WO1999005110A1 - Benzoyluree amorphe et vermicides pour animaux a sang chaud renfermant comme principe actif ladite benzoyluree - Google Patents

Benzoyluree amorphe et vermicides pour animaux a sang chaud renfermant comme principe actif ladite benzoyluree Download PDF

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Publication number
WO1999005110A1
WO1999005110A1 PCT/JP1998/003296 JP9803296W WO9905110A1 WO 1999005110 A1 WO1999005110 A1 WO 1999005110A1 JP 9803296 W JP9803296 W JP 9803296W WO 9905110 A1 WO9905110 A1 WO 9905110A1
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WO
WIPO (PCT)
Prior art keywords
amorphous
composition
benzoyl
phenyl
dichloro
Prior art date
Application number
PCT/JP1998/003296
Other languages
English (en)
Japanese (ja)
Inventor
Masanari Kato
Yoshiaki Ishihara
Mikio Miyaji
Ichiro Nakano
Original Assignee
Ishihara Sangyo Kaisha Ltd.
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
Application filed by Ishihara Sangyo Kaisha Ltd. filed Critical Ishihara Sangyo Kaisha Ltd.
Priority to AU83569/98A priority Critical patent/AU8356998A/en
Publication of WO1999005110A1 publication Critical patent/WO1999005110A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof

Definitions

  • the present invention relates to an amorphous benzoylrea, a benzoylrea composition comprising an amorphous benzoylrea and a water-soluble polymer compound or a cyclic host compound, a method for producing the same, and a parasite of a warm-blooded animal containing the amorphous benzoylrea as an active ingredient. It relates to a control agent.
  • pets such as dogs and cats
  • animal parasites such as fleas, mites, lice, true mites, grubs, flies, coccils, fluke, tapeworms, hookworms, and, in particular, fleas.
  • Irritation and itching can irritate dogs and cats and cause allergic dermatitis and anemia.
  • it can also parasitize the owner, causing redness and rashes, causing severe itching and causing allergies such as atopic dermatitis.
  • Benzoiruurea compounds containing the base Nzoiruurea compound the force and has a parasite control effect of warm-blooded animals?, Since these compounds are generally hardly soluble in extremely in water, for example an animal Oral administration of a pesticidal agent results in poor absorption from the gastrointestinal tract, etc., and the blood concentration of the active ingredient does not rise sufficiently, so it is possible to sufficiently exert the control effect on the in vivo and extracorporeal parasites of warm-blooded animals Can not. In order to enhance the effect of controlling parasites, it is necessary to increase the dose.However, there are concerns about adverse reactions and disorders caused by large doses, and effective use of smaller doses to effectively control internal and external parasites. Is required.
  • An object of the present invention is to provide an amorphous benzoyl perea or an amorphous benzoyl perea capable of greatly improving absorption from the digestive tract when administered orally to a warm-blooded animal, and a water-soluble polymer compound or a cyclic host compound.
  • An object of the present invention is to provide an amorphous benzoylurea composition.
  • Another object of the present invention is to provide an agent for controlling endoparasites and extracorporeal parasites of a warm-blooded animal, which comprises amorphous benzoylrea as an active ingredient and exhibits an excellent control effect even when administered in a small amount. .
  • the first invention of the present invention is an amorphous N— (2,6-difluorobenzoyl) -1N, 1 [3,5-dichloro-4- (3-chloro-1-5-) Triflu-l-methyl-l-2-pyridyl-l-oxy) phenyl] ⁇ rea
  • the second invention is amorphous N- (2,6-difluorobenzoyl) -lN,-[3,5-dichloro-4-]
  • the fourth invention is a warm-blooded animal parasite control agent comprising amorphous benzoyl perylene as an active ingredient.
  • the present inventors have conducted various studies with the aim of enhancing the absorption from the digestive tract when the benzoyl rearea is orally administered to a warm-blooded animal, and as a result, the benzoyl rearea has been made amorphous or A benzoylperia composition comprising an amorphous benzoylperia and a water-soluble polymer compound or a cyclic host compound, which enhances absorption from the digestive tract when the benzoylperrea is orally administered to a warm-blooded animal. And completed the present invention.
  • the benzoyl urea is a generally known compound, for example, a compound produced by a method described in JP-A-54-125677, or a method analogous thereto.
  • the compound amorphous for example, it can be obtained by quenching the solution, changing the composition of the solvent rapidly, or spray-drying the solution.
  • a benzoyl perea composition comprising an amorphous benzoyl perea and a water-soluble polymer compound or a cyclic host compound is, for example, as described in (1) benzoyl perea and a water-soluble polymer compound or a cyclic host compound as a solvent as described above.
  • a method of removing the solvent from the dissolved solution (2) a method in which benzoyl perylene is mixed with a water-soluble polymer compound and pulverized with a grinder, or (3) a saturated solution method, a coprecipitation method, a lyophilization method, mixed kneading method. force by a conventional method base Nzoiruurea such mixing grinding method can be prepared by a method that Sessu wrapped annularly host compound?, the industrial process is desirable for the (1) .
  • the amorphous benzoyl rea in the amorphous benzoyl urea or benzoyl rea composition of the present invention is not necessarily required to be entirely amorphous when, for example, the crystalline benzoyl rea is changed from the crystalline benzoyl rea to amorphous.
  • the ability to increase the absorption from the gastrointestinal tract when administered orally to blood animals can be attributed to the fact that benzoylrea is amorphous, so that virtually all of it is amorphous. Power s desirable to be with.
  • water-soluble polymer compound used in the present invention examples include polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate phthalate, carboxymethylcellulose, and carboxymethylethyl.
  • the cyclic host compound used in the present invention is a compound capable of including various organic compounds inside the compound. Examples thereof include ⁇ , ⁇ , arcyclodextrin, branched glucose or branched maltose substitution. Cyclodextrin and the like, and one or more components selected from these groups can be used.
  • the mixing ratio of the water-soluble polymer compound or the cyclic host compound to the benzoyl rea is different depending on the components to be used, and cannot be generally specified. Parts, preferably 1 to 5 parts by weight.
  • the solvent used together with the water-soluble polymer compound or the cyclic host compound may be any of the above-mentioned benzoyl perylene and ⁇ or any solvent that dissolves the water-soluble polymer compound or the cyclic host compound. It is desirable to dissolve both the water-soluble polymer compound and the cyclic host compound.
  • the solvent include alcohols such as methanol and ethanol, ketones such as acetone, ethers such as tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and chloroform, and ethyl acetate. And the like, among which ethanol, acetone, tetrahydrofuran, methylene chloride and the like are preferable.
  • the amount of the solvent used is 500 parts by weight or less, preferably 30 to 200 parts by weight, and preferably 1 part by weight of the water-soluble polymer compound or cyclic host compound, based on 1 part by weight of the benzoyl urea. To 100 parts by weight or less, preferably 8 to 15 parts by weight.
  • the benzoyl urea in a solvent and then dissolve the water-soluble polymer compound or the cyclic host compound therein. It is also possible to simultaneously mix the respective solutions dissolved in the same. If the dissolution rate is low at the time of dissolving each of these components, the solvent may be preliminarily dissolved by heating to a temperature below the boiling point.
  • a method for removing a solvent from a solution in which the benzoyl rea and the water-soluble polymer compound or the cyclic host compound are dissolved is usually industrially practiced. Examples thereof include a method of heating under normal pressure or reduced pressure, a thin film drying method, a spray drying method, and a freeze drying method.
  • a method for removing the residual solvent in the preparation a method for performing the following post-treatment on the composition obtained by removing the solvent by an ordinary method, for example, a hammer mill if necessary
  • a method of removing the residual solvent by pulverizing with a pin mill or the like, finely pulverizing with a jet mill or the like, and then drying under normal pressure or reduced pressure.
  • composition obtained by such a method or the composition from which the residual solvent has been removed it can be formulated into tablets, capsules, granules, powders, fine granules and the like by a usual method.
  • Examples of in vivo and extracorporeal parasites of host animals such as dogs, cats, rabbits, deer, guinea pigs, squirrels, hamsters, ferrets, zoo animals and the like that can be controlled by the present invention include mites (mesostigmatide, scabies mite) , Dermatoid mites, scabies, crabs), ticks (soft and hard), lice (blood-sucking, stinging), fleas (dog fleas, cat fleas, oriental rat flea), typical lice (bed lice, squash), blood-sucking Sex fly larvae
  • mites meostigmatide, scabies mite
  • ticks soft and hard
  • lice blood-sucking, stinging
  • fleas dog fleas, cat fleas, oriental rat flea
  • typical lice bed lice, squash
  • blood-sucking Sex fly larvae Such as ar
  • the parasite control agent of the present invention can be administered at a ratio of about 0.01 to about 100 mg as an active ingredient per kg of body weight of the host animal.
  • the best rate of control for a given parasite on a given animal must be determined individually, but in most cases the optimal rate will be about 0.25 to 100 O / kg of host animal body weight. mg.
  • This dose may be given once or in divided doses at relatively short intervals of 1 to 5 days.
  • the parasite control agent of the present invention may be administered to an animal by direct injection of an amorphous benzoyl urea.
  • Sprinkles are used as a sprinkling agent that is well dispersed in feed, or are formulated into pellets, pastes, capsules, tablets, granules, powders, fine granules, etc. and added to the feed or administered separately There is a way to do that.
  • a carrier used in these preparations and the like a carrier power 5 ′ generally used in the field of veterinary medicine can be used.
  • a carrier power 5 ′ generally used in the field of veterinary medicine can be used.
  • a liquid carrier include water, N-methylpyrrolidone, vegetable oil, and the like. Clay, talc, dried molasses, etc., and if necessary, auxiliary agents such as dispersants and surfactants may be used.
  • the parasite control agent of the present invention can be used in combination with a drug, a growth promoter, vitamins, minerals and the like known in the veterinary field, and in that case, a synergistic effect may be exhibited.
  • pharmaceuticals, vitamins and minerals known in the field of veterinary medicine that can be used in combination with the amorphous benzoylperrea of the present invention include, for example, abamectin, ivermectin, milbemycin, norlinomycin, monensin, Salinomycin, oxytetracycline, levamisole, etc., vitamin
  • A, B, C, D, E, thiamine, etc. sodium, calcium, magnesium, copper, zinc, cobalt, phosphorous, sulfur, iodine force? Like.
  • the amorphous benzoylrea of the present invention can significantly improve the absorption from the gastrointestinal tract by oral administration to warm-blooded animals, and is therefore expected to have an excellent parasite control effect, and also suppresses adverse reactions and disorders caused by large doses can do.
  • FIG. 1 shows Example 1 (composition A), Example 2 (composition B), Example 3 (composition C), Comparative Example 1 (composition D) and untreated crystal form N— (2 , 6-difluorobenzoyl) 1 N, 1 [3,5-dichloro-4- (3-chloro-1-5-trifluoromethyl-12-pyridyloxy) phenyl] x-ray powder of untreated benzoyl peryl Show the evening.
  • the obtained product is dried under reduced pressure (1.0 mmHg or less) at 80 to 90 ° C for 5 hours, and then centrifuged by a centrifugal crusher [manufactured by Nippon Seiki Seisakusho, using a 0.12 m / m screen]. And pulverized at 10,000 rpm to obtain 21.8 g of a composition A.
  • composition A was analyzed by powder X-ray diffraction to obtain a physical mixture of benzoyl perea described in Comparative Example 1 and hydroxypropylmethyl cellulose cellulose [trade name; HP-55] (described later).
  • a comparison with composition D) was made.
  • the powder X-ray diffraction pattern of the above-mentioned composition A showed a halopattern as shown in FIG. 1 and also had a different diffraction pattern from that of composition D shown in FIG. Benzoylperea was found to be amorphous.
  • composition A was observed with a polarizing microscope at a specific angle where the knock ground was darkest and the crystal glowed strongly. However, it was found that most of them were amorphous.
  • N- (2,6-difluorobenzoyl) -1-N,-[3,5-dichloro-1-41 (3-chloro-5-trifluoromethyl-2-pyridyloxy) phenyl] urea 5.03 g Add 100 ml of acetone and heat to about 50 ° C to dissolve. On the other hand, polyvinylpyrrolidone K-30 [manufactured by Nacalai Tesque, Inc.] 25.05 g was added to 50 ml of acetone and 50 ml of ethanol. Heat to C and dissolve.
  • composition B was visually observed with a polarizing microscope in the same manner as in Example 1, and as a result, it was found that crystals were found to be present in a very small part of the composition. understood.
  • Add 200 ml of acetone to 5.00 g and heat to about 50 ° C. After dissolution, insoluble materials were removed by natural filtration, and these solvents were distilled off under reduced pressure using an evaporator on a water bath at about 80 ° C.
  • the obtained product is dried at 80 to 90 ° C for 3 hours under reduced pressure (1.0 mmHg or less), and then centrifuged and crushed (manufactured by Nippon Seiki Seisakusho, using a 0.1 m / m screen). And pulverized at 100,000 O rpm to obtain 18.07 g of a composition C.
  • composition C was visually observed with a polarizing microscope in the same manner as in Example 1 above. As a result, no intensely shining point indicating the presence of crystals was observed, and it was confirmed that the composition C was amorphous . Was.
  • composition D was visually observed with a polarizing microscope in the same manner as in Example 1 above, and as a result, many intensely shining points indicating the presence of crystals were observed, and it was found that the composition was in a crystalline form.
  • a drug absorption test using a rat was performed under the following test conditions.
  • Dosage and administration method The sample was suspended in a 0.5% CMC-Na aqueous solution adjusted to pH 4, and administered orally by gavage at a dose of 5 Omg / kg by using a force neule.
  • Samples include compositions A, B, C and D and N- (2,6-difluorobenzoyl) -N,-[3,5-dichloro-14- (3-chloro-5-trifluoromethyl-2-pyridyloxy) phenyl Perezia (abbreviated as benzoylperrea drug substance) was used.
  • Blood collection method Rat tail vein was wounded with a razor, and approximately 1501 blood was collected. Blood was collected at 1, 3, 5, 8, 12, 24, 48 hours post-dose.
  • Cmax is N— (2,6-diflurobenzoyl) -N, 1- [3,5-Dichro-l-41- (3-cl-l-5-trifluoromethyl-2-pyridyl) ) [Phenyl] means the maximum blood concentration of rare.
  • AUC is N- (2,6-difluorobenzoyl) -1-N, 1- [3,5-dichloro-14- (3_chloro-5_trifluoromethyl-2-pyridyloxy) phenyl] ⁇ rea Refers to the area under the blood concentration.
  • composition A is filled into a capsule to form a capsule.
  • the mixture After adding 0.5 kg of sodium carboxymethylcellulose and 30 g of magnesium stearate to the composition AlOKg and mixing, the mixture is made into tablets by a direct compression method.
  • Non-Parreux 101 (trade name; manufactured by Freund Corporation) 470 g was placed in a centrifugal fluidized-granulation coating machine, and N— (2, 6—difluo benzoyl) —N, 1 [3, 5— Dichloro-4- (3-chloro-1--5-trifluoromethyl-2-pyridyloxy) phenyl] perylene 5 g and hydroxypropylmethylcellulose phthalate [trade name; HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.] ] A solution of 25 g in 300 ml of acetone is sprayed and dried to obtain granules.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

N-(2,6-difluorobenzoyl)-N-[3,5-dichloro-4-(3-chloro-5-trifluorométhyl-2-pyridyloxy)-phényl]urée amorphe et son procédé de fabrication. Le procédé consiste à dissoudre la N-(2,6-difluorobenzoyl)-N-[3,5-dichloro-4-(3-chloro-5-trifluorométhyl-2-pyridyloxy)-phényl]urée et un composé d'un polymère hydrosoluble dans un solvant, puis à extraire le solvant de la solution obtenue.
PCT/JP1998/003296 1997-07-25 1998-07-23 Benzoyluree amorphe et vermicides pour animaux a sang chaud renfermant comme principe actif ladite benzoyluree WO1999005110A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU83569/98A AU8356998A (en) 1997-07-25 1998-07-23 Amorphous benzoylurea and vermicides for warm-blooded animals containing the same as the active ingredient

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP21579797 1997-07-25
JP9/215797 1997-07-25

Publications (1)

Publication Number Publication Date
WO1999005110A1 true WO1999005110A1 (fr) 1999-02-04

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PCT/JP1998/003296 WO1999005110A1 (fr) 1997-07-25 1998-07-23 Benzoyluree amorphe et vermicides pour animaux a sang chaud renfermant comme principe actif ladite benzoyluree

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WO (1) WO1999005110A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1912358A1 (fr) 1994-09-12 2008-04-16 Koninklijke Philips Electronics N.V. Transmission simultanée dans un réseau à fréquence unique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62501418A (ja) * 1984-12-28 1987-06-11 ユニオン　カ−バイド　コ−ポレ−シヨン 温血動物の体内寄生虫及び体外寄生虫を防除するためのアシル尿素化合物の使用
JPH02206A (ja) * 1987-11-11 1990-01-05 Fujisawa Pharmaceut Co Ltd エキシホンと水溶性高分子化合物とを含有することを特徴とする新規製剤
JPH04159228A (ja) * 1990-10-22 1992-06-02 Lion Corp 医薬用製剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62501418A (ja) * 1984-12-28 1987-06-11 ユニオン　カ−バイド　コ−ポレ−シヨン 温血動物の体内寄生虫及び体外寄生虫を防除するためのアシル尿素化合物の使用
JPH02206A (ja) * 1987-11-11 1990-01-05 Fujisawa Pharmaceut Co Ltd エキシホンと水溶性高分子化合物とを含有することを特徴とする新規製剤
JPH04159228A (ja) * 1990-10-22 1992-06-02 Lion Corp 医薬用製剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JANARUSHA I.: "RECENT TECHNOLOGY OF MANUFACTURING PHARMACEUTICAL PREPARATIONS AND ITS APPLICATIONS I.", RECENT TECHNOLOGY OF MANUFACTURING PHARMACEUTICAL PREPARATIONSAND ITS APPLICATION, XX, XX, 1 January 1983 (1983-01-01), XX, pages 157 - 159., XP002913855 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1912358A1 (fr) 1994-09-12 2008-04-16 Koninklijke Philips Electronics N.V. Transmission simultanée dans un réseau à fréquence unique

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