WO1999005110A1

WO1999005110A1 - Amorphous benzoylurea and vermicides for warm-blooded animals containing the same as the active ingredient

Info

Publication number: WO1999005110A1
Application number: PCT/JP1998/003296
Authority: WO
Inventors: Masanari Kato; Yoshiaki Ishihara; Mikio Miyaji; Ichiro Nakano
Original assignee: Ishihara Sangyo Kaisha Ltd.
Priority date: 1997-07-25
Filing date: 1998-07-23
Publication date: 1999-02-04
Also published as: AU8356998A

Abstract

Amorphous N-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-phenyl]urea; and a process for producing the same by dissolving N-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]urea and a water-soluble polymer compound in a solvent and then removing the solvent from the resultant solution.

Description

Specification

Amorphous Benzoylrea and parasite control agents for warm-blooded animals using it as an active ingredient

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.

Background art

N-(2,6-difluorobenzoyl) 1 N, 1 [3,5-dichloro-1 4—

(3-chloro-1-5-trifluoromethyl-2-pyridyloxy) phenyl] urea is a known compound and is known to have a controlling effect on in vivo and extracorporeal parasites of warm-blooded animals. Japanese Translation of PCT International Publication No. 62_50101418).

In recent years, pets, such as dogs and cats, have been bred indoors. These pets are usually infested with 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. In addition, it can also parasitize the owner, causing redness and rashes, causing severe itching and causing allergies such as atopic dermatitis. There is a need for a method to effectively control ectoparasites.

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.

Disclosure of the invention 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. .

To summarize the present invention, 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] ゥ rea, and the second invention is amorphous N- (2,6-difluorobenzoyl) -lN,-[3,5-dichloro-4-]

(3-chloro-5_trifluoromethyl-12-pyridyloxy) phenyl] a benzoyl pereria composition comprising urea and a water-soluble polymer compound or a cyclic host compound. A process for producing the benzoylperia composition according to the above, comprising: N— (2,6-difluorobenzoyl) -N ′ — [3,5-dichloro-1-41- (3-chloro-5-trifluoromethyl-2-) Pyridyloxy) phenyl] ゥ rea and a water-soluble polymer compound are dissolved in a solvent, and the solvent is removed to form an amorphous benzoyl-rea composition comprising the benzoyl rea and the water-soluble polymer compound. 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. In order to make 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.

In addition, 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.

Examples of the water-soluble polymer compound used in the present invention include polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate phthalate, carboxymethylcellulose, and carboxymethylethyl. Cellulose, solid polyethylene glycol, hydroxypropyl mouth methyl cellulose phthalate, acetate succinate of hydroxypropylmethylcellulose, methacrylic acid ethyl acrylate copolymer, methacrylic acid methacrylic acid methyl methacrylate copolymer, ethyl methacrylate methacrylic acid Methyl methacrylate / trimethylammonium methacrylate copolymer, methyl acrylate methacrylic acid / methyl methacrylate copolymer, dimethylaminoethyl Taku Relate-methacrylic acid copolymer and the like, can be used alone or in combination of two or more components selected from these groups. Among these, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and cellulose acetate Tartrate, methacrylic acid methacrylate copolymer, methacrylic acid methyl methacrylate copolymer, and the like are preferred because they have enteric properties, and hydroxypropyl methylcellulose phthalate is more preferred. The cyclic host compound used in the present invention is a compound capable of including various organic compounds inside the compound. Examples thereof include α, β, 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 Ζ 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. Examples of 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.

Next, it is preferable to dissolve 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.

Further, 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.

As 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 There is 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.

Using the 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 Such as arthropods, nematodes (pinworms, lungworms, hookworms, benthic, nodular worms, stomach parasites, roundworms, chinensis) Tapeworms (tapeworms) and trematodes (flukes, schistosomiasis), and the like protozoa such as Kokushijiumu. In general, 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. In addition, it is desirable to appropriately select the dosage, the number of administrations, the administration period, and the like according to the desired control period, the degree of parasite infestation, the health condition of the host animal, and the like.

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. There is also a method in which the drug is administered by dissolving or suspending in drinking water. As a carrier used in these preparations and the like, a carrier power ⁵ ′ generally used in the field of veterinary medicine can be used.Examples of 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.

Further, 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. For example, 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.

BRIEF DESCRIPTION OF THE FIGURES

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.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the ability to describe the examples in order to explain the present invention in more detail is not intended to limit the present invention.

Example 1 H

N— (2,6-dibenzo mouth) one N, one [3,5-dichloro mouth one—

(3-chloro-5-trifluoromethyl-2-pyridyloxy) phenyl] urea 5.00 g and hydroxypropylmethylcellulose phthalate (trade name; HP-55, Shin-Etsu Chemical Co., Ltd.) 25.10 g Acetone (300 ml) was added, and the mixture was dissolved by heating to about 50 ° C., and insoluble substances were removed by natural filtration, and these solvents were distilled off under reduced pressure using an evaporator on a water bath of about 8 Ot :.

Next, 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.

Next, the above 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. As a result, 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. Untreated crystalline form of N- (2,6-difluorobenzoyl) -1-N,-[3,5-dichloro-4-(3-chloro-1-5-methyltrimethyl-2-methylpyridyloxy) phenyl] N The powder X-ray diffraction pattern of the rare is also shown in FIG. 1 (in the figure, untreated benzoyl rare).

Furthermore, the 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.

Example 2

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. these After mixing the two solutions, insolubles were removed by natural filtration, and these solvents could be distilled off under reduced pressure using an evaporator on a water bath at about 80 ° C. Next, 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 10,000 rpm to obtain 22.21 g of a composition B.

By examining the crystallinity of Benzoylrea of this composition B in the same manner as in Example 1 above, it was found to be amorphous (the powder X-ray diffraction pattern of composition B is shown in FIG. 1). Shows a halo pattern as shown in FIG.

Further, the 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.

Example 3

N- (2,6-difluorobenzoyl) 1 N, 1 [3,5-dichloro-4- (3-chloro-5-trifluoromethyl-2-pyridyloxy) phenyl] urea 5.00 g and polyvinyl Pyrrolidone VA-64 (trade name; K 0 1 1 idon VA-64, manufactured by B-S FF Co.) 2 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.

Next, 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.

By examining the crystallinity of the benzoylrea of the composition C in the same manner as in Example 1 above, it was found to be amorphous (the powder X-ray diffraction pattern of the composition C is shown in FIG. Shows a halo pattern as shown in FIG.

Further, the 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.

Comparative Example 1

N- (2,6-difluorobenzoyl) 1 N, 1 [3,5-dichloro-41 (3-Chloro-5-trifluoromethyl-1-pyridyloxy) phenyl] Urea 5.0 g of hydroxypropylmethylcellulose phthalate [trade name; HP-155, Shin-Etsu Chemical Co., Ltd.] Add 2.53 g and pulverize with a centrifugal pulverizer [manufactured by Nippon Seiki Seisakusho Co., Ltd., using 0.12 m / m screen] at 100,000 i "pm to obtain composition D8 8 g were obtained.

Next, 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.

Test example 1 (absorption test)

A drug absorption test using a rat was performed under the following test conditions.

Animal; Rat Crj: GS (male, 8 weeks old), n = 4

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.

Feeding conditions; free feeding, free water

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.

Measurement of blood concentration: 200 μl of phthalic acid-di-n-amylacetonitrile solution was added to serum 501 separated from the collected blood, mixed for 5 seconds, and further centrifuged. To prepare a supernatant. This supernatant was subjected to an HP LC (C18 reverse phase column, column temperature: 40 ° C, mobile phase: acetonitrile water 4: 1 mixture, flow rate 1 ml / min, detection wavelength: UV 260, Injection volume: Measured over 50 ^ 1). The results are shown in Table 1 below. 6

10 Table 1

(Note 1) 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.

(Note 2) AUC is N- (2,6-difluorobenzoyl) -1-N, 1- [3,5-dichloro-14- (3_chloro-5_trifluoromethyl-2-pyridyloxy) phenyl] ゥ rea Refers to the area under the blood concentration.

(Note 3) The test results are shown as the average soil standard deviation (n = 4). As is evident from the above results, amorphous benzoyl perire is expected to have a higher drug concentration in the blood and to be more effective in controlling parasites than crystalline benzoyl peryl.

Formulation Example 1

The composition A is filled into a capsule to form a capsule.

Formulation Example 2

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.

Formulation Example 3

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.

Claims

The scope of the claims

1. Amorphous N— (2,6—difluorobenzoyl) -1-N, — [3,5-dichloro-1-4- (3—chloro-5—trifluoromethyl-1-2-pyridyloxy) phenyl] .

2. Amorphous N— (2,6-difluorobenzoyl) -1-N, 1- [3,5-dichloro-1-4- (3_chloro-5-trifluoromethyl-2-pyridyloxy) phenyl] A benzoylurea composition comprising a water-soluble polymer compound or a cyclic host compound.

3. Amorphous N- (2,6-difluorobenzoyl) -1-N '-[3,5-dichloro-1-41 (3-chloro-5-trifluoromethyl-2--2-pyridyloxy) phenyl] 3. The benzoyl perea composition according to claim 2, comprising a perea and a water-soluble polymer compound.

4. N— (2,6-difluorobenzoyl) -1-N, 1- [3,5-dichloro-4- (3-chloro-5-trifluoromethyl-12-pyridyloxy) phenyl] ゥ Rare and water-soluble polymer A method for producing a benzoyl perea composition, comprising: removing a solvent from a solution in which a compound is dissolved in a solvent; and forming a benzoyl perea composition comprising the amorphous benzoyl perea and a water-soluble polymer compound.

5. Amorphous N— (2,6-difluorobenzoyl) -1-N '— [3,5-dichloro-1-41 (3—chloro-1-5-trifluoromethyl-1-2-pyridyloxy) phenyl A parasite control agent for warm-blooded animals, comprising urea as an active ingredient.

6. The parasite control agent according to claim 5, which controls dog or cat parasites.

7. The parasite control agent according to claim 5, which controls dog or cat fleas.