EXHIBIT 1005
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`IllllllllllllllllIllll|||||I||||I|||||||l|||l||||||||||||||||I||l||||||l||l
`USOO6426333B1
`
`(12) United States Patent
`US 6,426,333 B1
`(10) Patent N0.:
`Huet et al.
`
`(45) Date of Patent: Jul. 30, 2002
`
`(54) SPOT-ON FORMULATIONS FOR
`COMBATING PARASITES
`
`(75)
`
`Inventors: Anne-Marie Huet; Bruno Julia;
`Jean-Pierre Etchegaray, all of
`Toulouse; André Wei], Cugnaux;
`Philippe Jeannin, Tournefeuille, all of
`(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. N0.: 09/376,736
`
`(22)
`
`Filed:
`
`Aug. 17, 1999
`
`(Under 37 CFR 1.47)
`
`9/1996 Banks
`5,556,868 A
`9/1996 Huang et 211.
`5,556,873 A
`10/1996 Senbo
`5,567,429 A
`............... 374/341
`5,580,843 A * 12/1996 Stetter et a1.
`5,602,107 A *
`2/1997 Choi
`........................... 514/30
`5,608,077 A
`3/1997 Hatton et a1.
`5,614,182 A
`3/1997 Davidson et al.
`5,677,332 A
`10/1997 Banks
`5,700,460 A
`12/1997 Davirhon et a1.
`5,714,191 A
`2/1998 Hutton et 31.
`5,723,488 A
`3/1998 Walshe
`5,733,887 A
`3/1998 Walshe
`5,739,083 A
`4/1998 Endo et al.
`5,747,519 A
`5/1998 Kodama et a1.
`5,817,688 A
`10/1998 Huang et a1.
`5,883,080 A
`3/1999 Dutton et a1.
`5,916,618 A
`6/1999 Hatton et al.
`5,916,909 A
`6/1999 Kodama et al.
`5,972,330 A
`10/1999 Sugiura et :11.
`5,977,156 A
`11/1999 Duvert et a1.
`5,981,500 A
`11/1999 Bishop et al.
`6,054,140 A "'
`4/2000 Lamberti
`.................... 424/405
`
`Related US. Application Data
`
`FOREIGN PATENT DOCUMENTS
`
`(63) Continuation~in-part of application No. 09/271,470, filed on
`Mar. 17, 1999, which is a continuation-in-part of application
`No. PCT/FR97/01548, filed on Sep. 15, 1997.
`
`(30)
`
`Foreign Application Priority Data
`
`Sep. 19, 1996
`
`(FR)
`
`............................................ 96 11446
`
`A61K 31/70; A01N 25/02
`Int. Cl.7
`(51)
`514/30; 424/405; 424/406
`...............
`(52) US. Cl.
`(58) Field of Search ............................ 574/30; 424/405,
`424/407, 484—488
`
`
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4/1981 Plath et a1.
`4,260,775 A
`11/1981 Plath et a1.
`4,298,749 A
`5/1984 Dusza et al.
`4,451,479 A
`8/1984 Kitano ....................... 424/232
`4,468,390 A *
`1/1985 Hatton et al.
`4,496,390 A
`2/1989 Jensen—Korte et al.
`4,803,215 A
`7/1989 Lindig et a1.
`4,845,089 A
`10/1990 Buntain et a1.
`4,963,575 A
`10/1991 Hatton et a].
`5,055,482 A
`12/1991 Hafner et a1.
`5,077,278 A
`4/1992 Roberts et al.
`5,104,994 A
`1/1993 Roberts et a1.
`5,177,100 A
`8/1993 Hatton et al.
`5,232,940 A
`8/1993 Huang et a1.
`5,236,938 A
`8/1993 Rosegay
`5,240,915 A
`............... 546/279
`5,360,910 A * 11/1994 Huang et al.
`5,387,509 A
`2/1995 Hawrylik et al.
`5,516,787 A
`5/1996 Takada
`5,547,974 A
`8/1996 Hatton et a1.
`
`W0
`W0
`
`WO95/20877
`WO 00/30449
`
`*
`
`8/1995
`6/2000
`
`* cited by examiner
`
`Primary Examiner—Neil S. Levy
`(74) Attorney, Agent, or Firm—Frommer Lawrence &
`Haug LLP; William S. Frommer; Thomas J. Kowalski
`
`(57)
`
`ABSTRACT
`
`In particular this invention provides for spot-on composi-
`tions for the treatment or prophylaxis of parasite infestations
`in mammals or birds which comprise:
`(1) a composition comprising
`(A) an effective amount of a 1-pheny1pyrazole deriva-
`tive; and/or
`03) an effective amount of a macrocyclic lactone anti-
`helmintic or antiparasitic agent;
`(2) an acceptable liquid carrier vehicle; and
`(3) optionally, a crystallization inhibitor.
`
`The invention also provides for a method of treating para-
`sitic infestations or for the prophylaxis of parasite infesta-
`tions in mammals or birds which comprises topically apply—
`ing to said mammal treating parasitic infestations or for the
`prophylaxis of parasite infestations in mammals or birds
`which comprises topically applying to said mammal or bird
`an effective amount of a composition according to the
`present invention.
`
`15 Claims, N0 Drawings
`
`

`

`1
`SPOT-ON FORMULATIONS FOR
`COMBATING PARASITES
`
`RELATED APPLICATIONS
`
`This application is a continuation-in—part of application
`U.S. Ser. No. 09/271,470, filed Mar. 17, 1999, now pending
`which in turn is a continuation—in—part of copending Inter-
`national Application PCT/FR97/01548 having an interna-
`tional filing date of Sep. 15, 1997, and designating the U.S.
`and claiming priority from French Application No.
`96/11446, filed Sep. 19, 1996. Reference is also made to:
`US. applications Ser. No. 08/719,942, filed Sep. 25, 1996,
`08/692,430, filed Aug. 5, 1996, Ser. No. 08/863,182, filed
`May 27, 1997, Ser. No. 08/692,113, filed Aug. 5, 1996, Ser.
`No. 08/863,392, filed May 27, 1997, and Ser. No. 08/891,
`047, filed Jul. 10, 1997; French Application No. 97 03709,
`filed Mar. 26, 1997; and PCT/FR98/00601. All of the
`above-mentioned applications, as well as all documents
`cited herein and documents referenced or cited in documents
`cited herein, are hereby incorporated herein by reference.
`FIELD OF THE INVENTION
`
`This invention relates to spot-on formulations for com-
`bating parasites in birds and mammals. In particular, this
`invention provides for spot-on formulations comprising a
`composition comprising a 1-N—phenylpyrazole derivative
`and/or a macrolide anthelmintic or antiparasitic agent, and a
`pharmaceutically or veterinary acceptable liquid carrier
`vehicle. This invention also provides for to an improved
`method for eradicating, controlling, and preventing parasite
`infestation in birds and mammals.
`
`BACKGROUND OF THE INVENTION
`
`Animals such as mammals and birds are often susceptible
`to parasite infestations. These parasites may be
`ectoparasites, such as insects, and endoparasites such as
`filariae and worms.
`
`Domesticated animal, such as cats and dogs, are often
`infested with one or more of the following ectoparasites:
`cat and dog fleas (Ctenocephalides felis, Ctenocephalides
`sp. and the like),
`ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp.,
`Amblyoma sp. and the like), and
`galls (Demodex sp., Sarcoptes sp., Otodectes sp. and the
`like).
`Fleas are a particular problem because not only do they
`adversely affect the health of the animal or human, but they
`also cause a great deal of psychological stress. Moreover,
`fleas are also vectors of pathogenic agents in animals, such
`as dog tapeworm (Dipylidium caninum), and humans.
`Similarly,
`ticks are also harmful
`to the physical and
`psychological health of the animal or human. However, the
`most serious problem associated with ticks is that they are
`the vector of pathogenic agents, agents which cause diseases
`in both humans and animal. Major diseases which are caused
`by ticks include borrelioses (Lyme disease caused by Bor-
`relia burgdorferi), babesioses (or piroplasmoses caused by
`Babesia sp.) and rickettsioses (also known as Rocky Moun-
`tain spotted fever). Ticks also release toxins which cause
`inflammation or paralysis in the host. Occasionally, these
`toxins are fatal to the host.
`Moreover, galls are particularly difficult to combat since
`there are very few active substances which act on these
`parasites and they require frequent treatment.
`Likewise, farm animals are also susceptible to parasite
`infestations. For example, cattle are affected by a large
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`US 6,426,333 B1
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`2
`
`number of parasites. A parasite which is very prevalent
`among farm animals is a tick genus Boophilus, especially
`those of the species microplus (cattle tick), decoloratus and
`anulatus. Ticks, such as Boophilus microplus, are particu-
`larly difficult to control because they live in the pasture
`where the farm animals graze. Other important parasites of
`cattle and sheep are listed as follows in order of decreasing
`importance:
`myiases such as Dermatobia hominis (known as Berne 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.; and
`galls such as Sarcoptes scabiei and Psoroptes ovis.
`The above list is not exhaustive and other ectoparasites are
`well known in the art to be harmful to animals and humans.
`These include, for example migrating dipterous larvae.
`Animals and humans also suffer from endoparasitical
`infections including, for example, helminthiasis which is
`most frequently caused by a group of parasitic worms
`described as nematodes or roundworms. These parasites
`cause severe economic losses in pigs, sheep, horses, and
`cattle as well as affecting domestic animals and poultry.
`Other parasites which occur in the gastrointestinal tract of
`animals and humans include Ancylostoma, Anecator,
`Ascaris, Strongyloides, Trichinella, Capillaria, Roxocara,
`Toxascaris, Trichiris, Enterobius and parasites which are
`found in the blood or other tissues and organs such as filarial
`worms and the extra intestinal stages of Strogyloides, Toxo-
`cara and Trichinella,
`
`Many insecticides exist in the art for treating parasites.
`These insecticides vary in their effectiveness to a particular
`parasite as well as their cost. However the results of these
`insecticides is not always satisfactory because of,
`for
`example, the development of resistance by the parasite to the
`therapeutic agent, as is the case, for example, with
`carbamates, organophosphorus compounds and pyrethroids.
`Moreover, there is at the present time no truly effective
`method for controlling both ticks and helminths and less still
`an effective way of controlling the set of parasites indicated
`above. Thus, there is a need in the art for more effective
`antiparasitic formulation treatment and protection of animal
`and birds for a wide range of parasites. Moreover, there is a
`need in the art for antiparasitic formulation which is easy to
`use on any type of domestic animal, irrespective of its size
`and the nature of its coat and which do not need to be
`
`sprinkled over the entire body of the mammal or bird.
`A new family of insecticides based on l-N-
`phenylpyrazoles is described in Patents EP-A—295,217 and
`EP-A—352,944. The compounds of the families defined in
`these patents are extremely active and one of these
`compounds, 1—[2,6.C12-4-CF3 phenyl]-3—CN-4-[SO—-CF3]-
`5-NH2 pyrazole, or fipronil, is particularly eflective, not only
`against crop parasites but also against ectoparasites of
`mammals and birds. Fipronil
`is particularly, but not
`exclusively, effective against fleas and ticks.
`Endectocidal compounds, which exhibit a degree of activ-
`ity against a wide range endoparasites, are known in the art.
`These compounds possess a macrocyclic lactone ring and
`are known in the art to be particularly effective against
`ectoparasites,
`including lice, blowflies, mites, migrating
`dipterous larvae, and ticks, as well as endoparasites, such as
`nematodes and roundworms. Compounds of this group
`
`

`

`US 6,426,333 B1
`
`3
`include averrnectins, milbemycins, and derivatives of these
`compounds, for example, ivermectin. Such substances are
`described, for example, in US. Pat. Nos. 3,950,360 and
`4,199,569.
`While it is known in the art that it is sometimes possible
`to combine various parasiticides in order to broaden the
`antip arasitical spectrum, it is not possible to predict, a priori,
`which combinations will work for a particular animal or
`disease state. For this reason, the results of various combi-
`nations is not always successful and there is a need in the art
`for more effective formulations which may be easily admin—
`istered to the animal. The effectiveness of formulations
`comprising l-N-phenylpyrazole derivatives and macrolide
`lactone anthelmintic or parasitic agents, such as
`avermectins,
`ivermectins and milbemycin, against an
`endoparasite or an ectoparasite in a specific host is espe-
`cially difficult
`to predict because of the numerous and
`complex host—parasite interactions.
`Patent application AU-A—16 427/95 very broadly men-
`tions the combination of a substituted 1-N—pyrazole deriva-
`tives with an avermectin,
`ivermectin or moxidectin in a
`discussion involving among a very large number of insec-
`ticides or parasiticides of various types, including fipronil.
`However, this patent application does not provide specific
`guidance to the skilled artisan on how to formulate a
`1-N-pyrazole derivative with an avermectin or milbemycin
`type compound, let alone how to formulate a spot-on com-
`position comprising these compounds. Moreover, the appli-
`cation does not indicate which specific parasites are suscep-
`tible to what specific combination.
`Various methods of formulating antiparasitical formula-
`tions are known in the art. These include oral formulations,
`baits, dietary supplements, powders, shampoos, etc. Formu-
`lations for localized topical applications of antiparasitical
`formulations are also known in the art. For example, pour-on
`solutions comprising l-N-phenylpyrazoles, such as fipronil,
`are known in the art and are described in copending appli-
`cation Ser. No. 08/933,016, herein incorporated by refer-
`ence. Other methods of formulating antiparasitic agents
`include spot-on formulations.
`Spot-on formulations are well known techniques for topi-
`cally delivering an antiparasitic agent to a limited area of the
`host. For example, US. Pat. No. 5,045,536 describes such
`formulations for ectoparasites. Moreover,
`it
`is generally
`known in the art to formulate avermectin and milbemycin
`derivatives as spot—on formulations. See, e.g. US. Pat. No.
`5,045,536; EP 677,054; US. Pat. No. 5,733,877; US. Pat.
`No. 5,677,332; US. Pat. No. 5,556,868; and US. Pat. No.
`5,723,488. However, as discussed in US. Pat. No. 5,045,
`536, a large number of solvent systems described in the art
`provide formulations for localized topical application which
`cause irritancy or toxicity to the host. Hence, there is a need
`in the art both for more effect and less irritant or toxic
`formulations. Thus, there is a need in the art for a spot—on
`formulation which is effect against a wide range of
`endoparasites and ectoparasites in birds and mammals.
`SUMMARY OF THE INVENTION
`
`The invention provides for spot-on formulations for the
`treatment or prophylaxis of parasites of mammals and birds,
`and in particular, cats, dogs, horses, chickens, sheep and
`cattle with the aim of ridding these hosts of all the parasites
`commonly encountered by birds and mammals. The inven-
`tion also provides for eifective and lasting destruction of
`ectoparasites, such as fleas, ticks, itch mites and lice, and of
`endoparasites, nematodes, such as filariae, and roundworms
`of the digestive tract of animals and humans.
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`
`In particular this invention provides for spot-on formula-
`tions for the treatment or prophylaxis of parasite infestations
`in mammals or birds which comprise:
`(1) a composition comprising
`(A) an effective amount of a 1-N-phenylpyrazole
`derivative; and/or
`(B) an effective amount of a macrocyclic lactone anti-
`helmintic or antiparasitic agent;
`(2) a pharmaceutically or veterinary liquid carrier vehicle;
`and
`
`(3) optionally, a crystallization inhibitor.
`The invention also provides for an easy method of treating
`parasitic infestations or for the prophylaxis of parasite
`infestations in mammals or birds which comprises topically
`applying to said mammal or bird an effective amount of a
`formulation according to the present invention.
`This invention also provides for spot-on formulations
`comprising a combination comprising a compound of for-
`mula (I) and a macrocyclic lactone which exhibit synergistic
`activity against parasites when compared to formulations
`which contain only one class of therapeutic agent.
`This invention further provides for formulations which,
`when applied locally, will diffuse over the entire body of the
`host and then dry, without crystallizing, and which do not
`affect
`the appearance of the coat after drying by, for
`example, leaving crystals or making the coat sticky. This has
`the further advantage in animals which groom themselves of
`not being orally ingested, where the therapeutic agent might
`not be well tolerated orally or might interact with other
`therapeutic agents.
`The very high effectiveness of the method and of the
`formulations according to the invention provides not only
`for a high instantaneous effectiveness but also for an effec-
`tiveness of very long duration after the treatment of the
`animal.
`These and other embodiments are disclosed or are obvi-
`ous from and encompassed by,
`the following Detailed
`Description.
`
`DETAILED DESCRIPTION
`
`This invention provides for a spot-on formulation for the
`treatment and prophylaxis of parasite infestation in mam-
`mals or birds which comprises
`(1) a composition comprising
`(A) an eifective amount of at least one compound of the
`formula
`
`R2
`
`R1
`
`(1)
`
`R4
`
`R11
`
`/
`
`\
`N/ N
`
`\ X
`I /
`
`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 an
`NRSRG, S(O),,,R7, C(O)R7 or C(O)OR7, alkyl,
`haloalkyl or 08 radical or an —N=C (R9) (R10)
`radical;
`
`

`

`US 6,426,333 B1
`
`5
`R5 and R5 independently represent a hydrogen atom
`or an alkyl, haloalkyl, C(O)alkyl, S(O),CF3 or
`alkoxycarbonyl radical or R5 and R6 can together
`form a divalent alkylene radical which is option-
`ally interrupted by one or two divalent heteroat-
`oms;
`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 an optionally substituted aryl or an
`optionally substituted heteroaryl group;
`R11 and R12 represent, independently of one another,
`hydrogen, halogen CN or N02;
`R13 represents a halogen atom or a haloalkyl,
`haloalkoxy, S(O)qCF3 or SFS group;
`m, n, q and r represent, independently of one another,
`an integer equal to 0, 1 or 2;
`X represents a trivalent nitrogen atom or a C-R12
`radical, the three other valencies of the carbon
`atom forming part of the aromatic ring;
`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 else R2 is 4,5—dicyanoimidazol-2-y1, R4 is
`Cl, R11 is Cl, R13 is CF3 and X is C—Cl; and/or
`(B) a pharmaceutical or veterinary effective amount of
`a macrocyclic lactone antihelmintic or antiparasitic
`agent;
`(2) a pharmaceutically or veterinary acceptable liquid
`carrier vehicle; and
`(3) optionally, a crystallization inhibitor
`More preferably, this invention provides for a spot—on
`formulation which comprises:
`(1) a composition comprising
`(A) an eifective amount of a compound of formula (I)
`wherein
`
`R1 is a halogen atom, CN or methyl;
`R2 is S(O)nR3 or 4,5-dicyanoimidazol-2-yl or
`haloalkyl;
`R3 is C1—C6-alkyl or C1—C6—haloalkyl;
`R4 represents a hydrogen or halogen atom; or a
`radical NR5R6, S(O)mR7, C(O)R., or C(O)OR7,
`allyl, haloalkyl or 0R8 or a radical —N=C(R9)
`(R10);
`R5 and R6 independently represent a hydrogen atom
`or a C1—C6-alkyl, C1-C6-haloalkyl, C(O)C1—C6-
`alkyl, S(O)rCF3, C1—C6-acyl or C1—C6-
`alkoxycarbonyl radical; or R5 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 or
`sulphur;
`R7 represents a C1—C5—alkyl or C1—C6-haloalky1
`radical;
`R8 represents a C1—C6-alkyl or C1—C6—haloalkyl
`radical or a hydrogen atom;
`R9 represents a C1—C5-alkyl radical or a hydrogen
`atom;
`R10 represents an optionally substituted phenyl or
`optionally substituted heteroaryl group wherein
`the substituents are selected from the group con-
`sisting of halogen, OH, —O—C1—-C5-alkyl,
`—S—Cl—C5-alkyl, cyano or C1—C5—alkyl;
`R11 and R12, independently of one another represent
`hydrogen, halogen, CN or N02;
`R13 represents a halogen, C1-C5—haloalkyl, C1—C6-
`haloalkoxy, S(O)qu3 or SF5 group, and/or
`
`6
`
`(B) an effective amount of a macrocyclic lactone
`selected from the group consisting of avermectins,
`ivermectin, abamectin, doramectin, moxidectin,
`selamectin, milbemycins and their derivatives;
`(2) the liquid carrier vehicle comprises a solvent and a
`cosolvent wherein the solvent
`is selected from the
`
`group consisting of acetone, acetonitrile, benzyl
`alcohol, butyl diglycol, dimethylacetamide,
`dimethylforrnamide, dipropylene glycol n-butyl ether,
`ethanol, isopropanol, methanol, ethylene glycol mono—
`ethyl ether, ethylene glycol monomethyl ether,
`monomethylacetamide, dipropylene glycol monom-
`ethyl ether, liquid polyoxyethylene glycols, propylene
`glycol,
`2-pyrrolidone,
`in
`particular
`N—methylpyrrolidone, diethylene glycol monoethyl
`ether, ethylene glycol, diethyl phthalate fatty acid
`esters, such as the diethyl ester or diisobutyl adipate,
`and a mixture of at least two of these solvents and the
`cosolvent
`is selected from the group consisting of
`absolute ethanol, isopropanol or methanol.
`(3) a crystallization inhibitor selected from the group
`consisting of an anionic surfactant,
`a cationic
`surfactant, a non-ionic surfactant, an amine salt, an
`amphoteric surfactant or polyvinylpyrrolidone, polyvi-
`nyl alcohols, copolymers of vinyl acetate and
`Vinylpyrrolidone, polyethylene glycols, benzyl alcohol,
`mannitol, glycerol, sorbitol, polyoxyethylenated sorbi—
`tan esters;
`lecithin, sodium carboxymethylcellulose,
`and acrylic derivatives, or a mixture of these crystal-
`lization inhibitors.
`
`Especially preferred are spot-on formulations described
`above wherein both compounds of formula I and a macro-
`cyclic lactone antihelmintic or antiparasitic agent are
`present. Especially more preferred are more composition
`wherein the ring formed by the divalent alkylene radical
`representing R5 and R6 and the nitrogen atom to which R5
`and R6 are attached has 5, 6 or 7 members or wherein R1 is
`CN, R3 is C1—C5-haloalkyl, R4 is NH2, R11 and R12 are,
`independently of one another, hydrogen or halogen and R13
`is C1—C6-haloalkyl.
`Most especially preferred are spot-on compositions,
`wherein the composition comprises:
`(A) 1-[2,6—C12-4-CF3 phenyl]—3-CN-4—[SO-CF3]-5-NH2
`pyrazole; and
`(B) ivermectin and milbemectin; or
`where the composition comprises
`(A) 1-[2,6-C12-4-CF3 phenyl]-3-CN—4-[SO-CF3]-5-NH2
`pyrazole; and
`(B) selamectin,
`The phenylpyrazoles (“compound A”) as a class are
`known in the art and are described, for example, in copend-
`ing applications U.S. Ser. Nos. 07/719,942; 08/933,016;
`09/174,598; 08/863,182; and 08/863,692, as well as in US.
`Pat. No. 5,576,429; US. Pat. No. 5,122,530, and EP 295
`177, the disclosures of which, as well as the references cited
`herein, are incorporated by reference. This class of insecti-
`cides is known to possess excellent activity against insects.
`such as ticks and fleas.
`
`The macrocyclic lactone antihelmintic or parasitic agents
`(“compound B”) are well known to a person skilled in the art
`and are easily obtained either commercially or through
`techniques know in the art. Reference is made to the widely
`available technical and commercial
`literature. For
`avermectins, ivermectin and abamectin, reference may be
`made,
`for example,
`to the work “Ivermectin and
`Abamectin”, 1989, by M. H. Fischer and H. Mrozik, Will-
`
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`US 6,426,333 B1
`
`7
`iam C. Campbell, published by Springer Verlag., or Albers-
`Schonberg
`et
`a1.
`(1981),
`“Avermectins
`Structure
`Determination”, J. Am. Chem. Soc., 103, 4216—4221. For
`doramectin, “Veterinary Parasitology”, vol. 49, No. 1, July
`1993, 5—15 may in particular be consulted. For
`milbemycins, reference may be made, inter alia, to Davies
`H. G. et al., 1986, “Avermectins and Milbemycins”, Nat.
`Prod. Rep., 3, 87—121, Mrozik H. et al., 1983, Synthesis of
`Milbemycins from Avermectins, Tetrahedron Lett., 24,
`5333—5336, US. Pat. No. 4,134,973 and EP 677,054.
`Compounds (B) are either natural products or are semi-
`synthetic derivatives thereof. The structure of at least certain
`compounds (B) are closely related, e.g., by sharing a com-
`plex 16—membered macrocyclic lactone ring. The natural
`product avermectins are disclosed in US. Pat. No. 4,310,519
`to Albers-Schdnberg, et al., and the 22,23-dihydro avermec-
`tin compounds are disclosed in Chabala, et al., US. Pat. No.
`4,199,569. Mention is also made of Kitano, US. Pat. No.
`4,468,390, Beuvry et al., US. Pat. No. 5,824,653, European
`Patent Application 0 007 812 A1, published Jun. 2, 1980,
`UK. Patent Specification 1 390 336, published Apr. 9, 1975,
`European Patent Application 0 002 916 A2, and Ancare New
`Zealand Patent No. 237 086, inter alia. Naturally occurring
`milbemycins are described in Aoki et al., US. Pat. No.
`3,950,360 as well as in the various references cited in “The
`Merck Index” 12’” ed., S. Budavari, Ed., Merck & Co., Inc.
`Whitehouse Station, NJ. (1996). Semisynthetic derivatives
`of these classes of compounds are well known in the art and
`are described, for example, in US. Pat. No. 5,077,308, US.
`Pat. No. 4,859,657, US. Pat. No. 4,963,582, US. Pat.
`4,855,317, US. Pat. No. 4,871,719, US. Pat. No. 4,874,749,
`US. Pat. No. 4,427,663, US. Pat. No. 4,310,519, US. Pat.
`No. 4,199,569, US. Pat. No. 5,055,596, US. Pat. No.
`4,973,711, US. Pat. No. 4,978,677, US. Pat. No. 4,920,148
`and EP 667,054.
`Particularly preferred macrocyclic lactones are avermec-
`tin derivatives which are monosaccharides and have a
`5-oxime substituent. Particularly preferred derivatives are:
`
`(I)
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`OCH;
`
`HO
`
`
`
`wherein the broken line at the 22—23 position represents an
`optional bond, R1, when present, is a hydrogen or a hydroxyl
`group, R2 is, for example, alkyl or cycloalkyl group and R3
`is, for example, hydrogen or alkyl. An especially preferred
`compound of this general structure is selamectin which has
`the following structure:
`
`65
`
`on,“
`
`H3O
`
`OCH;
`
`o
`
`HON
`
`These compounds are known in the art and are described for
`example in EP 667,054.
`The alkyl radicals of the definition of the compounds (A)
`of the formula (I) generally comprise from 1 to 6 carbon
`atoms. The ring formed by the divalent alkylene radical
`representing R5 and R6 and the nitrogen atom to which R5
`and R6 are attached is generally a 5-, 6- or 7-membered ring.
`A preferred class of compounds (A) of formula (I) com—
`prises the compounds such that R1 is CN, R3 is haloalkyl, R4
`is NHZ, R11 and R12 are, independently of one another, a
`halogen atom and R13 is haloalkyl. Preferably still, X is
`C—R12.A compound of formula (I) which is very particu-
`larly preferred in the invention is 1-[2,6-C12-4-CF3phenyl]-
`3-CN-4-[SO—CF3]—5—NH2 pyrazole or fipronil.
`More generally, compounds (A) are pyrazoles such as
`phenylpyrazoles and N-arylpyrazoles, and reference is made
`to, for example, US. Pat. No. 5,567,429, US. Pat. No.
`5,122,530, EP 295,117, and EP 846,686 A1 (or Banks GB
`9,625,045, filed Nov. 30, 1996 also believed to be equivalent
`to US. Ser. No. 309,229, filed Nov. 17, 1997).
`Compounds of formula (I) can be prepared according to
`one or other of the processes described in Patent Applica—
`tions W0 87/3781, 93/6089 and 94/21606 or European
`Patent Application 295,117 or any other process coming
`within the competence of a person skilled in the art who is
`an expert in chemical synthesis. For the chemical prepara-
`tion of the products of the invention, a person skilled in the
`art is regarded as having at his disposal, inter alia, the entire
`contents of “Chemical Abstracts” and of the documents
`which are cited therein.
`Administration of the inventive formulation may be inter-
`mittent in time and may be administered daily, weekly,
`biweekly, monthly, bimonthly, quarterly, or even for longer
`durations of time. The time period between treatments
`depends upon factors such as the parasite(s) being treated,
`the degree of infestation, the type of mammal or bird and the
`environment where it resides. It is well within the skill level
`of the practitioner to determine a specific administration
`period for a particular situation. This invention contemplates
`a method for permanently combating a parasite in an envi-
`ronment in which the animal is subjected to strong parasitic
`pressure where the administration is at a frequency far below
`a daily administration in this case. For example,
`it
`is
`preferable for the treatment according to the invention to be
`carried out monthly on dogs and on cats.
`Spot-on formulations may be prepared by dissolving the
`active ingredients into the pharmaceutically or veterinary
`acceptable vehicle. Alternatively, the spot-on formulation
`can be prepared by encapsulation of the to leave a residue of
`
`

`

`US 6,426,333 B1
`
`9
`the therapeutic agent on the surface of the animal. These
`formulations will vary with regard to the weight of the
`therapeutic agent
`in the combination depending on the
`species of host animal to be treated, the severity and type of
`infection and the body weight of the host. The compounds
`may be administered continuously, particularly for
`prophylaxis, by known methods. Generally, a dose of from
`about 0.001 to about 10 mg per kg of body weight given as
`a single dose or in divided doses for a period of from 1 to
`5 days will be satisfactory but, of course,
`there can be
`instance where higher or lower dosage ranges are indicated
`and such are within the scope of this invention. It is well
`within the routine skill of the practitioner to determine a
`particular dosing regimen for a specific host and parasite.
`Preferably, a single formulation containing the com-
`pounds (A) and (B) in a substantially liquid carrier and in a
`form which makes possible a single application, or an
`application repeated a small number of times, will be
`administered to the animal over a highly localized region of
`the animal, preferably between the two shoulders.
`Remarkably, it has been discovered that such a formulation
`is highly effective against both the targeted ectoparasites and
`the targeted endoparasites.
`The treatment is preferably carried out so as to administer
`to the host, on a single occasion, a dose containing between
`about 0.001 and about 100 mg/kg of derivative (A) and
`containing between about 0.1 and about 1000 itng of
`compound of type (B), in particular in the case of a direct
`topical administration.
`The amount of compound (A) for birds and animals which
`are small in size is preferably greater than about 0.01 mg and
`in a particularly preferred way between about 1 and about 50
`mg/kg of weight of animal.
`It also may be preferable to use controlled—release for-
`mulations. However, due to the persistence of the activity of
`fipronil and of compounds (B), it may be preferable for
`reasons of simplicity to use conventional vehicles.
`This invention also provides for a method for cleaning the
`coats and the skin of animals by removal of the parasites
`which are present and of their waste and excreta. The
`animals treated thus exhibit a coat which is more pleasing to
`the eye and more pleasant to the touch.
`While not wishing to be bound by theory, it is believed
`that the invention spot-on formulation work by the dose
`dissolving in the natural oils of the host’s skin, fur or
`feathers. From there,
`the therapeutic agent(s) distribute
`around the host’s body through the sebaceous glands of the
`skin. The therapeutic agent also remains in the sebaceous
`glands. Thus, the glands provide a natural reservoir for the
`therapeutic agent which allows for the agent to be drained
`back out to the follicles to reapply itself to the skin and hair.
`This, in turn, provides for longer time periods between
`application as well as not having to re-administer the dose
`after the host becomes wet because of rain, bathes, etc.
`Moreover, the inventive formulation have the further advan-
`tage in self-grooming animals of not being directly depos-
`ited of the skin or fur where the animals could orally ingest
`the therapeutic agent, thereby becoming sick or possibly
`interacting with other therapeutic agent being orally admin-
`istered.
`The invention also relates to such a method with a
`therapeutic aim intended for the treatment and prevention of
`parasitoses having pathogenic consequences.
`In another preferred embodiment
`this provides for a
`composition for combating fleas in small mammals,
`in
`particular dogs and cats, characterized in that it contains at
`least one compound (A) of formula (I) as defined above and
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`at least one endectocidal compound (B), in amounts and
`proportions having a parasitical effectiveness for fleas and
`worms, in a vehicle acceptable for the animal.
`The preferred class of compounds of formula (I) is that
`which has been defined above.
`
`A compound of formula (I) which is very particularly
`preferred in the invention is 1-[2,6-C12'4—CF3 phenyl]—3-
`CN-4-[SO—CF3]—5-NH2 pyrazole.
`Among the compounds of type (B), for small animals, a
`compound selected from the group formed by ivermectin,
`selamectin and milbemectin is especially preferred.
`The effective amount in a dose