LUTTE CONTRE LES ARTHROPODES CHEZ LES RONGEURS

CONTROL OF ARTHROPODS IN RODENTS

Abrégé français

Cette invention concerne une méthode de contrôle des ectoparasites de petits rongeurs, et sert donc à prévenir la transmission des maladies par les arthropodes vecteurs.

Abrégé anglais

The present invention provides a method for controlling ectoparasites of small rodents, thereby preventing the transmission of diseases by arthropod vectors.

Revendications

CLAIMS:
1. A system for controlling ectoparasites of small
rodents in an outdoor environment comprising one or more
enclosures of appropriate size for small rodents adapted for
placement outdoors in a locus at which said rodents are
expected, said enclosures having one or more peripheral
openings allowing entry and egress of rodents therein, each
of said enclosures including at least one applicator
arranged to contact rodents that enter said enclosure, and
providing a composition consisting essentially of an
ectoparasiticide and inactive ingredients on said
applicator; said applicator being arranged and said
composition being provided to apply an ectoparasiticidally
effective amount of the composition to the skin or hair of
said rodents upon contact with said applicator, wherein the
applicator is inaccessible to contact with a human hand from
said one or more peripheral openings, and further wherein
the ectoparasiticide is a compound of formula (XX):
<IMG>
wherein:
R201 is cyano, C(O) alkyl, C(S)NH2, alkyl, C(=NOH)NH2
or C (=NNH2)NH2 ;
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R202 is S(O)h R203, C2-C3 alkenyl, C2-C3 haloalkenyl,
cycloalkyl, halocycloalkyl or C2-C3 alkynyl;
R203 is alkyl or haloalkyl;
R204 is -N (R205)C(O)CR206R207R208, -N(R205)C(O)aryl, or
-N(R205)C(0)OR207;
R205 is alkyl, haloalkyl, cycloalkyl,
halocycloalkyl, cycloalkylalkyl, halocycloalkylalkyl,
alkoxyalkyl, haloalkoxyalkyl, C3-C5 alkenyl, C3-C5
haloalkenyl, C3-C5 alkynyl, or C3-C5 haloalkynyl;
R206 is alkoxy, haloalkoxy, alkoxyalkyl,
haloalkoxyalkyl, formyloxy, alkylcarbonyloxy,
haloalkylcarbonyloxy, alkylthio, haloalkylthio,
alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,
haloalkylsulfonyl, alkylamino, dialkylamino, haloalkylamino,
di(haloalkyl)amino, cycloalkyloxy, halocycloalkyloxy,
alkoxyalkoxy, haloalkoxyalkoxy, alkoxyalkoxyalkoxy, aryloxy,
or arylalkoxy;
R207 and R208 are independently hydrogen, alkyl,
haloalkyl, cycloalkyl, or halocycloalkyl;
X1 is selected from nitrogen and C-R212;
R211 and R212 are independently selected from
halogen, hydrogen, CN and NO2;
R213 is selected from halogen, haloalkyl,
haloalkoxy, -S(O)k CF3, and -SF5; and
h and k are independently selected from 0, 1,
and 2;
or veterinarily acceptable salts thereof;
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said ectoparasiticide being present in said composition in
an amount of from 0.1% to 5% by weight and present in said
one or more enclosures in an amount of from 0.001 gram
to 2.0 grams per enclosure.
2. The system of claim 1 for controlling arthropod
ectoparasites.
3. The system of claim 1 or 2 for controlling
ectoparasites of rodents selected from mouse, rat, vole,
chipmunk and squirrel.
4. The system according to any one of claims 1 to 3
wherein the ectoparasites are ticks of the genus Ixodes.
5. The system of any one of claims 1 to 4, wherein
said composition is hydrophobic.
6. The system of any one of claims 1 to 5, wherein
the amount of ectoparasiticide is from 0.100 gram per
enclosure to 2.0 grams per enclosure.
7. The system according to any one of claims 1 to 6
wherein the percent by weight of the ectoparasiticide in the
composition is from 0.25% to 1%.
8. The system according to any one of claims 1 to 7
wherein the one or more enclosures further comprise a
foodstuff for the rodent.
9. The system according to any one of claims 1 to 8
wherein from one to ten enclosures are placed per hectare of
said outdoor environment.
10. The system according to any one of claims 1 to 9
wherein each enclosure defines a passageway through which a
rodent is attracted to proceed.
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11. The system according to claim 10 wherein the
applicator is disposed in the passageway.
12. The system according to any one of claims 1 to 11
wherein the applicator is disposed adjacent to or near one
of the one or more peripheral openings.
13. The system according to any one of claims 1 to 12
wherein the applicator is rechargeable from the outside of
the enclosure without necessity to open the enclosure.
14. The system according to any one of claims 1 to 13
wherein the applicator is replaceable.
15. The system according to any one of claims 1 to 14
wherein the applicator is a small mop head or a brush.
16. A system for preventing the transmission of
diseases by arthropod vectors comprising one or more
enclosures of appropriate size for small rodents adapted for
placement outdoors in a locus at which said rodents are
expected, said enclosures having one or more peripheral
openings allowing entry and egress of rodents therein, said
enclosure including at least one applicator arranged to
contact rodents that enter said enclosure, and a composition
consisting essentially of an ectoparasiticide having the
formula
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<IMG>
also known as 3-cyano-l-(2,6-dichloro-4-trifluoromethyl)
phenyl-5-N-(ethoxyacetyl)-N-methyl-4-
trifluoromethylsulfinylpyrazole, and inactive ingredients,
on said applicator; said applicator being arranged and said
composition being provided to apply an ectoparasiticidally
effective amount of ectoparasiticide to the skin or hair of
said rodents upon contact with said applicator, and wherein
said applicator is inaccessible to a human hand from said
one or more peripheral openings.
17. The system according to claim 16, wherein the
percent by weight of the ectoparasiticide in the composition
is from 0.4% to 0.9%.
18. A system for controlling ectoparasites of small
rodents comprising one or more enclosures of appropriate
size for small rodents adapted for placement outdoors at a
transition zone between a woodland and a property where
humans dwell, said enclosures having one or more peripheral
openings allowing entry and egress of rodents therein, each
of said enclosures comprising at least one applicator
arranged to contact rodents that enter said enclosure, and a
composition consisting essentially of an ectoparasiticide
and inactive ingredients on said applicator; said applicator
being arranged and said composition being provided to apply
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an ectoparasiticidally effective amount of the composition
to the skin or hair of said rodents upon contact with said
applicator, wherein said applicator is inaccessible to
contact with a human hand from said one or more peripheral
openings and further wherein said ectoparasiticide is a
compound of formula (XX):
<IMG>
wherein:
R201 is cyano, C(O)alkyl, C(S)NH2, alkyl, C(=NOH)NH2
or C(=NNH2)NH2;
R202 is S(O)h R203, C2-C3 alkenyl, C2-C3 haloalkenyl,
cycloalkyl, halocycloalkyl or C2-C3 alkynyl;
R203 is alkyl or haloalkyl;
R204 is -N(R205)C(O)CR206R207R208, -N(R205)C(O)aryl , or
-N(R205)C(0)OR207;
R205 is alkyl, haloalkyl, cycloalkyl,
halocycloalkyl, cycloalkylalkyl, halocycloalkylalkyl,
alkoxyalkyl, haloalkoxyalkyl, C3-C5 alkenyl, C3-C5
haloalkenyl, C3-C5 alkynyl, or C3-C5 haloalkynyl;
R206 is alkoxy, haloalkoxy, alkoxyalkyl,
haloalkoxyalkyl, formyloxy, alkylcarbonyloxy,
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haloalkylcarbonyloxy, alkylthio, haloalkylthio,
alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,
haloalkylsulfonyl, alkylamino, dialkylamino, haloalkylamino,
di(haloalkyl)amino, cycloalkyloxy, halocycloalkyloxy,
alkoxyalkoxy, haloalkoxyalkoxy, alkoxyalkoxyalkoxy, aryloxy,
or arylalkoxy;
R207 and R208 are independently hydrogen, alkyl,
haloalkyl, cycloalkyl, or halocycloalkyl;
X1 is selected from nitrogen and C-R212;
R211 and R212 are independently selected from
halogen, hydrogen, CN and NO2;
R213 is selected from halogen, haloalkyl,
haloalkoxy, -S(O)k CF3, and -SF5; and
h and k are independently selected from 0, 1,
and 2;
or veterinarily acceptable salts thereof;
said ectoparasiticide being present in said composition in
an amount of from 0.1% to 5% by weight and present in said
one or more enclosures in an amount of from 0.001 gram
to 2.0 grams per enclosure.
19. The system according to claim 18, wherein two or
more of said enclosures are used and the enclosures are
spaced apart from one another at a distance of from 10
to 50 feet.
20. The system according to claim 18 or 19, wherein
two or more of said enclosures are used and the enclosures
are spaced apart from one another at a distance of from 20
to 40 feet.
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21. The system according to any one of claims 18
to 20, wherein said transition zone contains from 1 to 50
enclosures per hectare.
22. The system according to any one of claims 18
to 21, wherein said enclosures are replaced, or the
ectoparasiticide within said enclosures is replenished, from
once to three times per year.
23. A system for controlling ectoparasites of small
rodents comprising one or more enclosures of appropriate
size to said rodents adapted for outdoor environment in an
area to be treated, said enclosures having one or more
peripheral openings allowing entry and egress of rodents
therein, each of said enclosures comprising at least one
applicator arranged to contact rodents that enter said
enclosure, and a composition consisting essentially of an
ectoparasiticide and inactive ingredients on said
applicator; said applicator being arranged and said
composition being provided to apply an ectoparasiticidally
effective amount of the composition to the skin or hair of
said rodents upon contact with said applicator, wherein said
applicator is inaccessible to contact with a human hand from
said one or more peripheral openings and further wherein
said ectoparasiticide is a compound of formula (XX):
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<IMG>
wherein:
R20l is cyano, C(O) alkyl , C(S)NH2, alkyl, C(=NOH) NH2
or C(=NNH2)NH2;
R202 is S(O)h R203, C2-C3 alkenyl, C2-C3 haloalkenyl,
cycloalkyl, halocycloalkyl or C2-C3 alkynyl;
R203 is alkyl or haloalkyl;
R204 is -N(R205) C(O)CR206R207R208, -N(R205)C(O) aryl, or
-N(R205)C(0)OR207;
R205 is alkyl, haloalkyl, cycloalkyl,
halocycloalkyl, cycloalkylalkyl, halocycloalkylalkyl,
alkoxyalkyl, haloalkoxyalkyl, C3-C5 alkenyl, C3-C5
haloalkenyl, C3-C5 alkynyl, or C3-C5 haloalkynyl;
R206 is alkoxy, haloalkoxy, alkoxyalkyl,
haloalkoxyalkyl, formyloxy, alkylcarbonyloxy,
haloalkylcarbonyloxy, alkylthio, haloalkylthio,
alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,
haloalkylsulfonyl, alkylamino, dialkylamino, haloalkylamino,
di(haloalkyl)amino, cycloalkyloxy, halocycloalkyloxy,
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alkoxyalkoxy, haloalkoxyalkoxy, alkoxyalkoxyalkoxy, aryloxy,
or arylalkoxy;
R207 and R208 are independently hydrogen, alkyl,
haloalkyl, cycloalkyl, or halocycloalkyl;
X1 is selected from nitrogen and C-R212;
R211 and R212 are independently selected from
halogen, hydrogen, CN and NO2;
R213 is selected from halogen, haloalkyl,
haloalkoxy, -S (O)k CF3, and -SF5; and
h and k are independently selected from 0, 1,
and 2;
or veterinarily acceptable salts thereof;
said ectoparasiticide being present in said composition in
an amount of from 0.1% to 5% by weight and present in said
one or more enclosures in an amount of from 0.001 gram
to 2.0 grams per enclosure.
24. The system according to claim 23, wherein two or
more of said enclosures are used and the enclosures are
spaced apart from one another at a distance of from 10
to 50 feet.
25. The system according to claim 23 or 24, wherein
two or more of said enclosures are used and the enclosures
are spaced apart from one another at a distance of from 20
to 40 feet.
26. The system according to any one of claims 23
to 25, wherein said area to be treated contains from 1 to 50
enclosures per hectare.
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27. The system according to any one of claims 23
to 26, wherein said enclosures are replaced, or the
ectoparasiticide within said enclosures is replenished, from
once to three times per year.
28. The system according to any one of claims 23
to 27, wherein said area to be treated contains from 2 to 40
enclosures per hectare.
29. The system according to any one of claims 23
to 28, wherein said area to be treated contains from 10
to 35 enclosures per hectare.
30. Use, for controlling ectoparasites of small
rodents in an outdoor environment, of a compound of
formula (XX) :
<IMG>
wherein:
R201 is cyano, C(O) alkyl, C(S)NH2, alkyl, C(=NOH)NH2
or C(=NNH2)NH2 ;
R202 is S(O)h R203, C2-C3 alkenyl, C2-C3 haloalkenyl,
cycloalkyl, halocycloalkyl or C2-C3 alkynyl;
R203 is alkyl or haloalkyl;
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R204 is -N(R205)C(O)CR206R207R208, -N(R205)C(0) aryl, or
-N(R205)C(0)OR207;
R205 is alkyl, haloalkyl, cycloalkyl,
halocycloalkyl, cycloalkylalkyl, halocycloalkylalkyl,
alkoxyalkyl, haloalkoxyalkyl, C3-C5 alkenyl, C3-C5
haloalkenyl, C3-C5 alkynyl, or C3-C5 haloalkynyl;
R206 is alkoxy, haloalkoxy, alkoxyalkyl,
haloalkoxyalkyl, formyloxy, alkylcarbonyloxy,
haloalkylcarbonyloxy, alkylthio, haloalkylthio,
alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,
haloalkylsulfonyl, alkylamino, dialkylamino, haloalkylamino,
di(haloalkyl)amino, cycloalkyloxy, halocycloalkyloxy,
alkoxyalkoxy, haloalkoxyalkoxy, alkoxyalkoxyalkoxy, aryloxy,
or arylalkoxy;
R207 and R208 are independently hydrogen, alkyl,
haloalkyl, cycloalkyl, or halocycloalkyl;
X1 is selected from nitrogen and C-R212;
R211 and R212 are independently selected from
halogen, hydrogen, CN and NO2;
R213 is selected from halogen, haloalkyl,
haloalkoxy, -S(O)k CF3, and -SF5; and
h and k are independently selected from 0, 1,
and 2;
or veterinarily acceptable salts thereof, in a
composition also comprising inactive ingredients, in
combination with one or more enclosures of appropriate size
for small rodents and adapted for an outdoor environment,
said compound being present in said composition in an amount
of from 0.1% to 5% by weight and present in said one or more
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enclosures in an amount of from 0.001 gram to 2.0 grams per
enclosure, said enclosures having one or more peripheral
openings allowing entry and egress of rodents therein, each
of said enclosures including at least one applicator
arranged to contact rodents that enter said enclosure; said
applicator being arranged and said composition being
provided on said applicator so as to apply an
ectoparasiticidally effective amount of the composition to
the skin or hair of said rodents upon contact with said
applicator, wherein the applicator is inaccessible to
contact with a human hand from said one or more peripheral
openings.
31. The use of claim 30 for controlling arthropods
ectoparasites.
32. The use of claim 30 or 31 for controlling
ectoparasites of rodents selected from mouse, rat, vole,
chipmunk and squirrel.
33. The use according to any one of claims 30 to 32
wherein the ectoparasites are ticks of the genus ixodes.
34. The use of any one of claims 30 to 33, wherein
said composition is hydrophobic.
35. The use of any one of claims 30 to 34, wherein the
amount of ectoparasiticide is from 0.100 gram per enclosure
to 2.0 grams per enclosure.
36. The use according to any one of claims 30 to 35
wherein the percent by weight of the ectoparasiticide in the
composition is from 0.25% to 1%.
37. The use according to any one of claims 30 to 36
wherein the one or more enclosures further comprise a
foodstuff for the rodent.
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38. The use according to any one of claims 30 to 37
wherein from one to ten enclosures are placed per hectare of
said outdoor environment.
39. The use according to any one of claims 30 to 37,
wherein said outdoor environment contains from 1 to 50
enclosures per hectare.
40. The use according to any one of claims 30 to 39
wherein each enclosure defines a passageway through which a
rodent is attracted to proceed.
41. The use according to claim 40 wherein the
applicator is disposed in the passageway.
42. The use according to any one of claims 30 to 41
wherein the applicator is disposed adjacent to or near one
of the one or more peripheral openings.
43. The use according to any one of claims 30 to 42
wherein the applicator is rechargeable from the outside of
the enclosure without necessity to open the enclosure.
44. The use according to any one of claims 30 to 43
wherein the applicator is replaceable.
45. The use according to any one of claims 30 to 44
wherein the applicator is a small mop head or a brush.
46. The use according to any one of claims 30 to 45,
wherein two or more of said enclosures are used and the
enclosures are spaced apart from one another at a distance
of from 10 to 50 feet.
47. The use according to claim 46, wherein two or more
of said enclosures are used and the enclosures are spaced
apart from one another at a distance of from 20 to 40 feet.
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48. The use according to any one of claims 30 to 37,
wherein said outdoor environment contains from 2 to 40
enclosures per hectare.
49. The use according to any one of claims 30 to 37,
wherein said outdoor environment contains from 10 to 35
enclosures per hectare.
50. The use according to any one of claims 30 to 49,
wherein said enclosures are replaced, or the ectoparasiticide
within said enclosures is replenished, from once to three
times per year.
51. Use, for preventing the transmission of diseases
by arthropod vectors, of an ectoparasiticide having the
formula
<IMG>
also known as 3-cyano-l-(2,6-dichloro-4-trifluoromethyl)
phenyl-5-N-(ethoxyacetyl)-N-methyl-4-
trifluoromethylsulfinylpyrazole, in a composition also
comprising an inactive ingredient in combination with one or
more enclosures of appropriate size for small rodents, said
enclosures having one or more peripheral openings allowing
entry and egress of rodents therein, said enclosure
including at least one applicator arranged to contact
rodents that enter said enclosure; said applicator being
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arranged and said composition being provided on said
applicator so as to apply an ectoparasiticidally effective
amount of ectoparasiticide to the skin or hair of said
rodents upon contact with said applicator, and wherein said
applicator is inaccessible to a human hand from said one or
more peripheral openings.
52. The use according to claim 51, wherein the percent
by weight of the ectoparasiticide in the composition is
from 0.4% to 0.9%.
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Description

CA 02311881 2004-01-23
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CONTROL OF ARTHROPODS IN RODENTS
FIELD OF THE INVENTION
The present invention relates to a method of
controlling ectoparasitic vectors of diseases, particularly
bacterial or viral diseases.
BACKGROUND OF THE INVENTION
Lyme disease was first recognized in the United
States in 1975, after a mysterious outbreak of arthritis
near Lyme, Connecticut. Since then, reports of Lyme disease
have increased dramatically, and the disease has become an
important public
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health problem in some areas of the United States. Lyme disease is an
infection caused
by Borrelia burgdorferi, a member of the family of spirochetes, or corkscrew-
shaped
bacteria.
Lyme disease is spread by the bite of ticks of the genus Ixodes that are
infected with Borrelia burgdorferi. The deer (or bear) tick, Ixodes
scapularis, which
normally feeds on the white-footed mouse, the white-tailed deer, other
mammals, and
birds, is responsible for transmitting Lyme disease bacteria to humans in the
northeastern
a.nd north-central United States. In these regions, this tick is also
responsible for the
spreading of babesiosis, a disease caused by a malaria-like parasite. On the
Pacific Coast,
the bacteria are transmitted to humans by the westem black-legged tick, I.
pacificus.
Another newly recognized and serious disease that is transmitted by both I.
scapularis
and I. pa.cif cus is human granulocytic ehrlichiosis, the pathogen of which is
a rickettsial
bacterium.
Ixodes ticks are much smaller than common dog and cattle ticks. In their
larval and nymphal stages, they are no bigger than a pinhead. Adult ticks are
slightly
larger. Ticks can attach to any part of the human body but often attach to the
more
hidden and hairy areas such as the groin, armpits, and scalp. Research in the
eastern
United States has indicated that, for the most part, ticks transmit Lyme
disease to humans
during the nymphal stage, probably because nymphs are more likely to feed on a
person
and are rarely noticed because of their small size (less than two mm). Thus,
the nymphs
typically have ample time to feed and transmit the infection since ticks are
most likely to
transmit infection after approximately two or more days of feeding.
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Tick larvae are smaller than the nymphs, but they rarely carry the infection
at the time of feeding and are probably not important in the transmission of
Ly'me disease
to humans.
Adult ticks can transmit the disease, but since they are larger and more
likely to be removed from a person's body within a few hours, they are less
likely than
the nymphs to have sufficient time to transmit the infection. Moreover, adult
Ixodes ticks
are most active during the cooler months of the year, when outdoor activity is
limited.
Adults quest for hosts on grasses, shrubs and brush at heights of up to one
meter.
Immature Ixodes search for host animals from the tips of grasses and shrubs
(not from
trees) and leaf litter near the ground and transfer to animals or persons that
brush against
these substrates. Ticks only crawl; they do not fly or jump. Ticks found on
the scalp
usually have crawled there from lower parts of the body. Ticks feed on blood
by
inserting their mouth parts (not their whole bodies) into the skin of a host
animal. They
are slow feeders: a complete blood meal can take several days. As they feed,
their bodies
slowly enlarge.
Although in theory Lyme disease could spread through blood transfusions
or other contact with infected blood or urine, no such transmission has been
documented.
There is no evidence that a person can get Lyme disease from the air, food or
water, from
sexual contact, or directly from wild or domestic animals. There is no
convincing
evidence that Lyme disease can be transmitted by insects such as mosquitoes,
flies, or
fleas. Campers, hikers, outdoor workers, and others who frequent wooded,
brushy, and
grassy places are commonly exposed to ticks, and this may be important in the
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transmission of Lyme disease in some areas. Because new homes are often built
in
wooded areas, transmission of Lyme disease near homes has become an important
problem in some areas of the United States. The risk of exposure to ticks is
greatest in
the woods and garden fringe areas of properties, but ticks may also be carried
by animals
into lawns and gardens.
Geographic distribution of Lyme disease is wide in northern temperate
regions of the world. In the United States, the highest incidence occurs in
the Northeast,
from Massachusetts to Maryland. Incidence is also notable in the North-central
states,
especially Wisconsin and Minnesota, and the West Coast, particularly northem
California. For Lyme disease to exist in an area, at least three closely
interrelated
elements must be present in nature: the Lyme disease bacteria, ticks that can
transmit
them, and mammals (such as mice and deer) to provide food for the ticks in
their various
life stages. Ticks that transmit Lyme disease can be found in temperate
regions that may
have periods of very low or high temperature and a constant high relative
humidity at
ground level. Knowing the complex life cycle of the ticks that transmit Lyme
disease is
important in understanding the risk of acquiring the disease and in fmding
ways to
prevent it: The life cycle of these ticks requires two years to complete.
Adult ticks feed
and mate on large animals, especially deer, in the fall and early spring.
Female ticks then
drop off these animals to lay eggs on the ground. By summer, eggs hatch into
larvae.
Larvae feed on mice and other small mammals and birds in the summer and early
fall and
then are inactive until the next spring when they molt into nymphs. Nymphs
feed on
small rodents and other small mammals and birds in the late spring and summer
and molt
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into adults in the fall, completing the 2-year life cycle. Larvae and nymphs
typically
become infected with Lyme disease bacteria when they feed on infected small
animals,
particularly the white-footed mouse. The bacteria remain in the tick as it
changes from
larva to nymph or from nymph to adult. Infected nymphs and adult ticks then
bite and
transmit Lyme disease bacteria to other small rodents, other animals, and
humans, all in
the course of their normal feeding behavior. Lyme disease in domestic animals
Domestic
animals may become infected with Lyme disease bacteria and some of these
(dogs, for
instance) may develop arthritis. Domestic animals can carry infected ticks
into areas
where humans live, but whether pet owners are more likely than others to get
Lyme
disease is unknown.
There are proposed solutions to the prevention of transmission of tick-
borne parasites to humans. For exarnple, United States Patents 5,648,398,
5,346,922,
and 5,227,406 describe insect repellent compositions which are claimed to
repel ticks.
However, the use a repellent does not eliminate the vector itself but serves
as a
"chemical shield" against the ticks so that they will have to find another
mammalian host.
There are generally no lmown solutions to arrest the spread of Lyme disease
and/or other
diseases spread by ticks.
SLTMMARY OF THE INVENTION
An object of the present invention is to provide a method of controlling
ticks in non-domestic mammals.
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Another object of present invention is to provide
a method of preventing the transmission of diseases by
arthropod vectors.
These and other objects are met in whole or in
part by the present invention.
According to one aspect of the present invention,
there is provided a system for controlling ectoparasites of
small rodents in an outdoor environment comprising one or
more enclosures of appropriate size for small rodents
adapted for placement outdoors in a locus at which said
rodents are expected, said enclosures having one or more
peripheral openings allowing entry and egress of rodents
therein, each of said enclosures including at least one
applicator arranged to contact rodents that enter said
enclosure, and providing a composition consisting
essentially of an ectoparasiticide and inactive ingredients
on said applicator; said applicator being arranged and said
composition being provided to apply an ectoparasiticidally
effective amount of the composition to the skin or hair of
said rodents upon contact with said applicator, wherein the
applicator is inaccessible to contact with a human hand from
said one or more peripheral openings, and further wherein
the ectoparasiticide is a compound of formula (XX):
R202 R201
~ \N
R204 N"
R211
X1
R213
(XX)
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wherein:
R201 is cyano, C(O) alkyl, C(S) NHZ, alkyl, C(=NOH) NH2
or C (=NNH2) NHZ;
R202 is S(0) hR203r CZ-C3 alkenyl, C2-C3 haloalkenyl,
cycloalkyl, halocycloalkyl or CZ-C3 alkynyl;
R203 is alkyl or haloalkyl;
R204 is -N (R205) C (0) CR206R207R208, -N (R205) C(0) aryl, or
-N (R205) C (0) OR207;
R205 is alkyl, haloalkyl, cycloalkyl,
halocycloalkyl, cycloalkylalkyl, halocycloalkylalkyl,
alkoxyalkyl, haloalkoxyalkyl, C3-C5 alkenyl, C3-C5
haloalkenyl, C3-C5 alkynyl, or C3-C5 haloalkynyl;
R206 is alkoxy, haloalkoxy, alkoxyalkyl,
haloalkoxyalkyl, formyloxy, alkylcarbonyloxy,
haloalkylcarbonyloxy, alkylthio, haloalkylthio,
alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,
haloalkylsulfonyl, alkylamino, dialkylamino, haloalkylamino,
di(haloalkyl)amino, cycloalkyloxy, halocycloalkyloxy,
alkoxyalkoxy, haloalkoxyalkoxy, alkoxyalkoxyalkoxy, aryloxy,
or arylalkoxy;
R207 and R208 are independently hydrogen, alkyl,
haloalkyl, cycloalkyl, or halocycloalkyl;
X1 is selected from nitrogen and C-R212;
R211 and R212 are independently selected from
halogen, hydrogen, CN and NO2;
R213 is selected from halogen, haloalkyl,
haloalkoxy, -S (0) kCF3r and -SF5; and
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h and k are independently selected from 0, 1,
and 2;
or veterinarily acceptable salts thereof.
According to another aspect of the present
invention, there is provided a system for preventing the
transmission of diseases by arthropod vectors comprising one
or more enclosures of appropriate size for small rodents
adapted for placement outdoors in a locus at which said
rodents are expected, said enclosures having one or more
peripheral openings allowing entry and egress of rodents
therein, said enclosure including at least one applicator
arranged to contact rodents that enter said enclosure, and a
composition consisting essentially of an ectoparasiticide
having the formula
0
0 CF3-S CN
I ~ \
CH3CH2-O-CH2-C-N N"~ N
CH3 CI CI
IC
CF3
also known as 3-cyano-l-(2,6-dichloro-4-trifluoromethyl)
phenyl-5-N-(ethoxyacetyl)-N-methyl-4-
trifluoromethylsulfinylpyrazole, and inactive ingredients,
on said applicator; said applicator being arranged and said
composition being provided to apply an ectoparasiticidally
effective amount of ectoparasiticide to the skin or hair of
said rodents upon contact with said applicator, and wherein
- 6b -

_. _ ,....
,~...,... .~,........~...W,~..
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said applicator is inaccessible to a human hand from said
one or more peripheral openings.
According to still another aspect of the present
invention, there is provided the system as described herein,
wherein the percent by weight of the ectoparasiticide in the
composition is from 0.4% to 0.9%.
According to yet another aspect of the present
invention, there is provided a system for controlling
ectoparasites of small rodents comprising one or more
enclosures of appropriate size to said rodents adapted for
outdoor environment in an area to be treated, said
enclosures having one or more peripheral openings allowing
entry and egress of rodents therein, each of said enclosures
comprising at least one applicator arranged to contact
rodents that enter said enclosure, and a composition
consisting essentially of an ectoparasiticide and inactive
ingredients on said applicator; said applicator being
arranged and said composition being provided to apply an
ectoparasiticidally effective amount of the composition to
the skin or hair of said rodents upon contact with said
applicator, wherein said applicator is inaccessible to
contact with a human hand from said one or more peripheral
openings and further wherein said ectoparasiticide is a
compound of formula (XX):
R202 R201
R204 IV~
R211 Xl
R213
(XX)
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wherein:
R201 is cyano, C(O)alkyl, C(S)NH2, alkyl, C(=NOH) NH2
or C (=NNH2) NH2;
R202 is S(0) hR203r C2-C3 alkenyl, C2-C3 haloalkenyl,
cycloalkyl, halocycloalkyl or C2-C3 alkynyl;
R203 is alkyl or haloalkyl;
R204 is -N (R205) C(O) CR2o6R207R208, -N (R205) C(0) aryl, or
-N (R205) C (0) OR207;
R205 is alkyl, haloalkyl, cycloalkyl,
halocycloalkyl, cycloalkylalkyl, halocycloalkylalkyl,
alkoxyalkyl, haloalkoxyalkyl, C3-C5 alkenyl, C3-C5
haloalkenyl, C3-C5 alkynyl, or C3-C5 haloalkynyl;
R206 is alkoxy, haloalkoxy, alkoxyalkyl,
haloalkoxyalkyl, formyloxy, alkylcarbonyloxy,
haloalkylcarbonyloxy, alkylthio, haloalkylthio,
alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,
haloalkylsulfonyl, alkylamino, dialkylamino, haloalkylamino,
di(haloalkyl)amino, cycloalkyloxy, halocycloalkyloxy,
alkoxyalkoxy, haloalkoxyalkoxy, alkoxyalkoxyalkoxy, aryloxy,
or arylalkoxy;
R207 and R208 are independently hydrogen, alkyl,
haloalkyl, cycloalkyl, or halocycloalkyl;
X1 is selected from nitrogen and C-R212;
R211 and R212 are independently selected from
halogen, hydrogen, CN and N02;
R213 is selected from halogen, haloalkyl,
haloalkoxy, -S (O) kCF3r and -SF5; and
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h and k are independently selected from 0, 1,
and 2;
or veterinarily acceptable salts thereof;
said ectoparasiticide being present in said composition in
an amount of from 0.1% to 5% by weight and present in said
one or more enclosures in an amount of from 0.001 gram
to 2.0 grams per enclosure.
According to a further aspect of the present
invention, there is provided use, for controlling
ectoparasites of small rodents in an outdoor environment, of
a compound of formula (XX):
R202 R201
R204 \N
N"'
R211
X1
R213
(XX)
wherein:
R201 is cyano, C(O)alkyl, C(S)NH2, alkyl, C(=NOH) NH2
or C (=NNH2) NH2;
R202 is S(0) hR203r C2-C3 alkenyl, CZ-C3 haloalkenyl,
cycloalkyl, halocycloalkyl or C2-C3 alkynyl;
R203 is alkyl or haloalkyl;
R204 is -N (R205) C(0) CR206R207R208. -N (R205) C(0) aryl, or
-N (R205) C (0) 0R207;
- 6e -

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R205 is alkyl, haloalkyl, cycloalkyl,
halocycloalkyl, cycloalkylalkyl, halocycloalkylalkyl,
alkoxyalkyl, haloalkoxyalkyl, C3-C5 alkenyl, C3-C5
haloalkenyl, C3-C5 alkynyl, or C3-C5 haloalkynyl;
R206 is alkoxy, haloalkoxy, alkoxyalkyl,
haloalkoxyalkyl, formyloxy, alkylcarbonyloxy,
haloalkylcarbonyloxy, alkylthio, haloalkylthio,
alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,
haloalkylsulfonyl, alkylamino, dialkylamino, haloalkylamino,
di(haloalkyl)amino, cycloalkyloxy, halocycloalkyloxy,
alkoxyalkoxy, haloalkoxyalkoxy, alkoxyalkoxyalkoxy, aryloxy,
or arylalkoxy;
R207 and R208 are independently hydrogen, alkyl,
haloalkyl, cycloalkyl, or halocycloalkyl;
X1 is selected from nitrogen and C-R212;
R211 and R212 are independently selected from
halogen, hydrogen, CN and NOZ;
R213 is selected from halogen, haloalkyl,
haloalkoxy, -S (0) kCF3r and -SF5; and
h and k are independently selected from 0, 1,
and 2;
or veterinarily acceptable salts thereof, in a
composition also comprising inactive ingredients, in
combination with one or more enclosures of appropriate size
for small rodents and adapted for an outdoor environment,
said enclosures having one or more peripheral openings
allowing entry and egress of rodents therein, each of said
enclosures including at least one applicator arranged to
contact rodents that enter said enclosure; said applicator
being arranged and said composition being provided on said
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applicator so as to apply an ectoparasiticidally effective
amount of the composition to the skin or hair of said
rodents upon contact with said applicator, wherein the
applicator is inaccessible to contact with a human hand from
said one or more peripheral openings.
According to yet a further aspect of the present
invention, there is provided use, for preventing the
transmission of diseases by arthropod vectors, of an
ectoparasiticide having the formula
0
I
0 CF3-S CN
I
CH3CH2-O-CH2-C-N \
/ N
I
CH3 Ci Ci
CF3
also known as 3-cyano-l-(2,6-dichloro-4-trifluoromethyl)
phenyl-5-N-(ethoxyacetyl)-N-methyl-4-
trifluoromethylsulfinylpyrazole, in a composition also
comprising an inactive ingredient in combination with one or
more enclosures of appropriate size for small rodents, said
enclosures having one or more peripheral openings allowing
entry and egress of rodents therein, said enclosure
including at least one applicator arranged to contact
rodents that enter said enclosure; said applicator being
arranged and said composition being provided on said
applicator so as to apply an ectoparasiticidally effective
amount of ectoparasiticide to the skin or hair of said
rodents upon contact with said applicator, and wherein said
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applicator is inaccessible to a human hand from said one or
more peripheral openings.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method of
controlling ectoparasites of small rodents comprising
providing one or more enclosures of appropriate size to such
rodents, the enclosures having one or more peripheral
openings allowing entry and egress of rodents, the enclosure
including at least one applicator arranged to contact a
rodent; providing a composition comprising an
ectoparasiticide on the applicator; and placing one or more
enclosures in a locus where the rodents are expected,
wherein the applicator is arranged and the composition is
provided to apply an effective amount of the composition to
the skin or hair of the rodent upon contact with the
applicator.
The method of the present invention is useful for
the control of arthropods that are vectors of diseases such
as Lyme disease, Rocky Mountain Spotted Fever, Ehrlichiosis
or Babesiosis. In particular, the present invention is
useful for control of ticks of the genus Ixodes, including
1. scapularis, I. pacificus, I spinipalpis, Dermacentor
variabilis and D. andersoni. The present invention is
effective in arresting the transmission of an infective
agent such as Borrelia burgdorferi from the treated rodent
to another mammal such as a deer, mouse, chipmunk or human.
In a preferred embodiment
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the treated rodent is a mouse (e.g., Peromyscus spp.) especially the white-
footed mouse,
P. leocopus, rat (e.g., Rattus spp. or Neotoma spp.), chipmunk (e.g., Tamias
spp.), vole
(e.g., Microtus spp.) or squirrel (e.g., Sciurus spp., Tamiasciurus spp. or
Spermophilus
spp)-
Ectoparasiticides are irnown to those of ordinary skill in the art and are
commercially available. A preferred ectoparasiticide according to the present
invention is
a compound of formula (I):
R2 Ri
~ \N
Rd N
R" X
R13
(I)
wherein:
R, is cyano, acetyl, C(S)NH2, alkyl, haloalkyl, C(=NOH)NHZ or
C(=NNHz)NHZ;
R2 is S(O) rk R~; C2-C3 alkenyl, C:-C3haloalkenyl, cycloalkyl,
halocycloalkyl or C2-C3 alkynyl;
R3 is alkyl or haloalkyl;
R4 is -N= C(RS)-R6, N=C(Rs)-(R,)-Rg, or -N(R.9)-C(R5)=NRs;
RS is hydrogen; alkyl; or alkyl substituted by halogen, alkoxy, haloalkoxy
or -S(O)mRts;
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R~ and R, each independently represent hydrogen, alkyl, C3-C5 alkenyl or
C3-C5 alkynyl; or
alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino,
alkylamino, dialkylamino, cyano or -S(O),õR15; or alkyl substituted by phenyl
or pyridyl
each of which is optionally substituted with one or more groups selected from
halogen,
nitro and alkyl; or
R4 and R7 may form together with the nitrogen to which they are attached
a 3 to 7 membered ring which may additionally contain one or more heteroatoms
selected
from oxygen, nitrogen or sulfur;
Rg is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, RI,CO- or
-S(O),Rio;
R), R,o and Rõ are alkyl or haloalkyl;
Rõ and R12 are independently selected from halogen, hydrogen, CN and
NOZ;
R13 is selected from halogen, haloallcyl, haloalkoxy, -S(O)qCF3i and -SF5;
RS5 is alkyl or haloalkyl;
X is selected from nitrogen and C-R12;
Z is 0, S(O)a; or NR,;
a, m, n and q are independently selected from 0, 1, and 2; and
t is 0 or 2; and veterinarily acceptable salts thereof.
Another preferred ectoparasiticide according to the present invention is a
compound of formula (XX):
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R
pau
0.ii XI
(XX)
wherein:
R201 is cyano, C(O)alkyl, C(S)NH2i allcyl, C(=NOH)NH2 or
C(=NNH2)NHZ;
R202 is S(O)hR203, C2-C3 alkenyl, C2-C3 haloalkenyl, cycloalkyl,
halocycloalkyl or C2-C3 alkynyl;
R203 is alkyl or haloalkyl;
R204 is -N(R20s)C(O)CR206R2o7R2oa, -N(R2os)C(O)aryl, or
-N(R20s)C(O)OR207;
R205 is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl,
halocycloalkylalkyl, alkoxyalkyl, haloalkoxyalkyl, C3-C5 alkenyl, C3-C5
haloalkenyl,
C3-CS alkynyl, C3-CS haloalkynyl;
R-2a,s is hydrogen, halogen, alkoxy, haloalkoxy, alkoxyalkyl,
haloalkoxyalkyl, formyloxy, alkylcarbonyloxy, haloalkylcarbonyloxy, alkylthio,
haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,
haloalkylsulfonyl,
alkylarnino, dialkylamino, haloalkylamino, di(haloalkyl)arnino, cycloalkyloxy,
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halocycloalkyloxy, alkoxyalkoxy, haloalkoxyalkoxy, alkoxyalkoxyalkoxy,
aryloxy, or
arylalkoxy;
R20, and R208 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, or
halocycloalkyl; or R207 and R20s may form together with the carbon. to which
they are
attached a 3 to 7 membered ring which additionally may contain one or more
heteroatoms
selected from nitrogen, oxygen and sulfur;
X, is selected from nitrogen and C-%,,;
R21, and RZIZ are independently selected from halogen, hydrogen, CN and
NO2;
R213 is selected from halogen, haloalkyl, haloalkoxy, -S(O)kCF3, and -SFS;
and
h and k are independently selected from 0, 1, and 2;
and veterinarily acceptable salts thereof.
By the term "veterinarily acceptable salts" is meant salts the anions of
which are known and accepted in the art for the formation of salts for
veterinary use.
Suitable acid addition salts, e.g. formed by compounds of formulae (I) and
(XX)
containing a basic nitrogen atom, e.g. an amino group, include salts with
inorganic acids,
for example hydrochlorides, sulphates, phosphates and nitrates and salts with
organic
acids for example acetic acid.
Unless otherwise specified, alkyl and alkoxy groups are generally lower
alkyl and alkoxy groups, that is having from one to six carbon atoms,
preferably from one
to four carbon atoms. Generally, the haloalkyl, haloalkoxy and alkylamino
groups have
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from one to four carbon atoms. The haloalkyl and haloalkoxy groups can bear
one or
more halogen atoms; preferred groups of this type include -CF3 and -OCF3.
Cycloalkyl
groups generally have from 3 to 6 carbon atoms, preferably from 3 to 5 carbon
atoms and
may be substituted by one or more halogen atoms. Alkenyl, haloalkenyl,
al.kynyl, and
haloalkynyl groups generally contain from 3 to 5 carbon atoms. By the term
aryl is
generally meant phenyl, pyridyl, furyl, and thiopheneyl, each of which is
optionally
substituted by one or more halogen, alkyl, haloalkyl, nitro, alkoxy,
haloalkoxy, hydroxy,
amino, alkylamino or dialkylamino. In compounds of formula (I), by the term
substituted
alkyl is meant alkyl which is substituted by one or more halogen, alkoxy,
haloalkoxy,
amino, alkylamino, dialkylamino, cyano or -S(O),,R15; or alkyl substituted by
phenyl or
pyridyl each of which is optionally substituted with one or more groups
selected from
halogen, nitro and alkyl; wherein R15 is alkyl or haloalkyl and m is zero, one
or two.
Preferably in compounds of formula (1), alkyl groups are generally substituted
by from
one to five halogen atoms, preferably from one to three halogen atoms.
Chlorine and
fluorine atoms are preferred.
Compounds of fonnula (I) wherein Ra is -N=C(R,)-Z-R6i Z is NR, and R6
represents a hydrogen atom may exist as the tautomeric double bond isomer form
-NH-C(RS)=N-R,. It is to be understood that both such forms are embraced by
the present
invention.
In compounds of formula (XX) the following examples of radicals are
provided:
An example of cycloalkylalkyl is cyclopropyhnethyl;
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an example of cycloalkoxy is cyclopropyloxy;
an example of alkoxyalkyl is CH3OCH2-;
an example of alkoxyalkoxy is CH3OCH2O-;
An example of alkoxyalkoxyalkoxy is CH30CH2OCH2O-;
An example of aryloxy is the phenoxy radical; and
An example of the arylalkoxy radical is ben2yloxy or 2-phenylethoxy.
Generally, in dialkylamino or di(haloalkyl) amino radicals, the alkyl and
haloalkyl groups on nitrogen may be chosen independently of one another.
It is also to be understood that enantiomeric and diastereomeric forms of
the compounds of formulae (I) and (XX) and salts thereof are embraced by the
present
invention. Compounds of formula (I) may be generally prepared according to
known
processes, for example as described in European Patent Application 511845 or
other
processes according to the knowledge of a man skilled in the art of chemical
synthesis.
A preferred class of compounds of formula (I) for use in the control of
parasites in animals are those wherein:
R, is cyano or alkyl;
R2 is S(O)nR3;
R3 is alkyl or haloalkyl;
R,, is -N=C(R5)-Z-R,,;
R5 is hydrogen, alkyl or haloalkyl;
Z is 0, S(O)a; or NR7;
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R~ and R, are independently selected from hydrogen and unsubstituted or
substituted alkyl; or
R6 and R., may form together with the nitrogen to which they are attached
a 3 to 7 membered ring which may additionally contain one or more heteroatoms
selected
from oxygen, nitrogen or sulfur; X is selected from nitrogen and C-R12;
R, L and R12 are independently selected from halogen, hydrogen, CN and
NO2;
R13 is selected from halogen, haloalkyl, haloalkoxy, -S(O)qCF3, and -SFS;
a, n and q are independently selected from 0, 1, and 2.
Preferably R( , is alkyl which is substituted by one or more halogen, alkoxy,
haloalkoxy, amino, alkylamino, dialkylamino, sulfide, sulfoxide, sulfone, or
phenyl or
pyridyl moieties of which each phenyl or pyridyl moiety is optionally
substituted with
one or more groups selected from halo, nitro, and alkyl.
Preferably the compound useful in the method of the invention has one or
more of the following features:
R, is cyano;
R, is -N=C(RS)-Z-R6 and Z is -NR7;
X is C-R12i R11 and R12 represent a chlorine atom; and R13 is CF3, OCF3 or
-SFs;
R12 is -S(O)õCF3 and n is 0, 1, or 2.
A further preferred class of compounds of forinula (I) for use in the
method of the present invention are those wherein:
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R, is cyano or alkyl; Rs is -N=C(R5)-Z-RG; and R5 is hydrogen or C1-C3
alkyl.
The compounds of formula (I), preferably have one or more of the
following features:
R, is cyano or methyl;
R3 is halomethyl (preferably CF3);
Rõ and R12 each independently represent a halogen atom;
X is C-R12;
R13 is haloalkyl (preferably CF3), haloalkoxy (preferably OCF3), or -SFs;
or
n is 0, 1 or 2(preferably 0 or 1).
A further preferred class of compounds of formula (I) for use in the control
of parasites in animals are those wherein:
Rlis cyano;
R2 is S(O)nR,;
R3 is halomethyl;
R4 is -N=C(R5)-Z-R.6;
ZisNR,;
RS is hydrogen or alkyl;
R6 and R7 each independently represent hydrogen, alkyl, alkenyl or
alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy,
amino,
alkylamino, dialkylamino, cyano or -S(O)mR15i or alkyl substituted by phenyl
or pyridyl
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which rings are optionally substituted with one or more groups selected from
halogen,
nitro and alkyl;
X is selected from nitrogen and C-R12;
Rl l and R12 each independently represent a halogen atom;
R13 is selected from haloalkyl, haloalkoxy and -SFS;
Rt5 is alkyl or haloallcyl; and
m and n are independently selected from 0, 1, and 2.
A further preferred class of compounds of formula (I) is that wherein:
R, is cyano;
R2 is S(O),,CF3;
R4 is -N=C(RS)-Z-R6 or -N=C(R$)-N(R+Ra;
Z is NR7;
R5 is hydrogen or alkyl;
R6 and R7 each independently represent hydrogen, all.yl, alkenyl or
alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy,
amino)
alkylamino, dialkylamino, cyano or -S(O)mRL5; or methyl substituted by phenyl
or
pyridyl which rings are optionally substituted with one or more groups
selected from
halogen, nitro and alkyl;
R8 is alkoxy, haloalkoxy, arnino, alkylamino, dialkylamino or -S(O)tRta;
X is selected from nitrogen and C-R12;
Rio and R15 independently represent alkyl or haloalkyl;
Rõ and R12 each represent a chlorine atom;
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R13 is CF3 or -SFS; and
mandnare0, 1 or2;andtis0or2.
A further preferred class of compounds of formula (I) are those wherein:
R, is cyano;
R2is S(O),CF3;
R4 is -N=C(R5)-Z R6;
ZisNR7i
R5 is hydrogen or methyl;
Rf, and R, each independently represent hydrogen, alkyl, alkenyl or
alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy,
arnino,
alkylamino, dialkylamino, cyano or -S(O)mRis; or alkyl substituted by phenyl
or pyridyl
which rings are optionally substituted with one or more groups selected from
halogen,
nitro and alkyl;
X is C-R12;
Rõ and R, 2 each represent a chlorine atom;
Rt3 is CF3 or -SF5;
R1S is alkyl or haloalkyl;
m is zero, one or two; and
nis0or1.
A further preferred class of compounds of formula (I) are those wherein:
R, is cyano;
R2 is S(O)õCF3;
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R4 is -N=C(RS)-Z-R6;
ZisNR7;
RS and R7 each represent a hydrogen atom;
R6 is alkyl or haloalkyl;
X is C-R12;
Rll and R12each represent a chlorine atom;
R13 is CF3 or -SF5; and
n is 0.
Compounds of formula (XX) which are preferred according to the present
invention are those wherein:
R201 is cyano;
R202 is S(O)hR203;
RZ,õ is alkyl or haloalkyl;
RZOy is - N(R2os)C(0)CR20tRZO7Ra0s;
R2()5 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl and
halocycloalkylalkyl;
R206 is alkoxy, haloalkoxy, or hydrogen;
R207 and R208 are independently hydrogen, alkyl, or haloalkyl; or
R207 and R2,)$ may form together with the carbon to which they are attached
a 3 to 7 membered ring which additionally may contain one or more heteroatoms
selected
from nitrogen, oxygen and sulfur;
X, is selected from nitrogen and C-R2tz;
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R2t i and R,1z are independently selected from halogen, hydrogen, CN and
NO2;
R213 is selected from halogen, haloalkyl, haloalkoxy, -S(O)kCF3, and -SF5;
and
h and k are independently selected from 0, 1, and 2.
A preferred group of compounds of fornzula (XX) is that wherein the ring
which is formed by R207 and R248 is interrupted by one or more heteroatoms,
more
preferably one oxygen atom.
The compounds of formula (XX) of the present invention preferably have
one or more of the following features:
RZ(,, is cyano;
R203 is halomethyl, preferably CF3;
Rm and R212 are independently halogen;
X, is C-R212;
R213 is haloalkyl, haloalkoxy or -SF5; or
h is 0 or 1, or 2, preferably 0 or 1.
A preferred class of compounds that wherein R204 is
N(R205) C(0)CR2o6R2a7R2o8.
Another preferred class of compounds that wherein R204 is
N(R205)C(O)aryl.
Another preferred class of compounds that wherein R204 is
N(R205)C(O)OR207.
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Preferably R2as is C1-C4 alkyl, more preferably C,-C2 alkyl, most
preferably methyl.
Preferably R206is alkoxy, most preferably methoxy, ethoxy or propoxy.
Preferably R207 and R2D8 are both hydrogen.
In another aspect of the present invention, compounds of formula (XX)
wherein R204 is -N(R205)C(O)CR206It207R208, N(R205)C(O)aryl, or
N(R205)C(O)OR207 are generally prepared from compounds of formula (XXI):
R2o2 R2n1
R2os\ N
H N
R2l1
X1
~
R213
(XXI)
respectively by reaction with halides of formulae X2C(O)CR206R207R208,
X2C(O)aryl,
or X2C(O)OIZ207, wherein R201, R202, R205, R206, R207, R208, R211, R213, and
X1
are defined above and wherein X2 is a halogen atom. The reaction is generally
carried
out in the presence of a base, generally using from I to 10 molar equivalents
of the
halide, and is preferably conducted in the presence of an organic solvent such
as
tetrahydrofuran, methylene chloride, at a temperature of from 0 C to 150 C.
Compounds of formula (XXI) may be prepared from a compound of formula (XXII):
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:R201
N N
R2I 1
I x`I
R213
(XXII)
by reaction with a compound of formula (XXIII):
X2R205 (XXIII)
wherein R201, R202, R205, R21 1, R213, Xl and X2 are defined above. Compounds
of
formula (XXIII) are generally known in the art as alkylhalides or substituted
alkylhalides.
Compounds of formula XXII may be prepared by methods described in
International
Patent Publications WO 87/3781, WO 93/6089, WO 94/21606, WO 97/07102, WO
98/24767, , WO 98/28277, WO 98/28278 and WO 98/28279, European Patent
Application 295117, 659745, 846686, and United States Patent 5232940 or other
methods known to the person skilled in the art.
Alternatively compounds of fonnula (XXI) may be prepared by reduction
of compounds of formula (XXIV):
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R202 R201
H ~t5N
alkylO N R2i i
Xi
R213
(XXIV)
wherein R201, R202, R211, R213 and Xl are defined above. The reduction
generally is
effected by the use of a standard hydride ion donor, for example sodium
borohydride or
sodium cyanoborohydride. The reaction is generally effected in an polar
solvent such as
ethanol or methanol and generally using from 1 to 10 rnolar equivalents of the
hydride,
and is preferably conducted at ternperature of from -100 C to 150 C.
Compounds of formula (X)GV) may be prepared using methods described
in EP 295117, WO 97/22593 or other methods known to those skilled in the art.
A particularly preferred compound for use in the method of the present
invention is 3-cyano-l-(2,6-dichloro-4-trifluoromethyl )phenyl-5-N-
(ethoxyacetyl)-N-
methyl-4 trifluoromethylsulfinyl-pyrazole.
Most preferably, the following compowlds of formula (I) and (XX) are
preferred according to the present invention as listed in Tables 1 to 13. The
Compound
Numbers are for identification purposes only. The following symbols are hereby
defined:
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Me means methyl; Et means ethyl; n-Pr means n-propyl; i-Pr means isopropyl; n-
Bu
means n-Butyl, and n-Pent means n-Pentyl; Cy means cyclopropyl.
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Ta le1
Compounds of formula (I) wherein R, is cyano; R2 is SCF3; Rl, is Cl, X is
C-Cl, Rj is -N=C(RS)ZR6, Z is NR7, R7 is H, and R13 is CF3 or SFS.
Compound Compound
Number Number R;
(R13=CF3) (R13=SFs)
201-1 201-2 Me Me
202-1 202-2 Me Et
203-1 203-2 Me n-Pr
204-1 204-2 Me i-Pr
205-1 205-2 Me n-Bu
206-1 206-2 H H
207-1 207-2 H Et
208-1 208-2 H n-Pr
209-1 209-2 H i-Pr
210-1 210-2 H n-Bu
211-1 211-2 H CH2CF3
212-1 212-2 H (CH2)2CF3
213-1 213-2 H CHZOMe
214-1 214-2 H (CH2)20CF3
215-1 215-2 Me CH2CF3
216-1 216-2 Me (CH2)2CF2217-1 217-2 Me (CH2)2OMe
218-1 218-2 Me (CH2)2NMe2
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Table 2
Compounds of formula (I) wherein R, is cyano; Rl, is Cl; R4 is
-N-C(R5)ZR6 and Z is NR7.
Cmp R2 RS Rh R7 X R13
d No.
219 SCF3 H CH3 CH3 C-Cl CF3
220 SO2CF3 H CH3 CH3 C-Cl CF3
221 SCF3 H CH2CN H C-Cl CF3
222 SCF3 H CH3 H C-Cl CF3
223 SOCF3 H CH2Ph H C-Cl CF3
224 SCF3 H CH2Ph H C-Cl CF3
225 SOCF3 H CH3 H C-Cl CF3
226 SOCF3 H CH3 H C-Cl CF3
227 SOCF3 H CH2CF3 H C-Cl CF3
228 SO2CF3 H 2-propynyl H C-Cl CF3
229 SO2CF3 H CH2Ph H C-Cl CF3
230 SOZCF3 H CH2CF3 H C-Cl CF3
231 SOCF3 H CH3 H C-Cl CF3
232 SCF3 H CH2CF3 CH3 C-Cl CF3
233 SCF3 H CH2CF3 H C-Cl CF3
234 SCF3 H 2-propynyl H C-Cl CF3
235 SCF3 H 2-propynyl H C-Cl CF3
236 SOCF3 H 2-propynyl H C-Cl CF3
237 SCF3 H CH2OEt H N CF3
238 SCF3 H CH2OCH2CF3 CH3 C-Cl CF3
L239 SO2CF3 H CH2CF3 CH3 C-Cl SFS
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Cmp R2 RS R6 R7 X R13
d No.
240 SCF3 H CHZCF, H N SFS
241 SOCF3 H CH2CH2CF3 C-Cl CF3
242 SOZCF3 H (CH2)3CH3 C-Cl CF3
243 SCF3 H (CH2)2N(CH3)Z C-Cl CF3
244 SO2CF3 CH3 CHZ(4-C1 Ph) C-Cl CF3
245 SCF3 H CH2SO2CF3 C-Cl CF3
246 SCF3 H CH2(4-pyridyl) C-Cl CF3
247 SCF3 H CH2(3-NO2 Ph) C-Cl CF3
248 SCF3 H CH2CH2SCH3 C-Cl CF3
249 SOCF3 H CH2CF3 CH3 C-Cl CF3
Note: Compound number 232 is the acetate salt, and compound number 233
is the citrate salt.
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Table 3
Compounds of formula (I) wherein R, is cyano; Rõ is Cl; and R4 is
-N=C(Rs)-N(R,)-Rg.
Cmp Rz R5 Ra R, ~ R13
d No.
250 SCF3 H OEt H C-Cl CF3
251 SCF3 H NHCH3 H C-Cl CF3
252 SCF3 H NHCH3 CH3 C-Cl CF3
253 SCF1 H OCH2CF3 H C-Cl CF3
254 SCF3 H N(CH3)2 H N SF5
255 SCF3 H NH2 H C-Cl CF3
256 SCF3 H S-nPr H C-Cl CF3
257 SOzCF, Et S-nPr H C-Cl SF5
258 SCF3 H SO2CH3 H C-Cl CF3
The following compounds of formula (XX) are preferred according to the
present invention as listed in Tables 4-12.
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Table 4
Compounds of formula (XX) wherein R20, is cyano; R202 is SCF3i R204 is
N(R20S)C(O)CR206R2D7R208; R20, and R208=H; R21 is Cl, Xi is C-Cl, and R213 is
CF3 or SFs.
Compound Compound
Number Number R205 R206
(P-213=CF3) (R213=SF3)
1-1 1-2 Me H
2-1 2-2 Me OMe
3-1 3-2 Me OEt
4-1 4-2 Me 0-i-Pr
5-1 5-2 Me 0-n-Bu
6-1 6-2 Et H
7-1 7-2 Et OMe
8-1 8-2 Et OEt
9-1 9-2 Et 0-i-Pr
10-1 10-2 Et 0-n-Bu
11-1 11-2 n-Pr H
12-1 12-2 n-Pr OMe
13-1 13-2 n-Pr OEt
14-1 14-2 n-Pr 0-i-Pr
15-1 15-2 n-Pr 0-n-Bu
16-1 16-2 i-Pr H
17-1 17-2 i-Pr OMe
18-1 18-2 i-Pr OEt
19-1 19-2 i-Pr 0-i-Pr
20-1 20-2 i-Pr 0-n-Bu
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Compound Compound
Number Number R205 R206
(R213=CF3) (R213=SF5)
21-1 21-2 n-Bu H
22-1 22-2 n-Bu OMe
23-1 23-2 n-Bu OEt
24-1 24-2 n-Bu 0-i-Pr
25-1 25-2 n-Bu 0-n-Bu
26-1 26-2 CH2Cy H
27-1 27-2 CHzCy OMe
28-1 28-2 CH2Cy OEt
29-1 29-2 CH2Cy 0-i-Pr
30-1 30-2 CH2Cy 0-n-Bu
31-1 31-2 CH2CCH H
32-1 32-2 CH2CCH OMe
33-1 33-2 CH2CCH OEt
34-1 34-2 CH2CCH 0-i-Pr
35-1 35-2 CH2CCH 0-n-Bu
36-1 36-2 Me OAc
37-1 37-2 Me CH2OMe
38-1 38-2 Me CH2OEt
39-1 39-2 Me 0-i-Pr
40-1 40-2 Me 0-n-Bu
41-1 41-2 Me OCH2CF3
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Table 5
Compounds of formula (XX) wherein R201 is cyano; R20 . is S(O)CF3; R:04
is N(R205)C(O)CR206R.2o7R2ox; R207 and RZOg=H; Riõ is Cl, Xi is C-Cl, and R213
is CF3 or
SFS.
Compound Compound
Number Number R205 R206
(+`213=CF3) (R21]=SFs)
1-3 1-4 Me H
2-3 2-4 Me OMe
3-3 3-4 Me OEt
4-3 4-4 Me 0-i-Pr
5-3 5-4 Me 0-n-Bu
6-3 6-4 Et H
7-3 7-4 Et OMe
8-3 8-4 Et OEt
9-3 9-4 Et 0-i-Pr
10-3 10-4 Et 0-n-Bu
11-3 11-4 n-Pr H
12-3 12-4 n-Pr OMe
13-3 13-4 n-Pr OEt
14-3 14-4 n-Pr 0-i-Pr
15-3 15-4 n-Pr 0-n-Bu
16-3 16-4 i-Pr H
17-3 17-4 i-Pr OMe
18-3 18-4 i-Pr OEt
19-3 19-4 i-Pr 0-i-Pr
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Compound Compound
Number Number R205 R206
(Rz13 CF3) (R213=SF5)
20-3 20-4 i-Pr O-n-Bu
21-3 21-4 n-Bu H
22-3 22-4 n-Bu OMe
23-3 23-4 n-Bu OEt
24-3 24-4 n-Bu 0-i-Pr
25-3 25-4 n-Bu 0-n-Bu
26-3 26-4 CH2Cy H
27-3 27-4 CH2Cy OMe
28-3 28-4 CH2Cy OEt
29-3 29-4 CH2Cy 0-i-Pr
30-3 30-4 CH2Cy 0-n-Bu
31-3 31-4 CH2CCH H
32-3 32-4 CH2CCH OMe
33-3 33-4 CH2CCH OEt
34-3 34-4 CH2CCH 0-i-Pr
35-3 35-4 CH2CCH 0-n-Bu
36-3 36-4 Me OAc
37-3 37-4 Me CH2OMe
3 8-3 38-4 Me CH2OEt
39-3 39-4 Me 0-i-Pr
40-3 40-4 Me O-n-Bu
41-3 41-4 Me OCH2CF3
Compound 3-3 was separated into its enantiomers (R)3-3 and (S)3-3.
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Table 6
Compounds of formula (XX) wherein R2pI is cyano; R201 is S(0)2CF3; R204
is N(R205)C(O)CR? 06R2o7R2o8; R207 and R208-H; R211 is Cl, X, is C-Cl, and
R213 is CF3 or
SFS.
Compound Compound
Number Number R205 R2oa
(R213=CF3) (R213-SF5)
1-5 1-6 Me H
2-5 2-6 Me OMe
3-5 3-6 Me OEt
4-5 4-6 Me 0-i-Pr
5-5 5-6 Me 0-n-Bu
6-5 6-6 Et H
7-5 7-6 Et OMe
8-5 8-6 Et OEt
9-5 9-6 Et 0-i-Pr
10-5 10-6 Et 0-n-Bu
11-5 11-6 n-Pr H
12-5 12-6 n-Pr OMe
13-5 13-6 n-Pr OEt
14-5 14-6 n-Pr 0-i-Pr
15-5 15-6 n-Pr 0-n-Bu
16-5 16-6 i-Pr H
17-5 17-6 i-Pr OMe
18-5 18-6 i-Pr OEt
19-5 19-6 i-Pr 0-i-Pr
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Compound Compound
Number Number R205 R206
(R213=CF3) (RZ13-SF5)
20-5 20-6 i-Pr 0-n-Bu
21-5 21-6 n-Bu H
22-5 22-6 n-Bu OMe
23-5 23-6 n-Bu OEt
24-5 24-6 n-Bu 0-i-Pr
25-5 25-6 n-Bu O-n-Bu
26-5 26-6 CH2Cy H
27-5 27-6 CH2Cy OMe
28-5 28-6 CH2Cy OBt
29-5 29-6 CH2Cy O-i-Pr
30-5 30-6 CHzCy 0-n-Bu
31-5 31-6 CH2CCH H
32-5 32-6 CH2CCH OMe
33-5 33-6 CH2CCH OEt
34-5 34-6 CH2CCH 0-i-Pr
35-5 35-6 CH2CCH 0-n-Bu
36-5 36-6 Me OAc
37-5 37-6 Me CHZOMe
38-5 38-6 Me CHZOEt
39-5 39-6 Me 0-i-Pr
40-5 40-6 Me O-n-Bu
41-5 41-6 Me OCHZCF3
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Table 7
Compounds of formula (XX) wherein R2al is cyano; R202 is SCF3; R20, is
N(R205)C(O)CR206R201R208i R2,1 is Cl, X, is C-Cl, and RZ13 is CF3 or SFg.
Compound Compound
Number Number R205 R206 R2o7, Rzoe
(R213=CF3) (R213=SF5)
1-7 1-8 Me H -CH2CH2CH2O-
2-7 2-8 Et H -CHZCH.CH2O-
3-7 3-8 i-Pr H -CH2CHZCH2O-
4-7 4-8 Pr H -CH2CH2CH2O-
5-7 5-8 Bu H -CH2CHZCH2O-
6-7 6-8 Cy H -CH2CH2CH2O-
7-7 7-8 CH2Cy H -CH2CH2CH2O-
Compound 1-7 was also separated into its enantiomers, called (R)1-7 and (S)1-
7.
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Table
Compounds of formula (XX) wherein R201 is cyano; R202 is S(O)CF3; R201
is N(R203)C(O)CR206R2(,7R208; RZ11 is Cl, Xi is C-Cl, and R213 is CF3 or SF5.
Compound Compound
Number Number R205 R206 R207sR208
(R2)3=CF3) (R213=SF5)
1-9 1-10 Me H -CH2CH2CH2O-
2-9 2-10 Et H -CH2CH2CH2O-
3-9 3-10 i-Pr H -CH2CH2CH2O-
4-9 4-10 Pr H -CH2CH2CH2O-
5-9 5-10 Bu H -CH2CH2CH2O-
6-9 6-10 CH2Cy H -CH2CH2CH2O-
7-9 7-10 Cy H L -CH2CH2CH2O-
Compound 1-9 was separated into its diastereomers, (R,R)1-9, (S,R)1-9, (S,S)1-
9, and
(R,S)1-9. The first designation of absolute configuration refers to the
configuration
of the sulfoxide moiety, the second to the chiral carbon.
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Table 9
Compounds of formula (XX) wherein R201 is cyano; R202 is S(O)2CF3; R204
is N(R205)C(O)CR206R2o7R20g; R21 is Cl, X, is C-Cl, and R213 is CF3 or SF5.
I Compound Compound
Number Number R2os R206 R20>> R208
(R213=CF3) (R213=SF5)
1-11 1-12A Me H -CH2CH2CH2O-
2-11 2-12A Et H -CH2CH2CH2O-
3-11 3-12A i-Pr H -CH2CH2CH2O-
4-11 4-12A Pr H -CH2CH2CH2O-
5-11 5-12A Bu H -CH2CH2CHZ0-
6-11 6-12A Cy H -CH2CH2CF420-
7-11 7-12A CH2Cy H -CH2CH2CH2O-
Compound 1-11 was separated into its diastereomers, (R)1-11 and (S)1-11.
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Table 10
Compounds of formula (XX) wherein R20L is cyano; Rjo, is
N(RZOs)C(0)CR206R.207R2oa; R207 and Rioa are H; R211 is Cl, X, is C-Cl, and
R213 is CF3 or
SFS.
Compound Compound
Number Number R2ns R2o6
(R213-CF3) (R213-SF3)
R202=SCF3
1-12 1-13 Cy H
2-12 2-13 Cy OMe
3-12 3-13 Cy OEt
4-12 4-13 Cy 0-i-Pr
5-12 5-13 Cy 0-n-Bu
R202=S(O)CF3
6-12 6-13 Cy H
7-12 7-13 Cy OMe
8-12 8-13 Cy OEt
9-12 9-13 Cy 0-i-Pr
10-12 10-13 Cy 0-n-Bu
R202=S(0)2CF3
11-12 11-13 n-Pr H
12-12 12-13 n-Pr OMe
13-12 13-13 n-Pr OEt
14-12 14-13 n-Pr 0-i-Pr
15-12 15-13 n-Pr 0-n-Bu,
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Table 11
Compounds of formula (XX) wherein R201 is cyano; R204 is
N(R24S)C(O)CRZO,; R211 is Cl, X, is C-Cl, and R213 is CF3 or SF5.
Compound Compound
Number Number R2ps R207
(R213-CF3) ("`213-SF3)
R202 is SCF3
67-1 67-2 Me Me
68-1 68-2 Me Et
69-1 69-2 Me i-Pr
70-1 70-2 Me n-Pr
71-1 71-2 Et Me
72-1 72-2 Et Et
73-1 73-2 Et i-Pr
74-1 74-2 Et n-Pr
75-1 75-2 n-Pr Me
76-1 76-2 n-Pr Et
77-1 77-2 ii-Pr i=Pr
78-1 78-2 n-Pr n-Pr
79-1 79-2 i-Pr Me
80-1 80-2 i-Pr Et
81-1 81-2 i-Pr i-Pr
82-1 82-2 i-Pr n-Pr
R202 is S(O)CF3
83-1 83-2 Me Me
84-1 84-2 Me Et
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Compound Compound
Number Number RzaS Rin7
(P'213-CF3) (R213--SF5)
85-1 85-2 Me i-Pr
86-1 86-2 Me n-Pr
87-1 87-2 Et Me
88-1 88-2 Et Et
89-1 89-2 Et i-Pr
90-1 90-2 Et n-Pr
91-1 91-2 n=Pr Me
92-1 92-2 n-Pr Et
93-1 93-2 n-Pr i-Pr
94-1 94-2 n-Pr n-Pr
95-1 95-2 i-Pr Me
96-1 96-2 i-Pr Et
97-1 97-2 i-Pr i-Pr
98-1 98-2 i-Pr n-Pr
RZOZ is S(O)2CF3
99-1 99-2 Me Me
100-1 100-2 Me Et
101-1 101-2 Me i-Pr
102-1 102-2 Me n-Pr
103-1 103-2 Et Me
104-1 104-2 Et Et
105-1 105-2 Et i-Pr
106-1 106-2 Et n-Pr
107-1 107-2 n-Pr Me
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Compound Compound
Number Number R2U5 R207
(R213'-CF3) (R213-SF5)
108-1 108-2 n-Pr Et
109-1 109-2 n-Pr i-Pr
110-1 110-2 n-Pr n-Pr
111-1 111-2 i-Pr Me
112-1 112-2 i-Pr Et
113-1 113-2 i-Pr i-Pr
114-1 114-2 i-Pr n-Pr
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Table 12
Compounds of formula (XX) wherein R201 is cyano; R202 is S(O)hCF3; R204
is N(R2fls)C(O)CR206RZ0,R2pg; R211 is Cl, X, is C-Cl, and R213 is CF3 or SF5.
Compound Compound h R2os R206 R207 Rzos
Number Number
(R213--CF'3) (R213 5Fs)
115-1 115-2 0 Me H Me Me
116-1 116-2 0 Me OEt H Me
117-1 117-2 0 Me H cyclopropyl
118-1 118-2 0 Me OMe H Me
119-1 119-2 0 Me OEt Me Me
120-1 120-2 2 Me OCH2CH2OMe H H
121-1 121-2 0 Me H -CH2CH2CH2CH2O-
122-1 122-2 1 Me OEt H Me
123-1 123-2 0 Me H H Me
124-1 124-2 0 Me H H Et
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Table 13
Compounds of formula (XX) wherein R20, is cyano; R202 is S(O)hCF3; R204
is N(R205)C(O)aryl; R21 is Cl, X, is C-Cl, R205 is CH3; and R213 is CF3 or
SFS. Within this
table the following symbols are defined:
Ph means phenyl; Fu means furyl
Th means the thiophene radical
Pyr means pyridyl
Compound Compound
Number Number aryl
(R213--CF3) (R2,3=SF5)
R202 is SCF3
125-1 125-2 Ph
126-1 126-2 4-OMe-Ph
127-1 127-2 4-CF3-Ph
128-1 128-2 2-Th
129-1 129-2 3-Th
130-1. 130-2 2-Fu
131-1 131-2 3-Fu
132-1 132-2 2-Pyr
133-1 133-2 3-Pyr
134-1 134-2 4-Pyr
135-1 135-2 6-C1-2-Pyr
136-1 136-2 6-CF3-2-Pyr
137-1 137-2 5-C1-2-Fu
138-1 138-2 5-CF3-2-Fu
139-1 139-2 5-OMe-2-Th
140-1 140-2 5-CF3-2-Th
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Compound Compound
Number Number aryl
tR213--CF3) (R213=SF5)
R201 is S(O)CF3
125-3 125-4 Ph
126-3 126-4 4-OMe-Ph
127-3 127-4 4-CF3-Ph
128-3 128-4 2-Th
129-3 129-4 3-Th
130-3 130-4 2-Fu
131-3 131-4 3-Fu
132-3 132-4 2-Pyr
133-3 133-4 3-Pyr
134-3 134-4 4-Pyr
135-3 135-4 6-C1-2-Pyr
136-3 136-4 6-CF3-2-Pyr
137-3 137-4 5-C1-2-Fu
138-3 138-4 5-CF3-2-Fu
139-3 139-4 5-OMe-2-Th
140-3 140-4 5-CF3-2-Th
R202 is S(O)2CF3
125-5 125-6 Ph
126-5 126-6 4-OMe-Ph
127-5 127-6 4-CF3-Ph
128-5 128-6 2-Th
129-5 129-6 3-Th
130-6 130-6 2-Fu
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Compound Compound
Number Number aryl
(Rz [3=CF3) (R2 i3=SF5)
131-5 131-6 3-Fu
132-5 132-6 2-Pyr
133-5 133-6 3-Pyr
134-5 134-6 4-Pyr
135-5 135-6 6-C1-2-Pyr
136-5 136-6 6-CF3-2-Pyr
137-5 137-6 5-C1-2-Fu
138-5 138-6 5-CF3-2-Fu
139-5 139-6 5-OMe-2-Th
140-5 140-6 5-CF3-2-Th
The composition comprising the ectoparasiticide may further comprise
inactive ingredients such as carriers, diluents, solvents, cosolvents and
crystallization
inhibitors. The ectoparasiticide is present in an amount effective to reduce
larvae,
nymphs or ticks on a small rodent upon topical application. Preferably, the
ectoparasiticide, especially the compound of formula (I) or (XX), is present
in the
composition at a concentration of from 0.1 % to 5%, and preferably from 0.25%
to 1%,
and most preferably from 0.4% to 0.9% (weight/weight).
The composition is preferably substantially hydrophobic. Further, the
composition is long-lasting such that it can be transferred to rodents with
maintenance of
ectoparasiticidal activity for up to three months, preferably six to eight
months after
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placement at the locus, and more preferably for up to ten months, and most
preferably for
up to twelve months after placement at the locus.
In a preferred embodiment, the composition comprises a compound of
formula (I) or (XX), a crystallization inhibitor, an organic solvent, and an
organic
cosolvent. The composition is preferably hydrophobic. The crystallization
inhibitor is
prcferably present at a concentration of 1 to 20% (w/v), and more preferably 5
to 15%
(w/v).
A crystallization inhibitor prevents crystallization of the compound of
formula (1) or (XX) from the composition on the applicator or the hair or skin
of the
rodent. A crystallization inhibitor is defined by a test in which 0.3 ml of a
solution
containing 10% (w/v) of a compound of formula (I) or (XX) in a solvent as
defined
hereinbelow and 10% of the putative inhibitor is placed on a glass slide at 20
C for 24
hours. The presence of less than 10 crystals, a preferably few or no crystals,
by
observation with the naked eye after 24 hours is indicative of an inhibitor as
defined
herein.
Examples of crystallization inhibitors which can be used in the invention
include polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate
and
vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol,
sorbitol,
polyethoxylated sorbitan esters; lecithin, carboxymethylcellulose sodium,
acrylic
derivatives such as methacrylate and others;
anionic surfactants such as alkali metal stearates, especially of
sodium, of potassium or of ammonium; calcium stearate; triethanolamine
stearate,
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sodium abietate; cetylsulphates, especially sodium laurylsulphate and sodium
cetylsulphate; sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate;
fatty
acids, especially those derived from copra oil;
cationic surfactants such as water-soluble quaternary arnrnonium
salts of formula N*R'R"R"'R""Y in which the radicals R', R", R"', and R"" are,
independent of one another, optionally hydroxylated hydrocarbon radicals, and
Y' is an
anion of a strong acid, such as halide, sulphate and sulphonate anions;
including in
particular cetyltrimethylammonium bromide;
the amine salts of formula N"R'R"R"' in which the radicals R', R",
and R"' are, independent of one another, optionally hydroxylated hydrocarbon
radicals;
including in particular octadecylamine hydrochloride;
non-ionic surfactants such as optionally polyethoxylated sorbitan
esters, in particular Polysorbate 80, polyethoxylated alkyl ethers;
polyethylene glycol
stearate, polyethoxylated castor oil derivatives, polyglycerol esters,
polyethoxylated fatty
alcohols, polyethoxylated fatty acids, copolymers of ethylene oxide and
propylene oxide;
and
arnphoteric surfactants such as substituted lauryl betaine
compounds, or preferably a mixture of at least two of these.
Most preferably, a crystallization inhibitor pair will be used, namely the
combination of a surface-active agent and a filmogenic agent. Preferred
filmogenic
agents include different grades of polyvinylpyrrolidone, polyvinyl alcohol,
and
copolymers of vinyl acetate and vinylpyrrolidone. Preferred surface active
agents include
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non-ionic surfact.ants, preferably polyethoxylated esters of sorbitan and
especially the
different grades of poIysorbates, for example Polysorbate 80. The filmogenic
agent and
surface-activc agent may be incorporated in close or identical quantities the
total of which
is within the preferred conceiitration range for the crystallization inhibitor
as described
above.
The organic solvent preferably has a dielectric constant of from 10 to 35,
preferably from 20 and 30. The content of this organic solvent in the total
composition
preferably represents the remainder to 100% of the composition.
The organic cosolvent preferably has a boiling point lower than 100 C,
preferably lower than 80 C, and a dielectric constant of from 10 to 40,
preferably of from
20 to 30. The cosolvent is preferably present in the composition according to
a
weight/weight (w/w) ratio of co-solvent/solvent of from 1/15 to 1/2. The
cosolvent is
volatile in order to promote drying and is miscible with water and/or with the
solvent.
Altliough not preferred, the composition can optionally comprise water,
especially at a
rate from 0 to 30% volume/volume (v/v), preferably from 0 to 5%. The
composition
according to the invention may also comprise an antioxidant agent intended to
inhibit
oxidation in the air, this agent especially being present at a rate of from
0.005 to 1%
(W/V), preferably from 0.01 to 0.05%.
Examples of organic solvents according to the invention include acetone,
acetonitrile, benzyl alcohol, butyl diglycol, dimethyl acetatnide, dimethyl
fonnamide,
dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene
glycol
monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide,
dipropylene
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glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol,
2-pyrrolidone, especially N-methyl- pytrolidone, diethylene glycol monoethyl
ether,
ethylene glycol, diethyl phthalate, or a mixture of at least two of these.
Suitable cosolvents for use in the present compositions include alcohols,
such as absolute ethanol, isopropanol, and methanol. As antioxidant agent,
conventional
agents are especially used, such as butylhydroxyanisole, butyl-hydroxytoluene,
ascorbic
acid, sodium metabisulphite, propyl gallate, sodium thiosulphate, or a mixture
of at least
two of these.
Oils may advantageously be utilized in the compositions of the invention.
For example, heavy oils such as mineral or vegetable including corn, soybean
and peanut
oil, and petroleum fractions such as paraffinic or aromatic hydrocarbons may
be used.
The compositions according to the invention are generally prepared by
simple mixing of the constituents as defined above.
The method of the invention provides to the rodent a dose of
ectoparasiticide which is substantially harmIess to the rodent. Preferably the
amount of
active ingredient applied to the rodent is from 0.001 mg to about 1 mg per
application
within the bait, preferably from 0.01 mg to 0.05 mg. The method of the
invention also
provides a small dose per application such that if an individual rodent visits
the locus
multiple times, the rodent is not harmed.
Such a dose must be able to protect the rodent itself for a period of at least
one month, preferably from I to 3 months, and more preferably from 1 to 9
months. It is
also provided according to the present invention that the rodents are not
repelled from the
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enclosure so that they may be redosed by re-entering the enclosure. There may
be an
attractant associated with the enclosure which is highly attractive to the
rodents in order
to quickly dose many rodents within a predetermined area. A foodstuff may be
associated with the enclosure. Most preferably, there is no poison for the
rodent.
As a matter of an appropriate, safe method of providing such an enclosure
to rodents in the loci which they are inhabiting or expected to inhabit, which
loci are
generally near humans, it is highly preferred that the ectoparasiticide
composition in use
be substantially inaccessible to the human hand. That is the ordinary user of
such an
enclosure would not be able to reach in or on the enclosure and be dosed with
the
ectoparasiticide.
Generally, the enclosure is placed at a transition zone which zone defines
an interface between a woodland and a property where humans dwell. The
enclosures are
spaced one from another from 10 to 50 feet, preferably from 20 to 40 feet.
Generally the
enclosures are placed at the perimeter of the property. If the property is
itself a woodland
per se, there may be a grid of enclosures laid out to dose rodents within the
property. The
interface may be a verge.
Generally, there are from 1 to 50 enclosures placed per hectare within a
defined area to be treated, preferably from 2 to 40, and more preferably from
10 to 35
enclosures per hectare, or from 1 to 10 enclosures per hectare.
In a park or other public facility, enclosures may be spaced along trails
where humans may pass. Generally in such a setting, enclosures may be placed
on one or
both sides of a trail.
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Preferably the enclosures may be placed and replaced on a periodic basis.
In such a way, the method of the present invention provides a batrier to
arthropods which
may carry diseases. Each time the enclosures are replaced or replenished with
the
ectoparasiticide, the barrier is rejuvenated. The enclosures may be replaced
or
replenished from once per year to three times per year, depending on the
population of
rodents in the barrier locus.
In a particularly desirable aspect of the invention, there is provided a
method of interrupting a disease cycle caused by arthropods of small rodents
which
method comprises treating a defined area by providing one or more enclosures
of
appropriate size to such rodents, the enclosures having one or more peripheral
openings
allowing entry and egress of rodents, the enclosure including at least one
applicator
arranged to contact a rodent; providing a composition comprising an
ectoparasiticide on
the applicator; and placing one or more enclosures in a locus where the
rodents are
expected, wherein the applicator is arranged and the composition is provided
to apply an
effective amount of the composition to the skin or hair of the rodent upon
contact with
the applicator.
In this aspect of the invention there is not a general expunging of the
arthropod population away from the defined area, but rather a reduction in the
infectious
agent in that defined area.
The enclosure generally contains from 0.001 g to 2 g of active ingredient
per device preferably from 0.01 g to I g of active ingredient, most preferably
from 0.05 g
to 0.150 g per device.
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In general, in a highly preferred embodiment, the
amount of compound of formula (I) used per hectare is from
0.1 g/ha to 3 g/ha per 6 months of use. More preferably, the
amount of the compound of formula (I) is from 0.2 to 2 g per
hectare per 6 months. In this way, the method of according
to the invention may substantially reduce the number of
rodents with the parasite per predetermined land area.
In a preferred embodiment, the enclosure has at
least one peripheral opening to allow entry and egress of
rodents and an applicator provided with an ectoparasiticide
composition. More preferably, the enclosure further defines
a passageway through which a rodent is attracted to proceed.
As rodents are generally curious and seek out small spaces
in which to lodge themselves or burrow or find food, this is
a highly advantageous way in which to dose the rodents.
In the enclosure, the applicator is generally
disposed in the path of the rodent, that is in the
passageway. In one aspect, the system as described herein
wherein the applicator is disposed adjacent to or near one
of the one or more peripheral openings. The applicator may
be a small mop head, brush, wick, adsorbent panel or strip
attached to the top of the enclosure or may be an insert
lodged in a cavity in an interior wall which defines the
passageway. In one preferred embodiment, the applicator is
arranged to contact the anterior portion of a rodent that
has entered the enclosure. The enclosure may include a bait
located therein and the passageway is preferably arranged
between the opening and the bait. The applicator may be
rechargeable or replaceable, preferably from outside the
enclosure and without opening the enclosure. The
composition may be applied to the applicator in a manner
suitable to the particular applicator, for example, by
soaking or dipping the applicator in the
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composition, or painting, spraying, squirting or otherwise applying the
composition to the
applicator.
The enclosure preferably includes a lower member and an upper member
which are hinged together to form a boxlike enclosure that can be swung open
and closed.
The members are preferably made of plastic, such as injection molded plastic.
A suitable
enclosure is available from Bell Laboratories of Madison,Wisconsin and sold
under the
product name "Proteeta Jr. Bait Station". This enclosure is 6" x 5'/2" and 3"
high, and
has a durable hinge connecting the upper member and the lower member and
includes a
screw lock to secure the enclosure in a closed condition so that children or
larger animals
are not able to open the enclosure and reach the contents thereof.
In a preferred embodiment, the applicator comprising a flexible material is
attached to the upper member with a portion thereof hanging into the enclosure
such that
when a rodent enters and moves through the chamber, the fibrous strands of the
applicator rub across the fur or skin of the rodent and apply a small amount
of the
composition thereon to the skin or fur of the rodent. The flexible material
may be
strands a fibrous material, such as strands of cotton wick.
The following nonlimiting examples serve to further illustrate the present
invention.
Exarngle 1
A Protecta Jr. (Bell Laboratories, Madison, WI) mouse bait box is
modified as follows: a cotton yarn wick is stapled to the underside of the lid
just in front
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of the feeding area entry; two adsorbent nylon strips are affixed to the outer
edges of the
food block trays. Two to three ml. of an oil-based composition comprising 3-
eyano-l-
(2,6-dichloro-4-trifluoromethyl)phenyl-5 -N-(ethoxyacetyl)-N-rnethyl-4-
trifluoromethylsulfinylpyrozole (0.1% to 5.0%, w/w) is applied to the wick and
strip, and
the lid is closed and locked with a set screw.
Five to thirty modified bait boxes are set out per hectare of property where
mice are expected to be. Boxes are rebaited and wicks and strips replenished
at 4 week
intervals from April through August. Rodents entering the boxes come into
contact with
the wicks and/or strips containing the ectoparasiticide resulting in long-term
control of
Arthropods, especially ticks.
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