AU5432901A - Insecticidal combination effective against fleas on mammals, particularly cats and dogs - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: Merial DP Australia Documents received dn: 12 JUL 2001 ADDRESS FOR SERVICE: Batch No: I DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Insecticidal combination effective against fleas on mammals, particularly cats and dogs" The following statement is a full description of this invention, including the best method of performing it known to us: P.OPER\MKR\SPECI\731994-divdoc- 2/07/01 -1- INSECTICIDAL COMBINATION TO CONTROL MAMMAL FLEAS, IN PARTICULAR FLEAS ON CATS AND DOGS This is a divisional of application 25129/97, the disclosure of which is included herein in its entirety by way of reference.

The present invention relates to an improvement to the processes for controlling mammal fleas and in particular fleas on cats and dogs. The invention also relates to a novel composition for this use, based on a synergistic combination of parasiticides which are already known.

e• Lastly, the invention relates to the use of such alreadyknown parasiticides for the preparation of such a composition.

A novel class of l-N-arylpyrazole-based insecticides has been described in patents EP-A-295,217 and EP-A-352,944.

oo The compounds of the classes defined in these patents are highly active, and one of these compounds 1-[2,6-C1 2 4-CF 3 phenyl]3-CN 4-[SO-CF3]5-NH 2 pyrazole, whose common name is fipronil, has proven to be particularly effective not only against crop parasites but also against mammal ectoparasites and in particular, but not exclusively, fleas, ticks, flies and myiases.

Compounds with an ovicidal and/or larvicidal effect on the immature stages of various ectoparasites are already known, for example from patent US-A-5,439,924. Among these compounds (IGR) are featured insect growth regulator compounds which act either by blocking the development of the immature stages (eggs and larvae) into adult stages, or by inhibiting the synthesis of chitin.

f it P:\OPER\MKRSPECI\731994-div.doc- 2/07/01 -1A- Patent FR-A-2,713,889 is moreover known, which generally describes the combination of at least one compound of IGR (insect growth regulator) type, comprising compounds with juvenile hormone activity and chitin synthesis inhibitors, with at least one of three N-aryldiazole compounds, in particular fipronil, to control many harmful insects belonging to very varied orders.

The compositions may be used in very diverse forms, although the applications, for example veterinary, healthcare or plant-protection applications, for which these different forms are *e **ga P: OPER MKR SPECI 25129-97-044 doc-1.01 -2designed are not specified, nor are the parasites for which they are respectively intended.

The only application which may be thought to be veterinary is associated with the example of the manufacture of a pesticidal collar which is a slow-release formulation.

The invention proposes to improve the processes for controlling fleas and/or ectoparasites (particularly ticks) in small mammals, and in particular in cats and dogs.

An object of the invention is, in particular, to use 10 already-known parasiticides in order to prepare a Ce composition which is highly active against the fleas of these animals.

For the purposes of the present invention, the term flea is understood to refer to all the usual or accidental species of parasitic flea of the order Siphonaptera, and in particular the species Ctenocephalides, in particular C.

felis and C. canis, rat fleas (Xenopsylla cheopis) and human fleas (Pulex irritans).

The very high efficacy of the process and of the composition according to the invention implies not only high immediate efficacy but also very long-lasting efficacy after the animal has been treated.

The subject of the invention is a process for controlling the fleas and/or ectoparasites (particularly ticks) of small mammals, and in particular cats and dogs, over a long period, characterized in that the animal is treated by locally depositing a composition of the invention on the skin, preferably localized over a small surface area (spot-on application), in parasiticidally effective doses and proportions.

P:\OPER\MKR\SPECI\731994-div.doc-12/07/01 -3- According to one embodiment of the present invention there is provided a composition which provides small mammals with long-lasting protection against fleas, which includes at least one compound of formula

R

2

R,

R

4

N

R11

R

13

(I)

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 NRsRe, S(O)mR 7

C(O)R

7 C(0)O-R 7 alkyl, haloalkyl or OR 8 or a radical -N=C(R 9

(R

1 0 15 Rs and Rg independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)r-CF 3 radical; or Rs and Rg may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms;

R

7 represents an alkyl or a haloalkyl radical;

R

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

R

9 represents an alkyl radical or a hydrogen atom; P:OPER\MKRSPECr25129-97018 doc- I I/01 -4-

R

0 o 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

11 and R 12 represent, independently of each other, a hydrogen or halogen atom, or optionally 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

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 R 2 is S(O)nR 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl, R 3 is haloalkyl, R 4 is NH 2

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, R 1 is Cl, R 13 is CF 3 and X is =C-C1; and, at least one ovicidal compound of insect growth regulator (IGR) type, in a fluid vehicle which is acceptable to the mammal and suitable for local application on the skin.

According to another embodiment of the invention there is provided use of at least one compound belonging to the formula P:OPERIMKR\SPECI 2 529-97-01S doc-S01101 in which:

R

2

R,

'N

R11 R13

(I)

5 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 NRsR 6 S(O)mR 7

C(O)R

7 C(0)O-R 7 alkyl, haloalkyl or OR 8 or a radical -N=C(Rg) (Ro) Rs and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(0)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; R7 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;

R

11 and R 12 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO 2 P:\OPER\MKR\SPECI\731994-div.doc. 1207/01

R

13 represents a halogen atom or a haloalkyl, haloalkoxy, S(0)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

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 R2 is S(O)nR 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl, then R 3 is haloalkyl, R 4 is NH 2

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, R 11 is Cl, R 13 is CF 3 and X is =C-C1; and at least one ovicidal compound of insect growth regulator (IGR) type, for the preparation of a composition in a fluid vehicle for local application to the skin of small mammals for longlasting protection against fleas.

According to another embodiment of the invention there is provided a composition for application either separately or concomitant with a compound of formula as defined above for the provision of long-lasting protection against fleas in small mammals and which comprises at least one ovicidal compound in a fluid vehicle which is acceptable to mammals and suitable for local application on the skin, said vehicle comprising a crystallization inhibitor, and/or an organic solvent and/or an organic co-solvent.

According to another embodiment of the invention there is provided a method of providing small mammals with protection against fleas which comprises administering by P. OPER MKR SPECI'2129-97-044doc.14 02 01 local application to the skin of a mammal an effective amount of a composition which includes at least one compound(A) of formula

R

2

R,

pA? R4 N

R

13 5

(I)

5 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; 10 R 3 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-R7, alkyl, haloalkyl or ORs or a radical -N=C(R 9 (Rio) Rs and R 6 independently represent a hydrogen atom or an 15 alkyl, haloalkyl, C(0)alkyl, alkoxycarbonyl or S(O)r-CF 3 radical; or Rs and Rs may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms;

R

7 represents an alkyl or a haloalkyl radical;

R

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

R

9 represents an alkyl radical or a hydrogen atom;

R

0 o 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; P OPER MKR SPECI5129-97-044 doc-14 02 01

R

11 and R 12 represent, independently of each other, a hydrogen or halogen atom, or optionally 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

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 2 is S(O)nR 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl, R 3 is S haloalkyl, R 4 is NH 2

R

11 is Cl, R 13 is CF 3 and X is N; or R 2 .oo is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, R 1 is Cl, R 13 is CF 3 and X is =C-C1; and, at least one ovicidal compound of insect growth regulator (IGR) type, in a fluid vehicle which is acceptable to the mammal and suitable for local application on the skin.

According to a further embodiment of the invention :there is provided a method of providing small mammals with protection against ectoparasites which comprises administering by local application to the skin of a mammal an effective amount of a composition which includes at least one compound of formula P: OPER MKR SPECI 25129-97.044 doc-14 02 01

R

2

R

1 R4/ N

R

4 N

R

11 R13

(I)

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; 5 R 3 is alkyl or haloalkyl;

SR

4 represents a hydrogen or halogen atom; or a radical NRsR 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 (R10) Rs and R 6 independently represent a hydrogen atom or an 10 alkyl, haloalkyl, C(0)alkyl, alkoxycarbonyl or S(O)r-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;

R

7 represents an alkyl or a haloalkyl radical; 15 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

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

R

13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF 3 or SFs group; P. OPER MKR SPECI25129-97.044 do-l4 0 01 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 R 2 is S(O)nR 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl, R 3 is haloalkyl, R 4 is NH 2

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, R 11 is Cl, R 13 is CF 3 and X is =C-C1; and, at least one ovicidal compound of insect growth regulator (IGR) type, in a fluid vehicle which is acceptable to the mammal and suitable for local application on the skin.

Compounds of formula in which RI is CN will be selected most particularly. Compounds in which R 2 is S(O)nR 3 preferably with n=l, R 3 preferably being CF 3 or *fl.

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. Compounds in which R 11 is a halogen atom and those in which R 13 is haloalkyl, preferably CF3, are also preferred. Within the context of the present invention, compounds which combine two or more of these characteristics will advantageously be selected.

A preferred class of compounds of formula consists of compounds such that Ri is CN, R 3 is haloalkyl, R 4 is NH 2

R

11 and R 12 are, independently of each other, a halogen atom, and/or R 13 is haloalkyl.

In these compounds, R 3 preferably represents CF 3 or ethyl.

P OPER'MKR SPEI 25 1 29-97-044d..402 01 The alkyl radicals in the definition of the compounds of formula generally comprise from 1 to 6 carbon atoms.

The ring formed by the divalent alkylene radical representing Rs and R 6 as well as the nitrogen atom to which Rs and R 6 are attached, is generally a 6- or 7-membered ring.

A compound of formula which is most particularly preferred in the invention is 1-[2,6-C1 2 4-CF 3 phenyl]3-CN 4-

[SO-CF

3 5-NH 2 pyrazole, the common name of which is fipronil.

The two compounds which differ from the above by the S. following characteristics: n 0, R 3

CF

3 n 1, R3 ethyl.

may also be mentioned.

6 Among the compounds mention may be made in particular of compounds which mimic juvenile hormones, in particular: azadirachtin Agridyne diofenolan (Ciba Geigy) fenoxycarb (Ciba Geigy) hydroprene (Sandoz) kinoprene (Sandoz) methoprene (Sandoz) pyriproxyfen (Sumitomo/Mgk) tetrahydroazadirachtin (Agridyne) 4-chloro-2-(2-chloro-2methylpropyl)-5-(6-iodo-3-pyridylmethoxy)pyridizin- 3(2H)-one 15 and chitin-synthesis inhibitors, in particular: chlorfluazuron (Ishihara Sangyo) cyromazine (Ciba Geigy) Ott diflubenzuron (Solvay Duphar) fluazuron (Ciba Geigy) flucycloxuron (Solvay Duphar) flufenoxuron (Cyanamid) hexaflumuron (Dow Elanco) lufenuron (Ciba Geigy) tebufenozide (Rohm Haas) teflubenzuron (Cyanamid) triflumuron (Bayer) these compounds being defined by their international common name (The Pesticide Manual, 10th edition, 1994, Ed. Clive Tomlin, Great Britain).

As chitin-synthesis inhibitors, mention may also be made of compounds such as 1-(2,6difluorobenzoyl)-3-(2-fluoro-4- (trifluoromethyl)phenylurea, l-(2,6-difluorobenzoyl)-3- (2-fluoro-4-(l,l,2,2-tetrafluoroethoxy)phenylurea and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

Novaluron (Isagro, Italian company) may also be mentioned as a compound 7 The preferred compounds are methoprenes, pyriproxyfens, hydroprene, cyromazine, lufenuron and l-(2,6-difluorobenzoyl)-3-(2-fluoro-4- (trifluoromethyl)phenylurea.

Another preferred compound is again novaluron.

It is preferable for the administration of the two types of compound to be concomitant and preferably simultaneous.

It is preferable for the treatment according to the invention to be carried out every two or, preferably, every three months on cats and dogs.

Preferably, the treatment is carried out so as to administer to the animal a dose of from 0.1 to 15 and in particular from 1 to 20 mg/kg of derivative (A) and a dose of from 0.1 to 40 and in particular 1 to S: 30 mg/kg of compound The preferred doses are from 5 to 15 mg/kg for compound and from 0.5 to 15 mg/kg for the preferred compounds or 10 to 20 mg/kg for the other compounds "In another embodiment of the process according to the invention, compounds and may be applied in a distinct and separate manner over time. In this case, it is preferred to alternate the applications with an interval, for example of one month between two applications, the first application preferably being made with compound It is understood that the dosage values which are thus indicated are average values which may vary within a wide range, since, in practice, a formulation having defined doses of compound of 1-N-phenylpyrazole-type derivative and of compound (B) will be administered to animals having relatively different weights. Consequently, the doses actually applied are often smaller or larger by a factor which may be up to 2, 3 or 4 relative to the preferred dose, without entailing any toxic risk for the animal in the case of an overdose, and while at the same time -8 retaining real efficacy, possibly of shorter duration, in the case of an underdose.

The object of this process is non-therapeutic and relates in particular to the cleaning of animal hairs and skin by elimination of the parasites which are present, as well as their residues and dejections.

The treated animals thus have hair which is more pleasant to look at and to feel.

The invention also relates to such a process for therapeutic purposes, which is intended to treat and prevent parasitoses having pathogenic consequences.

In accordance with the present invention, the process described above may also be used to control ectoparasites, in particular ticks.

1 5 The subject of the invention is also a composition, in particular one for controlling fleas on 0 small mammals, characterized in that it includes, on the one hand, at least one compound of formula (I) as defined above, and, on the other hand, at least one compound defined above, in doses and proportions which have parasiticidal efficacy on fleas, in a fluid vehicle which is acceptable for the animal and convenient for local application to the skin, preferably localized over a small surface area.

Preferably, in formula

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(0)R7, C(O)R 7 alkyl, haloalkyl or OR 8 or a radical -N=C(R 9

(R

10

R

5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl or S(O)r-CF 3 radical; where 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 -9

R

9 represents an alkyl radical or a hydrogen atom

R

10 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

11 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)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 15 with the proviso that when R 1 is methyl, then

R

3 is haloalkyl, R 4 is NH 2

R

11 is Cl, R 13 is CF 3 and X is N.

:i Compounds of formula in which R 1 is CN will be selected most particularly. Compounds in which R 2 is S(O)nR3, 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 R1 2 being a halogen atom, will also be selected. Compounds in which R 11 is a halogen atom and those in which R 13 is haloalkyl, preferably CF 3 are also preferred. Within the context of the present invention, compounds which combine two or more of these S* "characteristics will advantageously be selected.

A preferred class of compounds of formula (I) consists of compounds such that R 1 is CN, R 3 is haloalkyl, R 4 is NH 2

R

11 and R 12 are, independently of each other, a halogen atom, and/or R 13 is haloalkyl.

In these compounds, R 3 preferably represents

CF

3 or ethyl.

A compound of formula which is most particularly preferred in the invention is 1-[2,6-Cl2 4-CF 3 phenyl]3-CN 4-[SO-CF 3 5-NH 2 pyrazole.

The two compounds which differ from the above by the following characteristics: 10 1- n 0, R3 CF 3 2- n 1, R 3 ethyl may also be mentioned.

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 disposal, inter alia, all of the contents of "Chemical Abstracts" and the documents cited therein.

15 Among the compounds of IGR type listed above, methoprenes, pyriproxyfens, hydroprene, cyromazine, lufenuron and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4- (trifluoromethyl)phenylurea are preferred.

Novaluron is also preferred.

The proportions, by weight, of compounds of oo formula and of compound are preferably between 80/20 and 20/80.

The fluid vehicle may be simple or complex and it is adapted to the route and mode of administration selected.

:The compositions for spot-on application can advantageously comprise: b) a crystallization inhibitor, in particular one which is present in a proportion of from 1 to preferably from 5 to 15%, this inhibitor satisfying the test according to which: 0.3 ml of a solution A comprising 10% of the compound of formula in the solvent defined in c) below, along with 10% of this inhibitor, are deposited on a glass slide at 20°C for 24 hours, after which it is observed with the naked eye that there are few or no crystals, in particular fewer than 10 crystals, preferably 0 crystals on the glass slide, 11 C) an organic solvent having a dielectric constant of between 10 and 35, preferably of between and 30, the content of this solvent c) in the overall composition preferably representing the difference to make the composition up to 100%, d) an organic cosolvent having a boiling point of below 100°C, preferably of below 80°C, and having a dielectric constant of between 10 and 40, preferably of between 20 and 30; this cosolvent may advantageously be present in the composition in a weight/weight ratio of between 1/15 and 1/2. The solvent is volatile, so as to serve in particular as a drying promoter, and is miscible with water and/or with the solvent c).

0 15 Although this is not preferred, the composition for spot-on application may optionally comprise water, S" in particular in a proportion of form 0 to 30% (volume per unit volume, in particular from 0 to The composition for spot-on application may 20 also comprise an antioxidant intended to inhibit air- .oe.ei oxidation, this agent being present in particular in a proportion of from 0.005 to 1% preferably from 0.01 to 0.05%.

The compositions according to the invention intended for pets, in particular cats and dogs, are generally applied by being deposited onto the skin ("spot-on" or "pour-on" application); this is generally a localized application over a surface area of less than 10 cm 2 especially of between 5 and 10 cm 2 in particular at two points and preferably localized between the animal's shoulders. Once deposited, the composition diffuses, in particular over the animal's entire body, and then dries without crystallizing or modifying the appearance (in particular absence of any whitish deposit or dusty appearance) or the feel of the fur.

The compositions for spot-on application according to the invention are particularly advantageous owing to their efficacy, their speed of 12 action and the pleasant appearance of the animal's fur after application and drying.

As organic solvent c) which can be used in the invention, mention may be made in particular of: 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.

15 As crystallization inhibitor b) which can be used in the invention, mention may be made in particular of: polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, acrylic derivatives such as methacrylates and the like, anionic surfactants such as alkaline stearates, in particular sodium, potassium or ammonium stearate; 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 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, 13 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 optionally polyoxyethylenated sorbitan esters, in particular polysorbate 80, polyoxyethylenated alkyl ethers; 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 substituted lauryl compounds of betaine, or preferably a mixture of at least two of S" these crystallization inhibitors.

In a particularly preferred manner, a crystallization inhibitor couple, namely the combination of a film-forming agent of polymeric type 20 and a surfactant, will be used. These agents will be chosen in particular from the compounds mentioned as crystallization inhibitor b).

Among the film-forming agents of polymeric type .*..which are particularly advantageous, mention may be made of: the various grades of polyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinyl acetate and vinylpyrrolidone.

As regards the surfactants, mention will be made most particularly of nonionic surfactants, preferably polyoxyethylenated sorbitan esters and in particular the various grades of polysorbate, for example polysorbate The film-forming agent and the surfactant may be incorporated, in particular, in similar or identical amounts within the limit of the total amounts of crystallization inhibitor mentioned elsewhere.

14 The couple thus produced ensures the objectives of absence of crystallization on the hairs and maintenance of the cosmetic appearance of the coat in a noteworthy manner, that is to say without any tendency towards stickiness or to a sticky appearance, despite the high concentration of active material.

As cosolvent mention may be made in particular of: absolute ethanol, isopropanol, methanol.

As antioxidant, standard agents are used in particular, such as: butylhydroxyanisole, butylhydroxytoluene, ascorbic acid, sodium metabisulphite, propyl gallate and sodium thiosulphate, or a mixture of not more than two of these agents.

SThe compositions for spot-on application 15 according to the invention are usually prepared by simple mixing of the constituents as defined earlier; advantageously, to begin with, the active material is *mixed in the main solvent and the other ingredients or adjuvants are then added.

20 The volume applied may be from about 0.3 to 1 ml, preferably about 0.5 ml for cats, and from about 0.3 to 3 ml for dogs, according to the weight of the animal.

In a particularly preferred manner, the composition according to the invention may be in the form of a concentrated emulsion, suspension or solution for spot-on application to a small area of the animal's skin, generally between the two shoulders (spot-on type solution). In a clearly less preferred manner, forms of solution or suspension to be sprayed, forms of solution, suspension or emulsion to be poured or spread onto the animal (pour-on type solution) an oil, a cream, an ointment or any other fluid formulation for topical administration may be provided.

Advantageously, the ready-to-use composition contains a dose of from 0.1 to 40 mg/kg of compound (A) of formula and 0.1 to 40 mg/kg of compound Preferably, a ready-to-use dosed formulation, in particular one for spot-on application, contains 1 15 to 20 mg/kg, preferably 2 to 10 mg/kg of compound in particular fipronil, and from 1 to 30 mg/kg, preferably 2 to 10 mg/kg, of preferred compound or to 20 mg/kg of other compound Advantageously, ready-to-use compositions dosed for 1-10, 10-20 and 20-40 kg animals respectively may be provided.

In another embodiment, provided for separate application over time, a composition may be made in the form of a kit separately combining, in the same packaging, a composition containing a compound of formula in particular fipronil, and a composition containing compound preferably pyriproxyfen, each of the compositions including a vehicle which allows it S• 15 to be applied onto the skin.

Preferably, each of the two compositions is provided for local spot-on application and, preferably, a container containing just the dose required is provided for each application.

Thus, for example, a kit may contain, in a package, three containers each containing a single dose of composition of compound and three containers each containing a single dose of composition of compound the containers being distinguished from the containers by markings, shapes or colours, as well as a notice specifying that the containers (A) and must be used alternately with an interval, for example, of one month, and starting, for example, with a container The compositions according to the invention, in particular those for spot-on application, have proven to be extremely effective for the very long-lasting treatment of fleas on mammals, and in particular small mammals such as cats and dogs.

The discovery that the compound such as fipronil, dissolves in the sebum so as to cover the entire animal and becomes concentrated in the sebaceous glands, from which it is gradually released over a very long period, is a plausible explanation of this long- 16 lasting efficacy for these compositions, and could perhaps also explain the long-lasting action of the associated compound They also have a certain efficacy against other parasitic insects and, in particular, ticks, and it is understood that the application of the composition according to the invention may be extended to the treatment of ectoparasites, or even endoparasites for which the composition proves to have real utility capable of being obtained practically, according to the criteria of the veterinary art.

Thus, for example, a composition based on fipronil and fluazuron may also be used in particular against ticks.

15 Where appropriate, the composition according to the invention may also comprise another insecticide, and in particular imidaclopride.

The subject of the invention is also the use of at least one compound of formula and of at least one compound of IGR type, as defined above, S" for the preparation of a composition as defined above.

Other advantages and characteristics of the invention will become apparent on reading the description which follows, which is given by way of non-limiting example.

The composition preparation example which follows includes, as compound of formula the compound known as fipronil.

By way of example to prepare a composition for local application to the skin according to the invention, the following components may advantageously be mixed together: al compound in a proportion of from 1 to (percentage as a weight per unit volume W/V) a2 compound of formula in a proportion of from 1 to 20%, preferably 5 to 15% (percentage as a weight per unit volume W/V).

By way of example, the compositions according to the invention comprise the following concentrations 17 of compounds and in a liquid medium comprising a representative of each of the components b, c and d. The total volume is 1 ml.

Example 1 fipronil pyriproxyfen Example 2 fipronil pyriproxyfen Example 3 fipronil pyriproxyfen Example 4 fipronil methoprene Example fipronil l-(2,6-difluorobenzoyl)-3-(2-fluoro-4trifluoromethyl)phenylurea Cats are infested with 100 fleas each, and are then reinfested every 10 days. Concomitant with the first manifestation, they receive a local skin application of 0.1 ml/kg of the composition according to Example 1. Two months after the treatment and ten days after the last infestation, no fleas are detected and the eggs collected are found to be non-viable.

Dogs treated according to the same procedure with compositions according to Examples 1 and 2 show the same efficacy of treatment two months after application of the composition.

P:OPER\MKR\SPECR\25129-97-01.doc- 1801/0 -18- 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.

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.

go* *oo

Claims (66)

1. A composition which provides small mammals with long- lasting protection against fleas, which includes at least one compound of formula R 2 R, R 4 N R11 *I Sin 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(0)O-R 7 alkyl, haloalkyl or ORe or a 15 radical -N=C(R 9 (Rio); Rs and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(0)alkyl, alkoxycarbonyl or S(0),-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; R 7 represents an alkyl or a haloalkyl radical; R 8 represents an alkyl or haloalkyl radical or a hydrogen atom; R 9 represents an alkyl radical or a hydrogen atom; P:OPER\MKR\SPECI\25129-97-018 doc-18/01/01 R 1 o represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, -0-alkyl, S-alkyl, cyano or alkyl; R 11 and R 12 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO 2 R 13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)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 RI is methyl, either R 2 is S(O)nR 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl, R 3 is haloalkyl, R 4 is NH 2 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, R 1 is Cl, R 13 is CF 3 and X is =C-C1; and, at least one ovicidal compound of insect growth regulator (IGR) type, in a fluid vehicle which is acceptable to the mammal and suitable for local application on the skin.

2. A composition according to claim 1, wherein the compound of formula is such that: Ri 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 NRsR 6 S mR7, C(O) alkyl, haloalkyl or OR 8 or a radical -N=C(R 9 (Rio); P:OPER\MIKRSPECI\25129-97-018 doc-I 01/01 -21- R 5 and R 6 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; 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 selected from 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 13 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 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, R 4 is NH2, R 1 is Cl, R 13 is CF 3 and X is N.

3. A composition according to claim 1 or 2, wherein Rs and R 6 together form a divalent alkylene radical which is interrupted with one or two oxygen or sulphur atoms.

4. A composition according to any one of claims 1 to 3, wherein the compound of formula is such that RI is CN. P:'OPER\MKR\SPECI25129-97-018.doc- 18//01 -22- A composition according to any one of claims 1 to 4, wherein the compound of formula is such that R 13 is haloalkyl.

6. The composition according to claim 5, wherein R 13 is CF 3

7. A composition according to any one of claims 1 to 6, wherein the compound of formula is such that R 2 is S(O) R 3 R 3 represents CF 3 or alkyl, or where n=0, R 3 represents CF 3

8. A composition according to claim 6, wherein R 2 is SOR 3 1

9. A composition according to claim 7, wherein R 3 represents methyl or ethyl. 9

10. A composition according to any one of claims 1 to 9, 9**o wherein the compound of formula is such that X is C-R 12 with R 12 being a halogen atom.

11. A composition according to any one of claims 1 to wherein the compound of formula is such that R 1 is CN, R 2 is S (O)nR 3 R 3 is haloalkyl, R 4 is NH 2 R 11 and R 12 are, independently of each other, a halogen atom, and/or R 13 is haloalkyl.

12. A composition according to any one of claims 1 to 11, wherein the compound of formula is: 1-[2,6-C1 2 4-CF 3 phenyl] 3-CN 4-[SO-CF3]5-NH 2 pyrazole. P:OPERIMKRI PECI2129-97-1 doc.-8/01/I0 -23-

13. A composition according to any one of claims 1 to 11, in which the compound of formula is one of the following compounds: 1: 1-[2,6-C1 2 4-CF 3 phenyl] 3-CN 4-[SO-CF 3 ]5-NH 2 pyrazole 2: 1-[2,6-C1 2 4-CF 3 phenyl] 3-CN 4-[SO-C 2 Hs]5-NH 2 pyrazole.

14. A composition according to any one of claims 1 to 13, wherein the compound is a compound which mimics juvenile hormones.

15. A composition according to claim 14, wherein the compound is selected from: azadirachtin diofenolan fenoxycarb hydroprene kinoprene methoprene pyriproxyfen tetrahydroazadirachtin and 4-chloro-2-(2-chloro-2-methyl-propyl)-5- (6-iodo-3-pyridylmethoxy)pyridizine-3-(2H)-one.

16. A composition according to any one of claims 1 to 9, wherein the compound is a chitin-synthesis inhibitor.

17. A composition according to claim 16, wherein the compound is selected from: chlorfluazuron cyromazine diflubenzuron fluazuron P:4)ER\MKRPSPECl25129-97410 doc- IOV101 -24- flucycloxuron flufenoxuron hexaflumuron lufenuron tebufenozide teflubenzuron triflumuron 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4- (trifluoromethyl)phenylurea and 1-(2,6-difluorobenzoyl)-3- (2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylurea.

18. A composition according to any one of claims 14 to 16, characterized in that the compound is chosen from methoprenes, pyriproxyfens, lufenuron, hydroprene, 15 cyromazine and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4- (trifluoromethyl)phenylurea. o

19. A composition according to claim 18, characterized in that the compound is pyriproxyfen. S. 20. A composition according to claim 18, characterized in S..that the compound is a methoprene.

21. A composition according to any one of claims 1 to wherein the proportions, by weight, of compounds of formula and of type are between 80/20 and 20/80.

22. A composition according to any one of claims 1 to 21, wherein the fluid vehicle and the concentration of the compounds and are adapted for point application to skin by deposition of a "spot-on" type. P:OPERMKR\SPECI25129-97-01 84.o- 1I/01I01

23. A composition according to any one of claims 1 to 21, wherein the fluid vehicle and the concentration of the compounds and are adapted for local application to skin by deposition of a "pour-on" type.

24. A composition according to claim 22, wherein the fluid vehicle and the concentration of compounds and are adapted for local application to a zone with a surface area of 10 cm 2 or less.

25. A composition according to claim 24, wherein the application is at two points.

26. A composition according to claim 24 or 25, wherein the application is localized between the animal's shoulders.

27. A composition according to any one of claims 1 to 26, which contains a dose of from 0.1 to 40 mg/kg of compound and from 0.1 to 40 mg/kg of compound

28. A composition according to claim 27, which contains a dose of from 1 to 20mg/kg of compound and from 1 to of compound (B)

29. A composition according to any one of claims 1 to 28, which additionally comprises a crystallization inhibitor A composition according to claim 29, wherein the crystallization inhibitor is present in a proportion of from 1 to 20% PVOPERUMKR'SPEC\512997-08 dw- 19/O1l0 -26-

31. A composition according to claim 30, wherein the crystallization inhibitor is present in a proportion of from 5 to 15%

32. A composition according to any one of claims 29 to 31, wherein the crystallization inhibitor 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 carboxymethyl cellulose, and acrylic derivatives; anionic surfactants; S- anionic surfactants; cationic surfactants; amine salts of formula in which the radicals R are optionally hydroxylated hydrocarbon radicals, non-ionic surfactants; amphoteric surfactants; and a mixture of at least two of these crystallization inhibitors. :33. A composition according to claim 32, wherein the crystallization inhibitor is a methacrylate.

34. A composition according to claim 32, wherein the anionic surfactant is selected from the group consisting of alkaline stearates; calcium stearate; triethanolamine stearate; sodium abietate; alkyl sulphates; sodium dodecylbenzenesulphonate; sodium dioctylsulphosuccinate; and fatty acids. P:OPERMKR\SPEC\25129-97-I0 doc-l.18/01, -27- A composition according to claim 34, wherein the crystallization inhibitor is sodium, potassium or ammonium stearate.

36. A composition according to claim 34, wherein the crystallization inhibitor is sodium lauryl sulphate or sodium cetyl sulphate.

37. A composition according to claim 34, wherein the crystallization inhibitor is a fatty acid derived from coconut oil.

38. A composition according to claim 32, wherein the cationic surfactant is selected from the group consisting of 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; cetyltrimethylammonium bromide; amine salts of formula in which the radicals R are optionally hydroxylated hydrocarbon radicals; and octadecylamine hydrochloride.

39. A composition according to claim 32, wherein the nonionic surfactant is a polyoxyethylenated sorbitan ester; polyethylene glycol stearate, polyoxyethylenated derivative of castor oil, polyglycerol ester, polyoxyethylenated fatty alcohol, polyoxyethylenated fatty acid, or copolymer of ethylene oxide and propylene oxide.

40. A composition according to claim 39, wherein the crystallization inhibitor is polysorbate 80 or polyoxyethylated alkyl ether. P:OPER\MKR\SPEC\25129-97-018 doc- /01/01 -28-

41. A composition according to claim 32, wherein the amphoteric surfactant comprises substituted lauryl compounds of betaine.

42. A composition according to any one of claims 23 to 41, which comprises a crystallization inhibitor couple formed by the combination of a film-forming agent of a polymeric type and a surfactant.

43. A composition according to claim 42, wherein said film- forming agent and said surfactant are in similar or identical amounts within the limit of the total amounts of crystallization inhibitor. o

44. A composition according to either claim 42 or 43, wherein the film-forming agent is chosen from: the various grades of polyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinyl acetate and vinyl pyrrolidone, and wherein the surfactant is chosen from non-ionic surfactants. A composition according to claim 44, wherein said non- ionic surfactants are polyoxyethylated sorbitan esters.

46. A composition according to claim 45, wherein said polyoxyethylated sorbitan esters are the various grades of polysorbate. P:OPER\MKRSPECI\2519-97.1o doc- 18/I001 -29-

47. A composition according to any one of claims 1 to 46, which additionally comprises an organic solvent having a dielectric constant of between 10 and

48. A composition according to claim 47, wherein said dielectric constant is between 20 and

49. A composition according to either claim 47 or 48, wherein the organic solvent is chosen from acetone, acetonitrile, benzyl alcohol, butyldiglycol, 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, N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.

50. A composition according to claim 49, wherein said organic solvent is chosen from N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate.

51. A composition according to any one of claims 47 to which additionally comprises an organic co-solvent (d) having a boiling point below 1000C, and having a dielectric constant of between 10 and 40, which is miscible with water and/or with the solvent P OPER IKR SPECI 25129-97-044 doc-14 02 01

52. A composition according to claim 51, wherein said organic co-solvent has a boiling point of below 80 0 C and/or has a dielectric constant of between 20 and

53. A composition according to either claim 51 or 52, wherein the co-solvent is present in a co-solvent (d)/solvent weight/weight ratio of between 1/15 and 1/2.

54. A composition according to any one of claims 51 to 53, wherein the co-solvent is chosen from absolute ethanol, isopropanol and methanol.

55. A composition according to any one of claims 1 to 54, characterized in that it is made in the form of a kit combining, separately, in the same packaging, at least one container containing a compound and at least one container containing a compound the containers for alternate use within an interval of one month.

56. A composition according to any one of claims 1 to which provides protection for 2 to 3 months.

57. A composition according to any one of claims 22 to 26 and 29 to 56, characterized in that it comprises 5 to 10% 1- [2,6-C1 2 4-CF 3 phenyl]3-CN 4-[SO-CF 3 ]5-NH 2 pyrazole and 5 to of pyriproxyfen.

58. A composition according to any one of claims 22 to 26 and 29 to 56, characterized in that it comprises 10% 1-[2,6- C1 2 4-CF 3 phenyl]3-CN 4-[SO-CF 3 ]5-NH 2 pyrazole and 30% of methoprene. P.OPER MKR SPECI 25129-97-044 doc-14 02 01 -31

59. A composition according to any one of claims 1 to 58, wherein the composition is applied to the mammal by local point application to the skin of the "spot-on" type. Use of at least one compound belonging to the formula in which: *9 a a (I) 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; P:OPER\MIKR\SPECI\25129-97-01.doc-18I101 -32- 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 OR 8 or a radical -N=C(R 9 (Rio); Rs and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(0)alkyl, alkoxycarbonyl or S(O) rCF 3 radical; or R 5 and Rg may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms; R 7 represents an alkyl or haloalkyl radical; Re 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, -0-alkyl, -S-alkyl, cyano or alkyl; R 1 and R 12 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO 2 R 13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)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 2 is S(O)nR 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl, then R 3 is haloalkyl, R 4 is NH 2 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, R 1 is Cl, R 13 is CF 3 and X is =C-C1; and at least one ovicidal compound of insect growth regulator (IGR) type, P:\OPERMKI SPEC731994-div.doc- I1207/01 -33 for the preparation of a composition in a fluid vehicle for local application to the skin of small mammals for long- lasting protection against fleas.

61. A use according to claim 60, wherein R 5 and R 6 may together form a divalent alkylene radical which may be interrupted by one or two oxygen or sulphur atoms.

62. The use according to claim 60 substantially as herein described with particular reference to the examples.

63. A composition for application either separately or concomitant with a compound of formula as defined in claim 1 for the provision of long-lasting protection against S. 15 fleas in small mammals and which comprises at least one ovicidal compound in a fluid vehicle which is acceptable to mammals and suitable for local application on the skin, said vehicle comprising a crystallization inhibitor, and/or an organic solvent and/or an organic co-solvent.

64. A composition as claimed in claim 63, wherein the S crystallization inhibitor is as defined in any one of claims 30 to 46.

65. A composition as claimed in either claim 63 or 64, wherein the organic solvent is as defined in any one of claims 47 to

66. A composition as claimed in any one of claims 63 to wherein the organic co-solvent is as defined in any one of claims 51 to 54. P. OPER MKR SPECI 25129-97-044 d- 14 02 01 -34-

67. A method of providing small mammals with protection against fleas which comprises administering by local application to the skin of a mammal an effective amount of a composition which includes at least one compound of formula R 2 R, R 4 N x R1,* R13 (I) 10 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 15 NRsR 6 S(O)mR 7 C(O)R 7 C(0)O-R 7 alkyl, haloalkyl or OR 8 or a radical -N=C(R 9 (Rio); Rs and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(0),-CF 3 radical; or Rs and Rg may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms; R 7 represents an alkyl or a haloalkyl radical; R 8 represents an alkyl or haloalkyl radical or a hydrogen atom; R 9 represents an alkyl radical or a hydrogen atom; P:OPER'MKR SPEC 25129-97-4 doc-14 02 01 R 10 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 11 and R 12 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO 2 R 13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)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 S. forming part of the aromatic ring; with the proviso that when Ri is methyl, either R 2 is S(O)nR 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl, R 3 is haloalkyl, R 4 is NH 2 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, R 11 is Cl, R 13 is CF 3 X is =C-Cl; and, at least one ovicidal compound of insect growth regulator (IGR) type, in a fluid vehicle which is S 20 acceptable to the mammal and suitable for local application on the skin. *a. e

68. The method according to claim 67, wherein the application is to a zone with a surface area of 10cm 2 or less.

69. The method according to claim 68, wherein the application is at two points.

70. The method according to either claim 68 or claim 69 wherein the application is localized between the mammal's shoulders. a M P.OPER MKRSPECI 25129-97-044 dc.14 02 01 -36-

71. A method of providing small mammals with protection against ectoparasites which comprises administering by local application to the skin of a mammal an effective amount of a composition which includes at least one compound of formula R 2 R 1 R 4 N 1 X R 13 (I) 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 NRsR 6 S(O)mR 7 C(O)R 7 C(O)O-R 7 alkyl, haloalkyl or OR 8 or a radical -N=C(Rg) (R 10 Rs and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(0)alkyl, alkoxycarbonyl or S(0)r-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; R 7 represents an alkyl or a haloalkyl radical; R 8 represents an alkyl or haloalkyl radical or a hydrogen atom; R 9 represents an alkyl radical or a hydrogen atom; P:\OPER\MKR\SPECIV731994-div.doc-12/07/01 -37- R 0 I 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 11 and R 12 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO 2 R 13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)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 Ri is methyl, either R 2 is S(O)nR 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl, R 3 is 15 haloalkyl, R 4 is NH 2 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, R 1 is Cl, R 13 is CF 3 and X is =C-C1; *g and, at least one ovicidal compound of insect growth regulator (IGR) type, in a fluid vehicle which is 20 acceptable to the mammal and suitable for local application on the skin. 99

72. The method according to claim 71 wherein said ectoparasites are ticks.

73. A composition according to claim 1, substantially as hereinbefore described with reference to the examples. DATED this 12th day of July, 2001 Merial By DAVIES COLLISON CAVE Patent Attorneys for the Applicant