EXHIBIT 1019
`
`

`

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`
`USOO6395765B1
`
`(12) United States Patent
`Etchegaray
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,395,765 B1
`*May 28, 2002
`
`(54) ANTIPARASITIC COMPOSITION FOR THE
`TREATMENT AND PROTECTION OF PETS
`
`(75)
`
`Inventor:
`
`Jean Pierre Etchegaray, Toulouse (FR)
`
`(73) Assignee: Merial, Lyons (FR)
`
`(*) Notice:
`
`This patent issued on a continued pros-
`ecution application filed under 37 CFR
`1.53(d), and is subject to the twenty year
`patent
`term provisions of 35 U.S.C.
`154(a)(2).
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. N0.: 08/719,942
`
`(22) Filed:
`
`Sep. 25, 1996
`
`(30)
`
`Foreign Application Priority Data
`
`EP
`EP
`EP
`FR
`WO
`W0
`WO
`wo
`WO
`
`005 1786
`0295 117
`0659745
`2713889
`90/09738
`93/06089
`96/16544
`98/42191
`01/30147
`
`5/1982
`12/1988
`6/1995
`6/1995
`9/1990
`4/1993
`6/1996
`*
`* 10/1998
`“‘
`5/2001
`
`OTHER PUBLICATIONS
`
`Martindale The Extra Pharmacopoeia, 29th ed., The Phar-
`maceutical Press, London, pp. 1246, 1247, 1437, 1989*
`STN International, File CABA, STN accession No.
`95:207958 J.Posta1 et a1. ‘Field efficacy of a mechanical
`pump spray formulation XP002007096 containing 0,25%
`fipronil in the treatment and control of flea infestation and
`associated dermatological signs in dogs and cats.’ & Veteri-
`nary Dermatology, vol. 6, No. 3, 1995, pp. 153—158.
`
`* cited by examiner
`
`Primary Examiner—John Pak
`(74) Attorney, Agent, or Firm—Frommer Lawrence &
`Haug LLP; William S. Frommer; Thomas J. Kowalski
`
`(57)
`
`ABSTRACT
`
`Composition which is useful in particular for the treatment
`and protection of domestic animals which are infested with
`parasites or are likely to be infested with them,
`these
`compositions comprising,
`in the form of a ready-to-use
`solution:
`
`a) an insecticidal active substance of formula (I),
`
`(51)
`
`Sep. 29, 1995
`Sep. 11, 1996
`
`(FR)
`(FR)
`
`............................................ 95 11685
`
`96 11278
`Int. Cl.7 ........................ A01N 25/02; A01N 25/22;
`A01N 25/30; A01N 43/56
`.................. 514/407; 514/156; 514/210.01;
`(52) U.S. Cl.
`514/211.01; 514/212.01; 514/218; 514/222.2;
`514/228.8; 514/241; 514/247; 514/277;
`514/359; 514/396; 514/397; 514/399; 514/403;
`514/406; 514/772; 514/772.1; 514/772.3;
`514/875; 514/937; 514/946; 514/947; 514/964;
`514/970; 514/971; 514/975
`(58) Field of Search ................................. 514/406, 407,
`514/875, 156, 210.01, 211.01, 212.01, 218,
`222.2, 228.2, 241, 247, 277, 359, 396,
`397, 399, 403, 772, 772.1, 772.3, 937,
`946, 947, 964, 970, 971, 975; 424/405
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`514/407
`5/1996 Takada
`5,516,787 A *
`
`424/410
`5,849,320 A ”‘ 12/1998 Turnblad et al.
`............ 424/408
`5,876,739 A *
`3/1999 Turnblad et a1.
`6,010,710 A *
`1/2000 Etchegaray ................. 424/405
`6,066,660 A *
`5/2000 Mizutani et al.
`..... 514/359
`6,090,751 A *
`7/2000 Chen ....................... 504/116
`6,096,329 A "‘
`8/2000 Jeannin ............ 424/405
`6,265,384 Bl *
`7/2001 Pearlman
`514/31
`FOREIGN PATENT DOCUMENTS
`
`
`
`b) a crystallization inhibitor,
`c) an organic solvent having a dielectric constant of
`between 10 and 35, preferably of between 20 and 30,
`d) an organic coosolvent having a boiling point below
`100° C., preferably below 80° C., and a dielectric
`constant of between 10 and 40, preferably of between
`20 and 30.
`~
`
`DE
`
`26 33 943
`
`2/1977
`
`33 Claims, No Drawings
`
`

`

`US 6,395,765 B1
`
`1
`ANTIPARASITIC COMPOSITION FOR THE
`TREATMENT AND PROTECTION OF PETS
`
`The present invention relates to a composition for the
`treatment and protection of animals which are infested with
`parasites or likely to be infested with them.
`More particularly, the aim of the invention is to control
`and eliminate the parasites which infest pets, and especially
`cats and dogs.
`Pets are often infested with one or more of the following
`parasites:
`cat and dog fleas (Ctenocephalides felis, Ctenocephalides
`sp. and the like),
`ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp.,
`Amblyoma sp. and the like)
`galls (Demodex sp., Sarcoptes sp., Otodectes sp. and the
`like).
`Fleas cause an animal a great deal of stress and are
`harmful to its health. Moreover, fleas are also vectors of
`pathogenic agents, such as dog tapeworm (Dipylidium
`caninum), and can also attack man.
`Similarly, ticks can also cause an animal stress and be
`harmful to its health. They can also be harmful to man.
`However, the most serious problem of ticks is that they are
`the vector of pathogenic agents which may affect the animal
`as much as man. Among the major diseases which need to
`be avoided, mention may be made of borrelioses (Lyme
`disease caused by Borrelia burgdorferi), babesioses (or
`piroplasmoses caused by Babesia sp.) and rickettsioses (also
`known as Rocky Mountain spotted fever). Ticks can also
`release toxins with paralysing and inflammatory properties,
`these toxins occasionally being fatal.
`Lastly, galls are particularly difficult to combat since there
`are very few active substances which act on these parasites,
`and they require frequent treatment.
`Many more or less active and more or less expensive
`insecticides exist. However, phenomena of resistance are
`often associated with their use, as is the case, for example,
`with carbamates, organophosphorus compounds and pyre-
`throids.
`
`international patent application WO-A—87/
`Moreover,
`03781 and European patent application EP-A-0,295,117
`describe a large family of N—phenyl-pyrazoles with a very
`broad spectrum of activity, including antiparasitic activities.
`The object of the invention is to provide novel antipara-
`sitic compositions for
`the treatment and protection of
`animals, these compositions being of great efficacy while at
`the same time being easy to use.
`Another object of the invention is to provide such com-
`positions which are easy to use on any type of domestic
`animal, irrespective of its size and the nature of its coat.
`Yet another object of the invention is to provide such
`compositions which are efiective and do not need to be
`sprinkled over the animal’s entire body.
`Yet another object of the invention is to provide such
`compositions which, when applied locally, will subse-
`quently diffuse over the animal’s entire body and then dry,
`while at the same time avoiding any phenomenon of crys-
`tallization as far as possible.
`Yet another object of the invention is to provide such
`compositions which, after drying, do not aflect the appear-
`ance of the coat and in particular do not leave crystals and
`do not make the coat sticky.
`These objects are achieved by the invention, the subject of
`which is antiparasitic compositions which are useful
`in
`particular in the treatment and protection of domestic ani-
`mals which are infested with parasites or are likely to be
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`4s
`
`50
`
`55
`
`60
`
`65
`
`2
`infested with them, these compositions comprising, in the
`form of a ready-to-use solution:
`a) an insecticidal active substance of formula (I),
`
`0)
`
`R2
`
`R1
`
`/
`
`\N
`N/
`
`R4
`
`I \
`/\(y)p
`
`in which:
`
`R1 is a halogen atom, CN or methyl;
`R2 is S(O),,R3 or 4,5-dicyanoimidazol-2-yl or
`haloalkyl;
`R3 is alkyl or haloalkyl, for example lower haloalkyl;
`R4 represents a hydrogen or halogen atom; or a radical
`NRSRG, S(O)mR7, C(O)R7 or C(O)OR7, alkyl,
`haloalkyl or 0R8 or a radical ——N=C (R9) (R10);
`R5 and R6 independently represents a hydrogen atom or
`an alkyl, haloakyl, C(O)alkyl, S(O),CF3, acyl or
`alkoxycabonyl radical; or R5 and R6 may together
`form a divalent alkylene radical which may be
`interrupted by one or two divalent hereto atoms such
`as oxygen or sulphur;
`R7 represents an alkyl or haloalkyl radical;
`R8 represents an alkyl or haloalkyl radical or a hydro-
`gen atom;
`R9 represents an alkyl radical or a hydrogen atom;
`R10 represents a phenyl or heteroaryl group optionally
`substituted with one or more halogen atoms or
`groups such as OH, —O-alkyl, —S—a1kyl, cyano or
`alkyl;
`Y represents a halogen atom or a haloalkyl or
`haloalkoxy radical, for example a lower haloalkoxy
`radical, or an SFS radical, with the possibility that:
`Y is CN or NO2 in positions 2 and 6 (with reference
`to the carbon of the phenyl ring which is attached
`to the pyrazole ring and designated 1);
`the carbon in position 2 of the phenyl ring is replaced
`by a trivalent nitrogen atom;
`Y is S(O),,CF3 in position 4 on the phenyl ring, but
`preferably haloalkyl, haloalkoxy or SFS;
`In, I], q and r represent, independently of each
`other, an integer equal to 0, 1 or 2;
`p is an integer equal to 1, 2, 3, 4 or 5, preferably equal
`to 1, 2 or 3, in particular 3;
`with the proviso that when R1 is methyl, then either R3
`is haloalkyl, R4 is NHZ, p is 2, Y in position 6 is C1,
`Y in position 4 is CF3 and the carbon in position 2
`of the phenyl
`is replaced by N; or R2 is 4,5-
`dicyanoimidazol-Z-yl, R4 is CI, p is 3, Y in position
`6 is C1, Y in position 4 is CF3 and the carbon in
`position 2 of the phenyl is replaced by =C—C1,
`it being possible for this compound of formula (I)
`advantageously to be present in the formulation in a
`proportion of from 1 to 20%, preferably from 5 to
`15% (percentages expressed as weight per unit
`volumeaW/V),
`in
`b) a crystallization inhibitor which is present,
`particular, in a proportion of from 1 to 20% (W/V),
`preferably from 5 to 15%, this inhibitor satisfying the
`
`

`

`US 6,395,765 B1
`
`3
`test according to which: 0.3 ml of a solution A com-
`prising 10% (W/V) of the compound of formula (I) in
`the solvent defined in c) below, and 10% of this
`inhibitor, are placed on a glass slide at 20° C. for 24
`hours, after which few or no crystals, in particularly
`fewer than 10 crystals, preferably 0 crystals, are seen
`with the naked eye on the glass slide,
`c) an organic solvent having a dielectric constant of
`between 10 and 35, preferably of between 20 and 30,
`the content of this solvent c) in the overall composition
`preferably representing the complement to 100% of the
`composition,
`(1) an organic co-solvent having a boiling point below
`100° C., preferably below 80° C., and having a dielec-
`tric constant of between 10 and 40, preferably of
`between 20 and 30; this co—solvent may advantageously
`be present in the composition in a d) /c) weight/weight
`(W/W) ratio of between 1/15 and 1/2. The solvent is
`volatile so as to act in particular as a drying promoter,
`and is miscible with water and/or with the solvent 0).
`Preferably, the insecticidal active substance corresponds
`to formula (11),
`
`(H)
`
`R2
`
`R1
`
`/
`
`\,
`N/
`
`R4
`
`Ru \ X
`l /
`
`R13
`
`in which:
`
`R1 is a halogen atom, CN or methyl;
`R2 is S(O),R3 or 4,5-dicyanoimidazol-2—yl or haloalkyl;
`R3 is alkyl or haloalkyl;
`R4 represents a hydrogen or halogen atom; or a radical
`NR5R6, S(O),,,R7, C(O)R7 or C(O)OR7, alkyl,
`haloalkyl or OR8 or a radical —N=C(R9) (R10);
`R5 and R6 independently represent a hydrogen atom or an
`alkyl, haloalkyl, C(O)a1kyl, S(O),CF3 or alkoxy carbo-
`nyl radical; or R5 and R5 may together form a divalent
`alkylene radical which may be interrupted by one or
`two divalent hetero atoms such as oxygen or sulphur;
`R7 represents an alkyl or haloalkyl radical;
`R8 represents an alkyl or haloalkyl radical or a hydrogen
`atom;
`
`R9 represents an alkyl radical or a hydrogen atom;
`R10 represents a phenyl or heteroaryl group optionally
`substituted with one or more halogen atoms or groups
`such as OH, —O-a1kyl, —S-a1kyl, cyano or alkyl;
`R11 and R12 represent, independently of each other, a
`hydrogen or halogen atom and possibly CN or N02, but
`with H or halogen being preferred;
`R13 represents a halogen atom or a haloalkyl, haloalkoxy,
`S(O),,CF3 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—Rlz, the other three valencies of the carbon atom
`forming part of the aromatic ring;
`
`4
`
`with the proviso that when R1 is methyl, then either R3 is
`haloalkyl, R4 is NHZ, R11 is Cl, R13 is CF3 and X is N;
`or R2 is 4,5-dicyanoimidazol-2—yl, R4 is Cl, R11 is Cl,
`R13 is CF3 and X is =C—Cl.
`The alkyl radicals in the definition of the compounds of
`formulae (1) and (II) generally comprise from 1 to 6 carbon
`atoms. The ring formed by the divalent alkylene radical
`representing R5 and R6, along with the nitrogen atom to
`which Rs and R5 are attached,
`is generally a 5-, 6- or
`7—membered ring.
`As a further preference, R1 is CN, R3 is haloalkyl, R4 is
`NHZ, R11 and R12 are,
`independently of each other, a
`halogen atom, and R13 is a haloalkyl. Preferably also, X is
`C—Rlz.
`Acompound (A) of formula (I) which is most particularly
`preferred in the invention is 1—[2,6—C12 4-CF3 phenyl] 3-CN
`4-[SO-CF3] S-NH2 pyrazole, whose common name is
`fipronil.
`The compounds of formula (I) may be prepared according
`to one or other of the processes described in patent appli-
`cations WO-A—87/3781, 93/6089 and 94/21606 or European
`patent application EP-A—295,117, or any other process
`which falls within the competence of a specialist skilled in
`the art of chemical synthesis. For the chemical production of
`the products of the invention, a person skilled in the art is
`considered as having at his disposal, inter alia, all of the
`contents of “Chemical Abstracts” and of the documents
`which are cited therein.
`
`the composition may
`Although this is not preferred,
`optionally comprise water, in particular in a proportion of
`from 0 to 30% (volume per unit volume V/V), in particular
`from 0 to 5%.
`
`The composition may also comprise an antioxidant
`intended to inhibit aerial oxidation, this agent being present
`in particular in a proportion of from 0.005 to 1% (W/V),
`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
`deposition on the skin (“spot on” or “pour on” application);
`this is generally a localized application to a region with a
`surface area of less than 10 cm2, especially between 5 and
`10 cm2, in particular at two points and preferably localized
`between the animal’s shoulders. After deposition, the com-
`position difiuses, in particular over the animal’s entire body,
`and then dries, without crystallizing or changing the appear-
`ance (in particular absence of any whitish deposit or of any
`dusty appearance) or the feel of the coat.
`The compositions according to the invention are particu-
`larly advantageous on the grounds of their efficacy, their
`speed of action and the pleasant appearance of the animal’s
`hair after application and drying.
`As organic solvent c) which can be used in the invention,
`mention may be made in particular of: acetone, acetonitrile,
`benzyl alcohol, butyl diglycol, dimethylacetamide,
`dimethylformamide, dipropylene glycol n-butyl ether,
`ethanol, isopropanol, methanol, ethylene glycol monoethyl
`ether, ethylene glycol monomethyl ether,
`monomethylacetamide, dipropylene glycol monomethyl
`ether,
`liquid polyoxyethylene glycols, propylene glycol,
`2—pyrrolidone, in particular N-methylpyrrolidone, diethyl-
`ene glycol monoethyl ether, ethylene glycol, diethyl
`phthalate, or a mixture of at least two of these solvents.
`The preferred solvents c) are the glycol ethers, in particu-
`lar diethylene glycol monoethyl ether and dipropylene gly-
`col monomethyl ether.
`As crystallization inhibitor b) which can be used in the
`invention, mention may be made in particular of:
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4o
`
`45
`
`50
`
`55
`
`60
`
`65
`
`

`

`5
`
`6
`
`US 6,395,765 B1
`
`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 dioctylsulphosuc-
`cinate; fatty acids,
`in particular those derived from
`coconut oil,
`cationic surfactants such as water-soluble quaternary
`ammonium salts of formula N+R'R"R"'R"" Y' in which
`the radicals R are hydrocarbon radicals, optionally
`hydroxylated, and Y is an anion of a strong acid such
`as halide, sulphate and sulphonate anions; cetyltrim-
`ethylammonium bromide is among the cationic surfac-
`tants which can be used,
`amine salts of formula N+R'R"R'" in which the radicals R
`are optionally hydroxylated hydrocarbon radicals; octa-
`decylamine hydrochloride is among the cationic sur-
`factants which can be used,
`nonionic surfactants such as optionally polyoxyethylena-
`ted sorbitan esters, in particular polysorbate 80, poly-
`oxyethylenated alkyl ethers; polyethylene glycol
`stearate, polyoxyethylenated derivatives of castor oil,
`polyglycerol esters, polyoxyethylenated fatty alcohols,
`polyoxyethylenated fatty acids, copolymers of ethylene
`oxide and propylene oxide,
`amphoteric surfactants such as lauryl—substituted betaine
`compounds, or preferably a mixture of at least two of
`these crystallization inhibitors.
`In a particularly preferred manner, use will be made of a
`crystallization inhibitor system, namely the combination of
`a film-forming agent of polymer type and a surfactant. These
`agents will be chosen in particular from the compounds
`mentioned as crystallization inhibitor b).
`Among the film-forming agents of polymer 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 polyoxyeth-
`ylenated sorbitan esters and in particular the various grades
`of polysorbate, for example polysorbate 80.
`The film-forming agent and the surfactant may in par-
`ticular be incorporated in similar or identical amounts within
`
`the limit of the total amounts of crystallization inhibitor
`which are mentioned elsewhere.
`
`in a noteworthy
`The system thus made up achieves,
`manner, the aims of absence of crystallization on the hair
`and of maintenance of the cosmetic appearance of the coat,
`that is to say without a tendency to stick together or to have
`a sticky appearance, despite high concentration of active
`substance.
`
`As co-solvent d), mention may be made in particular of:
`absolute ethanol, isopropanol (2-propanol), methanol.
`As antioxidant, standard agents are used in particular,
`such as: butylated hydroxyanisole, butylated
`hydroxytoluene, ascorbic acid, sodium metabisulphite, pro-
`pyl gallate, sodium thiosulphate, a mixture of not more than
`two of these antioxidants.
`
`The compositions according to the invention are usually
`prepared by simply mixing the constituents as defined
`above; advantageously, to begin with, the active substance is
`mixed into the main solvent, and the other ingredients or
`adjuvants are subsequently added.
`The subject of the present invention is also a method for
`the treatment and/or protection (preventive care) of animals
`against parasites, according to which an effective volume of
`a composition according to the invention is applied to a
`limited area of the animal, as is described above. The
`application is advantageously made at two points and/or on
`the animal’s back between the shoulders.
`The aim of the method may be non-therapeutic, when it
`concerns cleaning the animal’s hair and skin by eliminating
`the parasites present as well as their residues and excreta.
`The animal thus has a coat which is pleasant to look at and
`to feel. This also makes it possible to prevent the establish-
`ment of fleas in the house.
`
`The aim may also be therapeutic when it concerns treating
`a parasitosis which has pathogenic consequences.
`The volume applied may be about 0.3 to 1 m1, preferably
`about 0.5 ml for cats, and about 0.3 to 3 ml for dogs,
`depending on the weight of the animal.
`The volume of composition applied preferably corre-
`sponds to a dose of compound of formula (I) of between 0.3
`and 60 mg, in particular of between 5 and 15 mg, per kg.
`The examples which follow, which are given without any
`implied limitation, illustrate the invention and show how it
`may be carried out.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`EXAMPLES 1 to 12
`
`The compositions of Examples 1 to 12 are given in the
`following table:
`
`
`
`
`
`
`
`
`
`
`
`
`
`7.5
`
`15
`
`10
`
`10
`
`10
`
`10
`
`7.5
`
`15
`
`10
`
`10
`
`10
`
`_ Example No.
` 1 2 3 4 5 6 7 8 9 10 11 12
`
`
`
`
`
`
`Active
`10
`10
`10
`10
`10
`10
`10
`10
`10
`10
`10
`10
`principle (g)
`Ethanol cm3
`(s)
`Polyvinylpyr-
`rolidone (g)
`polysorbate 80
`(s)
`Butylated
`hydroxy-
`anisole (g)
`
`10
`
`5
`
`5
`
`5
`
`5
`
`5
`
`5
`
`0.02
`
`0.02
`
`0.02
`
`5
`
`5
`
`0
`
`5
`
`5
`
`0.02
`
`7.5
`
`5
`
`0
`
`5
`
`5
`
`5
`
`5
`
`5
`
`5
`
`0.02
`
`0.02
`
`0.02
`
`S
`
`5
`
`0
`
`5
`
`5
`
`0.02
`
`7.5
`
`5
`
`0
`
`

`

`US 6,395,765 B1
`
`-continued
`
`1
`
`2
`
`3
`
`4
`
`Example No.
`6
`7
`
`5
`
`8
`
`9
`
`10
`
`11
`
`12
`
`0.01
`
`0.01
`
`0.01
`
`0.01
`
`0.01
`
`qs
`
`100 cm3
`
`D
`
`Butylated
`hydroxy-
`toluene (g)
`Diethylene
`glycol mono-
`ethyl ether
`(an?)
`Dipropylene
`glycol mono-
`methyl ether
`
`(ms)
`
`0
`
`0.01
`
`0.01
`
`0.01
`
`0.01
`
`0.01
`
`O
`
`(15
`
`100 cm3
`
`the volume of diethylene glycol
`By way of example,
`monoethyl ether represented by qs is about 75 cm3 for the
`formula of Example 1.
`The following are mixed together, by stirring:
`10 g of active principle 1-[4—CF3 2, 6-C12 phenyl] 3-cyano
`4-[CF3—SO——] 5-NH2 pyrazole, all of the ethanol,
`60 cm3 of diethylene glycol monoethyl ether or of dipro-
`pylene glycol monomethyl ether (solvents),
`all of the polyvinylpyrrolidone (Kollidono® 17PF from
`BASF, Germany),
`all of the polysorbate 80 (Tween® from ICI),
`all of the butylated hydroxyanisole (if present),
`all of the butylated hydroxytoluene (if present).
`The mixture is made up to 100 cm3 with diethylene glycol
`monoethyl ether or with dipropylene glycol monomethyl
`ether (for Example 1,
`this corresponds to a remaining
`volume of about 15 cm3).
`Each mixture constitutes a concentrated solution S.
`
`3 dogs, weighing about 7, 14 and 28 kg respectively, are
`infested with 100 fleas each. Two days later, they are treated
`by cutaneous application of a solution S in a proportion of
`0.1 kag, in localized form over about 5 cm2 between the
`shoulders in the area of the withers. After 24 hours, the time
`required for complete drying, the appearance of the dogs’
`coat in the area of the deposition on the skin and elsewhere
`is identical
`to the initial appearance.
`In particular,
`the
`animal’s coat is neither tacky nor sticky when touched and
`the coat contains no bristled tufts.
`24 hours after treatment, the dogs are combed in order to
`remove and count any fleas which may be present. Then, at
`weekly intervals after the treatment, the animals are rein-
`fested in the same way as before. 24 hours after each
`experimental reinfestation, the animals are again combed in
`order to remove and count any fleas which may still be
`present. Over a period of 13 weeks, it was observed that
`there was a percentage reduction in the population of fleas
`which was maintained above 95% when compared with a
`control group which had not received the treatment accord-
`ing to the invention. Examples 12 to 24:
`For Examples 12 to 24, it suffices to replace, in the above
`table, Examples 1 to 12 by 12 to 24 respectively, with 12.5
`g of active principle. The amounts of the other constituents
`are unchanged, apart from the amount of solvent required for
`the complement to 100 cm3.
`The following ingredients are mixed together, by simple
`stirring:
`12.5 g of the compound of Example 1 all of the ethanol
`60 cm3 of diethylene glycol monoethyl ether or of
`dipropylene glycol monomethyl ether
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`all of the polyvinylpyrrolidone
`all of the polysorbate 80
`all of the butylated hydroxyanisole (if present)
`all of the butylated hydroxytoluene (if present).
`The mixture is made up to 100 cm3 with diethylene glycol
`monoethyl ether or with dipropylene glycol monomethyl
`ether.
`When used under the conditions described in Example 1,
`these mixtures lead to comparable results. A greater than
`95% reduction in the population of fleas is observed in less
`than 24 h when compared with the control group.
`What is claimed is:
`l. A composition for the treatment or protection of a
`domestic animal against parasitic infestation by topical
`application to a localized region with a surface area of less
`than 10 cm2 and diffusion therefrom over the animal’s body,
`the composition comprising, in the form of a ready-to-use
`solution:
`
`(a) an insecticidal active substance of the formula (I)
`
`(1)
`
`(top
`
`in which:
`R1 is a halogen atom, CN or methyl;
`R2 is S(O),,R3 or 4,5 dicyanoimidazol-Z-yl or
`haloalkyl;
`R3 is alkyl or haloalkyl;
`R4 represents a hydrogen or halogen atom; NR5R5,
`S(O),,,R7, C(O)R7, C(O)OR-,, alkyl, haloalkyl, OR8
`or —N=C(R9)(R10)§
`RS and R6 independently represent a hydrogen atom or
`an alkyl, haloalkyl, C(O)a1ky1, S(O),CF3, acyl or
`alkoxycarbonyl radical; or R5 and R5 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;
`R8 represents an alkyl or haloalkyl radical or a hydro-
`gen atom;
`R9 represents an alkyl radical or a hydrogen atom;
`R10 represents a phenyl or heteroaryl group optionally
`substituted with one or more halogen atoms;
`
`

`

`US 6,395,765 Bl
`
`10
`than 10 cm2 and dilfusion therefrom over the aninial’s body,
`the composition comprising, in the form of a ready—to—use
`solution:
`
`(a) an insecticidal active substance of the formula (II):
`
`(11)
`
`R2
`
`R1
`
`/
`
`\,
`N/
`
`R4
`
`R11
`
`\X
`
`/ R
`
`13
`
`|
`
`in which:
`R1 is a halogen atom, CN or methyl;
`R2 is S(O),,R3 or 4,5 dicyanoimidazol-Z-yl or
`haloalkyl;
`R3 is alkyl or haloalkyl;
`R4 represents a hydrogen or halogen atom; NRSRG,
`S(O),,,R7, C(O)R7, C(O)OR7, alkyl, haloalkyl, OR8
`or _N=C(R9)(R10);
`R5 and R6 independently represent a hydrogen atom or
`an alkyl, haloalkyl, C(O)alkyl, S(O),CF3, or alkoxy-
`carbonyl radical; or R5 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 haloalkyl radical;
`R8 represents an alkyl or haloalkyl radical or a hydro-
`gen atom;
`R9 represents an alkyl radical or a hydrogen atom;
`R10 represents a phenyl or heteroaryl group optionally
`substituted with one or more halogen atoms or one or
`more OH groups, —O-a1kyl groups, —S-a1ky1
`groups, cyano groups, or alky, groups;
`R11 represents a hydrogen or halogen atom, CN or
`N02;
`R13 represents a halogen atom or
`haloalkoxy, S(O)qCF3, or SF5 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—Rlz, the other three valencies of the carbon atom
`forming part of. the aromatic ring;
`R12 represents a hydrogen or halogen atom, CN or
`N02;
`with the proviso that when R1 is methyl, then either R3
`is haloalkyl, R4 is NH2, R11 is Cl, R13 is CF3 and X
`is N; or R2 is 4,5 dicyanoirmidazol-Z-yl, R4 is C1, R11
`is Cl, R13 is CF3 and X is C—Cl;
`(b) a crystallization inhibitor selected from the group
`consisting of polyvinylpyrrolidone, copolymers of
`vinyl acetate and vinylpyrrolidone, polyoxyethylenated
`sorbitan esters and mixtures thereof;
`
`a haloalkyl,
`
`(c) an organic solvent selected from the group consisting
`of acetone, benzyl alcohol, butyl diglycol, dipropylene
`glycol n-butyl ether, ethanol, isopropanol, methanol,
`ethylene glycol monoethyl ether, ethylene glycol
`monomethyl ether, dipropylene glycol monomethyl
`ether, propylene glycol, diethylene glycol monoethyl
`ether, ethylene glycol, and a mixture of at least two of
`these solvents; and
`
`9
`X represents carbon, a trivalent nitrogen atom or a
`radical Clez;
`R12 Cr)epresents a hydrogen or halogen atom, CN or
`N 2;
`Y represents SFS, a hydrogen, CN, N02, S(O),CF3, a
`halogen atom or a haloalkyl or haloalkoxy radical;
`m, n, and r represent, independently of each other, an
`integer equal to 0, 1 or 2; and
`p is an integer equal to 1, 2, 3, 4 or 5;
`with the proviso that when R1 is methyl, then either R3
`is haloalkyl, R4 is NHZ, p is 2, Y in position 6 is C1,
`Y in position 4 is CF3 and X is N; or R2 is
`4,5—dicyanolmidazol-2-yl, R4 is CI, p is 3, Y in
`position 6 is Cl, Y in position 4 is CF; and X is
`C———Cl;
`(b) a crystallization inhibitor selected from the group
`consisting of polyvinylpyrrolidone, copolymers of
`vinyl acetate and vinylpyrrolidone, polyoxyethylenated
`sorbitan esters and mixtures thereof,
`(0) an organic solvent selected from the group consisting
`of acetone, benzyl alcohol, butyl diglycol, dipropylene
`glycol n—butyl ether, ethanol, isopropanol, methanol,
`ethylene glycol monoethyl ether, ethylene glycol
`monomethyl ether, dipropylene glycol monomethyl
`ether, propylene glycol, diethylene glycol monoethyl
`ether, ethylene glycol, and a mixture of at least two of
`these solvents; and
`(d) an organic co-solvent selected from the group con-
`sisting of ethanol, isopropanol, and methanol; wherein,
`the compound of formula (I) is present in a proportion
`from 1 to 20% (W/V);
`the crystallization inhibitor is present in a proportion
`from 1 to 20% (W/V), and meets the following test:
`a 0.3 ml solution comprising 10% (W/V) of the
`compound of formula (I) in the organic solvent
`defined in (c), and 10% (W/V) of said crystallization
`inhibitor, placed on a glass slide at 20° C. for 24
`hours results in fewer than 10 crystals observed on
`the glass slide with the naked eye;
`the organic solvent (c) is present in the overall com-
`position in a proportion representing the compliment
`to 100% of the composition, with the organic
`co-solvent also present in a (d)/(c) weight/weight
`(W/W) ratio of between 1/15 and 1/2; and
`the organic co-solvent is miscible with water and/or
`solvent (c).
`2. The composition of claim 1 wherein X is carbon or the
`radical C—Rlz, Y is CN or NO2 in positions 2 and 6 of the
`phenyl ring.
`3. The composition of claim 1 X is carbon or the radical
`C—Rn, wherein Y is in position 4 on the phenyl ring and
`is selected from the group consisting of S(O),CF3, haloalkyl,
`haloalkoxy and SFS, wherein r represents an integer equal to
`0, 1 or 2.
`4. The composition according to claim 1 wherein alkyl
`radicals in compounds of formula (I) comprise from 1 to 6
`carbon atoms.
`
`5. The composition according to claim 1 wherein R5 and
`R5 form the divalent alkylene radical, which, along with the
`nitrogen atom to which R5 and R6 are attached, comprises a
`5-, 6- or 7-membered ring.
`6. The composition according to claim 1, wherein the
`compound of formula (I)
`is 1-[4-CF3 2,6-Cl2 phenyl]
`3-cyano 4-[CF3—SO] 5—NH2 pyramle.
`7. A composition for the treatment or protection of a
`domestic animal against parasitic infestation by topical
`application to a localized region with a surface area of less
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`

`

`11
`
`12
`
`US 6,395,765 B1
`
`(d) an organic co-solvent selected from the group con—
`sisting of ethanol, isopropanol, and methanol; wherein,
`the compound of formula (II) is present in a proportion
`from 1 to 20% (W/V);
`the crystallization inhibitor is present in a proportion from
`1 to 20% (W/V), and meets the following test: a 0.3 ml
`solution comprising 10% (W/V) of the compound of
`formula (II) in the organic solvent defined in (c), and
`10% (W/V) of said crystallization inhibitor, placed on
`a glass slide at 20° C. for 24 hours results in fewer than
`10 crystals observed on the glass slide with the naked
`eye;
`
`the organic solvent (c) is present in the overall composi-
`tion in a proportion representing the compliment to
`100% of the composition, with the organic co—solvent
`also present in a (d)/(c) weight/weight (W/W) ratio of
`between 1/15 and 1/2; and
`
`is miscible with water and/or
`
`the organic co-solvent
`solvent (c).
`8. The composition of claim 7 wherein X is a trivalent
`nitrogen atom.
`9. The composition according to claim 7 wherein R1 is
`CN, R3 is haloalkyl, R4 is NHZ, R11 and R12 are indepen-
`dently of each other a halogen atom, and R13 is a haloalkyl.
`10. The composition according to claim 7 wherein X is
`c—R,,.
`11. The composition according to claim 7 wherein alkyl
`radicals in compounds of formula (II) comprise from 1 to 6
`carbon atoms.
`
`12. The composition according to claim 7 wherein R5 and
`R5 form the divalent alkylene radical, which, along with the
`nitrogen atom to which R5 and R5 are attached, comprises a
`5-, 6- or 7-membered ring.
`13. The composition of any one of claims 1—12, wherein
`the compound of part (a) present in a proportion fiom 5 to
`15% (W/V).
`14. The composition of any one of claims 1—12, wherein
`the crystallization inhibitor is present in a proportion from 5
`to 15% (W/V).
`15. The composition of claim 13, wherein the crystalli—
`zation inhibitor is present in a proportion from 5 to 15%
`(WM.
`16. The composition of any one of claims 1—12, further
`comprising water present to 30% V/V.
`17. Th