AU2003257646B2

AU2003257646B2 - Direct pour-on skin solution for anitparasitic use in cattle and sheep

Info

Publication number: AU2003257646B2
Application number: AU2003257646A
Authority: AU
Inventors: Jean-Pierre Etchegaray
Original assignee: Merial SAS
Current assignee: Boehringer Ingelheim Animal Health USA Inc
Priority date: 1996-03-29
Filing date: 2003-10-24
Publication date: 2006-03-30
Anticipated expiration: 2017-03-26
Also published as: AU2003257646A1

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: Merial ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Direct pour-on skin solution for antiparasitic use in cattle and sheep" The following statement is a full description of this invention, including the best method of performing it known to us: Documcn12-24/10/03

A-

DIRECT POUR-ON SKIN SOLUTION FOR ANTIPARASITIC USE IN CATTLE AND SHEEP This application is a divisional of Australian Patent Application No. 71958/00, which is in turn a divisional application of Australian Patent Application No. 25130/97, the entire contents of these applications being incorporated herein by reference.

Documn2-24/1/03

-IB-

The present invention relates to a direct pour-on skin solution which contains an antiparasitic product and is intended to be applied topically to cattle and sheep.

The invention also relates to the use of antiparasitic compounds for the preparation of this skin solution, as well as to a treatment process relating thereto.

Cattle and sheep are affected by a large number of parasites.

The main ones are ticks of the genus Boophilus, among which mention may be made of the species microplus (cattle tick), .decoloratus andanulatus.

The other main parasites of cattle and sheep are indicated in order of decreasing importance: myiases such as Dermatobia hominis (known as Berne in Brazil) and Cochlyomia hominivorax (greenbottle); sheep myiases such as Lucilia sericata, Lucilia cuprina (known as blowfly strike in Australia,. New.

Zealand-and South Africa). These are flies whose larva constitutes the animal parasite.

flies proper, namely those whose adult constitutes the parasite, such as Haematobia irritans (horn fly).

lice such as Linognathus vitulorum, etc.

galls such as Sarcoptes scabiei and Psoroptes ovis.

Ticks, in particular Boophilus microplus, are very closely attached to the pasture in which they live and are particularly difficult to control.

There is at the present time no truly effective method for controlling ticks, and less still an effective way of controlling the set of parasites 2 indicated above.

WO-A-87/3781, EP-A-295,117 and EP-A-500,209 describe a class of insecticides which are N-phenylpyrazole derivatives. These compounds are given as having activity against a very large number of parasites, including Boophilus microplus, in fields as varied as agriculture, public health and veterinary medicine. The general teaching of these documents indicates that these insecticidal compounds may be administered via different routes; oral, parenteral, percutaneous and topical routes. Topical administration comprises, in particular, oral formulations, baits, dietary supplements, skin solutions (pour-on), solutions for spraying (sprays), baths, showers, jets, powders, greases, shampoos, creams, etc. The pour-on type skin solutions are designed for percutaneous administration.

Example 9 of EP-A-295,117 and Example 291 of EP-A- 500,209 describe a pour-on type skin solution containing insecticide and 85% dimethyl sulphoxide, for percutaneous administration of the insecticide.

EP-A-296,381 also describes pyrazole compounds having insecticidal activity in the field of agriculture, public health and veterinary medicine.

Boophilus microplus is one of the very many targets mentioned. There are very many forms of administration here also, and these include, for example, solutions, emulsions, suspensions, powders, pastes, granules and aerosols.

The problem which is posed is to find an effective means which is entirely suitable for controlling the parasites of cattle and sheep, in particular ticks, most particularly Boophilus microplus in cattle and in particular lice and blowfly in sheep, under the conditions in which these animals are reared.

The Applicant has found that it is possible P:NPER\KiiUI5130-97 sil2.do'-09/1110 -3to effectively control Boophilis microplus for cattle using a specific topical formulation. The Applicant has also found this formulation is effective against sheep lice and sheep flies known as "blowfly".

At least one embodiment of the present invention advantageously provides a novel composition which is entirely effective against Boophilis microplus and also against all of the other parasites described above such as, in particular, sheep lice and "blowfly"., this composition being entirely suitable for controlling these parasites under the conditions in which these animals are reared.

At least one embodiment of the invention advantageously provides a formulation which has a long period of efficacy, preferably- longer -than .or- equal- to two months.

At least one embodiment of the invention also advantageously provides a formulation which is quick and easy to use and entirely compatible with use on herds or flocks containing a large number of animals.

At least one embodiment of the invention also advantageously provides a formulation which is particularly suitable for extensive pasture rearing and for use intended to protect., .animals.. -during....the period- of rounding- up and finishing (Feed Lot in USA), namely the final period of rearing in which a large number of animals are herded into a small enclosure over an average period of two months preceding slaughter.

P:\OPER\Kbm\25130-97 sp3.doc-24/10/03 -3A- In a first embodiment of the present invention there is provided a method of eliminating parasites from cattle and sheep, comprising administration of 10 to 150 ml of a ready-to-use direct pour-on solution to the skin and hair of an animal in need thereof for contact against a parasite; said solution comprising from 0.05 to 25% weight/volume, relative to the total solution, of a compound of formula R2 R, R4

R

13 in which: RI is CN or methyl or a halogen atom;

R

2 is S(O)nR 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(O)mR 7

C(O)R

7

C(O)O-R

7 alkyl, haloalkyl or OR 8 or a radical -N=C (R 9 )(Rio);

R

5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl, or S(O)rCF 3 radical; or Rs and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur;

R

7 represents an alkyl or haloalkyl radical; Rg represents an alkyl or haloalkyl radical or a hydrogen atom;

R

9 represents an alkyl radical or a hydrogen atom; Rio represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, -O-alkyl, -S-alkyl, cyano or alkyl; Rl and R 1 2 represent, independently of each other, a hydrogen or halogen atom or CN or NO 2 P:\OPER\Kbm\25130-97 spc3doc.24/10/03 -3B-

R

1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF 5 group; m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-R 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that, when R 1 is methyl, either R 3 is haloalkyl, R 4 is NH 2

R

1 1 is Cl, Ri 3 is

CF

3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, R 11 is Cl, R 1 3 is CF 3 and X is =C-C1..

In a second embodiment of the present invention there is provided use of a compound corresponding to formula below: R I

N

R

1 3 in which:

R

1 is CN or methyl or a halogen atom;

R

2 is S(O)nR 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(O)mR 7

C(O)R

7

C(O)O-R

7 alkyl, haloalkyl or ORs or a radical -N=C (R 9 )(Rio);

R

5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl, or S(O)rCF 3 radical; or R 5 and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur;

R

7 represents an alkyl or haloalkyl radical; Rg represents an alkyl or haloalkyl radical or a hydrogen atom; P:\OPER\Kbm\25130-97 spc3.doc24/10/03 -3C-

R

9 represents an alkyl radical or a hydrogen atom; Rio represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, -O-alkyl, -S-alkyl, cyano or alkyl;

R

1 1 and R 1 2 represent, independently of each other, a hydrogen or halogen atom or CN or NO 2

R

1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF 5 group; m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-R 12 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that, when R 1 is methyl, either R 3 is haloalkyl, R 4 is NH 2

R

1 I is Cl, Ri 3 is CF 3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, RI is Cl, RI 3 is CF 3 and X is =C-Cl; in the preparation of a ready-to-use direct pour-on skin solution comprising 0.05 to weight/volume of the compound relative to the solution, for eliminating parasites from cattle and sheep, by administering 10 to 150 ml of the solution to the skin and hair of an animal for contact against parasites..

In a third embodiment of the present invention there is provided a ready-to-us direct pour-on solution when used for eliminating parasites from cattle and sheep by administration of 10 to 150 ml of the solution to the skin and hair of an animal for contact against parasites, said solution comprising 0.5 to 25% weight/volume, relative to the total solution, of a compound of formula R2 R, P:'OPER\Kbm\2513097 spc3,doc-24/1003 -3Din which: RI is CN or methyl or a halogen atom;

R

2 is S(O)nR 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(O)mR 7

C(O)R

7

C(O)O-R

7 alkyl, haloalkyl or ORs or a radical -N=C (R 9 )(Rio);

R

7 represents an alkyl or haloalkyl radical;

R

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

R

1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF 3 or SF 5 group; m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-RI 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that, when Ri is methyl, either R 3 is haloalkyl, R4 is NH 2

RI

1 is Cl, Ri 3 is

CF

3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, R 1 1 is Cl, Ri 3 is CF 3 and X is =C-C1..

4 The subject of the present invention is thus a direct pour-on skin solution, intended to eliminate parasites from cattle and sheep, most particularly ticks, especially Boophilus microplus in cattle and lice and blowfly in sheep, comprising from 0.05 to weight/volume, relative to the total solution, of a compound of formula (I)

RR

R

13 (1) in which: R, is CN or methyl or a halogen atom;

R

2 is S(O),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 NRsR 6 S(O)mR, C(O)R 7 C(O)O-R, alkyl, haloalkyl or OR, or a radical (Ro);

R

5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O),CF3 radical; or R s and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur; R, represents an alkyl or haloalkyl radical; R, represents an alkyl or haloalkyl radical or a hydrogen atom;

R

9 represents an alkyl radical or a hydrogen 5 atom;

R,

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

R

1 and R 12 represent, independently of each other, a hydrogen or halogen atom, or CN or NO 2

R

13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF 3 or SFs group; m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-R, 2 the other three valency positions of the carbon atom forming part of the aromatic. ring; with the proviso that, when R I is methyl, either R 3 is haloalkyl, R 4 is NH 2

R

11 is Cl, R.

3 is CF 3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R 4 is Cl,

R

11 is Cl, R 13 is CF 3 and X is =C-C1; in a ready-to-use solution with a total volume of 10 to 150ml per animal for delivery of the compound on the skin and hair for contact against a parasite.

Preferably, in formula R, is CN or methyl;

R

2 is S(O),R 3

R

3 is alkyl or haloalkyl;

R

4 represents a hydrogen or halogen atom; or a radical NRsR,, alkyl, haloalkyl or OR, or a radical Rs and R, independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl or S(O),CF 3 radical; or RS and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur;

R

7 represents an alkyl or haloalkyl radical; 6

R

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

R

9 represents an alkyl radical or a hydrogen atom; Ri, represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, -O-alkyl, -S-alkyl, cyano or alkyl; R, and R 12 represent, independently of each other, a hydrogen or halogen atom;

R

13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF 3 or SF s group; m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical. C-R 12 the. other-.three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that, when R, is methyl, then R 3 is haloalkyl, R 4 is NH 2 Rn 1 is Cl, R 13 is CF 3 and X is N.

However, low concentrations of from 0.05 to weight/volume, more particularly from 0.1 to are preferred. Optimally, the value is between 0.25 and in particular in the region of 1%.

The expression pour-on skin solution is understood to refer to a ready-to-use solution intended to be applied topically and locally on the animal, preferably on the animal's back and at several points or along the line of the back, and applied in low volume, preferably of 5 to 20 ml per 100 kg, preferably about ml per 100 kg, with a total volume of from 10 to 150 ml per animal, preferably limited to 50 ml.

The compound acts by simple contact, the parasite becoming impregnated with the compound on contact with the hair and the skin.

This. thereby affords, in a noteworthy 7 manner, a both perfect compatibility with the restrictions of use in extensive grazing, in terms of ease of use in particular, and a spectrum of activity and of efficacy, as well as a period of efficacy, which are suited to this type of rearing.

By working on the concentration of compound in particular of compound A, solutions having noteworthy activities are obtained with, in particular, two months of efficacy against Boophilus microplus, this result, never before-having-been achieved. Moreover, the solution according to the invention allows Boophilus microplus to be totally eliminated from an infested animal in less than 2 days.

As has been stated above, the solution according to the present invention is applied topically, in low volume, to the animal's back. The compound of formula then diffuses out in a noteworthy manner, this being reflected by a distribution of the compound over the animal's entire body. It has also been observed that the animals remained protected in the case of passage through water or exposure to rain.

The dose of compound of formula is preferably -between 0-.1 and 2 mg/kg (animal weight), preferably between 0.25 and 1.5 mg/kg, and in particular about 1 mg/kg.

The compounds of formula in which R, is CN will be selected most particularly. The compounds in which R 2 is S(O),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 preferably being CF 3 as well as those in which X C-R 12

R

12 being a halogen atom, will also be selected. The compounds in which R 11 is a halogen atom and those in which R 13 is haloalkyl, preferably CF 3 are also preferred. In the context of the present invention, compounds combining two or more of these charac- 8 teristics will advantageously be selected.

A preferred class of compounds of formula consists of compounds such that R I is CN, R 3 is haloalkyl, preferably CF 3 or ethyl, R 4 is NH,, Rn 1 and R 12 are, independently of each other, a halogen atom, and/or

R

13 is haloalkyl.

The alkyl radicals of the definition of the compounds of formula generally comprise 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 6- or 7-membered ring.

A most particularly preferred compound of the formula in the invention is 1-[2,6-CI2 4-CF 3 phenyl]3-CN 4--[SO-CF 3 ]5-NH2pyrazole, referred to hereinbelow as compound A. This compound A will be used in particular in a proportion of from 0.1 to 2% by weight, more particularly about relative to the total solution.

Mention may also be made of the two compounds which differ from the above by the following characteristics: 1- n 0,R 3

CF

3 2- n 1,R 3 ethyl.

The compounds of formula may be prepared according to one or other of the processes described in patent applications WO-A-87/3781, 93/6089, 94/21606 or European patent application EP-A-0,295,117,.or any other process which falls within the competence of a specialist skilled in the art of chemical synthesis. For the chemical preparation of the products of the invention, a person skilled in the art is considered as having at his or her disposal, inter alia, all the contents of "Chemical Abstracts" and the documents cited therein.

9 It is not departing from the scope of the present invention to incorporate other insecticides into the solution according to the present invention.

The solutions according to the invention, which are advantageously oily, generally comprise a diluent or vehicle and also a solvent (organic solvent) for the compound of formula if. the latter is not soluble in the diluent.

As organic solvent which can be used in the invention, mention may be made in particular of: acetyltributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, 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, in particular N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.

As vehicle or diluent, mention may be made in particular of: plant oils such as soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils such as petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, for example, medium-chain (C8 to C12 in particular) triglycerides.

An emollient and/or spreading and/or filmforming agent will preferably be added, this agent being selected in particular from: polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, 10 polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils, in particular polydimethylsiloxane (PDMS) oils, for example those containing silanol functionalities, or a 45V2 oil,.

anionic surfactants such as alkaline stearates, in particular sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulphates, in particular sodium lauryl sulphate and sodium cetyl sulphate; sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids, in particular those derived from coconut oil, cationic.surfactants such:as water-soluble quaternary ammonium salts of formula

Y-

in which the radicals R are optionally hydroxylated hydrocarbon radicals and Y- is an anion of a strong acid such as the halide, sulphate and sulphonate anions; cetyltrimethylammonium bromide is among the cationic surfactants which can be used, amine salts of formula in which the radicals R are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is among the cationic surfactants which can be used, nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated, in particular polysorbate 80, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, amphoteric surfactants such -as the 11 substituted lauryl compounds of betaine; or a mixture of at least two of these agents.

The solvent will be used in proportion with the concentration of the compound I and its solubility in this solvent.

For example, compound A has a solubility of 4.3% m/V in acetyl tributyl citrate. It will be sought to have the lowest possible volume.

The vehicle makes up the difference to 100%.

The emollient is preferably used in a proportion of from 0.1 to 10%, in particular from 0.25 to by volume.

The subject of the present invention is also a process the elimination of parasites, in particular Boophilus microplus, from cattle and sheep using a direct pour-on skin solution according to the present invention, so as obtain long-lasting and broadspectrum efficacy, the solution being applied to the animal's back, preferably along the line of the back at one or more points.

According to a first embodiment, the process consists in applying the solution to the animals in pasture and/or before they arrive in pasture, the application preferably being repeated every month, preferably every two months.

According to a second embodiment, the process consists in applying the solution to the animals before they arrive in the "feed Lot", it being possible for this application to be the final one before the animals are slaughtered.

Obviously, the process may also consist in combining these two embodiments, namely the first followed by the second.

In all cases, the efficacy advantageously makes it possible to stop any application 1 to 3 months before slaughter, in particular between 1.5 and 2.5 months, more particularly about two months before slaughter.

The solutions according to the invention may be applied using any means known per se, preferably using an applicator gun or a metering flask.

The aim of the method is not therapeutic and is, in particular, to cleanse the skin and the hairs of the animals by eliminating the parasites which are present thereon, as well as their residues and dejections. The result of this is that the animals are no longer stressed by the parasites and their bites, this having positive consequences, for example on their growth and the use of their food ration.

Another subject of the invention is a therapeutic method using the external device according to the invention, intended for the treatment and prevention of parasitoses having pathogenic consequences.

The subject of the present invention is also the use of the compounds I, in particular compound A, for the manufacture of a direct pour-on skin solution comprising the compound in a low volume and designed to release the compound (I) onto the skin and the hairs for a contact action against the parasites of cattle and sheep, in particular cattle ticks, such as Boophilus microplus, and sheep blowfly and lice.

The use according to the invention is directed towards producing skin solutions as described above The present invention provides a direct pour-on oily skin solution intended to eliminate parasites from cattle and sheep, most particularly ticks, especially Boophilus microplus in cattle and lice and blowfly in sheep, comprising from 0.05 to weight/volume, relative to the total solution, of a compound of formula R R, R13 in which: RI is CN or methyl or a halogen atom;

R

2 is S nR 3 or 4, 5-dicyanomidazol-2-yl or haloalkyl;

R

3 is alkyl or haloalkyl;

R

4 represents a hydrogen or halogen atom; or a radical NR 5 R6, S(O)mR 7

C(O)

R

7

C(O)R

7

C(O)O-R

7 alkyl, haloalkyl or OR 8 or a radical -N=C(R 9 )(Rio);

R

7 represents an alkyl or haloalkyl radical;

R

8 represents an alkyl or haloalky radical or a hydrogen atom;

R

1 and R 12 represent, independently of each other, a hydrogen or halogen atom or optionally CN or NO 2

R

1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(0) qCF3 or SFs group; m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-R 1 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that, when Ri is methyl, either R 3 is haloalkyl, R4 is NH 2 Rn 1 is C1, R 13 is CF 3 and X isN; or R2 is 4, 5-dicyanoimidazol-2-yl, R4 is Cl, R 11 is Cl, R 13 is

CF

3 and X is =C-C1; in a formulation at low volume, designed to release the compound onto the skin and the hairs for a contact action against parasites.

The present invention also provides a process for the control or elimination of external parasites from cattle and sheep, comprising topically applying to a localized region of the back of the cattle or sheep, and diffusion therefrom over the animal's body and/or in the sebaceous glands of the animal and thereby obtain said control or elimination, a parasitically effective amount of a direct pour-on skin solution comprising from 0.05 to 25% weight/volume, relative to the total solution, of a compound of formula below: R R,

R

13 wherein: RI is CN or methyl or a halogen atom;

R

2 is S(O) nR 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(O) mR 7

C(O)

R

7 C(O) O-R 7 alkyl, haloalkyl or ORs or a radical -N=C (R9) (Rio);

R

5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O) alkyl, alkoxycarbonyl, or S(O) rCF 3 radical; or R 5 and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur;

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; Rio represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, -O-alkyl, -S-alklyl, cyano or alkyl;

R

1 1 and RI 2 represent, independently of each other, a hydrogen or halogen atom or optionally CN or NO 2

R

1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O) qCF3 or SF group; m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-R 1 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that, when Ri is methyl, either R 3 is haloalkyl, R 4 is NH 2 Ri 1 is Cl, R 1 3 is CF 3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, Ri is Cl, RI 3 is

CF

3 and X is C-C1.

The present invention further provides a process for distributing an active agent over the body of cattle or sheep and/or in sebaceous glands of the cattle or sheep, and thereby control external parasites on or eliminate external parasites from the cattle or sheep, comprising topically applying to a localized region of the back of the cattle or sheep, and diffusion therefrom over the animal's body, a parasitically effective amount of a direct pour-on skin solution comprising the active agent comprising at least one compound corresponding to formula below: Ri 13 wherein:

R

1 is CN or methyl or a halogen atom;

R

2 is S(O) nR 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(O) mR7 C(O)

R

7 C(O) O-R 7 alkyl, haloalkyl or ORs or a radical -N=C (R 9 (Rio);

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; Rio represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, -O-alkyl, -S-alklyl, cyano or alkyl; R, and R 1 2 represent, independently of each other, a hydrogen or halogen atom or optionally CN or NO 2

R

1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(0) qCF3 or SF group; m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-RI 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that, when Ri is methyl, either R 3 is haloalkyl, R 4 is NH 2

R

11 is Cl, R 1 3 is CF 3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R4 is Cl, R 11 is Cl, R 13 is

CF

3 and X is C-C1.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

The present invention will now be described in greater detail with the aid of non-limiting embodiment examples which demonstrate the activity of the solutions according to the present invention, with 13 reference to the attached drawings in which: Figure 1 is a graph showing the efficacy, against Boophilus microplus, of skin solutions according to the invention, with a 0.25%, 0.5% and 1% content, relative to a control, this graph including, on the xaxis, the time in days after application of the skin solutions, and, on the y-axis to the left, the number of ticks counted on the animals on which.the skin solutions according to the invention are applied, and, on the yaxis to the right, the number of ticks counted in the controls; Figure 2 is a graph showing the population of ticks in animals which have received the placebo according to Example 2, with, on the x-axis, the time in days., and,..on the, y-axis.; the number of-ticks; and Figure 3 compares the efficacy of a skin solution according to the invention containing 1% compound A (solid circles) with a skin solution containing 1% flumethrin (rings), with, on the x-axis, the time in days, and, on the y-axis, the number of ticks.

EXAMPLE 1: Preparation of the solutions according to the invention.

Ingredient Function Amount Compound A active substance' x g polyoxypropylene 15 stearyl ether emollient 5 g acetyl tributyl citrate solvent 30 g soybean oil diluent qs 100 ml 14 x 0.25 g for 0.25% solution x 0.5 g for 0.5% solution x 1 g for 1% solution Compound A is dissolved in the solvent before being mixed with the.other ingredients..

EXAMPLE 2: Study of the efficacy of skin solut-ons according to the invention containing, respectively, 0.25, 0.50 and 1% compound A to combat Boophilus microplus.

The. study was. performed on 16 young male.

castrated Herefords (weight ranging between 114 and 172 kg).

Three skin solutions according to Example 1 were prepared: 1. 1% compound A 2. 0.5% compound A 3. 0.25% compound A A placebo was prepared, which differed from the skin solutions according to the invention in that it contained no compound A.

In the studies, 1 ml of skin solution or of placebo were used per 10 kg of animal weight.

The dose volume was applied along the line of the animal's back, from the head to the base of the tail.

Between days -24 and the animals were artificially infested on 11 occasions with 2,500 Boophilus microplus larvae. The aim of 24-day infestation is to ensure that all of the stages of Boophilus microplus are present on the animal (eggs, larvae, adults).

On day 0, the animals receive one of the skin solutions or the placebo.

15 Before the skin solutions or the placebo are applied, the number of ticks present on the various animals in the different groups are counted.

The following table indicates the values recorded, the weight of the animals and the dose of skin solution or of placebo which will be applied to each of these animals.

16 Group Animal No. Number of Weight Dose (ml) ticks (in kg) 1.00% 94 588 134 13.4 43 470 140 14.0 47 300 154 15.4 39 254 160 16.0 0.50% 34 706 145 14.5 99 452 143 14.3 48 375 114 11.4 201 153 15.3 0.25% 40 510 148 14.8 92 453 144 14.4 41 432 155 .15.5 36 236 171 17.1 Placebo 96 627 150 15.0 44 482 144 14.4 93 315 140 14.0 97 292 172 17.2 The blood-engorged female ticks which become detached are included in the count. The results are indicated in Figure 1.

A dose-dependent- effect is obtained with 100% efficacy for the skin solution according to the invention containing 1% compound A. The less-concentrated solutions nevertheless give noteworthy results.

The great rapidity of action of the solutions according to the invention is also noted, the 1% solution allowing Boophilus microplus to be totally eliminated in less than 2 days.

EXAMPLE, 3-: Comparison of efficacy between a skin solution according to the invention containing 1% compound A and a skin solution containing 1% flumethrin.

Animals of the same breed as those in Example 1 17 were used.

On day 0, the groups are treated with: skin solution containing 1% compound A skin solution containing 1% flumethrin (mineral oil and ethylhexyl alcohol excipient) placebo (excipient identical to the solution according to the invention) Table 2 below indicates, for each group, the weight of the animals, the dose of skin solution received and the dose of active substance applied.

18 Group Animal No. Weight Dose (ml) Dose (mg/kg)) 1% 719 141 14.1 1 Compound A 709 125 12.5 1 713 150 15.0 1 710 136 13.6 1 703 138 13.8 1 1% 706 145 14.5 1 flumethrin 711 136 13.6 1 715 132 13.2 1 702 142 14.2 1 701 127 12.7 1 Placebo 717 133 13.3. 0 707 133 13.3 0 704 134 13.4 0 718 132 13.2 0 708 143 14.3 0 From day 2 to day 32, the animals receive 5,000 Boophilus microplus larvae three times a week. From day 18 to 64, the blood-engorged female ticks which become detached are collected and counted.

The results are indicated in Figures 2 and 3, which demonstrate the total efficacy of the skin solution according to the invention.

EXAMPLE 4: Study of efficacy over time.

Skin solutions according to the invention containing 0.25, 0.5 or 1% compound Awhere used in this example.

The composition of these solutions is the same as for the above examples.

The cattle were preinfested so as to have all of the stages of Boophilus microplus present (infestation 19 with 5,000 larvae, 22 days, 15 days and 8 days before application of the skin solution).

After application of the skin solutions, the cattle are again infested with the larvae for 13 weeks, to determine the efficacy of the three concentrations.

The results are reported in Table 3 below: Weeks of infestation Efficacy index for each after treatment concentration .0 0.25% 0.5% 1 97.6 100 100 2 98.8 100 100 3 99.7 100 100 4 99.3 100 100 5 96.7 92.9 100 6 98.6 93.2 100 7 92.4 88.6 99.7 8 85.8 83.4 100 9 28.0 37.9 79.8 ;0 10 23.0 41.4 65.3 11 18.9 55.2 61.5 12 1.7 37.3 32.2 13 8.4 48.5 46.4 It is thus observed that noteworthy efficacy, which may last for two months or more, is obtained.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

P;OPERKbml25130-97 spc1 2 doc4 1100 -19A- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims

1. A direct pour-on oily skin solution intended to eliminate parasites from cattle and sheep, most particularly ticks, especially Boophilus microplus in cattle and lice and blowfly in sheep, comprising from 0.05 to 25% weight/volume, relative to the total solution, of a compound of formula R, R 13 (I) in which: RI is CN or methyl or a halogen atom; R 2 is S nR 3 or 4, 5-dicyanomidazol-2-yl or haloalkyl; R3 is alkyl or haloalkyl; R 4 represents a hydrogen or halogen atom; or a radical NRsR 6 S(O)mR 7 C(O) R 7 C(O)R 7 C(O)O-R 7 alkyl, haloalkyl or OR 8 or a radical -N=C(R 9 )(Rio); R 5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl, or S(O)rCF 3 radical; or Rs and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur; R 7 represents an alkyl or haloalkyl radical; Rs represents an alkyl or haloalky radical or a hydrogen atom; R 9 represents an alkyl radical or a hydrogen atom; Rio represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, -O-alkyl, -S-alkyl, cyano or alkyl; R 1 1 and RI2 represent, independently of each other, a hydrogen or halogen atom or optionally CN or NO 2 RI 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(0) qCF3 or SF group; m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-RI 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that, when R 1 is methyl, either R 3 is haloalkyl, R 4 is NH 2 R 11 is Cl, RI 3 is CF 3 and X is N; or R 2 is 4, 5-dicyanoimidazol-2-yl, R4 is Cl, R 1 1 is C1, Ri3 is CF 3 and X is =C-C1; in a formulation at low volume, designed to release the compound onto the skin and the hairs for a contact action against parasites.

2. A solution according to claim 1, wherein the compound of formula is such that: RI is CN or methyl; R 2 is S(0) nR 3 R 3 is alkyl or haloalkyl; R 4 represents a hydrogen or halogen atom; or a 1 radical NR 5 R 6 S(O) mR 7 C(O) R 7 alkyl, haloalkyl or OR 8 or a radical -N=C (R 9 (Rio); R 5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O) alkyl or S(0) rCF 3 radical; or Rs and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur; 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; Rio represents a phenyl or heteroaryl group optionally substituted withone or more halogen atoms or groups such as OH, -O-alkyl, -S-alkyl, cyano or alkyl; R 1 1 and Ri2 represent, independently of each other, a hydrogen or halogen atom; Ri 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(0) qCF3 or SF group; m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-RI 2 the other three valency positions of the carbon atom forming part of the aromatic ring; 22 with the proviso that, when RI is methyl, then R 3 is haloalkyl, R 4 is NH 2 R 1 I is Cl, Ri 3 is CF 3 and X is N.

3. A solution according to claim 1 or claim 2, wherein the compound of formula (I) is such that Ri is CN.

4. A solution according to any one of the preceding claims, wherein the compound of formula is such that R 1 3 is haloalkyl.

5. A solution according to any one of the preceding claims, wherein the compound of formula is such that R 1 3 is CF 3

6. A solution according to any one of the preceding claims, wherein the compound of formula is such that R 2 is S(O) nR 3

7. A solution according to any one of the preceding claims, wherein n R 3 being chosen among the group consisting of CF 3 methyl and ethyl.

8. A solution according to any one of claims 1 to 6, wherein n 0 and R 3 is CF 3

9. A solution according to any one of the preceding claims, wherein the compound of formula is such that X is C-RI 2 with R 12 being a halogen atom. A solution according to any one of the preceding claims, wherein the compound of formula is chosen from those in which Ri is CN, R 3 is haloalkyl, R 4 is NH 2 R 1 and R 1 2 are, independently of each other, a halogen atom and/or R 13 is haloalkyl.

11. A solution according to any one of the preceding claims, wherein the compound of formula is chosen among the group consisting of the compound A: 6-C1 2 4-CF 3 phenyl] 3-CN 4-[SO-CF 3 5-NH 2 pyrazole, and its derivatives with n O, R 3 CF 3 and n 1, R 3 ethyl.

12. A solution according to any one of the preceding claims, wherein the compound of formula is present in a proportion of from 0.05 to 10% weight/volume.

13. A solution according to any one of the preceding claims, wherein the compound of formula is present in a proportion of from 0.1 to 2%.

14. A solution according to any one of the preceding claims, wherein the compound of formula is present in a proportion of from 0.25 to A solution according to any one of the preceding claims, wherein the compound of formula is present in a proportion of about 1%.

16. A solution according to any one of the preceding claims, wherein the compound of formula is present in a proportion of from 0.05 to 10% weight/volume.

17. A solution according to any one of the preceding claims, wherein the compound of formula is present in a proportion of from 0.1 to 2%.

18. A solution according to any one of the preceding claims, wherein the compound of formula is present in a proportion of from 0.25 to

19. A solution according to any one of the preceding claims, wherein the compound of formula is present in a proportion of about 1%. A solution according to any one of the preceding claims, wherein it comprises a solvent for the compound and a diluent, optionally an emollient.

21. A solution according to claim 20, wherein the solvent is selected from the group consisting of: acetyl tributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethly ether, liquid polyyoxyethylene glycols, propylene glycol, 2-pyrrolidone, in particular N- methylpyrrolidone, diethylene glycol monethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at lest two of these solvents.

22. A solution according to claim 20 or claim 21, wherein the diluent is selected from the group consisting of: plant oils such as soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils such as petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, medium-chain (C8 to C12 in particular).

23. A solution according to any one of claims 20 to 22, wherein the emollient is selected from the group consisting of: polyvinylpyrrolidone,polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils, anionic surfactants such as alkaline stearates, in particular sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulphates, in particular sodium lauryl sulphate and sodium cetyl sulphate; sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids, in particular those derived from coconut oil, cationic surfactants such as water-soluble quaternary ammonium salts of formula N R'R" Y in which the radicals R are optionally hydroxylated hydrocarbon radicals, and Y- is an anion of a strong acid such as the halide, sulphate and sulphonate anions; cetyltrimethylammonium bromide is among the cationic surfactants which can be used, amine salts of formulate N R'R"R' in which the radicals R are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is among the cationic surfactants which can be used, nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylentated, in particular polysorbinate 80, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-15-stearyl ether; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, amphoteric surfactants such as the substituted lauryl compounds of betaine; or a mixture of at least two of these agents.

24. A solution according to any one of the preceding claims, wherein it is an oily solution. A solution according to any one of the preceding claims, wherein it is designated to ensure protection over a period longer than or equal to 2 months.

26. A solution according to any one of the preceding claims, wherein it is designated to ensure total elimination of Boophilus microplus in less than 2 days.

27. A process for the control or elimination of external parasites from cattle and sheep, comprising topically applying to a localized region of the back of the cattle or sheep, and diffusion therefrom over the animal's body and/or in the sebaceous glands of the animal and thereby obtain said control or elimination, a parasitically effective amount of a direct pour-on skin solution comprising from 0.05 to 25% weight/volume, relative to the total solution, of a compound of formula below: R R, R 1 is CN or methyl or a halogen atom; R 2 is S(O) nR 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(O) mR 7 C(O) R 7 C(O) O-R 7 alkyl, haloalkyl or OR 8 or a radical -N=C (R 9 (Rio); R 5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O) alkyl, alkoxycarbonyl, or S(O) rCF 3 radical; or R 5 and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur; 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; Rio represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, -O-alkyl, -S-alklyl, cyano or alkyl; R 1 I and RI2 represent, independently of each other, a hydrogen or halogen atom or optionally CN or NO 2 Ri 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O) qCF3 or SF group; m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-R 1 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that, when R 1 is methyl, either R 3 is haloalkyl, R 4 is NH 2 R 11 is C1, Ri3 is CF 3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, Ri is Cl, Ri 3 is CF 3 and X is C-C1.

28. A process for distributing an active agent over the body of cattle or sheep and/or in sebaceous glands of the cattle or sheep, and thereby control external parasites on or eliminate external parasites from the cattle or sheep, comprising topically applying to a localized region of the back of the cattle or sheep, and diffusion therefrom over the animal's body, a parasitically effective amount of a direct pour-on skin solution comprising the active agent comprising at least one compound corresponding to formula below: wherein: RI is CN or methyl or a halogen atom; R 2 is S(O) nR 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(O) mR 7 C(O) R 7 C(O) O-R 7 alkyl, haloalkyl or ORs or a radical -N=C (R 9 (Rio); R 5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O) alkyl, alkoxycarbonyl, or S(0) rCF 3 radical; or R 5 and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur; 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; Rio represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, -O-alkyl, -S-alklyl, cyano or alkyl; R 1 1 and RI 2 represent, independently of each other, a hydrogen or halogen atom or optionally CN or NO 2 R 1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O) qCF3 or SF group; m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-R 12 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that, when R 1 is methyl, either R 3 is haloalkyl, R 4 is NH 2 Ri 1 is Cl, R 1 3 is CF 3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R4 is Cl, R 11 is Cl, R 13 is CF 3 and X is C-C1.

29. A process according to claim 27 or claim 28, wherein the solution is applied in a volume from 10-150 ml per 100 kg of animal. A process according to claim 27 or claim 28, wherein the solution is applied with a total volume of about 50 ml per animal.

31. A process according to any one of claims 27 to 30, wherein the compound of formula is such that: RI is CN or methyl; R 2 is S(0) nR 3 R 3 is alkyl or haloalkyl; R4 represents a hydrogen or halogen atom; or a radical NRR 6 S(O)mR7, C(O)R 7 alkyl, haloalky or OR 8 or a radical -N=C(R 9 )(Rio); R 5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl or S(0) rCF 3 radical; or R 5 and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur; R 7 represents an alkyl or haloalkyl radical; Rs represents an alkyl or haloalkyl radical or a hydrogen atom; R 9 represents an alkyl radical or a hydrogen atom; Rio represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, -O-alkyl, -S-alkyl, cyano or alkyl; R 1 1 and R 1 2 represent, independently of each other, a hydrogen or halogen atom; R 1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O) qCF3 or SF group; m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-RI 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that, when R 1 is methyl, then R 3 is haloalkyl, R 4 is NH 2 Rn 1 is C1, R 1 3 is CF3 and X is N.

32. A process according to any one of claims 27 to 31, wherein the compound of formula is such that Ri is CN.

33. A process according to any one of claims 27 to 32, wherein the compound of formula is such that R13 is haloalkyl.

34. A process according to any one of claims 27 to 33, wherein the compound of formula is such that R 1 3 is CF 3 A process according to any one of claims 27 to 34, wherein the compound of formula is such that R 2 is S(O) nR 3

36. A process according to any one of claims 27 to 35, wherein n 1 and R 3 is chosen among the group consisting of CF 3 methyl and ethyl.

37. A process according to any one of claims 27 to 35, wherein n O, R 3 preferably being CF 3

38. A process according to any one of claims 27 to 37, wherein the compound of formula is such that X is C-R 1 2 with R 12 being a halogen atom.

39. A process according to any one of claims 27 to 38, wherein the compound of formula is such that RI is CN, R 3 is haloalkyl, R4 is NH 2 R 11 and RI 2 are, independently of each other, a halogen atom and/or R 1 3 is haloalkyl. A process according to any one of claims 27 to 38, wherein the compound of the formula is chosen among the group consisting of compound A: 1-[2,6-C1 2 4-CF3phenyl] 3-CN 4-[SO-CF 3 5-NH 2 pyrazole, and its derivatives with n 0, R 3 CF 3 and n 1, R 3 ethyl.

41. A process according to any one of claims 27 to 40, wherein the compound of formula is present in a proportion of from 0.05 to 10% weight/volume.

42. A process according to any one of claims 27 to 41, wherein the compound of formula is present in a proportion of from 0.1 to 2%.

43. A process according to any one of claims 27 to 42, wherein the compound of formula is present in a proportion of from 0.25 to

44. A process according to any one of claims 27 to 43, wherein the compound of formula is present in a proportion of about 1%. A process according to any one of claims 27 to 44, wherein the compound of formula is present in a proportion of from 0.05 to 10% weight/volume.

46. A process according to any one of claims 27 to 45, wherein t] formula is present in a proportion of from 0.1 to 2%.

47. A process according to any one of claims 27 to 46, wherein t] formula is present in a proportion of from 0.25 to

48. A process according to any one of claims 27 to 47, wherein tl formula is present in a proportion of about 1%.

49. A process according to any one of claims 27 to 48, wherein solution in a proportion of from 0.1 to 2 mg/kg (animal weight). he compound of he compound of he compound of one applies the A process according to any one of claims solution in a proportion of from 0.25 to 1.5 mg/kg.

51. A process according to any one of claims solution in a proportion of about 0.1 mg/kg.

52. A process according to any one of claims solution in a proportion of from 0.1 to 2 mg/kg.

53. A process according to any one of claims solution in a proportion of from 0.25 to 1.5 mg/kg.

54. A process according to any one of claims solution in a proportion of about 0.1 mg/kg. 27 to 49, wherein one applies the 27 to 50, wherein one applies the 27 to 51, wherein one applies the 27 to 52, wherein one applies the 27 to 53, wherein one applies the A process according to any one of claims 27 to 54, wherein one applies the solution to the animals in pasture or before they arrive in pasture.

56. A process according to any one of claims 27 to 55, wherein one applies the solution every two months.

57. A process according to any one of claims 27 to 56, wherein one applies the solution to the animals before they arrive in the Feed Lot, this application being the final one before the animal is slaughtered.

58. A process according to any one of claims 27 to 57, wherein when applied topically locally onto the animal's skin, the solution is designed to ensure protection for at least two months, in particular against Boophilus microplus.

59. A process according to any one of claims 27 to 58, wherein the solution is designed to ensure total elimination of Boophilus microplus in less than 2 days. A process according to any one of claims 27 to 59 wherein the solution further comprises a solvent for the compound and a diluent.

61. A process according to any one of claims 27 to 60 wherein the solution further comprises an emollient.

62. A process according to claim 60 or claim 61 wherein the solvent is selected from the group consisting of: acetyltributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, 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, in particular N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.

63. A process according to claim 62 wherein the 2-pyrrolidone is N- methylpyrollidone.

64. A process according to any one of claims 60 to 63, wherein the diluent is selected from the group consisting of: plant oils, mineral oils paraffin, silicone or aliphatic or cyclic or medium chain hydrocarbons. A process according to claim 64 wherein the plant oil is selected from soybean oil, groundout oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, or sunflower oil.

66. A process according to any one of claims 60 to 65, wherein the emollient is selected from the group consisting of: polyyinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils, in particular polydimethylsiloxane (PDMS)oils, for example those containing silanol functionalities, or a 45V2 oil, anionic surfactants such as alkaline stearates, in particular sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulphates, in particular sodium lauryl sulphate and sodium cetyl sulphate; sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids, in particular those derived from coconut oil, cationic surfactants such as water-soluble quaternary ammonium salts of formula N.sup.+ Y.sup.- in which the radicals R are optionally hydroxylated hydrocarbon radicals and Y.sup.- is an anion of a strong acid such as the halide, sulphate and sulphonate anions; cetyltrimethylammonium bromide is among the cationic surfactants which can be used, amine salts of formula N.sup.+ in which the radicals R are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is among the cationic surfactants which can be used, nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated, in particular polysorbate 80, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, amphoteric surfactants such as the substituted lauryl compounds of betaine; or a mixture of at least two of these agents.

67. A direct pour-on oily skin solution substantially as hereinbefore described with reference to the examples and/or the preferred embodiments and excluding, if any, comparative examples.

68. A process for the control or elimination of external parasites from cattle and sheep substantially as hereinbefore described with reference to the examples and/or the preferred embodiments and excluding, if any, comparative examples.

69. A process for distributing an active agent over the body of cattle or sheep and/or in sebaceous glands of the cattle or sheep substantially as hereinbefore described with reference to the examples and/or the preferred embodiments and excluding, if any, comparative examples. Dated this thirteenth day of February 2006 Merial Patent Attorneys for the Applicant: F B RICE CO