U.S. patent application number 10/392455 was filed with the patent office on 2003-12-25 for insect repellent compounds.
Invention is credited to Hallahan, David L..
Application Number | 20030235601 10/392455 |
Document ID | / |
Family ID | 28454757 |
Filed Date | 2003-12-25 |
United States Patent
Application |
20030235601 |
Kind Code |
A1 |
Hallahan, David L. |
December 25, 2003 |
Insect repellent compounds
Abstract
Dihydronepetalactone, a minor natural constituent of the
essential oil of catmints (Nepeta spp.) such as Nepeta cataria, has
been identified as an effective insect repellent compound.
Synthesis of dihydronepetalactone may be achieved by hydrogenation
of nepetalactone, the major constituent of catmint essential oils.
This compound, which also has fragrance properties, may be used
commercially for its insect repellent properties.
Inventors: |
Hallahan, David L.;
(Wilmington, DE) |
Correspondence
Address: |
E I DU PONT DE NEMOURS AND COMPANY
LEGAL PATENT RECORDS CENTER
BARLEY MILL PLAZA 25/1128
4417 LANCASTER PIKE
WILMINGTON
DE
19805
US
|
Family ID: |
28454757 |
Appl. No.: |
10/392455 |
Filed: |
March 19, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60366147 |
Mar 20, 2002 |
|
|
|
Current U.S.
Class: |
424/405 ;
442/123; 514/456 |
Current CPC
Class: |
A61P 17/02 20180101;
A01N 43/16 20130101; Y02A 50/30 20180101; Y10T 442/2525 20150401;
A01N 65/22 20130101; A01N 43/16 20130101; A01N 43/16 20130101 |
Class at
Publication: |
424/405 ;
514/456; 442/123 |
International
Class: |
A01N 025/00; A01N
043/16; B32B 027/12 |
Claims
What is claimed is:
1. An insect repellent composition comprising a
dihydronepetalactone, or a mixture of dihydronepetalactone
stereoisomers, represented by the general formula: 17
2. The composition of claim 1 wherein the dihydronepetalactone
stereoisomers are (9S)-dihydronepetalactone stereoisomers derived
from (7S)-nepetalactones.
3. The composition of claim 1 which comprises
1S,9S,5R,6R-5,9-dimethyl-3-o- xabicyclo[4.3.0]nonan-2-one.
4. The composition of claim 1 which comprises dihydronepetalactone
in an amount of at least about 0.001% by weight of the total weight
of the composition.
5. The composition of claim 1 which comprises dihydronepetalactone
in an amount of from about 0.001% to about 80% by weight of the
total weight of the composition.
6. The composition of claim 1 which comprises dihydronepetalactone
in an amount of from about 0.01% to about 50% by weight of the
total weight of the composition.
7. The composition of claim 1 which comprises one or more of the
members of the group consisting of an adjuvant, a carrier and an
insect repellent compound that is not a dihydronepetalactone.
8. The composition of claim 7, wherein the adjuvant is selected
from the group consisting of thickeners, buffering agents,
chelating agents, preservatives, fragrances, antioxidants, gelling
agents, stabilizers, surfactants, emolients, coloring agents, aloe
vera, waxes, and therapeutically or cosmetically active
ingredients.
9. The composition of claim 7, wherein the carrier is selected from
the group consisting of silicone, petrolatum, lanolin, liquid
hydrocarbons, agricultural spray oils, paraffin oil, tall oils,
liquid terpene hydrocarbons and terpene alcohols, aliphatic and
aromatic alcohols, esters, aldehydes, ketones, mineral oil, higher
alcohols, finely divided organic and inorganic solid materials.
10. The composition of claim 7, wherein the carrier comprises an
aerosol composition adapted to disperse the dihydronepetalactone
into the atmosphere by means of a compressed gas.
11. The composition of claim 7, wherein the non-hydronepetalactone
insect repellent is selected from the group consisting of: benzil,
benzyl benzoate, 2,3,4,5-bis(butyl-2-ene) tetrahydrofurfural,
butoxypolypropylene glycol, N-butylacetanilide,
normal-butyl-6,6-dimethyl- -5,6-dihydro-1,4-pyrone-2-carboxylate,
dibutyl adipate, dibutyl phthalate, di-normal-butyl succinate,
N,N-diethyl-meta-toluamide, dimethyl carbate, dimethyl phthalate,
2-ethyl-2-butyl-1,3-propanediol, 2-ethyl-1,3-hexanediol,
di-normal-propyl isocinchomeronate, 2-phenylcyclohexanol,
p-methane-3,8-diol, and normal-propyl N,N-diethylsuccinamate.
12. The composition of claim 1 which is repellent to insects
comprising biting insects, wood-boring insects, noxious insects,
and household pest insects.
13. The composition of claim 1 which is repellent to
mosquitoes.
14. The composition of claim 1 which has a skin surface evaporation
rate of at least a minimum effective evaporation rate.
15. The composition of claim 1 which has a skin surface evaporation
rate of at least a minimum effective evaporation rate for at least
five hours.
16. The composition of claim 1 which is in the form of a cologne, a
lotion, a spray, a cream, a gel, an ointment, a bath or shower gel,
a foam product, makeup, a deodorant, shampoo, a hair lacquer or
rinse or a personal soap.
17. The composition of claim 1 which is in the form of an insect
repellent article of manufacture.
18. The article of claim 17 which is applied to a human or animal
host.
19. The article of claim 17 which is selected from the group
consisting of air freshener, a candle, a scented articles, a fiber,
a sheets, cloth, paper, paint, ink, clay, wood, furniture,
carpeting, sanitary goods, a plastic, and a polymer.
20. A process for fabricating an insect repellent composition or an
insect repellent article of manufacture, comprising providing as
the composition or article, or incorporating into the composition
or article, a diihydronepetalactone, or a mixture of
dihydronepetalactone stereoisomers, represented by the general
formula: 18
21. A method of imparting, augmenting or enhancing the insect
repellent effect of an article, comprising the step of
incorporating into the article a diihydronepetalactone, or a
mixture of dihydronepetalactone stereoisomers, represented by the
general formula: 19
22. A method according to claim 20 wherein the dihydronepetalactone
stereoisomers are (9S)-dihydronepetalactone stereoisomers derived
from (7S)-nepetalactones.
23. A method according to claim 20 wherein the article is selected
from the group consisting of a cologne, a lotion, a spray, a cream,
a gel, an ointment, a bath or shower gel, a foam product, makeup, a
deodorant, shampoo, a hair lacquer or rinse, a personal soap
composition, air freshener, a candle, a scented article, a fiber, a
sheet, cloth, paper, paint, ink, clay, wood, furniture, carpeting,
sanitary goods, a plastic, and a polymer.
24. A method according to claim 23, wherein the article is applied
to a human or animal host.
25. A method of repelling insects comprising exposing the insects
to a diihydronepetalactone, or a mixture of dihydronepetalactone
stereoisomers, represented by the general formula: 20
26. The use of a diihydronepetalactone, or a mixture of
dihydronepetalactone stereoisomers, represented by the general
formula: 21as an insect repellent.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/366,147, filed Mar. 20, 2002, which is
incorporated in its entirety as a part hereof for all purposes.
FIELD OF THE INVENTION
[0002] 1. Field of the Invention The present invention relates to
the field of insect repellency, and the use of dihydronepetalactone
stereoisomers generally as repellent materials.
[0003] 2. Background of the Invention
[0004] Repellent substances generally cause insects to be driven
away from, or to reject, otherwise insect-acceptable food sources
or habitats. Most known repellents are only mildly toxic. A few of
the known repellents, in fact, are not active poisons at all but
rather prevent damage to plants/animals or articles of manufacture
by making insect food sources or living conditions unattractive or
offensive. Most current commercial insect repellents contain the
synthetic chemical N,N-diethyl-m-toluamide (DEET) as their primary
active ingredient. For instance, repellents sold under the major
commercial brand names such as Off!.RTM., Deep Woods Off!.RTM., and
Cutter.RTM. are all DEET based products and comprise 85% of insect
repellent sales (Consumer Reports Buying Guide, 1994 Special
Year-End Issue). Further, Consumer Reports tests indicated that
products with the highest concentration of DEET lasted the longest
against mosquitoes. Despite being an effective repellent, however,
this compound has certain drawbacks. Specifically, it possesses an
unpleasant odor and imparts a greasy feel to the skin. Although it
has recently been re-registered for use in the US by the EPA,
concerns have been raised as to its safety, particularly when
applied to children (Briassoulis, G.; Narlioglou, M.; Hatzis, T.
(2001) Human & Experimental Toxicology 20(1), 8-14). Studies
have demonstrated that high concentrations of DEET may give rise to
allergic or toxic reactions in some individuals. Other
disadvantages associated with DEET include: 1) it is a synthetic
chemical having a limited spectrum of activity; 2) DEET is a
powerful plasticizer and will dissolve or mar many plastics and
painted surfaces; and 3) DEET plasticizes the inert ingredients
typically used in topical formulations in order to lengthen the
time of effectiveness. This leads to DEET formulations with low
user acceptability.
[0005] As a result of the above limitations, DEET-free products
with repellent activity are finding favor with consumers, and
demand for compositions containing natural products (versus
synthetic chemicals such as DEET) is increasing. These DEET-free
repellent compounds require a combination of excellent repellency,
high residual activity and relatively little or no toxicity to
humans (or pets) and the environment. In response to these consumer
demands, there is an on-going need to develop new repellent
compounds which can be obtained from, or synthesized from, natural
plant materials and which are pleasant to use.
[0006] Many plant species produce essential oils (aromatic oils)
which are used as natural sources of insect repellent and fragrant
chemicals [Hay, R. K. M., Svoboda, K. P., Botany, in `Volatile Oil
Crops: their biology, chemistry and production`. Hay, R. K. M.,
Waterman, P. G. (eds.). Longman Group UK Limited (1993)].
Citronella oil, known for its general repellence towards insects,
is obtained from the graminaceous plants Cymbopogon winterianus and
C. nardus. Examples of plants used as sources of fragrant chemicals
include Melissa officinalis (Melissa), Perilla frutescens
(Perilla), Posostemon cablin (Patchouli) and various Lavandula spp.
(Lavender). All of these examples of plants yielding oil of value
to the fragrance industry are members of the Labiatae (Lamiaceae)
family. Plants of the genus Nepeta (catmints) are also members of
this family, and produce an essential oil which is a minor item of
commerce. This oil is very rich in a class of monoterpenoid
compounds known as iridoids [Inouye, H. Iridoids. Methods in Plant
Biochemistry 7:99-143 (1991)], more specifically the
methylcyclopentanoid nepetalactones [Clark, L. J. et al. The Plant
Journal, 11:1387-1393 (1997)] and derivatives.
[0007] Iridoid monoterpenoids have long been known to be effective
repellents to a variety of insect species (Eisner, T. Science
146:1318-1320 (1964); Eisner, T. Science 148:966-968 (1965);
Peterson, C. and J. Coats, Pesticide Outlook 12:154-158 (2001); and
Peterson, C. et al. Abstracts of Papers American Chemical Society,
(2001) 222 (1-2): AGRO73). U.S. Pat. No. 4,663,346 discloses insect
repellants with compositions containing bicyclic iridoid lactones
(e.g., iridomyrmecin). Further, U.S. Pat. No. 4,869,896 discloses
use of these bicyclic iridoid lactone compositions in potentiated
insect repellent mixtures with DEET.
[0008] Formal studies concerning the repellency of
dihydronepetalactones, a class of iridoid monoterpenoids derived
from nepetalactones (shown in FIG. 1), have been much less
conclusive and have failed to teach or imply that these compounds
exert a repellent effect on the common insect pests of human
society. For example, a study of the composition of the secretion
from anal glands of the ant Iridomyrmex nitidus showed that
isodihydronepetalactone was present in appreciable amounts,
together, with isoiridomyrmecin (Cavill, G. W. K., and D. V. Clark.
J. Insect Physiol. 13:131-135 (1967)). Although isoiridomyrmecin
was known at the time to possess good `knockdown` insecticidal
activity, no evidence was provided in support of a similar activity
for isodihydronepetalactone, and no investigation of this
compound's repellent effect (as distinct from insecticidal
activity) was made.
[0009] In a later publication by Cavill, G. W. K., et al.
(Tetrahedron 38:1931-1938 (1982)), the presence of
dihydronepetalactones in the defensive secretion of an ant was
again reported, but the authors concluded that the compound
iridodial (and not a dihydronepetalactone) was the basic repellent
constituent. 1
[0010] Most recently, Jefson, M., et al. (J. Chemical Ecology
9:159-180 (1983)) described the repellent effect of
dihydronepetalactone. Initial repellency caused by the undiluted
compound was measured with respect to the ant species Monomorium
destructor during feeding. After 25 seconds of exposure to the pure
dihydronepetalactone, approximately 50-60% of the ants ceased to
feed. However, further analyses of the repellency over a longer
time course were not presented, nor were analyses with anything
other than the pure undiluted compound. Repellency observed over
such short periods of time (seconds) with concentrated chemicals is
insufficient to allow prediction of efficacy in practical
applications such as in topical insect repellents.
[0011] There is consequently a continuing need for a
biologically-based compound having improved insect repellent
properties (with respect to DEET) and which is substantially
non-toxic or only mildly toxic to humans. Preferred repellents will
have activity against a wide variety of insects, including biting
insects, wood-boring insects, noxious insects, household pests, and
the like. Applicants have found that dihydronepetalactones perform
well as a new class of effective insect repellent compounds without
the disadvantageous properties characteristic of prior-art
compositions.
SUMMARY OF THE INVENTION
[0012] One embodiment of this invention is an insect repellent
composition or article that contains a dihydronepetalactone, or a
mixture of dihydronepetalactone stereoisomers, represented by the
general formula: 2
[0013] Another embodiment of this invention is a process for
fabricating an insect repellent composition or an insect repellent
article of manufacture by providing as the composition or article,
or incorporating into the composition or article, a
diihydronepetalactone, or a mixture of dihydronepetalactone
stereoisomers, as described above. A further embodiment of this
invention is a method of imparting, augmenting or enhancing the
insect repellent effect of an article by incorporating into the
article a diihydronepetalactone, or a mixture of
dihydronepetalactone stereoisomers, as described above.
[0014] Yet another embodiment of this invention is the use of a
diihydronepetalactone, or a mixture of dihydronepetalactone
stereoisomers, as described above as an insect repellent, and thus
in a method of repelling insects, the insects are exposed to a
diihydronepetalactone, or a mixture of dihydronepetalactone
stereoisomers, as described above.
BRIEF DESCRIPTION OF DRAWINGS
[0015] FIG. 1 shows the chemical structures of the
naturally-occurring iridoid (methylcyclopentanoid)
nepetalactones.
[0016] FIG. 2 shows the total ion chromatograms from combined gas
chromatography/mass spectrometry (GC-MS) analysis of a distilled
nepetalactone-enriched fraction from commercially-available catmint
oil (A), together with that of the material produced from this
fraction by hydrogenation (B).
[0017] FIG. 3 shows the mass spectra of the major constituents of
the nepetalactone-enriched fraction (A) and the hydrogenated
material (B) identified by GC-MS analysis.
[0018] FIG. 4 shows the .sup.13C NMR analysis performed on a
distilled nepetalactone-enriched fraction of commercially-available
catmint oil.
[0019] FIG. 5 shows the .sup.13C NMR spectrum obtained from
analysis of the dihydronepetalactones produced by hydrogenation of
a distilled nepetalactone-enriched fraction of
commercially-available catmint oil.
[0020] FIG. 6 shows the distribution of landing density of female
Aedes aegyptii mosquitoes on membranes treated with
dihydronepetalactones over time in an in vitro repellency test.
DETAILED DESCRIPTION OF THE INVENTION
[0021] As used herein, the term "nepetalactone" refers to the
compound having the general structure: 3
[0022] Four chiral centers are present within the
methylcyclopentanoid backbone of nepetalactone at carbons 4, 4a, 7
and 7a as shown above; (7S)-nepetalactones are produced by several
plants and insects. Dihydronepetalactones are defined by Formula 1:
4
[0023] Formula 1
[0024] wherein 1, 5, 6 and 9 indicate the four chiral centers of
the molecule and the structure encompasses all possible
stereoisomers of dihydronepetalactone. The structures of
dihydronepetalactone stereoisomers that may be derived from
(7S)-nepetalactones are shown below.
1 5 (1S,5S,9S,6R)-5,9-dimethyl-3- oxabicyclo[4.3.0]nonan-2-one 6
(1S,9S,5R,6R)-5,9-dimethyl- -3- oxabicyclo[4.3.0]nonan-2-one 7
(1S,5S,9S,6S)-5,9-dimet- hyl-3- oxabicyclo]4.3.0]nonan-2-one 8
(1S,9S,6S,5R)-5,9-dimethyl-3- oxabicyclo[4.3.0]nonan-2-one 9
(9S,5S,1R,6R)-5,9-dimethyl-3- oxabicyclo[4.3.0]nonan-2-one 10
(9S,1R,5R,6R)-5,9-dimethyl-3- oxabicyclo[4.3.0]nonan-2-one 11
(9S,6S,1R,5S)-5,9-dimethyl-3- oxabicyclo[4.3.0]nonan-2-one 12
(9S,6S,1R,5R)-5,9-dimethyl-3- oxabicyclo[4.3.0]nonan-2-one
[0025] As used herein, the term "dihydronepetalactones" or
"dihydronepetalactone mixtures" refers to any mixture of
dihydronepetalactone stereoisomers. The molar or mass composition
of each of these isomers relative to the whole dihydronepetalactone
composition can be variable. Dihydronepetalactones are abbreviated
as "DHN".
[0026] As used herein, the term "insect" refers to any member of a
large group of invertebrate animals characterized, in the adult
state (non-adult insect states include larva and pupa) by division
of the body into head, thorax, and abdomen, three pairs of legs,
and, often (but not always) two pairs of membranous wings. This
definition therefore includes a variety of biting insects (e.g.,
ants, bees, black flies, chiggers, fleas, green head flies,
mosquitoes, stable flies, ticks, wasps), wood-boring insects (e.g.,
termites), noxious insects (e.g., houseflies, cockroaches, lice,
roaches, wood lice), and household pests (e.g., flour and bean
beetles, dust mites, moths, silverfish, weevils).
[0027] As used herein, the term "host" hereinafter refers to any
plant or animal affected by insects. Typically, hosts are
considered to be insect-acceptable food sources or
insect-acceptable habitats.
[0028] As used herein, the term "insect susceptible article" will
refer to any item of commerce created by man, which is affected by
insects. This may include buildings, furniture, and the like.
Typically, these articles of manufacture are considered to be
insect-acceptable food sources or insect-acceptable habitats.
[0029] As used herein, the term "insect repellent" or "insect
repellent composition" or "repellent composition" will refer to a
compound or composition which deters insects from their preferred
hosts or insect-suitable articles of manufacture. Most known
repellents are not active poisons at all, but rather prevent damage
to plants/animals or articles of manufacture by making insect food
sources or living conditions unattractive or offensive. Typically,
insect repellents are a compound or composition that can be either
topically applied to the host; or, the compound or composition is
incorporated into an insect susceptible article to produce an
insect repellent article that deters insects from the nearby
3-dimensional space in which the host or article exists. In either
case, the affect of the insect repellent is to drive the insects
away from or to reject: 1.) the host, thereby minimizing the
frequency of insect "bites" to the host; or 2.) the insect
susceptible article, thereby protecting the article from insect
damage. Repellents may be in the form of gases (olfactory),
liquids, or solids (gustatory).
[0030] Some examples of well-known insect repellents include:
benzil; benzyl benzoate; 2,3,4,5-bis(butyl-2-ene)
tetrahydrofurfural (MGK Repellent 11); butoxypolypropylene glycol;
N-butylacetanilide;
normal-butyl-6,6-dimethyl-5,6-dihydro-1,4-pyrone-2-carboxylate
(Indalone); dibutyl adipate; dibutyl phthalate; di-normal-butyl
succinate (Tabatrex); N,N-diethyl-meta-toluamide (DEET); dimethyl
carbate (endo,endo)-dimethyl
bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate); dimethyl phthalate;
2-ethyl-2-butyl-1,3-propanediol; 2-ethyl-1,3-hexanediol (Rutgers
612); di-normal-propyl isocinchomeronate (MGK Repellent 326);
2-phenylcyclohexanol; p-methane-3,8-diol, and normal-propyl
N,N-diethylsuccinamate. Standard repellents for mosquitoes, ticks,
and the like are citronella oil (discussed below), dimethyl
phthalate, normal-butylmesityl oxide oxalate and 2-ethyl
hexanediol-1,3 (See, Kirk-Othmer Encyclopedia of Chemical
Technology, 2.sup.nd Ed., Vol. 11: 724-728; and The Condensed
Chemical Dictionary, 8.sup.th Ed., p 756).
[0031] In addition to the chemical compositions above, a variety of
effective insect repellents consist of essential oils and/or active
ingredients of essential oils. "Essential oils" are defined as any
class of volatile oils obtained from plants possessing the odor and
other characteristic properties of the plant. Examples of repellent
compounds that are essential oils include: almond bitter oil, anise
oil, basil oil, bay oil, caraway oil, cardamom oil, cedar oil,
celery oil, chamomile oil, cinnamon oil, citronella oil, clove oil,
coriander oil, cumin oil, dill oil, eucalyptus oil, fennel oil,
ginger oil, grapefruit oil, lemon oil, lime oil, mint oil, parsley
oil, peppermint oil, pepper oil, rose oil, spearmint oil (menthol),
sweet orange oil, thyme oil, turmeric oil, and oil of wintergreen.
Examples of active ingredients in essential oils are: citronellal,
methyl salicylate, ethyl salicylate, propyl salicylate,
citronellol, safrole, and limonene.
[0032] In contrast to an "insect repellent", an "insecticide" is a
compound or mixture which is capable of poisoning an insect via its
oral ingestion, by contact with the insect cuticle, or by fumigant
action through the air. Thus, an insecticide is a type of pesticide
designed to control insect life which is harmful to man (i.e.,
directly harmful as disease vectors, or indirectly harmful by
destruction of crops, food products, or textile fabrics). Several
well-known insecticides include: inorganic compounds (such as
arsenic, lead and copper); naturally occurring organic compounds
(such as rotenone, pyrethrins, nicotine, copper naphthenate and
petroleum derivatives); and synthetic organic compounds (such as
DDT, dieldrin, endrin, chlordane, lindane, para-dichlorobenzene and
parathion).
[0033] As used herein, the term "potentiated insect repellent
composition" refers to a repellent composition which produces a
result substantially in excess of that which reasonably could be
expected or predicted from the known effect of the components
either alone or additively. In the present invention, a potentiated
insect repellent composition will include dihydronepetalactones or
a mixture thereof, and at least one other insect repellent compound
that is not itself dihydronepetalactone (sometimes referred to as a
non-dihydronepetalactone insect repellent compound).
[0034] An "insect repellent composition" can be used as a component
of an "insect repellent article", wherein the term "insect
repellent article" refers to an article of manufacture possessing
insect repellency that is enhanced, altered, or augmented by the
insect repellent composition. As used herein with respect to insect
repellency, the terms "alter" and "modify" in their various forms
refer to a means of supplying or imparting insect repellency to a
composition, or augmenting the existing insect repellency
characteristics where natural repellency is deficient in some
regard, or supplementing the existing insect repellency to modify
its quality, or character. The term "enhance" is intended to mean
the intensification (without effecting a change in kind or quality
of repellency) of one or more repellency properties in an insect
repellent composition or insect repellent article.
[0035] In a preferred embodiment, the insect repellent composition
of this invention also functions as a fragrance composition since
it is capable of imparting a pleasing fragrance or aroma to the
insect repellent composition or to an insect repellent article.
Dihydronepetalactones are useful in an insect repellent composition
or article to enhance, alter, or augment the overall aroma or
fragrance of the composition or article. With respect to fragrance,
the terms "alter" and "modify" in their various forms refer to a
means of supplying or imparting a fragrance or aroma character or
note to otherwise bland substances or augmenting the existing aroma
characteristics where natural aroma is deficient in some regard or
supplementing the existing aroma impression to modify its quality,
character, or aroma. The term "enhance" is intended to mean the
intensification (without effecting a change in kind or quality of
aroma) of one or more aroma nuances and their organoleptic
impression of a fragrance, perfume composition, or one or more
perfumed articles.
[0036] The term "fragrance composition" is used herein to mean a
mixture of organic compounds including, for example, alcohols,
aldehydes, ketones, nitriles, esters, lactones, natural essential
oils, synthetic essential oils, and mercaptans, which are admixed
so that the combined odors of the individual components produce a
pleasant or desired fragrance. Such compositions usually contain:
(1) the main note or the "bouquet" or foundation stone of the
composition; (2) modifiers which round off and accompany the main
note; (3) fixatives which include odorous substances which lend a
particular note to the perfume throughout all stages of evaporation
and substances which retard evaporation; and (4) top notes which
are usually low-boiling, fresh-smelling materials.
[0037] In fragrance or aroma compositions, the individual component
will contribute its particular olfactory characteristics, but the
overall effect of the composition will be the sum of each of the
effects of each of the ingredients. Thus, the dihydronepetalactones
of this invention or mixtures thereof can be used to alter the
aroma characteristics of such compositions, for example, by
highlighting or moderating the olfactory reaction contributed by
another ingredient in the composition.
[0038] Dihydronepetalactones are known in the literature, for
example as minor constituents of the essential oils of several
labiate plants of the genus Nepeta (Regnier, F. E., et al.
Phytochemistry 6:1281-1289 (1967); DePooter, H. L., et al. Flavour
and Fragrance Journal 3:155-159 (1988); Handjieva, N. V. and S. S.
Popov J. Essential Oil Res. 8:639-643 (1996)). Additionally,
dihydronepetalactones have been identified as constituents of the
defensive secretions of certain insects, including rove beetles
(Jefson, M., et al. J. Chem. Ecol. 9:159-180 (1983)) and ants,
specifically Iridomyrmex species (Cavill, G. W. K. and D. V. Clark.
J. Insect Physiol. 13:131-135 (1967)). In those species that
possess dihydronepetalactones, it has been proposed that they are
biosynthetically derived from the iridoid monoterpene
iridodial.
[0039] The chemical synthesis of dihydronepetalactones and their
related iridoid monoterpenoid compounds has been described and
found to be conducted in a variety of ways. The following are
useful references relating to synthesis:
[0040] 1) Abelman, M. M. et al. J. Am. Chem. Soc. 104(14):4030-2
(1982)
[0041] 2) Fleming, I. and N. K. Terrett. Tetrahedron Lett. 25(44):
5103-5104 (1984); J. Chem. Soc., Perkin Trans. 1:2645-2650
(1998).
[0042] 3) Lee, E. and C. H. Yoon. J. Chem. Soc., Chem. Commun. 4:
479-81 (1994).
[0043] 4) Nagata, H. and K. Ogasawara. Tetrahedron Lett. 40(36):
6617-6620 (1999).
[0044] 5) Nangia, A. et al. Tetrahedron Lett. 35(22): 3755-8
(1994).
[0045] 6) Tanimori, S. and M. Nakayama. Agric. Biol. Chem. 55(4):
1181-1184 (1991).
[0046] 7) Uyehara, T. et al. J. Chem. Soc., Chem. Commun. 2:113-14
(1989); Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 32: 441-6
(1990); J. Org. Chem. 57(11): 3139-3145 (1992).
[0047] 8) Wolinsky, J. and E. J. Eustace. J. Org. Chem. 37(21):
3376-8 (1972).
[0048] 9) Wolinsky, J. and D. L. Nelson. Tetrahedron 25(17):
3767-74 (1969).
[0049] One preferred and convenient method for synthesis of the
dihydronepetalactone mixtures of the present invention is by
hydrogenation of nepetalactone. Catalysts such as platinum oxide
and palladium supported on strontium carbonate give
dihydronepalactone in 24-90% yields (Regnier, F. E., et al.
Phytochemistry 6:1281-1289 (1967)). Nepetalactone is a known
material that can be conveniently obtained in relatively pure form
from the essential oils isolated by various means from plants of
the genus Nepeta (catmints). Isolation of such oils is well known
in the art, and examples of methodology for oil extraction include
(but are not limited to) steam distillation, organic solvent
extraction, microwave-assisted organic solvent extraction,
supercritical fluid extraction, mechanical extraction and
enfleurage (initial cold extraction into fats followed by organic
solvent extraction).
[0050] The essential oils isolated from different Nepeta species
are well known to possess different proportions of each
naturally-occurring stereoisomer of nepetalactone (Regnier, F. E.,
et al. Phytochemistry 6:1281-1289 (1967); DePooter, H. L., et al.
Flavour and Fragrance Journal 3:155-159 (1988); Handjieva, N. V.
and S. S. Popov. J. Essential Oil Res. 8:639-643 (1996)). Thus,
from oil derived from any Nepeta species containing a mixture of
nepetalactones, a mixture of dihydronepetalactone stereoisomers
will be generated upon hydrogenation. Four chiral centers are
present within the methylcyclopentanoid backbone of the
nepetalactone at carbons 4, 4a, 7 and 7a as shown: 13
[0051] Thus it is clear that a total of eight pairs of
dihydronepetalactone enantiomers are possible after hydrogenation.
Of these, the naturally occurring stereoisomers described thus far
are (9S)-dihydronepetalactones. Preferred repellent materials in
accordance with the present invention include a mixture of any or
all of the possible stereoisomers of dihydronepetalactone. More
preferred repellent materials include a mixture of
(9S)-dihydronepetalactones. Most preferred are
(9S)-dihydronepetalactone stereoisomers derived from
(7S)-nepetalactones. This includes the compounds commonly known as
cis,trans-nepetalactone, cis,cis-nepetalactone,
trans,cis-nepetalactone, and trans,trans-nepetalactone, as
illustrated in FIG. 1.
[0052] Upon completion of the hydrogenation reaction, the resulting
mixture of isomer products may be separated by a conventional
method (e.g., preparative liquid chromatography) to yield each
highly purified pair of dihydronepetalactone diastereomers.
[0053] In addition to variation in nepetalactone stereoisomer
content between different Nepeta species, intra-species variation
is also known to exist. Plants of a given species may produce oils
with different compositions depending on the conditions of their
growth or growth stage at harvest. Additionally, within a single
species, Nepeta racemosa, variation in oil composition independent
of growth conditions or growth stage at harvest has been
demonstrated (Clark, L. J., et al. The Plant Journal, 11:1387-1393
(1997)). Plants of a single species exhibiting different oil
compositions are termed chemotypes, and it has been shown that in
Nepeta racemosa, chemotypes exhibiting marked differences in the
proportion of different nepetalactone stereoisomers exist (Clark,
L. J., et al., supra). Thus, the preferred process for producing
specific dihydronepetalactone enantiomers would be hydrogenation of
an oil from a Nepeta chemotype known to contain specific
nepetalactone stereoisomers.
[0054] The preferred process for producing the
dihydronepetalactones represented by Formula I in the present
invention, therefore, is by hydrogenation of nepetalactones from
plants with oils of defined nepetalactone stereoisomer content, an
industrially advantageous approach in terms of production cost and
its biological basis. Other processes are as disclosed in U.S.
Provisional Application No. 60/369,470, filed Apr. 3, 2002.
[0055] The dihydronepetalactones of the present invention possess
unique properties of insect repellency and are particularly
effective against a wide spectra of common insect pests, including
biting insects, wood-boring insects, noxious insects, and
household-pests.
[0056] The insect repellent compositions of this invention
containing dihydronepetalactones or mixtures thereof are effective
against a variety of insects which interfere with human society.
These insects include a variety of biting insects (e.g., ants,
bees, black flies, chiggers, fleas, green head flies, mosquitoes,
stable flies, ticks, wasps), wood-boring insects (e.g., termites),
noxious insects (e.g., houseflies, cockroaches, lice, roaches, wood
lice), and household pests (e.g., flour and bean beetles, dust
mites, moths, silverfish, weevils). In the case of mosquitoes,
which convey pathogenic microbes, these repellent properties are
additionally effective for preventing infection with such
diseases.
[0057] A wide variety of compounds possess insect repellent and/or
mosquito repellent activity, as evidenced by: 1.) the diversity of
chemical structures reported by the USDA to contain repellent
activity (Chemicals Evaluated as Insecticides and Repellents at
Orlando, Fla., compiled by W. V. King, U.S. Department of
Agriculture, Agricultural Research Service, Agriculture Handbook
No. 69); and 2.) by the variety of insect repellant active
materials present in insect repellent formations (See, e.g.,
European patent applications 97,812 and 97,813, and U.S. Pat. No.
4,127,672, U.S. Pat. No. 4,756,905, U.S. Pat. No. 5,465,685, U.S.
Pat. No. 5,489,433, U.S. Pat. No. 5,565,208, U.S. Pat. No.
5,672,337 and U.S. Pat. No. 5,716,602). In general, activity is
found in alcohols, amides, esters, ketones, acids, lactones, and
lactams; and to some degree, repellency activity does appear to
depend on the physical properties of these compounds.
[0058] One property that is important to overall insect repellency
is surface activity, as most (if not all) repellents contain both
polar and non-polar regions in their structure. A second property
is volatility. Insect repellents form an unusual class of compounds
where evaporation of the active ingredient from the host's skin
surface or from the insect repellent article is necessary for
effectiveness, as measured by the host's protection from insect
bites or the article's protection from insect damage. In the case
of a topical insect repellent, a certain minimum concentration of
repellent is needed in the air space directly above the skin
surface of the host in order to repel insects, and this
concentration is a measure of the potency of the repellent.
However, evaporation rate is also affected by the rate of skin
absorption--in most cases, penetration into and through the skin is
an undesirable mode of loss of compound from the skin surface.
Similar considerations must be made for insect repellent articles,
concerning the minimum concentration of repellent required in the
three-dimensional air space surrounding the article itself.
[0059] A variety of strategies are available to researchers
attempting to balance these properties of evaporation (and
optionally, penetration). First, it is possible to find a single
active ingredient having the right balance of physical properties.
Alternatively, the active ingredient could be formulated with
polymers and inert ingredients added to the active ingredient for
the purpose of modifying the persistence of the active ingredient
on the host's skin surface or within the insect repellent article.
However, adding inert ingredients to the active ingredient limits
the number of molecules of active ingredient on the surface of the
repellent film or article. Since a molecule must be on the surface
in order to evaporate, the evaporation rate is lowered. This
carries with it the negative consequence of diluting the
concentration of active ingredient that can be applied to the
host's skin surface or that is present on the surface of an insect
repellent article. This, in turn, reduces the overall potency of a
formulation containing inert ingredients. In a third alternative,
the active ingredient can be contained in microcapsules to control
rates of loss from the host's skin surface or insect repellent
article. Finally, another technique of limiting the evaporation
rate of active ingredient is to synthesize a precursor molecule,
which slowly disintegrates on the skin surface or insect repellent
article to release the active ingredient.
[0060] For example, release of the active ingredient may be, for
example, by sub-micron encapsulation, in which the active
ingredient is encapsulated (surrounded) within a skin nourishing
protein just the way air is captured within a balloon. The protein
may be used at, for example, a 20% concentration. An application of
repellent contains many of these protein capsules that are
suspended in either a water-based lotion, or water for spray
application. After contact with skin the protein capsules begin to
breakdown releasing the encapsulated dihydronepetalactone. The
process continues as each microscopic capsule is depleted then
replaced in succession by a new capsule that contacts the skin and
releases its active ingredient. The process may take up to 24 hours
for one application. Because protein's adherence to the skin is so
effective, these formulas are very resistant to perspiration
(sweat-off), and water. When applied they are dry and comfortable
with no greasiness. This system results in very effective
protection, but it is only effective when used on skin because
clothing does not have the capability to release the proteins. An
alternative system uses a polymer to encase the repellent, which
slows down early evaporation leaving more dihydronepetalactone
available for later evaporation. This system can often increase a
repellent's length of effectiveness by 25% to 50% over comparable
non-entrapped products, but often feels greasy because of the
presence of the polymer. In another alternative, a synergist is
used to keep stimulating the evaporation of the
dihydronepetalactone in the composition.
[0061] Regardless of the particular strategy applied to control
volatility of an insect repellent, each repellent must have a
minimum effective evaporation rate (MEER) from the skin surface or
insect repellent article to maintain the necessary minimum
concentration of repellent in the air space directly above the skin
surface/article for effective insect repellency. An evaporation
rate greater than the minimum effective evaporation rate (MEER)
results in a significant and undesirable mode of loss. The issue is
further complicated, however, since the MEER will change as a
function of conditions in the field. Both the avidity or biting
tendency of an insect and the concentration of insects in the
host's environment must be considered. For example, as the avidity
of mosquitoes increases, a higher MEER will be required. In an
environment having a low concentration of mosquitoes where those
mosquitoes are not hungry, the MEER could be as low as 2, or more
commonly 5, or 6. In contrast, in an environment having a high
concentration of hungry mosquitoes, the MEER might be as high as
12-15. Preferred in the present invention are insect compositions
wherein the skin surface evaporation rate is at least equal to a
minimum effective evaporation rate over a period of time where a
preferred period of time is about 5 hours.
[0062] In the present invention, a variety of carriers or diluents
for the above-disclosed dihydronepetalactones can be used. The
carrier allows the formulation to be adjusted to an effective
concentration of repellant molecules. When formulating a topical
insect repellent, preferably, the repellant molecules are mixed in
a dermatologically acceptable carrier. The carrier may further
provide water repellency, prevent skin irritation, and/or soothe
and condition skin. Factors to consider when selecting a carrier(s)
for any formulation of insect repellent include commercial
availability, cost, repellency, evaporation rate, odor, and
stability. Some carriers can themselves have repellent
properties.
[0063] For the present invention, the specific choice of a carrier,
if any, to be utilized in achieving the desired intimate admixture
with the final product can be any carrier conventionally used in
insect repellent formulations. The carrier, moreover, should
preferably also be one that will not be harmful to the environment.
Accordingly, the carrier can be any one of a variety of
commercially available organic and inorganic liquid, solid, or
semi-solid carriers or carrier formulations usable in formulating
insect repellent products. For example the carrier may include
silicone, petrolatum, lanolin or many of several other well known
carrier components.
[0064] Examples of organic liquid carriers include liquid aliphatic
hydrocarbons (e.g., pentane, hexane, heptane, nonane, decane and
their analogs) and liquid aromatic hydrocarbons. Examples of other
liquid hydrocarbons include oils produced by the distillation of
coal and the distillation of various types and grades of
petrochemical stocks, including kerosene oils which are obtained by
fractional distillation of petroleum.
[0065] Other petroleum oils include those generally referred to as
agricultural spray oils (e.g., the so-called light and medium spray
oils, consisting of middle fractions in the distillation of
petroleum and which are only slightly volatile). Such oils are
usually highly refined and may contain only minute amounts of
unsaturated compounds. Such oils, moreover, are generally. paraffin
oils and accordingly can be emulsified with water and an
emulsifier, diluted to lower concentrations, and used as sprays.
Tall oils, obtained from sulfate digestion of wood pulp, like the
paraffin oils, can similarly be used. Other organic liquid carriers
can include liquid terpene hydrocarbons and terpene alcohols such
as alpha-pinene, dipentene, terpineol, and the like.
[0066] Other carriers include silicone, petrolatum, lanolin, liquid
hydrocarbons, agricultural spray oils, paraffin oil, tall oils,
liquid terpene hydrocarbons and terpene alcohols, aliphatic and
aromatic alcohols, esters, aldehydes, ketones, mineral oil, higher
alcohols, finely divided organic and inorganic solid materials.
[0067] In addition to the above-mentioned liquid hydrocarbons, the
carrier can contain conventional emulsifying agents which can be
used for causing the dihydronepetalactone compounds to be dispersed
in, and diluted with, water for end-use application.
[0068] Still other liquid carriers can include organic solvents
such as aliphatic and aromatic alcohols, esters, aldehydes, and
ketones. Aliphatic monohydric alcohols include methyl, ethyl,
normal-propyl, isopropyl, normal-butyl, sec-butyl, and tert-butyl
alcohols. Suitable alcohols include glycols (such as ethylene and
propylene glycol) and pinacols. Suitable polyhydroxy alcohols
include glycerol, arabitol, erythritol, sorbitol, and the like.
Finally, suitable cyclic alcohols include cyclopentyl and
cyclohexyl alcohols.
[0069] Conventional aromatic and aliphatic esters, aldehydes and
ketones can be used as carriers, and occasionally are used in
combination with the above-mentioned alcohols. Still other liquid
carriers include relatively high-boiling petroleum products such as
mineral oil and higher alcohols (such as cetyl alcohol).
Additionally, conventional or so-called "stabilizers" (e.g.,
tert-butyl sulfinyl dimethyl dithiocarbonate) can be used in
conjunction with, or as a component of, the carrier or carriers
comprising the compositions of the present invention.
[0070] Solid carriers which can be used in the compositions of the
present invention include finely divided organic and inorganic
solid materials. Suitable finely divided solid inorganic carriers
include siliceous minerals such as synthetic and natural clay,
bentonite, attapulgite, fuller's earth, diatomaceous earth, kaolin,
mica, talc, finely divided quartz, and the like, as well as
synthetically prepared siliceous materials, such as silica aerogels
and precipitated and fume silicas. Examples of finely divided solid
organic materials include cellulose, sawdust, synthetic organic
polymers, and the like. Examples of semi-solid or colloidal
carriers include waxy solids, gels (such as petroleum jelly),
lanolin, and the like, and mixtures of well-known liquid and solid
substances which can provide semi-solid carrier products, for
providing effective repellency within the scope of the instant
invention.
[0071] Insect repellent compositions of the present invention
containing the dihydronepetalactones may also contain adjuvants
known in the art of personal care product formulations, such as
thickeners, buffering agents, chelating agents, preservatives,
fragrances, antioxidants, gelling agents, stabilizers, surfactants,
emolients, coloring agents, aloe vera, waxes, other penetration
enhancers and mixtures thereof, and therapeutically or cosmetically
active agents.
[0072] Additionally, the compositions of the present invention may
also contain other adjuvants such as one or more therapeutically or
cosmetically active ingredients. Exemplary therapeutic or
cosmetically active ingredients useful in the compositions of the
invention include fungicides, sunscreening agents, sunblocking
agents, vitamins, tanning agents, plant extracts, anti-inflammatory
agents, anti-oxidants, radical scavenging agents, retinoids,
alpha-hydroxy acids, emollients, antiseptics, antibiotics,
antibacterial agents or antihistamines, and may be present in an
amount effective for achieving the therapeutic or cosmetic result
desired.
[0073] Dihydronepetalactones may be utilized in the present
invention individually or combined in any proportion. As is
conventional in the art, the desired amount of an insect repellent
composition to be added to a given insect susceptible article with
properties of insect repellency is determined by the nature of the
product and other factors. These factors include both
considerations of cost and the nature of the other ingredients in
the insect repellent composition or repellent article, their
amounts, and the desired repellency effect. In general, the
composition of the repellent should contain sufficient amounts of
active insect repellant material to be efficacious in repelling the
insect from the host over a prolonged period of time (preferably,
for a period of at least several hours).
[0074] The amount of each dihydronepetalactone of Formula I or
mixtures thereof in an insect repellent composition or repellent
article in accordance with the present invention will generally not
exceed about 80% by weight based on the weight of the final
product, however, greater amounts may be utilized in certain
applications and this amount is not limiting. More preferably, a
suitable amount of dihydronepetalactone will be at least about
0.001% by weight and preferably about 0.01% up to about 50% by
weight; and more preferably, from about 0.01% to about 20% weight
percent, based on the weight of the composition or article.
Specific compositions will depend on the intended use.
[0075] The dihydronepetalactone repellent compositions of the
present invention can be formulated without a carrier and be
effective. More often, however, the insect repellent composition
will include a carrier and contain about 0.001-50% weight of the
disclosed compounds, and such compound is usually in intimate
mixture with the carrier to bring the active material into position
for repelling common insect pests, such as biting insects,
wood-boring insects, noxious insects, household pests, and the
like.
[0076] The compositions of the invention may be formulated and
packaged so as to deliver the product in a variety of forms
including as a solution, suspension, cream, ointment, gel, film or
spray, depending on the preferred method of use. The carrier may be
an aerosol composition adapted to disperse the dihydronepetalactone
into the atmosphere by means of a compressed gas.
[0077] In some cases, the dihydronepetalactone repellent
compositions of the present invention can be formulated with at
least one other insect repellent that is not itself
dihydronepetalactone to create a potentiated insect repellent
composition (see, for example, U.S. Pat. No. 4,869,896). In this
case, the effect of the dihydronepetalactone and the at least one
other insect repellent produce a repellency result substantially in
excess of that which reasonably could be expected or predicted from
the known effect of the components either alone or additively.
Exemplary other insect repellent compounds which may be used in a
potentiated insect repellent composition with dihydronepetalactones
include, but are not limited to: benzil; benzyl benzoate;
2,3,4,5-bis(butyl-2-ene) tetrahydrofurfural (MGK Repellent 11);
butoxypolypropylene glycol; N-butylacetanilide;
normal-butyl-6,6-dimethyl-5,6-dihydro-1,4-pyrone-2-ca- rboxylate
(Indalone); dibutyl adipate; dibutyl phthalate; di-normal-butyl
succinate (Tabatrex); N,N-diethyl-meta-toluamide (DEET); dimethyl
carbate (endo,endo)-dimethyl
bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate); dimethyl phthalate;
2-ethyl-2-butyl-1,3-propanediol; 2-ethyl-1,3-hexanediol (Rutgers
612); di-normal-propyl isocinchomeronate (MGK Repellent 326);
2-phenylcyclohexanol;normal-propyl N,N-diethylsuccinamate,
1-piperidinecarboxylic acid 2-(2-hydroxymethyl) 1-methylpropylester
(Bayrepel) and p-menthane-3,8-diol. Preferred is a potentiated
insect repellent composition comprising dihydronepetalactones (or a
mixture thereof) and DEET, Bayrepel or p-menthane-3,8-diol. Most
preferred is a potentiated insect repellent composition comprising
dihydronepetalactones (or a mixture thereof) and other natural
repellent molecules such as p-menthane-3,8-diol.
[0078] Desirable properties of a topical insect repellent article
include low toxicity, resistance to loss by water immersion or
sweating, low or no odor or at least a pleasant odor, ease of
application, and rapid formation of a dry tack-free surface film on
the host's skin. In order to obtain these properties, the
formulation for a topical insect repellent article should permit
insect-infested animals (e.g., dogs with fleas, poultry with lice,
cows with ticks, and humans) to be treated with an insect repellent
composition of the present invention by contacting the skin, fur or
feathers of such an animal with an effective amount of the
repellent article for repelling the insect from the animal host.
Thus, dispersing the article into the air or dispersing the
composition as a liquid mist or fine dust will permit the repellent
composition to fall on the desired host surfaces. Likewise,
directly spreading of the liquid/semi-solid/solid repellent article
on the host is an effective method of contacting the surface of the
host with an effective amount of the repellent composition.
[0079] Embodiments of the present invention which may be used as a
topical insect repellent articles, include (but are not limited
to): colognes, lotions, sprays, creams, gels, ointments, bath and
shower gels, foam products (e.g., shaving foams), makeup,
deodorants, shampoo, hair lacquers/hair rinses, and personal soap
compositions (e.g., hand soaps and bath/shower soaps).
[0080] This invention also relates to the use of
dihydronepetalactone mixtures as insect repellents in a variety of
articles which are susceptible to attack by insects. These outdoor
consumable products will generally, but not necessarily, comprise
an insect repellent composition of the invention, but will contain
an effective amount of dihydronepetalactone. Typical articles that
can be improved by the use of dihydronepetalactones and mixtures
thereof include, but are not limited to: air fresheners, candles,
other scented articles, fibers, sheets, cloth [e.g., for clothing,
nettings (mosquito netting), and other fabrics], paper, paint, ink,
clay, woods, furniture (e.g., for patios and decks), carpets,
sanitary goods, plastics, polymers, and the like.
[0081] The dihydronepetalactone compositions of this invention may
be blended with polymers, which may also involve a controlled
release systems. Compatible polymers may or may not be
biodegradable. Exemplary polymers are high density polyethylene or
low density polyethylene, biodegradable thermoplastic
polyurethanes, biodegradable ethylene polymers, and poly(epsilon
caprolactone) homopolymers and compositions containing the same as
disclosed in U.S. Pat. No. 4,496,467, U.S. Pat. No. 4,469,613 and
U.S. Pat. No. 4,548,764.
[0082] Dihydronepetalactones are particularly advantageous for use
as repellent materials in preparations of the present invention for
a variety of reasons.
[0083] First, the compounds are cost effective to produce, an
important consumer consideration when choosing an effective
repellent. Many commerically available repellent products are only
effective in relatively concentrated form, including as much as
5-30% (or more) repellent in a carrier, based on total weight. U.S.
Pat. No. 4,416,881 to McGovern et al., for example, discloses
repellent concentrations of 6.25-25% repellent in a carrier.
[0084] Secondly, the compounds are known natural compounds, thus
overcoming concerns raised against synthetic chemicals such as DEET
as the primary active ingredient in repellent compositions.
[0085] Finally, in addition to the natural repellent properties of
the dihydronepetalactone mixtures thus prepared, the compositions
also possess a unique and pleasant fragrance. The fragrance notes
of the subject compounds make them useful in imparting, altering,
augmenting or enhancing the overall olfactory component of an
insect repellent composition or article, for example, by utilizing
or moderating the olfactory reaction contributed by one or more
other ingredients in the composition. Specifically, the
dihydronepetalactones of the invention or mixtures thereof may be
utilized to either mask or modify the odor contributed by other
ingredients in the formulation of the final repellent composition
or article, and/or to enhance consumer appeal of a product by
imparting a characteristic perfume or aroma. It is expected that
the pleasant fragrance of dihydronepetalactones will possess much
greater appeal to consumers than other insect repellent compounds,
particularly DEET.
[0086] Dihydronepetalactones and their uses are also described in
U.S. Ser. No. 10/349,865, filed Jan. 23, 2003, which is
incorporated in its entirety as a part hereof for all purposes.
EXAMPLES
[0087] The present invention is further defined in the following
examples. It should be understood that these examples, while
indicating preferred embodiments of the invention, are given by way
of illustration only. From the above discussion and these examples,
one skilled in the art can ascertain the essential characteristics
of this invention, and without departing from the spirit and scope
thereof, can make various changes and modifications of the
invention to adapt it to various usages and conditions. The
notation below of w/v refers to the weight of the active ingredient
in grams in 100 mL of solution.
[0088] The meaning of abbreviations is as follows: "h" means
hour(s), "min" means minute(s), "sec" means second(s), "d" means
day(s), "mL" means milliliters, "L" means liters, "m/z" means mass
(m) to charge (z) ratio, "ppm" means parts per million, "mol %"
means percentage expressed on a molar basis, "Hz" means Hertz
(1/sec), and "psig" means pounds per square inch guage.
Example 1
Preparation of Nepetalactones by Fractional Steam Distillation of
oil of Nepeta cataria
[0089] A sample of commercially-available catnip oil, prepared by
steam distillation of herbaceous material from the catmint Nepeta
cataria, was obtained (Berj, Bloomfield, N.J., USA). Combined gas
chromatography--mass spectrometry (GC-MS) of this oil indicated
that the principal constituents were nepetalactone stereoisomers
(data not shown).
[0090] The nepetalactone fraction was further purified by
fractional distillation of this oil. FIG. 2A presents the GC-MS
total ion chromatogram of the nepetalactone-enriched fraction
prepared by fractional distillation of the commercial sample of
Nepeta cataria essential oil. The conditions employed were: column
HP5-MS, 25 m.times.0.2 mm; oven 120.degree. C., 2 min, 15.degree.
C./min, 210.degree. C., 5 min.; He @ 1 ml/min. Peaks with m/z 166
are nepetalactones). The unlabelled peaks correspond to minor
sesquiterpenoid contaminants. In FIG. 3A, the mass spectrum of the
major peak (6.03 min, nepetalactone) in FIG. 2A is shown. .sup.1H
and .sup.13C NMR analysis of the oil and the purified material was
also carried out, and the .sup.13C data is presented (FIG. 4). The
.sup.13C chemical shifts for the four possible stereoisomers
reported in the literature were compared to the spectra taken for
the sample. Three stereoisomers were detected and the amounts were
quantified based on the carbonyl region at around 170 ppm. The
chemical shifts, for both the original oil and the enriched
material, are provided in Table 1. Each carbon atom of nepetalatone
is identified, as shown in FIG. 4.
2TABLE 1 .sup.13C Chemical Shifts and Mol % Values of Nepetalactone
Stereoisomers Present in Commercial Sample of Essential Oil of
Catmint (Nepeta cataria) and in Fraction Purified by Steam
Distillation ESSENTIAL OIL PURIFIED FRACTION cis, trans- trans,
cis- cis, cis- cis, trans- trans, cis- cis, cis ATOM .delta. (ppm)
.delta. (ppm) .delta. (ppm) .delta. (ppm) .delta. (ppm) .delta.
(ppm) a 170.9 170.1 170.8 170.1 b 133.7 135.9 134.2 133.7 135.9
134.2 c 115.3 120.4 115.3 120.4 d 40.8 37.3 39.6 40.8 37.4 39.5 e
49.4 49.1 46.4 49.5 49.1 46.3 f 39.7 32.1 38.4 39.8 32.1 38.4 g
33.0 30.0 32.7 33.1 30.0 32.7 h 30.9 26.1 30.4 31.0 26.1 30.5 j
20.2 17.5 17.1 20.3 17.6 17.2 i 15.4 14.2 14.7 15.5 14.2 14.8 Mol %
80.20% 17.70% 2.10% 84.50% 14.30% 1.20%
[0091] This analysis indicated that in the oil, nepetalactones were
present in the following proportions: 80.2 mol %
cis,trans-nepetalactone, 17.7 mol % trans,cis-nepetalactone and 2.1
mol % cis,cis-nepetalactone. The data indicated the proportions of
nepetalactones in the purified material were 84.5 mol %
cis,trans-nepetalactone, 14.3 mol % trans,cis-nepetalactone and 1.2
mol % cis,cis-nepetalactone. GC-MS analysis of this purified
fraction indicated that it consisted predominantly of these
nepetalactones (m/z 166), accompanied by trace amounts of the
sesquiterpenoids caryophyllene and humulene (data not shown).
Example 2
Preparation of Dihydronepetalactones
[0092] 107 g of the distilled nepetalactone fraction of the catmint
oil prepared as described in Example 1 was dissolved in ethanol
(200 ml) and placed in a Fisher-Porter bottle with 12.7 g 2%
Pd/SrCO.sub.3 (Aldrich 41,461-1). The tube was evacuated and
backfilled with H.sub.2 two times, then charged with H.sub.2 at 30
psig. After 48 hr stirring at room temperature, the tube was vented
and the contents filtered over Celite to remove catalyst. The
solvent was removed under vacuum, yielding a clear oil.
[0093] GC-MS analysis (column HP5-MS, 25 m.times.0.2 mm; Oven
120.degree. C., 2 min, 15.degree. C./min, 210.degree. C., 5 min.;
He @ 1 ml/min) was conducted on this material. The total ion
chromatogram is presented in FIG. 2B. This analysis indicated that
the principal component (65.43% area; Rt 7.08 min) represented a
dihydronepetalactone isomer, with m/z 168; the mass spectrum of
this component is presented in FIG. 3B. This spectrum contains an
ion with m/z 113, diagnostic for dihydronepetalactones (Jefson, M.,
et al. J. Chemical Ecology 9:159-180 (1983)). Five additional
peaks, representing the remaining dihydronepetalactone
diastereomers which might be derived from the three nepetalactones
present in the starting material were also represented in the
chromatogram. These occurred at Rt 5.41 min, 6.8% area, m/z 168; Rt
5.93 min, area 1.2%, m/z 168; Rt 6.52 min, 4.88% area, mass 168; Rt
6.76 min, 13.8% area, m/z 168 and Rt 7.13 min, 1.25% area, m/z 168.
No residual nepetalactones were detected by GC-MS.
[0094] .sup.1H, .sup.13C and a series of 2D NMR analyses were also
performed. The carbonyl region of the .sup.13C NMR spectrum (FIG.
5) showed at least five spin systems, one of them in larger amounts
than the other four (ca. 75%). Very little residual nepetalactone
was detected.
[0095] Based on the analysis of coupling constants and the
intensities of the different NOE cross peaks observed, the
stereochemistry of the principal component of the material was
determined to be the dihydronepetalactone of Formula 2 (9S,5S,1
R,6R)-5,9-dimethyl-3-oxabicycl- o[4.3.0]nonan-2-one). 14
[0096] The distance between the methyl group (i) and proton (d) is
longer than the distance between the methyl group (j) and the
proton (e), an observation consistent with the cis-trans
stereochemical configuration.
[0097] The stereoisomer isodihydronepetalactone (9S,5R,
1R,6R)-5,9-dimethyl-3-oxabicyclo[4.3.0]nonan-2-one; (Formula 3) was
similarly identified by .sup.13C chemical shifts and is present in
3.6%. 15
[0098] Thus the GC-MS and NMR data indicate that hydrogenation of
the mixture of nepetalactone stereoisomers yielded the
corresponding dihydronepetalactone diastereomers, as expected. The
pair of diastereomers (Formula 2 and Formula 3) derived from
cis,trans-nepetalactone (84.5 Mol % of the starting material) were
the predominant dihydronepetalactones, at 78.6% of the mixture
following hydrogenation.
Example 3
Repellency Testing of a Dihydronepetalactone Mixture
[0099] The dihydronepetalactone mixture prepared in accordance with
Example 2 was evaluated for its repellent effects against female
Aedes aegypti mosquitoes. These tests were carried out under
contract by Insect Control & Research, Inc. (Baltimore,
Md.).
[0100] Approximately 250 female Aedes aegypti mosquitoes were
introduced into a chamber containing 5 wells, each covered by a
Baudruche membrane. Wells were filled with bovine blood, containing
sodium citrate (to prevent clotting) and ATP (72 mg ATP disodium
salt per 26 ml of blood), and heated to 37.degree. C. A volume of
25 .mu.l of isopropyl alcohol, containing putative repellent
chemicals (Table 2), was applied to each membrane.
3TABLE 2 Experimental Design Applied for Repellency Testing Purpose
Compound Concentration Untreated Control Isopropyl alcohol 100%
Positive Control Isopropyl alcohol with DEET 1.0% (w/v)
Experimental Samples Isopropyl alcohol with 1.0% (w/v)
Dihydronepetalactone 2.5% (w/v) 5.0% (w/v)
[0101] After 5 min, 4 day-old female mosquitoes were added to the
chamber. The number of mosquitoes probing the membranes for each
treatment was recorded at 2 min intervals over 20 min. All data
presented is from three replicate experiments.
[0102] Table 3 presents the effect of dihydronepetalactone
concentration with respect to the amount of time taken before the
female A. aegypti mosquitoes first probed each membrane.
4TABLE 3 Effect of Dihydronepetalactone Concentraton on Mean Time
to "First Probing" Repellent Concentration Mean Time (min)
Isopropyl alcohol (untreated 4.6 control) 1% DEET (positive
control) 12 1% DHN 8 2.5% DHN 9.3 5% DHN 18
[0103] Mosquitoes began landing on the untreated control well
within 4.6 min. Dihydronepetalactone at 5% concentration was found
to discourage mosquito "first probing" for approximately 18 min,
compared to 12 min for DEET (at 1% w/v). Lower concentrations of
dihydronepetalactone (1% and 2.5% w/v) were found to inhibit first
probing for an average of 8 and 9.3 min, respectively.
[0104] The distribution of landing density by female A. aegypti on
membranes treated with dihydronepetalactones was analyzed over
time, as shown graphically in FIG. 6. Dihydronepetalactone at 5%
concentration was found to almost eliminate mosquito landings for
20 minutes, while DEET (1% w/v) permitted 2 mosquitoes to land in
this experiment. Again, lower concentrations of
dihydronepetalactone (1% and 2.5% w/v) were found to exhibit
repellency (as compared to the untreated control), but at lower
levels than the positive control (DEET at 1% w/v).
[0105] The total number of landings permitted on each membrane
during the course of the experiments were determined, and the
results are summarized in Table 4.
5TABLE 4 Number of Landings Permitted According to Repellency
Concentration Repellent Concentration Mean Number of Landings
Isopropyl alcohol (untreated 58.99 control) 1% DEET (positive
control) 4.66 1% DHN 14 2.5% DHN 6.33 5% DHN 0.33
[0106] Again, the data shows that at all concentrations tested
dihydronepetalactone was repellent, although significantly
increased repellency with respect to 1% DEET was observed only at
5% (w/v).
[0107] Cumulatively, this data show that at all three
concentrations tested, treatment with dihydronepetalactone
significantly reduced probing of the membranes over the course of
the experiment (20 min) as compared to the isopropyl alcohol
treatment. At concentrations of 2.5% and 5.0%,
dihydronepetalactones had effectiveness as a repellent of
mosquitoes for the entire observation period. There was also a
direct relationship between dihydronepetalactone concentration and
the time elapsed for the first mosquito to land and begin probing
the membrane. Overall, the data indicates that the mixture of
dihydronepetalactones employed in these experiments was an
effective repellent, although repellency equivalent to DEET was
observed only with higher concentrations.
Example 4
Preparation of Dihydronepetalactones from Trans,
Cis-Nepetalactone
[0108] It has been shown that trans,cis-nepetalactone (4aS, 7S,
7aS- or E,Z-nepetalactone), is more effective than either the
cis,trans-(Z,E-) nepetalactone or unfractionated catmint essential
oil in repelling the german cockroach (Peterson, C. J. et al.
(2002) Household and Structural Insects, 95 (2), 377-380).
Accordingly, we determined to purify trans,cis-nepetalactone for
hydrogenation to the corresponding dihydronepetalactones and
repellency testing of these derivatives. A number of plants were
grown from seed of the catmint Nepeta racemosa (Chiltern Seeds,
Cumbria, UK). Leaf pairs plucked from individual plants were
immersed in ethyl acetate and after 2 h the solvent was removed and
the extracts analyzed by gas chromatography. Plants producing
preponderantly trans,cis-nepetalactone in their oils were thus
identified (Clark, L. J., et al. (1997) The Plant Journal,
11:1387-1393), and grown to maturity. Leaf material from these
plants was harvested, freeze-dried, extracted into ethyl acetate,
and the extracts concentrated. Nepetalactone was purified from the
concentrated extract by silica gel chromatography in hexane/ethyl
acetate (9:1) followed by preparative thin-layer chromatography on
silica using the same solvent mixture. After removal of the solvent
and re-dissolving in hexane, the trans,cis-nepetalactone was
crystallized on dry ice. GC-MS and NMR (.sup.1H and .sup.13C)
analysis confirmed the identity of the crystalline material as
trans,cis-nepetalactone. The .sup.13C chemical shifts, compared to
the chemical shifts of Table 1, are shown in Table 5.
6TABLE 5 .sup.13C chemical shifts of the nepetalactone sample
prepared in Example 4, compared to the chemical shifts of trans,
cis-nepetalactone (from Table 1) trans, cis- nepetalactone Sample
Atom .delta. (ppm) .delta. (ppm) a 170.1 170.3 b 135.9 136.0 c
120.4 120.5 d 37.3 37.5 e 49.1 49.3 f 32.1 32.2 g 30.0 30.1 h 26.1
26.3 j 17.5 17.7 i 14.2 14.4
[0109] Hydrogenation of the trans,cis-nepetalactone thus prepared
was carried out in ethanol using ESCAT#142 catalyst (Englehart) at
50.degree. C. for 4 h. GC-MS and NMR (.sup.1H and .sup.13C)
confirmed that the trans,cis-nepetalactone had been quantitatively
converted to the corresponding dihydronepetalactone stereoisomers,
with one in significant excess. NMR analysis of the major
diastereomer: .sup.1H NMR (500 MHz, CDCl.sub.3): d 0.97 (d, 3H,
J=6.28 Hz), 0.98 (d, 3H, J=6.94 Hz) 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 13.2 Hz), 2.51
(m, 1H), 3.78 (tr, 1H, J=11.1 Hz), 4.33 (dd, 1H, J=5.73 and 11.32
Hz); .sup.13C (500 MHz, CDCl.sub.3): d 15.43, 18.09, 27.95, 30.81,
31.58, 35.70, 42.51, 51.40, 76.18, 172.03. The .sup.13C NMR
spectrum indicated that this major diastereomer constituted ca.
93.7% of the preparation. Based on the observed couplings for the
methylene to the lactone oxygen, the stereogenic methine carbon
bearing methyl group, the methyl group itself and the bridgehead
methine, it is concluded that the diastereomer is most likely the
(1S,9S,5R,6R)-5,9-dimethyl-3-oxabicyclo[4- .3.0]nonan-2-one) of
Formula 4. 16
[0110] The magnitude of the observed couplings are consistent with
dihedral angles between the protons on vicinal carbon atoms in the
above structure according to the Karplus equation (ref.
Spectrophotometric Identification of Organic Compounds, 4th.
edition, Robert M. Silverstein, G. Clayton Bassler and Terence C.
Morill, 1981, page 208-210).
Example 5
Repellency Testing of Dihydronepetalactones Prepared by
Hydrogenation of Trans,Cis-Nepetalactone
[0111] The dihydronepetalactone prepared according to Example 4,
consisting predominantly of 1
S,9S,5R,6R-5,9-dimethyl-3-oxabicyclo[4.3.0]- nonan-2-one; Formula
4, was tested for repellency against Aedes aegypti mosquitoes
essentially as described in Example 3. The experimental design is
summarized in Table 6, and all data presented is from five
replicate experiments.
7TABLE 6 Experimental Design Applied for Repellency Testing Purpose
Compound Concentration Untreated Control Isopropyl alcohol 100%
Positive Control Isopropyl alcohol with DEET 1.0% (w/v)
Experimental Samples Isopropyl alcohol with 1.0% (w/v)
Dihydronepetalactone 0.5% (w/v) 0.2% (w/v)
[0112] Table 7 presents the effect of dihydronepetalactone
concentration with respect to the amount of time taken before the
female A. aegyptii mosquitoes first probed each membrane.
8TABLE 7 Effect of Dihydronepetalactone Concentraton on Mean Time
to "First Probing" Repellent Concentration Mean Time (min)
Isopropyl alcohol (untreated control) 8.0 1% DEET (positive
control) 14.8 1% DHN 16.0 0.5% DHN 10.4 0.2% DHN 8.4
[0113] Dihydronepetalactone at 1% concentration was found to
discourage mosquito "first probing" for approximately 16 min,
marginally better than (but statistically indistinguishable from)
DEET at the same concentration, where mean time to first probe was
14.8 min. Lower concentrations of dihydronepetalactone (0.5% and
0.2% w/v) were found to inhibit first probing for an average of
10.4 and 8.4 min, respectively.
[0114] The distribution of landing density by female A. aegypti on
membranes treated with dihydronepetalactones was analyzed over
time, as shown graphically in FIG. 7. Dihydronepetalactone at 1.0%
concentration was found to completely eliminate mosquito landings
for 10 minutes, while DEET (1% w/v) permitted mosquitoes to land by
8 min. Again, lower concentrations of dihydronepetalactone (0.5%
and 0.2% w/v) were found to exhibit repellency (as compared to the
untreated control), but at lower levels than the positive control
(DEET at 1% (w/v)).
[0115] The total number of landings permitted on each membrane
during the course of the experiments were determined, and the
results are summarized in Table 8.
9TABLE 8 Number of Landings Permitted According to Repellent and
Concentration During 2 minute Observation Periods Repellent
Concentration Mean Number of Landings Isopropyl alcohol (untreated
18.17 control) 1% DEET (positive control) 4.8 1% DHN 4.0 0.5% DHN
16.2 0.2% DHN 23.2
[0116] Again, this data indicates that 1% dihydronepetalactone
exhibited equivalent repellent activity to 1% DEET.
[0117] Cumulatively, this data show that at all three
concentrations tested, treatment with dihydronepetalactone
significantly reduced probing of the membranes over the course of
the experiment (20 min) as compared to the isopropyl alcohol
treatment. At all concentrations tested, dihydronepetalactones had
effectiveness as a repellent of mosquitoes for the entire
observation period. There was also a direct relationship between
dihydronepetalactone concentration and the time elapsed for the
first mosquito to land and begin probing the membrane. Overall, the
data indicate that the dihydronepetalactones derived from
hydrogenation of trans,cis-nepetalactone are an effective
repellent, and equivalent to DEET in efficacy in these tests.
* * * * *