distribution in time at various pest repellants.

Fig. 7 has shown trans, cis-nepetalactone ¹³C NMR analyzes.

Fig. 8 shown by trans, the derive dihydro nepetalactone that obtains of the hydrogenation of cis-nepetalactone ¹³C NMR analyzes.

Fig. 9 shown in the test of external anthelmintic activity, and by cis, trans-nepetalactone hydrogenation dihydro nepetalactone that obtains of deriving carries out duration of test to female yellow-fever mosquito, sounds out density distribution in time.

Figure 10 has shown in external anthelmintic activity test, at various pest repellants stable fly (stable fly genus) is carried out duration of test, the distribution in time of landing density.

Figure 11 carries out duration of test at various pest repellants to Anopheles mosquito (white sufficient mosquito), souning out Density Distribution schemes over time, shown in external anthelmintic activity test, female anopheles (white sufficient anopheles) has been carried out duration of test, soundd out density distribution in time at various pest repellants.

Embodiment

Nepetalactone is the compound with following formula:

As implied above, four chiral centres be positioned at 4 on the methyl cyclopentane sample skeleton of nepetalactone, 4a, 7 and 7a position carbon atom on; (7S)-nepetalactone can obtain by some plants and insect.

Known dihydro nepetalactone is accessory constituent (Regnier, people such as F.E., (1967), Phytochemistry, the 6:1281-1289 of some Nepeta labiate essential oil; DePooter, people such as H.L., (1988), Flavour and Fragrance Journal, 3:155-159; Handjieva, N.V. and S.S.Popov, (1996), J.Essential OilRes., 8:639-643).Dihydro nepetalactone is as shown in the formula 1 definition:

Formula 1

Wherein 1,5,6 and 9 the expression molecules four chiral centres, and shown in structure comprise all stereoisomers of dihydro nepetalactone.Can be as follows by the derive structure of the dihydro nepetalactone stereoisomer that obtains of (7S)-nepetalactone.

The compound title is as follows:

(1S, 5S, 9S, 6R)-5, the 9-dimethyl (1S, 9S, 5R, 6R)-5, the 9-dimethyl

-3-oxabicyclo [4.3.0]-ninth of the ten Heavenly Stems-2-ketone-3-oxabicyclo [4.3.0]-ninth of the ten Heavenly Stems-2-ketone

(1S, 5S, 9S, 6S)-5, the 9-dimethyl (1S, 9S, 6S, 5R)-5, the 9-dimethyl

(9S, 5S, 1R, 6R)-5, the 9-dimethyl (9S, 1R, 5R, 6R)-5, the 9-dimethyl

(9S, 6S, 1R, 5S)-5, the 9-dimethyl (9S, 6S, 1R, 5R)-5, the 9-dimethyl

" dihydro nepetalactone " (DHN) is appreciated that and comprises any and whole dihydro nepetalactone stereoisomer and composition thereof, unless describe concrete isomer or mixture in detail.When dihydro nepetalactone is prepared by the natural existence of nepetalactone source, can expect that there are some differences in stereoisomer on molar concentration.In any case being prepared by natural existence source is preferred manufacturing procedure.

People such as Regnier, op.cit. disclose by nepetalactone and have prepared DHN, carry out from the nepetalactone that Nepeta (Catnip) essential oil separates by catalytic hydrogenation.Thus, a kind of preferred and facilitated method of synthesizing dihydro nepetalactone is exactly with nepetalactone hydrogenation, and described nepetalactone is the pure relatively nepetalactone that obtains from the essential oil that separates from Nepeta (Catnip) by several different methods.Catalyzer for example platinum oxide and palladium (being carried on the strontium carbonate) obtain productive rate be 24～90% dihydro nepetalactone (people such as Regnier, op.cit.).Particularly preferred method is disclosed among the U. S. application SN 10/405,444, and this application is filed on April 2nd, 2003, and for various purposes, the full text of this application is incorporated herein by the part of this paper.The method that essential oil separates is well known in the art, the example that extracts the method for oil includes, but is not limited to the organic solvent extraction of steaming, organic solvent extraction, microwave promotion, supercritical fluid extracting, mechanical extraction and fragrance of a flower absorption method (at first cold extraction is then used organic solvent extraction again in grease).

As everyone knows, the essential oil that separates from different Nepeta species has each naturally occurring stereoisomer (people such as Regnier, the op.cit. of the nepetalactone of different proportion; People such as DePooter, op.cit.; People such as handjieva, op.cit.).Therefore, the DHN that the oil that is obtained by any Nepeta species prepares must be the mixture of its stereoisomer, and the composition of described mixture depends on the concrete species of the Nepeta that obtains mixture.

As mentioned above, the intraskeletal carbon 4 of methyl cyclopentane sample that four chiral centres are present in nepetalactone, 4a, 7 and the 7a position on, as follows:

Behind the hydrogenation of nepetalactone, may there be eight pairs of dihydro nepetalactone enantiomters altogether.In these stereoisomers, disclosed up to now naturally occurring stereoisomer is (9S)-dihydro nepetalactone.Preferred pest repellant material comprises the mixture of any or all possible dihydro nepetalactone stereoisomer according to the present invention.Further preferred pest repellant material comprises (9S)-dihydro nepetalactone mixture.(9S)-dihydro nepetalactone stereoisomer of deriving and obtaining most preferably by (7S)-nepetalactone.It comprises and is commonly referred to cis, trans-nepetalactone, cis, and cis-nepetalactone, trans, cis-nepetalactone and trans, the compound of trans-nepetalactone, as shown in Figure 1.The preferred main stereoisomer that obtains by schizonepeta (cis, trans and trans, cis).

After hydrogenation was finished, the mixture of the isomer products of gained can obtain separating by conventional method (for example preparation property liquid chromatography), thereby obtains each to highly purified dihydro nepetalactone diastereoisomer.This allow with to specific insect the most effective and efficient manner use multiple different diastereoisomer.Preferably from plant, isolate concrete nepetalactone isomer, to be translated into its corresponding a pair of diastereoisomer by hydrogenation.

Between different Nepeta species, the difference on the nepetalactone alloisomerism body burden, also knownly in same species, also there are differences.The plant of given species can produce the essential oil with different component, and this depends on the condition of their growths or residing vegetative stage when results.In fact, in pale reddish brown Catnip, have been found that difference that oil forms and growth conditions or the stage of growth when results have nothing to do (Clark, people such as L.J., op.cit.).The plant that demonstrates the single species of different oil compositions is known as chemical type (chemotypes).In pale reddish brown Catnip, exist in the chemical type that demonstrates significant difference in the different nepetalactone stereoisomer ratios.Therefore, the method for preferably producing specific dihydro nepetalactone enantiomter is the oil that hydrogenation is extracted by the known Nepeta chemical type that contains specific nepetalactone stereoisomer.

The insect that is expelled by the present composition comprises any one in the big class of invertebrate, it is characterized in that it is divided into head, chest and belly, the three pairs of foots and (but also not being full of) two pairs of film wings usually at adult stage (the non-adult stage comprises larva and pupa) body.Therefore, this definition include but not limited to the multiple people of stinging insect (for example ant, honeybee, black fly, trombiculid, flea, bluebottle, mosquito, stable fly, tick, wasp), bore wooden insect (for example termite), kissing bug is arranged (for example housefly, camphor cockroach, louse, cockroach, wood louse) and house insect (for example meal beetle worm and beans beetle, dirt mite, moth, moth, weevil).In one embodiment, for example, DHN composition of the present invention is effective pest repellant of common insect in the broad range, for example above-mentioned those insects mentioned of common insect, comprise equally and sting the people insect, bore wooden insect, kissing bug and household insect are arranged, the most particularly comprise mosquito, stable fly and tick (for example deer tick).

In another embodiment, DHN composition of the present invention can effectively expel following any or various insects, and described insect is selected from honeybee, black fly, trombiculid, flea, bluebottle, mosquito, stable fly, tick, wasp, brill wood insect, housefly, camphor cockroach, louse, cockroach, wood louse, meal beetle worm and beans beetle, dirt mite, moth, moth and weevil.Yet, can also be one or more insects that are selected from above-mentioned subgroup by the insect that expelled, described subgroup is made up of one or more insects of omitting in the whole insect group described in first of this section.Therefore, can just be selected from the insect situation of any scope subgroup that can form by above-mentioned whole insect group, organize the insect of having omitted when forming subgroup but can get rid of by whole insect by the insect that expelled.In addition, the subgroup that the various insects of being omitted by above-named whole insect group forms can be the independent part of whole insect group, so makes the insect that is expelled get rid of all other insects of whole insect group.

The host is any plant or animal that influenced by insect.It is generally acknowledged that the host is insect foods acceptable source or the acceptable site of insect.The host can be animal (including but not limited to pet and/or other performing animal), the mankind, plant or what is called " the responsive goods of insect ", and described " the responsive goods of insect " comprise any no life goods that influenced by insect.This can comprise building and furniture or the like.

In another embodiment of the present invention,, DHN is incorporated among host's (for example responsive goods of insect) to form the expelling parasite goods based on stoping insect to drop on the goods or stoping insect to occupy the purpose of goods surrounding space.The situation that this technical scheme is used in expection is that before using DHN compositions-treated of the present invention, goods may demonstrate the situation of the anthelmintic activity of some degree.In this case, can expect the application of the invention DHN composition, the anthelmintic activity of goods will be enhanced.

Pest repellant is compound or the composition of any prevention insect near the host.Should be appreciated that above-mentioned usage needs the compound of very high surface concentration to distinguish before not producing appreciable impact to compound with short run effect and the compound that demonstrates long-term beneficial effect and/or to the insect state.

Thus, term " pest repellant " expression is compared when not handling and is given compound or the composition that the host protects the insect ability." protective effect " causes the remarkable minimizing of insect number on the statistics ideally; for example can measure effectively it by the average guard time of measuring in the test (" CPT ") fully; in described test, insect is observed near the behavior of treated animal (comprising the mankind) and treated inanimate surfaces.Average CPT is meant the average length of repeated test time, in test insect is being landed, is souning out or biting (being to sting under the situation of people insect) or (being under the situation of reptile (for example tick or the trombiculid)) time before of creeping is observed and [consulting first on the treatment surface, US EPA Office of Prevention for example, Pesticides and ToxicSubstances product performance test guidelines OPPTS 810.3700; And Fradin, M.S., Day, J.F. (2002), New England Journal of Medicine, 347,13-18].In an illustrative embodiment of the present invention, insect repellent compositions herein has statistically the average CPT that can not distinguish with DEET.At the average CPT that shows DHN composition and DEET in the undistinguishable test of statistics, employed experimental condition (amount that comprises active component) must undoubtedly be equal to, if perhaps be not equal to, must only be the difference of mode, described mode hinder the result who carries out for the purpose of quoting described existence condition as proof to use.

As mentioned above, compare with DEET, DHN is comparatively favourable on performance.In addition, DHN can advantageously be prepared by the natural nepetalactone that exists that stems from plant, yet DEET and many other pest repellants are not by natural origin preparation, and natural origin is that the consumer considers important factor when selecting effective pest repellant.The preparation of being undertaken by natural origin also provides the potential possibility of low production cost.

The aspect that the present invention is especially surprising is DHN in the effective anthelmintic activity of performance, also provides sizable improvement with respect to the smell of DEET.DHN compound of the present invention and composition have pleasant fragrance.The fragrance characteristic of DHN material makes them can be used for giving, change, increasing or strengthen the overall sense of smell component of insect repellent compositions or goods, for example, and by the olfaction reaction that utilizes or mitigation is caused by one or more other compositions in the composition.Clear and definite, DHN composition of the present invention can be used for sheltering or change the smell that other composition of preparation by final insect repellent compositions or goods causes, and/or strengthen the attraction of product the consumer by giving feature fragrance or fragrance.

The effectiveness that should be appreciated that DHN or any pest repellant depends on that active component is with the lip-deep surface concentration of the host of its application.Many compounds as known in the art are in order to show the anthelmintic activity use that is not always the case, yet, just they only show anthelmintic activity under dense relatively form.Consult, people's such as McGovern United States Patent (USP) 4,416,881 for example, this patent disclosure concentration be the application of 6.25～25% pest repellant.In other art technology representative case, usually find that DEET concentration was far below 1% o'clock needs repeated application, until obtaining effective surface concentration, yet being higher than 30%, concentration will cause too high surface concentration, this not only wastes but also can promote undesirable side effect to produce.Thereby another advantage of the present invention is that DHN not only provides effective anthelmintic activity when concentration and the concentration that is used for DEET are similar, and DHN can use be up to and comprise pure DHN concentration (promptly, if expectation, composition can contain 100% DHN by weight herein).Effective disinsectization performance of DHN provides multiple choices for the Economic Application of DHN active component in the wide range of concentration level.

In one embodiment of the present invention, the DHN of effective dose is incorporated into is suitable for being applied in the composition of host plant or animal, advantageous applications is to human skin.Suitable compositions comprises DHN and excipient, the preferred alcohols of excipient (for example isopropyl alcohol), washing lotion (for example, such as at many face cream well known in the art) or siliceous clay.Preferred DHN is present in the insect repellent compositions of the present invention with about 0.1%～30% concentration by weight, and is preferably about by weight 0.5%～20%, and most preferably about by weight 1%～15%.

For pest repellant produce to be renderd a service, the evaporation rate of the active component that evaporates from host's skin or treatment articles must be fully high, to produce targeted insect had the vapour density of Expected Results like this.Yet it is too high with the pest repellant on the exhausted surface to reach a balance-evaporation rate between the duration in the repellent effect of evaporation rate and expectation, causes loss of effectiveness.Many extraneous factors all can influence evaporation rate, for example the temperature of environmental temperature, treatment surface and existence or do not have air-flow.The present composition has and is at least the minimum effectively skin surface evaporation rate of evaporation rate, and preferably has and continue at least 5 hours the skin surface evaporation rate that is at least minimum effective evaporation rate.

Generally, infiltrating and see through skin is undesirable mode that causes the loss of skin surface compound.For example, known pest repellant is absorbed in the human skin, can cause the worry of genotoxic potential on the one hand, and obviously will from active pest repellant, remove the absorptive amount of pest repellant.Must similarly consider for the pest repellant goods.

Though DHN can provide effective anthelmintic activity under general service condition, under some environment, can eligibly reduce its evaporation rate.If expectation can be used the evaporation rate that multiple strategy reduces DHN.For example, a kind of method is that DHN and polymer or other inert component are used in combination, and forces DHN to need to see through mixture before can evaporating and is transferred to its surface.Yet, if the result has diluted the concentration that can be applied to host's skin surface or be present in the DHN solution on the pest repellant product surface, do the overall efficiency that can reduce preparation like this, this must consider in the evaporation policy selection.In addition, the active component trace can be encapsulated into capsule with the percent of loss of control on host's skin surface or the pest repellant goods.Again in addition, can prepare slowly cracked precursor molecule on skin surface or pest repellant goods with release of active ingredients.

For example, can wherein only active component be encapsulated in the protein of (centering on) nourishes rough skin by for example submicron capsule release of active ingredients according to the mode that inflates air to air bag.Protein can use with for example 20% concentration.A kind of application of pest repellant comprises many these classes and is suspended in the protein capsule that is used for spray application in water base washing lotion or the water.After skin contacted, the protein capsule began disintegration, discharged the dihydro nepetalactone in incapsulating.

When each tiny capsules exhausts, when the new capsule that then is touched skin then and discharges its active component substituted, this step was proceeded.This method is once used and can be continued 24 hours.Because protein is very significant to the adhesivity of skin, so these preparations very sweat proof (perspiration) and water.

When using, they are dry and comfortable, do not have greasy feeling.This system can produce very effective protection, and is effective when still only being used in it on skin, because clothes does not have the ability that discharges protein.Alternative system uses the polymer overmold pest repellant, has slowed down early stage evaporation like this and remaining dihydro nepetalactone that can be used for the later stage evaporation more.Compare with non-encapsulating products, this system can make increase by 25%～50% the effective time of pest repellant usually, but because the existence of polymer can feel greasy usually.In another kind of alternative system, synergist is used for the evaporation of dihydro nepetalactone in the continuous stimulating composition.

In the present invention, can use variety carrier or thinner for above-mentioned disclosed dihydro nepetalactone.Described carrier can be adjusted to preparation the valid density of pest repellant molecule.When being mixed with when being suitable for human or zoodermic local pest repellant, preferably the pest repellant molecule is sneaked on the dermatology in the acceptable carrier.Carrier can further provide water repellency, prevent skin irritatin and/or mitigation and conditioning skin.

The factor that should consider when selection is used for one or more carriers of any pest repellant preparation comprises market value of purchase, cost, anthelmintic activity, evaporation rate, smell and stability.Self just has the expelling parasite characteristic some carriers.In addition, carrier also should preferably can not produce the carrier of harm to environment.

Being suitable for carrier of the present invention is known one or more commercially available organic and inorganic fluidised forms, solid-state or semisolid carrier or carrier formulation in preparation pest repellant product scope.For example, carrier can comprise silicone, vaseline or lanolin.

The example of organic liquid carrier comprises liquid fat family hydrocarbon (for example pentane, hexane, heptane, nonane, decane and analog thereof) and aromatic liquid hydrocarbon.The example of other liquefied hydrocarbon comprises that the petrochemical material by coal distillation and polytype and grade distills the oil that is produced, and comprises the kerosene that obtains through petroleum fractionating.

Other petroleum-type comprises the oils (for example, so-called light-duty and intermediate spray oils is made up of and only slightly volatilization the midbarrel in the petroleum distillation) that is commonly referred to agriculture spray oil.Above-mentioned oil is normally highly refined, and may only contain the unsaturated compound of trace.In addition, this class oil is paraffin oils normally, and in view of the above can water and emulsifier emulsification, be diluted to low concentration and as spray oil.The tall oil that uses sulfuric acid lixiviate wood pulp to be obtained, the same with paraffin oils, also can similarly use.Other organic liquid carrier can comprise liquid terpene hydrocarbon and terpenol, for example australene, dipentene and terpineol or the like.

Other carrier comprises aliphatic and aromatic alcohols, ester, aldehyde and ketone, mineral oil, higher alcohol, organic and solid inorganic material in small, broken bits.Except above-mentioned liquefied hydrocarbon, carrier can comprise conventional emulsifier, is diluted to be used for terminal applies by water thereby described emulsifier can be used for making the dihydro nepetalactone compound to be dispersed in the water.

Aliphatic monobasic alcohol comprises methyl alcohol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butanol, sec-butyl alcohol and the tert-butyl alcohol.Suitable alcohol comprises dihydroxylic alcohols (for example ethylene glycol and propane diols) and pinacol.Suitable polyhydroxy-alcohol comprises glycerine, arabitol, erythritol and sorbierite or the like.At last, Shi Yi cyclic alcohol comprises cyclopentanol and cyclohexanol.

In addition, conventional or so-called " stabilizing agent " (for example tert-butyl group sulfinyl Methyl disulfide is for carbonic ester) can be used for uniting with carrier or the carrier that comprises the present composition and uses or as one of its component.

The solid-state carrier that can be used for the present composition comprises organic and inorganic solid matter in small, broken bits.Suitable in small, broken bits solid-state inorganic carrier comprises siliceous ore deposit (for example synthetic and natural clay, bentonite, Attagel, bleaching earth, diatomite, kaolin, mica, talcum and quartz in small, broken bits or the like) and the synthetic siliceous substance (for example white carbon and precipitation and gas-phase silica) that obtains.The example of solid-state organic substance in small, broken bits comprises cellulose, sawdust and synthetic organic polymer or the like.The example of semisolid or colloid bearer comprises waxy solid, gel (for example vaseline oil) and lanolin or the like, and well-knownly can provide the liquid state of semisolid vector product and the mixture of solid matter, described mixture is used to provide the effective anthelmintic activity in the scope of the invention.

The insect repellent compositions of the present invention that comprises dihydro nepetalactone can also comprise the known assistant agent of personal care product's formulation art, for example thickener, buffer, chelating agent, preservative, flavouring agent, antioxidant, gelling agent, stabilizing agent, surfactant, softening agent, colouring agent, aloe liquid, wax, other penetration enhancers and composition thereof and therapeutic activity agent or cosmetic activating agent.

Therapeutic activity composition or the cosmetic active component useful to the present composition comprise fungicide, opacifier, sun-screening agent, vitamin, tanning agent, plant extracts, antiphlogistic, antioxidant, radical scavenger, biostearin, α-alkyd, emollient, preservative, antibiotic, antibacterial agent or antihistaminic, and they can exist with the effective dose that reaches expectation acology or dressing effect.

The present composition also can mix with non-dihydro nepetalactone pest repellant, non-dihydro nepetalactone for example is included in following compound: diphenylthanedione, benzoic acid benzyl ester, 2,3,4, two (but-2-ene) tetrahydrofurfurals of 5-, the butoxy polypropylene glycol, N-butyl-monoacetylaniline, 6,6-dimethyl-5,6-dihydro-1, pyrokomane-2-formic acid n-butyl, dibutyl adipate, dibutyl phthalate, dibutyl succinate, N, a N-diethyl-toluamide, dimethyl carbate, repefral, 2-ethyl-2-butyl-1, ammediol, 2-ethyl-1, the 3-hexylene glycol, pyridine 2,5-dioctyl phthalate di-n-propyl ester, the 2-phenylcyclohexanol, right-

Alkane-3,8-two pure and mild N are in the N-diethyl succinamic acid n-propyl.

In order to satisfy the needs of any concrete application, DHN composition of the present invention can comprise the above-mentioned assistant agent of many kinds.The concrete ratio of each composition will be determined similarly according to the needs of using.Yet, the preferred present composition should comprise by weight the DHN at least about 0.001%, perhaps about by weight DHN of 0.001%～about 80%, perhaps about by weight DHN of 0.01%～about 30%, perhaps about by weight DHN of 0.1%～about 30%, preferably about by weight 0.5%～about 20%, most preferably about by weight 1%～about 15%.Generally speaking, insect repellent compositions should comprise the active pest repellant material of abundant amount, effectively insect is expelled the host (preferably to continue the time of several hrs at least) in one period.

Dihydro nepetalactone can use with the form of the mixture of single diastereoisomer or multiple diastereoisomer in the present invention, perhaps is used in combination with other pest repellant.DHN can use with any concentration that specifically needing to be suitable for, and comprises and uses pure DHN.Yet the amount that is expected at according to the DHN in insect repellent compositions of the present invention or the pest repellant goods will be no more than about by weight 80% usually.

Can prepare and pack the present composition, thereby can send product in a variety of forms, comprise forming solution, suspension, cream, paste, gel, film or spray agent, this depends on the method for preferred use.Carrier can be to be suitable for dihydro nepetalactone is scattered in aerosol combination in the atmosphere by Compressed Gas.

The desirable characteristic of local pest repellant comprise hypotoxicity, to the repellence of the water logging or the loss of perspiring, slight or do not have smell or be pleasant smell at least, be easy to use and on host's skin, form rapidly dry sticking pellicle.In order to obtain these performances, the preparation that is used for local expelling parasite goods should satisfy: by contact skin, fur or the feather of described animal with the pest repellant goods of effective dose, the animal (dog of flea, the poultry that lice is arranged, the cow that tick is arranged and the mankind are for example arranged) of infestation by insect is handled with insect repellent compositions of the present invention, insect is expelled the animal reservoir.Therefore, goods are scattered in atmosphere or composition is dispersed into liquid mist or fine dust can be so that insect repellent compositions drops on the host surface of expectation.Equally, the liquid state/semisolid/direct dispersion of solid-state pest repellant goods on the host is the effective ways that make host's face contact effective dose insect repellent compositions.

Special in the pleasant fragranced relevant with DHN, the further embodiment of the present invention is that DHN is incorporated in the product that does not have anthelmintic activity substantially, so that described product provides the anthelmintic activity of significant degree.Described product includes, but is not limited to Gulong perfume, washing lotion, spray agent, cream, gel, paste is taken a shower and shower gels agent, frothed product (for example pruning foams), cosmetics, deodorant, shampoo, hair lacquer/profit are sent out agent and individual soap combination (soap and the shower/shower soap of for example washing one's hands).

The present invention's embodiment of expection in addition is by incorporating DHN into goods, making it in the multiple embodiment that effective anthelmintic activity is provided in the responsive goods that insect is destroyed.In a kind of general embodiment, goods are outdoor goods, but needn't be.The goods of expection include but not limited to air freshener, candle, multiple flavor article, fiber, coverlet, textile, paper, coating, ink, clay, timber, furniture (for example garden is used and decorated and use furniture), carpet, amenities, plastics and polymer or the like.

In one embodiment, evaporation rate and the sustained release with dihydro nepetalactone and combination of polymers so that plasticity, reduction to be provided.Above-mentioned polymer can be biodegradable suitable polymer, include but not limited to high density polyethylene (HDPE), low density polyethylene (LDPE), biodegradable thermoplastic polyurethane, biodegradable ethylene polymer and poly-(ε-caprolactone) homopolymers, and with for example U.S.4,496,467, U.S.4,469,613 and U.S.4, disclosed composition comprises identical composition in 548,764.Preferred biodegradable polymer comprises DuPont

Biodegradable polyesters and poly-L-lactide.

The present invention also relates to make the method for DHN, wherein use palladium catalyst.Term " catalyzer " is meant as used herein influences chemical reaction rate (rather than molecular balance) and the material of no chemical change ground separation from described method.

It (is not SrCO that the preparation method who is used for formula (XVI) dihydro nepetalactone relates in being carried on catalyst carrier ₃) on palladium exist down, according to following scheme formula (XV) nepetalactone is carried out hydrogenation:

Term " promoter " is a kind of with the compound of its adding with enhancing catalyzer physics or chemical property as used herein.Chemical promoter can strengthen catalyst activity usually and can in the chemically treated arbitrary steps of catalytic component it be incorporated in the catalyzer.Chemical promoter can strengthen the physics or the chemical property of catalyzer usually, but the side reaction that also it can be added to prevent from not expect takes place." metallic promoter agent " is a kind of with the metallic compound of its adding with enhancing catalyzer physics or chemical property.

The hydrogenation of nepetalactone is carried out in the presence of suitable reactive metal hydrogenation catalyst.Augustine, Heterogeneous Catalysis for the Synthetic Chemist, Marcel Decker, New York discloses acceptable solvent, catalyzer, the apparatus and method that generally speaking are used for hydrogenation among the N.Y. (1996).Many hydrogenation catalysts all are effectively, include, but is not limited to iridium, palladium, rhodium, nickel, ruthenium, platinum and rhenium and compound, its composition and its load form thereof the hydrogenation catalyst as main component.

The metallic catalyst that is used for the inventive method can be as supported catalyst or as non-loaded catalyzer.Supported catalyst is that a kind of wherein active catalyst is deposited on the catalyzer on the carrier mass by the following method, to active catalyst spray, immersion or physical mixed, then carry out drying, calcining and if necessary, method by for example reduction or oxidation activates it, so is deposited on the carrier mass.Often the material as carrier is the porosu solid with high total surface area (outside and inner total surface area), and described high total surface area can provide high concentration active site/Unit Weight catalyzer.Catalyst carrier can strengthen catalyst performance, and because use active metal catalyst more effective, so common preferred negative carried catalyst.The catalyzer that does not load on the catalyst carrier is supported catalyst not.

Catalyst carrier can be any solid-state, inert substance, includes but not limited to oxide, for example silica, aluminium oxide, titanium dioxide, calcium carbonate, barium sulfate and carbon.Catalyst carrier can be pulvis, particle and pill or the like form.Preferred carrier mass of the present invention is selected from carbon, aluminium oxide, silica, cimita (silica-alumina), titanium dioxide, titanium aluminium stone (titania-alumina), titanium silica (titania-silica), barium, calcium and its compound and composition thereof.Suitable carrier comprises carbon, SiO ₂, CaCO ₃, BaSO ₄And Al ₂O ₃In addition, the metal of supported catalyst can have identical carrier mass or different carrier mass.

In one embodiment of the present invention, more preferably carrier is a carbon.Further preferred carrier (especially carbon) is that surface area is greater than 100～200m ²The carrier of/g.Further preferred carrier (especially carbon) is at least 300m for surface area ²The carrier of/g.

Commercially available can be used for that carbon of the present invention comprises sale be the carbon of following trade mark: Bameby﹠amp; Sutcliffe ^TM, Darco ^TM, Nuchar ^TM, Columbia JXN ^TM, ColumbiaLCK ^TM, Calgon PCB ^TM, Calgon BPL ^TM, Westvaco ^TMWith BarnabyCheny NB ^TM(commercially available registration mark is same commercially available carbon for for example Calsicat C, Sibunit C or CalgonC ).

The combination of preferred catalytic metal and carrier system comprises the palladium (for example in ESCAT#142 catalyzer (Englehart)) that is adsorbed on the carbon.

Though the percetage by weight of catalyzer on carrier is also indecisive, should be appreciated that the high more reaction of percetage by weight of metal is carried out soon more.The content of preferable alloy in supported catalyst is about 0.1wt%～about 20wt% of supported catalyst gross weight (catalyst weight adds vehicle weight).More preferably the content of catalytic metal is the about 1wt%～about 10wt% that accounts for the supported catalyst gross weight.Further the content of preferred catalytic metal is the about 3wt%～about 7wt% that accounts for the supported catalyst gross weight.

Optional metals promoter can be used with catalytic metal in the methods of the invention.Suitable metallic promoter agent comprises: the 1) element of periodic table the 1st family and the 2nd family; 2) tin, copper, gold, silver and composition thereof; With 3) composition of periodic table the 8th family's metal of less amount.

Temperature, solvent, catalyzer, pressure and mixing rate all are the parameters that influences hydrogenation.Can adjust these relationship between parameters, thus the conversion ratio that in the reaction of described method, obtains expecting, reaction rate and selectivity.

In the context of the present invention, preferred temperature is about 25 ℃～250 ℃, more preferably about 50 ℃～about 150 ℃, and most preferably be about 50 ℃～100 ℃.Hydrogen Vapor Pressure is preferably about 0.1～about 20MPa, more preferably about 0.3～10MPa, and most preferably be about 0.3～4MPa.Reaction can not add solvent or carry out in the presence of solvent.Effectively solvent comprises the solvent that field of hydrogenation is known, for example hydro carbons, ethers and alcohols.Most preferably alcohols, especially low-grade alkane alcohol, for example methyl alcohol, ethanol, propyl alcohol, butanols and amylalcohol.In the reaction of carrying out according to embodiment preferred, can be obtained up to is 70% selectivity less, and wherein general selectivity is at least 85%.Selectivity is that the material that transforms is the percetage by weight of dihydro nepetalactone, and wherein the material of Zhuan Huaing is that part of raw material that participates in hydrogenation.

Method of the present invention can carry out (consulting with batch (-type), order batch (-type) (being many batch reactors) or continuation mode in the normally used equipment of any continuation method, for example, H.S.Fogler, Elementary Chemical Reaction Engineering, Prentice-Hall Co., Ltd, NJ, USA).To remove by the separating method that is generally used for this separation as the condensed water of product.

After hydrogenation is finished, can separate by the dihydro nepetalactone isomer product mixture of conventional method (for example by distillation, by crystallization or by preparation property liquid chromatogram), thereby it is right to obtain highly purified dihydro nepetalactone enantiomter gained.Chiral chromatogram can be used for separating enantiomter.

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

Embodiment

Among the embodiment, symbol " w/v " is meant the weight of active component (unit is a gram) in 100mL solution hereinafter.

Other abbreviation that uses is as follows: " h " expression hour, " min " expression minute, " sec " represents second, " d " represents the sky, and " mL " represents milliliter, and " L " represents to rise, the ratio of " m/z " expression quality (m) and electric charge (z), " ppm " expression 1,000,000/, " mol% " expression is in the percentage of mole, and pound/square inch gauge is represented in " Hz " expression hertz (1/ second) and " psig ".

Embodiment 1

The preparation of the nepetalactone that is undertaken by the steam distillation catnip oil

By the draft material of steaming from the Catnip Nepeta, prepare commercially available catnip oil sample (

, Bloomfield, NJ, USA).The gas chromatography-mass spectrography of primary sample oil (GC-MS) the analysis showed that its key component is nepetalactone stereoisomer (Fig. 1).Yet the oil of purchase is highly polluted natural products, can desirably make with extra care to obtain the nepetalactone of purifying extract.We carry out rectifying to it and have higher and more lower boiling impurity to remove to compare with nepetalactone.

Thus, prepare nepetalactone cut (2 liters of capacity by fractionation to the oil that receives; 12 inches x1 inch packed columns with 0.24 ＂ SS filling; Variable backflow head; About 2mmHg, the cut between collecting 80 ℃～99 ℃).Fig. 2 A has shown the GC-MS total ion chromatogram by the cut of the enrichment nepetalactone of schizonepeta essential oil commercial sample fractionation preparation.Operating condition is: HP5-MS post, 25m x 0.2mm; 120 ℃ in baking oven, 2min, 15 ℃/min, 210 ℃, 5min; The He of 1ml/min.M/z is that 166 peak is a nepetalactone; Unmarked peak is corresponding to a spot of sesquiterpenoid impurity.

The mass spectrogram that in Fig. 3 A, has shown main peak among Fig. 2 A (6.03min, nepetalactone).Described oil and purifying substance have also been carried out ¹H and ¹³C NMR analyzes, and has listed ¹³C data (Fig. 4).With four kinds of possible stereoisomers reporting in the document ¹³The spectrogram that C chemical shift and sample obtain compares.Detecting three kinds of stereoisomers, serves as that carry out quantitatively it on the basis with near the carbonyl zone that is positioned at the 170ppm.

The chemical shift of original oil and enriched fractions all is provided in the table 1.Each carbon atom of nepetalactone obtains evaluation, as shown in Figure 4.

Table 1

The commercial sample and the heating up in a steamer that are present in Catnip (schizonepeta) essential oil through the steaming purifying Nepetalactone stereoisomer in the branch ¹³ C chemical shift and mol% value

This analysis showed that in described oil, nepetalactone exists with following ratio: the 80.2mol% cis, and trans-nepetalactone, 17.7mol% is trans, cis-nepetalactone and 2.1mol% cis, cis-nepetalactone.These data show that the ratio of nepetalactone in purifying substance is: the 84.5mol% cis, and trans-nepetalactone, 14.3mol% is trans, cis nepetalactone and 1.2mol% cis, cis nepetalactone.The GC-MS of this purifying cut the analysis showed that it mainly is made up of these nepetalactones (m/z166), with micro-sesquiterpenoids caryophyllene and humulene (data not shown).

Embodiment 2

The preparation of dihydro nepetalactone

107g is dissolved in the ethanol (200ml) as the nepetalactone cut that is obtained by the distillation of Catnip oil as described in the embodiment 1, and is placed on 12.7g 2%Pd/SrCO is housed ₃(Aldrich41 is 461-1) in the Fisher-Porter flask of catalyzer.With the test tube emptying with use H ₂Inflate twice, charge into the H of 30psig then ₂After at room temperature stirring 48h, with the test tube emptying and with content by diatomite filtration to remove catalyzer.

Solvent is removed under vacuum, obtained transparent grease.

Above-mentioned substance is carried out GC-MS analyze (HP5-MS post, 25m x 0.2mm; 120 ℃ in baking oven, 2min, 15 ℃/min, 210 ℃, 5min; The He of 1ml/min).Total ion chromatogram is shown in accompanying drawing 2B.This analysis showed that, main component (65.43% area; Rt 7.08min) be the dihydro nepetalactone isomer, m/z is 168; The mass spectrum of this component is shown in Fig. 3 B.It is 113 ion that described spectrogram contains a m/z, be confirmed as dihydro nepetalactone (Jefson, people such as M., op.cit).Five additional peaks of expression residue dihydro nepetalactone diastereoisomer are also shown in the chromatogram, and described dihydro nepetalactone diastereoisomer may be derived by three kinds of nepetalactones that are present in the raw material.These peaks appear at: Rt 5.41min, and 6.8% area, m/z 168; Rt 5.93min, 1.2% area, m/z 168; Rt 6.52min, 4.88% area, quality 168; Rt 6.76min, 13.8% area, m/z 168 and Rt 7.13min, 1.25% area, m/z 168.Do not detect remaining nepetalactone by GC-MS.

Also this material has been carried out ¹H, ¹³C and serial 2D NMR analyze. ¹³The carbonyl zone of C NMR spectrogram (accompanying drawing 5) shows at least five spin systems of existence, and the amount of one of them spin system is greater than other four (about 75%).Detect few remaining nepetalactone.

According to the intensity that coupling constant analysis and observed different N OE pass through the peak, the spatial chemistry of determining described material main component is the dihydro nepetalactone ((9S, 5S, 1R, 6R)-5,9-dimethyl-3-oxabicyclo [4.3.0] ninth of the ten Heavenly Stems-2-ketone) of formula 2.

Formula 2

Distance between methyl (i) and the proton (d) is greater than the distance between methyl (j) and the proton (e), and this observed result is consistent with suitable-inverted stereo chemical structure.

Similarly, by ¹³The C chemical shift, the different dihydro nepetalactone of stereoisomer ((9S, 5R, 1R, 6R)-5, and 9-dimethyl-3-oxabicyclo [4.3.0] ninth of the ten Heavenly Stems-2-ketone (formula 3)) obtained evaluation, it exists with 3.6%.

Formula 3

Thus, GC-MS and NMR data show that as expected, the hydrogenation of nepetalactone stereoisomer mixture obtains corresponding dihydro nepetalactone diastereoisomer.By cis, trans-nepetalactone (84.5Mol% of raw material) derives and the diastereoisomer that comes is main dihydro nepetalactone to (formula 2 and formula 3), accounts for 78.6% of mixture after the hydrogenation.

Embodiment 3

The anthelmintic activity test of dihydro nepetalactone mixture

DHN according to embodiment 2 (called after " mDHN ") preparation is estimated its anthelminthic effect for female yellow-fever mosquito.

About 250 female yellow-fever mosquitos are incorporated into contain the indoor of 5 holes, each Kong Douyong Baudruche (animal intestinal tube) film covers.To be full of the ox blood that contains sodium citrate (preventing to condense) and ATP (every 26ml blood contains 72mg ATP disodium salt) in the hole, and be heated to 37 ℃.The isopropyl alcohol that will contain a kind of 25 μ l volumes of specimen as shown in table 2 puts on each film.

Table 2

The experimental scheme that is used for the anthelmintic activity test

After 5 minutes, add 4 the biggest female mosquitoes indoor.In 20 minutes, carry out record every 2 minutes numbers to the mosquito of the exploration film that is used for each time processing.The mean value of three repeated tests of each data representation.

Table 3 has shown female yellow-fever mosquito sounds out the time of being experienced before respectively handling film first.Numerical value in the bracket is the standard error of mean (SEM) of three repeated tests.

Table 3

Dihydro nepetalactone concentration is to " souning out first " influence of average time

Mosquito begins to sound out untreated control wells in 4.6 minutes.Find that the time that 5% dihydro nepetalactone concentration stops mosquito " to be soundd out first " is about 19 minutes, " souning out first " time that in contrast to DEET (1%w/v) is 12 minutes.The dihydro nepetalactone (1%w/v and 2.5%w/v) of finding low concentration stops be respectively the average time of souning out first 8 minutes and 9.3 minutes.

Landing/exploration the Density Distribution of female yellow-fever mosquito on the film of handling through dihydro nepetalactone analyzed over time, distributed shown in the chart among Fig. 6.Allow the exploration sum on each film during the confirmed test, and will the results are summarized in the table 4.Find that concentration is that 5% DHN almost can eliminate mosquito and sounds out and reach 20 minutes, only write down indivedual explorations in whole 20 minute testing time, and DEET (1%w/v) allows average 4.55 mosquitoes landing.The same DHN (1%w/v and 2.5%w/v) of low concentration that finds also shows anthelmintic activity (comparing with untreated contrast), still compares with positive control (DEET 1%w/v) to be in reduced levels.

Table 4

Exploration number of times according to the permission of pest repellant concentration

Data show that equally dihydro nepetalactone all has anthelmintic activity under all test concentrations, although only just observe the anthelmintic activity that significantly increases with respect to 1%DEET when 5% (w/v).

Embodiment 4

By trans, cis-nepetalactone prepares dihydro nepetalactone

All (the Chiltern seed, Cumbria UK) grows up to many plants by the pale reddish brown Catnip seed of Catnip.The leaf that picks up from individual plants to immersing in the ethyl acetate, after 2 hours is removed solvent and by gas-chromatography leachate analyzed.Thus, determined that main generation is trans in their oil, (Clark, people such as L.J. op.cit.), and cultivate their ripe the plant of cis-nepetalactone.The blade material of these plants is gathered, concentrated in the freeze drying, immersion ethyl acetate and with leachate.By silica gel chromatography (hexane/ethyl acetate (9:1)) purifying nepetalactone from the leachate that concentrates, use identical solvent mixture on silica, to carry out purifying then by the preparation of lamina chromatogram.After solvent removed and being dissolved in hexane again, to trans, cis-nepetalactone carries out crystallization on dry ice.GC-MS and NMR ( ¹H and ¹³C) it is trans analyzing this crystalline material of confirmation, cis-nepetalactone.With the chemical shift of table 1 contrast should ¹³The C chemical shift is as shown in table 5.

The nepetalactone sample for preparing among table 5. embodiment 4 ¹³The C chemical shift, with trans, the chemical shift of cis-nepetalactone (table 1) compares

In ethanol, use ESCAT#142 catalyzer (Englehart) 50 ℃ of will prepare so down trans, cis-nepetalactone hydrogenation 4 hours.GC-MS and NMR ( ¹H and ¹³C) confirmation is trans, and cis-nepetalactone has been converted into corresponding dihydro nepetalactone stereoisomer quantitatively, and one of them is significantly excessive.The NMR of main diastereoisomer analyzes: ¹HNMR (500MHz, CDCl ₃): d0.97 (d, 3H, J=6.28Hz), 0.98 (d, 3H, J=6.94Hz) d 1.24 (m, 2H), 1.74 (m, 1H), 1.77 (m, 2H), 1.99 (m, 2H), 2.12 (dd, 1H, J=6.86 and 13.2Hz), 2.51 (m, 1H), 3.78 (tr, 1H, J=11.1Hz), 4.33 (dd, 1H, J=5.73 and 11.32Hz); ¹³C (500MHz, CDCl ₃): d 15.43,18.09,27.95,30.81,31.58,35.70,42.51,51.40,76.18,172.03. ¹³C NMR spectrum (accompanying drawing 8) shows that this main diastereoisomer accounts for about 93.7% of product.The coupling of to methylene and lactone oxygen, the alloisomerism methine carbon that has methyl, methyl self and end of the bridge methine according to the observation, can infer diastereoisomer most likely (1S, 9S, the 5R of formula 4,6R)-5,9-dimethyl-3-oxabicyclo [4.3.0] ninth of the ten Heavenly Stems-2-ketone.

Formula 4

The numerical value of observed coupling with according to the Karplus equation (referring to, Spectrophotometric Identification of Organic Compounds, the 4th edition, Robert M.Silverstein, G.Clayton Bassler and Terence C.Morill, 1981,208-210 page or leaf) the dihedral angle unanimity between proton on the adjacent carbon atom in the said structure that calculates.

Embodiment 5

Trans by hydrogenation, the anthelmintic activity examination of the dihydro nepetalactone of cis-nepetalactone preparation Test

Basically as described in the embodiment 3, the dihydro nepetalactone (formula 4) of preparation among the embodiment 4 is carried out anthelmintic activity test at yellow-fever mosquito.Experimental scheme is summarized in the table 6, and shown data all derive from repeated test five times.

Table 6

The experimental scheme that is used for the anthelmintic activity test

Table 7 has shown that DHN concentration sounds out the influence of respectively handling the time of being experienced before the film first for female yellow-fever mosquito.

Table 7

Dihydro nepetalactone concentration is to the influence of average time of reaching " first sound out "

Find that concentration is the time that 1% dihydro nepetalactone stops mosquito " to be soundd out first " to be approximately 16 minutes.DEET under same concentrations shows that be 14.8 minutes the average time of souning out first.The dihydro nepetalactone (0.5%w/v and 0.2%w/v) of finding low concentration stops be respectively the average time of souning out first 9.6 minutes and 8.4 minutes.

Density Distribution is soundd out in the landing of female yellow-fever mosquito on the film of handling through dihydro nepetalactone analyzed over time, shown in chart among Fig. 9.The sum that permission is soundd out on each film during the confirmed test, and will the results are summarized in the table 8.Find concentration be 1.0% DHN to get rid of the time that mosquito sounds out fully be 10 minutes, and the time that DEET (1%w/v) allows mosquito to begin to sound out is 6 minutes.The same dihydro nepetalactone (0.5%w/v and 0.2%w/v) of low concentration of finding also shows anthelmintic activity (comparing with untreated contrast), but under than the lower level of positive control (DEET 1% (w/v)).

Table 8

In 20 minute observation period, allowed the number of times soundd out according to pest repellant and concentration

Handle for each pest repellant, in each observation period, use following equation that anthelmintic activity percentage is calculated:

The % anthelmintic activity=100-[(T/C) * 100]

Wherein:

The mosquito of T=replication when time tx is soundd out the mean value of the number of times of handling the hole

C=mosquito when time tx is soundd out the average time of IPA control wells

Then gained percentage is carried out arcsine and transform, and utilize anthelmintic activity to carry out variance analysis (ANOVA) according to five replication value calculating.The multiple ratio of the use Student-Newman-Keuls test value of averaging.The average arcsine that will derive from ANOVA then transforms back percentage.The results are shown in the table 9.

Table 9

Average anthelmintic activity percentage according to ANOVA calculating

1% DHN ranks the first on anthelmintic activity, and with 1%DEET undistinguishable statistically.

Embodiment 6

Dihydro nepetalactone is at the anthelmintic activity test of stable fly (stable fly genus)

Basically according to embodiment 3 described methods, to by trans, cis-nepetalactone hydrogenation is derived the DHN that obtains (mainly by 1S, 9S, 5R, 6R-5,9-dimethyl-3-oxabicyclo [4.3.0] ninth of the ten Heavenly Stems-2-ketone (formula 4) is formed) (called after " test specimen #1 ") and according to dihydro nepetalactone mixture (the called after test specimen #2 of embodiment 2 preparations; MDHN) anthelmintic activity that belongs at stable fly is tested.The difference of the DHN of DHN and embodiment 4 preparations is as used herein, it be derived from by tank oil (Berje, NJ) crystallization obtain trans, the hydrogenization of cis-nepetalactone (is used Pd/SrCO ₃Catalyzer).In these trials, comprised other positive control compound, promptly right

Alkane-3,8-glycol (PMD) is obtained from Takasago International Corp. (U.S.), Rockleigh, NJ.Experimental scheme is summarized in the table 10, and all data that present all are the mean value of five repeated tests.

Table 10

Use experimental scheme at the anthelmintic activity test of stable fly

In these trials, the correct time of " landing " first can not be determined, because in five repeated tests for each test variable, has three times or more times landing betides 2 minutes first and exposed to the open air before the phase.

The landing Density Distribution of stable fly on the film of handling through dihydro nepetalactone analyzed over time, shown in chart among Figure 10.Allow the landing sum on each film during the confirmed test, and will the results are summarized in the table 11.Insect is exposed to landing beginning behind the instrument connection, and can sees that after about 5 minutes the peak reduces in time gradually.Generally speaking, the landing number of times on the film that the dihydro nepetalactone that with concentration is 1% is handled significantly is less than observed landing number of times on (IPA) film that is being untreated, and with suitable with the landing number of times on the film of DEET (1%w/v) processing.In expelling landing, right in entire test

Alkane-3,8-glycol (PMD) is than dihydro nepetalactone or DEET poor efficiency more, though and can observe some initial anthelmintic activities, this compound will become invalid after 6 minutes.These data show that equally 1% dihydro nepetalactone shows the anthelmintic activity suitable with 1% DEET.

Table 11

Number of times test period permission landing in 20 minutes

As described in embodiment 5, carry out analysis of anthelmintic activity percentage and statistical analysis, the results are shown in the table 12.

Table 12

Average anthelmintic activity percentage according to ANOVA calculating

MDHN, DEET and DHN show well equally statistically, 43.2～55.5% anthelmintic activity is provided, and all is better than PMD statistically, and when contrasting with IPA, PMD has only provided 4.7% anthelmintic activity.

Embodiment 7

Dihydro nepetalactone is to the anthelmintic activity test of Anopheles mosquito (white sufficient anopheles)

Basically according to embodiment 3 described methods, to by trans, cis-nepetalactone hydrogenation is derived the DHN that obtains (mainly by 1S, 9S, 5R, 6R-5,9-dimethyl-3-oxabicyclo [4.3.0] ninth of the ten Heavenly Stems-2-ketone (formula 4) is formed) (called after " test specimen #1 ") and according to dihydro nepetalactone mixture (the called after test specimen #2 of embodiment 2 preparations; MDHN) test at 100 anthelmintic activities of not raising ripe female white sufficient anopheles.The difference of the DHN of DHN and embodiment 4 preparations is as used herein, it be derived from by tank oil (Berje, Bloomfield, NJ) crystallization obtain trans, the hydrogenization of cis-nepetalactone (is used Pd/SrCO ₃Catalyzer).Once more PMD is included as other contrast.Experimental scheme is summarized in the table 13, and all data all are the mean value of five repeated tests.

Table 13 The experimental scheme that is used for the test of Anopheles mosquito anthelmintic activity

In these trials, the correct time that reaches " first sound out " can not be determined, because in five repeated tests for each variable, has twice or more times exploration betides 2 minutes first and exposed to the open air before the phase.Sound out Density Distribution at the landing of Anopheles mosquito on the film of handling through dihydro nepetalactone and analyze over time, shown in chart among Figure 11.Insect is exposed to sounds out beginning behind the instrument connection, and after this in time carrying out and increase gradually.Generally speaking, in whole test, the landing number of times on the film that the dihydro nepetalactone that with concentration is 1% is handled significantly is less than observed landing number of times on (IPA) film that is being untreated.

Allow the exploration sum on each film to determine to duration of test, and will the results are summarized in the table 14.Data show, and compare with the DEET of isoconcentration or PMD are one of any, and 1% dihydro nepetalactone demonstrates higher anthelmintic activity.

Table 14

Number of times test period permission landing in 20 minutes

As described in embodiment 5, carry out analysis of anthelmintic activity percentage and statistical analysis, the results are shown in the table 15.

Table 15

Average anthelmintic activity percentage according to ANOVA calculating

MDHN is better than DEET statistically and 46.1% anthelmintic activity is provided.DHN equates with mDHN statistically, also equates with DEET statistically, and 32.9% anthelmintic activity is provided.DEET and PMD provide 13.3% and 11.5% anthelmintic activity respectively, and effectiveness statistically equates.

Embodiment 8

Dihydro nepetalactone is to the anthelmintic activity of deer tick (the hard tick of omoplate)

To as among the embodiment 7 preparation by trans, cis-nepetalactone hydrogenation is derived the DHN that obtains (mainly by 1S, 9S, 5R, 6R-5,9-dimethyl-3-oxabicyclo [4.3.0] ninth of the ten Heavenly Stems-2-ketone (formula 4) is formed) and test at the anthelmintic activity of the hard tick naiad of omoplate (I Scapularis) according to the dihydro nepetalactone mixture of embodiment 2 preparations, DEET is comprised in test as positive control.

25 each compound of μ l (concentration is 30% (w/v) in isopropyl alcohol) are applied in the circle of diameter 4cm, and described circle is worn on the left forearm of six male volunteers.Each volunteer has two kinds of pest repellants that are applied to separately in the circle on this forearm; The circle that is worn over a diameter 4cm on another arm is handled the contrast that attracts with as tick.

The hard tick naiad of deer tick omoplate of the not feeding of laboratory cultures is inserted 1mm on the cotton swab is untreated in the circle

If observe normal exploratory behaviour, and/or insect creeps in unprocessed zone, just thinks that it is qualified and is placed on processing region then.The qualified tick that to explore on processing region in 60 seconds or creep is not recorded as and is expelled.The qualified tick that to not explore on processing region in 60 seconds or creep is recorded as and is expelled.In addition, will creep on the processing region but the qualified tick that fell down from above in other 60 seconds is recorded as and is expelled.

In about one hour interval, 5 qualified ticks that provide to each processing circle are provided each volunteer.Continue to expose to the open air, in any one group of 5 tick that provide, have 3 to be considered to " being lured ".Same or exposing to the open air in the phase subsequently, first non-tick that expels is called first and lures tick, be second to lure tick subsequently.Determine to lure the time of tick to think the time of the whole anthelmintic activities of this volunteer ' termination ' first.

Table 16

DHN, mDHN and the DEET of 30% (w/v) are applied topically to human aspiration The average guard time fully that avoids the hard tick of deer tick omoplate during the person

Data (table 16) show that it is 124 minutes that DEET provides the average guard time fully that avoids the hard tick of deer tick omoplate, and be 109 minutes the effective time of DHN similarly simultaneously, and mDHN (mixing of DHN diastereoisomer) is 85 minutes.Thus, obvious DHN and mDHN are the pest repellants to the deer tick.Carry out ANOVA for guard time, show that DHN, mDHN and DEET are undistinguishables at them aspect the anthelmintic activity persistence of these ticks on statistics.

Embodiment 9

The dihydro nepetalactone that is applied to the human subject is lived at the expelling parasite of white sufficient Anopheles mosquito The property

Use ripe human volunteer, to as among the embodiment 7 preparation by trans, cis-nepetalactone hydrogenation is derived the DHN that obtains (mainly by 1S, 9S, 5R, 6R-5,9-dimethyl-3-oxabicyclo [4.3.0] ninth of the ten Heavenly Stems-2-ketone (formula 4) is formed) and test according to the anthelmintic activity of the dihydro nepetalactone mixture dialogue foot anopheles of embodiment 2 preparations, DEET is added as positive control.Use has each test cage (2 * 2 * 2 feet) two opposite side one sides of two sleeve pipe ingates, in central authorities a handrail is arranged.With the side and the top shields and with bottom fit on mirror so that observe.The female mosquitoes of 200 maturations is put into the test cage, never took food blood and stopped their normal diet (10% sucrose) before use in 24 hours of described mosquito.Each volunteer has been confirmed to be attracting ability in advance, has 10 mosquitoes to drop on them in 30 seconds and stretches on the undressed forearm in the cage.

Each compound of 1.0ml (being 5% or 10% (w/v)) is applied to 250cm on the forearm of six male volunteers in isopropyl alcohol ²The zone in, the remainder of limbs handled making insect inaccessible.Different pest repellants is applied to separately on each volunteer's the forearm.The pest repellant that makes application placed 5 fens clock times of test cage every 30 minutes with forearm after dry 30 minutes, and the number of times that mosquito was soundd out or bites during each was exposed to the open air carries out record.Anthelmintic activity for each pest repellant on each volunteer ends to carry out record.Ending to be defined as the time of determining to bite generation first; Biting to be defined as once and bite what confirm first, is thereafter same or bite next second time of exposing to the open air in the phase.Data show is in table 17, as average guard time fully.Data show that DHN and mDHN have given the protection fully (for example being respectively 3.5 and 5 hours) that significantly avoids for a long time biting under 10% (w/v), and this is comparable to the complete guard time that DEET provided under same concentrations.

Use ANOVA that data are analyzed, and these data show 5% and 10%mDHN solution on rendeing a service respectively with 5% and 10%DEET be undistinguishable.5% and 10%DHN solution, though equate with corresponding mDHN solution statistically, provided short guard time.

Table 17

Concentration is that the dihydro nepetalactone of 5% and 10% (w/v) is applied topically to human volunteer, at the average guard time fully of female white sufficient Anopheles mosquito.

Claims

1. one kind prepares method for compositions, and described composition comprises dihydro nepetalactone or dihydro nepetalactone stereoisomer mixture, and wherein said dihydro nepetalactone is by shown in the following general formula:

And wherein said method comprises:

(a) provide the draft material that contains Nepeta (Catnip),

(b) from described draft material, extract the oil that contains nepetalactone,

(c) in the presence of hydrogenation catalyst, but under the situation that does not have thinner, make described oil contact with hydrogen with provide the 9-S dihydro nepetalactone and

(d) reclaim the 9-S dihydro nepetalactone that so produces, and it is mixed with carrier and/or cosmetic assistant agent.

2. one kind prepares method for compositions, and described composition comprises dihydro nepetalactone or dihydro nepetalactone stereoisomer mixture, and wherein said dihydro nepetalactone is by shown in the following general formula:

And wherein said method comprises:

(a) provide the draft material that contains Nepeta (Catnip),

(b) from described draft material, extract the oil that contains nepetalactone,

(c) in the presence of hydrogenation catalyst, and in the presence of the alcohols thinner, make described oil contact with hydrogen with provide the 9-S dihydro nepetalactone and

(d) reclaim the 9-S dihydro nepetalactone that so produces, exist as the form of mixture with described alcohols thinner.

3. claim 1 or 2 method, wherein said draft material comprises the schizonepeta kind.

4. the method for claim 3, wherein step (a) comprises the schizonepeta chemical type of selecting to produce oil, and described oil contains, and with trans, the amount of cis-nepetalactone is compared, and the cis of more content is trans-nepetalactone.

5. claim 1 or 2 method, wherein said hydrogenation catalyst comprise and are selected from following material: iridium, palladium, rhodium, nickel, ruthenium, platinum, rhenium, their combination and their compound; Perhaps described hydrogenation catalyst loads on and is selected from the following carrier mass: oxide, silica, aluminium oxide, titanium dioxide, calcium carbonate, barium sulfate and carbon black.

6. claim 1 or 2 method wherein, are extracted oil through steaming from described draft material.

7. the method for claim 2, wherein step (d) also comprises the mixture of distillation 9-S dihydro nepetalactone and pure thinner.

8. claim 2 or 7 method further comprise product are mixed with carrier and/or cosmetic assistant agent.

9. claim 1 or 8 method, wherein said assistant agent comprises one or more following materials: thickener, buffer, chelating agent, preservative, flavouring agent, antioxidant, gelling agent, stabilizing agent, surfactant, emollient, colouring agent, aloe, wax, fungicide, opacifier, sun-screening agent, vitamin, tanning agent, plant extracts, antiphlogistic, radical scavenger, biostearin, α-alkyd, disinfectant, antibiotic, antibacterial agent and antihistaminic.

10. claim 1 or 2 method further comprise described composition are made following form: solution, suspension, cream, paste, gel, spray agent, dust or play brewage.

11. the method for claim 1 or 2 further comprises the following steps: to incorporate described composition into following products: Gulong perfume, cosmetics, deodorant, shampoo, hair lacquer, profit are sent out agent, soap combination, air freshener, candle, flavor article, fiber, coverlet, textile, paper, coating, ink, clay, timber, furniture, carpet, amenities, plastics or polymer.