WO2001095715A2

WO2001095715A2 - Control of arthropods in rodents

Info

Publication number: WO2001095715A2
Application number: PCT/EP2001/007479
Authority: WO
Inventors: Gary O. Maupin; Marc C. Dolan; Patrick Doyle Lowder
Original assignee: Bayer Cropscience S.A.
Priority date: 2000-06-16
Filing date: 2001-06-14
Publication date: 2001-12-20
Also published as: WO2001095715A3; CA2311881A1; CA2311881C; AU2001285791A1

Abstract

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 aplicator 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 whith the applicator.

Description

CONTROL OF ARTHROPODS IN RODENTS

The present invention relates to a method of controlling ectoparasitic

vectors of diseases, particularly bacterial or viral diseases.

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

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 scapular is, 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

and 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 western black-legged tick, I. pacificus.

Another newly recognized and serious disease that is transmitted by both I. scapularis

and I. pacificus 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.

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 Lyme 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

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 northern

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 finding 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

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 example, 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 known solutions to arrest the spread of Lyme disease and/or other

diseases spread by ticks.

An object of the present invention is to provide a method of controlling

ticks in non-domestic mammals. 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.

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 I. 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

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 known 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):

(I)

wherein:

R_j is cyano, acetyl, C(S)NH₂, alkyl, haloalkyl, C(=NOH)NH₂ or

C(=NNH₂)NH₂;

R₂ is S(O) R ; C₂-C₃ alkenyl, C₂-C₃ haloalkenyl, cycloalkyl, halocycloalkyl

or C₂-C₃ alkynyl;

R is alkyl or haloalkyl;

R is hydrogen; alkyl; or alkyl substituted by halogen, alkoxy, haloalkoxy

or -S(O)mR₁₅;

Rg and R₇ 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)_mR_]5; 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

Rg 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;

R_g is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, R_MCO- or

-S(O)_tR₁₀;

Rg, R₁₀ and R₁₄ are alkyl or haloalkyl;

R_u and R₁₂ are independently selected from halogen, hydrogen, CN and

NO₂;

R,₃ is selected from halogen, haloalkyl, haloalkoxy, -S(O)_qCF₃, and -SF₅;

R₁₅ is alkyl or haloalkyl;

X is selected from nitrogen and C-R₁₂;

Z is O, S(O)_a; orNR₇;

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):

wherein:

R₂₀₁ is cyano, C(O)alkyl, C(S)NH₂, alkyl, C(=NOH)NH₂ or

C(=NNH₂)NH₂;

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(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈, -N(R₂₀₅)C(O)aryl, or

-N(R₂₀₅)C(O)OR₂₀₇; R₂₀₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl,

halocycloalkylalkyl, alkoxyalkyl, haloalkoxyalkyl, C₃-C₅ alkenyl, C₃-C₅ haloalkenyl,

C₃-C₅ alkynyl, C₃-C₅ haloalkynyl;

R_20S is hydrogen, halogen, 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; or R₂₀₇ and R₂₀₈ 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-R₂ι₂; R_2U and R_2I2 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;

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

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, alkynyl, 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)_mR_]5; 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 R_l5 is alkyl or haloalkyl and m is zero, one or two.

Preferably in compounds of formula (I), 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 formula (I) wherein R₄ is -N=C(R₅)-Z-R₆, Z is NR₇ and R₆

represents a hydrogen atom may exist as the tautomeric double bond isomer form

-NH-C(R₅)=^::N-R₇. 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 cyclopropylmethyl;

an example of cycloalkoxy is cyclopropyloxy;

an example of alkoxyalkyl is CH₃OCH₂-;

an example of alkoxyalkoxy is CH₃OCH₂O-;

An example of alkoxyalkoxyalkoxy is CH₃OCH₂OCH₂O-;

An example of aryloxy is the phenoxy radical; and

An example of the arylalkoxy radical is benzyloxy 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;

R₄ is -N=C(R₅)-Z-R₆;

R₅ is hydrogen, alkyl or haloalkyl;

Z is O, S(O)_a; or NR₇;

Rj; and R₇ are independently selected from hydrogen and unsubstituted or

substituted alkyl; or

Rg and R₇ may form together with the nitrogen to which they are attached

from oxygen, nitrogen or sulfur; X is selected from nitrogen and C-R,₂;

R_u and R₁₂ are independently selected from halogen, hydrogen, CN and

NO₂;

R₁₃ is selected from halogen, haloalkyl, haloalkoxy, -S(O)_qCF₃. and -SF₅;

a, n and q are independently selected from 0, 1, and 2.

Preferably Rg 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;

R₄ is -N=C(R₅)-Z-R₆ and Z is -NR₇;

X is C-R₁₂; R_u and R₁₂ represent a chlorine atom; and R, ₃ is CF₃, OCF₃ or

-SF₅;

R₁₂ is -S(O)_nCF₃ and n is 0, 1, or 2.

A further preferred class of compounds of formula (I) for use in the

method of the present invention are those wherein:

R_Y is cyano or alkyl; R₄ is -N=C(R₅)-Z-R₆; and R₅ is hydrogen or C,-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);

R_n and R₁₂ each independently represent a halogen atom;

X is C-R₁₂;

R₁₃ is haloalkyl (preferably CF₃), haloalkoxy (preferably OCF₃), or -SF₅;

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:

Rj is cyano;

R₂ is S(O)nR₃; R₃ is halomethyl;

R₄ is -N=C(R₅)-Z-R₆;

Z is NR₇;

R₅ 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)mR₁₅; 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 selected from nitrogen and C-R_I2;

R_u and R₁₂ each independently represent a halogen atom;

R₁₃ is selected from haloalkyl, haloalkoxy and -SF₅;

R₁₅ is alkyl or haloalkyl; 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)_nCF₃;

R₄ is -N=C(R₅)-Z-R₆ or -N=C(R₅)-N(R₇)-R₈;

Z is NR₇;

R₅ is hydrogen or alkyl;

Rg and R₇ each independently represent hydrogen, alkyl, alkenyl or

alkylamino, dialkylamino, cyano or -S(O)_mR,₅; 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, amino, alkylamino, dialkylamino or -S(O),R₁₀;

X is selected from nitrogen and C-R₁₂;

R₁₀ and R₁₅ independently represent alkyl or haloalkyl;

R_π and R_!2 each represent a chlorine atom;

R₁₃ is CF₃ or -SF₅; and

m and n are 0, 1 or 2; and t is 0 or 2.

A further preferred class of compounds of formula (I) are those wherein:

Rj is cyano;

R₂ is S(O)_nCF₃;

R₄ is -N=C(R₅)-Z-R₆;

Z is NR₇;

R₅ is hydrogen or methyl;

Rg and R₇ each independently represent hydrogen, alkyl, alkenyl or

alkylamino, dialkylamino, cyano or -S(O)_mR_IS; or alkyl substituted by phenyl or pyridyl

nitro and alkyl;

X is C-R₁₂;

R_π and R₁₂ each represent a chlorine atom;

R,₃ is CF₃ or -SF₅;

R₁₅ is alkyl or haloalkyl;

m is zero, one or two; and n is 0 or 1.

A further preferred class of compounds of formula (I) are tliose wherein:

R, is cyano;

R₂ is S(O)_nCF₃;

R₄ is -N=C(R₅)-Z-R₆;

Z is NR₇;

R₅ and R₇ each represent a hydrogen atom;

Rg is alkyl or haloalkyl;

X is C-R₁₂;

R_π and R₁₂ each 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:

R₂₀, is cyano;

R₂₀₂ is S(O)_hR₂₀₃;

R₂₀₃ is alkyl or haloalkyl;

R₂₀₄ is - N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈;

R₂₀₅ 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 R₂₀₈ 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;

Xj is selected from nitrogen and C-R₂₁ ;

R₂₁₁ and R₂₁₂ 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 formula (XX) is that wherein the ring

which is formed by R₂₀₇ and R₂₀₈ 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:

R₂₀ι is cyano;

R₂₀₃ is halomethyl, preferably CF3;

R₂₁₁ and R₂₁₂ are independently halogen;

-Λ-_i is -R_2j ;

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(O)CR₂₀₆R₂₀₇R₂₀₈.

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.

Preferably R₂₀₅ is C_rC₄ alkyl, more preferably C,-C₂ alkyl, most

preferably methyl.

Preferably R₂₀₆ is alkoxy, most preferably methoxy, ethoxy or propoxy.

Preferably R₂₀₇ and R_20S are both hydrogen.

In another aspect of the present invention, compounds of formula (XX)

wherein R204 is -N(R205)C(O)CR206R207R208, N(R205)C(O)aryl, or

N(R205)C(O)OR207 are generally prepared from compounds of formula (XXI):

respectively by reaction with halides of formulae X2C(O)CR206R207R208, X2C(O)aryl,

or X2C(O)OR207, wherein R201, R202, R205, R206, R207, R208, R211, R213, and XI

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 1 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):

(XXII)

by reaction with a compound of formula (XXIII):

X2R205(XXIII)

wherein R201, R202, R205, R211, R213, XI 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 formula (XXI) may be prepared by reduction

of compounds of formula (XXIV):

(XXIV)

wherein R201, R202, R211, R213 and XI 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 molar equivalents of the hydride,

and is preferably conducted at temperature of from -100°C to 150°C.

Compounds of formula (XXIV) 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 trifluoromethylsulfiny 1-pyrazole .

Most preferably, the following compounds 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:

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. Table 1

Compounds of formula (I) wherein R\ is cyano; R2 is SCF3; R\ \ X is C-Cl, R4 is -N=C(R₅)ZR₆, Z is NR7, R7 is H, and R₁₃ is r SF5.

Table 2

Compounds of formula (I) wherein R\ is cyano; R\ \ is Cl; R4 is N=C(R5)ZR₆ and Z is NR7.

Note: Compound number 232 is the acetate salt, and compound number 233 is the citrate salt.

Table 3 Compounds of formula (I) wherein R is cyano; R\ \ is Cl; and R4 is -N=C(R₅)-N(R₇)-R₈.

The following compounds of formula (XX) are preferred according to the present invention as listed in Tables 4-12.

Table 4 Compounds of formula (XX) wherein R201 ^1S cyano; R202 is

SCF3; R₂04 is N(R₂05)C(O)CR₂06R207 208; R207 and R₂₀₈ =H; R ι 1 is Cl, Xi is C-Cl, and R2131S CF3 or SF5.

Table 5 Compounds of formula (XX) wherein R20I is cyano; R202 i

S(O)CF₃; R₂04 is N(R₂05)C(O)CR₂06 207 208; 207 and R₂₀8 =H; R₂ιι is Cl, Xi is C-Cl, and R₂B is CF3 or SF5.

Compoun - was separate nto its enantiomers R3-3 and S3-3

Table 6 Compounds of formula (XX) wherein R20I is cyano; R202 i S(O)₂CF₃; R₂04 is N(R₂05)C(O)CR₂06R207R208; R207 and R₂₀8 H; R₂ι 1 is Cl, Xi is C-Cl, and R213 is CF3 or SF5.

Table 7 Compounds of formula (XX) wherein R20I is cyano; R202 i SCF3; R₂04 is N(R₂05)C(O)CR₂06R207 208; R211 is Cl; Xj is C-Cl; andR2i3isCF3orSF5-

Table 8 Compounds of formula (XX) wherein R20I i cyano; R202 is

S(O)CF₃; R₂04 is N(R₂05)C(O)CR₂06R207 208; R21 1 ^{is C1}> ^xl ^{is C}"^CI; and R213 is CF3 or SF5.

Compoimd 1-9 was separated into its diastereomers, (R,R)l-9, (S,R)l-9, (S,S)l-9, (R,S)l-9. The first designation of absolute configuration refers to the configuration of the sulfoxide moiety, the second to the chiral carbon.

Table 9 Compounds of formula (XX) wherein R20I is cyano; R202 is S(O)₂CF₃; R₂04 N(R₂05)C(O)CR₂06R207R208; R211 i Cl; Xi is C- Cl; and R213 is CF3 or SF5-

Compound 1-11 was also separated into its diastereomers, (R)l-l 1 and (S)l-l 1 .

Table 10 Compounds of formula (XX) wherein R20I i cyano; R204 ^ιs N(R₂05)C(O)CR₂06R207R208; R207 and R₂₀8 are H; R₂1 1 is Cl, Xj is C-Cl; and R₂13 is CF₃ or SF5.

Table 11 Compounds of formula (XX) wherein R20I i cyano; R204 is -N(R205)C(O)OR₂₀7; R211 is Cl; Xi is C-Cl, and R₂ι₃ is CF₃ or

SF₅.

Table 12 Compounds of formula (XX) wherein R20I i cyano; R202 i S(O)_hCF₃; R₂₀ s N(R₂05)C(O)CR₂06R207R208; R211 i Cl; Xi is C- Cl, andR2i3isCF₃orSF5.

Table 13 Compounds of formula (XX) wherein R201 is cyano; R202 is S(O)_hCF₃; R204 i N(R₂05)C(O)aryl; R₂\ 1 is Cl; Xj is C-Cl, R₂₀5 is CH₃; and R213 is CF3 or SF5. Within this table the following symbols are defined:

Ph means phenyl; Fu means furyl Th means the thiophene radical Pyr means pyridyl

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), 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

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), a crystallization inhibitor, an organic solvent, and an organic cosolvent. The

composition is preferably hydrophobic. The crystallization inhibitor is preferably 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 (I) 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) 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, 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 ammonium

salts of formula N⁺R'R"R*"R'"Υ in which the radicals R', R", R'"₅ 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

amphoteric 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

non-ionic surfactants, preferably polyethoxylated esters of sorbitan and especially the different grades of polysorbates, for example Polysorbate 80. The filmogenic agent and

surface-active agent may be incorporated in close or identical quantities the total of which

is within the preferred concentration 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.

Although 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 acetamide, dimethyl formamide,

dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol

monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene

glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol,

2-pyrrolidone, especially N-methyl- pyrrolidone, 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 paraffmic or aromatic hydrocarbons may be used.

The compositions according to the invention are generally prepared by

simple mixing of the constituents as defined above.

Commercially available formulations of fipronil including FRONTLINE®

from Merial, Inc and ADONIS® from Aventis CropScience S.A., Lyon, France, are

suitable for use as the composition of the present invention.

The method of the invention provides to the rodent a dose of

ectoparasiticide which is substantially harmless 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 1 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 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.

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.

Preferably the enclosures may be placed and replaced on a periodic basis. In such a way, the method of the present invention provides a barrier 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 lg of active ingredient

per device preferably from 0.01 g to 1 g of active ingredient, most preferably from 0.05 g

to 0.150 g per device.

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. 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

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 "Protecta Jr. Bait Station". This enclosure is 6" x 5 7₂" 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.

Example 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

of the feeding area entry; two adsorbent nylon strips are affixed to the outer edges of the

food block trays. Two to three milliliters (mL) of an oil-based composition comprising 3-

cyano-l-(2,6-dichloro-4-trifluoromethyl)phenyl-5-N-(ethoxyacetyl)-N-methyl-4-

trifluoromethylsulfϊnylpyrazole (0.1% to 0.5% 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.

Claims

1. 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; wherein the ectoparasiticide is

a compound of formula (I):

(I) wherein:

R_λ is cyano, acetyl, C(S)NH₂, alkyl, haloalkyl, C(=NOH)NH₂ or

C(=NNH₂)NH₂;

or C₂-C₃ alkynyl; R is alkyl or haloalkyl;

R is hydrogen; alkyl; or alkyl substituted by halogen, alkoxy, haloalkoxy

or -S(O)mR₁₅;

R₆ and R₇ 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)_mR₁₅; 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

R^ and R₇ may form together with the nitrogen to which they are attached

from oxygen, nitrogen or sulfur;

R_g is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, R_MCO- or

Rg, R₁₀ and R₁₄ are alkyl or haloalkyl;

R_n and R₁₂ are independently selected from halogen, hydrogen, CN and

NO₂;

R₁₃ is selected from halogen, haloalkyl, haloalkoxy, -S(O)_qCF₃, and -SF₅;

R₁₅ is alkyl or haloalkyl;

X is selected from nitrogen and C-R_]2;

Z is O, S(O)_a; o NR₇; a, m, n and q are independently selected from 0, 1, and 2; and

t is 0 or 2; and veterinarily acceptable salts thereof;

or of formula (XX):

(XX)

wherein:

R₂₀₁ is cyano, C(O)alkyl, C(S)NH₂, alkyl, C(=NOH)NH₂ or

C(=NNH₂)NH₂;

R₂₀₂ is S(O)_hR₂₀₃, C₂-C₃ alkenyl, C₂-C₃ haloalkenyl, cycloalkyl, halocycloalkyl or C₂-C₃ alkynyl;

R₂₀₃ is alkyl or haloalkyl;

C₃-C₅ alkynyl, C₃-C₅ haloalkynyl;

R₂o₆ is hydrogen, halogen, alkoxy, haloalkoxy, alkoxyalkyl,

haloalkoxyalkyl, formyloxy, alkylcarbonyloxy, haloalkylcarbonyloxy, alkylthio,

alkylamino, dialkylamino, haloalkylamino, di(haloalkyl)amino, cycloalkyloxy,

arylalkoxy;

selected from nitrogen, oxygen and sulfur;

X, is selected from nitrogen and C-R₂₁₂;

NO 2>

R₂₁₃ is selected from halogen, haloalkyl, haloalkoxy, -S(O)kCF₃, and -SF 5' and

h and k are independently selected from 0, 1, and 2;

and veterinarily acceptable salts thereof.

2. The method of claim 1 wherein the ectoparasites are arthropods.

3. The method according to claim 1 wherein the rodent is a mouse, rat, vole,

chipmunk or squirrel.

4. The method according to claim 2 wherein the ectoparasites are ticks of the genus

Ixodes.

5. The method according to claim 1 wherein the composition is hydrophobic.

6. The method according to claim 1 wherein the applicator is inaccessible to the

human hand.

7. The method according to claim 1 wherein the amount of ectoparasiticide is from

0.100 grams per enclosure to 2 grams per enclosure.

8. The method according to claim 1 wherein the percent by weight of the

ectoparasiticide in the composition is from 1% to 20%.

9. The method according to claim 1 wherein the device further comprises a foodstuff

for the rodent.

10. The method according to claim 1 wherein from one to ten enclosures are placed

per hectare.

11. The method according to claim 1 wherein the enclosure further defines a

passageway through which a rodent is attracted to proceed.

12. The method according to claim 1 wherein the applicator is disposed in the

passageway.

13. The method according to claim 1 wherein the applicator is disposed adjacent to or

near the opening.

14. The method according to claim 1 wherein the applicator is rechargeable from the

outside of the enclosure without necessity to open the enclosure.

15. The method according to claim 1 wherein the applicator is replaceable.

16. The method according to claim 1 wherein the applicator is a small mop head.

17. The method according to claim 1 wherein the applicator is a brush.

18. A method of interrupting or preventing a the transmission of diseases 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, which ectoparasiticide is a compound of formula (I) or

formula (XX) as defined in claim 1 ; 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.