Classifications

• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N49/00—Biocides, pest repellants or attractants, or plant growth regulators, containing compounds containing the group, wherein m+n>=1, both X together may also mean —Y— or a direct carbon-to-carbon bond, and the carbon atoms marked with an asterisk are not part of any ring system other than that which may be formed by the atoms X, the carbon atoms in square brackets being part of any acyclic or cyclic structure, or the group, wherein A means a carbon atom or Y, n>=0, and not more than one of these carbon atoms being a member of the same ring system, e.g. juvenile insect hormones or mimics thereof
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S424/00—Drug, bio-affecting and body treating compositions
  • Y10S424/10—Insect repellent

Definitions

• This invention relates to synergistic insect repellent compositions, in particular compositions based on insect repellents such as p-menthane-3,8-diols and as synergist acetals, particularly those resulting from the acid catalysed cyclization of citronellal.
• BACKGROUND ART Compositions that repel insects, particularly insect pests such as mosquitoes, flies and fleas, are widely used to prevent animals from being bitten by such insects.
• the importance of preventing biting is essentially two-fold. Firstly, there are a number of insects which are capable of infecting animals with disease causing parasites, an example being the transmission of Plasmodium by mosquitoes to ci se malaria. Secondly, in many cases whether disease is transmitted or not, the bite can be extremely irritating.
• Man is one animal that suffers from biting insects. Man also suffers irritation from non-biting, annoying insects such as domestic flies and from insects that transmit disease by contact.
• compositions having repellency to some or a number of insect species include the active ingredient N,N-diethyl-m-toluamide (DEET) .
• DEET N,N-diethyl-m-toluamide
• compositions based on DEET are in the form of lotions or aerosols to be applied or sprayed onto t;.a exposed skin.
• Such compositions may include a variety of other ingredients such as film forming agents to enhance substantivity to the skin and potentiators such as those disclosed in WO89/06904-A.
• compositions that are known repellents include various extracts of naturally occurring compounds obtained from eucalyptus species.
• One series of naturally occurring compounds obtained from Eucalyptus citriodora are the p-menthane-3,8-diols. These compounds are known to exert a repellent effect on insect pests such as mosquitoes and fleas.
• JP60-199804-A (Nippon ayaku KK) , it is disclosed that the cis and trans p-menthane-3,8-diols are effective insect repellents, as are a number of analogues.
• This patent application teaches that the p-menthane-3,8-diols may be prepared using the method disclosed in J. Am. Chem. Soc. 25. r 2367 (1953). Using (+)-citronellal as the starting material and a reaction time of 27 hours at room temperature cis:trans p-menthane-3,8-diols in a ratio of 5:2 are obtained. These compounds are obtained in pure form following chromatographic separation and recrystallization.
• EP 367140-A (Takiron Co. Ltd) also relates to the use of p-menthane-3,8-diols as insect repellents.
• This application teaches slow-release compositions wherein the diols are included in compositions with an ethylene/vinyl acetate copolymer.
• the p-menthane-3,8-diols are effective insect repellents, even the most efficient routes of synthesis currently known results in products that are so costly that repellent compositions including these menthanediols are too expensive compared with known alternatives.
• the cis isomer may be isolated from the above mixture and used in its pure form.
• the cost of the impure mixture is significantly lower than that of cis isomer of 99% purity.
• the present applicants evaluated the insect repellency of the mi ⁇ ure. It was found to be unsatisfactory. It was, however, found that when the compounds of boiling point about the same as citronellal or below were removed from the impure mixture, the resultant composition possessed an exceptionally high level of repellency. In fact the level of repellency observed was somewhat greater than would have been expected in view of the increased concentration of the p-menthane-3,8-diols.
• the present invention therefore provides an insect-repellent composition
• an insect-repellent composition comprising one or more insect repellents of the formula X:
• R is hydrogen or an alkyl group containing 1-4 carbon atoms; and R. and R- are the same or different and are alkyl groups containing 1-4 carbon atoms; and a synergistic amount of at least one compound of the formula Z:
• composition is substantially free of insect repellents having a boiling point less than about 80 C at a pressure of 4mm Hg.
• Such a composition may be prepared by the acid catalysed cyclization of the citronellal derivative
• the diol X results from the reaction of the protonated starting material with water.
• the diol X may reversibly react with further starting material under the acid-catalysed conditions to give the bicyclic acetal Z.
• the present inventors have found that it is a group of high molecular weight compounds of boiling point substantially higher than the p-menthane-3,8-diols that are synergistic with the p-menthane-3,8-diols.
• This high molecular weight group includes two main components which are acetals, of the formula C and D:
• each of these components comprises a mixture of two diastereoisomeric compounds, epimeric at the acetal carbon. It is to be understood that relative stereochemistry only is depicted in the structures: no limitation as to absolute configuration is intended, and the enantiomers of the structures depicted also fall within the scope of the invention.
• citronellal acts as an antagonist in these compositions.
• acetals are known compounds being disclosed by Stoll and Bolle, Helv. Chim. Acta, 21, 1 (1948). This paper discloses on page 1, a compound (II) being an acetal that may be formed by the acid hydrolysis of the bisulphite addition compound of citronellal. On page 4, the synthesis of acetal (II) is described where the compound is found to have a boiling point of 127 ,30°C at 0.03mm Hg.
• p-menthane-3,8-diols fall within the scope of compounds of the formula X when R,, R. and R- are methyl groups, and are preferred insect repellents of the present invention.
• p-Menthane-3,8-diol is 2-hydroxy-a, a,4-trimethylcyclohexanemethanol and has four possible diastereoisomers, all of them pairs of enantiomers, arising from the three chiral centres at the 1, 2 and 4 carbon atoms.
• stereoisomers of the p-menthane-3,8-diols are within the scope of the present invention, particularly those arising from the acid cyclization of the (+) isomer and the racemic mixture.
• Mixtures c the cis and trans p-menthane-3,8-diols are particularly preferred, generally in a weight ratio of 2.5:1 to _ i:l.
• the compounds of the formula Z are acetals, preferably with either or all of the groups R-., R., R 5 methyl. Most preferably a compound of the formula Z is: ⁇
• Particularly preferred compounds of the formula Z comprise the two diastereoisomers of formula C and D:
• the components C and D may be included individually in the compositions of the invention, preferably as a mixture.
• a particularly desirable method for forming such compositions is to acid cyclize citronellal.
• the products of such a reaction will include the diols and acetals of formulae C and D.
• the unreacted citronellal and other low boiling compounds may be removed by fractional distillation to give a synergized insect repellent composition that can then be used as a base to form a variety of insect repellent products.
• Such products include personal use products such as aerosols, lotions, gels, roll-ons, pumps and sticks; foggers and bombs; vaporizers and inistrips for use for example in repelling moths from clothing; aerosols, pumps and powders for use on animals inducing domestic pets; and electrically operated vaporizers.
• fractional distillation will be conducted such that compounds of boiling point less than about 80°C at 4mm Hg, most preferably less than about 100°C at 4mm Hg will be removed.
• compositions of the invention will generally include the insect repellent of formula X or Y and compound of the formula Z in a weight ratio of from 99:1 to 1:99.
• a preferred range is 38:1 to 1:19, most preferably 19:1 to 1.6:1.
• a particularly preferred ratio is 3.5:1 to 1.3:1.
• compositions include compounds of the formula C and D and the mixture of cis-p-menthane-3,8-diol and trans-p-menthane-3,8-diol, it is preferred that they are included in concentrations of 20-40% w/w and 57-63% w/w respectively, with the diols in a weight ratio of 1.6:1 to 1.4:1.
• MODES FOR CARRYING OUT THE INVENTION In order to better understand the nature of the invention, a series of tests was conducted using a number of compositions of varying cis and trans p-menthane-3,8- diol content in the presence and absence of acetals of formula C and D. These tests sought to evaluate repellency against mosquitoes and domestic flies.
• Figure 1 is a graph of % repellency achieved against mosquitoes of the species Aedes aegypti with varying levels of compositions including cis and trans p-menthane-3,8-diols with and without acetals of formulae C a D. These acetals are referred to on the graph as "hea. _es”.
• Figure 1 there is shown a graph of the results obtained against mosquitoes. From this it is evident that the only compositions of 100% or greater repellency were those that included the acetals. Furthermore, generally compositions including the acetals had greater repellency than those without but having the same menthanediol content. This is particularly evident at about the 10% menthanediol level, where repellency of about 105% was obtained with 6% acetal content.
• pairs of formulations one of the pair having a relatively high concentration of menthanediol and a low concentration of acetals C and D and the other of the pair having a relatively low concentration of menthanediol and a relatively high concentration of acetals C and D, were tested for repellency against mosquitoes and flies.
• Each formulation was in the form of a lotion.
• These lotion formulations were as follows:
• Glycerol 10 Denatured absolute 52 40 35 53.4 40 38.5 ethanol
• Carbopol 940 0.8 0.6 0.6 0 0.6 0.6
• Crodolan is a trade mark of Croda Chemicals Carbopol is a trade mark of B.F. Goodrich & Co. Teric is a trade mark of I.C.I.
• menthanediol concentration can be maintained with an increased level of acetals being used to achieve the higher repellency.
• compositions of the invention As previously mentioned a convenient method for forming preferred synergistic insect repellent compositions of the invention is to subject citronellal to acid catalysed cyclization. Specifically, these compositions have been formed as follows:
• citronellal is reacted with 20kg of 5% sulphuric acid for a period of at least 5 hours, preferably 24 hours.
• the mixture is stirred throughout the reaction which is conducted under ambient conditions at a temperature not less than 10 C.
• the mixture contains about 15-20% low boiling materials, including citronellal about 50-60% p-menthane-3,8-diols and about 20% acetals.
• citronellal is within the latter fraction and me ⁇ be reused in this form.
• the fraction remaining, which boils at greater than about IOC C, includes cis and trans p-menthane-3,8-diols and the acetals C and D.
• the citronellal starting material can be substantially pure (+), (-) or ( ⁇ ) , or may be a Eucalyptus citriodora oil containing about 85% citronellal.
• compositions suitable for applications to the human skin may be readily produced by those skilled in the art.
• Such compositions include particularly aerosol and lotion forms, which may contain 5-50% w/w of the composition of the invention.
• compositions are as follows: Lotion
• Emulsifiers, fatty alcohol and preservatives are combined with heating and stirring until homogeneous. To this homogeneous mixture is added the active with heating at about 50-60°C. Water and thickener are then added with stirring and finally the perfume is added.
• Aerosol To the ethanol is added the isopropyl myristate with stirring. The active is then added, followed by the perfume to form a concentrate. Propellant is added in the requisite amount to the concentrate in an aerosol container.
• the synergistic insect repellents of the invention have been found to be effective against flies and mosquitoes. It is to be expected that compositions of the invention will be effective against a variety of other insects including cockroaches, fleas, sandflies, mites, clothes moths and the like. In some cases additional insect repellent compounds may be required to achieve an appropriate level of repellency or the concentration of the synergistic insect repellent composition of the invention may need to be appropriately adjusted.

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• Life Sciences & Earth Sciences (AREA)
• Agronomy & Crop Science (AREA)
• Insects & Arthropods (AREA)
• Pest Control & Pesticides (AREA)
• Plant Pathology (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Dentistry (AREA)
• General Health & Medical Sciences (AREA)
• Wood Science & Technology (AREA)
• Zoology (AREA)
• Environmental Sciences (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 1991
  • 1991-08-02 ZM ZM33/91A patent/ZM3391A1/xx unknown
  • 1991-08-05 AU AU83376/91A patent/AU650042B2/en not_active Ceased
  • 1991-08-05 US US07/983,572 patent/US5298250A/en not_active Expired - Fee Related
  • 1991-08-05 BR BR919106719A patent/BR9106719A/pt not_active Application Discontinuation
  • 1991-08-05 HK HK98105906A patent/HK1007096A1/en not_active IP Right Cessation
  • 1991-08-05 CA CA002088687A patent/CA2088687A1/en not_active Abandoned
  • 1991-08-05 EP EP91914740A patent/EP0543883B1/en not_active Expired - Lifetime
  • 1991-08-05 DK DK91914740.5T patent/DK0543883T3/da not_active Application Discontinuation
  • 1991-08-05 SG SG1996001506A patent/SG42338A1/en unknown
  • 1991-08-05 WO PCT/AU1991/000343 patent/WO1992002136A1/en not_active Ceased
  • 1991-08-05 ZA ZA916141A patent/ZA916141B/xx unknown
  • 1991-08-06 IN IN714DE1991 patent/IN179228B/en unknown
  • 1991-08-06 MX MX9100538A patent/MX9100538A/es unknown
  • 1991-08-06 NZ NZ239282A patent/NZ239282A/xx unknown
  • 1991-08-06 ZW ZW110/91A patent/ZW11091A1/xx unknown
  • 1991-08-06 MY MYPI91001418A patent/MY107439A/en unknown
• 1996
  • 1996-02-14 GR GR960400376T patent/GR3018975T3/el unknown

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