AU2005201861A1

AU2005201861A1 - Insecticidal combination effective against fleas on mammals, particularly cats and dogs

Info

Publication number: AU2005201861A1
Application number: AU2005201861A
Authority: AU
Inventors: Philippe Jeannin
Original assignee: Merial SAS
Current assignee: Boehringer Ingelheim Animal Health USA Inc
Priority date: 1996-03-29
Filing date: 2005-05-03
Publication date: 2005-05-26
Anticipated expiration: 2017-03-26
Also published as: AU2005201861B2

Description

I INSECTICIDAL COMBINATION TO CONTROL MAMMAL FLEAS, IN SPARTICULAR FLEAS ON CATS AND DOGS This is a divisional of application 54329/01, the disclosure of which is included 1, herein in its entirety by way of reference.

The present invention relates to an improvement to the process for controlling C' 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 Swhich are already known. Lastly, the invention relates to the use of such alreadyknown parasiticides for the preparation of such a composition.

A novel class of 1-N-arylpyrazole-based insecticides has been described in Patents EP-A-295,217 and EP-A-352,944. 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-CF 3 ]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 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.

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 composition may be used in very diverse forms, although the applications, for example veterinary, healthcare or plant-protection applications, for which these different forms are m:\specifications\500000\503000\503395clmjep.doc designed are not specified, nor are the parasites for which they are respectively c intended.

SThe 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 0 ectoparasites (particularly ticks) in small mammals, and in particular in cats and dogs.

The present invention desirably provides, in particular, the use already-known parasiticides in order to prepare a composition which is highly active against the fleas S 10 of these animals.

,I 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.

The present invention provides a composition which provides small mammals with long-lasting protection against fleas, which includes at least one compound of formula

R

2

R

1

R

4

N

0 in which: SRI is CN or methyl or a halogen atom;

SR

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)mR7, I\ C(O)R 7

C(O)O-R

7 alkyl, haloalkyl or OR 8 or a radical -N=C (R 9 (Rio); 00

R

5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)r-CF 3 radical; or R 5 and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent 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; 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 optionally CN or NO 2

R

i3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-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 2 is S(O)nR 3 or dicyanoimidazol-2-yl or haloalkyl, R 3 is haloalkyl, R 4 is NH 2

R

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

R

4 is Cl, RIl is Cl, R 13 is CF 3 and X is =C-Cl; 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 synergistic spot-on application or local synergistic pour-on application on the skin.

The present invention also provides a synergistic spot-on composition for the long lasting protection against ectoparasites on mammals which comprises synergistic amounts at least one compound of the formula:

R

11 00 cR 13

(I)

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;

R

3 is alkyl or haloalkyl;

R

4 represents a hydrogen or halogen atom; or a radical NRsR 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, alkoxycarbonyl or S(O)r-CF 3 radical; Rs and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms or;

R

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

R

9 represents an alkyl radical or a hydrogen atom; Rio represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or one or more substituents selected from the group consisting of OH, -O-alkyl, S-alkyl, cyano or alkyl;

R

1 and R 1 2 represent, independently of each other, hydrogen, halogen, CN or

NO

2

R

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

R

1 1 is Cl, RI 3 is CF 3 and X is N; or

R

2 is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, R 1 l is Cl, Ri 3 is CF 3 and X is =C-Cl; at least one insect growth regulator (IGR) that mimics juvenile hormones; c imidacloprid; and a fluid vehicle comprising at least one customary spot-on formulation adjuvant.

The present invention also provides a composition which provides small mammals with long-lasting protection against fleas, which includes at least one 00 compound of formula 1 R 2 Ri 010

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 NR 5

R

6 S(O)mR7,

C(O)R

7

C(O)O-R

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

R

5 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;

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

R

1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF group; Sm, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; o 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 2 is S(O)nR 3 or 0 dicyanoimidazol-2-yl or haloalkyl, R 3 is haloalkyl, R 4 is NH 2 Ri, is Cl, RI3 is CF 3 and O X is N; or R 2 is 4 ,5-dicyanoimidazol-2-yl,

R

4 is Cl, R 11 is Cl, Ri 3 is CF 3 and X is =C-C1; t and, at least one ovicidal compound wherein compound is not 010 lufenuron, of insect growth regulator (IGR) type, in a fluid vehicle which is acceptable to the mammal and suitable for local synergistic spot-on application or local synergistic pour-on application on the skin.

The present invention also provides use of at least one compound belonging to the formula

R

2

R,

R

4

N

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;

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, 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;

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 cmore halogen atoms or groups such as OH, -O-alkyl, -S-alkyl, cyano or alkyl;

R

11 and R 1 2 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO 2 I\N R 13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SFs 00 group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or n 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 dicyanoimidazol-2-yl or haloalkyl, then R 3 is haloalkyl, R 4 is NH 2

R

11 is Cl, R 1 3 is CF 3 and X is N; or R2 is 4,5-dicyanoimidazol-2-yl, R4 is Cl, R1 is Cl, Ri3 is CF 3 and X is =C-C1; and at least one ovicidal compound wherein compound is not lufenuron, of insect growth regulator (IGR) type, for the preparation of a composition in a fluid vehicle for local synergistic spoton application to the skin of small mammals for long-lasting protection against fleas.

The present invention also provides 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 1

R

4

N

R11

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; CM 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, alkoxycarbonyl or S(O)r-CF 3 radical; or Rs and R 6 may together form a O divalent alkylene radical which may be interrupted by one or two divalent hetero t atoms; O 10 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; 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 1 2 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO 2

R

1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-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 2 is S(O)nR 3 or dicyanoimidazol-2-yl or haloalkyl, R 3 is haloalkyl, R 4 is NH 2 RI is Cl, Ri 3 is CF 3 and X is N; or R 2 is 4, 5-dicyanoimidazol-2-yl, R 4 is Cl, R 1 1 is Cl, Ri3 is CF 3 and X is =C- Cl; and, at least one ovicidal compound wherein compound is not lufenuron, of insect growth regulator (IGR) type, in a fluid vehicle which is acceptable to the mammal and suitable for local synergistic spot-on application.on the skin.

The present invention also provides 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

\N

NR N

NO

00

S^R

13 O 10 (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)mR7,

C(O)R

7

C(O)O-R

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

R

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

R

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

R

1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or 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-RI 2 the other three valency positions of the carbon atom forming part of the aromatic ring; Swith the proviso that when R 1 is methyl, either R 2 is S(O)nR 3 or c dicyanoimidazol-2-yl or haloalkyl, R 3 is haloalkyl, R4 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 1 3 is CF 3 and X is =C- C1; 0 and, at least one ovicidal compound wherein compound is not lufenuron, 00 of insect growth regulator (IGR) type, in a fluid vehicle which is acceptable to the 0 mammal and suitable for local synergistic spot-on application on the skin.

SThe present invention further provides a synergistic spot-on composition for the 0 10 long lasting protection against ectoparasites on mammals which comprises synergistic amounts at least one compound of the formula:

R

2 Ri

R

4

N

R

11 X

R

13

(I)

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;

R

3 is alkyl or haloalkyl;

R

4 represents a hydrogen or halogen atom; or a radical NRsR 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

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 one or more substituents selected from the group consisting of O OH, -O-alkyl, S-alkyl, cyano or alkyl;

R

11 and R 12 represent, independently of each other, hydrogen, halogen, CN or

SNO

2 o0 RI 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF group; In m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 8 10 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, 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, Ri3 is CF 3 and X is =C-Cl; at least one insect growth regulator (IGR) that mimics juvenile hormones wherein the IGR is not lufenuron; imidacloprid; and a fluid vehicle comprising at least one customary spot-on formulation adjuvant.

The present invention also provides a composition which provides small mammals with long-lasting protection against fleas, which includes at least one compound of formula

R

2

R

1 R N

R

13 in which:

(I)

R

1 is CN or methyl or a halogen atom; R2 is S(O)nR3 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 ORs or a radical -N=C (R9) (Rio); Rs and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)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 0 atoms;

R

7 represents an alkyl or a haloalkyl radical; Rg represents an alkyl or haloalkyl radical or a hydrogen atom; 00 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 RI2 represent, independently of each other, a hydrogen or halogen atom, C1 or optionally CN or NO 2

R

1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(0)qCF3 or SF group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-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 dicyanoimidazol-2-yl or haloalkyl, 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, R 11 is Cl, RI 3 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 synergistic spot-on or local synergistic pour-on application on the skin, wherein the compound (B) is a compound which mimics juvenile hormones.

The present invention further provides a composition which provides small mammals with long-lasting protection against fleas, which includes at least one compound of formula

R

2

R

1

N

R

4

N

R

1 1 X

R

13 in which:

(I)

I .f jI SRI is CN or methyl or a halogen atom; R2 is S(O)nR 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl; R3 is alkyl or haloalkyl; 0 R 4 represents a hydrogen or halogen atom; or a radical NRsR, S(O)mR7,

C(O)R

7 C(0)O-R 7 alkyl, haloalkyl or ORs or a radical -N=C (R 9 (Rio); Rs and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, o0 C(O)alkyl, alkoxycarbonyl or S(O),-CF 3 radical; or Rs and R6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms; R7 represents an alkyl or a haloalkyl radical; C1 R represents an alkyl or haloalkyl radical or a hydrogen atom;

R

1 1 and R 1 2 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 SF group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-R 1 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that when R1 is methyl, either R2 is S(O)nR3 or dicyanoimidazol-2-yl or haloalkyl, R3 is haloalkyl, R 4 is NH 2 R,1 is Cl, R 13 is CF 3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, Ru is Cl, Ri 3 is CF 3 and X is =C-Cl; 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 synergistic spot-on or local synergistic pour-on application on the skin, wherein the fluid vehicle and the concentration of compounds and are adapted for local application to a zone with a surface area of 10cm 2 or less.

,I

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 00

R

2

R

1 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;

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 ORE 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(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;

R

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

R

9 represents an alkyl radical or a hydrogen atom; -4-

R

10 represents a phenyl or heteroaryl group optionally cn 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 00 5 hydrogen or halogen atom, or optionally CN or NO 2 0 R 13 represents a halogen atom or a haloalkyl, in haloalkoxy, S(O)qCF3 or SF 5 group; Sm, n, q and r represent, independently of each other,

(N

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),R

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.

According to another embodiment of the invention there is provided use of at least one compound belonging to the formula 2 in which:

O

R

2

R

1 N

RN

R13

(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;

R

4 represents a hydrogen or halogen atom; or a radical

NR

5

R

6

S(O)

3

R

7

C(O)R

7 C(0)O-R 7 alkyl, haloalkyl or OR 8 or a radical (Rio) Rs and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(0)alkyl, alkoxycarbonyl or S(0)rCF 3 radical; or Rs and Rg 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; Ro 1 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, n 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; 00 5 X represents a trivalent nitrogen atom or a radical O C-R 12 the other three valency positions of the carbon atom l forming part of the aromatic ring; Swith the proviso that when RI 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 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 local application to the skin of a mammal an effective amount of a composition which includes at least one O compound(A) of formula IND R 2

R

1 00 I N SR N

R

13

(I)

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 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(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;

R

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

R

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

R

13 represents a halogen atom or a haloalkyl, ND 5 haloalkoxy, S(0)qCF3 or SFs group; 00 m, n, q and r represent, independently of each other, CI an integer equal to 0, 1 or 2; SX represents a trivalent nitrogen atom or a radical C- CN

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 1 3 is CF 3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, R 1 is Cl, Ri3 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

OO

RN 13 C' 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 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

(R

1 i); Rs and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)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;

R

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

R

9 represents an alkyl radical or a hydrogen atom;

R

10 represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, -0-alkyl, S-alkyl, cyano or alkyl;

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, O an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C- ND 5 R 12 the other three valency positions of the carbon atom 00 forming part of the aromatic ring; r C with the proviso that when Ri is methyl, either R 2 is S(0)nR 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl, R 3 is

C

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.

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 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 CF 3 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 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.

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 ND 5 Rs and R 6 are attached, is generally a 6- or 7-membered 00 ring.

qi A compound of formula which is most particularly Spreferred 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 following characteristics: 1- n 0, R 3

CF

3 2- n 1, R 3 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) io pyriproxyfen (Sumitomo/Mgk) tetrahydroazadirachtin (Agridyne) 4-chloro-2-(2-chloro-2methylpropyl)-5-(6-iodo-3-pyridylmethoxy)pyridizin- 3(2H)-one and chitin-synthesis inhibitors, in particular: chlorfluazuron (Ishihara Sangyo) cyromazine (Ciba Geigy) 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-(1,1,2,2-tetrafluoroethoxy)phenylurea and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

Novaluron (Isagro, Italian company) may also be mentioned as a compound S- 7 The preferred compounds are methoprenes, C-i pyriproxyfens, hydroprene, cyromazine, lufenuron and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4- (trifluoromethyl)phenylurea.

Another preferred compound is again novaluron.

It is preferable for the administration of the ND two types of compound to be concomitant and preferably 00 simultaneous.

S 10 It is preferable for the treatment according to Sthe invention to be carried out every two or, 0 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 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 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 n 8 retaining real efficacy, possibly of shorter duration, C in the case of an underdose.

CThe 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 ND pleasant to look at and to feel.

00 The invention also relates to such a process Cl 10 for therapeutic purposes, which is intended to treat and prevent parasitoses having pathogenic consequences.

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

The subject of the invention is also a composition, in particular one for controlling fleas on 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)nR3

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 alkyl, haloalkyl or ORg 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 n 9

R

9 represents an alkyl radical or a hydrogen CI atom

R

10 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 ID

R

13 represents a halogen atom or a haloalkyl, Shaloalkoxy, S(O)qCF3 or SF 5 group C 1 0 m, n, q and r represent, independently of each Iother, an integer equal to 0, 1 or 2 SX 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, then

R

3 is haloalkyl, R 4 is NH 2

R

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

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

R

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

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: n 10 1- n 0, R3 CF 3 C1 2- n 1, R3 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 \D other process which falls within the competence of a 00 specialist skilled in the art of chemical synthesis.

For the chemical preparation of the products of the n invention, a person skilled in the art is considered as 0 having at his disposal, inter alia, all of the contents of "Chemical Abstracts" and the documents cited therein.

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

Novaluron is also preferred.

The proportions, by weight, of compounds of 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, S- 11 Sc) an organic solvent having a dielectric C constant of between 10 and 35, preferably of between Cand 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 11 dielectric constant of between 10 and 40, preferably of 00 between 20 and 30; this cosolvent may advantageously be ci 10 present in the composition in a weight/weight S(W/W) ratio of between 1/15 and 1/2. The solvent is c volatile, so as to serve in particular as a drying promoter, and is miscible with water and/or with the solvent c).

Although this is not preferred, the composition for spot-on application may optionally comprise water, 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 also comprise an antioxidant intended to inhibit airoxidation, 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 A 12 action and the pleasant appearance of the animal's fur c after application and drying.

As organic solvent c) which can be used in the invention, mention may be made in particular of: n 5 acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ND ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene Cl 10 glycol monomethyl ether, liquid polyoxyethylene Sglycols,. propylene glycol, 2-pyrrolidone, in particular C- N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.

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, In 13- O amine salts of formula in which the radicals R are optionally hydroxylated hydrocarbon Cradicals; 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; D polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, CI 10 polyoxyethylenated fatty alcohols, polyoxyethylenated 0 fatty acids, copolymers of ethylene oxide and propylene C- oxide, amphoteric surfactants such as substituted lauryl compounds of betaine, or preferably a mixture of at least two of these crystallization inhibitors.

In a particularly preferred manner, a crystallization inhibitor couple, namely the combination of a film-forming agent of polymeric type 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 note- M worthy manner, that is to say without any tendency O towards stickiness or to a sticky appearance, despite the high concentration of active material.

As cosolvent mention may be made in 00 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.

The compositions for spot-on application 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.

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 to 20 mg/kg, preferably 2 to 10 mg/kg of compound in particular fipronil, and from 1 to 30 mg/kg, Cpreferably 2 to 10 mg/kg, of preferred compound or to 20 mg/kg of other compound SAdvantageously, ready-to-use compositions dosed for 1-10, 10-20 and 20-40 kg animals respectively may be provided.

\O

oO .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 packag- Sing, a composition containing a compound of formula Ci in particular fipronil, and a composition containing compound preferably pyriproxyfen, each of the compositions including a vehicle which allows it 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 longn 16- O lasting efficacy for these compositions, and could c perhaps also explain the long-lasting action of the associated compound They also have a certain efficacy against other C 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 ND treatment of ectoparasites, or even endoparasites for 00 which the composition proves to have real utility capable of being obtained practically, according to the Scriteria of the veterinary art.

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

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, 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 S- 17 of compounds and in a liquid medium CI comprising a representative of each of the components t b, c and d. The total volume is 1 ml.

Example 1 fipronil pyriproxyfen ND Example 2 00 fipronil C- 10 pyriproxyfen In SExample 3 fipronil pyriproxyfen Example 4 fipronil methoprene Example fipronil 1-(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.

-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

\O

oO 5 stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of Sintegers 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.

Claims

1. A composition which provides small mammals with long-lasting protection against fleas, which includes at least one compound of formula R 2 R 1 R 4 N R1 R 13 in which: RI 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 NR 5 R 6 S(O)mR7, C(O)R 7 C(0)O-R 7 alkyl, haloalkyl or ORE 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(O)rCF3 radical; or R 5 and R6 may together form a divalent alkylene radical .which may be interrupted by one or two divalent hetero atoms; R7 represents an alkyl or a haloalkyl radical; Rs 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; Ru and Ri2 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO 2 R 1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-RI 2 the other three valency positions of the carbon atom forming part of the aromatic ring; Swith the proviso that when Ri is methyl, either R 2 is S(O)nR 3 or dicyanoimidazol-2-yl or haloalkyl, R 3 is haloalkyl, R 4 is NH 2 RII is Cl, R 1 3 is CF 3 and c X is N; or R 2 is 4 ,5-dicyanoimidazol-2-yl, R4 is Cl, R 1 I is Cl, R 1 3 is CF 3 and X is =C-CI; 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 synergistic N spot-on or local synergistic pour-on application on the skin, wherein the compound (B) is a compound which mimics juvenile hormones.

2. A composition according to claim 1, wherein the compound of formula is such that: Ri is CN or methyl R2 is S(O)nR 3 R3 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 alkyl, haloalkyl or ORs or a radical -N=C (R 9 (Rio); Rs and R independently represent a hydrogen atom or an alkyl, haloalkyl, C(O) alkyl or S(O)r-CF 3 radical; or R5 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; RI1 and R12 represent, independently of each other, a hydrogen or halogen atom; R13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-R 1 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that when RI is methyl, then R 3 is haloalkyl, R4 is NH 2 R I is Cl, R 1 3 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. 21 (N S4. A composition according to any one of claims 1 to 3, wherein the compound of Sformula is such that RI is CN. A composition according to any one of claims 1 to 4, wherein the compound of formula is such that R 1 3 is haloalkyl. 00 S6. 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)nR 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

9. A composition according to claim 7, wherein R 3 represents methyl or ethyl. A composition according to any one of claims 1 to 9, wherein the compound of formula is such that X is C-R 12 with R 2 being a halogen atom.

11. A composition according to any one of claims 1 to 10, wherein the compound of formula is such that RI is CN, R 2 is S(O)nR 3 R 3 is haloalkyl, R 4 is NH 2 R 1 1 and R 12 are, independently of each other, a halogen atom, and/or R 1 3 is haloalkyl.

12. A composition according to any one of claims 1 to 11, wherein the compound of formula is: 6-C1 2 4-CF 3 phenyl] 3-CN 4-[SO-CF 3 5-NH 2 pyrazole.

13. A composition according to any one of claims 1 to 1.1, in which the compound of formula is one of the following compounds: 1: 6-C1 2 4-CF 3 phenyl] 3-CN 4-[SO-CF 3 5-NH 2 pyrazole 2: 6-C1 2 4-CF 3 phenyl] 3-CN 4-[SO-C 2 H 5 5-NH 2 pyrazole.

14. A composition according to any one of claims 1 to 13, wherein the compound is selected from: azadirachtin diofenolan fenoxycarb Shydroprene c kinoprene methoprene pyriproxyfen IND tetrahydroazadirachtin 00oo Sand 4 -chloro-2-(2-chloro-2-methyl-propyl)-5- C 6 -iodo-3-pyridylmethoxy)pyridizine-3-(2H)-one. O 10 15. A composition according to any one of claims 1 to 14, wherein the compound is selected from a methoprene, a pyriproxyfen or a hydroprene.

16. A composition according to any one of claims 1 to 15, wherein the compound is selected from a methoprene or a pyriproxyfen.

17. A composition according to any one of claims 1 to 15, wherein the compound is a hydroprene.

18. A composition according to any one of claims 1 to 15, wherein the compound is a pyriproxyfen.

19. A composition according to any one of claims 1 to 15, wherein the compound is a methoprene.

20. A composition according to any one of claims 1 to 19, wherein the proportions, by weight, of compounds of formula and of type are between 80/20 and 20/80.

21. A composition according to any one of claims 1 to 20, 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.

22. A composition according to any one of claims 1 to 20, 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.

23. A composition according to claim 21, wherein the fluid vehicle and the Sconcentration of compounds and are adapted for local application to a zone Swith a surface area of 10 cm 2 or less. S 5 24. A composition according to any one of claims I to 23, which contains a dose of N from 0.1 to 40 mg/kg of compound and from 0.1 to 40 mg/kg of compound 00 CN 25. A composition according to claim 24, which contains a dose of from 1 to t 20mg/kg of compound and from 1 to 30mg/kg of compound 0

26. A composition according to any one of claims 1 to 25, which additionally comprises a crystallization inhibitor

27. A composition according to claim 26, wherein the crystallization inhibitor is present in a proportion of from 1 to 20%

28. A composition according to claim 27, wherein the crystallization inhibitor is present in a proportion of from 5 to 15%

29. A composition according to any one of claims to 26 to 28, wherein the crystallization inhibitor is selected from the group consisting of: S 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; cationic surfactants; amine salts of formula N+R'R"R' 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. A composition according to claim 29, wherein the crystallization inhibitor is a methacrylate.

31. A composition according to claim 29, wherein the anionic surfactant is selected from the group consisting of alkaline stearates; calcium stearate; triethanolamine Sstearate; sbdium abietate; alkyl sulphates; sodium dodecylbenzenesulphonate; sodium dioctylsulphosuccinate; and fatty acids. O 32. A composition according to claim 31, wherein the crystallization inhibitor is sodium, potassium or ammonium stearate. O

33. A composition according to claim 31, wherein the crystallization inhibitor is 0 10 sodium lauryl sulphate or sodium cetyl sulphate.

34. A composition according to claim 31, wherein the crystallization inhibitor is a fatty acid derived from coconut oil.

35. A composition according to claim 29, wherein the cationic surfactant is selected from the group consisting of water-soluble quatemary 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.

36. A composition according to claim 29, 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.

37. A composition according to claim 36, wherein the crystallization inhibitor is polysorbate 80 or polyoxyethylated alkyl ether. 30 38. A composition according to claim 29, wherein the amphoteric surfactant comprises substituted lauryl compounds of betaine.

39. A composition according to any one of claims 22 to 38, which comprises a crystallization inhibitor couple formed by the combination of a film-forming agent of a polymeric type and a surfactant. A composition according to claim 39, wherein said film-forming agent and said Ssurfactant are in similar or identical amounts within the limit of the total amounts of crystallization inhibitor.

41. A composition according to either claim 39 or 40, wherein the film-forming IN agent is chosen from: o00 .the various grades of polyvinylpyrrolidone, C polyvinyl alcohols, and copolymers of vinyl acetate and vinyl pyrrolidone, O 10 and wherein the surfactant is chosen from non-ionic surfactants.

42. A composition according to claim 41, wherein said non-ionic surfactants are polyoxyethylated sorbitan esters.

43. A composition according to claim 42, wherein said polyoxyethylated sorbitan esters are the various grades ofpolysorbate.

44. A composition according to any one of claims 1 to 43 which additionally comprises an organic solvent having a dielectric constant of between 10 and A composition according to claim 44, wherein said dielectric constant is between 20 and

46. A composition according to either claim 44 or 45 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.

47. A composition according to claim 46, wherein said organic solvent is chosen from N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate.

48. A composition according to any one of claims 44 to 47, which additionally Scomprises an organic co-solvent having a boiling point below 100°C, and having a g dielectric constant of between 10 and 40, which is miscible with water and/or with the solvent S O 49. A composition according to claim 48 wherein said organic co-solvent has a boiling point of below 80 0 C and/or has a dielectric constant of between 20 and A composition according to either claim 48 or 49, wherein the co-solvent is 1 10 present in a co-solvent /solvent weight/weight ratio of between 1/15 and 1/2.

51. A composition according to any one of claims 48 to 50, wherein the co-solvent is chosen from absolute ethanol, isopropanol and methanol.

52. A composition according to any one of claims 1 to 51, which provides protection for 2 to 3 months.

53. A composition according to any one of claims 21 to 23 and 28 to 52, characterized in that it comprises 5 to 10% 6-Cl2 4-CF 3 phenyl] 3-CN 4-[SO-CF 3 2 pyrazole and 5 to 20% ofpyriproxyfen.

54. A composition according to any one of claims 21 to 23 and 28 to 53, characterized in that it comprises 10% 1-[2,6-C12 4-CF 3 phenyl] 3-CN 4-[SO-CF 3 NH 2 pyrazole and 30% of methoprene. A composition according to any one of claims 1 to 54, wherein the composition is applied to the mammal by local point application to the skin of the "spot-on" type.

56. A composition when used for application either in a distinct and separate manner over time or concomitant with a compound of formula as defined in claim 1 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. 0 27

57. A composition as claimed in claim 56, wherein the crystallization inhibitor is as O defined in any one of claims 27 to 43.

58. A composition as claimed in either claim 56 or 57 wherein the organic solvent is 00 as defined in any one of claims 44 to 47. S59. A composition as claimed in any one of claims 56 to 58, wherein the organic co- Ssolvent is as defined in any one of claims 48 to 51. cN A composition which provides small mammals with long-lasting protection against fleas, which includes at least one compound of formula R 2 R, (I) in which: RI is CN or methyl or a halogen atom; R2 is S(O)nR 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl; R3 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 or a radical -N=C (R9) (Rio); Rs and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)rCF 3 radical; or Rs and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms; R7 represents an alkyl or a haloalkyl radical; c R 8 represents an alkyl or haloalkyl radical or a hydrogen atom; SR 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-alcyl, S-alkyl, cyano or alkyl; Ri and R 1 2 represent, independently of each other, a hydrogen or halogen atom, IN or optionally CN or NO 2 00 SR 1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF 3 or SF N group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or O 10 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 2 is S(O)nR 3 or 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, RI1 is Cl, RI 3 is CF 3 and X is =C-Cl; 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 synergistic spot-on or local synergistic pour-on application on the skin, wherein the fluid vehicle and the concentration of compounds and are adapted for local application to a zone with a surface area of 10cm 2 or less.

61. A composition according to claim 60, 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 NR 5 R 6 S(O)mR7, 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)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 haloalkyl radical; R 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; 29 SRI 1 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)qCF3 or SF 8 group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; Oo 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; I with the proviso that when RI is methyl, then R 3 is haloalkyl, R 4 is NH 2 RII is SCl, Ri 3 is CF 3 and X is N.

62. A composition according to claim 60 or 61, wherein Rs and R together form a divalent alkylene radical which is interrupted with one or two oxygen or sulphur atoms.

63. A composition according to any one of claims 60 to 62, wherein the compound of formula is such that Ri is CN.

64. A composition according to any one of claims 60 to 63, wherein the compound of formula is such that RI 3 is haloalkyl.

65. The composition according to claim 64, wherein R 13 is CF 3

66. A composition according to any one of claims 60 to 65, wherein the compound of formula is such that R 2 is S(O),R 3 R3 represents CF 3 or alkyl, or where n=0, R 3 represents CF 3

67. A composition according to claim 65, wherein R 2 is SOR 3

68. A composition according to claim 66, wherein R 3 represents methyl or ethyl.

69. A composition according to any one of claims 60 to 68, wherein the compound of formula is such that X is C-RI 2 with R1 2 being a halogen atom. A composition according to any one of claims 60 to 69, wherein the compound of formula is such that RP is CN, R 2 is S(O)nR 3 R 3 is haloalkyl, R 4 is NH 2 R 11 and RI 2 are, independently of each other, a halogen atom, and/or R 13 is haloalkyl. O

71. A composition according to any one of claims 60 to 70, wherein the compound of formula is: 6-C1 2 4-CF 3 phenyl] 3-CN 4-[SO-CF 3 5-NH 2 pyrazole.

72. A composition according to any one of claims 60 to 70, in which the compound O of formula is one of the following compounds: S 1-2,6- 4-CF3 phenyl] 3-CN 4-[SO-CF3 5-NH pyrale 2: 6-Cl 2 4-CF 3 phenyl] 3-CN 4-[SO-C2Hs] 5-NH 2 pyrazole. O N, 2: 6-Cl 2 4-CF 3 phenyl] 3-CN 4-[SO-C 2 Hs] 5-NH 2 pyrazole. ,1 10 73. A composition according to any one of claims 60 to 72, wherein the compound is a compound which mimics juvenile hormones.

74. A composition according to claim 73, 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. A composition according to any one of claims 60 to 68, wherein the compound is a chitin-synthesis inhibitor.

76. A composition according to claim 75, wherein the compound is selected from: chlorfluazuron cyromazine diflubenzuron fluazuron flucycloxuron flufenoxuron Shexaflumuron Slufenuron tebufenozide teflubenzuron triflumuron O 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. 0 77. A composition according to any one of claims 73 to 75, characterized in that the o 10 compound is chosen from methoprenes, pyriproxyfens, lufenuron, hydroprene, cyromazine and 1-( 2 6 -difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea.

78. A composition according to claim 77, characterized in that the compound is pyriproxyfen.

79. A composition according to claim 77 characterized in that the compound is a methoprene. A composition according to any one of claims 60 to 79, wherein the proportions, by weight, of compounds of formula and of type are between 80/20 and 20/80.

81. A composition according to any one of claims 60 to 80, 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.

82. A composition according to any one of claims 60 to 80, 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.

83. A composition according to any one of claims 60 to 82, which contains a dose of from 0.1 to 40 mg/kg of compound and from 0.1 to 40 mg/kg of compound

84. A composition according to claim 83, which contains a dose of from 1 to 20mg/kg of compound and from 1 to 30mg/kg of compound 32 A composition according to any one of claims 60 to 84, which additionally comprises a crystallization inhibitor

86. A composition according to claim 85, wherein the crystallization inhibitor is present in a proportion of from 1 to 20% \O 00

87. A composition according to claim 86, wherein the crystallization inhibitor is Spresent in a proportion of from 5 to 15% c 10 88. A composition according to any one of claims to 85 to 87, 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; 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.

89. A composition according to claim 88, wherein the crystallization inhibitor is a methacrylate. A composition according to claim 88, 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.

91. A composition according to claim 90, wherein the crystallization inhibitor is sodium, potassium or ammonium stearate.

92. A composition according to claim 90, wherein the crystallization inhibitor is sodium lauryl sulphate or sodium cetyl sulphate.

93. A composition according to claim 90, wherein the crystallization inhibitor is a Sfatty acid derived from coconut oil. S 5 94. A composition according to claim 88, wherein the cationic surfactant is selected N from the group consisting of water-soluble quaternary ammonium salts of formula g Y in which the radicals R are optionally hydroxylated hydrocarbon radicals and T is an anion of a strong acid; cetyltrimethylammonium bromide; amine a salts of formula in which the radicals R are optionally hydroxylated 0 10 hydrocarbon radicals; and octadecylamine hydrochloride. A composition according to claim 88, 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.

96. A composition according to claim 95, wherein the crystallization inhibitor is polysorbate 80 or polyoxyethylated alkyl ether.

97. A composition according to claim 88, wherein the amphoteric surfactant comprises substituted lauryl compounds of betaine.

98. A composition according to any one of claims 82 to 97, which comprises a crystallization inhibitor couple formed by the combination of a film-forming agent of a polymeric type and a surfactant.

99. A composition according to claim 98, wherein said film-forming agent and said surfactant are in similar or identical amounts within the limit of the total amounts of crystallization inhibitor.

100. A composition according to either claim 98 or 99, 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. k 101. A composition according to claim 100, wherein said non-ionic surfactants are polyoxyethylated sorbitan esters.

102. A composition according to claim 101, wherein said polyoxyethylated sorbitan OC esters are the various grades of polysorbate. c

103. A composition according to any one of claims 60 to 102 which additionally O comprises an organic solvent having a dielectric constant of between 10 and cq

104. A composition according to claim 103, wherein said dielectric constant is between 20 and

105. A composition according to either claim 103 or 104 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.

106. A composition according to claim 105, wherein said organic solvent is chosen from N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate.

107. A composition according to any one of claims 103 to 106, which additionally comprises an organic co-solvent having a boiling point below 100 0 C, and having a dielectric constant of between 10 and 40, which is miscible with water and/or with the solvent

108. A composition according to claim 107 wherein said organic co-solvent has a boiling point of below 80 0 C and/or has a dielectric constant of between 20 and

109. A composition according to either claim 107 or 108, wherein the co-solvent (d) Sis present in a co-solvent /solvent weight/weight ratio of between 1/15 c and 1/2. S 5 110. A composition according to any one of claims 107 to 109, wherein the co- IO solvent is chosen from absolute ethanol, isopropanol and methanol. 00

111. A composition according to any one of claims 60 to 110, which provides protection for 2 to 3 months.

112. A composition according to any one of claims 81 to 82 and 87 to 111, characterized in that it comprises 5 to 10% 6-Cl 2 4-CF 3 phenyl] 3-CN 4-[SO-CF 3 2 pyrazole and 5 to 20% ofpyriproxyfen.

113. A composition according to any one of claims 81 to 82 and 87 to 111, characterized in that it comprises 10% 1-[2,6-C1 2 4-CF 3 phenyl] 3-CN 4-[SO-CF 3 NH 2 pyrazole and 30% ofmethoprene.

114. A composition according to any one of claims 60 to 113, wherein the composition is applied to the mammal by local point application to the skin of the "spot-on" type.

115. A composition when used for application either in a distinct and separate manner over time or concomitant with a compound of formula as defined in claim 60 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.

116. A composition as claimed in claim 115, wherein the crystallization inhibitor is as defined in any one of claims 86 to 102.

117. A composition as claimed in either claim 115 or 116 wherein the organic solvent is as defined in any one of claims 103 to 106. S118. A composition as claimed in any one of claims 115 to 117, wherein the organic c co-solvent is as defined in any one of claims 107 to 110.

119. A synergistic spot-on composition for the long lasting protection against ND 5 ectoparasites on mammals which comprises synergistic amounts 00 at least one compound of the formula: 0R 2 R (I) in whichW R is CN or methyl or a halogen atom; K 13 in which: Ri is CN or methyl or a halogen atom; R2 is S(O).R 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 NRsR 6 S(O)mR7, 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, alkoxycarbonyl or S(O)r-CF 3 radical; R5 and R% may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms or; R 7 represents an alkyl or haloalkyl radical; R8 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 one or more substituents selected from the group consisting of OH, -O-alkyl, S-alkyl, cyano or alkyl; Ril and RI2 represent, independently of each other, hydrogen, halogen, CN or NO 2 P g p Ri 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(0)qCF3 or SF group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-RI 2 the other three valency oO 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 R 1 1 is Cl, Ri 3 is CF 3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R 4 is CI, R 11 is Cl, R1 3 is CF 3 and X is =C-Cl; S(B) at least one insect growth regulator (IGR) that mimics juvenile hormones; cI 10 imidacloprid; and a fluid vehicle comprising at least one customary spot-on formulation adjuvant.

120. The synergistic spot-on composition according to claim 119, which comprises a compound of formula wherein: R 1 is CN or methyl; R2 is S(O)nR 3 R 3 is alkyl or haloalkyl; R 4 represents a hydrogen or halogen atom; or a radical NR 5 sR, S(O)mR7, C(O)R 7 alkyl, haloalkyl or OpR or a radical -N=C(R 9 (Rio); Rs and R independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl or S(O)r-CF 3 radical; or Rs and R6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms selected from the group consisting of oxygen and sulphur; R 7 represents an alkyl or haloalkyl radical; Rg 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 one or more substituents selected from the group consisting of OH, -O-alkyl, S-alkyl, cyano or alkyl; R 1 1 and R1 2 represent, independently of each other, a hydrogen or halogen atom; Ri 3 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-Ri 2 the other three valency positions of the carbon atom forming part of the aromatic ring; C with the proviso that when Ri is methyl, then R3 is haloalkyl, R4 is NH 2 R, is Cl, R13 is CF 3 and X is N; a fluid vehicle. O

121. The synergistic spot-on composition according to any one of claims 119 or 120, which comprises a compound of formula wherein RI is CN. \O 00

122. The synergistic spot-on composition according to any one of claims 119 to 121 which comprises a compound of formula wherein R13 is haloalkyl. CN 10 123. The synergistic spot-on composition according to any one of claims 119 to 122, which comprises a compound of formula wherein R2 is S(O)nR 3 where when n=l, R3 is CF 3 or alkyl, or where n=0, R3 is CF 3

124. The synergistic spot-on composition according to any one of claims 119 to 123, which comprises a compound of formula where X is C-RI 2 where R12 is a halogen atom.

125. The synergistic spot-on composition according to any one of claims 119 to 124, which comprises a compound of formula where Ri is CN, R3 is haloalkyl, R4 is NH2, Ru and Ri2 are, independently of each other, a halogen atom, and/or R13 is haloalkyl.

126. The syngergistic spot-on composition according to any one of claims 119 to 125, in which the compound of formula is 1-[2,6-C1 2 4-CF 3 phenyl]3-CN 4 -[SO- CF 3 ]5-NH 2 pyrazole.

127. The synergistic spot-on composition according to any one of claims 119 to 126, in which the compound of formula is compounds 1-[2,6-C1 2 4-CF 3 phenyl]3-CN 4- [S-CF 3 ]5-NH 2 pyrazole or 1-[2,6-C1 2 4-CF 3 phenyl]3-CN 4-[SO-C 2 Hs]5-NH 2 pyrazole.

128. The synergistic spot-on composition according to any one of claims 119 to 127, wherein the compound which mimics juvenile hormones is selected from the group consisting of: azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadrirachtin, and 4 -chloro- 2 -(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy) 3(2H)-one.

129. The synergistic spot-on composition according to any one of claims wherein IGR is methoprene. pyridizine- 119 to 128,

130. The synergistic spot-on composition according to any one of claims 119 to 129, wherein in that the proportions, by weight, of compounds to the compounds are between 80/20 and 20/80.

131. The synergistic spot-on composition according to any one of claims 119 to 130, wherein the fluid vehicle and the concentration of the compounds and are applied locally on a zone with a surface area of less then 10 cm 2

132. The synergistic spot-on composition according to any one of claims 119 to 131, wherein amount of compound is from 0.1 to 40 mg/kg and the amount of compound is from 0.1 to 40 mg/kg.

133. The synergistic spot-on composition according to any one of claims 119 to 132, wherein the amount of compound is from 1 to 20 mg/kg, and the amount of compound is from 1 to 30 mg/kg.

134. The synergistic spot-on composition according to any one of claims 119 to 133, which further comprises a crystallization inhibitor which is present in a proportion of from 1 to 20%

135. The synergistic spot-on composition according to claim 134, 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, c polyoxyethylenated sorbitan esters, lecithin, sodium carboxymethylcellulose, acrylic derivatives, Sat least one anionic surfactants, at least one cationic surfactant, at least one amine salt of the formula N 30 in which the radicals R are NO optionally hydroxylated hydrocarbon radicals; at least one non-ionic surfactant, CI at least one amphoteric surfactant, and O a mixture of at least two of these crystallization inhibitors.

136. The synergistic spot-on composition according to claim 135, wherein: the anionic surfactants is alkaline stearate, calcium stearate; triethanolamine stearate; sodium abietate; alkyl sulphates, sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; and fatty acids; the cationic surfactant is a water-soluble quaternary ammonium salts of formula N Y in which the radicals R are optionally hydroxylated hydrocarbon radicals and Y" is an anion of a strong acid; the amine salt octadecylamine hydrochloride; the nonionic surfactant is polysorbate 80, polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenate derivatives of castor oil, polyglycerol esters, polyoxyethylenate fatty alcohols polyoxyethylenate fatty acids, copolymers of ethylene oxide and propylene oxide; the amphoteric surfactant is a substituted lauryl compounds of betaine.

137. The synergistic spot-on composition according to claim 135, wherein the crystallization inhibitor is a crystallization inhibitor couple formed by the combination of a film-forming agent of polymeric type and a surfactant.

138., The synergistic spot-on composition according to claim 137, wherein the film- forming agent is polyvinylpyrrolidone, polyvinyl alcohols, or copolymers of vinyl acetate and vinyl pyrrolidone, and the surfactant is an ionic surfactants.

139. The synergistic spot-on composition according to any one of claims 119 to 138, wherein the fluid vehicle comprises an organic solvent having a dielectric constant of between 10 and

140. The synergistic spot-on composition according to claim 139, wherein the Sorganic solvent is selected from the group consisting of 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 N ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate, and a mixture of at least two C of these solvents. O O 10 141. The synergistic spot-on composition according to claim 139, wherein the fluid vehicle further comprises an organic co-solvent having a boiling point below 100°C, a dielectric constant of between 10 and 40, and is miscible with water and/or with the solvent and present in a weight ratio of co-solvent:solvent between 1:15 and 1:2.

142. The synergistic spot-on composition according to claim 141, wherein the co- solvent is absolute ethanol, isopropanol or methanol.

143. The synergistic spot-on composition according to any one of claims 119 to 142, characterized in that it affords protection for 2 to 3 months.

144. A method for controlling ectoparasites in mammals over a long duration of time which comprises applying locally to the skin of a mammal a synergistically effective amount of a synergistic spot-on composition according to claim 119.

145. The method according to claim 144, wherein the mammal is a cat or dog.

146. The method according to claim 144 or 145, wherein the proportions, by weight, of compounds to compounds are between 80/20 and 20/80.

147. The method according to any one of claims 144 to 146, wherein the synergistic spot-on composition comprises from 0.1 to 40 mg/kg of compound and from 0.1 to mg/kg of compound

148. The method according to any one of claims 144 to 147, wherein the synergistic spot-on composition comprises from 1 to 20 mg/kg and from 1 to 30 mg/kg of compound S149. The method according to any one of claims 144 to 148, wherein the ectoparasite Cr is a flea or tick.

150. The method according to any one of claims 144 to 149, wherein the synergistic ND spot-on composition comprises from 2 to I0 mg/kg of compound 00

151. The method according to any one of claims 144 to 150, wherein the duration is two months.

152. The method according to any one of claims 144 to 151, wherein the duration is three months.

153. The method according to any one of claims 144 to 152, wherein the synergistic spot-on composition comprises offipronil, methoprene and imidacloprid.

154. A composition according to any one of claims 1 to 143 substantially as hereinbefore described with reference to the examples.

155. A method according to any one of claims 144 to 153 substantially as hereinbefore described with reference to the examples.

156. A composition which provides small mammals with long-lasting protection against fleas, which.includes at least one compound of formula R 2 R 1 /L (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; 0 R 3 is alkyl or haloalkyl; R 4 represents a hydrogen or halogen atom; or a radical NRsR 6 S(O)mR7, C(O)R 7 C(0)O-R 7 alkyl, haloalkyl or ORs or a radical -N=C (R 9 (Rio); O R5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)r-CF 3 radical; or R 5 and Re may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero Satoms; C 10 R 7 represents an alkyl or a haloalkyl radical; R 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 R 1 2 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO 2 R 1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-RI 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that when RI is methyl, either R2 is S(O)nR3 or dicyanoimidazol-2-yl or haloalkyl, R 3 is haloalkyl, R4 is NH 2 R, is Cl, R 1 3 is CF 3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R4 is Cl, R11 is Cl, Ri 3 is CF 3 and X is =C-Cl; and, at least one ovicidal compound wherein compound is not lufenuron, of insect growth regulator (IGR) type, in a fluid vehicle which is acceptable to the mammal and suitable for local synergistic spot-on or local synergistic pour-on application on the skin.

157. A composition according to claim 156, wherein the compound of formula is such that: RI is CN or methyl R2 is S(O)nR3 R3 is alkyl or haloalkyl R4 represents a hydrogen or halogen atom; or a radical NRsR, S(O)mR7, SC(O)R 7 alkyl, haloalkyl or ORs or a radical -N=C (R9) (Rio); R 5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O) alkyl or S(O)r-CF 3 radical; or R and R 6 may together form a divalent alkylene radical S 5 which may be interrupted by one or two divalent hetero atoms; IN R7 represents an alkyl or haloalkyl radical; Rs represents an alkyl or haloalkyl radical or a hydrogen atom; NC R 9 represents an alkyl radical or a hydrogen atom; SRio represents a phenyl or heteroaryl group optionally substituted with one or 10 more halogen atoms or groups selected from OH, -O-alkyl, S-alkyl, cyano or alkyl; R1I and Ri2 represent, independently of each other, a hydrogen or halogen atom; R13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-R 12 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that when Ri is methyl, then R3 is haloalkyl, R 4 is NH 2 RI1 is Cl, Ri3 is CF 3 and X is N.

158. A composition according to claim 156 or 157, wherein Rs and R6 together form a divalent alkylene radical which is interrupted with one or two oxygen or sulphur atoms.

159. A composition according to any one of claims 156 to 158, wherein the compound of formula is such that Ri is CN.

160. A composition according to any one of claims 156 to 159, wherein the compound of formula is such that RI3 is haloalkyl.

161. The composition according to claim 160, wherein Ri3 is CF 3

162. A composition according to any one of claims 156 to 161, wherein the compound of formula is such that R2 is S(O)nR 3 R3 represents CF 3 or alkyl, or where n=0, R3 represents CF 3

163. A composition according to claim 162, wherein R 2 is SOR 3 S164. A composition according to claim 163, wherein R 3 represents methyl or ethyl.

165. A composition according to any one of claims 156 to 164, wherein the Scompound of formula is such that X is C-R 1 2 with R 1 2 being a halogen atom. .1 166. A composition according to any one of claims 156 to 165, wherein the compound of formula is such that Ri is CN, R 2 is S(O)nR 3 R 3 is haloalkyl, R4 is NH 2 R 11 and R 1 2 are, independently of each other, a halogen atom, and/or R 1 3 is haloalkyl.

167. A composition according to any one of claims 156 to 166, wherein the compound of formula is: 6-C12 4-CF 3 phenyl] 3-CN 4-[SO-CF 3 5-NH 2 pyrazole.

168. A composition according to any one of claims 156 to 166, in which the compound of formula is one of the following compounds: 1: 6-C1 2 4-CF 3 phenyl] 3-CN 4-[SO-CF 3 5-NH 2 pyrazole 2: 6-C1 2 4-CF 3 phenyl] 3-CN 4-[SO-C2H 5 5-NH 2 pyrazole.

169. A composition according to any one of claims 156 to 168, wherein the compound is a compound which mimics juvenile hormones.

170. A composition according to claim 169, 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.

171. A composition according to any one of claims 156 to 164, wherein the en compound is a chitin-synthesis inhibitor. O

172. A composition according to claim 171, wherein the compound is selected IN0 from: Schlorfluazuron Scyromazine Sdiflubenzuron 0 10 fluazuron flucycloxuron flufenoxuron hexaflumuron 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.

173. A composition according to any one of claims 169 to 171, characterized in that the compound is chosen from methoprenes, pyriproxyfens, hydroprene, cyromazine and 1-( 2 ,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea.

174. A composition according to claim 173, characterized in that the compound (B) is pyriproxyfen.

175. A composition according to claim 173, characterized in that the compound (B) is a methoprene.

176. A composition according to any one of claims 175, wherein the proportions, by weight, of compounds of formula and of type are between 80/20 and 20/80.

177. A composition according to any one of claims 156 to 176, 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.

178. A composition according to any one of claims 156 to 176, wherein the fluid vehicle and the concentration of the compounds and are adapted for local CM application to skin by deposition of a "pour-on" type.

179. A composition according to claim 177, wherein the fluid vehicle and the I concentration of compounds and are adapted for local application to a zone 00 Swith a surface area of 10 cm 2 or less. O

180. A composition according to any one of claims 156 to 179, which contains a dose 0 10 of from 0.1 to 40 mg/kg of compound and from 0.1 to 40 mg/kg of compound

181. A composition according to claim 180, which contains a dose of from 1 to of compound and from 1 to 30mg/kg of compound

182. A composition according to any one of claims 156 to 181, which additionally comprises a crystallization inhibitor (b)

183. A composition according to claim 182, wherein the crystallization inhibitor (b) is present in a proportion of from 1 to 20%

184. A composition according to claim 183, wherein the crystallization inhibitor (b) is present in a proportion of from 5 to 15%

185. A composition according to any one of claims to 182 to 184, 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; 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.

186. A composition according to claim 185, wherein the crystallization inhibitor is a ¢C methacrylate. O

187. A composition according to claim 185, wherein the anionic surfactant is selected ND from the group consisting of alkaline stearates; calcium stearate; triethanolamine 00 stearate; sodium abietate; alkyl sulphates; sodium dodecylbenzenesulphonate; sodium dioctylsulphosuccinate; and fatty acids. 0 10 188. A composition according to claim 187, wherein the crystallization inhibitor is sodium, potassium or ammonium stearate.

189. A composition according to claim 187, wherein the crystallization inhibitor is sodium lauryl sulphate or sodium cetyl sulphate.

190. A composition according to claim 187, wherein the crystallization inhibitor is a fatty acid derived from coconut oil.

191. A composition according to claim 185, 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.

192. A composition according to claim 185, 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.

193. A composition according to claim 192, wherein the crystallization inhibitor is polysorbate 80 or polyoxyethylated alkyl ether.

194. A composition according to claim 185, wherein the amphoteric surfactant comprises substituted lauryl compounds of betaine.

195. A composition according to any one of claims 178 to 194, which comprises a crystallization inhibitor couple formed by the combination of a film-forming agent of a Mc polymeric type and a surfactant. O

196. A composition according to claim 195, wherein said film-forming agent and ND said surfactant are in similar or identical amounts within the limit of the total amounts 00 of crystallization inhibitor.

197. A composition according to either claim 195 or 196, wherein the film-forming O 10 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.

198. A composition according to claim 197, wherein said non-ionic surfactants are polyoxyethylated sorbitan esters.

199. A composition according to claim 198, wherein said polyoxyethylated sorbitan esters are the various grades ofpolysorbate.

200. A composition according to any one of claims 156 to 199 which additionally comprises an organic solvent having a dielectric constant of between 10 and

201. A composition according to claim 200, wherein said dielectric constant is between 20 and

202. A composition according to either claim 200 or 201 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.

203. A composition according to claim 202, wherein said organic solvent is Schosen from N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol mc and diethyl phthalate.

204. A composition according to any one of claims 200 to 203, which additionally NO comprises an organic co-solvent having a boiling point below 100 0 C, and having a 00 Sdielectric constant of between 10 and 40, which is miscible with water and/or with the solvent O 10 205. A composition according to claim 204 wherein said organic co-solvent has a boiling point of below 80 0 C and/or has a dielectric constant of between 20 and

206. A composition according to either claim 204 or 205, wherein the co-solvent (d) is present in a co-solvent /solvent weight/weight ratio of between 1/15 and 1/2.

207. A composition according to any one of claims 204 to 206, wherein the co- solvent is chosen from absolute ethanol, isopropanoland methanol.

208. A composition according to any one of claims 156 to 207, which provides protection for 2 to 3 months.

209. A composition according to any one of claims 177 to 179 and 184 to 208, characterized in that it comprises 5 to 10% 6-C1 2 4-CF 3 phenyl] 3-CN 4-[SO-CF 3 5-NH 2 pyrazole and 5 to 20% ofpyriproxyfen.

210. A composition according to any one of claims 177 to 179 and 184 to 208, characterized in that it comprises 10% 1-[2,6-C1 2 4-CF 3 phenyl] 3-CN 4-[SO-CF 3 NH 2 pyrazole and 30% of methoprene.

211. A composition according to any one of claims 156 to 210, wherein the composition is applied to the mammal by local point application to the skin of the "spot-on" type.

212. Use of at least one compound belonging to the formula R 13 00 0 10 in which: RI is CN or methyl or a halogen atom; R2 is S(O)nR 3 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,, S(O)mR7, 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, 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; R 7 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 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 12 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO 2 R 1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF 3 or SF group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-R 1 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that when RI is methyl, either R2 is S(O).R 3 or dicyanoimidazol-2-yl or haloalkyl, then R 3 is haloalkyl, R 4 is NH 2 Ri is Cl, Ri3 is CF 3 and X is N; or R2 is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, Ru is Cl, R13 is CF 3 and X is =C-C1; 1 and at least one ovicidal compound wherein compound is not lufenuron, of insect growth regulator (IGR) type, Ccr for the preparation of a composition in a fluid vehicle for local synergistic spot- on application to the skin of small mammals for long-lasting protection against fleas. \O 213. Use according to claim 212, wherein R 5 and R may together form a divalent 00 alkylene radical which may be interrupted by one or two oxygen or sulphur atoms. tI 214. Use according to claim 212 substantially as herein before described with reference to the examples.

215. A composition when used for application either in a distinct and separate manner over time or concomitant with a compound of formula as defined in claim 98 for the provision of long-lasting protection against fleas in small mammals and which comprises at least one ovicidal compound wherein compound is not lufenuron 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.

216. A composition as claimed in claim 215, wherein the crystallization inhibitor is as defined in any one of claims 183 to 199.

217. A composition as claimed in either claim 215 or 216 wherein the organic solvent is as defined in any one of claims 200 to 203.

218. A composition as claimed in any one of claims 215 to 217, wherein the organic co-solvent is as defined in any one of claims 204 to 207.

219. 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 00 O 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; R3 is alkyl or haloalkyl; R 4 represents a hydrogen or halogen atom; or a radical NRsR 6 S(O)mR7, C(O)R 7 C(0)O-R 7 alkyl, haloalkyl or OR or a radical -N=C (Rg) (Rio); Rs and Re independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)r-CF3 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; Rlo 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 Ri2 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO 2 R13 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 R 2 is S(O).R 3 or dicyanoimidazol-2-yl or haloalkyl, R 3 is haloalkyl, R 4 is NH 2 R 11 is Cl, Ri 3 is CF 3 and X is N; or R2 is 4, 5-dicyanoimidazol-2-yl, R 4 is Cl, Ru is Cl, Ri3 is CF 3 and X is =C- Cl; 1and, at least one ovicidal compound wherein compound is not lufenuron, of insect growth regulator (IGR) type, in a fluid vehicle which is acceptable to the M mammal and suitable for local synergistic spot-on application on the skin. S 5 220. The method according to claim 219, wherein the application is to a zone with a IN surface area of 10cm 2 or less. 00oo

221. The method according to claim 220, wherein the application is at two points. O 10 222. The method according to either claim 220 or claim 221, wherein the application is localized between the mammal's shoulders.

223.. 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 N R 4 N R1 X R 13 S(I) in which: RI is CN or methyl or a halogen atom; R2 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 NR5R%, 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); Rs and R% independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)r-CF 3 radical; or Rs and %R may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms; I ct R 7 represents an alkyl or a haloalkyl radical; SRs 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 5 more halogen atoms or groups such a OH, -0-alkyl, S-alkyl, cyano or alkyl; IND RI 1 and R 12 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO 2 Cl R 1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF 3 or SF S group; S 10 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 2 is S(O)nR 3 or dicyanoimidazol-2-yl or haloalkyl, R 3 is haloalkyl, R 4 is NH 2 RI 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, R 11 is Cl, R 13 is CF 3 and X is =C- Cl; and, at least one ovicidal compound wherein compound is not lufenuron, of insect growth regulator (IGR) type, in a fluid vehicle which is acceptable to the mammal and suitable for local synergistic spot-on application on the skin.

224. The method according to claim 223, wherein said ectoparasites are ticks.

225. A synergistic spot-on composition for the long lasting protection against ectoparasites on mammals which comprises synergistic amounts at least one compound of the formula: R 2 R 1 IR N R W'I in which: SRI is CN or methyl or a halogen atom; R2 is S(O)nR 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl; R3 is alkyl or haloalkyl; R 4 represents a hydrogen or halogen atom; or a radical NR 5 R 6 S(O)mR7, SC(O)R 7 C(0)O-R 7 alkyl, haloalkyl, or OR 8 or a radical -N=C(R 9 (Rio); 0_ R 5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)r-CF 3 radical; Rs and R 6 may together form a in divalent alkylene radical which may be interrupted by.one or two divalent hetero atoms or; R7 represents an alkyl or haloalkyl radical; R8 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 one or more substituents selected from the group consisting of OH, -O-alkyl, S-alkyl, cyano or alkyl; R 1 1 and R 1 2 represent, independently of each other, hydrogen, halogen, CN or NO 2 R 1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a radical C-R12, the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that when Ri is methyl, then R3 is haloalkyl, R4 is NH 2 R1. is Cl, Ri 3 is CF 3 and X is N; or R2 is 4,5-dicyanoimidazol-2-yl, R4 is Cl, Rn is Cl, R 1 3 is CF 3 and X is =C-Cl; at least one insect growth regulator (IGR) that mimics juvenile hormones wherein the IGR is not lufenuron; imidacloprid; and a fluid vehicle comprising at least one customary spot-on formulation adjuvant.

226. The synergistic spot-on composition according to claim 225, which comprises a compound of formula wherein: RI is CN or methyl; .R2is S(O)nR3; R3 is alkyl or haloalkyl; R 4 represents a hydrogen or halogen atom; or a radical NRsR 6 S(O)mR7, SC(O)R 7 alkyl, haloalkyl or OR or a radical -N=C(R 9 (Rio); SR 5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl 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 selected from the IN group consisting of oxygen and sulphur; O R 7 represents an alkyl or haloalkyl radical; Rs represents an alkyl or haloalkyl radical or a hydrogen atom; I R 9 represents an alkyl radical or a hydrogen atom; 0 10 Rio represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or one or more substituents selected from the group consisting of OH, -0-alkyl, S-alkyl, cyano or alkyl; RII and R 1 2 represent, independently of each other, a hydrogen or halogen atom; R 1 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(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-RI 2 the other three valency positions of the carbon atom forming part of the aromatic ring; with the proviso that when R 1 is methyl, then R3 is haloalkyl, R4 is NH 2 RI is Cl, RI3 is CF 3 and X is N; a fluid vehicle.

227. The synergistic spot-on composition according to any one of claims 225 or 226, which comprises a compound of formula wherein RI is CN.

228. The synergistic spot-on composition according to any one of claims 225 to 227 which comprises a compound of formula wherein Ri3 is haloalkyl.

229. The synergistic spot-on composition according to any one of claims 225 to 228, which comprises a compound of formula wherein R2 is S(O)nR 3 where when n=l, R3 is CF 3 or alkyl, or where n=0, R3 is CF 3

230. The synergistic spot-on composition according to any one of claims 225 to 229, which comprises a compound of formula where X is C-R 1 2 where R 12 is a halogen atom. S231. The synergistic spot-on composition according to any one of claims 225 to 230, Swhich comprises a compound of formula where Ri is CN, R 3 is haloalkyl, R 4 is SINH 2 R 11 and R 12 are, independently of each other, a halogen atom, and/or R 1 3 is 0 haloalkyl. O 232. The syngergistic spot-on composition according to any one of claims 225 to 00 231, in which the compound of formula is 1-[2,6-C1 2 4-CF 3 phenyl]3-CN 4 -[SO- SCF 3 ]5-NH 2 pyrazole.

233. The synergistic spot-on composition according to any one of claims 225 to 232, in which the compound of formula is compounds 1-[2,6-Cl2 4-CF 3 phenyl]3-CN 4- [S-CF 3 ]5-NH 2 pyrazole or 1-[2,6-C1 2 4-CF 3 phenyl]3-CN 4-[SO-C 2 H 5 ]5-NH 2 pyrazole.

234. The synergistic spot-on composition according to any one of claims 225 to 233, wherein the compound which mimics juvenile hormones is selected from the group consisting of: azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadrirachtin, and 4 -chloro-2-(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy) pyridizine- 3(2H)-one.

235. The synergistic spot-on composition according to any one of claims 225 to 234, wherein IGR is methoprene.

236. The synergistic spot-on composition according to any one of claims 225 to 235, wherein in that the proportions, by weight, of compounds to the compounds are between 80/20 and 20/80.

237. The synergistic spot-on composition according to any one of claims 225 to 236, Swherein the fluid vehicle and the concentration of the compounds and are applied locally on a zone with a surface area of less then 10 cm 2

238. The synergistic spot-on composition according to any one of claims 225 to 237, wherein amount of compound is from 0.1 to 40 mg/kg and the amount of 00 compound is from 0.1 to 40 mg/kg. It 239. The synergistic spot-on composition according to any one of claims 225 to 238, wherein the amount of compound is from 1 to 20 mg/kg, and the amount of compound is from 1 to 30 mg/kg.

240. The synergistic spot-on composition according to any one of claims 225 to 239, which further comprises a crystallization inhibitor which is present in a proportion of from 1 to 20%

241. The synergistic spot-on composition according to claim 240, 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 carboxymethylcellulose, acrylic derivatives, at least one anionic surfactants, at least one cationic surfactant, at least one amine salt of the formula N 30 in which the radicals R are optionally hydroxylated hydrocarbon radicals; at least one non-ionic surfactant, at least one amphoteric surfactant, and a mixture of at least two of these crystallization inhibitors.

242. The synergistic spot-on composition according to claim 241, wherein: the anionic surfactants is alkaline stearate, calcium stearate; triethanolamine stearate; sodium abietate; alkyl sulphates, sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; and fatty acids; the cationic surfactant is a 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; the amine salt octadecylamine hydrochloride; the nonionic surfactant is polysorbate 80, polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenate derivatives of castor oil, polyglycerol esters, polyoxyethylenate fatty alcohols polyoxyethylenate fatty acids, copolymers of ethylene oxide and propylene oxide; the amphoteric surfactant is a substituted lauryl compounds of betaine.

243. The synergistic spot-on composition according to claim 241, wherein the crystallization inhibitor is a crystallization inhibitor couple formed by the combination of a film-forming agent of polymeric type and a surfactant.

244. The synergistic spot-on composition according to claim 243, wherein the film- forming agent is polyvinylpyrrolidone, polyvinyl alcohols, or copolymers of vinyl acetate and vinyl pyrrolidone, and the surfactant is an ionic surfactants.

245. The synergistic spot-on composition according to any one of claims 225 to 244, wherein the fluid vehicle comprises an organic solvent having a dielectric constant of between 10 and

246. The synergistic spot-on composition according to claim 245, wherein the organic solvent is selected from the group consisting of 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, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate, and a mixture of at least two of these solvents.

247. The synergistic spot-on composition according to claim 245, wherein the fluid vehicle further comprises an organic co-solvent having a boiling point below 100°C, a dielectric constant of between 10 and 40, and is miscible with water and/or with the solvent and present in a weight ratio of co-solvent:solvent between 1:15 and 1:2. S62

259. The method according to any one of claims 250 to 258, wherein the synergistic c spot-on composition comprises of fipronil, methoprene and imidacloprid. g

260. A kit, when used for topical application of a compound according to claim 1 and a compound according to claim 1 to the skin of a mammal, comprising, separately in the same packaging at least one container containing an effective amount of compound and at least a fluid vehicle, at least one container containing an 00 effective amount of compound and at least one fluid vehicle, wherein the containers 0 comprising compounds and are to be used alternatively with an interval. S

261. A kit, when used for topical application of a compound according to claim 119 and a compound according to claim 119 to the skin of a mammal, comprising, separately in the same packaging at least one container containing an effective amount of compound and at least a fluid vehicle, at least one container containing an effective amount of compound and at least one fluid vehicle, and at least one container containing an effective amount of imidacloprid and at least one fluid vehicle, wherein the containers comprising compound compound and imidacloprid are to be used alternatively with an interval.

262. A kit according to claim 260 or claim 261 substantially as hereinbefore described with reference to the examples.

263. A composition according to any one of claims 156 to 249 substantially as hereinbefore described with reference to the examples.

264. A method according to any one of claim 250 to 259 substantially as hereinbefore described with reference to the examples. Dated this third day of May 2005 Merial Patent Attorneys for the Applicant: F.B. RICE CO