WO1997036484A1 - Flea and tick control collar containing n-phenylpyrazole for use on cats and dogs - Google Patents

Abstract

A collar or other external device for pets, particularly cats and dogs, consisting of a matrix incorporating 0.1-40 wt %, preferably 1-15 wt %, based on the weight of the collar, of a substance that is effective against ectoparasites such as fleas and ticks and consists of at least one compound of formula (I). Said collar or other external device is designed to be effective for over six months against fleas and over three months against ticks. Efficacy is even maintained for several weeks after the collar or other external device is removed or lost, or when the release rate of the compound varies.

Description

 Anti-flea and anti-tick collar for dogs and cats, based on N-phenylpyrazolβ

The present invention relates to an external antiparasitic device, in particular a collar, for pets, in particular for dogs and cats, active against ectoparasites of these animals, in particular fleas and ticks.

It also relates to the use of active compounds for the manufacture of such collars or external devices, as well as to a treatment method relating thereto.

The invention relates mainly to fleas of the genus Ctenocephalides, in particular C. felis and C. canis, and ticks, in particular of the genus Rhipicephalus, in particular sanguineus, as well as chiggers (Trombicula automnalis), which are mites attacking mainly hunting dogs.

Collars have long been produced for the elimination of common ectoparasites from dogs and cats. These necklaces consist of a matrix, usually a plastic matrix, incorporating between 5 and 40% of active substance and capable of releasing it over time. These collars are therefore theoretically intended to provide lasting protection.

However, despite the activity claims, the collars do not have the effectiveness required in the field to ensure the actual elimination of these parasites. The cause may be the low activity of the active substance included in the matrix. Another cause may be the accelerated degradation of these active substances under the influence of climatic factors, such as light, heat, rain. Finally, the control of the release of the active substance from the matrix is greatly overestimated. The release is generally difficult and variable, it can depend strongly on the manufacturing conditions which may vary from one batch to another, and the conditions of use, in particular climatic variations and in particular the humidity and temperature, etc. In addition, only a relatively small amount of the active ingredient incorporated is actually released and it proves difficult to want to control and optimize the release. Another drawback of the collars encountered in practice results in the mode of use of this device which can, of course, be removed, worn irregularly or even be torn off when the animal is moving, for example, in brush; the problem is particularly critical for hunting dogs from which the collar is removed before a hunting party when they are going to be confronted with an environment loaded with fleas and ticks.

Patent applications WO-A-87/03781 and EP-A-0295 117 have proposed insecticides from the N-phenylpyrazole family. These substances are described as being active against a very large number of parasites encountered in various fields, namely agriculture, public health, human and veterinary medicine. In the latter area, these substances can act in particular against fleas and ticks from pets, such as cats and dogs. These substances can be applied in different ways, namely by the oral, parenteral, percutaneous or topical route. The latter type of administration itself covers various possibilities, namely sprays, powders, baths, showers, jets, greases, shampoos, creams, waxes, preparations of the skin solution type (pour-on) and external devices such as as earrings and necklaces to ensure local or systematic treatment. EP-A-0 295 117 and EP-A-0 500 209 propose a composition for slow release which can be put in the form of a necklace or ear loops to fight against harmful insects. Such a formulation may comprise from 0.5 to 25% of active material, from 75 to 99.5% of polyvinyl chloride and a catalytic amount of a plasticizer, dioctyl phthalate.

French patent application FR-A-2 713 889 describes a pesticidal composition containing an insect growth regulator and an N-aryldiazole derivative chosen from derivatives 4- (2-bromo-1,2,2,2- tetrafluoroethyl) -1- (3 ~ chloro-5-trifluoromethylpyridine-2-yl) -2-methylimidazole, 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) -4- trifluoro ethylsulfinylpyrazole and 5-amino-3-cyano-l- (2,6-dichloro - 4 - trifluor ome thylpheny l) - 4 - trifluoromethylthiopyrazole. As in the earlier documents discussed above, the compositions target a large number of insects in different fields, and various types of formulations. The dog flea and the cat flea are targeted. Among the formulations proposed, this document lists the resinous preparations which can be put in the form of pesticide collars for animals.

None of these documents describes, however, the use of pesticide collars comprising a compound of the N-phenylpyrazole family for combating fleas and ticks from pets such as dogs and cats which make it possible to ensure an effective high level and long lasting against these parasites.

As with the pesticide compounds of the prior art, the specialist could expect to encounter the conventional problems of release from the collars and therefore of activity.

Doesn't French patent application FR-A-2713 889 propose the association of such compounds with a regulator of insect growth? The publications C. Genchi et al., Professione Veterinaria n ° l, supplement 1995, pages 19 to 22, JM Postal, Professione Veterinaria n ° l, supplement 1995, pages 17 and 18 and A. Searle et al., Australian Veterinary Practitioner , volume 25, n ° 3, 1995, pages 157 and 158, propose rather to fight effectively against fleas and ticks using a sprayable solution (spray) containing this type of active compound.

However, the Applicant has surprisingly found that, despite the fact that these N-phenylpyrazoles encounter the same release difficulties as the products of the prior art, it was however possible to obtain collars which are perfectly effective in removing ectoparasites from dogs and cats over a very long period, for example from 6 to 18 months, and that, in addition, the effectiveness extended well beyond the withdrawal of the collar, namely over a period which may equal or exceed two months, so that we can then have a perfectly effective collar whatever the conditions of use. Because the protection is extended after the collar has been removed, it is understood that irregular use, voluntary or resulting from loss of the collar, does not jeopardize the protection enjoyed by the animal.

In addition, the Applicant has found that this long-term effectiveness was obtained with concentrations of active substance in the matrix constituting the collar much lower than conventional products. It was also found that this efficiency was obtained in a very short time after the installation of the collars, in particular an efficiency greater than 95% in 24 h against fleas and greater than 90% in 48 h against ticks.

It has been found very surprisingly that the compounds according to the invention, very lipophilic and with high vapor pressure (low volatility), have a very strong affinity for the sebum which usually covers the animal's coat (skin and hair) so that this compound, upon release, is taken up by this sebum, as a result of which there is a translocation phenomenon ensuring distribution of active substance throughout the body of the animal. In addition, and this is a remarkable point, these active substances are concentrated in the sebaceous glands which become a reservoir ensuring a very long efficiency and making it possible to compensate for the absence of the collar, by releasing the active substance by passive diffusion.

Thanks to this phenomenon, the variations in release of the active substance by the collar due, for example, to a variation in climatic conditions, are compensated by the possibilities of release by the sebaceous glands.

It has also been found that, after a bath which may eventually lead to the elimination of the sebum distributed over the animal's body, the animal again becomes protected very quickly, in the presence or in the absence of the collar, by the fact that the secretion of new sebum is accompanied by a release, by the sebaceous glands, of the active substance which they contain.

The present invention therefore relates to a collar or other external flea and anti-tick device for pets, in particular for dogs and cats, made of a matrix in which is incorporated from 0.1 to 40% by weight. , with respect to the collar, of an active substance against ectoparasites such as fleas and ticks, formed of at least one compound corresponding to the following formula (I):

in which :

R _L is CN or methyl or a halogen atom;

R ₂ is S (0) _n R ₃ or 4, 5-dicyanoimidazol 2-yl or haloalkyl R ₃ is alkyl or haloalkyl;

R ₄ represents a hydrogen or halogen atom; or a radical NR _S R ₆ , S (0) _m R ₇ , C (0) R ₇ , C (0) 0-R ₇ , alkyl, haloalkyl or 0R ₈ or a radical -N = C (R ₉ ) ( R ₁₀ ); R ₅ and R ₆ independently represent the hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, alkoxycarbonyl, S (0) _r CF ₃ radical; or R ₅ and R ₆ may together form a divalent alkylene radical which may be interrupted by one or two divalent heteroatoms, such as oxygen or sulfur; R ₇ represents an alkyl or haloalkyl radical;

R ₈ represents an alkyl or haloalkyl radical or a hydrogen atom;

R ₉ represents an alkyl radical or a hydrogen atom;

R ₁₀ represents a phenyl or heteroaryl group optionally substituted by one or more halogen atoms or groups such as OH, -O-alkyl, -S-alkyl, cyano, or alkyl;

R _1X and R ₁₂ represent, independently of one another, a hydrogen or halogen atom, or optionally CN or N0 ₂ ;

R ₁₃ represents a halogen atom or a haloalkyl, haloalkoxy, S (0) _q CF ₃ or SF _{5 group} ; m, n, q, r represent, independently of one another, an integer equal to 0, 1 or 2;

X represents a trivalent nitrogen atom or a C- R ₁₂ radical, the other three valences of the carbon atom being part of the aromatic ring; with the proviso that, when R _x is methyl, either R ₃ is haloalkyl, R ₄ is H ₂ , R _u is Cl, R ₁₃ is CF ₃ , and X is N; either R ₂ is 4, 5-dicyanoimidazol 2-yl, R „is Cl, R _u is Cl, R ₁₃ is CF ₃ and X is = C-C1; this collar or other external device being designed to ensure at least more than 6 months of effectiveness against fleas and at least more than 3 months of effectiveness against ticks, the effectiveness even being preferably maintained for several weeks in the event of withdrawal or loss of the collar or other external device or variation in the rate of release of compound (I) by the matrix.

Preferably, in formula (I), Ri is CN or methyl;

R ₂ is S (0) _n R ₃ ;

R ₃ is alkyl or haloalkyl;

R ₄ represents a hydrogen or halogen atom; or a radical NR ₅ R ₆ , S (0) _m R ₇ , C (0) R ₇ , alkyl, haloalkyl or 0R ₈ or a radical -N = C (R ₉ ) (R ₁₀ );

R ₅ and R ₆ independently represent the hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, S (0) _r CF ₃ radical; or R ₅ and R ₆ may together form a divalent alkylene radical which may be interrupted by one or two divalent heteroatoms, such as oxygen or sulfur;

R ₇ represents an alkyl radical. or haloalkyl;

R ₈ represents an alkyl or haloalkyl radical or a hydrogen atom; R ₉ represents an alkyl radical or a hydrogen atom;

R ₁₀ represents a phenyl or heteroaryl group optionally substituted by one or more halogen atoms or groups such as OH, -O-alkyl, -S-alkyl, cyano, or alkyl;

R _u and R ₁₂ represent, independently of one another, a hydrogen or halogen atom;

R ₁₃ represents a halogen atom or a haloalkyl, haloalkoxy, S (0) _q CF ₃ or SF _{S group} ; m, n, q, r represent, independently of one another, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a C- R ₁₂ radical, the other three valences of the carbon atom being part of the aromatic ring; with the proviso that, when R _x is methyl, then R ₃ is haloalkyl, R _t is NH ₂ , R _u is Cl, R ₁₃ is CF ₃ , and X is N. We will particularly retain the compounds of formula

(I) in which R _x is CN. We will also retain the compounds in which R ₂ is S (0) _n R ₃ , preferably with n = 1, R ₃ preferably being CF ₃ or alkyl, for example methyl or ethyl, or alternatively n = 0, R ₃ being preferably CF ₃ , as well as those in which X = CR ₁₂ , R ₁₂ being a halogen atom. Preference is also given to the compounds in which R _u is a halogen atom as well as those in which R ₁₃ is haloalkyl, preferably CF ₃ . In the context of the present invention, advantageously retain the compounds combining two or more of these characteristics.

A preferred class of compounds of formula (I) consists of the compounds such that R _x is CN, R ₃ is haloalkyl, preferably CF ₃ , or ethyl, R ₄ is NH ₂ , R and R ₁₂ are independently one on the other a halogen atom, and / or

R ₁₃ is haloalkyl.

The alkyl radicals of the definition of the compounds of formulas (I) generally contain from 1 to 6 carbon atoms. The ring formed by the divalent alkylene radical representing R ₅ and R _{6 as} well as the nitrogen atom to which R ₅ and R ₆ are attached, is generally a 5, 6 or 7-membered ring.

A compound of formula (I) very particularly preferred in the invention is l- [2,6-Cl ₂ 4-CF ₃ phenyl] 3-CN 4- [SO-CF ₃ ] 5-NH ₂ pyrazole, hereinafter referred to as -after compound A.

We can also cite the two compounds which differ from the previous A by the following characteristics: 1- n = 0, R ₃ = CF ₃

2 - n = 1, R ₃ = ethyl.

The preparation of compounds of formula (I) can be made according to one or the other of the methods described in patent applications OA-87/3781, 93/6089, 94/21606 or European patent EP-A-0295 117, or any other process falling within the competence of a person skilled in the art of chemical synthesis. For the chemical production of the products of the invention, those skilled in the art are considered to have at their disposal, among other things, all the content of the "Chemical Abstracts" and of the documents cited therein.

However, low concentrations of 1 to 15% by weight are preferred and more particularly, in particular for compound A, from 1.25 to 10%.

Optimally, the compound (I) and in particular the compound A is present in the collar at a rate of 2 to 6% by weight, more particularly from 2, 5 to 5% by weight.

It is of course possible to add to compound A any other insecticide which we deem useful. These insecticides can be presented in the same matrix as the compound according to the invention. One can also use a composite collar made of at least two parts each including a different active substance. In the context of the invention, dies usually used for making collars can be used. As preferred examples, mention may be made of matrices based on PVC (polyvinyl chloride), as described in US-A-3 318 769, 3 852 416 and 4 150 109 and 5 437 869, and other vinyl polymers.

The plasticizers can in particular be chosen from adipates, phthalates, phosphates and citrates.

One or more plasticizers will preferably be added to the PVC, in particular chosen from the following compounds: - diethyl phthalate

- Dioctyle sebaçate

- Dioctyle adipate

- Diisodecyl phthalate

- Acetyl tributyl citrate - Diethyl hexyl phthalate

- Di-n-butyl phthalate

- Benzyl butyl phthalate

- acetyl tributyl citrate

- tricresyl phosphate - 2-ethylhexyl diphenyl phosphate.

Even more preferably, a PVC matrix will be used in the presence of a residual primary plasticizer and a secondary plasticizer, in particular according to EP-A-0 539 295 and EP-A-0 537 998. Among the secondary plasticizers, can quote the following products:

- Acetyl triethyl citrate

- Triethyl citrate

- Triacetin - Diethylene glycol monoethyl ether

- Triphenyl phosphate.

You can also add a standard stabilizer to it.

By external device in the sense of this invention means any device that can be attached externally to the animal to perform the same function as the collar.

By acting on the concentration and / or the composition of the matrix, it is possible to produce collars or other external devices according to the invention ensuring effective and long-lasting protection against fleas. One can make necklaces or other external devices having an effectiveness higher than 6 months, in particular higher or equal to 12 or 18 months, even in the event of more or less prolonged withdrawal of the collar or external device. If the collar or device is removed, the effective protection period can range from 2 to 3 months.

By acting on the concentration and / or the composition of the matrix, it is possible to produce collars or other external devices according to the invention ensuring effective and long-lasting protection against ticks. One can make collars or external devices having an effectiveness higher than 3 months, in particular higher or equal to 12 or 15 months, even in the event of more or less prolonged withdrawal of the collar or external device. If the collar or external device is removed, the effective protection period can range from 1 to 2 months.

It is remarkable that this total effectiveness and of very long duration is obtained by the only compound according to the invention without the addition of another insecticide. The present invention also relates to a method of eliminating ectoparasites, in particular fleas and ticks, from pets such as dogs and cats, in which at least one collar or other external device is attached to the animal in accordance with the invention and the animal is provided with effective long-term protection against these parasites, even in the event of removal of the collar or other external device. The duration indications have been given above. Preferably, it is recommended that, in accordance with the method according to the invention, the collar or external device, after its first application, remains on the animal for at least 24 hours so that enough active substance is passed over the animal and that the sebaceous glands may have stored this active substance. The objective of this method is non-therapeutic and in particular relates to the cleaning of animal hair and skin by elimination of the parasites which are present as well as their residues and excrements. The treated animals thus present a more pleasant coat to the eye and to the touch.

The invention also relates to such a method for therapeutic purposes, intended to treat and prevent parasitic diseases having pathogenic consequences.

The present invention also relates to the use of a compound corresponding to formula I for the production of a collar or other external device intended to be attached to a pet, in particular dogs and cats, capable of ensuring a prevention and treatment of fleas and ticks with a high degree of effectiveness and over a period exceeding 6 months against fleas and 3 months against ticks, the efficacy preferably being maintained for several weeks in the event of withdrawal or loss of the collar or external device or variation in release of compound (I) from the collar or external device. The devices described above are targeted. Preferably, the compound of formula I is incorporated in an amount of 0.1 to 40% by weight, preferably from 1 to 15% by weight, in a matrix intended to form the collar or other external device.

Even more preferably, this compound will be incorporated in an amount of 1.25 to 10% by weight, in particular from 2 to 6% and more preferably still from 2.5 to 5%.

In particular, the use according to the invention aims to produce collars or external devices having, against fleas, an efficiency greater than 95%, or even greater than 98 or 99%.

For ticks, the desired efficiency exceeds 80% or 90%.

Similarly, the use according to the invention aims, against fleas, to obtain a long-term efficacy greater than or equal to 12 months and even 18 months.

For ticks, this duration is more than 12 months, or even more than 15 months.

More preferably, the use according to the invention aims to the production of collars or other external devices making it possible to obtain an efficiency maintained in the absence of the collar or external device over a period ranging from 2 to 3 months, or more, against fleas and from 1 to 2 months, or more, against ticks.

The present invention will now be described in more detail with the aid of nonlimiting examples from which will emerge other features and advantages of the invention.

EXAMPLE 1:

Necklace with 10% of compound A.

The following two types of collars were prepared (mixing, then extrusion):

Formulation 1: PVC 50.0% stabilizer 0.5% epoxidized soybean oil ... 5.0% diiso octyl adipate 34.5% compound A 10.0%

Formulation 2: PVC 50.0% stabilizing 0.5% epoxidized soybean oil .... 5.0% 2-ethylhexyldiphenyl .... phosphate 34.5% compound A 10.0% (% by weight).

For the tests, 9 adult dogs were chosen who had not received an insecticide or acaricide for at least 40 days. The dogs were washed with an insecticide-free shampoo and combed to remove any existing parasites. The dogs were divided into groups of 3: Group A: Untreated controls Group B:

Necklace with 10% of compound A - formulation 1. Group C:

Collar with 10% of compound A - formulation 2. Dogs are infested with approximately 100 + 10 cat fleas Ctenocephalides felis (Unfed cat fleas in English) and 50 + 2 ticks Rhipicephalus sanguineus (Brown dog tick in English).

The treatment follows the following general scheme: DAY -2 infestation with fleas and ticks. 0 fitting necklaces. 2 comb count of fleas and ticks.

7 infestation with ticks.

8 infestation with fleas. 9 comb counting.

35 infestation with ticks.

36 flea infestation.

37 comb counting.

63 infestation with ticks. 64 flea infestation.

65 comb counting.

The same process is continued with flea and tick infestation every month as long as satisfactory efficacy is found. Hair samples were taken from:

J 205 and J 261 for all dogs.

The collars were removed on D 149 on dogs 363 and 289, on D 177 for dogs 87 and 300 and on D 205 for dogs 256 and 335. The concentrations on the hairs of active substance according to the invention obtained at times J 205 and J 261 are presented in Tables 1 and 2 respectively, in μg / g of hair.

Table 1; Concentration of active substance according to the invention on the hair at J 205.

Table Concentration of active substance according to the invention, on the hair at J 261.

ND = non déterminé

ND = not determined

There is an active distribution of texture on the hair: the concentrations in the different zones are higher with the formulation of group C and relatively homogeneous from one zone to another.

The active substance concentrations are still detectable 16 weeks after removing the collar and are still effective at this time.

Tables 3, 4 and 5 allow a correlation, concentration / activity.

Table 3: Concentration / activity relationship at D 149.

CONCENTRATION DOG (μg.g ^'1 ) ACTIVITY (1)

UNDER THE BACK AND SIDE SIDES TICK

N ^c NECKLACE MID MIN MAX

GROUP B

363,559.5 15.6 10.7 24.8 GROUP C

289,871.3 48.9 30.8 94.4

(1) number of fleas and ticks present on the dog

Table 4; Relation concentra activ

: D number of fleas and ticks present on the dog

17

Table 5: Concentration / activity relationship on D 261.

CONCENTRATION DOG (μg.g ^"1 ) ACTIVITY (1)

UNDER THE BACK AND SIDE SIDES TIC CHIPS N ° COLLAR MEDIUM MIN MAX

(1) number of fleas and ticks present on the dog. AVERAGE = average MIN = minimum MAX = maximum

LOQ = limit of quantification = 0.25 μg / g On D 261, the activity vis-à-vis fleas is 100% in all dogs, except one dog (presence of a flea).

The minimum effective concentrations (on the coat) against fleas and ticks are determined at approximately: - 20 micrograms per gram of coat for ticks - 1 microgram per gram of coat for fleas.

With these formulations, an activity of at least 5 months on ticks and at least 9 months on fleas is observed.

EXAMPLE 2; 6 groups of 8 dogs were made:

- A: Control group: collar without active substance.

- B: Reference product: collar against fleas and ticks on the market, containing 8% of Chlorpyrifos (0,0-Diethyl 0- (3,5,6- trichloro-2-pyridyl) phosphorothioa e; noted ref. in the tables.

- C: Necklace with 2.5% of compound A.

- D: Necklace with 5% of compound A

- E: Necklace with 10% of compound A

The necklaces were produced with the same ingredients as formulation 2 of Example 1, with the addition of a pigment (titanium dioxide).

The tests follow the following scheme: -2 flea and tick infestation 0 fitting of collars 2 counting with a comb

7 tick reinfestation

8 flea reinfestation

9 comb counting

35 tick reinfestation

36 flea reinfestation

37 comb counting

We continue on this principle from month to month. Infestations and reinfestations are carried out at the rate of: 100 + 10 fleas 50 + 3 ticks

Tables 6 and 7 show the average efficacy results.

Table 6 Ourcenta e of efficiency on calculated uce

Tableau 7 ; pourcentage d'efficacité sur tique, calculé en moyenne géométrique.

Table 7; percentage efficiency on tick, calculated as geometric mean.

Claims

1. Collar or other external anti-flea and anti-tick device, for pets, in particular for dogs and cats, made of a matrix in which is incorporated from 0.1 to 40% by weight, preferably 1 at 15% by weight, relative to the collar, of an active substance against fleas and ticks, formed of at least one compound corresponding to the following formula (I):

in which : Rj_ is CN or methyl or a halogen atom; R ₂ is S (0) _n R ₃ or 4, 5-dicyanoimidazol 2-yl or haloalkyl; R ₃ is alkyl or haloalkyl; R ₄ represents a hydrogen or halogen atom; or a radical NR ₅ R _S , S (0) _ra R ₇ , C (0) R ₇ , C (0) 0-R ₇ , alkyl, haloalkyl or OR ₈ or a radical -N = C (R ₉ ) ( R ₁₀ ); R ₅ and R ₆ independently represent the hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, alkoxycarbonyl, S (0) _r CF ₃ radical; or R ₅ and R ₆ may together form a divalent alkylene radical which may be interrupted by one or two divalent heteroatoms, such as oxygen or sulfur; R ₇ represents an alkyl or haloalkyl radical; R _a represents an alkyl or haloalkyl radical or a hydrogen atom; R ₉ represents an alkyl radical or a hydrogen atom; R ₁₀ represents a phenyl or heteroaryl group ^"optionally substituted by one or more halogen atoms or groups such as OH, -0-alkyl, -S-alkyl, cyano, or alkyl; R _u and R ₁₂ represent, independently of one another, a hydrogen or halogen atom, or optionally CN or NO,; R ₁₃ represents a halogen atom or a haloalkyl, haloalkoxy, S (0) _q CF ₃ or SF _{5 group} ; m, n, q, r represent, independently of one another, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a C- R ₁₂ radical, the other three valences of the carbon atom being part of the aromatic ring; with the proviso that when R _x is methyl, either R ₃ is haloalkyl, R ₄ is NH ₂ , R _1L is Cl, R ₁₃ is CF ₃ , and X is N; either R ₂ is 4, 5-dicyanoimidazol 2-yl, R ₄ is Cl, R _u is Cl, R ₁₃ is CF ₃ and X is = C-C1; this collar or other external device being designed to ensure more than 6 months of effectiveness against fleas and more than 3 months of effectiveness against ticks, the effectiveness even being preferably maintained for several weeks in the event of withdrawal or loss of the collar or other external device or of variation of release of the compound (I) by the matrix. 2. Necklace according to claim 1, characterized in that the compound of formula (I) is such that: R _r is CN or methyl; R ₂ is S (0) _n R ₃ ; R ₃ is alkyl or haloalkyl; R ₄ represents a hydrogen or halogen atom; or a radical NR ₅ R ₆ , S (0) _m R ₇ , C (0) R ₇ , alkyl, haloalkyl or OR ₈ or a radical -N = C (R ₉ ) (R ₁₀ ); R ₅ and R ₆ independently represent the hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, S (0) _r CF ₃ radical; or R _s and R ₆ may together form a divalent alkylene radical which may be interrupted by one or two divalent heteroatoms, such as oxygen or sulfur; R ₇ represents an alkyl or haloalkyl radical; R ₈ represents an alkyl or haloalkyl radical or a hydrogen atom; R ₉ represents an alkyl radical or a hydrogen atom; - R ₁₀ represents a phenyl or heteroaryl group optionally substituted by one or more halogen atoms or groups such as OH, -O-alkyl, -S-alkyl, cyano, or alkyl; R _u and R ₁₂ represent, independently of one another, a hydrogen or halogen atom; R ₁₃ represents a halogen atom or a haloalkyl, haloalkoxy, S (0) _q CF ₃ or SF _{5 group} ; m, n, q, r represent, independently of one another, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a C- R ₁₂ radical, the other three valences of the carbon atom being part of the aromatic ring; with the proviso that when R _t is methyl then R ₃ is haloalkyl, R ₄ is NH ₂ , R is Cl, R ₁₃ is CF ₃ , and X is N. 3. Necklace according to claim 1 or 2, characterized in that the compound of formula (I) is such that R _x is CN. 4. Necklace according to one of claims 1 to 3, characterized in that the compound of formula (I) is such that R ₁₃ is haloalkyl, preferably CF ₃ . 5. Necklace according to one of claims 1 to 4, characterized in that the compound of formula (I) is such that R ₂ is S (0) _n R ₃ , preferably with n = 1, R ₃ preferably being CF ₃ or alkyl, in particular methyl or ethyl, or n = 0, R ₃ preferably being CF ₃ . 6. Necklace according to one of claims 1 to 5, characterized in that the compound of formula (I) is such that X is CR ₁₂ with R ₁₂ being a halogen atom. 7. Necklace according to one of claims 1 to 6, characterized in that the compound of formula (I) is chosen from those in which R _x is CN, R ₃ is haloalkyl, R ₄ is NH ₂ , R and R ₁₂ are independently of each other a halogen atom, and / or R ₁₃ is haloalkyl. 8. Necklace according to claim 2, characterized in that the compound of formula (I) is: l- [2,6-Cl ₂ 4-CF ₃ phenyl] 3-CN 4- [SO-CF ₃ ] 5-NH ₂ pyrazole. 9. Necklace according to any one of claims 1 to 8, characterized in that it comprises from 1.25 to 10% of active substance. ^{^} 10. Necklace according to any one of claims 1 to 8, characterized in that it comprises from 2 to 6%, preferably from 2.5 to 5% of active substance. 11. Necklace according to any one of claims 1 to 10, characterized in that the effectiveness is maintained in the event of withdrawal or loss of the collar or external device, over a period ranging from 2 to 3 months against fleas and from 1 to 2 months against ticks. 12. Necklace according to claim 11, characterized in that it comprises a concentration of active substance ensuring effective protection against fleas of duration greater than or equal to 12 or 18 months. 13. Collar according to claim 11, characterized in that it comprises a concentration of active substance ensuring effective protection against ticks of duration greater than or equal to 12 or 15 months. 14. Use of a compound corresponding to the following formula (I):

in which : R _x is CN or methyl or a halogen atom; R ₂ is S (0) _n R ₃ or 4, 5-dicyanoimidazol 2-yl or haloalkyl; R ₃ is alkyl or haloalkyl; R ₄ represents a hydrogen or halogen atom; or a radical NR ₅ R ₆ , S (0) _m R ₇ , C (0) R ₇ , C (0) 0-R ₇ , alkyl, haloalkyl or OR ₈ or a radical -N = C (R ₉ ) ( R ₁₀ ); R ₅ and R ₆ independently represent the hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, alkoxycarbonyl, S (0) _r CF ₃ radical; or R ₅ and R ₆ may together form a divalent alkylene radical which may be interrupted by one or two divalent heteroatoms, such as oxygen or sulfur; R ₇ represents an alkyl or haloalkyl radical; R ₈ represents an alkyl or haloalkyl radical or a hydrogen atom; R ₉ represents an alkyl radical or a hydrogen atom; R ₁₀ represents a phenyl or heteroaryl group optionally substituted by one or more halogen atoms or groups such as OH, -O-alkyl, -S-alkyl, cyano, or alkyl; R _u and R ₁₂ represent, independently of one another, a hydrogen or halogen atom or optionally CN or N0 ₂ ; R ₁₃ represents a halogen atom or a haloalkyl, haloalkoxy, S (0) _q CF ₃ or SF _{5 group} ; m, n, q, r represent, independently of one another, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a C- R ₁₂ radical, the other three valences of the carbon atom being part of the aromatic ring; with the proviso that when R _x is methyl, either R ₃ is haloalkyl, R ₄ is NH ₂ , R _u is Cl, R ₁₃ is CF ₃ , and X is N; either R ₂ is 4,5-dicyanoimidazol 2-yl, R ₄ is Cl, R _n is Cl, R ₁₃ is CF ₃ and X is = C-C1; for the production of a collar or other external device intended to be attached to a pet, in particular dog and cat, and capable of ensuring the prevention and treatment of fleas and ticks to a high degree of efficiency and on a duration exceeding 6 months against fleas and 3 months against ticks, the effectiveness even being maintained preferably several weeks in the event of withdrawal of the collar or external device or variation in release of the compound (I) by the collar or external device. 15. Use according to claim 14, characterized in that the compound of formula (I) is such that: Ri is CN or methyl; R ₂ is S (0) _n R ₃ ; R ₃ is alkyl or haloalkyl; R ₄ represents a hydrogen or halogen atom; or a radical NR ₅ R ₆ , S (0) _m R _{7 /} C (0) R ₇ , alkyl, haloalkyl or 0R ₈ or a radical -N = C (R ₉ ) (R ₁₀ ); R ₅ and R ₆ independently represent the hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, S (O) _r CF ₃ radical; or R ₅ and R ₆ may together form a divalent alkylene radical which may be interrupted by one or two divalent heteroatoms, such as oxygen or sulfur; R ₇ represents an alkyl or haloalkyl radical; R ₈ represents an alkyl or haloalkyl radical or a hydrogen atom; R ₉ represents an alkyl radical or a hydrogen atom; R ₁₀ represents a phenyl or heteroaryl group optionally substituted by one or more halogen atoms or groups such as OH, -O-alkyl, -S-alkyl, cyano, or alkyl; R _u and R ₁₂ represent, independently of one another, a hydrogen or halogen atom; R ₁₃ represents a halogen atom or a haloalkyl, haloalkoxy, S (0) _q CF ₃ or SF _{5 group} ; m, n, q, r represent, independently of one another, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a C- R ₁₂ radical, the other three valences of the carbon atom being part of the aromatic ring; with the proviso that when R _t is methyl then R ₃ is haloalkyl, R ₄ is NH ₂ , R _1X is Cl, R ₁₃ is CF ₃ , and X is N. 16. Use according to claim 14 or 15, characterized in that the compound of formula (I) is such that R _x is CN. 17. Use according to one of claims 14 to 16, characterized in that the compound of formula (I) is such that R ₁₃ is haloalkyl, preferably CF ₃ . 18. Use according to one of claims 14 to 17, characterized in that the compound of formula (I) is such that R ₂ is S (0) _n R ₃ , preferably with n = 1, R ₃ preferably being CF ₃ or alkyl, in particular methyl or ethyl, or n = 0, R ₃ preferably being CF ₃ . 19. Use according to one of claims 14 to 18, characterized in that the compound of formula (I) is such that X is CR ₁₂ with R ₁₂ being a halogen atom. 20. Use according to one of claims 14 to 19, characterized in that the compound of formula (I) is such that R _x is CN, R ₃ is haloalkyl, R ₄ is NH ₂ , R _u and R ₁₂ are ^' independently of each other, a halogen atom, and / or R ₁₃ is haloalkyl. 21. Use according to claim 15, characterized in that the compound of formula (I) is: 1- [2,6-Cl ₂ 4-CF ₃ phenyl] 3-CN 4- [S0-CF ₃ ] 5-NH ₂ pyrazole. 22. Use according to one of claims 14 to 21, characterized in that the compound of formula (I) is incorporated in an amount of 0.1 to 40% by weight, preferably from 1 to 15% by weight, in a matrix intended to form the collar or other external device. 23. Use according to one of claims 14 to 21, characterized in that the compound of formula (I) is incorporated in an amount of 1.25 to 10% by weight, in particular from 2 to 6%, preferably from 2, 5 to 5% by weight, in a matrix intended to form the collar or other external device. 24. Use according to one of claims 14 to 23, characterized in that, against fleas, the efficiency is greater than 95%. 25. Use according to one of claims 14 to 23, characterized in that, against fleas, the efficiency is greater than 98% or 99%. 26. Use according to one of claims 14 to 23, characterized in that, against ticks, the efficiency is greater than 80% or 90%. 27. Use according to one of claims 14 to 26, characterized in that, against fleas, the long-term effectiveness is greater than or equal to 12 months. 28. Use according to one of claims 14 to 26, characterized in that, against fleas, the long-term effectiveness is greater than or equal to 18 months. 29. Use according to one of claims 14 to 26, characterized in that, against ticks, the long-term effectiveness is greater than or equal to 12 months. 30. Use according to one of claims 14 to 26, characterized in that, against ticks, the long-term effectiveness is greater than or equal to 15 months. 31. Use according to any one of claims 14 to 30, characterized in that the effectiveness is maintained in the event of withdrawal or loss of the collar or external device, over a period ranging from 2 to 3 months against fleas and 1 to 2 months against ticks. 32. Anti-flea and anti-tick treatment process for domestic animals, in particular dogs and cats, in which at least one collar or other external device as described is attached to the animal, and under the conditions indicated, in any one of the preceding claims.