JP2003201204A - Parasite exterminating composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a composition having a high exterminating activity against endo- and ectoparasites within a wide range and having excellent controlling effects on various disease injuries caused by insects and the parasites living in animals. <P>SOLUTION: This parasite exterminating composition comprises one or more kinds of first ingredients selected from a compound, etc., represented by general formula (I) [wherein, R<SP>1</SP>is methyl group or the like; R<SP>2</SP>is acetyl group or the like] and one or more kinds of second ingredients selected from praziquantels, etc., as active ingredients. <P>COPYRIGHT: (C)2003,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a parasite control composition containing a milbemycin derivative (first component) and a second component as active ingredients, and a method for using the same.

[0001]

2. Description of the Related Art Compounds of the milbemycin and avermectin series are known to have excellent insecticidal activity against a wide range of parasites. The milbemycin derivative represented by the following general formula (I) of the present invention, The compositions containing them and their biological activity are not known hitherto.

[0002]

DISCLOSURE OF THE INVENTION The present inventor has a wide range of internal and external parasites including ectoparasites such as fleas, gastrointestinal parasites such as roundworms, and endoparasites such as heartworm,
In both oral and topical administration, as a result of extensive studies aimed at obtaining a composition exhibiting a strong activity, a composition containing a specific milbemycin derivative and a second component such as praziquantel as an active ingredient is excellent. The present invention has been completed by the discovery that it exhibits parasiticidal activity.

[0003]

The present invention has the general formula

[0004]

[Chemical 2]

[Wherein R ¹ represents a methyl group, an ethyl group, an isopropyl group or an s-butyl group, and R ² represents an acetyl group, a methoxyacetyl group, a trifluoroacetyl group,
A cyanoacetyl group or a methanesulfonyl group is shown. ]
One or more first components selected from milbemycin derivatives consisting of a compound represented by: or a salt thereof, and
1 selected from the group consisting of praziquantel, fipronil, benzimidazole and neonicotinoids
TECHNICAL FIELD The present invention relates to a parasite control composition containing one or more second components as an active ingredient, and a method of using the same.

The compound represented by the above formula (I), which is the active ingredient of the present invention, is in a wide range including ectoparasites such as fleas, gastrointestinal parasites such as roundworms and endoparasites such as heartworm. It is a compound that shows strong activity against ectoparasites both in oral and topical administration.

In the compound (I) which is the active ingredient of the present invention, (1) R ¹ is preferably a methyl group or an ethyl group, and (2) R ² is preferably a methoxyacetyl group. is there.

In the compound (I) which is the active ingredient of the present invention, R ¹ is preferably a methyl group or an ethyl group, and R ² is a methoxyacetyl group.

Representative examples of the compound (I) which is the active ingredient of the present invention include the compounds listed in the following table, but the compound (I) is not limited to these compounds. Absent.

In the table, "Me" represents a methyl group and "Et"
Represents an ethyl group, "iPr" represents an isopropyl group, and "sBu" represents an s-butyl group.

[0011]

[Table 1]

[0012]

[Chemical 3]

─────────────────────────────────── Example compound number R ¹ R ² ───── ────────────────────────────── 1 Et MeCO 2 Et CF ₃ CO 3 Et NCCH ₂ CO 4 Et MeOCH ₂ CO 5 Et MeSO ₂ 6 Me MeCO 7 Me CF ₃ CO 8 Me NCCH ₂ CO 9 Me MeOCH ₂ CO 10 Me MeSO ₂ 11 iPr MeCO 12 iPr CF ₃ CO 13 iPr NCCH ₂ CO 14 iPr MeOCH ₂ CO 15 iPr MeSO ₂ 16 sBu MeCO 17 sBu CF ₃ CO 18 sBu NCCH ₂ CO 19 sBu MeOCH ₂ CO 20 sBu MeSO ₂ ────────────────────────────────── In the compound (I) which is the active ingredient of the present invention, preferable compounds are exemplified compound numbers 1, 2, 3, 4, 5, 6,
Nos. 7, 9, 10, 13, 14, 15, 16, 17, 19 or 20 compounds, more preferably Exemplified Compound Nos. 1, 3, 4, 5, 6, 7, 9 or 10 Compounds, and even more preferably, Exemplified Compound Nos. 1, 3, 4,
It is compound No. 5, 9, or 10.

When compound (I) or a salt thereof, which is the active ingredient of the present invention, has an asymmetric carbon atom in the molecule, there may be stereoisomers having R or S coordination.
Each of them, or any of their compounds in any proportion, are encompassed by the present invention. Such stereoisomers are prepared, for example, by synthesizing the compound (I) using an optically resolved raw material compound or optically synthesizing the synthesized compound (I) by a conventional optical resolution or separation method. be able to.

Compound (I) or a salt thereof which is an active ingredient of the present invention can be made into a solvate, and such a solvate salt is also included in the active ingredient of the present invention. For example, the compound (I) may absorb water by adsorbing water or becoming a hydrate by leaving it in the air or recrystallizing, and a compound salt containing such water. Also included in the milbemycin derivative which is the active ingredient of the present invention.

Praziquantel, which is the active ingredient of the present invention, is less effective against milbemycin and avermectin (Pa
rasitorogy Today, Vol 1, No 1, 10-17, 1985) -A compound that is effective against tapeworms.

[0017]

[Chemical 4]

[Wherein, when n is 1, praziquantel, n
When is 2, it is Epsiplantel. ] It is a compound represented by these.

The active ingredient of the present invention, fipronil, is a compound having immediate effect on arthropods such as insects and mites.

[0020]

[Chemical 5]

Fipronil represented by (JP-A-63-31677)
No. 1), the following formula

[0022]

[Chemical 6]

Vanilliprole represented by (Japanese Patent Laid-Open No. 10-33867
No. 8) and the following formula

[0024]

[Chemical 7]

[In the formula, when R is a methyl group and X is a chlorine atom, it is acetoprol, and when R is an ethyl group and X is a trifluoromethyl group, it is ethiprole. ] Compounds represented by the following are known, and in addition to these, WO98 / 4035
9, WO98 / 02042, WO98 / 45274, W
O98 / 28277, WO98 / 28278, WO98
/ 28279, WO99 / 31070, WO00 / 62
616, WO01 / 07413 or WO01 / 0061
The compounds described in Japanese Patent Publication No. 4 are mentioned. Of these, preferred is fipronil or valiniprol.

The benzimidazoles, which are the active ingredients of the present invention, are used as a repellent for gastrointestinal parasites. For example, albendazole, flubendazole and mebendazole are known (The benzimidazole an).
thelmintics-chemistry andbiological activity, S.
Sharma and S. Auzar, Progress in Drug Research Vo
l 27, 85-161).

As the neonicotinoids which are the active ingredients of the present invention, for example, imidacloprid, thiamethoxam, nitenpyram and acetamiprid are known. Among them, imidacloprid is used as a flea control agent for local administration, like fipronil. ing.

The second component of the present invention is preferably praziquantel or fipronil, more preferably praziquantel, epsiprantel or fipronil.

[0029]

BEST MODE FOR CARRYING OUT THE INVENTION The milbemycin derivative which is the active ingredient of the present invention can be produced by the methods of steps A to D shown below.

[0030]

[Chemical 8]

[0031]

[Chemical 9]

In the formula, R ¹ and R ² have the same meanings as described above, and X represents a nitro group or a group represented by the formula —NR ² H.

The starting compound, a 15-hydroxymilbemycin derivative having the general formula (III), is a known compound described in JP-A-60-158191.

(Step A) Step A is compound (III)
In the presence of trifluoromethanesulfonic acid or its trimethylsilyl ester, which is a strong organic acid, in an inert solvent, the general formula

[0035]

[Chemical 10]

This is a step of producing a compound represented by the general formula (IV) by reacting a carboxylic acid represented by:

The amount of trifluoromethanesulfonic acid or its trimethylsilyl ester used is, in principle, a catalytic amount and does not require 1 equivalent to the compound (III), but it is not limited to the reactivity of the carboxylic acid used. It can change significantly depending on the difference.

If an inorganic compound powder is added to the reaction system, the reaction may be promoted and good results may be given in some cases. Examples of such an inorganic compound include copper trifluoromethanesulfonate, cuprous iodide, zinc iodide, cobalt iodide, metal salts such as nickel iodide, celite, silica gel, alumina, and the like. Are copper salts such as copper trifluoromethanesulfonate and cuprous iodide, and most preferably cuprous iodide.

When the carboxylic acid used is poorly soluble in the solvent,
Silyl esters of carboxylic acids can be used.
In this case, a method of reacting a carboxylic acid with an equivalent amount of allyltrimethylsilane using trifluoromethanesulfonic acid or its trimethylsilyl ester as a catalyst and adding the compound (III) to the resulting solution of trimethylsilyl ester can be used.

The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Preferably, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, 1,2
And halogenated hydrocarbons such as dichloroethane and chloroform.

The reaction temperature is -10 ° C to 100 ° C,
The temperature is preferably 0 ° C to 50 ° C. The reaction time varies depending mainly on the reaction temperature, the starting compound or the type of solvent used, but is usually 5 minutes to 6 hours, and preferably,
10 minutes to 2 hours.

(Step B) In step B, compound (IV) is added to
By reacting with a reducing agent such as sodium borohydride in an inert solvent and converting the carbonyl group at the 5-position into a hydroxy group, the compound represented by the general formula (V) or the compound which is the active ingredient of the present invention ( It is a process of manufacturing I).

The reducing agent used is not particularly limited as long as it is known to reduce a carbonyl group to a hydroxy group, and is, for example, metallic boron hydrogen such as sodium borohydride or lithium borohydride. It is preferably sodium borohydride.

The reaction solvent may be used without particular limitation as long as it does not participate in the reaction, but lower alcohols such as methanol, ethanol and propanol, and ethers such as tetrahydrofuran and dimethoxyethane are particularly preferable. .

The reaction temperature is usually 0 ° C. to 50 ° C., and the reaction time is usually 1 hour to 10 hours.

(Step C) Step C is a step of reducing the nitro group of compound (V) in an inert solvent to produce a compound represented by the general formula (VI) having an amino group.

For the reduction of the nitro group, a commonly used method can be used. One of such examples is catalytic reduction using a noble metal catalyst. Preferable examples of the catalyst used in the reaction include palladium-carbon, palladium-barium sulfate, platinum oxide and the like.

Suitable examples of the solvent used in the reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and esters such as ethyl acetate.

The reaction temperature is usually 10 ° C. to 80 ° C., and the reaction time is usually 10 minutes to 5 hours.

Another suitable reduction method is reduction with zinc dust in an acetic acid solvent.

The reaction temperature is usually 0 ° C. to room temperature,
The reaction time is usually 30 minutes to 12 hours.

As a more preferable reduction method, reduction with sodium borohydride in the presence of a nickel catalyst can be mentioned.

As the nickel catalyst, nickel salts such as nickel chloride and nickel bromide can be used, but a triphenylphosphine complex of these nickel salts is preferable.

Suitable solvents for use in the reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane.

The reaction temperature is usually 0 ° C. to room temperature,
The reaction time is usually about 10 minutes to 120 minutes.

(Step D) In step D, the amino group of the compound represented by the compound (VI) and the compound represented by the formula R ² —O are used in an inert solvent.
A compound represented by the compound (I) which is the active ingredient of the present invention by reacting with an acid represented by H (wherein R ² has the same meaning as described above) or a reactive derivative thereof. Is a process of manufacturing.

Examples of the reactive derivative of the acid represented by the formula R ² —OH include acid halides (acid chloride, acid bromide, etc.), acid anhydrides, mixed acid anhydrides, active esters, active amides and the like. Examples include those usually used in the reaction.

When the acid represented by the formula R ² —OH is used, for example, dicyclohexylcarbodiimide (DC
C), 2-chloro-1-methylpyridinium iodide, p-
A dehydrating agent such as toluenesulfonic acid, sulfuric acid is used, and such a dehydrating agent is preferably 2-chloro-1-methylpyridinium iodide. The amount of the dehydrating agent used is represented by the formula R ² −
It is usually 1 to 5 equivalents relative to the acid represented by OH,
It is preferably 1 to 2 equivalents.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hydrocarbons such as hexane, petroleum ether, benzene and toluene, chloroform, Of methylene chloride, halogenated hydrocarbons such as 1,2-dichloroethane, ethers such as ethyl ether, tetrahydroplan, amides such as N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide and acetonitrile. Such nitriles as well as mixtures of these solvents and the like, preferably dichloromethane or 1,2-dichloroethane.

The reaction temperature is usually -70 ° C to 90 ° C, preferably 0 ° C to 60 ° C. The reaction time is
The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but is usually 15 minutes to 1 day and night, preferably 30 minutes to 6 hours.

When the above reactive derivative is an acid halide,
The reaction is preferably carried out in the presence of a base, and suitable bases include, for example, triethylamine, N, N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1,
5-diazabicyclo [4.3.0] nonene-5 (DB
N) and organic bases such as 1,8-diazabicyclo [5.4.0] undecene-7 (DBU).

The amount of the acid halide used is the compound (V
It is usually 1 to 10 equivalents relative to I), and the amount of the base used is usually 2 to 8 equivalents.

The solvent, reaction temperature, reaction time and the like used in the reaction are the same as those when the carboxylic acid itself is used.

The reaction temperature is usually 0 ° C. to 50 ° C., and the reaction time is usually 5 minutes to 2 hours.

After completion of the reaction in each of the above steps, the respective desired compounds (IV), (V) and (I) are isolated from the reaction mixture by a well-known method, and if necessary, such as column chromatography. Purified by known means.

The natural milbemycins and their related compounds, which are the starting materials for the compound (III), are fermentation products and may be either a single compound or a mixture thereof. Therefore, the compound (I) can also be produced as a single compound or a mixture.

The milbemycin derivative, which is the active ingredient of the present invention, can be mixed with the other active ingredient, the second ingredient, in a fixed ratio and processed into a preparation suitable for oral or topical administration.

Examples of the combination of the milbemycin derivative and the second component include compound (I) and praziquantel, compound (I) and fipronil, and compound (I), praziquantel and fipronil. When a plurality of compounds are used as the second component, the compounding ratio of the compounds may vary depending on the way of combining and the use. For example, as the weight ratio of compound (I) to 1, fipronil is 0.2 and praziquantel. Can be used.

In the composition of the present invention, the compounding ratio of the second component to the compound (I) varies depending on the type and use of the second component used. For example, when the second component is fipronil, it is usually 0.1. To 5, preferably 0.2
When the second component is praziquantel, it is usually 0.1 to 2, preferably 0.2 to 0.5, and when the second component is benzimidazole, It is usually 1.0 to 100, preferably 2.0.
When the second component is a neonicotinoid, it is usually 0.2 to 10, and preferably 0.5 to 2.0. When a plurality of compounds are used as the second component, the compounding ratio of each component can be set within the above range.

When the composition of the present invention is used as an endo-ectoparasite control agent in animals or humans, it can be orally administered as a liquid beverage. Liquid beverages are usually
Solutions, suspensions or dispersions with suitable non-toxic solvents or water with suspending agents such as bentonite and wetting agents or other excipients. Liquid beverages also usually contain an antifoaming agent. The content of the active ingredient in a beverage formulation such as a liquid beverage is usually 0.01 to 0.5% by mass, preferably 0.01 to 0.1% by mass.

When it is desired to administer the compositions of the present invention orally in a dry, solid, unit dosage form, capsules, pills or tablets containing the desired amount of active ingredient will generally be employed. These use forms are such that the active ingredient is homogeneously mixed with suitable finely divided diluents, fillers, disintegrating agents and / or binders, such as starch, lactose, talc, magnesium stearate, vegetable gums and the like. Manufactured by Such unit dosage formulations can vary widely in weight and content of anthelmintic agents, depending on the type of host animal being treated, the degree of infection, and the type of parasite and the body weight of the host.

When the composition of the present invention is administered by animal feed, the composition is homogeneously dispersed in the feed, used as a top dressing or used in the form of pellets. In order to achieve the desired antiparasitic effect, the content of the active ingredient in the final feed is usually 0.
It is 0001 to 0.02 mass%.

Further, the product dissolved or dispersed in a liquid carrier excipient can be parenterally administered to animals by injection in the forestomach, intramuscularly, intratracheally or subcutaneously. For parenteral administration, the active ingredient is preferably mixed with a suitable vegetable oil such as peanut oil, cottonseed oil. The amount of active ingredient in such a formulation is usually 0.05 to 50% by weight.

Furthermore, another desirable administration form is a method in which the drug is dissolved in a solvent and directly administered topically. As such a solvent, ethanol, isopropanol, oleyl alcohol, alcohols such as benzyl alcohol, carboxylic acids such as lauric acid and oleic acid, ethyl lactate, isopropyl myristate, which are known to enhance transdermal absorbability, are known. It is preferable to use an ester such as propylene carbonate, a sulfoxide such as dimethyl sulfoxide, an amide such as N-methylpyrrolidone, or a mixed solvent thereof.

The amount of the active ingredient used in the present invention varies depending on the type of animal to be treated and the type and degree of parasite infection, but it is usually 0.
01 to 100 mg, preferably 0.5 to 5
It is 0.0 mg, and oral administration is preferable. Such a dose may be given at once or in divided doses over a relatively short period of time, such as 1 to 5 days.

The composition of the present invention has a high control activity against a wide range of endo- and ectoparasites, and exhibits an excellent control effect against insects parasitic on animals and various diseases caused by the parasites.

That is, the composition of the present invention exhibits an excellent insecticidal effect against fleas parasitic on pets and humans, and is extremely effective as a pesticide for these.

The target fleas include, for example, cat fleas (Ctenocephalides felis) and fleas (Ctenocephali).
des canis) and the like.

In the field of veterinary medicine, the compositions according to the invention can be used against various harmful animal parasites (endo- and ectoparasites), for example insects and helminths. Examples of such animal parasites include horse flies (Gasterophilus spp.), Sand flies (Stomoxys spp.),
White lice (Trichodectes spp.) And reed turtles (Rhodnius spp.)
p.), bull fly (Hypoderma spp.), sheep fly (Oestrus
spp.) and horn louse (Haematopinus spp.). In addition, the composition of the present invention comprises a tick (Ixodidae) and an arachnid (Dermanyssid-a) that parasitize animals.
e), Acarinae (Sarcoptidae), Acaridae (Argas
idae), Demodexidae, Psoroptidae, etc., with excellent acaricidal activity.

The composition of the present invention has excellent parasiticidal activity as an anthelmintic agent for animals and humans, and particularly, for pigs, sheep and
Effective against nematodes that infect domestic animals such as goats, cows, horses, dogs, cats and chickens, poultry and pets. Examples of such nematodes include genus Haemonchus, genus Trichostrongylus, and genus Ostertergia.
Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Esphagostomum
ophagostomum), Chabertia (Chabertia), Trichuris (Storongylu)
s), genus Tricononema (Trichonema), genus Dichtyocaulus, genus Capillaria, genus Heterakis, genus Toxocara, genus Ascaridia, genus Oxyuris
, Ancylostoma, Uncinaria, Toxascaris and Parascaris. In particular, some species of the genera Nematodillus, Cooperia and Esagogostomum attack the intestinal tract, while those of the genus Hemonx and Ostertagia parasitize the stomach and parasites of the Tichtiocaurus parasite in the lungs. However, the compositions of the present invention also show activity in these. Further, the parasites of the family Filariidae and Setariaidae are found in the heart and blood vessels, other tissues and organs such as subcutaneous and lymphatic tissues, but the composition of the present invention also has activity in these. Show.

The composition of the present invention is also active against tapeworms and trematodes. Examples of tapeworms include dog tapeworm (Dipylidiu).
m caninum), tapeworm (Taenia taeniaeformis), tapeworm
(Taenia solium), Taenia saginata (Taenia saginata), Reduced tapeworm (Hymenolepis diminuta), Beneden tapeworm (Moniezia)
benedeni), broad-segment cleft tapeworm (Diphyllobothrium latum),
Dictyostelium japonicum (Diphyllobothrium erinacei), Echinococcus granulosus and Echinoco
ccus multilocularis), and examples of flukes include, for example, fluke (Fasciola hepatica, F. gigantic).
a), Paragonimus westermani
i), hypertrophic fluke (Fasciolopsic bruski), pancreatic fluke (Eurytrem
a pancreaticum, E.coelomaticum), liver fluke (Clonorchis
sinensis), Schistosoma japonicum,
Mention may be made of S. haematobium and S. mansoni.

The composition of the present invention is also useful against parasites that infect humans, and examples of human gastrointestinal parasites include those of the genus Ancylostoma, Necator, Ascaris. Asdaris, Strongyloides, Trichinera
nella), Capillaria, Triculis
(Trichuris) and Enterobius.

The composition of the present invention is of the genus Wuchereri of the family Heartworm, which is another medically important parasite found in the blood or other tissues and organs outside the digestive tract.
a), Brugia, Onchocec
a), Dirofilaria and Loa, Loa, and Dracunculidae, Deacunculus parasites and intestinal parasites It also shows activity in the genus Tess and Trichinella.

Hereinafter, the composition of the present invention will be described in more detail with reference to Reference Examples and Test Examples, but the composition of the present invention is not limited thereto.

[0085]

【Example】

[0086]

Reference Example 1 13- [1- (4-methoxyacetylaminophenyl) cyclopentanecarbonyloxy] -5-
Hydroxymilbemycin A4 (I: R ¹ = Et, R ² = MeOCH
₂ CO, compound number 4) (1) 13- [1- (4-nitrophenyl) cyclopentanecarbonyloxy] -5-oxomilbemycin A4 (IV: R ¹ = Et, X = NO ₂ , step A) 1- (4-Nitrophenyl) cyclopentanecarboxylic acid (10.13 g, 40.0 mmol) was suspended in dichloromethane (150 ml), trifluoromethanesulfonic acid (0.18 ml) was added,
The mixture was stirred under a nitrogen stream for 20 minutes. In the obtained transparent reaction solution,
15-hydroxy-5-oxomilbemycin A4 (5.
57 g, 10.0 mmol) was added and stirring was continued for another 30 minutes. After the reaction is completed, the reaction solution is poured into 4% aqueous sodium hydrogencarbonate,
It was extracted with ethyl acetate. The extract was washed with 4% aqueous sodium hydrogen carbonate solution and water, dried over magnesium sulfate, and the solvent was evaporated. The resulting residue containing 13- [1- (4-nitrophenyl) cyclopentanecarbonyloxy] -5-oxomilbemycin A4 was used in the next step without further purification.

(2) 13- [1- (4-Nitrophenyl) cyclopentanecarbonyloxy] -5-hydroxymilbemycin A4 (V: R ¹ = Et, Step B) The 5-oxo derivative obtained in Step A was Methanol (200 ml)
Soluble borohydride (1.5
2 g, 40 mmol) and boron trifluoride / ether adduct (2
(Droplet) was added and stirred for 10 minutes. After completion of the reaction, ethyl acetate (400 ml) was added to the reaction solution, washed with water three times, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1/1) to give 6.79 g of 13-.
[1- (4-Nitrophenyl) cyclopentanecarbonyloxy] -5-hydroxymilbemycin A4 was obtained.

Nuclear magnetic resonance spectrum (400 MHz) δ (pp
m): 8.16 (2H, d, 7.9Hz), 7.53 (2H, d, J = 7.9Hz), 5.70
~ 5.90 (2H, m), 5.37 (1H, s), 5.25 ~ 5.40 (3H, m), 4.8
4 (1H, d, J = 10.6Hz), 4.67 and 4.63 (2H, AB-q, J = 14.4
Hz), 4.28 (1H, m), 4.07 (1H, s), 3.94 (1H, d, J = 6.4H
z), 3.55 (1H, m), 3.25 (1H, m), 3.02 (1H, m), 1.88 (3
H, s), 1.29 (3H, s), 0.99 (3H, t, J = 7.3Hz), 0.82 (3H,
d, J = 6.5Hz), 0.77 (3H, d, J = 6.4Hz).

(3) 13- [1- (4-aminophenyl) cyclopentanecarbonyloxy] -5-hydroxymilbemycin A4 (VI: R ¹ = Et, step C) The nitro form obtained in (2) was converted to acetic acid. Dissolve in ethyl (100 ml), add triphenylphosphine complex of methanol (100 ml) and nickel (II) chloride (1.12 g, 1.7 mmol), and add sodium borohydride (100 mg, under ice cooling).
2.6 mmol) was added slowly over 10 minutes. After stirring for further 10 minutes, ethyl acetate (70 ml) was added to the reaction solution, washed three times with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized by adding ethyl acetate / hexane to obtain 5.87 g of 13- [1- (4-aminophenyl) cyclopentanecarbonyloxy] -5-hydroxymilbemycin A4 as crystals.

Melting point 235-239 ° C.

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.16 (2H, d, J = 8.6Hz), 6.65 (2H, d, 8.6Hz), 5.77
~ 5.84 (2H, m), 5.44 (1H, s), 5.32 ~ 5.43 (3H, m), 4.8
4 (1H, d, J = 10.5Hz), 4.70 and 4.73 (2H, AB-q, J = 14.5
Hz), 4.33 (1H, m), 4.13 (1H, s), 4.00 (1H, d, J = 6.2H
z), 3.54 (1H, m), 3.30 (1H, m), 3.09 (1H, m), 1.92 (3
H, s), 1.36 (3H, s), 1.01 (3H, t, J = 7.3Hz), 0.87 (3H,
d, J = 6.5Hz), 0.82 (3H, d, J = 6.5Hz).

(4) 13- [1- (4-methoxyacetylaminophenyl) cyclopentanecarbonyloxy] -5-hydroxymilbemycin A4 (I: R ¹ = E
t, R ² = MeOCH ₂ CO, compound No. 4, step D) The amino compound (4.48 g, 6.0 mmol) obtained in (3) was dissolved in tetrahydrofuran (60 ml), and pyridine (0.5
2 ml, 6.4 mmol) and methoxyacetyl chloride (0.58
(ml, 6.2 mmol) was added and the mixture was stirred for 10 minutes. After the reaction,
Ethyl acetate (250 ml) was added to the reaction solution, which was washed with 0.5 mol / L citric acid, water, 4% aqueous sodium hydrogencarbonate and water in this order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 2/1), 4.
38 g of the desired compound was obtained.

Nuclear magnetic resonance spectrum (400 MHz) δ (pp
m): 8.20 (1H, s), 7.49 (2H, d, J = 8.6Hz), 7.29 (2H,
d, J = 8.6Hz), 5.77 (1H, m), 5.74 (1H, m), 5.39 (1H,
s), 5.27 ~ 5.37 (3H, m), 4.80 (1H, d, J = 10.5Hz), 4.6
8 and 4.64 (2H, AB-q, J = 14.5Hz), 4.28 (1H, m), 4.08
(1H, s), 4.01 (2H, s), 3.95 (1H, d, J = 6.4Hz), 3.54 (1
H, m), 3.51 (3H, s), 3.25 (1H, m), 3.01 (1H, m), 2.64 (2
H, m), 2.32 (1H, d, J = 8.1Hz), 1.87 (3H, s), 0.96 (3H,
t, J = 7.3Hz), 0.82 (3H, d, J = 6.5Hz), 0.76 (3H, d, J =
6.5Hz).

[0094]

Reference Example 2 13 [1- (4-Acetylaminophenyl) cyclopentanecarbonyloxy] -5-hydroxymilbemycin A4 (I: R ¹ = Et, R ² = MeCO, Compound No. 1) Reference Example 1 (4) In the same manner as in Reference Example 1 (4) except that acetic anhydride was used in place of methoxyacetyl chloride, the title compound was produced (yield of step D: 89.
8%).

Nuclear magnetic resonance spectrum (400 MHz) δ (pp
m): 7.41 (2H, d, J = 8.6Hz), 7.27 (2H, d, 8.6Hz), 5.70
~ 5.80 (2H, m), 5.39 (1H, s), 5.25 ~ 5.40 (3H, m), 4.8
0 (1H, d, J = 10.6Hz), 4.64 and 4.68 (2H, AB-q, J = 14.2
Hz), 4.28 (1H, dd, J = 6.3 and 8.4Hz), 4.07 (1H, s), 3.
95 (1H, d, J = 6.3Hz), 3.54 (1H, m), 3.25 (1H, m), 3.01
(1H, m), 2.61 (2H, 2), 2.33 (1H, d, J = 8.4Hz), 1.87 (3
H, s), 1.58 (3H, s), 0.96 (3H, t, J = 7.3Hz), 0.82 (3H,
d, J = 6.5Hz), 0.76 (3H, d, J = 6.5Hz).

[0096]

Reference Example 3 13- [1- (4-Cyanoacetylaminophenyl) cyclopentanecarbonyloxy] -5-hydroxymilbemycin A4 (I: R ¹ = Et, R ² = NCCH ₂ C
O, Compound No. 3) The title compound was produced in the same manner as in Reference Example 1 (4) except that cyanoacetyl chloride was used instead of methoxyacetyl chloride in Reference Example 1 (4) (yield of step D). : 89.8%).

Nuclear magnetic resonance spectrum (400 MHz) δ (pp
m): 7.68 (1H, s), 7.42 (2H, d, J = 8.7Hz), 7.33 (2H,
d, 8.7Hz), 5.72 ~ 5.77 (2H, m), 5.39 (1H, s), 5.28 ~
5.37 (3H, m), 4.81 (1H, d, J = 10.6Hz), 4.64 and 4.68
(2H, AB-q, J = 14.5Hz), 4.29 (1H, m), 4.07 (1H, s), 3.9
5 (1H, d, J = 6.2Hz), 3.55 (2H, s), 3.52 (1H, m), 3.25 (1
H, m), 3.01 (1H, m), 2.62 (2H, 2), 2.32 (1H, d, J = 8.2H
z), 1.87 (3H, s), 0.96 (3H, t, J = 7.3Hz), 0.82 (3H, d,
J = 6.5Hz), 0.76 (3H, d, J = 6.5Hz).

[0098]

[Reference Example 4] 13- [1- (4-methanesulfonylaminophenyl) cyclopentanecarbonyloxy] -5
-Hydroxymilbemycin A4 (I: R ¹ = Et, R ² = Me
SO ₂ , Compound No. 5) The title compound was produced in the same manner as in Reference Example 1 (4) except that methanesulfonyl chloride was used instead of methoxyacetyl chloride in Reference Example 1 (4) (the yield of Step D). Rate: 88.2%).

Nuclear magnetic resonance spectrum (400 MHz) δ (pp
m): 7.32 (2H, d, J = 8.7Hz), 7.14 (2H, d, 8.7Hz), 6.47
(1H, s), 5.70 ~ 5.80 (2H, m), 5.39 (1H, s), 5.25 ~ 5.3
7 (3H, m), 4.80 (1H, d, J = 10.6Hz), 4.64 and 4.68 (2H,
AB-q, J = 14.0Hz), 4.28 (1H, dd, J = 6.4 and 8.2Hz),
4.07 (1H, s), 3.95 (1H, d, J = 6.4Hz), 3.54 (1H, m), 3.2
5 (1H, m), 3.01 (1H, m), 2.93 (3H, s), 2.62 (2H, 2),
2.33 (1H, d, J = 8.2Hz), 1.87 (3H, s), 0.96 (3H, t, J = 7.
3Hz), 0.82 (3H, d, J = 6.5Hz), 0.74 (3H, d, J = 6.5Hz).

[0100]

Reference Example 5 13- [1- (4-methoxyacetylaminophenyl) cyclopentanecarbonyloxy] -5-
Hydroxymilbemycin A3 (I: R ¹ = Me, R ² = MeOC
H ₂ CO, Compound No. 9) (1) 13- [1- (4-aminophenyl) cyclopentanecarbonyloxy] -5-hydroxymilbemycin A3 (VI: R ¹ = Me, Steps A to C) In Reference Example 1 , 15-hydroxy-5-oxomilbemycin A4 was used in place of 15-hydroxy-5-oxomilbemycin A3 in Reference Example 1 (1) to
13- [1- (4-Aminophenyl) cyclopentanecarbonyloxy] -5-hydroxymilbemycin A3 was obtained in the same manner as in (3).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.11 (2H, d, J = 8.5Hz), 6.60 (2H, d, 8.5Hz), 5.71
~ 5.78 (2H, m), 5.38 (1H, s), 5.25 ~ 5.40 (3H, m), 4.8
0 (1H, d, J = 10.6Hz), 4.65 and 4.68 (2H, AB-q, J = 13.9
Hz), 4.28 (1H, m), 4.08 (1H, s), 3.95 (1H, d, J = 6.1H
z), 3.59 (2H, broad-s), 3.52 (1H, m), 3.18-3.26 (2H,
m), 2.57 (2H, m), 1.87 (3H, s), 1.31 (3H, s), 1.13 (3
H, d, J = 6.4Hz), 0.83 (3H, d, J = 6.5Hz), 0.77 (3H, d, J
= 6.6Hz).

(2) 13- [1- (4-methoxyacetylaminophenyl) cyclopentanecarbonyloxy] -5-hydroxymilbemycin A3 (I: R ¹ = M
e, R ² = MeOCH ₂ CO, compound number 9, step D) Using the amino compound obtained in (1), the title compound was obtained in the same manner as in Reference Example 1 (4) (yield: 92.3% ).

Nuclear magnetic resonance spectrum (400 MHz) δ (pp
m): 8.21 (1H, s), 7.49 (2H, d, J = 8.6Hz), 7.29 (2H,
d, 8.6Hz), 5.71 ~ 5.78 (2H, m), 5.38 (1H, s), 5.24 ~
5.36 (3H, m), 4.80 (1H, d, J = 10.6Hz), 4.64 and 4.68
(2H, AB-q, J = 13.7Hz), 4.28 (1H, m), 4.07 (1H, s), 4.0
1 (2H, s), 3.95 (1H, d, J = 6.3Hz), 3.51 (3H, s), 3.50
(1H, m), 3.18-3.26 (2H, m), 2.61 (2H, m), 1.87 (3H,
s), 1.28 (3H, s), 1.13 (3H, d, J = 6.3Hz), 0.83 (3H, d,
J = 6.6Hz), 0.76 (3H, d, J = 6.5Hz).

[0104]

[Test Example 1] Oral test Compound of Reference Example 1 (5 mg / kg) and praziquantel (1.25 mg / kg)
(mg / kg) was encapsulated in gelatin in a predetermined amount to prepare a preparation for oral test. As a control, the compound was prepared using the compound of Reference Example 1 alone and fipronil alone, and tested.

Dipylidium caninum and dog worm (T
oxocara canis) naturally infected dogs (2 in each test area)
The preparation was orally administered once. In addition, the infection of dog tapeworm is
Three days before drug administration, it was confirmed by excretion of a piece of dog tapeworm into feces. Infection with canine worm was confirmed by excretion of worm eggs immediately before drug administration. On the 10th day after the administration, the dogs were dissected and the number of surviving C. elegans and Ascaris was counted.

As a result, the combined use of the compound of Reference Example 1 and praziquantel was effective against anthelminths of two kinds of parasites, tapeworm and dogworm. On the other hand, the single use of the compound of Reference Example 1 was effective against the anthelminth of Ascaris suum, but was not effective against the anthelmintic of Ascariasis. In addition, praziquantel alone was effective against tapeworms, but was not effective against anthelminths.

[0107]

[Test Example 2] Spot-on test (tick control test) Compound of Reference Example 1 (10 g) and fipronil (3.8 g)
Was mixed, and the mixture was dissolved in a mixture of benzyl alcohol and propylene carbonate (9: 1) so that the total volume was 100 ml, and 0.05% BHT was further added to prepare a spot-on preparation. As a control, Reference Example 1
The formulations were prepared by using the compound alone in Example 1 and fipronil alone, and tested.

[0108] On the back of the neck of dogs (2 dogs in each test group) naturally infected with mites, the above-mentioned preparation for spot-on in which the dose of the compound of Reference Example 1 was 5 mg / kg was dropped, and dropped for 3 days. Later each dog was examined for tick infection.

As a result, the combined use of the compound of Reference Example 1 and fipronil was effective for the treatment of mite infection, despite the small dosage of fipronil. On the other hand, the single use of the compound of Reference Example 1 was ineffective in the treatment of tick infection. In addition, single use of fipronil was ineffective in treating mite infection due to its low dose.

[0110]

[Test Example 3] Spot-on test (flea extermination test) Cat flea was pre-infected, and after three days the fleas collected from the dog body surface were counted to determine the infection rate (usually 70-90%) for each dog. Using Oita Beagle dogs (4 to 7 months old, 4 dogs), as in Test Example 2, the dose of the compound of Reference Example 1 was 5 mg / kg and the spot-on preparation was applied to each dog's shoulder. Drip between the shells and 100, 100, per dog on days 7, 21 and 28 after dosing
Three cats were infected with a cat flea, the number of collections collected from the dog body surface was counted 3 days later, and the extermination rate was calculated from the ratio of the collection rate after administration and the recovery rate before administration.

As a result, fleas were not collected from the body surface at the 7th, 21st and 28th days after administration, and the extermination rate was 28%.
It was 100% even after a day. In contrast, no significant change in the infection rate was observed in the four dogs in the drug-free group, which were conducted at the same time.

[0112]

INDUSTRIAL APPLICABILITY The composition of the present invention has a high controlling activity against a wide range of endo-ectoparasites, and exhibits an excellent controlling effect against insects parasitic on animals and various diseases caused by parasites.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/415 A61K 31/415 31/4985 31/4985 A61P 33/00 171 A61P 33/00 171 33/10 33/10 33/14 33/14 43/00 121 43/00 121 (72) Inventor Toshimitsu Toyama 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Toshihiko Namba Tokyo 1-58, Hiromachi, Shinagawa-ku Sankyo Stock Company F-term (reference) 4C086 AA01 AA02 BC36 CA03 CB09 MA02 MA04 MA52 MA63 NA05 ZB37 ZB39 ZC61 ZC75 4H011 AC01 AC04 BA06 BB09 BB21 BC03 BC06 BC09 DA13 DF04

Claims (6)

[Claims] 1. A general formula: [In the formula, R ¹ represents a methyl group, an ethyl group, an isopropyl group, or an s-butyl group, and R ² represents an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a cyanoacetyl group, or a methanesulfonyl group. ] One or more first components selected from milbemycin derivatives consisting of the compound represented by the formula or a salt thereof, and 1 selected from the group consisting of praziquantel, fipronil, benzimidazoles and neonicotinoids. A parasite control composition containing one or more second components as active ingredients. 2. The parasite control composition according to claim 1, wherein R ¹ is a methyl group or an ethyl group. 3. The parasite control composition according to claim 1, wherein R ² is a methoxyacetyl group. 4. The parasite control composition according to any one of claims 1 to 3, wherein the second component is praziquantel or fipronil. 5. The parasite control composition according to any one of claims 1 to 3, wherein the second component is praziquantel, epsiprantel or fipronil. 6. A parasite control composition according to any one of claims 1 to 5 is orally or locally administered,
How to control internal and external parasites.