AU763484B2 - Direct pour-on skin solution for antiparasitic use in cattle and sheep - Google Patents

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:

A-

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

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 and anulatus.

The other main parasites of cattle and sheep are indicated in order of decreasing importance: myiases such as Dermatobia hominis (known 20 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 25 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.

30 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 15% 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 25 mentioned. There are very many forms of administration .**here also, and these include, for example, solutions, emulsions, suspensions, powders, pastes, granules and aerosols.

e• The problem which is posed is to find an effective means which is entirely suitable for *i 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 'OWPEmrK.. 7513G-97 pc2.do-OII II0 -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 i 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 25 small enclosure over an average period of two months preceding slaughter.

eo P.1OPER\PDBSpcci2365260 spc4 doc-1/0403 -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 oily 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,

N

R,

X

R

13 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 OR 8 or a radical -N=C (R 9 )(Rio); 15 R 5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl, 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; 20 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-alkyl, cyano or alkyl;

R

1 and R 1 2 represent, independently of each other, a hydrogen or halogen atom or CN or NO 2 P:OPER(KbU 5130-97 spc3oc.d-212/ -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-RI 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that, when R, 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,

R

4 is Cl, Rl 1 is Cl, R 13 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: R2 R, R4 R13 R3 is alkyl or haloalkyl; R4 represents a hydrogen or halogen atom; or a radical NRsR6, S(O)mR7, C(O)RT, iC(O)O-R 7 alkyl, haloalkyl or OR 8 or a radical -N=C (R 9 )(Rio); 20 R and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl, or S(O),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 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; P:'OPERPDBSpcci2365260 spe4.doc-01/04103

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 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-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

1 1 is Cl, Ri3 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, R 1 3 is CF 3 and X is =C-Cl; in the preparation of a ready-to-use direct pour-on skin oily 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 oily 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 20 against parasites, said solution comprising 0.5 to 25% weight/volume, relative to the total solution, of a compound of formula

*N

R4

R,

o Rx R R 13 P.lOPER\KbMn25130-97 spc3.doc-2/l 1/00 -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; R4 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),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;

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-alkyl, cyano or alkyl; RII and RI2 represent, independently of each other, a hydrogen or halogen atom or CN or N0 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 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 is Cl, RI 3 is

CF

3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R4 is Cl, Rn 1 is Cl, R 1 3 is CF 3 and X is =C-C1.

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

R

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

R

4 represents a hydrogen or halogen atom; or a radical NR 5

R

6 S(0).R C(O) C(0)O-R 7 alkyl, haloalkyl or OR 8 or a radical (R 10 RS and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O),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 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; Ri 0 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

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

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,, R 11 is Cl, R 13 is CF 3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, is Cl, R 13 is CF 3 and X is =C-C1; Sin 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 RI 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 NR 5

R

6 alkyl, haloalkyl or OR, or a radical -N=C(R 9

(R

0 Rs and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl or S(O),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 hetero atoms, such as oxygen or sulphur;

R

7 represents an alkyl or haloalkyl radical; -6 R, represents an alkyl or haloalkyl radical or a hydrogen atom;

R

9 represents an alkyl radical or a hydrogen atom; Ro 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 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 Ri is methyl, then R 3 is haloalkyl, R 4 is NH,, R 11 is Cl, R 1 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 I 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 20 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 25 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 CF3, as well as those in which X =C-R 12

R

1 being a halogen atom, will also be selected. The compounds in which R 1 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, is CN, R 3 is haloalkyl, preferably CF 3 or ethyl, R 4 is NH 2 Ri, and R 12 are, independently of each other, a halogen atom, and/or

R

1 3 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-C1 2 4-CF 3 phenyl]3-CN 4- [SO-CF 3 ]5-NH 2 pyrazole, 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.

S. 20 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.

25 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, 20 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: 25 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 film- ~forming 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 N Yin 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; 20 cetyltrimethylammonium bromide is among the cationic surfactants which can be used, amine salts of formula in which

S

the radicals R are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is among the 25 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 for 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 broad- 2 spectrum 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, theprocess 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 12 makes it possible to stop any application 1 to 3 months before slaughter, in particular between 1.5 and 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 anapplicator gun or a metering flask.

The aim of the method is not therapeutic and is, in particular, to cleanse'theskin 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 on 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 0prevention of parasitoses having pathogenic 20 consequences.

00 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 lowvolume and designed 25 to release the compound onto the skin and the hairs 0.0.

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 30 directed towards producing skin solutions as described above.

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 20 days, and, on the y-axis, the number of ticks.

g i EXAMPLE 1: Preparation of the solutions according to the *.oo Sinvention.

25 Ingredient Function Amount i .11. -r 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 solutions 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: 20 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 25 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.

o *o.

*ooo* o 16 *c

S

*SS.

S

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 10 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.

o "o 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: 25 Study of efficacy over time.

Skin solutions according to the invention containing 0.25, 0.5 or 1% compound A where 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 4 4 4 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.XFERIbmU25130-97 spe2.docm-Ol 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.

*o .o

Claims (59)

1. A method of eliminating parasites from cattle and sheep, comprising administration of to 150 ml of a ready-to-use direct pour-on oily solution to the skin and hair of an animal in need thereof for contact against a parasite; said solution comprising from 0.05 to weight/volume, relative to the total solution, of a compound of formula R2 R, N R4 R, X R 1 3 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; SR 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; 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; RI, and Ri2 represent, independently of each other, a hydrogen or halogen atom or CN or NO 2 P:\OPEPAKBMUS13G-97 CLAIMS2.DOC- 22/11100 -21- 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, R 4 is NH 2 R 11 is Cl, RI3 is CF 3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, R, 1 is Cl, R 13 is CF 3 and X is =C-C1.

2. A method according to claim 1 wherein: R 1 is CN or methyl; R 2 is S(O)nR 3 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 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, 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; R7 represents an alkyl or haloalkyl radical; R 7 represents an alkyl or haloalkyl radical or a hydrogen atom; R9 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 RI 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 5 group; S 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 Ri is methyl, then R 3 is haloalkyl, R4 is NH 2 Rln is Cl, R 13 is CF 3 and X is N.

3. A method according to claim 1 or claim 2 wherein R 1 is CN. P:-OPER'iKBM\25130-97 CLAIMS.DOC 22/111M -22-

4. A method according to any one of claims 1 to 3 wherein RI3 is haloalkyl. A method according to claim 4 wherein R 1 3 is CF 3

6. A method according to any one of claims I to 5 wherein R 2 is S(O)nR 3

7. A method according to claim 6 wherein n=l.

8. A method according to claim 6 wherein R 3 is CF 3 or alkyl.

9. A method according to claim 8 wherein R 3 is methyl or ethyl. A method according to claim 6 wherein n=0.

11. A method according to claim 10 wherein R 3 is CF 3

12. A method according to any one of claims 1 to 11 wherein X is C-Ri 2 with R 1 2 being a O. halogen atom.

13. A method according to any one of claims 1 to 8 or 10 to 12 wherein the compound of formula is chosen from those in which Ri is CN, R3 is haloalkyl, R 4 is NH 2 Rl and RI 2 are, "independently of each other, a halogen atom and/or Ri3 is haloalkyl.

14. A method according to claim 1 wherein the compound of formula is: 1-[2,6-C1 2 4-CF 3 phenyl]3-CN 4-[SO-CF 3 5-NH 2 pyrazole.

15. A method according to any one of claims 1 to 14 wherein the ready-to-use solution is administered in a volume of 5 to 20 ml per 100 kg of animal.

16. A method according to claim 15 wherein the solution is administered in a volume of about 10 ml per 100 kg of animal.

17. A method according to any one of claims 1 to 14 wherein the ready-to-use solution is administered in a total volume of 50 ml per animal.

18. A method according to any one of claims 1 to 17 wherein the parasites are cattle ticks or sheep blowfly or lice. P:OPERRUMU 5130-97 CLAIMS2.OC- 22/I /O -23-

19. A method according to claim 18 wherein the cattle ticks are Boophilus microplus. A method according to any one of claims 1 to 19 wherein the solution comprises from 0.05 to 10% weight/volume of compound of formula

21. A method according to claim 20 wherein the solution comprises from 0.1 to 2% of compound of formula

22. A method according to claim 21 wherein the solution comprises from 0.25 to 1.5% of compound of formula

23. A method according to claim 22 wherein the solution comprises about 1% of compound of formula

24. A method according to any one of claims 1 to 23 wherein the solution further comprises a solvent for the compound and a diluent.

25. A method according to claim 24 wherein the solution further comprises an emollient.

26. A method according to claim 24 or claim 25 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, dimethyl-acetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, mono-methylacetamide, dipropylene glycol S*.i monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, diethylene *i glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.

27. A method according to claim 26 wherein the 2-pyrrolidone is N-methylpyrrolidone.

28. A method according to claim 24 or claim 25, wherein the diluent is selected from the group consisting of: P:\OPER\KBMUS]130-9 CLMMS2.DOC- 22/11/00 -24- plant oils, mineral oils, paraffin, silicone, or aliphatic or cyclic or medium chain hydrocarbons.

29. A method according to claim 28 wherein the plant oil is selected from soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, or sunflower oil. A method according to claim 28 wherein the mineral oil is petrolatum and the medium chain hydrocarbon is Cs-C12.

31. A method according to any one of claims 25 to 30, 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; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulphates, sodium dodecylbenze-nesulphonate, sodium dioctylsulphosuccinate; fatty acids, cationic surfactants, amine salts of formula in which the radicals R are optionally hydroxylated hydrocarbon radicals, nonionic surfactants, oo amphoteric surfactants, or a mixture of at least two of these agents. S32. A method according to claim 31 wherein: when the emollient is an alkaline stearate it is selected from sodium, potassium or ammonium stearate, when the emollient is an alkyl sulphate it is selected from sodium lauryl sulphate or sodium cetyl sulphate, when the emollient is a fatty acid it is derived from coconut oil, when the emollient is a cationic surfactant it is a water-soluble quaternary ammonium salt of formula in which the radicals R are optionally hydroxylated hydrocarbon radicals and Y- is an anion of a strong acid, P:\OPER\PDB\SPECI\2365260 CLAIMS I.DOC 2/4/03 when the emollient is a nonionic surfactant it is an optionally polyoxyethylenated sorbitan ester.

33. A method according to claim 32 wherein the Y- of the cationic surfactant is a halide, sulphate or sulphonate ion.

34. A method according to claim 33 wherein the cationic surfactant is cetyltrimethylammonium bromide. A method according to claim 32 wherein sorbitan ester is polysorbate polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as stearyl ether; polyethylene glycol stearate, polyoxy-ethylenated derivatives of castor oil, polyglyceral esters, polyoxyethylenated fatty alcohols, polyoxy-ethylenated fatty acids, copolymers of ethylene oxide and propylene oxide.

36. A method according to claim 31 wherein the amphoteric surfactant is a substituted lauryl compound of betaine.

37. A method according to any one of claims 1 to 36 wherein administration of a compound of formula provides protection over a period longer than or equal to 2 months.

38. A method according to any one of claims 1 to 37 wherein administration of a compound S of formula provides total elimination of Boophilus microplus in less than two days.

39. A method according to any one of claims 1 to 38 wherein administration occurs before the animal enters a feed lot. A method according to any one of claims 1 to 39 wherein administration occurs every month.

41. A method according to any one of claims 1 to 39 wherein administration occurs every two months. P:\OPER\PDB\SPECI\2365260 CLAIMS .DOC 2/4/03 -26-

42. A method according to claim 40 or claim 41 wherein administration ceases one to three months before slaughter.

43. Use of a compound corresponding to formula below: R2 R, N Rl3 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 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; RI1 and RI 2 represent, independently of each other, a hydrogen or halogen atom or CN or NO 2 Ri 3 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; P:\OPER\PDB\SPECI\2365260 CLAIMS IDOC- 2/4/03 -27- X represents a trivalent nitrogen atom or a radical C-R12, 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 NH2, RI, is Cl, Ri3 is CF 3 and X is N; or Rz is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, Rn 1 is Cl, Ri 3 is CF 3 and X is =C-Cl; in the preparation of a ready-to-use direct pour-on skin oily 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.

44. Use according to claim 43 wherein: R, is CN or methyl; R 2 is S(O)nR 3 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(0)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(O)rCF 3 radical; or R 5 and Re 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; o 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; RI and R 12 represent, independently of each other, a hydrogen or halogen 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-R 1 2 the other three valency positions of the carbon atom forming part of the aromatic ring; i1 with the proviso that, when R, is methyl, then R 3 is haloalkyl, R 4 is NH 2 R 1 is Cl, RI 3 is CF 3 and X is N. o* P:\OPER\PDB\SPECI\2365260 CLAIMS I.DOC- 1/403 -28- Use according to claim 43 or claim 44 wherein R 13 is haloalkyl.

46. Use according to claim 45 wherein R 3 is CF 3

47. Use according to any one of claims 43 to 46 wherein the compound of formula is such that R 2 is S(O)nR 3

48. Use according to claim 47 wherein n=l.

49. Use according to claim 48 wherein R 3 is CF 3 or alkyl. Use according to claim 49 wherein R 3 is methyl or ethyl.

51. Use according to claim 47 wherein n=0.

52. Use according to claim 51 wherein R 3 is CF 3

53. Use according to any one of claims 43 to 52 wherein X is C-RI 2 with RI2 being a halogen atom.

54. Use according to claim 43 or claim 44 wherein RI is CN, R 3 is haloalkyl, R 4 is NH 2 R I and R 1 2 are, independently of each other, a halogen atom and/or RI 3 is haloalkyl. Use according to claim 43 or claim 44 wherein the compound of the formula is: 1-[2,6-Cl 2 4-CF 3 phenyl]3-CN 4-[SO-CF 3 5-NH 2 pyrazole.

56. Use according to any one of claims 43 to 55 wherein the solution is for administration in a volume of 5 to 20 ml, per 100 kg.

57. Use according to claim 56 wherein the solution is for administration in a volume of about 10 ml per 100 kg of animal.

58. Use according to any one of claims 43 to 55 wherein the solution is for administration in a total volume of 50 ml.

59. Use according to any one of claims 43 to 58 wherein the parasites are cattle ticks or a a P:\OPER\PDB\SPECI\2365260 CLAIMS I.DOC 2/4/03 -29- sheep blowfly and lice. Use according to claim 59 wherein the cattle ticks are Boophilus microplus.

61. Use according to any one of claims 43 to 60 wherein the solution is for administration at a rate of 0.1 to 2 mg/kg.

62. Use according to claim 61 wherein the rate is 0.25 to 1.5 mg/kg.

63. Use according to claim 62 wherein the rate is about 0.1 mg/kg.

64. Use according to any one of claims 43 to 61 wherein administration of the solution provides protection for at least two months. Use according to any one of claims 60 to 64 wherein the solution is for total elimination of Boophilus microplus in less than two days.

66. Use according to any one of claims 43 to 65 wherein the solution is for administration to the animal before the animal enters into a feed lot.

67. Use according to claim 66 wherein the solution is for administration every month.

68. Use according to claim 67 wherein the solution is for administration every two months.

69. A ready-to-use direct pour-on oily 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 o*oo ooo o* *o 30-97 CLAIMS2.DOC 22/11/00 R2 R, \1N R 1 3 in which: R 1 is CN or methyl or a halogen atom; R2 is S(O)nR3 or 4,5-dicyanoimidazol-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(0)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, i: .alkoxycarbonyl, or S(O)rCF 3 radical; or R 5 and R 6 may together form a divalent alkylene radical Swhich may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur; R 7 represents an alkyl or haloalkyl radical; Srepresents an alkyl or haloalyl radical or a hydrogen atom; R represents an alky 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; RI and Ri 2 represent, independently of each other, a hydrogen or halogen atom or CN Sor NO 2 SR 13 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 RI is methyl, either R3 is haloalkyl, R4 is NH 2 R 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 1 1 is Cl, R 1 3 is CF 3 and X is =C-C1. P:\OPER\PDB\SPECI\2365260 CLAIMS I.DOC 4/4/03 -31 A method of eliminating parasites from cattle and sheep according to claim 1, substantially as hereinbefore described with reference to the Examples.

71. A use according to claim 43 substantially as hereinbefore described with reference to the Examples.

72. An oily solution according to claim 69 substantially as hereinbefore described with reference to the Examples. DATED this 4th April, 2003 MERIAL by DAVIES COLLISON CAVE Patent Attorneys for the Applicant 0 0* *..000 o$ 0 0 0 oo00 *oo **o go *o