• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    A method and composition in particular for controlling fleas in small mammals characterized in that the composition comprises at least one insecticide of the 1N-arylpyrazole type, especially fipronil, and on the other hand at least one compound of the insect growth regulating (IGR) type in doses and conditions which are parasitically effective against fleas in a liquid vehicle acceptable to the animal and convenient for local application to the skin, preferably located to a small surface area.
    公开号:DK201370137A
    申请号:DKP201370137
    申请日:2013-03-11
    公开日:2013-03-11
    发明作者:Philippe Jeannin
    申请人:Merial Sas；
    IPC主号:
    专利说明:

    The present invention relates to an improvement in the methods for controlling fleas in mammals and in particular to fleas in cats and dogs. The invention also relates to a novel composition for this use, which is based on the synergistic combination of parasiticides already known. Finally, the invention relates to the use of such already known parasiticides for the preparation of such a composition.
    A novel class 1-N-arylpyrazole-based insecticide has been disclosed in EP Patent A-295,217 and A-352,944. The compounds of the classes defined in these patents are highly active, and one of these compounds 1- [2,6-Cl2-4-CF3-phenyl] -3-CN-4- [SO-CF3] -5-NH2-pyrazole , whose common name is fipronil, has been found to be particularly effective against not only crop parasites but also against mammalian ectoparasites and in particular, but not exclusively, fleas, mites, flies and myiasis.
    Compounds having an ovicidal and / or larvicidal effect on the immature stages of various ectoparasites are already known from e.g. U.S. Patent A-5,439,924. Among these compounds are insect growth regulatory (IGR) compounds which act either by blocking the development of the immature stages (eggs and larvae) to adult stages or by inhibiting the synthesis of chitin.
    Furthermore, FR patent specification A-2,713,889, which generally describes the combination of at least one compound of the insect growth regulatory (IGR) type comprising compounds with juvenile hormone activity and chitin synthesis inhibitors with at least one of three N-aryldiazole compounds, especially fipronil, is known to combat many harmful insects belonging to highly varied orders.
    The compositions can be used in very different forms, without specifying what uses, e.g. veterinary, health or plant protection, these various forms are determined or to which parasites to which they are designated respectively.
    The only use which is likely to be veterinary is associated with the example of the preparation of a pesticide collar which is a slow release formulation.
    According to the invention, an improvement is made in the methods for controlling fleas in small mammals and especially in cats and dogs.
    In particular, the invention aims to use already known parasiticides to produce a composition which is highly active against the fleas of these animals.
    Finally, the object of the invention is to provide a novel composition which is thus manufactured and especially intended for the control of fleas.
    The term fleas is to be understood in the sense of the present invention as referring to all the common or random species of parasitic fleas of the order Siphonaptera and especially the species Ctenocephalides, especially C. felis and C. canis, rat fleas (Xenopsylla cheopis) and human fleas (Pulex irritans).
    The very high efficiency of the method and of the composition of the invention implies not only high immediate efficiency but also very long-lasting efficiency after the animal has been treated.
    The invention has for its object to provide a method for controlling fleas in small mammals and especially in cats and dogs for a long period of time, characterized in that the animal is treated locally on the skin, preferably localized to a small surface area (spot -on administration), to apply at least one compound (A) of formula (I) in parasitically effective doses and ratios
    in which:
    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 halogenoalkyl; R 3 is alkyl or haloalkyl; R4 represents a hydrogen or halogen atom; or an NR5R6, S (O) mR7-, C (O) R7-, C (O) 0 -R7-, alkyl, haloalkyl or OR8 group or an -N = C (R9) (R10) - group; R5 and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, alkoxycarbonyl or S (O) r-CF3 group; or R5 and R6 together may form a divalent alkyl group which may be interrupted by one or two divalent heteroatoms such as oxygen or sulfur; R7 represents an alkyl or haloalkyl group; R8 represents an alkyl or haloalkyl group or a hydrogen atom;
    Rg represents an alkyl group or a hydrogen atom;
    R 1 represents a phenyl or heteroaryl group optionally substituted by one or more halogen atoms, or groups such as -OH, -O-alkyl, -S-alkyl, cyano or alkyl;
    Ru and R 12 independently each represent a hydrogen or halogen atom or optionally CN or NO 2; R13 represents a halogen atom or a haloalkyl, halogenoalkoxy, S (O) qCF3 or SF5 group; m, n, q and r are each independently an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a C-R12 group, wherein the other three valence positions of the carbon atom form part of the aromatic ring; with the proviso that when R 1 is methyl, R 3 is either haloalkyl, R 4 is NH 2, Ru is Cl, R 13 is CF 3 and X is N; or R2 is 4,5-dicyanoimidazol-2-yl, R4 is Cl, Ru is Cl, Ri3 is CF3 and X is = C-C1; and, on the other hand, at least one compound (B) of the insect growth regulatory (IGR) type in a liquid vehicle acceptable to the animal and suitable for local application to the skin.
    In formula (I), it is preferred that:
    R 1 is CN or methyl; R 2 is S (O) n R 3; R 3 is alkyl or haloalkyl; R4 represents a hydrogen or halogen atom; or an NR 5 R 6, S (O) m R 7, C (O) R 7, alkyl, haloalkyl or OR 6 group or an -N = C (R 9) (R 10) group; R5 and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C (O) alkyl or S (O) r-CF3 group; or R 5 and R 5 together may form a divalent alkylene group which may be interrupted by one or two divalent heteroatoms such as oxygen or sulfur; R7 represents an alkyl or haloalkyl group;
    Rg represents an alkyl or haloalkyl group or a hydrogen atom; R9 represents an alkyl group or a hydrogen atom;
    R 10 represents a phenyl or heteroaryl group optionally substituted by one or more halogen atoms or groups such as -OH, -O-alkyl, -S-alkyl, cyano or alkyl;
    Ru and R 12 independently each represent a hydrogen or halogen atom; R13 represents a halogen atom or a haloalkyl, halogenoalkoxy, S (O) qCF3 or SF5 group; m, n, q and r are each independently an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a C-Ri 2 group, wherein the other three valence positions of the carbon atom form part of the aromatic ring; with the proviso that when R 1 is methyl, then R 3 is haloalkyl, R 4 is NH 2, Ru is Cl, Ri 3 is CF 3 and X is N.
    In particular, compounds of formula (I) wherein R 1 is CN are considered. Compounds wherein R 2 is S (O) n R 3, where n is preferably 1, R 3 is preferably CF 3 or alkyl, e.g. methyl or ethyl, or alternatively n is 0 and R 3 is preferably CF 3 as well as those in which X is C-R 12 where R 12 is a halogen atom is also considered. Compounds in which Ru is a halogen atom and those in which R 13 is haloalkyl, preferably CF 3, are also preferred. Advantageously, compounds which combine two or more of these characteristics will be considered within the scope of the present invention.
    A preferred class of compounds of formula (I) consists of such compounds wherein R 1 is CN, R 3 is haloalkyl, R 4 is NH 2, R 8 and R 12 are each independently a halogen atom and / or R 13 is halo alkyl.
    In these compounds, R 3 represents preferably CF 3 or ethyl.
    The alkyl groups in the definition of the compounds of formula (I) generally comprise from 1 to 6 carbon atoms. The ring formed by the divalent alkylene group representing R5 and R6, as well as the nitrogen atom to which R5 and R6 are attached, is generally a 5-, 6- or 7-membered ring.
    A compound of formula (I) which is particularly preferred in the present invention is 1- [2,6-C12-4-CF3-phenyl] -3-CN-4- [SO-CF3] -5-NH2 -pyrazole, whose common name is fipronil.
    The two compounds which differ from the above by the following characteristics: 1- n = 0, R3 = CF3 2- n = 1 R3 = ethyl may also be mentioned.
    In particular, compounds (B) include compounds that mimic juvenile hormones, in particular azadirachtin (Agridyne) diophenolane (Ciba Geigy) phenoxycarb (Ciba Geigy) hydroprene (Sandoz) quinoprene (Sandoz) methoprene (Sandoz) pyriproxyphene (Sumitomo / Mgkid) tetrahydrin ) 4-Chloro-2- (2-chloro-2-methylpropyl) -5- (6-iodo-3-pyridylmethoxy) pyridizin-3 (2H) -one and the chitin synthesis inhibitors, in particular: chlorfluazuron (Ishihara Sangyo) cyromazine (Ciba Geigy) diflubenzuron (Solvay Duphar) fluazuron (Ciba Geigy) flucycloxuron (Solvay Duphar) flufenoxuron (cyanamide) hexaflumuron (Dow Elanco) lufenuron (Ciba Geigy) tebufenozide (Rohm & Haas) teflenz compounds are defined by their international, common name (The Pesticice Manual, 10th ed., 1994, editor Clive Tomlin, United Kingdom).
    As chitin synthesis inhibitors may also be mentioned compounds such as 1- (2,6-difluorobenzoyl) -3- (2-fluoro-4- (trifluoromethyl) phenylurea, 1- (2,6-difluorobenzoyl) -3- (2-fluoro -4- (1,1,2,2-tetrafluoroethoxy) phenylurea and 1- (2,6-difluorobenzoyl) -3- (2-fluoro-4-trifluoromethyl) phenylurea.
    Novaluron (Isagro, Italian company) can also be mentioned as compound (B).
    The preferred compounds (B) are methoprene, pyriproxyphenes, hydroprene, cyromazine, lufenuron and 1- (2,6-difluorobenzoyl) -3- (2-fluoro-4-trifluoromethyl) phenylurea.
    Another preferred compound (B) is additional novaluron.
    It is preferred that the administration of the two types of compounds be parallel and preferably joint.
    It is preferred that the treatment of the invention be performed every two or preferably every three months on cats and dogs.
    Preferably, the treatment is carried out such that a dose of 0.1 to 40 and in particular of 1 to 20 mg / kg for derivative (A) and a dose of 0.1 to 40 and in particular 1 to 30 mg / kg is administered to the animal. kg of compound (B).
    The preferred dosages are from 5 to 15 mg / kg with respect to compound (A) and from 0.5 to 15 mg / kg with respect to preferred compounds (B), or from 10 to 20 mg / kg with respect to the other compounds. compounds (B).
    In another embodiment of the method according to the invention, compounds (A) and (B) can be administered in a temporally separated and divided manner. In this case, it is preferred to allow the administrations to alternate with an interval of e.g. 1 month between two administrations, the first administration being preferably done with compound (A).
    It will be apparent that the dose values thus indicated are average values which may vary over a wide range, since in practice a formulation with specified doses of compound (A) of the derivative of 1-N-phenyl-pyrazole the type and compound (B) will be administered to animals of relatively different weights. As a result, the doses actually administered are often smaller or larger by a factor that may be up to 2, 3 or 4 relative to the preferred dose without causing any toxic risk to the animal in the event of an overdose, while at the same time. a true efficiency of possible lesser duration is maintained in the case of a sub-dose.
    The purpose of this method is non-therapeutic and particularly concerns the purification of the animal's hair and skin by eliminating the parasites present as well as their remnants and excrement. Thus, the treated animals have hair that is more comfortable to look at and touch.
    The invention also relates to such a method for therapeutic purposes which is intended to treat and counteract parasitoses with pathogenic consequences.
    In accordance with the present invention, the method described above can also be used to control ectoparasites, especially blood mites.
    It is also an object of the invention to provide a composition and, in particular, a composition for controlling fleas on small mammals, characterized in that it comprises, on the one hand, at least one compound (A) of formula (I) as set forth above and in on the other hand, at least one compound (B) set forth above in doses and ratios having a parasitic effect on fleas, in a liquid vehicle acceptable to the animal and convenient for local application to the skin, preferably located to a small surface area.
    It is preferred in formula (I) that:
    R 1 is CN or methyl; R 2 is S (O) n R 3; R 3 is alkyl or haloalkyl; R4 represents a hydrogen or halogen atom; or an NR 5 R 6, S (O) m R 7, C (O) R 7, alkyl, haloalkyl or OR 8 group or an -N = C (R 9) (R 10) group; R5 and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C (O) alkyl or S (O) r-CF3 group; or R5 and Rg together may form a divalent alkylene group which may be interrupted by one or two divalent heteroatoms such as oxygen or sulfur; R7 represents an alkyl or haloalkyl group; R8 represents an alkyl or haloalkyl group or a hydrogen atom;
    Rg represents an alkyl group or a hydrogen atom;
    R 10 represents a phenyl or heteroaryl group optionally substituted by one or more halogen atoms or groups such as -OH, -O-alkyl, -S-alkyl, cyano or alkyl;
    Ru and R 12 independently each represent a hydrogen or halogen atom; R13 represents a halogen atom or a haloalkyl, halogenoalkoxy, S (O) qCF3 or SF5 group; m, n, q and r are each independently an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a C-Ri 2 group, wherein the other three valence positions of the carbon atom form part of the aromatic ring; with the proviso that when Rx is methyl, then R3 is haloalkyl, R4 is NH2, Ru is Cl, RX3 is CF3 and X is N.
    In particular, the compounds of formula (I) wherein Rx is CN are considered. Compounds wherein R 2 is S (O) n R 3, where n is preferably 1, R 3 is preferably CF 3 or alkyl, e.g. methyl or ethyl, or alternatively n is 0 and R 3 is preferably CF 3 as well as those in which X is equal to C-RX 2 where R 12 is a halogen atom is also considered. Compounds in which Ru is a halogen atom and those in which R 1 is haloalkyl, preferably CF 3, are also preferred. Within the scope of the present invention, compounds which combine two or more of these characteristics will be advantageously considered.
    A preferred class of compounds of formula (I) consists of such compounds wherein Rx is CN, R3 is haloalkyl, R4 is NH2, Ru and RX2 are each independently a halogen atom and / or RX3 is haloalkyl.
    In these compounds, R 3 preferably represents CF 3 or ethyl.
    A compound of formula (I) which is particularly preferred according to the invention is 1- [2,6-Cl2-4-CF3-phenyl] -3-CN-4- [SO-CF3] -5-NH2-pyrazole .
    The two compounds which differ from the above are characterized by the following characteristics: 1- η = O, R 3 = CF 3 2- n = 1 R 3 = ethyl may also be mentioned.
    The compounds of formula (I) can be prepared according to one of the methods described in patent application WO-A-87/3781, 93/6089, 94/21606 or European patent application EP-A-0.295.117, or any other method which falls within the expertise of a person skilled in chemical synthesis. For the chemical preparation of the products according to the invention, the person skilled in the art is considered to have, inter alia, the complete content of "Chemical Abstracts" and the documents cited therein.
    Among the above-mentioned compounds of the IGR type, methoprene, pyriproxyphenes, hydroprene, cyromazine, lufenuron and 1- (2,6-difluorobenzoyl) -3- (2-fluoro-4-trifluoromethyl) phenylurea are preferred.
    Novaluron is also preferred.
    The weight ratios of the compounds of formula (I) to compound (B) are preferably between 80/20 and 20/80.
    The liquid vehicle can be simple or complex and is adapted to the chosen route of administration and method.
    Advantages of spot-on administration (spot-on administration) may advantageously comprise: b) a crystallization inhibitor which is particularly present in a ratio of 1 to 20% (w / v), preferably from 5 to 15%, inhibitor satisfies the sample according to which: 0.3 ml of a solution A comprising 10% (w / v) of the compound of formula (I) in the ic) below, together with 10% of this inhibitor, is deposited on a slide at 20 ° C for 24 hours, after which it is observed with the naked eye whether there are few or no crystals, especially fewer than 10 crystals and preferably 0 crystals, on the preparation glass; c) an organic solvent having a dielectric constant of between 10 and 35; preferably between 20 and 30, the content of this solvent c) in the total composition preferably being the difference which supplements the composition up to 100%, d) an organic co-solvent having a boiling point below 100 ° C, preferably preferably below 80 ° C, and with a dielectric constant of between 10 and 40, preferably between 20 and 30, this co-solvent being advantageously present in the composition in a d) / c) w / w ratio (W / W) between 1/15 and 1/2. The solvent is volatile, in particular, it serves as a drying promoter and is miscible with water and / or with solvent c).
    While not preferred, the spot-on administration composition may optionally comprise water, especially to an extent of 0 to 30% (v / v, v / v), in particular from 0 to 5%.
    The spot-on administration composition may also comprise an antioxidant which is intended to inhibit oxidation with air, this agent being particularly present in a ratio of 0.005 to 1% (w / v) and preferably 0.01 to 0.05%.
    The compositions of the invention, which are intended for pet animals, especially cats and dogs, are generally administered by application to the skin ("spot-on" or "pour-on" administration); this is generally a local administration within a surface area of less than 10 cm 2, especially between 5 and 10 cm 2, and especially at two points and preferably located between the shoulders of the animal. Once applied, it especially spreads throughout the animal's body and then dries without crystallizing or modifying the appearance of the coat (especially in the absence of any whitish deposit or dusty appearance) or the grip of the coat.
    The spot-on administration compositions of the present invention are particularly advantageous because of their effect, rate of action, and the pleasing appearance of the animal's fur after administration and drying.
    As organic solvent c) which can be used according to the invention may be mentioned in particular: acetone, acetonitrile, benzyl alcohol, butyldiglycol, dimethylacetamide, dimethylformamide, dipropylene glycol-n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, especially N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethylphthalate or a mixture of at least two of these solvents.
    As crystallization inhibitor b) which can be used according to the invention, in particular, mention may be made of: -polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylene sorbedol; lecithin, sodium carboxymethyl cellulose, acrylic derivatives such as methacrylates and the like, anionic surfactants such as alkali metal stearates, especially sodium, potassium or ammonium stearate; calcium stearate; triethanolamine; natriumabietat; alkyl sulfates, especially sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate; fatty acids, especially those derived from coconut oil, cationic surfactants such as water-soluble quaternary ammonium salts of formula N + R'R''R '' 'R' '', Y_, wherein the groups R are optionally hydroxylated hydrocarbon groups, and Y "is an anion of a strong acid such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants that can be used, amine salts of the formula N octadecyl amine hydrochloride is among the cationic surfactants that can be used, nonionic surfactants such as optionally polyoxyethylenated sorbitan esters, especially polysorbate 80, polyoxyethylene alkylated ethers; polyethylene glycol stearate, polyoxyethylene fatty acids, , copolymers of ethylene oxide and propylene oxide, amphoteric surfactants such as substituted betaine lauryl compounds, or preferably a mixture of at least two of these crystallization inhibitors.
    In a particularly preferred way, a crystallization inhibitor pair, namely the combination of a polymer-type film-forming agent and a surfactant, will be used. In particular, these agents will be selected from the compounds mentioned as crystallization inhibitor b).
    Among the polymeric film-forming agents which are particularly advantageous are the following: - the various polyvinylpyrrolidone grades, -polyvinyl alcohols, and copolymers of vinyl acetate and vinylpyrrolidone.
    In the case of surfactants, nonionic surfactants and preferably polyoxyethylenated sorbitan esters, and in particular various polysorbate grades, are particularly preferred. polysorbate 80.
    The film-forming agent and surfactant can be incorporated in preferably equal or identical amounts within the limit of the total amount of the other-mentioned crystallization inhibitor.
    The pair thus produced ensures the purpose of the absence of crystallization on the hairs and the maintenance of the cosmetic appearance of the coat in a remarkable manner, ie. without any tendency to stickiness or to sticky appearance, despite the high concentration of active material.
    As co-solvent d), in particular, absolute alcohol, isopropanol and methanol can be mentioned.
    In particular, as antioxidant, conventional agents such as: butyl hydroxyanisole, butyl hydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate and sodium thiosulfate, or a mixture of not more than two of these agents are used.
    The spot-on administration compositions of the invention are usually prepared by simple mixing of the ingredients as previously indicated; advantageously mixed initially with the active material in the main solvent and the other ingredients or adjuvants then added.
    The volume administered may be from approx. 0.3 to 1 ml and preferably approx. 0.5 ml for cats, and from approx. 0.3 to 3 ml for dogs according to animal weight.
    In a particularly preferred manner, the composition of the invention may be in the form of a concentrated emulsion, suspension or solution for spot-on administration on a small area of the animal's skin generally between the two shoulders (spot-on type solution). In a distinctly less preferred way, forms of solution or suspension may be provided for atomization, dissolution, suspension or emulsion for pouring or spreading on the animal (pour-on type solution), oil, cream, ointment or any other liquid formulation. for topical administration.
    Advantageously, the ready-to-use composition contains a dose of 0.1 to 40 mg / kg of compound (A) of formula (I) and 0.1 to 40 mg / kg of compound (B).
    Preferably, a ready-to-use dosage formulation contains, in particular, one for spot-on administration of 1 to 20 mg / kg and especially 2 to 10 mg / kg of compound (A), especially fibronil, and from 1 to 30 mg / kg and preferably 2 to 10 mg. / kg of a preferred compound (B) or 10 to 20 mg / kg of another compound (B).
    Advantageously, ready-to-use dosage preparations for animals weighing 1-10, 10-20 and 20-40 kg, respectively, can be provided.
    In another embodiment intended for time-divided administration, a composition in the form of a kit divided into the same package can be combined combining a composition containing a compound of formula (I), in particular fipronil, and a composition containing compound (B ), preferably the pyriproxyfen, each of the compositions including a vehicle which permits its administration to the skin.
    Preferably, each of the two compositions is intended for local spot-on administration, and preferably a container containing just the required dose is provided for each administration.
    Thus, a set in a package, e.g. contain three containers, each containing a single dose of compound (A), and three containers, each containing a single dose of compound (B), the (A) containers being separated from the (B) containers by labels, shapes or colors as well as a note specifying that (A) containers and (Containers) should be used alternately at an interval of, for example, one month, starting with, for example, an (A) container.
    The compositions of the invention and in particular the compositions for spot-on administration have proven to be extremely effective for the very long-term treatment of fleas on mammals and especially small mammals such as cats and dogs.
    The discovery that compound (A) such as fibronil is dissolved in sebum so that the whole animal is covered and concentrated in the sebaceous glands from which it is gradually released over a very long period of time is a likely explanation for this long-lasting effect of these preparations and may also could explain the long-lasting effect of the associated compound (B).
    They also have some effect on other parasitic insects and especially on blood mites, and it will be apparent that the administration of the composition of the invention can be extended to a treatment for ectoparasites or even endoparasites for which the preparation is found to be of real benefit. which is practically capable of being achieved in accordance with criteria in the veterinary field.
    Thus, e.g. a preparation based on fibronil and fluazuron is also used against especially blood mites.
    Where appropriate, the composition of the invention may also comprise another insecticide and in particular imidaclopride.
    The invention also relates to the use of at least one compound (A) of formula (I) and of at least one compound (B) of the IGR type as set forth above for the preparation of a composition as set forth above.
    Other advantages and features of the invention will become apparent from the non-limiting examples set forth in the description below.
    The formulation example which follows comprises as compound (A) of formula (I) the compound known as fibronil.
    For example. to prepare a composition for topical administration to the skin in accordance with the invention, the following ingredients may advantageously be mixed together: a1 - compound (B) in a ratio of 1 to 20% (percent by weight per volume w / v) a2 - compound (A) of formula (I) in a ratio of 1 to 20%, preferably 5 to 15%, (percent as weight per volume weight / vol).
    By way of example, the compositions of the invention comprise the following concentrations (w / v) of compounds (A) and (B) in a liquid medium comprising a representative of each of components b, c and d. The total volume is 1 ml.
    Example 1 fipronil 10% pyriproxyphene 5%
    Example 2 fipronil 5% pyriproxyphene 5%
    Example 3 Fipronil 5% Pyriproxyphene 20%
    Example 4 Fipronil 10% Methoprene 30%
    Example 5 fipronil 10% 1- (2,6-difluorobenzoyl) -3- (2-fluoro-4-trifluoromethyl) phenylurea 5%.
    Cats are each attacked with 100 fleas and re-attacked every 10 days. At the time of the first manifestation, they receive a topical administration to the skin of 0.1 mg / kg of the composition of Example 1. Two months after the treatment and 10 days after the last exposure to attack, no fleas are detected and the collected eggs appear to be non-viable.
    Dogs treated according to the same procedure with compositions of Examples 1 and 2 exhibit the same effect of treatment 2 months after administration of the preparation.
    权利要求:
    Claims (39)
    [1]
    Composition for long-term protection against fleas in small mammals and especially in cats and dogs, characterized in that it comprises, on the one hand, at least one compound (A) of formula (I)

    [2]
    Composition according to claim 1, characterized in that the compound of formula (I) is such that: R 1 is CN or methyl; R 2 is S (O) n R 3; R 3 is alkyl or haloalkyl; R4 represents a hydrogen or halogen atom; or an NR5 R6 / S (O) mR7, C (O) R7, alkyl, haloalkyl or OR8 group or an -N = C (R9) (R10) group; R5 and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C (O) alkyl or S (O) r-CF3 group; or R5 and R6 together may form a divalent alkylene group which may be interrupted by one or two divalent heteroatoms such as oxygen or sulfur; R7 represents an alkyl or haloalkyl group; R0 represents an alkyl or haloalkyl group or a hydrogen atom; R9 represents an alkyl group or a hydrogen atom; R 10 represents a phenyl or heteroaryl group optionally substituted by one or more halogen atoms or groups such as -OH, -O-alkyl, -S-alkyl, cyano or alkyl; Ru and R 12 independently each represent a hydrogen or halogen atom; R 1 represents a halogen atom or a haloalkyl, haloalkoxy, S (O) qCF 3 or SF 5 group; m, n, q and r are each independently an integer equal to 0, 1 or 2; X represents a trivalent nitrogen atom or a C-Ri 2 group wherein the other three valence positions of the carbon atom form part of the aromatic ring; with the proviso that when R 1 is methyl, then R 3 is halo-alkyl, R 4 is NH 2, Ru is Cl, Ri 3 is CF 3 and X is N.
    [3]
    Composition according to claim 1 or 2, characterized in that the compound of formula (I) is such that R 1 is CN.
    [4]
    Composition according to any one of claims 1-3, characterized in that the compound of formula (I) is such that R 1 is haloalkyl, preferably CF 3.
    [5]
    Composition according to one of claims 1-4, characterized in that the compound of formula (I) is such that R 2 is S (O) n R 3, where n is preferably 1, R 3 is preferably CF 3 or alkyl and especially methyl or ethyl or n is 0 and R 3 is preferably CF 3.
    [6]
    Composition according to any one of claims 1-5, characterized in that the compound of formula (I) is such that X is C-R 12, where R 1 is a halogen atom.
    [7]
    Composition according to one of claims 1-6, characterized in that the compound of formula (I) is such that R1 is CN, R3 is haloalkyl, R4 is NH2, Ru and Ri2 are each independently a halogen atom and / or R13 is haloalkyl.
    [8]
    Composition according to any one of claims 1-7, characterized in that the compound of formula (I) is: 1- [2,6-Cl2-4-CF3-phenyl] -3-CN-4- [SO -CF3] -5-NH2-pyrazole
    [9]
    A composition according to any one of claims 1-7, wherein the compound of formula (I) is one of the following compounds: 1: 1- [2,6-Cl2-4-CF3-phenyl] -3-CN-4 - [S-CF3] -5-NH2-pyrazole; 2: 1- [2,6-Cl2-4-CF3-phenyl] -3-CN-4- [SO-C2H5] -5-NH2-pyrazole.
    [10]
    Composition according to one of claims 1-9, characterized in that the compound (B) is a compound which mimics juvenile hormones, in particular: azadirachtin diophenolan phenoxycarb hydroprene quinoprene methoprene pyriproxyphen tetrahydroazadirachtin and 4-chloro-2- (2-chloro-2 -methylpropyl) -5- (6-iodo-3-pyridylmethoxy) pyridizin-3 (2H) -one
    [11]
    Composition according to one of Claims 1 to 9, characterized in that the compound (B) is a chitin synthesis inhibitor, in particular: -3- (2-fluoro-4- (trifluoromethyl) phenylurea, - (2,6-difluorobenzoyl) -3- (2-fluoro-4- (1,1,2,2-tetrafluoroethoxy) phenylurea and 1- (2, β-difluorobenzoyl) -3- (2-fluoro-4-trifluoromethyl) phenylurea.
    [12]
    The composition of any of claims 1-9. characterized in that compound (B) is novaluron.
    [13]
    Composition according to one of claims 10-12, characterized in that the IGR-type compound is selected from methoprenes, pyriproxyphenes, lufenuron, hydroprene, cyromazine and 1- (2,6-difluorobenzoyl) -3- (2). -fluoro-4- (trifluoromethyl) phenylurea.
    [14]
    Composition according to claim 13, characterized in that the IGR-type compound is the pyriproxyphene.
    [15]
    Composition according to claim 13, characterized in that the IGR-type compound is a methoprene.
    [16]
    Composition according to one of claims 1 to 15, characterized in that the weight-based ratio between compounds (A) of formula (I) and type (B) compounds is between 80/20 and 20/80.
    [17]
    Composition according to one of claims 1 to 16, characterized in that the liquid vehicle and the concentration of compounds (A) and (B) are adapted for punctual "spot-on" administration by application to the skin.
    [18]
    Preparation according to any one of claims 1-16, characterized in that the liquid vehicle and the concentration of compounds (A) and (B) are adapted for local administration of the "pour-on" type when deposited on the skin.
    [19]
    Composition according to claim 17, characterized in that the liquid vehicle and the concentration of compounds (A) and (B) are adapted for local administration in a zone with a surface area of less than 10 cm 2, especially between 5 and 10 cm 2, and especially in 2 points and preferably located between the shoulders of the animal.
    [20]
    Composition according to any one of claims 1-19, characterized in that it contains a dose of 0.1 to 40 mg / kg of compound (A) and from 0.1 to 40 mg / kg of compound (B).
    [21]
    Composition according to claim 20, characterized in that it contains a dose of from 1 to 20 mg / kg, in particular from 2 to 10 mg / kg of compound (A), and from 1 to 30 mg / kg, especially from 2 to 10 mg. 20 mg / kg of compound (B).
    [22]
    Composition according to any one of claims 1-21, characterized in that it also comprises a crystallization inhibitor (b) which is preferably present in a ratio of 1 to 20% (w / v) and preferably 5 to 15. %.
    [23]
    Composition according to claim 22, characterized in that the crystallization inhibitor (b) is selected from: polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylene; lecithin, sodium carboxymethyl cellulose, acrylic derivatives such as methacrylates and the like, anionic surfactants such as alkali metal stearates, especially sodium, potassium or ammonium stearate; calcium stearate; triethanolamine; natriumabietat; alkyl sulfates, especially sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate; fatty acids, especially those derived from coconut oil, cationic surfactants such as water-soluble quaternary ammonium salts of the formula N + R Y ~ is an anion of a strong acid such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants that can be used, amine salts of the formula hydroxylated hydrocarbon groups; octadecylamine hydrochloride is among the cationic surfactants that can be used, nonionic surfactants such as optionally polyoxyethylenated sorbitan esters especially polysorbate 80, polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated, fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, amphoteric surfactants such as substituted lauryl compounds of betaine, or preferably a mixture of these is a mixture of
    [24]
    Composition according to any one of claims 22 and 23, characterized in that it comprises a crystallization inhibitor pair formed by the combination of a polymer-type film-forming agent and a surfactant, especially in proximate or identical amounts within the limit of the total crystallization inhibitor amounts. .
    [25]
    Composition according to claim 24, characterized in that the film-forming agent is selected from: the various polyvinylpyrrolidone grades, polyvinyl alcohols, and copolymers of vinyl acetate and vinylpyrrolidone and in that the surfactant is selected from nonionic surfactants, preferably polyoxyethylene-sorbitan esters, especially the various polyvalent esters, .
    [26]
    Composition according to any one of claims 1-25, characterized in that it comprises an organic solvent (c) having a dielectric constant of between 10 and 35, preferably 20 and 30, the content of which of the total composition preferably makes the difference. to 100% of the preparation.
    [27]
    Composition according to claim 26, characterized in that the organic solvent (c) is selected from acetone, acetonitrile, benzyl alcohol, butyldiglycol, dimethylacetamide, dimethylformamide, dipropylene glycol-n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethyl acetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, especially N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate, or a mixture of at least two of these.
    [28]
    Composition according to any one of claims 26 and 27, characterized in that it also comprises an organic co-solvent (d) having a boiling point below 100 ° C, preferably below 80 ° C, and having a dielectric constant of between 10 and 40, preferably between 20 and 30, which co-solvent is miscible with water and / or with the solvent (c), said co-solvent being present in particular in a co-solvent (d) / solvent (c) weight ratio (w / w) of 1/15 and 1/2.
    [29]
    Composition according to claim 28, characterized in that the co-solvent (d) is selected from absolute ethanol, isopropanol and methanol.
    [30]
    Composition according to any one of claims 1-29, characterized in that it is made in the form of a set which separately combines in the same package at least one container containing a compound (A) and at least one container for compound (B). and a message specifying that the containers should be used alternately at intervals of one month in particular.
    [31]
    Composition according to any one of claims 1-30, characterized in that it provides protection for 2 to 3 months.
    [32]
    Composition according to any one of claims 17-19 and 22-31, characterized in that it comprises 5-10% 1- [2,6-Cl2-4-CF3-phenyl] -3-CN- 4- [SO-CF3] -5- NH2-pyrazole and 5-20% pyriproxyphenes.
    [33]
    Composition according to any one of claims 17-19 and 22-31, characterized in that it comprises 10% 1- [2,6-Cl2-4-CF3-phenyl] -3-CN-4- [SO-CF3] -5-NH2 ~ pyrazole and 30% methoprene.
    [34]
    Use of at least one compound (A) of formula (I), on the one hand,

    [35]
    Use according to claim 34 for the preparation of a composition according to any one of claims 1-33.
    [36]
    Use of a composition according to any one of claims 1-33 for the control of ectoparasites, especially blood mites.
    [37]
    37. A method for controlling fleas in small mammals and especially in cats and dogs for a long period of time, characterized in that the animal is treated by applying topically to the skin parasitically effective doses and ratios of a composition according to any one of claims 1 -33.
    [38]
    The method according to claim 37, characterized in that the animal is treated by localized spot-on skin of the spot-on type.
    [39]
    The method of any one of claims 37 and 38 for controlling ectoparasites, especially blood mites.
    类似技术:
    公开号 | 公开日 | 专利标题
    DK177397B1|2013-03-18|Preparation for long-term protection against fleas in mammals, especially cats and dogs
    US9968617B2|2018-05-15|Local topical administration formulations containing indoxacarb
    US6010710A|2000-01-04|Direct pour-on skin solution for antiparasitic use in cattle and sheep
    US20110288141A1|2011-11-24|Local topical administration formulations containing fipronil
    DK201370137A|2013-03-11|Insecticide combination against fleas in mammals
    DK177441B1|2013-05-27|Composition for long-term protection against fleas in mammals, especially cats and dogs
    AU2005201861B2|2007-03-08|Insecticidal combination effective against fleas on mammals, particularly cats and dogs
    AU779593B2|2005-02-03|Insecticidal combination effective against fleas on mammals, particularly cats and dogs
    AU763484B2|2003-07-24|Direct pour-on skin solution for antiparasitic use in cattle and sheep
    SE531435C2|2009-04-07|Insecticide compound against fleas in mammals, especially dogs and cats
    同族专利:
    公开号 | 公开日
    DK178513B1|2016-04-25|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE3029426A1|1980-08-02|1982-03-11|Bayer Ag, 5090 Leverkusen|AGAINST EFFECTIVE POUR-ON FORMULATIONS|
    GB8713768D0|1987-06-12|1987-07-15|May & Baker Ltd|Compositions of matter|
    NO179282C|1991-01-18|1996-09-11|Rhone Poulenc Agrochimie|New 1- pyrazole compounds for control of insect pests|
    JP3715994B2|1993-12-21|2005-11-16|住友化学株式会社|Pest control agent|
    法律状态:
    2017-03-27| PUP| Patent expired|Expiry date: 20330311 |
    优先权:
    申请号 | 申请日 | 专利标题
    DK201170008|2011-01-07|
    DKPA201170008A|DK177441B1|1997-11-27|2011-01-07|Composition for long-term protection against fleas in mammals, especially cats and dogs|
    DK201370137|2013-03-11|
    DKPA201370137A|DK178513B1|2011-01-07|2013-03-11|Insecticide combination preparation for use against mammalian blood mites, especially cats and dogs|DKPA201370137A| DK178513B1|2011-01-07|2013-03-11|Insecticide combination preparation for use against mammalian blood mites, especially cats and dogs|
    [返回顶部]