[go: up one dir, main page]

US20020081327A1 - Direct pour-on antiparasitic skin solution and methods for treating, preventing and controlling myasis - Google Patents

Direct pour-on antiparasitic skin solution and methods for treating, preventing and controlling myasis Download PDF

Info

Publication number
US20020081327A1
US20020081327A1 US09/450,186 US45018699A US2002081327A1 US 20020081327 A1 US20020081327 A1 US 20020081327A1 US 45018699 A US45018699 A US 45018699A US 2002081327 A1 US2002081327 A1 US 2002081327A1
Authority
US
United States
Prior art keywords
compound
alkyl
haloalkyl
formula
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
US09/450,186
Other versions
US6413542B1 (en
Inventor
Jean-Pierre Etchegaray
Philippe Jeannin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Animal Health France SAS
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from FR9604209A external-priority patent/FR2746595B1/en
Priority claimed from FR9610312A external-priority patent/FR2752525B1/en
Priority claimed from FR9703708A external-priority patent/FR2747015B1/en
Priority claimed from US08/933,016 external-priority patent/US6010710A/en
Priority to US09/450,186 priority Critical patent/US6413542B1/en
Application filed by Individual filed Critical Individual
Assigned to MERIAL reassignment MERIAL ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ETCHEGARAY, JEAN-PIERRE, JEANNIN, PHILIPPE
Assigned to MERIAL reassignment MERIAL ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ETCHEGARAY, JEAN-PIERRE, JEANNIN, PHILIPPE
Priority to US10/120,691 priority patent/US6797724B2/en
Publication of US20020081327A1 publication Critical patent/US20020081327A1/en
Publication of US6413542B1 publication Critical patent/US6413542B1/en
Application granted granted Critical
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having no bond to a nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles

Definitions

  • 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.
  • the main ones are ticks of the genus Boophilus, among which mention may be made of the species microplus (cattle tick), decoloratus and anulatus.
  • 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 in Australia, 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).
  • galls such as Sarcoptes scabiei and Psoroptes ovis.
  • Ticks in particular Boophilus microplus, are very closely attached to the pasture in which they live and are particularly difficult to control.
  • 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 Boophilus microplus, 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, percutaneous and topical routes.
  • Topical administration comprises, in particular, oral formulations, baits, dietary supplements, skin solutions (pour-on), solutions for spraying (sprays), baths, showers, jets, powders, greases, shampoos, creams, etc.
  • Example 9 of EP-A-295,117 and Example 29I 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.
  • 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 effective means which is entirely suitable for controlling the parasites of cattle and sheep, in particular ticks, most particularly Boophilus microplus in cattle and in particular lice and blowfly in sheep, under the conditions in which these animals are reared.
  • Boophilus microplus for cattle using a specific topical formulation.
  • 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 controlling these parasites under the conditions in which these animals are reared.
  • Another aim of the invention is to provide such a formulation which has a long period of efficacy, preferably longer than or equal to two months.
  • Another aim of the invention is to provide such a formulation 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 formulation 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 skin solution, intended to eliminate parasites from cattle and sheep, most particularly ticks, especially Boophilus 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 1 is CN or methyl or a halogen atom
  • R 2 is S(O) n R 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl;
  • R 3 is alkyl or haloalkyl
  • R 4 represents a hydrogen or halogen atom; or a radical NR 5 R 6 , S(O) m R 7 , C(O)R 7 , C(O)O—R 7 , alkyl, haloalkyl or OR 8 or a radical —N ⁇ C(R 9 )(R 10 ) ;
  • R 5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O) r CF 3 radical; or R 5 and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur;
  • R 7 represents an alkyl or haloalkyl radical
  • R 8 represents an alkyl or haloalkyl radical or a hydrogen atom
  • R 9 represents an alkyl radical or a hydrogen atom
  • R 10 represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, —O-alkyl, —S-alkyl, cyano or alkyl;
  • R 11 and R 12 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO 2 ;
  • R 13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O) q CF 3 or SF 5 group;
  • m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2;
  • X represents a trivalent nitrogen atom or a radical C—R 12 , the other three valency positions of the carbon atom forming part of the aromatic ring;
  • R 1 when R 1 is methyl, either R 3 is haloalkyl, R 4 is NH 2 , R 11 is Cl, R 13 is CF 3 and X is N; or R 2 is 4,5-dicyanoimidazol-2-yl, R 4 is Cl, R 11 is Cl, R 13 is CF 3 and X is ⁇ C—C1;
  • R 1 is CN or methyl
  • R 2 is S(O) n R 3 ;
  • R 3 is alkyl or haloalkyl
  • R 4 represents a hydrogen or halogen atom; or a radical NR 5 R 6 , S(O) m R 7 , C(O)R 7 , alkyl, haloalkyl or OR 8 or a radical —N ⁇ C(R 9 )(R 10 );
  • R 5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl or S(O) r CF 3 radical; or R 5 and R 6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur;
  • R 7 represents an alkyl or haloalkyl radical
  • R 8 represents an alkyl or haloalkyl radical or a hydrogen atom
  • R 9 represents an alkyl radical or a hydrogen atom
  • R 10 represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, —O-alkyl, —S-alkyl, cyano or alkyl;
  • R 11 and R 12 represent, independently of each other, a hydrogen or halogen atom
  • R 13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O) q CF 3 or SF 5 group;
  • m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2;
  • X represents a trivalent nitrogen atom or a radical C—R 12 , the other three valency positions of the carbon atom forming part of the aromatic ring;
  • R 1 when R 1 is methyl, then R 3 is haloalkyl, R 4 is NH 2 , R 11 is Cl, R 13 is CF 3 and X is N.
  • 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.
  • the compound acts by simple contact, the parasite becoming impregnated with the compound on contact with the hairs and the skin.
  • the solution according to the present invention is applied topically, in low volume, to the animal's back.
  • the compound of formula (I) then diffuses 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 protected in the case of passage through water or exposure to rain.
  • the dose of compound of formula (I) is preferably 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.
  • R 1 is CN
  • R 11 is a halogen atom and those in which R 13 is haloalkyl, preferably CF 3
  • 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 R 1 is CN, R 3 is haloalkyl, preferably CF 3 , or ethyl, R 4 is NH 2 , R 11 and R 12 are, independently of each other, a halogen atom, and/or R 13 is haloalkyl.
  • the alkyl radicals may contain generally from 1 to 6 carbon atoms.
  • the cycle formed between the divalent alkylene radical representing R 5 and R 6 , as well as with the nitrogen atom to which R 5 and R 6 are attached, may be generally a cycle of 5, 6 or 7 links.
  • a most particularly preferred compound of the formula (I) in the invention is 1-[2,6-Cl 2 4-CF 3 phenyl]3-CN 4-[SO—CF 3 ]5-NH 2 pyrazole, referred to hereinbelow as compound A.
  • This compound A will be used in particular in a proportion of from 0.1 to 2% by weight, more particularly about 1%, relative to the total solution.
  • R 3 ethyl
  • the compounds of formula (I) may be prepared according to one or other of the processes described in patent applications WO-A-87/3781, 93/6089, 94/21606 or European patent application EP-A-0,295,117, or any other process which falls within the competence of a specialist skilled in the art of chemical synthesis.
  • 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.
  • 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.
  • 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, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, in particular N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.
  • acetyltributyl citrate fatty acid esters such as the dimethyl ester, diis
  • 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 particular 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, polydiorganosiloxane oils, in particular polydimethylsiloxane (PDMS) oils, for example those containing silanol functionalities, or a 45V2 oil,
  • PDMS polydimethylsiloxane
  • 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 dioctylsulphosuccinate; 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 cationic surfactants which can be used,
  • nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated, in particular polysorbate 80, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide,
  • sorbitan esters which are optionally polyoxyethylenated, in particular polysorbate 80, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated
  • amphoteric surfactants such as the substituted lauryl compounds of betaine
  • the solvent will be used in proportion with the concentration of the compound I and its solubility in this solvent.
  • 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 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 Boophilus 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 efficacy, the solution being applied to the animal's back, preferably along the line of the back at one or more points.
  • 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.
  • 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.
  • the process may also consist in combining these two embodiments, namely the first followed by the second.
  • the efficacy 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.
  • solutions according to the invention may be applied using any means known per se, preferably using an applicator gun or a metering flask.
  • the aim of the method is not therapeutic and is, in 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 Boophilus microplus, and sheep blowfly and lice.
  • the use according to the invention is directed towards producing skin solutions as described above.
  • FIG. 1 is a graph showing the efficacy, 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 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;
  • FIG. 3 compares the efficacy 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.
  • Compound A is dissolved in the solvent before being mixed with the other ingredients.
  • a placebo was prepared, which differed from the skin solutions according to the invention in that it contained no compound A.
  • the dose volume was applied along the line of the animal's back, from the head to the base of the tail.
  • Table 2 indicates, for each group, the weight of the animals, the dose of skin solution received and the dose of active substance applied.
  • FIGS. 2 and 3 demonstrate the total efficacy of the skin solution according to the invention.
  • composition of these solutions is the same as for the above examples.
  • the cattle were preinfested so as to have all of the stages of Boophilus microplus present (infestation with 5,000 larvae, 22 days, 15 days and 8 days before application of the skin solution).

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Plant Pathology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

The direct pour-on skin solution intended to eliminate parasites, in particular Boophilus microplus, from cattle and sheep comprises from 0.05 to 25%, preferably from 0.05 to 10%, and in particular from 0.1 to 2% weight/volume, relative to the total solution, of a compound of formula (I):
Figure US20020081327A1-20020627-C00001
in a formulation at low volume, designed to release the compound (I) onto the skin and the hairs for a contact action against parasites.

Description

  • 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. [0001]
  • 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. [0002]
  • Cattle and sheep are affected by a large number of parasites. [0003]
  • The main ones are ticks of the genus Boophilus, among which mention may be made of the species [0004] microplus (cattle tick), decoloratus and anulatus.
  • The other main parasites of cattle and sheep are indicated in order of decreasing importance: [0005]
  • myiases such as [0006] Dermatobia hominis (known as Berne in Brazil) and Cochlyomia hominivorax (greenbottle); sheep myiases such as Lucilia sericata, Lucilia cuprina (known as blowfly strike in Australia, 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 [0007] Haematobia irritans (horn fly).
  • lice such as [0008] Linognathus vitulorum, etc.
  • galls such as [0009] Sarcoptes scabiei and Psoroptes ovis.
  • Ticks, in particular [0010] Boophilus microplus, are very closely attached to the pasture in which they live and are particularly difficult to control.
  • There is at the present time no truly effective method for controlling ticks, and less still an effective way of controlling the set of parasites indicated above. [0011]
  • 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 [0012] Boophilus microplus, 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, percutaneous and topical routes. Topical administration comprises, in particular, oral formulations, baits, dietary supplements, skin solutions (pour-on), solutions for spraying (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 29I 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.
  • EP-A-296,381 also describes pyrazole compounds having insecticidal activity in the field of agriculture, public health and veterinary medicine. [0013] 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 effective means which is entirely suitable for controlling the parasites of cattle and sheep, in particular ticks, most particularly [0014] Boophilus 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 [0015] 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 [0016] 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 controlling these parasites under the conditions in which these animals are reared.
  • Another aim of the invention is to provide such a formulation which has a long period of efficacy, preferably longer than or equal to two months. [0017]
  • Another aim of the invention is to provide such a formulation which is quick and easy to use and entirely compatible with use on herds or flocks containing a large number of animals. [0018]
  • Another aim of the invention is to provide such a formulation 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. [0019]
  • The subject of the present invention is thus a direct pour-on skin solution, intended to eliminate parasites from cattle and sheep, most particularly ticks, especially [0020] Boophilus 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)
    Figure US20020081327A1-20020627-C00002
  • in which: [0021]
  • R[0022] 1 is CN or methyl or a halogen atom;
  • R[0023] 2 is S(O)nR3 or 4,5-dicyanoimidazol-2-yl or haloalkyl;
  • R[0024] 3 is alkyl or haloalkyl;
  • R[0025] 4 represents a hydrogen or halogen atom; or a radical NR5R6, S(O)mR7, C(O)R7, C(O)O—R7, alkyl, haloalkyl or OR8 or a radical —N═C(R9)(R10) ;
  • R[0026] 5 and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)rCF3 radical; or R5 and R6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur;
  • R[0027] 7 represents an alkyl or haloalkyl radical;
  • R[0028] 8 represents an alkyl or haloalkyl radical or a hydrogen atom;
  • R[0029] 9 represents an alkyl radical or a hydrogen atom;
  • R[0030] 10 represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, —O-alkyl, —S-alkyl, cyano or alkyl;
  • R[0031] 11 and R12 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO2;
  • R[0032] 13 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; [0033]
  • X represents a trivalent nitrogen atom or a radical C—R[0034] 12, the other three valency positions of the carbon atom forming part of the aromatic ring;
  • with the proviso that, when R[0035] 1 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—C1;
  • in a formulation at low volume, designed to release the compound (I) onto the skin and the hairs for a contact action against parasites. [0036]
  • Preferably, in formula (I), [0037]
  • R[0038] 1 is CN or methyl;
  • R[0039] 2 is S(O)nR3;
  • R[0040] 3 is alkyl or haloalkyl;
  • R[0041] 4 represents a hydrogen or halogen atom; or a radical NR5R6, S(O)mR7, C(O)R7, alkyl, haloalkyl or OR8 or a radical —N═C(R9)(R10);
  • R[0042] 5 and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl or S(O)rCF3 radical; or R5 and R6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur;
  • R[0043] 7 represents an alkyl or haloalkyl radical;
  • R[0044] 8 represents an alkyl or haloalkyl radical or a hydrogen atom;
  • R[0045] 9 represents an alkyl radical or a hydrogen atom;
  • R[0046] 10 represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, —O-alkyl, —S-alkyl, cyano or alkyl;
  • R[0047] 11 and R12 represent, independently of each other, a hydrogen or halogen atom;
  • R[0048] 13 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; [0049]
  • X represents a trivalent nitrogen atom or a radical C—R[0050] 12, the other three valency positions of the carbon atom forming part of the aromatic ring;
  • with the proviso that, when R[0051] 1 is methyl, then R3 is 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%. [0052]
  • 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. [0053]
  • The compound acts by simple contact, the parasite becoming impregnated with the compound on contact with the hairs and the skin. [0054]
  • This thereby affords, 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 efficacy, as well as a period of efficacy, which are suited to this type of rearing. [0055]
  • By working on the concentration of compound (I), in particular of compound A, solutions having noteworthy activities are obtained with, in particular, two months of efficacy against [0056] Boophilus microplus, this result never before having been achieved. Moreover, the solution according 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 diffuses 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 protected in the case of passage through water or exposure to rain. [0057]
  • The dose of compound of formula (I) is preferably 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. [0058]
  • The compounds of formula (I) in which R[0059] 1 is CN will be selected most particularly. The compounds in which R2 is S(O)nR3, 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 R[0060] 1 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 R[0061] 5 and R6, as well as with the nitrogen atom to which R5 and R6 are attached, may be generally a cycle of 5, 6 or 7 links.
  • A most particularly preferred compound of the formula (I) in the invention is 1-[2,6-Cl[0062] 2 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 proportion 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: [0063]
  • 1−n=0, [0064]
  • 2−n=1, [0065]
  • R[0066] 3=CF3
  • R[0067] 3=ethyl.
  • The compounds of formula (I) may be prepared according to one or other of the processes described in patent applications WO-A-87/3781, 93/6089, 94/21606 or European patent application EP-A-0,295,117, or any other process which falls within the competence of a specialist skilled in the art of chemical synthesis. For the chemical preparation of the products of the invention, a person skilled in the art is considered as having at his or her disposal, inter alia, all the contents of “Chemical Abstracts” and the documents cited therein. [0068]
  • It is not departing from the scope of the present invention to incorporate other insecticides into the solution according to the present invention. [0069]
  • 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. [0070]
  • 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, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, in particular N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents. [0071]
  • As vehicle or diluent, mention may be made in particular of: [0072]
  • 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. [0073]
  • An emollient and/or spreading and/or film-forming agent will preferably be added, this agent being selected in particular from: [0074]
  • polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils, in particular polydimethylsiloxane (PDMS) oils, for example those containing silanol functionalities, or a 45V2 oil, [0075]
  • 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 dioctylsulphosuccinate; fatty acids, in particular those derived from coconut oil, [0076]
  • cationic surfactants such as water-soluble quaternary ammonium salts of formula N[0077] +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 cationic surfactants which can be used,
  • amine salts of formula N[0078] +R′R″R′″ in which the radicals R are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is among the cationic surfactants which can be used,
  • nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated, in [0079] particular polysorbate 80, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; 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 the substituted lauryl compounds of betaine; [0080]
  • or a mixture of at least two of these agents. [0081]
  • The solvent will be used in proportion with the concentration of the compound I and its solubility in this solvent. [0082]
  • 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. [0083]
  • The vehicle makes up the difference to 100%. [0084]
  • The emollient is preferably used in a proportion of from 0.1 to 10%, in particular from 0.25 to 5%, by volume. [0085]
  • The subject of the present invention is also a process for the elimination of parasites, in particular [0086] Boophilus 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 efficacy, 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. [0087]
  • 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. [0088]
  • Obviously, the process may also consist in combining these two embodiments, namely the first followed by the second. [0089]
  • In all cases, the efficacy advantageously makes it possible to stop any [0090] 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 applicator gun or a metering flask. [0091]
  • The aim of the method is not therapeutic and is, in 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. [0092]
  • 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. [0093]
  • 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 [0094] Boophilus microplus, and sheep blowfly and lice.
  • The use according to the invention is directed towards producing skin solutions as described above.[0095]
  • 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, with reference to the attached drawings in which: [0096]
  • FIG. 1 is a graph showing the efficacy, against [0097] 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 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 [0098]
  • FIG. 3 compares the efficacy 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.[0099]
    • EXAMPLE 1
  • Preparation of the Solutions According to the Invention [0100]
    Ingredient Function Amount
    Compound A active substance  x g
    polyoxypropylene 15 stearyl ether emollient  5 g
    acetyl tributyl citrate solvent 30 g
    soybean oil diluent qs 100 ml
  • Compound A is dissolved in the solvent before being mixed with the other ingredients. [0101]
    • EXAMPLE 2
  • Study of the efficacy of skin solutions according to the invention containing, respectively, 0.25, 0.50 and 1% compound A to combat [0102] Boophilus microplus.
  • The study was performed on 16 young male castrated Herefords (weight ranging between 114 and 172 kg). [0103]
  • Three skin solutions according to Example 1 were prepared: [0104]
  • 1. 1% compound A [0105]
  • 2. 0.5% compound A [0106]
  • 3. 0.25% compound A [0107]
  • A placebo was prepared, which differed from the skin solutions according to the invention in that it contained no compound A. [0108]
  • In the studies, 1 ml of skin solution or of placebo were used per 10 kg of animal weight. [0109]
  • The dose volume was applied along the line of the animal's back, from the head to the base of the tail. [0110]
  • Between days −24 and −1, the animals were artificially infested on 11 occasions with 2,500 [0111] 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 [0112] day 0, the animals receive one of the skin solutions or the placebo.
  • Before the skin solutions or the placebo are applied, the number of ticks present on the various animals in the different groups are counted. [0113]
  • The following table indicates the values recorded, the weight of the animals and the dose of skin solution or of placebo which will be applied to each of these animals. [0114]
    Number of Weight
    Group Animal No. ticks (in kg) Dose (ml)
    1.00% 94 588 134 13.4
    43 470 140 14.0
    47 300 154 15.4
    39 254 160 16.0
    0.50% 34 706 145 14.5
    99 452 143 14.3
    48 375 114 11.4
    45 201 153 15.3
    0.25% 40 510 148 14.8
    92 453 144 14.4
    41 432 155 15.5
    36 236 171 17.1
    Placebo 96 627 150 15.0
    44 482 144 14.4
    93 315 140 14.0
    97 292 172 17.2
  • The blood-engorged female ticks which become detached are included in the count. The results are indicated in FIG. 1. [0115]
  • A dose-dependent effect is obtained with 100% efficacy for the skin solution according to the invention containing 1% compound A. The less-concentrated solutions nevertheless give noteworthy results. [0116]
  • The great rapidity of action of the solutions according to the invention is also noted, the 1% solution allowing [0117] Boophilus microplus to be totally eliminated in less than 2 days.
    • EXAMPLE 3
  • Comparison of efficacy between a skin solution according to the invention containing 1% compound A and a skin solution containing 1% flumethrin. [0118]
  • Animals of the same breed as those in Example 1 were used. [0119]
  • On [0120] day 0, the groups are treated with:
  • skin solution containing 1% compound A [0121]
  • skin solution containing 1% flumethrin (mineral oil and ethylhexyl alcohol excipient) [0122]
  • placebo (excipient identical to the solution according to the invention) [0123]
  • Table 2 below indicates, for each group, the weight of the animals, the dose of skin solution received and the dose of active substance applied. [0124]
    Group Animal No. Weight Dose (ml) Dose (mg/kg)−)
    1% 719 141 14.1 1
    Compound A 709 125 12.5 1
    713 150 15.0 1
    710 136 13.6 1
    703 138 13.8 1
    1% 706 145 14.5 1
    flumethrin 711 136 13.6 1
    715 132 13.2 1
    702 142 14.2 1
    701 127 12.7 1
    Placebo 717 133 13.3 0
    707 133 13.3 0
    704 134 13.4 0
    718 132 13.2 0
    708 143 14.3 0
  • From [0125] day 2 to day 32, the animals receive 5,000 Boophilus microplus larvae three times a week. From day 18 to 64, the blood-engorged female ticks which become detached are collected and counted.
  • The results are indicated in FIGS. 2 and 3, which demonstrate the total efficacy of the skin solution according to the invention. [0126]
    • EXAMPLE 4
  • Study of efficacy over time. [0127]
  • Skin solutions according to the invention containing 0.25, 0.5 or 1% compound A where used in this example. [0128]
  • The composition of these solutions is the same as for the above examples. [0129]
  • The cattle were preinfested so as to have all of the stages of [0130] Boophilus microplus present (infestation with 5,000 larvae, 22 days, 15 days and 8 days before application of the skin solution).
  • After application of the skin solutions, the cattle are again infested with the larvae for 13 weeks, to determine the efficacy of the three concentrations. [0131]
  • The results are reported in Table 3 below: [0132]
    Efficacy index for each
    Weeks of infestation concentration
    after treatment 0.25% 0.5% 1.0%
    1 97.6 100 100
    2 98.8 100 100
    3 99.7 100 100
    4 99.3 100 100
    5 96.7 92.9 100
    6 98.6 93.2 100
    7 92.4 88.6 99.7
    8 85.8 83.4 100
    9 28.0 37.9 79.8
    10 23.0 41.4 65.3
    11 18.9 55.2 61.5
    12 1.7 37.3 32.2
    13 8.4 48.5 46.4
  • It is thus observed that noteworthy efficacy, which may last for two months or more, is obtained. [0133]

Claims (59)

1. Direct pour-on skin solution intended to eliminate parasites from cattle and sheep, most particularly ticks, especially Boophilus 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):
Figure US20020081327A1-20020627-C00003
in which:
R1 is CN or methyl or a halogen atom;
R2 is S(O)nR3 or 4,5-dicyanoimidazol-2-yl or haloalkyl;
R3 is alkyl or haloalkyl;
R4 represents a hydrogen or halogen atom; or a radical NR5R6, S(O)mR7, C(O)R7, C(O)O—R7, 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)alkyl, alkoxycarbonyl, or S(O)rCF3 radical; or R5 and R6 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, —S-alkyl, cyano or alkyl;
R11 and R12 represent, independently of each other, a hydrogen or halogen atom or optionally CN or NO2;
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—R12, 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 (I) onto the skin and the hairs for a contact action against parasites.
2. Solution according to claim 1, wherein the compound of formula (I) is such that:
R1 is CN or methyl;
R2 is S(O)nR3;
R3 is alkyl or haloalkyl;
R4 represents a hydrogen or halogen atom; or a 1 radical NR5R6, S(O)mR7, C(O)R7, 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)alkyl or S(O)rCF3 radical; or R5 and R6 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, —S-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 r represent, independently of each other, an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a radical C—R2, the other three valency positions of the carbon atom forming part of the aromatic ring;
with the proviso that, when R1 is methyl, then R3 is haloalkyl, R4 is NH2, R11 is Cl, R13 is CF3 and X is N.
3. Solution according to claim 2, wherein the compound of formula (I) is such that R1 is CN.
4. Solution according to claim 2, wherein the compound of formula (I) is such that R13 is haloalkyl.
5. Solution according to claim 2, wherein the compound of formula (I) is such that R13 is CF3.
6. Solution according to claim 2, wherein the compound of formula (I) is such that R2 is S(O)nR3.
7. Solution according to claim 6, wherein n=1, R3 being chosen among the group consisting of CF3, methyl and ethyl.
8. Solution according to claim 6, wherein n=0 and R3 is CF3.
9. Solution according to claim 2, wherein the compound of formula (I) is such that X is C—R12 with R12 being a halogen atom.
10. Solution according to claim 2, wherein the compound of formula (I) is chosen from those in which R1 is CN, R3 is haloalkyl, R4 is NH2, R11 and R12 are, independently of each other, a halogen atom and/or R13 is haloalkyl.
11. Solution according to claim 2, wherein the compound of formula (I) is chosen among the group consisting of the compound A:
1-[2,6-Cl2 4-CF3phenyl]3-CN 4-[SO—CF3] 5-NH2pyrazole, and its derivatives with n=0, R3=CF3 and n=1, R3=ethyl.
12. Solution according to claim 2, wherein the compound of formula is present in a proportion of from 0.05 to 10% weight/volume.
13. Solution according to claim 2, wherein the compound of formula (I) is present in a proportion of from 0.1 to 2%.
14. Solution according to claim 2, wherein the compound of formula (I) is present in a proportion of from 0.25 to 1.5%.
15. Solution according to claim 2, wherein the compound of formula (I) is present in a proportion of about 1%.
16. Solution according to claim 11, wherein the compound of formula is present in a proportion of from 0.05 to 10% weight/volume.
17. Solution according to claim 11, wherein the compound of formula (I) is present in a proportion of from 0.1 to 2%.
18. Solution according to claim 11, wherein the compound of formula (I) is present in a proportion of from 0.25 to 1.5%.
19. Solution according to claim 11, wherein the compound of formula (I) is present in a proportion of about 1%.
20. Solution according to claim 2, wherein it comprises a solvent for the compound (I) and a diluent, optionally an emollient.
21. Solution according to claim 20, wherein the solvent is selected from the group consisting of:
acetyl tributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, in particular N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.
22. Solution according to claim 20, wherein the diluent is selected from the group consisting 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, medium-chain (C8 to C12 in particular).
23. Solution according to claim 20, wherein the emollient is selected from the group consisting of:
polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils,
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 dioctylsulphosuccinate; 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 cationic surfactants which can be used,
amine salts of formula N−R′R″R′″ in which the radicals R are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is among the cationic surfactants which can be used,
nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated, in particular polysorbate 80, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-15-stearyl ether; 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 the substituted lauryl compounds of betaine;
or a mixture of at least two of these agents.
24. Solution according to claim 2, wherein it is an oily solution.
25. Solution according to claim 2, wherein it is designed to ensure protection over a period longer than or equal to 2 months.
26. Solution according to claim 2, wherein it is designed to ensure total elimination of Boophilus microplus in less than 2 days.
27. Process for the elimination of external parasites from cattle and sheep, most particularly ticks, especially Boophilus microplus in cattle and lice and blowfly in sheep, wherein one applies on the cattle or sheep a direct pour-on skin solution comprising from 0.05 to 25% weight/volume, relative to the total solution, of a compound of formula (I) below:
Figure US20020081327A1-20020627-C00004
in which:
R1 is CN or methyl or a halogen atom;
R2 is S(O)nR3 or 4,5-dicyanoimidazol-2-yl or haloalkyl;
R3 is alkyl or haloalkyl;
R4 represents a hydrogen or halogen atom; or a radical NR5R6, S(O)mR7, C(O)R7, C(O)O—R7, 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)alkyl, alkoxycarbonyl, or S(O)rCF3 radical; or R5 and R6 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, —S-alkyl, cyano or alkyl;
R11 and R12 represent, independently of each other, a hydrogen or halogen atom or optionally CN or NO2;
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—R12, 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;
the compound (I) being formulated in a direct pour-on skin solution comprising the compound (I) in a low volume, designed to release the compound (I) onto the skin and the hairs for a contact action against the parasites.
28. Process according to claim 27, wherein the solution is applied in a volume of 5 to 20 ml per 100 kg of animal.
29. Process according to claim 27, wherein the solution is applied in a volume of about 10 ml per 100 kg of animal.
30. Process according to claim 27, wherein the solution is applied with a total volume of from 10 to 150 ml per animal.
31. Process according to claim 27, wherein the compound of formula (I) is such that:
R1 is CN or methyl;
R2 is S(O)nR3;
R3 is alkyl or haloalkyl;
R4 represents a hydrogen or halogen atom; or a radical NR R6, S(O)mR7, C(O)R7, 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)alkyl or S(O)rCF3 radical; or R5 and R6 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, —S-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 r represent, independently of each other, an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a radical C—R12, the other three valency positions of the carbon atom forming part of the aromatic ring;
with the proviso that, when R1 is methyl, then R3 is haloalkyl, R4 is NH2, R11 is Cl, R13 is CF3 and X is N.
32. Process according to claim 31, wherein the compound of formula (I) is such that R1 is CN.
33. Process according to claim 31, wherein the compound of formula (I) is such that R13 is haloalkyl.
34. Process according to claim 31, wherein the compound of formula (I) is such that R13 is CF3.
35. Process according to claim 31, wherein the compound of formula (I) is such that R2 is S(O)nR3.
36. Process according to claim 35, wherein n=1 and R3 is chosen among the group consisting of CF3, methyl and ethyl.
37. Process according to claim 35, wherein n=0, R3 preferably being CF3.
38. Process according to claim 31, wherein the compound of formula (I) is such that X is C—R12 with R12 being a halogen atom.
39. Process according to claim 31, wherein the compound of formula (I) is such that R1 is CN, R3 is haloalkyl, R4 is NH2, R11 and R12 are, independently of each other, a halogen atom and/or R13 is haloalkyl.
40. Process according to claim 31, wherein the compound of the formula (I) is chosen among the group consisting of compound A:
1-[2,6-Cl2 4-CF3phenyl]3-CN 4-[SO—CF3] 5-NH2pyrazole, and its derivatives with n=0, R3=CF3 and n=1, R3=ethyl.
41. Process according to claim 31, wherein the compound of formula is present in a proportion of from 0.05 to 10% weight/volume.
42. Process according to claim 31, wherein the compound of formula (I) is present in a proportion of from 0.1 to 2%.
43. Process according to claim 31, wherein the compound of formula (I) is present in a proportion of from 0.25 to 1.5%.
44. Process according to claim 31, wherein the compound of formula (I) is present in a proportion of about 1%.
45. Process according to claim 40, wherein the compound of formula is present in a proportion of from 0.05 to 10% weight/volume.
46. Process according to claim 40, wherein the compound of formula (I) is present in a proportion of from 0.1 to 2%.
47. Process according to claim 40, wherein the compound of formula (I) is present in a proportion of from 0.25 to 1.5%.
48. Process according to claim 40, wherein the compound of formula (I) is present in a proportion of about 1%.
49. Process according to claim 31, wherein one applies the solution in a proportion of from 0.1 to 2 mg/kg.
50. Process according to claim 31, wherein one applies the solution in a proportion of from 0.25 to 1.5 mg/kg.
51. Process according to claim 31, wherein one applies the solution in a proportion of about 0.1 mg/kg.
52. Process according to claim 40, wherein one applies the solution in a proportion of from 0.1 to 2 mg/kg.
53. Process according to claim 40, wherein one applies the solution in a proportion of from 0.25 to 1.5 mg/kg.
54. Process according to claim 40, wherein one applies the solution in a proportion of about 0.1 mg/kg.
55. Process according to claim 31, wherein one applies the solution to the animals in pasture or before they arrive in pasture.
56. Process according to claim 31, wherein one applies the solution every two months.
57. Process according to claim 31, wherein one applies the solution to the animals before they arrive in the Feed Lot, this application being the final one before the animal is slaughtered.
58. Process according to claim 31, wherein when applied topically locally onto the animal's skin, the solution is designed to ensure protection for at least two months, in particular against Boophilus microplus.
59. Process according to claim 31, wherein the solution is designed to ensure total elimination of Boophilus microplus in less than 2 days.
US09/450,186 1996-03-29 1999-11-29 Direct pour-on antiparasitic skin solution and methods for treating, preventing and controlling myasis Expired - Lifetime US6413542B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09/450,186 US6413542B1 (en) 1996-03-29 1999-11-29 Direct pour-on antiparasitic skin solution and methods for treating, preventing and controlling myasis
US10/120,691 US6797724B2 (en) 1996-03-29 2002-04-11 Direct spot-on antiparasitic skin solution for domestic animals

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
FR9604209A FR2746595B1 (en) 1996-03-29 1996-03-29 SKIN SOLUTION FOR DIRECT DEPOSIT FOR PEST CONTROL IN CATTLE AND SHEEP
FR9604209 1996-03-29
US69217896A 1996-08-05 1996-08-05
FR9610312A FR2752525B1 (en) 1996-08-20 1996-08-20 METHOD FOR CONTROLLING MYIA OF CATTLE AND SHEEP HERBS AND COMPOSITIONS FOR CARRYING OUT SAID METHOD
FR9610312 1996-08-20
FR9703708A FR2747015B1 (en) 1996-03-29 1997-03-26 SKIN SOLUTION FOR DIRECT DEPOSIT FOR PEST CONTROL IN CATTLE AND SHEEP
FR9703708 1997-03-26
US09/051,693 US6001384A (en) 1996-08-20 1997-08-19 Method for fighting against myiasis affecting cattle and sheep populations and compositions for implementing same
US08/933,016 US6010710A (en) 1996-03-29 1997-09-18 Direct pour-on skin solution for antiparasitic use in cattle and sheep
US09/450,186 US6413542B1 (en) 1996-03-29 1999-11-29 Direct pour-on antiparasitic skin solution and methods for treating, preventing and controlling myasis

Related Parent Applications (3)

Application Number Title Priority Date Filing Date
PCT/FR1997/001504 Continuation-In-Part WO1998007423A1 (en) 1996-08-20 1997-08-19 Method for fighting against myases affecting cattle and sheep populations and compositions for implementing same
US09/051,693 Continuation-In-Part US6001384A (en) 1996-03-29 1997-08-19 Method for fighting against myiasis affecting cattle and sheep populations and compositions for implementing same
US08/933,016 Continuation-In-Part US6010710A (en) 1996-03-29 1997-09-18 Direct pour-on skin solution for antiparasitic use in cattle and sheep

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US08/933,016 Continuation-In-Part US6010710A (en) 1996-03-29 1997-09-18 Direct pour-on skin solution for antiparasitic use in cattle and sheep
US10/120,691 Division US6797724B2 (en) 1996-03-29 2002-04-11 Direct spot-on antiparasitic skin solution for domestic animals

Publications (2)

Publication Number Publication Date
US20020081327A1 true US20020081327A1 (en) 2002-06-27
US6413542B1 US6413542B1 (en) 2002-07-02

Family

ID=27546420

Family Applications (2)

Application Number Title Priority Date Filing Date
US09/450,186 Expired - Lifetime US6413542B1 (en) 1996-03-29 1999-11-29 Direct pour-on antiparasitic skin solution and methods for treating, preventing and controlling myasis
US10/120,691 Expired - Lifetime US6797724B2 (en) 1996-03-29 2002-04-11 Direct spot-on antiparasitic skin solution for domestic animals

Family Applications After (1)

Application Number Title Priority Date Filing Date
US10/120,691 Expired - Lifetime US6797724B2 (en) 1996-03-29 2002-04-11 Direct spot-on antiparasitic skin solution for domestic animals

Country Status (1)

Country Link
US (2) US6413542B1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090137524A1 (en) * 2003-12-18 2009-05-28 Denis Billen Substituted arylpyrazoles
US9457088B2 (en) 2012-02-23 2016-10-04 Merial, Inc. Topical compositions comprising fipronil and permethrin and methods of use

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2739255B1 (en) * 1995-09-29 1998-09-04 Rhone Merieux PEST CONTROL COMPOSITION FOR THE TREATMENT AND PROTECTION OF PETS
US7262214B2 (en) 2003-02-26 2007-08-28 Merial Limited 1-N-arylpyrazole derivatives in prevention of arthropod-borne and mosquito-borne diseases
MXPA05010659A (en) 2003-04-04 2005-12-12 Merial Ltd Topical anthelmintic veterinary formulations.
US7531186B2 (en) 2003-12-17 2009-05-12 Merial Limited Topical formulations comprising 1-N-arylpyrazole derivatives and amitraz
US7671034B2 (en) 2003-12-19 2010-03-02 Merial Limited Stabilized formulation of ivermectin feed premix with an extended shelf life
WO2006007630A1 (en) * 2004-07-22 2006-01-26 Jurox Pty Ltd Aqueous insecticidal/parasiticide formulation
AU2007323077A1 (en) * 2006-11-21 2008-05-29 Mitam Ltd. Formulations of entomopathogenic fungi for insect control
US9173728B2 (en) 2008-11-19 2015-11-03 Merial Inc. Multi-cavity container having offset indentures for dispensing fluids
JP5755143B2 (en) 2008-11-19 2015-07-29 メリアル リミテッド Compositions comprising arylpyrazole and / or formamidine, methods and uses thereof
WO2010070210A1 (en) * 2008-12-16 2010-06-24 Virbac Pharmaceutical composition containing an n-phenylpyrazole derivative, and use thereof for preparing a topical veterinary drug for flea control
UA108641C2 (en) 2010-04-02 2015-05-25 PARASITICID COMPOSITION CONTAINING FOUR ACTIVE AGENTS AND METHOD OF APPLICATION
US20120265159A1 (en) 2011-04-12 2012-10-18 Velcera, Inc. Device for storing and dispensing a medicament
KR102066757B1 (en) 2011-11-17 2020-01-15 뵈링거 잉겔하임 애니멀 헬스 유에스에이 인코포레이티드 Compositions comprising an aryl pyrazole and a substituted imidazole, methods and uses thereof
MX373388B (en) 2014-01-20 2020-05-12 Boehringer Ingelheim Animal Health Usa Inc TOPICAL DELIVERY FORMULATION.
WO2016069983A1 (en) 2014-10-31 2016-05-06 Merial, Inc. Parasiticidal composition comprising fipronil
US9943387B2 (en) 2016-06-29 2018-04-17 International Business Machines Corporation Unmanned aerial vehicle-based system for livestock parasite amelioration

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3355736B2 (en) 1993-12-20 2002-12-09 住友化学工業株式会社 Insecticide, acaricide composition
GB8713768D0 (en) 1987-06-12 1987-07-15 May & Baker Ltd Compositions of matter
US5232940A (en) 1985-12-20 1993-08-03 Hatton Leslie R Derivatives of N-phenylpyrazoles
GB8816915D0 (en) 1988-07-15 1988-08-17 May & Baker Ltd New compositions of matter
CA2036148A1 (en) 1990-06-29 1991-12-30 Hiroki Tomioka A 1-phenylimidazole derivative and its production and use
JP3715994B2 (en) 1993-12-21 2005-11-16 住友化学株式会社 Pest control agent
US5801189A (en) 1995-04-05 1998-09-01 Rhone-Poulenc Agriculture Limited Method for combating insects
US6010710A (en) 1996-03-29 2000-01-04 Merial Direct pour-on skin solution for antiparasitic use in cattle and sheep
FR2752525B1 (en) 1996-08-20 2000-05-05 Rhone Merieux METHOD FOR CONTROLLING MYIA OF CATTLE AND SHEEP HERBS AND COMPOSITIONS FOR CARRYING OUT SAID METHOD
US5885607A (en) 1996-03-29 1999-03-23 Rhone Merieux N-phenylpyrazole-based anti-flea and anti-tick external device for cats and dogs
DE19650197A1 (en) 1996-12-04 1998-06-10 Bayer Ag 3-thiocarbamoylpyrazole derivatives
WO1998039972A1 (en) 1997-03-11 1998-09-17 Rhone-Poulenc Agro Pesticidal combination
US6256430B1 (en) * 1998-11-23 2001-07-03 Agere Systems Inc. Optical crossconnect system comprising reconfigurable light-reflecting devices

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090137524A1 (en) * 2003-12-18 2009-05-28 Denis Billen Substituted arylpyrazoles
US7960426B2 (en) 2003-12-18 2011-06-14 Pfizer Limited Substituted arylpyrazoles
US20110196011A1 (en) * 2003-12-18 2011-08-11 Pfizer Limited Substituted arylpyrazoles
US8084486B2 (en) 2003-12-18 2011-12-27 Pfizer Limited Substituted arylpyrazoles
US9457088B2 (en) 2012-02-23 2016-10-04 Merial, Inc. Topical compositions comprising fipronil and permethrin and methods of use
US9949953B2 (en) 2012-02-23 2018-04-24 Merial Inc. Topical compositions comprising fipronil and permethrin and methods of use
US10646473B2 (en) 2012-02-23 2020-05-12 Boehringer Ingelheim Animal Health USA Inc. Topical compositions comprising fipronil and permethrin and methods of use

Also Published As

Publication number Publication date
US6797724B2 (en) 2004-09-28
US20020155147A1 (en) 2002-10-24
US6413542B1 (en) 2002-07-02

Similar Documents

Publication Publication Date Title
US6010710A (en) Direct pour-on skin solution for antiparasitic use in cattle and sheep
US6001384A (en) Method for fighting against myiasis affecting cattle and sheep populations and compositions for implementing same
US6797724B2 (en) Direct spot-on antiparasitic skin solution for domestic animals
US6395765B1 (en) Antiparasitic composition for the treatment and protection of pets
KR20150085091A (en) Local topical administration formulations containing indoxacarb
WO2010026370A1 (en) A topical ectoparasiticide composition
AT506843B1 (en) DIRECTLY ADAPTABLE TO THE SKIN TO REMOVE PARASITES IN BOVINE ANIMALS AND SHEEP
EP0915654B1 (en) Process and composition for the antiparasitic treatment of the surroundings of animals
AU763484B2 (en) Direct pour-on skin solution for antiparasitic use in cattle and sheep
AU2003257646B2 (en) Direct pour-on skin solution for anitparasitic use in cattle and sheep
US20060046988A1 (en) Methoprene formulations for the control of tick infestations
US6524603B1 (en) Process and composition for the antiparasitic treatment of the surroundings of animals
MXPA97009092A (en) Cutaneous solution for direct deposit intended for the elimination of parasites in cattle and sheep, use of a composite in such solution and treatment procedure for cattle and sheep with such solution
SE531435C2 (en) Insecticide compound against fleas in mammals, especially dogs and cats
MXPA98003000A (en) Method for fighting against myases affecting cattle and sheep populations and compositions for implementing same

Legal Events

Date Code Title Description
AS Assignment

Owner name: MERIAL, FRANCE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ETCHEGARAY, JEAN-PIERRE;JEANNIN, PHILIPPE;REEL/FRAME:010626/0930

Effective date: 20000111

AS Assignment

Owner name: MERIAL, FRANCE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ETCHEGARAY, JEAN-PIERRE;JEANNIN, PHILIPPE;REEL/FRAME:010691/0657

Effective date: 19960805

STCF Information on status: patent grant

Free format text: PATENTED CASE

CC Certificate of correction
FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

FEPP Fee payment procedure

Free format text: PAYER NUMBER DE-ASSIGNED (ORIGINAL EVENT CODE: RMPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 8

FPAY Fee payment

Year of fee payment: 12