EXHIBIT 1020EXHIBIT 1020
`
`

`
`(12) United States Patent
`Etchegaray et al.
`
`(10) Patent No.:
`
`(45) Date of Patent:
`
`US 6,797,724 B2
`Sep. 28, 2004
`
`US006797724B2
`
`(54) DIRECT SPOT-ON ANTIPARASITIC SKIN
`SOLUTION FOR DOMESTIC ANIMALS
`
`(75)
`
`Inventors: Jean-Pierre Etchegaray, Toulouse
`(FR); Philippe Jeannin, Tournefeuille
`(FR)
`
`(73) Assignee: Merial, Lyons (FR)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 10/120,691
`
`(22) Filed:
`
`Apr. 11, 2002
`
`(65)
`
`Prior Publication Data
`US 2002/0155147 A1 Oct. 24, 2002
`
`Related U.S. Application Data
`
`(60) Division of application No. 09/450,186, filed on Nov. 29,
`1999, which is a continuation-in-part of application No.
`08/933,016, filed on Sep. 18, 1997, now Pat. No. 6,010,710,
`which is a continuation-in-part of application No. 08/692,
`178, filed on Aug. 5, 1996, now abandoned, and a continu-
`ation-in-part of application No. 09/051,693, filed as appli-
`cation No. PCT/FR97/01504 on Aug. 19, 1997, now Pat. No.
`6,001,384.
`
`(30)
`
`Foreign Application Priority Data
`
`5,567,429 A
`5,885,607 A
`6,001,384 A
`6,010,710 A
`6,256,430 B1 *
`
`10/1996 Senbo
`3/1999 Jeannin
`12/1999 Jeannin
`1/2000 Etchegaray
`7/2001 Jin et al.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`
`0 295 117 A1
`
`12/1988
`
`* cited by examiner
`
`Primary Examiner—Neil S. Levy
`(74) Attorney, Agent, or Firm—Frommer Lawrence &
`Haug LLP; Thomas J. Kowalski; Mark W. Russell
`
`(57)
`
`ABSTRACT
`
`A spot-on composition for the treatment or protection of a
`domestic animal against parasitic infestation comprising,
`
`(a) an insecticidal active substance of the formula (X):
`
`(X)
`
`I-I2N(S)C
`
`S(O)CF3
`
`N
`
`\
`
`\N
`
`Cl
`
`NH:
`Cl
`
`Mar. 29, 1996
`Aug. 20, 1996
`Mar. 26, 1997
`
`(FR)
`(FR)
`(FR)
`
`.......................................... .. 96 04209
`. . . . . . .
`. . . .. 96 10312
`. . . . . . . . . .
`. . . . .. 97 03708
`
`. . . . . . .
`
`Int. Cl.7 .............................................. .. A01N 43/56
`(51)
`(52) U.S.Cl.
`..................... .. 514/407; 514/404; 514/406;
`424/405; 424/406; 424/407
`(58) Field of Search ............................... .. 514/341, 346,
`514/404, 406, 407
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,963,575 A
`5,232,940 A
`5,516,787 A
`
`10/1990 Buntain et al.
`8/1993 Hatton et al.
`5/1996 Takada
`
`CF3
`
`(b) an organic solvent; and
`
`(c) a vehicle; and
`
`(d) an emollient; wherein the composition comprises from
`0.05 to 25% weight/Volume of the compound of formula
`(X), and the compound of formula ()0 is applied in a dose
`between 0.1 and 2 mg/kg animal weight.
`
`25 Claims, 2 Drawing Sheets
`
`
`
`. 0
`
`A
`4
`
`2
`0
`-—o—
`TREATED 0.25%
`
`6 81012141518 20 22 24161520
`:9...
`:0:
`1 —-o—-
`CONTROL
`TREATED 1%
`TREATED 0.5%
`
`

`
`U.S. Patent
`
`Sep. 28, 2004
`
`Sheet 1 of2
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`US 6,797,724 B2
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`120
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`10.0
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`80
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`60
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`40
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`'20
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`TREATED 0,25%
`
`TREATED 0.5%
`
`TREATED 1%
`
`CONTROL
`
`FIG. 1
`
`

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`U.S. PatentU.S. Patent
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`Sep. 28, 2004Sep. 28, 2004
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`Sheet 2 0f2Sheet 2 0f2
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`Us 6,797,724 B2Us 6,797,724 B2
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`

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`US 6,797,724 B2
`
`1
`DIRECT SPOT-ON ANTIPARASITIC SKIN
`SOLUTION FOR DOMESTIC ANIMALS
`
`This application is a divisional of application Ser. No.
`09/450,186, filed Nov. 29, 1999, which continuation-in-part
`of US. application Ser. No. 08/933,016, filed Sep. 18, 1997,
`now allowed, which is in turn a continuation-in-part of
`application U.S. Ser. No. 08/692,178, filed Aug. 5, 1996,
`now abandoned, which claims priority to, French patent
`application No. 96 04 209 filed Mar. 29, 1996, and French
`patent application No. 97 03 708 filed Mar. 26, 1997; and
`this application is also a continuation-in-part of US. appli-
`cation Ser. No. 09/051,693, filed Jul. 27, 1998, now allowed,
`which in turn is the National Phase of International Appli-
`cation PCT/FR97/01504 having an international filing date
`of Aug. 19, 1997, and designating the US. and claiming
`priority from French patent application No. 96 10 312, filed
`Aug. 20, 1996.
`Reference is also made to: U.S. application Ser. No.
`09/271,470 filed Mar. 17, 1999, now pending, which is a
`continuation-in-part of International Application PCT/
`FR97/01548, having an international filing date of Sep. 15,
`1997 and designating the U.S., and claiming priority to
`French application No. 96 11 446 filed Sep. 19, 1996; US.
`application Ser. No. 09/376,736, filed Aug. 17, 1999, now
`pending, which is a continuation-in-part of U.S. application
`Ser. No. 09/271,470 filed on Mar. 17, 1999, now pending,
`which is a continuation-in-part of International Application
`PCT/FR97/01548, having an international filing date of Sep.
`15, 1997 and designating the U.S., and claiming priority to
`French application No. 96 11 446 filed Sep. 19, 1996; U.S.
`application Ser. No. 09/381,794, filed Sep. 24, 1999, now
`pending, which in turn is the National Phase of International
`Application No. PCT/FR98/00601 having an international
`filing date of Mar. 25, 1998 and designating the U.S., and
`claiming priority to French application No. 97 03 709, filed
`Mar. 26, 1997; U.S. application Ser. No. 08/891,047, filed
`Jul. 10, 1997, now pending, which claims priority from
`French application No. 96 08 703 filed Jul. 11, 1996 and
`French application No. 97 03 025 filed Mar. 13, 1997; U.S.
`application Ser. No. 08/863,692 filed Mar. 27, 1997, now
`allowed, which is a continuation-in-part of US application
`Ser. No. 08/692,113 filed Aug. 5, 1996, now abandoned,
`which claims priority to French patent application 96 04
`208, filed Mar. 29, 1996 and French application No. 97 03
`711 filed Mar. 26, 1997; U.S. application Ser. No. 08/719,
`942 filed Sep. 25, 1996, which claim priority to French
`application No. 95 11 685 filed Sep. 29, 1995 and French
`application No. 96 11 278 filed Sep. 11, 1996; and U.S.
`application Ser. No. 09/174,598 filed Oct. 19, 1998, now
`pending, which is a divisional application of U.S. applica-
`tion Ser. No. 08/863,182 filed Mar. 27, 1997, now U.S. Pat.
`No. 5,885,607, which is a continuation-in-part of U.S.
`application Ser. No. 08/692,430 filed Aug. 5, 1996, now
`abandoned, and which claims priority to French application
`No. 96 04 206 filed Mar. 29, 1996 and French application
`No. 97 03 707 filed Mar. 26, 1997.
`Each of the herein cited patent applications, and all
`documents cited in the text or during the prosecution of the
`herein cited patent applications (“application cited
`documents”)-—either cited by the Examiner (e.g., Patent
`Office, such as the U.S. or French Patent Office or WIPO or
`Searching Authority) or by the applicant(s)—as well as all
`documents cited or referenced in application cited
`documents, are hereby incorporated herein by reference.
`Further, all documents cited herein (“herein cited
`documents”) and all documents cited or referenced in herein
`cited documents are hereby incorporated herein by refer-
`ence.
`
`Further, the following documents are hereby incorpo-
`rated herein by reference:
`
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`2
`U.S. Pat. No. 5,885,607, issued to Jeannin on Mar. 23,
`1999;
`U.S. Pat. No. 5,801,189, issued to Twinn on Sep. 1, 1998;
`U.S. Pat. No. 5,232,940, issued to Hatton on Aug. 3,
`1993;
`U.S. Pat. No. 5,122,530, issued to Tomioka on Jun. 16,
`1992;
`U.S. Pat. No. 5,567,429, issued to Senbo on Oct. 22,
`1996;
`U.S. Pat. No. 4,963,575, issued to Buntain on Oct. 16,
`1990;
`U.S. Pat. No. 5.516,787, issued to Takada on May 14,
`1996;
`U.S. Pat. No. 5,629,334, issued to Takada on May 13,
`1997;
`EP 0 295 117 with an international filing date of Jun. 10,
`1988;
`PCT/EP98/01224 with an international filing date of
`Mar. 1, 1998;
`PCT/EP97/06503 with an international filing date of
`Nov. 21, 1997;
`Bloomquist, J. R., Ion Channels as Targets for
`Insecticides, Annu. Rev. Entomol.; Vol. 41,163—90 (1996);
`Hainzl, D. et al, Mechanisms for Selective Toxicity of
`Fipronil Insecticide and Its Sulfone Metabolite and Desulfi-
`nylPhotoproduct, Chem. Res. Toxical; Vol. 11(12), 1529-35
`(1998);
`Hainzi, D. et al, Fipronil Insecticide: Novel Photochemi-
`cal Desulfinylation with Retention of Neurotoxicity, Proc.
`Natl. Acad. Sci. USA; Nov. 12;93(23), 12764-7 (1996); and
`Cochet, P. et al, Skin Distribution of Fipronil by Microau-
`toradiography following Topical Administration to the
`Beagle Dog, Eur: J. Drug Metab. Pharmacokinet. Jul—Sep;
`22(3): 211-6 (1997).
`This invention envisions compounds, compositions, for-
`mulations and methods of use involving a phenylpyrazole as
`depicted herein or in herein cited documents; and phe-
`nylpyrazoles depicted herein or in herein cited documents
`can be used in the compositions, formulations and methods
`of herein cited patent applications. Further, the invention
`envisions compounds that degrade, e.g., biodegrade or pho-
`todegrade or chemically degrade,
`to phenylpyrazoles as
`depicted herein or in herein cited documents or to same or
`similar derivatives of phenylpyrazoles herein depicted from
`degradation (e.g., biodegradation, photodegradation,
`chemical, degradation); for instance, if a herein depicted
`phenylpyrazole degrades to compound “X”, the invention
`envisions compounds “X” and other phenylpyrazoles that
`degrade to compound “X”. The invention also envisions
`compositions, formulations, and methods of use involving
`compounds that degrade to phenylpyrazoles as depicted
`herein or in herein cited documents or to same or similar
`derivatives of phenylpyrazoles herein depicted from degra-
`dation;
`for example, pour-on formulations, spot-on
`formulations, formulations and/or methods for distribution
`in sebacious glands, formulations and/or methods of
`preventing, treating, controlling, and/or combating myasis,
`and the like, as well as in compositions, formulations, and
`uses of herein cited patent applications. (A compound that
`degrades to a phenylpyrazole herein depicted or
`that
`degrades to a same or similar derivative of a phenylpyrazole
`herein depicted from degradation, e.g., a phenylpyrazole that
`degrades to compound “X” that is a degradation derivative
`of a herein depicted phenylpyrazole is herein termed a
`“pro-pp-compound”.) More in particular, herein depicted
`phenylpyrazoles as well as those of documents cited herein,
`e.g. PCT/EP97/06503 or WO 98/24769, which is equivalent
`to U.S. Pat. No. 6,265,430, degrade to the active compound
`fipronil sulfide (sulfide on the 4 position) and thus,
`the
`invention comprehends the use of phenylpyrazoles depicted
`herein and in documents cited herein that degrade to fipronil
`
`

`
`3
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`4
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`US 6,797,724 B2
`
`in for example, pour-on formulations, spot-on
`sulfide,
`formulations, formulations and/or methods for distribution
`in sebacious glands,
`formulations and/or methods of
`preventing, treating, controlling, and/or combating myasis,
`and the like, as well as in compositions, formulations, and
`uses of herein cited patent applications. Ethaprol (or a
`4-elhylsulfoxide derivative of herein depicted
`phenylpyrazole) as well as compounds of the herein formula
`wherein there is a sulfideat the 4 position and/or R1 =CN,
`SO and/or R3=CF3 or alkyl (e.g., 4-haloalkyl sulfoxide
`sulfones, 3-cyanos, 3-cyano—pro—pp—compounds) are useful,
`e.g.,
`in pour-on formulations and methods. Formulations,
`compositions and methods of use can include an additional
`active ingredient, such as a macrolide antibiotic and/or an
`insect growth regulator (IGR), or the like, which can be
`admixed with or administered separately from, e.g.,
`sequentially, with the phenylpyrazole and/or pro-pp-
`compound (or the macrolide antibiotic and/or IGR can itself,
`without the phenylpyrazole and/or pro-pp—compound, be the
`active ingredient in the formulation, such as pour-on or
`spot-on formulation or a formulation for distribution in the
`sebacious glands, as disclosed herein arm herein cited patent
`applications). These and other embodiments are provided in
`this text.
`The present invention relates to a direct pour-on skin
`solution which contains an antiparasitic product and is
`intended to be applied topically to cattle and sheep.
`The invention also relates to the use of antiparasitic
`compounds for the preparation of this skin solution, as well
`as to a treatment process relating thereto.
`Cattle and sheep are affected by a large number of
`parasites.
`The main ones are ticks of the genus Boophilus, among
`which mention may be made of the species microplus (cattle
`tick), decoloratus and anulatus.
`The other main parasites of cattle and sheep are indicated
`in order of decreasing importance:
`myiases such as Dermatobia hominis (known as Beme in
`Brazil) and Cochlyomia hominivorax (greenbottle);
`sheep myiases such as Lucilia sericata, Lucilia cuprina
`(known as blowfly strike inAustralia, New Zealand and
`South Africa). These are flies whose larva constitutes
`the animal parasite.
`flies proper, namely those whose adult constitutes the
`parasite, such as Haematobia irritans (horn fly).
`lice such as Linognathus vitulorum, etc.
`galls such as Sarcoptes scabiei and Psoroptes ovis.
`Ticks, in particular Boophilus micmplus, are very closely
`attached to the pasture in which they live and are particularly
`diflicult to control.
`There is at the present time no truly elfective method for
`controlling ticks, and less still an elfective way of control-
`ling the set of parasites indicated above.
`WO—A-87/3781, EP-A-295,117 and EP—A-500,209
`describe a class of insecticides which are N-phenyl—pyrazole
`derivatives. These compounds are given as having activity
`against a very large number of parasites, including Boophi-
`lus micraplus, in fields as varied as agriculture, public health
`and veterinary medicine. The general
`teaching of these
`documents indicates that these insecticidal compounds may
`be administered via different routes; oral, parenteral, percu-
`taneous and topical
`routes. Topical administration
`comprises,
`in particular, oral formulations, baits, dietary
`supplements, skin solutions (pour-on), solutions for spray-
`ing (sprays), baths, showers,
`jets, powders, greases,
`shampoos, creams, etc. The pour-on type skin solutions are
`designed for percutaneous administration. Example 9 of
`EP-A-295,117 and Example 291 of EP—A-500,209 describe
`a pour-on type skin solution containing 15% insecticide and
`85% dimethyl sulphoxide, for percutaneous administration
`of the insecticide.
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`EP-A-296,381 also describes pyrazole compounds having
`insecticidal activity in the field of agriculture, public health
`and veterinary medicine. Boophilus microplus is one of the
`very many targets mentioned. There are very many forms of
`administration here also, and these include, for example,
`solutions, emulsions, suspensions, powders, pastes, granules
`and aerosols.
`The problem which is posed is to find an eifective means
`which is entirely suitable for controlling the, parasites of
`cattle and sheep, in particular ticks, most particularly Boo-
`philus microplus in cattle and in particular lice and blowfly
`in sheep, under the conditions in which these animals are
`reared
`The Applicant has found that it is possible to effectively
`control Boophilus microplus for cattle using a specific
`topical formulation. The Applicant has also found that this
`formulation is effective against sheep lice and sheep flies
`known as “blowfly”.
`The aim of the present invention is thus to provide a novel
`composition which is entirely effective against Boophilus
`microplus and also against all of the other parasites
`described above such as,
`in particular, sheep lice and
`“blowfly”, this composition being entirely suitable for con-
`trolling these parasites under the conditions in which these
`animals are reared.
`Another aim of the invention is to provide such a formu-
`lation which has a long period of eflicacy, preferably longer
`than or equal to two months.
`Another aim of the invention is to provide such a formu-
`lation which is quick and easy to use and entirely compatible
`with use on herds or flocks containing a large number of
`animals.
`Another aim of the invention is to provide such a formu-
`lation which is particularly suitable for extensive pasture
`rearing and for use intended to protect animals during the
`period of rounding up and finishing (Feed Lot in USA),
`namely the final period of rearing in which a large number
`of animals are herded into a small enclosure over an average
`period of two months preceding slaughter.
`The subject of the present
`invention is thus a direct
`pour-on slcin solution, intended to eliminate parasites from
`cattle and sheep, most particularly ticks, especially Boophi-
`lus microplus in cattle and lice and blowfly in sheep,
`comprising from 0.05 to 25% weight/volume, relative to the
`total solution, of a compound of formula (I)
`
`R;
`
`R,
`
`(1)
`
`R4
`
`Ru
`
`/
`
`\,
`N/
`
`\ X
`
`/
`
`R13
`
`in which:
`
`R1 is CN or methyl or a halogen atom;
`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
`NR5R5R6, S(O),,,R7, C(O)R7, C(O)O—R7, alkyl, haloalkyl
`or OR8, or a radical —N=C (R9) (R10);
`R5 and R5 independently represent a hydrogen atom or an
`alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O),CF3
`radical; or R5 and R5 may together form a divalent alkylene
`
`

`
`US 6,797,724 B2
`
`5
`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-alkyl, —S-alkyl, cyano or alkyl;
`R11 and R12 represent, independently of each other, a
`hydrogen or halogen atom, or optionally CN or N02;
`R13 represents a halogen atom or a haloalkyl, 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——R 12, the other three valency positions of the carbon atom
`forming part of the aromatic ring;
`with the proviso that, when R1 is methyl, either R3 is
`haloalkyl, R4 is NH2, 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;
`in a formulation at low volume, designed to release the
`compound (1) onto the skin and the hairs for a contact
`action against parasites.
`Preferably, in formula (I), R1 is CN or methyl;
`R2 is S(O),,R3;
`R3 is alkyl or haloalkyl;
`R4 represents a hydrogen or halogen atom; or a radical
`NR5R5, S(O)mR.,, C(O)R.,, alkyl, haloalkyl or OR3 or a
`radical —N=C (R9) (R10);
`R5 and R5 independently represent a hydrogen atom or an
`alkyl, haloalkyl, C(O)alky1 or S(O),CF3 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-alkyl, <9-alkyl, cyano or alkyl;
`R11 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 SF5 group;
`m, n, q, and I 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;
`then R3 is
`with the proviso that, when R1 is methyl,
`haloalkyl, R4 is NH2, R11 is Cl, R13 is CF3 and X is N.
`However, low concentrations of from 0.05 to 10% weight/
`volume, more particularly from 0.1 to 2%, are preferred.
`Optimally, the value is between 0.25 and 1.5%, in particular
`in the region of 1%.
`The expression pour-on skin solution is understood to
`refer to a ready-to-use solution intended to be applied
`topically and locally on the animal, Preferably on the
`animal’s back and at several points or along the line of the
`back, and applied in low volume, preferably of 5 to 20 ml per
`100 kg, preferably about 10 ml per 100 kg, with a total
`volume of from 10 to 150 ml per animal, preferably limited
`to 50 ml.
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`6
`the parasite
`The compound acts by simple contact,
`becoming impregnated with the compound on contact with
`the hairs and the skin.
`
`This thereby afiords, in a noteworthy manner, a both
`perfect compatibility with the restrictions of use in extensive
`grazing, in terms of ease of use in particular, and a spectrum
`of activity and of eflicacy, as well as a period of eflicacy,
`which are suited to this type of rearing.
`By working on the concentration of compound (I), in
`particular of compound A, solutions having note-worthy
`activities are obtained with, in particular, two months of
`efficacy against Boophilus microplus,
`this result never
`before having been achieved. Moreover, the solution accord-
`ing to the invention allows Boophilus microplus to be totally
`eliminated from an infested animal in less than 2 days.
`As has been stated above, the solution according to the
`present invention is applied topically, in low volume, to the
`animal’s back. The compound of formula (I) then difluses
`out
`in a noteworthy manner,
`this being reflected by a
`distribution of the compound over the animal’s entire body.
`It has also been observed that the animals remained pro-
`tected in the case of passage through Water or exposure to
`rain.
`
`is preferably
`The dose of compound of formula (I)
`between 0.1 and 2 mg/kg (animal weight), preferably
`between 0.25 and 1.5 mg/kg, and in particular about 1
`mg/kg.
`The compounds of formula (I) in which R1 is CN will be
`selected most particularly. The compounds in which R2 is
`S(O),,R3, preferably with n=1, R3 preferably being CF3 or
`alkyl, for example methyl or ethyl, or alternatively n=0, R3
`preferably being CF3, as well as those in which X=C-R12,
`R12 being a halogen atom, will also be selected. The
`compounds in which R11 is a halogen atom and those in
`which R13 is haloalkyl, preferably CF3, are also preferred. In
`the context of the present invention, compounds combining
`two or more of these characteristics will advantageously be
`selected.
`
`A preferred class of compounds of formula (I) consists of
`compounds such that R1 is CN, R3 is haloalkyl, preferably
`CF3, or ethyl, R4 is NH2, R11 and R12 are, independently of
`each other, a halogen atom, and/or R13 is haloalkyl.
`In the present invention, the alkyl radicals may contain
`generally from 1 to 6 carbon atoms. The cycle formed
`between the divalent alkylene radical representing R5 and
`R5, as well as with the nitrogen atom to which R5 and R5 are
`attached, may be generally a cycle of 5, 6 or 7 links.
`Amost particularly preferred compound of the formula (I)
`in the invention is 1-[2,6-C12 4-CF3phenyl]3-CN 4-[SO-
`CF3]5-NH2pyrazole, referred to hereinbelow as compound
`A. This compound A will be used in particular in a propor-
`tion of from 0.1 to 2% by weight, more particularly about
`1%, relative to the total solution.
`Mention may also be made of the two compounds which
`differ from the above by the following characteristics:
`1-n-0, R3=CF3
`2-n=1, R3=ethyl.
`The compounds of formula (I) may be prepared according
`to one or other of the processes described in patent appli-
`cations W0-A-87/3781, 93/6089, 94/21606 or European
`patent application EP-A-0,295,117, or any other process
`which falls within the competence of a specialist skilled in
`the art of chemical synthesis. For the chemical preparation
`of the products of the invention, a person skilled in the art
`is considered as having at his or her disposal, inter alia, all
`the contents of “Chemical Abstracts” and the documents
`cited therein.
`
`

`
`US 6,797,724 B2
`
`7
`It is not departing from the scope of the present invention
`to incorporate other insecticides into the solution according
`to the present invention.
`The solutions according to the invention, which are
`advantageously oily, generally comprise a diluent or Vehicle
`and also a solvent (organic solvent) for the compound of
`formula (I) if the latter is not soluble in the diluent.
`As organic solvent which can be used in the invention,
`mention may be made in particular of: acetyltributyl citrate,
`fatty acid esters such as the dimethyl ester, diisobutyl
`adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol,
`dimethylacetamide, dimethylforrnamide, dipropylene glycol
`n-butyl ether, ethanol, isopropanol, methanol, ethylene gly-
`col 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 and diethyl
`phthalate, or a mixture of at least two of these solvents.
`As vehicle or diluent, mention may be made in particular
`
`of:
`
`plant oils such as soybean oil, groundnut oil, castor oil,
`corn oil, cotton oil, olive oil, grape seed oil, sunflower
`oil, etc.; mineral oils such as petrolatum, paraffin,
`silicone, etc.; aliphatic or cyclic hydrocarbons or
`alternatively, for example, medium—chain (C8 to C12 in
`particular) triglycerides.
`An emollient and/or spreading and/or film-forming agent
`will preferably be added, this agent being selected in par-
`ticular from:
`
`polyvinylpyrrolidone, polyvinyl alcohols, copolymers of
`vinyl acetate and vinylpyrrolidone, polyethylene
`glycols, benzyl alcohol, mannitol, glycerol, sorbitol,
`polyoxyethylenated sorbitan esters;
`lecithin, sodium
`carboxymethylcellulose, silicone oils, polydiorganosi-
`loxane oils,
`in particular polydimethylsiloxane
`(PDMS) oils, for example those containing silanol
`functionalities, or a 45V2 oil,
`anionic surfactants such as alkaline stearates, in particular
`sodium, potassium or ammonium stearates; calcium
`stearate,
`triethanolamine stearate; sodium abietate;
`alkyl sulphates, in particular sodium lauryl sulphate
`and
`sodium cetyl
`sulphate;
`sodium
`dodecylbenzenesulphonate, sodium 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 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 cat-
`ionic surfactants 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 sorbitan esters, which are
`optionally polyoxyethylenated,
`in particular polysor-
`bate 80, polyoxyethylenated alkyl ethers; polyoxypro-
`pylated fatty alcohols such as polyoxypropylene-styrol
`ether; polyethylene glycol stearate, polyoxyethylenated
`derivatives of castor oil, polyglycerol esters, polyoxy-
`ethylenated fatty alcohols, polyoxyethylenated fatty
`acids, copolymers of ethylene oxide and propylene
`oxide,
`
`8
`amphoteric surfactants such as the substituted lauryl com-
`pounds of betaine;
`or a mixture of at least two of these agents.
`The solvent will be used in proportion with the concen-
`tration of the compound I and its solubility in this solvent.
`For example, compound A has a solubility of 4.3% m/V
`in acetyl tributyl citrate. It will be sought to have the lowest
`possible volume.
`The vehicle makes up the dilference to 100%.
`The emollient is preferably used in a proportion of from
`0.1 to 10%, in particular from 0.25 to 5%, by volume.
`The subject of the present invention is also a process for
`the elimination of parasites,
`in particular Baophilus
`microplus, from cattle and sheep using a direct pour-on skin
`solution according to the present invention, so as obtain
`long-lasting and broad-spectrum efiicacy, the solution being
`applied to the animal’s back, preferably along the line of the
`back at one or more points.
`According to a first embodiment, the process consists in
`applying the solution to the animals in pasture and/or before
`they arrive in pasture,
`the application preferably being
`repeated every month, preferably every two months.
`According to a second embodiment, the process consists
`in applying the solution to the animals before they arrive in
`the “feed Lot”, it being possible for this application to be the
`final one before the animals are slaughtered.
`Obviously,
`the process may also consist in combining
`these two embodiments, namely the first followed by the
`second.
`In all cases, the eflicacy advantageously makes it possible
`to stop any application 1 to 3 months before slaughter, in
`particular between 1.5 and 2.5 months, more particularly
`about two months before slaughter.
`The solutions according to the invention may be applied
`using any means known per se, preferably using an appli-
`cator gun or a metering flask.
`in
`therapeutic and is,
`The aim of the method is not
`particular, to cleanse the skin and the hairs of the animals by
`eliminating the parasites which are present thereon, as well
`as their residues and dejections. The result of this is that the
`animals are no longer stressed by the parasites and their
`bites, this having positive consequences, for example on
`their growth and on the use of their food ration.
`Another subject of the invention is a therapeutic method
`using the external device according to the invention,
`intended for the treatment and prevention of parasitoses
`having pathogenic consequences.
`The subject of the present invention is also the use of the
`compounds I, in particular compound A, for the manufacture
`of a direct pour-on skin solution comprising the compound
`(I) in a low volume and designed to release the compound
`(I) onto the skin and the hairs for a contact action against the
`parasites of cattle and sheep, in particular cattle ticks, such
`as Baophilus microplus, and sheep blowfly and lice.
`The use according to the invention is directed towards
`producing skin solutions as described above.
`The present invention will now be described in greater
`detail with the aid of non-limiting embodiment examples
`which demonstrate the activity of the solutions according to
`the present invention, Will] reference to the attached draw-
`ings in which:
`FIG. 1 is a graph showing the eflicacy, against Boophilus
`microplus, of skin solutions according to the invention, with
`a 0.25%, 0.5% and 1% content, relative to a control, this
`graph including, on the x-axis,
`the time in days after
`application of the skin solutions, and, on the y-axis to the
`left, the number of ticks counted on the animals on which the
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`

`
`US 6,797,724 B2
`
`9
`skin solutions according to the invention are applied, and, on
`the y-axis to the right, the number of ticks counted in the
`controls;
`FIG. 2 is a graph showing the population of ticks in
`animals which have received the placebo according to
`Example 2, with, on the x-axis, the time in days, and, on the
`y-axis, the number of ticks; and
`FIG. 3 compares the eflicacy of a skin solution according
`to the invention containing 1% compound A (solid circles)
`with a skin solution containing 1% flumethrin (rings), with,
`on the x-axis,
`the time in days, and, on the y-axis, the
`number of ticks.
`
`EXAMPLE 1
`
`Preparation of the Solutions According to the
`Invention
`
`Ingredient
`
`Compound A
`polyoxypropylene 15 sbearyl ether
`acetyl tributyl citrate
`soybean oil
`
`x - 0.25 g for 0.25% solution
`x - 0.5 g for 0.5% solution
`x = 1 g for 1% solution
`
`Function
`
`active substance
`emollient
`solvent
`diluent
`
`Amount
`
`x g
`5 g
`30 g
`qs 100 ml
`
`x-0.25 g for 0.25% solution
`x-0.5 g for 0.5% solution
`x=l g for 1% solution
`Compound A is dissolved in the solvent before being
`mixed with the other ingredients.
`
`EXAMPLE 2
`
`Study of the efiicacy of skin solutions according to the
`invention containing, respectively, 0.25, 0.50 and 1% com-
`pound A to combat Boophilus microplus.
`The study was performed on 16 young male castrated
`Herefords (weight ranging between 114 and 172 kg).
`Three skin solutions according to Example 1 were pre-
`pared:
`1. 1% compound A
`2. 0.5% compound A
`3. 0.25% compound A
`
`A placebo was prepared, which dilfered from the skin
`solutions according to the invention in that it contained no
`compound A.
`In the studies, 1 ml of skin solution or of placebo were
`used per 10 kg of animal weight.
`The dose volume was applied along the line of the
`animal’s back, from the head to the base of the tail.
`
`Between days -24 and -1, the animals were artificially
`infested on 11 occasions with 2,500 Boophilus microplus
`larvae. The aim of 24-day infestation is to ensure that all of
`the stages of Boophilus microplus are present on the animal
`(eggs, larvae, adults).
`On day 0, the