WO2008056608A1

WO2008056608A1 - Avermectin monoglycoside derivatives

Info

Publication number: WO2008056608A1
Application number: PCT/JP2007/071398
Authority: WO
Inventors: Satoru Kondo; Hiroyuki Okita; Daigo Okamura; Shuji Itakura; Jun Suzuki; Katsuhiko Iwasaki; Hideyuki Murakami; Tsunehiro Kido
Original assignee: Hokko Chemical Industry Co., Ltd.
Priority date: 2006-11-07
Filing date: 2007-11-02
Publication date: 2008-05-15
Also published as: JP2010006703A

Abstract

The invention aims at providing novel 4'-substituted avermectin monoglycoside derivatives which have excellent miticidal, insecticidal or antiparasitic activity and exert excellent control activity against mites or excellent effects against various disease damages caused by animal parasites. The invention provides avermectin monoglycoside derivatives represented by the general formula (I) or salts thereof; and miticides, insecticides or antiparasitics containing the same as the active ingredient: [wherein R1 is isopropyl or sec-butyl; and A is a five- or six-membered or fused ring containing one or more atoms which are selected from the group consisting of oxygen, nitrogen and sulfur and may be the same or different with the provisos that the ring may be unsubstituted or substituted with one or two substituents and that when A is a nitrogen-containing ring, N-oxide may be formed.]

Description

Specification

Avermectin monoglycoside derivatives

Technical field

[0001] The present invention provides an acaricidal agent by adding a heterocyclic carbonyl group to the 4'-position hydroxyl group of a monodeandrose glycoside of avermectins from which one oleandrose is eliminated from avermectins. And avermectin monoglycoside derivatives with enhanced anthelmintic, nematicidal or insecticidal activity. Background art

[0002] Avermectins are a series of 16-membered ring macrolide compounds, which are known compounds represented by the following formula (II) (see Patent Document 1).

[Chemical 1]

Ri Compound name

s- ₄ H ₉ avermectin B _la

1-C ₃ h ₇ Avermectin B _lb

[0003] Monoglycoside derivatives of avermectins are known compounds represented by the following formula (III) (see Patent Document 2).

[0004] The avermectins are known to have acaricidal, anthelmintic or insecticidal activity, and various substitutions are made at their 4 "-position or the 4'-position hydroxyl group of the monooleandrose glycoside of avermectins. Semisynthetic avermectins into which a group has been introduced have also been reported to have the above biological activity.

[0005] Avermectins having a substituent by an ester bond at the 4 "-position of avermectins or the 4'-position of monooleandrose glycosides of avermectins include substituted or unsubstituted lower alkanoic acids and benzoic acids. Also known is an avermectin derivative ester-bonded at the 4 "-position of avermectins or the 4'-position hydroxyl group of monooleandrose glycosides of avermectins (Patent Document 3) reference).

[0006] Semi-synthetic avermethatins in which various substituents are introduced into the 5-position hydroxyl group of avermectins have also been reported to have the above biological activity! As avermectins having an ester bond at the 5-position hydroxyl group, avermectin derivatives in which a chrysanthemic acid derivative, a heterocyclic carboxylic acid derivative or the like is ester-bonded to the 5-position hydroxyl group are known (see Patent Document 4).

[0007] As described above, a number of reports have been made on avermectin derivatives. Force of unsubstituted or substituted heterocyclic carboxylic acid derivatives S, ester bond to 4'-hydroxyl group of monooleandrose glycosides of avermectins The avermectin derivative thus obtained has not yet been reported.

Patent Document 1: JP-A 52-151197 Patent Document 2: U.S. Pat.No. 4,206,205

Patent Document 3: Japanese Patent Laid-Open No. 54-61197

Patent Document 4: Chinese Patent CN1302805

Disclosure of the invention

Problems to be solved by the invention

[0008] Avermectins have been put into practical use as acaricide, anthelmintic or insecticide! /, And are all classified as poisonous or deleterious substances with high toxicity. In particular, avermectin Bla / Blb shows high acaricidal activity, but its use is limited because it is itself a toxic equivalent. An object of the present invention is to provide a novel avermectin derivative compound having superior acaricidal, insecticidal or anthelmintic activity and / or low toxicity and high safety against mites, plant pests or animal parasites It is to be.

Means for solving the problem

[0009] The present inventors examined the effects of various avermectin derivative compounds in order to provide agro-horticultural acaricides, insecticides or antiparasitic agents against animal parasites that meet the above objectives. As a result, the ability of avermectin derivatives newly formed by ester-bonding heterocyclic carboxylic acid derivatives to the 4'-position hydroxyl group of monooleandrose glycosides of avermectins Strong biological activity and / or low toxicity and high as shown below The present invention has been found to have safety, and the present invention has been completed.

[0010] That is, the present invention relates to the general formula (I)

[0011] (wherein R represents an isopropyl or sec-butyl group, A represents a heterocyclic ring, oxygen

1

A 5-membered ring, a 6-membered ring or a condensed ring containing the same or different one or two or more atoms selected from the group consisting of an atom, a nitrogen atom and a sulfur atom, which ring is an unsubstituted ring Or a halogen atom, a nitro group, a cyano group, a carboxyl group, C

1 to C 6 alkyl group, c to c haloalkyl group, hydroxyl group, thiol group, amino group, c

1 6 1 to c

6 rualkyloxy group, C-C haloalkyloxy group, C

1 6 1-C alkylthio group, C

6 1 ~ C

6 alkylsulfoxyl group, c-c alkylsulfonyl group, c-C alkylamino group, C

1 6 1 6 1

~ C alkylcarbonyl group, C ~ C alkyloxycarbonyl group, C ~ C alkano

6 1 6 1 6 When the above A, which may be substituted with 1 to 4 substituents selected from an ilyamino group, contains a nitrogen atom as its ring constituent atom, the nitrogen atom Forms an N-oxide! /, Even! / ) Avermectin monoglycoside derivatives or salts thereof, and acaricides and insecticides or insecticides containing these as active ingredients.

[0012] Further preferably in the present invention, A in the general formula (I) is thiadiazole, age-old diazazoinole, thi-day phen, thiazole, isothiazole, iso-aged zonazore, oxazole, benzisothiazole, cinnoline, pyridine, Pyridazine, benzothiadia zonore, benzoxaziazolene, furan, pyrozinole, pyrazonole, imidazonole, triazole, tetrazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, benzofuran, benzothiophene, indanol, benzoimidazole, benzoimidazole Nore, benzo Triazonole, benzoxazonole, benzisoxazonole, benzothiazonole, pyrimidine, triazine, tetrazine, and pyrazine (the power of these rings being unsubstituted, or

, Halogen atom, nitro group, cyano group, canolepoxinole group, c

1-c alkyl group, c

6 1 to c

6 mouth alkyl group, hydroxyl group, thiol group, amino group, C

1-C alkyloxy group, C

6 1

~ C haloalkyloxy group, c ~ c alkylthio group, c ~ c alkylsulfoxyl

6 1 6 1 6

Group, C-C alkylsulfonyl group, C-C canolequinoleamino group, C-C alkylcarbo

1 6 1 6 1 6 From nyl, c-c alkyloxycarbonyl and c-c alkanoylamino groups

1 6 1 6

When the above-mentioned A, which may be substituted with the same or different selected 1 to 4 substituents, contains a nitrogen atom as its ring-constituting atom, the nitrogen atom forms an N-oxide. Then! / But! )! /, Or avermectin monoglycoside derivative or its salt. .

[0013] More preferable compounds include a force in which A in the general formula (I) is an avermectin monoglycoside derivative that is thiadiazole or a salt thereof, or avermectin in which A in the general formula (I) is cinnoline. It is a monoglycoside derivative or a salt thereof.

[0014] The present invention is also the use of the avermectin monoglycoside derivative represented by the above general formula (I) or a salt thereof for acaricidal and insecticidal or anthelmintic action.

[0015] The present invention also relates to an acaricidal method, an insecticidal method, or an anthelmintic method, wherein the general formula (

A method using the avermectin monoglycoside derivative represented by I) or a salt thereof.

The invention's effect

[0016] The novel 4'-substituted avermectin monoglycoside derivative of the present invention represented by the general formula (I) has an acaricidal, insecticidal or anthelmintic activity and is effective for controlling mites or animal parasites. It shows excellent effects against various diseases caused by the disease. In particular, for mites, both avenolemethatin and mites that are difficult to market are effective. In addition, the novel compound of the present invention provides a miticide, insecticide or anthelmintic agent with low toxicity, classified as a normal product according to the classification based on the Poisonous and Deleterious Substances Control Law, and highly safe for human livestock. That's the power S.

[0017] That is, the compound of the present invention is a tranquil family (Tetrany) that is parasitic on fruit trees, vegetables and flower buds. It has acaricidal activity against adults and eggs of ticks such as chidae and Eriophydae, parasitoids (kodidae), Dermanyssidae and Sarcoptidae that parasitize animals. The existing acaricides that can be used with potatoes are no longer effective, and have become a problem in recent years, and have an excellent effect against drug-resistant mites! Examples of such ticks can include the following ticks. For example, Nami Hadaji, Kanzaka Hadaji, Tangerine Spider Mite, Apple Spider Mite, Tyano Dust Mite, Tangerine Sabida II, etc. can be mentioned.

[0018] The compound of the present invention can also be used as an insecticide due to its strong insecticidal effect, and can be used for a wide variety of harmful insects, harmful sucking insects, chewing without causing phytotoxicity to cultivated plants. Exhibits accurate control against sexual insects and other plant parasitic insects. In addition, it can be used to control stored insects and sanitary insects, and can be applied to eliminate them.

BEST MODE FOR CARRYING OUT THE INVENTION

[0019] The compounds of the present invention are described in detail below.

In the general formula (I), examples of the heterocyclic ring constituting the A moiety include thiadiazole, oxadiazanole, thiophene, thiazole, isothiazole, isoxazanole, oxazol, benzisothiazole, cinnoline, pyridine, pyridazine, Benzothiadiazole, benzoxaziazonore, furan, pyrozinole, pyrazonore, imidazonole, triazonore, tetrazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, benzofuran, benzothiophene, indanol, indazonozore, benzoimidazolorizore Nitrogen, oxygen or sulfur sources such as mononole, benzoxazonole, benzoisoxazonole, benzothiazonole, pyrimidine, triazine, tetrazine, and pyrazine Examples thereof include a 5-membered ring, a 6-membered ring or a heterocyclic ring having one or two or more atoms selected from the children as a ring atom.

[0020] Examples of the "halogen atom" included in the heterocyclic substituent group include fluorine, chlorine, bromine and iodine atoms.

[0021] The "C C alkyl group" included as one of the substituent groups of the heterocyclic ring has carbon number;

1 6

Linear or branched alkyl groups, examples of which include methyl, ethyl, n Propyl group, isopropyl group, n butyl group, isobutyl group, sec butyl group, tert butyl group, n pentyl group, isopentyl group, 2-methylbutyl group, neopentinole group, n hexyl group, 4-methylpentyl group, 3 methylpentyl group, 2-methylpentyl group, 3,3-dimethylbutyl group, 1,1-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group, 1-methyl-1-ethylpropyl group, 1,2-dimethyl group Examples thereof include a butyl group, a 2-methyl-1-ethylpropyl group, and a 2,2-dimethylbutyl group.

[0022] The "C C haloalkyl group" included as one of the substituent groups of the heterocyclic ring has a carbon number of 1 to

1 6

Examples are 6 straight-chain or branched, and examples include fluoromethyl group, chloromethylol group, bromomethyl group, odomethyl group, difluoromethyl group, dichloromethyl group, trichloromethyl group, 2-fluoroethyl group, and 2-chloroethyl group. Group, 2-bromoethyl group, 1-fluoroethyl group, 1,1-difluoroethyl group, 2, 2,2-trifluoroethyl group, pentafluoroethyl group, 1 fluoropropyl group, 3-fluoropropyl group, 2- Chloropropynole group, 3-chloropropinole group, 3-iodopropinole group, heptafluororeinopropinole group, 1 fluorobutyl group, 4 fluorobutyl group, 1 chlorobutyl group, 5-fluorofluoropentyl group, 6-fluorine hexyl group, Fluorine, salt or the like on the above CC alkyl group such as tridecafluoro hexyl group A halogen atom such as bromine or iodine formation

1 6

Means a combined alkyl group.

[0023] "C C alkoxy group (alkyloxy group) included as one of the substituent groups of the heterocyclic ring

1 6

Group) ”is a group in which a linear or branched alkyl group having 1 to 6 carbon atoms is bonded to an oxygen atom. Examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group. Group, n butoxy group, isobutoxy group, sec butoxy group, tert butoxy group, n pentoxy group, isopentoxy group, 2-methylbutoxy group, neopentoxy group, n-hexoxy group, 4-methylpentoxy group, 3-methylpentoxy group Group, 2-methylpentoxy group, 3,3 dimethyl / leptoxy group, 1,1 dimethyl / lbutoxy group, 1,3-dimethyl / leptoxy group, 2,3-dimethylbutoxy group, 1 ethylbutoxy group, 1-methyl-1 ethyl group Examples thereof include a propoxy group, 1,2-dimethylenobutoxy group, 2-methinole-1-ethinorepropoxy group, 2,2-dimethylenobutoxy group and the like. The “CC haloalkyloxy group” included as one of the substituent groups of the heterocyclic ring is, for example,

1 6

For example, a linear or branched alkyl group having 1 to 6 carbon atoms is bonded to an oxygen atom, and one or more halogens selected from the group consisting of fluorine, chlorine, bromine or iodine Means one or more substituted atoms. Examples include fluoromethoxy group, chloromethoxy group, bromomethoxy group, odomethoxy group, difluoromethoxy group, dichloromethoxy group, trichloromethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 2-bromoethoxy group. Group, 1 fluoroethoxy group, 1, 1-difluoroethoxy group, 2, 2, 2-trifluorofluoro group, pentafluoroethoxy group, 1 fluoropropoxy group, 3 fluoropropoxy group, 2 Black mouth propoxy group, 3 Black mouth propoxy group, 3 Rhodopropoxy group, Heptafluoroisopropoxy group, 1 Fluorobutoxy group, 4-Fluorobutoxy group, 1 Chlorobutoxy group, 5-Fluoropentoxy group, 6— Examples thereof include a fluoroxy hexoxy group and a tridecafluor hexoxy group.

[0025] In the general formula (I), "C included as a group of substituents of the heterocyclic ring constituting the A moiety"

1

`` C alkylthio group '' is a straight or branched alkyl group having 6 to 6 carbon atoms;

6

Examples thereof include methylthio group, ethylthio group, n-propinothio group, isopropylthio group, n butylthio group, isobutylthio group, sec butylthio group, tert butylthio group, n pentylthio group, Isopentylthio group, 2-methylbutylthio group, neopentylthio group, n-hexylthio group, 4 methylpentylthio group, 3 methylpentylthio group, 2 methylpentylthio group, 3, 3 dimethylbutylthio group, 1, 1 dimethylbutylthio group, 1,3 dimethylbutylthio group, 2,3 dimethylol butylthio group, 1-ethylbutylthio group, 1-methyl-1-ethylpropylthio group, 1,2-dimethylbutylthio group, 2-methyl- Examples thereof include 1-ethylpropylthio group and 2,2-dimethylbutylthio group.

In the general formula (I), “C included as one of the substituent groups of the heterocyclic ring constituting the A moiety”

1

The “C alkylsulfoxyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms.

6

Examples are groups bonded to the sulfur atom of a sulfoxyl group. Examples thereof include methylsulfoxyl group, n-butylsulfoxyl group, isobutylsulfoxyl group, sec-butylsulfoxy group. Nore group, tert butylsulfoxyl group, n pentylsulfoxyl group, isopentyls norefoxyl group, 2-methylbutylsulfoxyl group, neopentylsulfoxyl group, n-hexylsulfoxyl group, 4 methylpentylsulfoxyl group, 3- Methylpentyls noroxyl group, 2 Methylpentylsulfoxyl group, 3, 3 Dimethylbutylsulfoxy group

And the like.

In the general formula (I), “C included as a group of substituents of the heterocyclic ring constituting the A moiety”

1

`` C alkylsulfonyl group '' is a straight or branched alkyl group having 1 to 6 carbon atoms.

6

Examples thereof include a group bonded to a sulfur atom of a sulfonyl group. Examples thereof include a methylsulfonyl group, an ethylsulfonyl group, an npropylsulfonyl group, an isopropylsulfonyl group, an n-butinosenorephoninore group, and an isobutinoresnorehole. Ninore group, sec Butinolesnorehoninore group, tert Butinosenosulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group, 2-methinore butinoresnorehoninore group, neopentinoresnorehoninore group, n Hexinores nolehoninole group, 4-methylpentylsulfonyl group, 3 methylpentylsulfonyl group, 2 methylpentylsulfonyl group, 3,3-dimethylbutylsulfonyl group, 1,1 dimethylbutylsulfonanol group, 1,3 Dimethylbutylsulfonyl group, 2, 3 Dimethylbutylsulfonyl group, 1-ethylbutylsulfonyl group 1-methyl-1-ethylpropylsulfonyl group, 1, 2

Examples thereof include 2-dimethylbutylsulfonyl group.

[0028] In the general formula (I), "C included as one of the substituent groups of the heterocyclic ring constituting the A moiety"

1

`` C alkylamino group '' is a linear or branched alkyl group having 1 to 6 carbon atoms.

6

Or two bonded groups with a nitrogen atom, and when there are two alkyl groups, the alkyl groups may be the same or different. Examples include methylamino group, dimethylamino group, ethylamino group, jetylamino group, n-propylamino group, di-n-propylamino group, isopropylamino group, n-butynoleamino group, di-n-butylamino group, iso-butylamino group, sec -Butylamino group, tert-butylamino group, n-pentylamino group, isopentylamino group, 2-methylbutylamino group, neopentylamino group, n-hexylamino group, 4-methylpentylamino group, 3-methylpentylamino group, 2-methylpentyl group Amino group, 3,3-dimethylbutylamino group, 1,1-dimethylbutylamino group, 1,3-dimethylbutylamino group, 2,3 dimethylbutylamino group, 1-ethylbutylamino group Examples thereof include a 1-methyl-1-ethylpropylamino group, a 1,2-dimethylbutylamino group, a 2-methyl-1-ethylpropinoleamino group, and a 2,2-dimethylbutylamino group.

[0029] In the general formula (I), "C C included as a substituent group of the heterocyclic ring constituting the A moiety"

The “1 6 alkylcarbonyl group” is a group in which a linear or branched alkyl group having 1 to 6 carbon atoms is bonded to a carbon atom of a strong sulfonyl group. Examples thereof include a acetyl group, ethynole group and the like. Carbonyl group, n propylcarbonyl group, isopropylcarbonyl group, n butynole carbonyl group, isobutylcarbonyl group, sec butylcarbonyl group, tert butynole carbonyl group, n pentylcarbonyl group, isopentylcarbonyl group, 2-methylbutynolecanonole ponole group , Neopentinorecanoleponinole group, n-Hexinorecanoleponinole group, 4-Methylpentylcarbonyl group, 3 Methylpentylcarbonyl group, 2 Methylpentylcarbonyl group, 3, 3-Dimethylbutylcarbonyl group, 1, 1 -Dimethylbutylcarbo 2-nole group, 1, 3 Dimethylbutylcarbonyl group, 2, 3 Methylbutylcarbonyl group, 1-ethylbutylcarbonyl group, 1-methyl-1-ethylpropylcarbonyl group, 1,2-dimethylbutylcarbonyl group, 2-methyl-1-ethylpropylcarbonyl group, 2,2-dimethylbutylcarbonyl group, etc. It can be illustrated.

In the general formula (I), “C C included as one of the substituent groups of the heterocyclic ring constituting the A portion

A `` 1 6 alkyloxycarbonyl group '' is a group formed by bonding to an oxygen atom of a linear or branched alkyl group, force S carbonyloxy group having 6 to 6 carbon atoms. Carbonyl group, ethoxycarbonyl group, n propoxycarbonyl group, isopropoxycarbonyl group, n butoxycarbonyl group, isobutoxycarbonyl group, sec butoxycarbonyl group, tert butoxycarbonyl group, n pentoxycarbonyl group, isopentoxycarbonyl group, 2- Methylbutoxycarbonyl group, neopentoxycarbonyl group, hexoxycarbonyl group, 4-methylpentoxycarbonyl group, 3-methylpentoxyca Norebonyl group, 2-methylpentoxycarbonyl group, 3, 3 dimethylbutoxycarbonyl

, 3-Dimethylbutoxycarbonyl group, 1-Ethylbutoxycarbonyl group, 1-Methyl-1-etinorepropoxycananolepinore group, 1,2-Dimethylenobutoxycanorepoinole group, 2-Methylenole 1-ethylpropoxy group The ability to display carbonyl groups, 2,2-dimethylbutoxycarbonyl groups, etc.

[0031] The "C C alkanoylamino group" included as one of the substituent groups of the heterocyclic ring is, for example,

1 6

For example, it means an amino group having an alkanol group having 1 to 6 carbon atoms such as formylamino group, acetylamino group, propionylamino group, butyrylamino group.

[0032] In the present invention, as the salt of the avermectin monoglycoside derivative represented by the general formula (I), a pharmacologically acceptable salt is preferable. And salts with acids, inorganic acids, organic bases or inorganic bases.

Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, benzoic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, succinic acid, succinic acid, malic acid, methanesulfonic acid, Examples include salts with benzenesulfonic acid, p-toluenesulfonic acid, and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethinole) methylamine], tert-butylamine, Examples include salts with cyclohexylamine, benzenolamine, dicyclohexylamine, N, N dibenzylethylenediamine.

Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt and the like.

Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like. Among the above-mentioned salts, salts with organic acids or organic bases are preferred. Further, as salts with organic acids, salts with acetic acid, benzoic acid, etc. are preferred. Examples of salts with organic bases include triethylamine. I like the salt!

In addition, the salt in this invention is not limited to said salt at all.

Examples of typical substituents on the 4′-position hydroxyl group of the novel avermectin monooleandrose glycoside derivative in the present invention are shown in Tables 11 to 13 below. However, the present invention is not limited to the compounds having the substituents exemplified in these tables.

[0034] In Table 11 to Table 13, the retention time (HPLC retention time) in high performance liquid chromatography is described as the physicochemical property value of the compound of the present invention having each substituent. Regarding the HPLC retention time, the measurement conditions (column used, eluent, flow rate, etc.) will be described in detail in the examples described later.

[0035] [Table 1-1]

//: / O 86εϊ / -0 / -00ί1 £ 80SAV ε

[Table 1-2]

[Table 1-3] Compound HPLC retention time number AB _1a B _1b

27 16.86 15.92

28

XT 16.86 15.92

29 15.49 14.38

30 8.61 6.68

]

-8]

[0036] Process for producing the compound of the present invention

The compound represented by the general formula (I) of the present invention can be produced by the method shown in the following process diagram.

[0037] [Process for producing the compound of the present invention represented by the general formula (I)]

[Chemical 4]

The natural product avermectin Bl represented by the general formula (II), which is the starting material of this production method, can be fermented and produced according to a known method described in Patent Document 1 or the like. A commercially available product can also be used. Commercially available avermectin is ranked 25th A mixture of avermectin Bla and avermectin Bib substituted with til and isopropyl groups, respectively, and the composition contains about 96% "Bla" component and about 4% "Bib" component. The avermectin as a starting material for the compound of general formula (I) can be either a single compound obtained by further purifying a mixture of avermectin Bla and avermectin Bib, or a mixture thereof.

[0039] The heterocyclic compound represented by the general formula (V), which is another starting material of the present production method, can be produced by a known method, or a commercially available product can be used.

[0040] [Chemical 5]

0 to OH (V)

[0041] Hereinafter, a method for producing the compound of the present invention represented by the general formula (I) from avermectins (II) will be described in detail step by step.

[0042] [Production process 1]

Production process 1 is a process for producing an avermectin monooleandrose glycoside by acid hydrolysis or alcoholysis of one oleandrose at the end of avermectin.

Examples of the acid used include inorganic acids such as sulfuric acid or hydrochloric acid, and organic acids such as trifluoroacetic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and parachlorobenzenesulfonic acid. It is sulfuric acid. The amount of acid used can vary greatly depending on the power at which about 1 equivalent is preferred, the type of acid and solvent used.

Examples of the solvent used in the reaction include water, methanol, ethanol, 1 propanol, 2 propanol, 1-butanol, 2-butanol, and t-butanol. Of these, 2-propanol is preferred. In addition, a solvent that does not inhibit the reaction and dissolves the starting material to some extent may be added to the solvent used in the reaction. Preferably, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform; ethyl acetate and acetate Esters such as mouth pills; ethers such as jetyl ether, tetrahydrofuran, dioxane, dimethoxetane, dimethinorenolemamide, dimethylacetamide

Raise the power of S.

The reaction temperature is −10 ° C. to 100 ° C., preferably 10 ° C. to 50 ° C. The reaction time mainly depends on the reaction temperature or the type of solvent used, but is usually 5 hours, 100 hours. Preferably, it is 10 hours to 50 hours.

[0043] [Production process 2]

Production process 2 is a process for protecting the 5-position hydroxyl group of avermectin monooleandrose glycoside. The hydroxyl group at the 7 position is very reactive and need not be protected. As a protecting group, it reacts with the 5-position hydroxyl group with good selectivity, does not affect the reaction at the 4'-position hydroxyl group, and can be easily removed without affecting other parts of the molecule. Any of them can be used.

Examples of the protecting group for the 5-position hydroxyl group of the avermectin monooleandrose glycoside represented by R in the general formula (IV) include trimethylsilyl group, triethylsilyl group, triisopropylaminosilyl group, dimethylisopropylsilyl group, t- Butyldimethylsilyl group, t-butyl diphenyleno !! Nore group, 卜!; ^ Nzinoresi !; Nore group, 卜!; P-xy !; Noresi !; Nore group, 卜!; Phenonosyllinole group, Diphenylmethylsilyl group, Di-t Examples include tri-substituted silyl groups such as -butylmethylsilyl group, t-butylmethoxyphenylsilyl group, and tbutoxydiphenylsilyl group. A trialkylsilyl group is preferable, and a t-butyldimethylsilanol group is particularly preferable.

Avermectin monooleandrose glycoside is dissolved in an aprotic solvent such as dimethylformamide, and imidazole is added as a base. By adding t-butyldimethylsilyl chloride to this solution and reacting it, the 5-position hydroxyl group is almost selectively protected. The reaction temperature is 10 ° C to 50 ° C, preferably 0 ° C to 25 ° C. The reaction time depends mainly on the reaction temperature or the type of solvent used. The force is usually 0.5 hours. The force is also 24 hours. Preferably, it is 0.5 hours to 3 hours.

[0044] [Manufacturing process 3] Production process 3 is a reaction in which an acid represented by A-COOH (general formula (V)) or a reactive derivative thereof is esterified to the 4 ′ position of the avermectin monooleandrose glycoside in which the 5-position is protected. is there.

Examples of the reactive derivative of the acid represented by the general formula (V) include acid halides (acid chloride, acid bromide, etc.), acid anhydrides, mixed acid anhydrides, active esters, active amides, etc. What is used is mentioned.

In the case of using an acid represented by the general formula (V), for example, dicyclooctyl carpositimide (DCC), 2-iodine chloride 1-methylpyridinium, 2-chloro chloride 1,3- Dehydrating agents such as dimethylimidazoline (DMC), 1-ethyl-3- (3-dimethylaminopropyl) carpositimide (EDC) hydrochloride, p-toluenesulfonic acid and sulfuric acid are used. Preferable examples include 2-chloro-1,3-dimethylimidazolium chloride. The amount used is usually !! to 5 equivalents, preferably;! To 2 equivalents, relative to the acid represented by the general formula (V).

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. Preferably, hydrocarbons such as hexane, petroleum ether, benzene, and toluene, Halogenated hydrocarbons such as form, methylene chloride, 1,2-dichloroethane, ethers such as jetyl ether and tetrahydrofuran, sulfoxides such as dimethyl sulfoxide, nitriles such as acetonitrile, and the like. Mixtures of solvents, etc., particularly preferably methylene chloride or 1,2-dichloroethane. The reaction temperature is usually between -10 ° C and 90 ° C, preferably between 0 ° C and 60 ° C. The reaction time varies mainly depending on the reaction temperature, raw material compound, reaction reagent or the type of solvent used, but is usually 15 minutes to 24 hours, preferably 30 minutes to 12 hours.

When an acid halide represented by the general formula (V) is used, the reaction is carried out in the presence of a base. Examples of suitable bases include triethylamine, N, N-dimethylaniline, pyridine, 4-dimethylamine. And organic bases such as minopyridine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN) or 1,8-diazabicyclo [5.4.0] undecene-7 (DBU). The acid halide represented by formula (V) is usually used in an amount of 1 to 10 equivalents, and the base is usually used in an amount of 2 to 8 equivalents. The solvent used for the reaction is the same as in the case of using carboxylic acid itself. The reaction is usually carried out at 0 ° C to 50 ° C, and the reaction time is 5 minutes to 12 hours. [0045] [Manufacturing process 4]

Production step 4 is a step of removing the 5-position protecting group introduced in production step 2 from the 4 ′ O heterocyclic carbonyl avermectin monooleandrose glycoside derivative by acid treatment.

Acids used include inorganic acids such as sulfuric acid, hydrochloric acid or hydrofluoric acid, acetic acid, triphenoloacetic acid, trifnoleolomethanesulphonic acid, benzenesulfonic acid, paratonoleensnolephonic acid, parachlorobenzenesulfone. Preference is given to organic acids such as acids, and other various H ⁺ type strongly acidic or weakly acidic ion exchangers. Paratoluenesulfonic acid is preferred. The amount of acid used is a force that can vary greatly depending on the type of acid and solvent used, usually from 0.;! To 10 equivalents. The amount is preferably 0.5 to 2 equivalents.

Solvents used for the reaction include water, methanol, ethanol, 1 propanol, 2 propanol, 1-butanol, alcohols such as 2-butanol and t-butanol, and aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, and cycloform; esters such as ethyl acetate and propyl acetate; ethers such as jetyl ether, tetrahydrofuran, dioxane, and dimethoxetane, dimethyl Key words such as norehonolemamide and dimethylacetamide

I'm curious to cite the laver. These mixed solvents may be used.

Further, if necessary, an organic base such as ammonia, triethylamine, pyridine, tetrapropylamine, or crown ether may be added to the reaction solvent.

The reaction temperature is 10 ° C to 100 ° C, preferably 0 ° C to 30 ° C. The reaction time is usually 10 minutes to 50 hours, depending on the reaction temperature or the type of solvent used. Preferably, it is 0.5 hours to 5 hours.

[0046] After the reaction in each of the above production steps;! To 4, the target reaction product compound is isolated from the reaction mixture by a well-known method and, if necessary, by a known means such as column chromatography. It may be purified.

[0047] The novel 4'-substituted avermectin monoglycoside derivative of the present invention represented by the above general formula (I) has an acaricidal, insecticidal or anthelmintic activity and is effective for controlling mites or animal parasites. One Excellent effect against various diseases caused by In particular, for mites, excellent effects are shown even for mites that do not work well with avermethatin or commercial agents. Moreover, the novel compound of the present invention is classified as a normal product with low toxicity, and can provide an acaricide, insecticide or anthelmintic agent that is highly safe for human livestock.

[0048] That is, the compounds of the present invention include adults and eggs of mites such as Tetrany chidae and Eriophydae that parasitize fruit trees, vegetables, and flowers, and ticks (Ixodidae) that parasitize animals. ), Mites such as Dermanyssidae and Sarcop tidae, have an acaricidal activity! / It also has an excellent killing effect against drug-resistant mites. Examples of such ticks include urticae, kanza spider mites, citrus spider mites, apple spider mites, chianodokoridani, mandarin oranges, and the like.

[0049] The compounds of the present invention also show a strong insecticidal effect. They can therefore also be used as insecticides. That is, the compound of the present invention exerts an accurate control effect against a wide variety of harmful insect pests, harmful sucking insects, chewable insects and other plant parasitic insects without causing phytotoxicity to cultivated plants. To do. In addition, it can be used for the control of stored pests and sanitary pests, and can be applied to eliminate them.

[0050] Examples of such pests include the following pests. Insects such as Coleoptera, Azuki beetles, Kokuzoumushi, Kokunosutomodoki, Nijuyahoshitento, Tobiiro Naposo-kotsume, Himekogane, Colorado potato beetle, Matsuno madrid insect, Mysidae , Beetles, caterpillars, hornworms, moths, yukameichu, lantern moths, kona madarameiga, kakakumonhamaki, codling moths, power braga, moth migiga, etc .; Aphid, peach aphid, apple aphid, moth aphid, two radish aphids, pear peas, chivalaneus bugs, bed bugs , Onshikkona lice, psyllid like; Thysanoptera pests, for example, Frankliniella thistle © Ma, palmi thistle © Ma, Negiazamiuma like; Orthoptera pests, for example, mole crickets, grasshoppers, etc., Dictyoptera pests, for example, Ji Ganoderma cockroaches, cicada monkeys, etc .; Coleopterous insects, for example, Crested termites, house termites, etc .; It is also useful as a nematicide to control soil nematodes, which are problematic in upland crops and vegetables, and pinewood nematodes that parasitize pine and cause pine wilt.

[0051] In addition, it is effective for use against various harmful animal parasitic insects (internal and external parasites). Examples of such animal parasitic insects include the following pests. For example, you can use the power S to cite fly flies, fly flies, white lice, sand turtles, ticks, and nunomids.

[0052] Furthermore, the compound of the present invention has excellent parasiticidal activity as an anthelmintic against animal and human parasites.

In particular, it is effective against the following nematodes that infect livestock, poultry and pets such as pigs, hidges, goats, horses, horses, dogs, cats and chickens. Hemonx, Tricostlongils, Ostertagia, Nematogillus, Couperia, Ascaris, Bnostomam, Esphagostomaum, Shoveltia, Trichyulis, Strongillus, Triconema, Ditatiosaurus Genus, Carilla, Heterakis, Toxocarra, Ascaridia, Oxylus, Ankylostoma, Uncinaria, Toxacaris and Parascalia.

Some species of the genus Nematogillus, Couperia and Esophagostoma attack the intestine, while those of the genus Hemonx and Ostertagia parasitize the stomach, and parasites of the genus Dyatiocaurus are found in the lungs The force S, the compounds of the present invention also show activity against these. In addition, the Philariaceae parasites are the forces found in other tissues and organs such as the heart and blood vessels, subcutaneous and lymphatic tissues. The compounds of the present invention are also active against them.

[0053] The compounds of the present invention are also useful against parasites that infect humans. For example, the most common parasites that parasitize the human digestive tract, Ankylostoma, Necatol, Wascalis, Strangleroides, Trichinella, Cabrilla, Trichyulis and Enterobius, Found in outside blood or other tissues and organs Special parasites of the other medically important parasites of the genus Buchereria, Filgia, Onchocerca and Roar, and the Serpentine nematode, Drakrunklus, as well as intestinal parasites It is also active in Stromboloides spp. And Trihinella spp.

[0054] When the compound of the present invention is used as an anthelmintic agent in animals and humans, it can be orally administered as a liquid beverage. Beverages are usually prepared as solutions, suspensions or dispersions using suitable non-toxic solvents or water, together with suspending agents such as bentonite and wetting agents or other excipients. Generally, when used as a beverage form, an antifoaming agent is included. In beverage formulations, the compound of the present invention is generally contained in an amount of about 0.01 to 0.5% by weight, preferably 0.01 to 0.1% by weight.

[0055] It is desirable to administer orally in a dry solid unit use form! In some cases, it is preferred to use capsules, pills or tablets containing the desired amount of a compound of the invention. These forms of use consist of active ingredients combined with suitable pulverized diluents, fillers, disintegrants and / or binders such as starch, lactose, talc, magnesium stearate, plant gum and the like. Manufactured by mixing homogeneously. Such unit use formulations can vary widely with respect to the weight and content of the anthelmintic, 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.

[0056] When administered together with animal feed, the compound of the present invention is used as a force, a top dressing, or in the form of pellets to uniformly disperse the feed. In order to achieve the desired antiparasitic effect, it is preferred that the compound of the present invention is mixed in the final feed in an amount of 0.000;

In addition, a compound in which the compound of the present invention is dissolved or dispersed in a suitable solvent or a liquid carrier such as water can be administered parenterally to animals by injection into the stomach, intramuscularly, intratracheally or subcutaneously. Touch with S.

For parenteral administration, the compound of the present invention is preferably used by mixing with an appropriate vegetable oil such as peanut oil or cottonseed oil. In parenteral administration formulations, it is generally preferable to contain 0.05 to 50% by weight of the compound of the present invention.

[0057] Further, the compound of the present invention may be a suitable simple substance such as dimethyl sulfoxide or a hydrocarbon solvent. It can also be made into a preparation that can be administered topically by mixing with. Such formulations are applied directly to the external surface of the animal by spraying or direct injection.

[0058] The optimal amount of compound of the present invention to obtain the best results depends on the type of animal being treated and the type and extent of parasitic infection, but is generally about 0.01 to 1 kg animal weight; It is preferable to orally administer 0.5-50. Omg << preferably. The compounds of the present invention are given over such a short period of time as 1 to 5 days, in such a dose or in divided doses.

[0059] When the compound of the present invention is used as an agricultural or horticultural agent, it may be used alone, but it is preferable to use it by formulating a conventional formulation in the art depending on the purpose. That is, the compound of the general formula (I) or a salt thereof and an appropriate carrier, surfactant, or other formulation adjuvant can be blended to prepare a formulation generally used as an agrochemical formulation. For example, according to conventional methods, wettable powder, granular wettable powder, emulsion, liquid, flowable powder, powder, DL (driftless type) powder, flow dust, fine powder, granule, tablet, spray, microcapsule It can be formulated into a seed coating agent. The dosage forms that can be formulated are not limited to those listed here.

[0060] Solid carriers used in the above formulation include kaolin, bentonite, clay, montmorillonite, talc, vermiculite, attapul guide, diatomaceous earth, silica sand, synthetic silicate, calcium carbonate, calcium phosphate, alumina, white Examples include carbon, ammonium sulfate, urea, starch, crystalline cellulose, soybean flour, talmi husk flour, and tobacco stem flour.

[0061] Liquid carriers include water, alcohols (eg, methanol, ethanol, isopropyl alcohol, ethylene glycol, glycerin, etc.), ethers (eg, dioxane, tetrahydrofuran, etc.), ketones (eg, acetone, methyl ester). Tilketone, cyclohexanone, etc.), esters (eg, glycerin esters of fatty acids, phthalate esters, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), aliphatic or alicyclic hydrocarbons (eg, cyclohexane) Hexane, paraffins, etc.), aromatic hydrocarbons (eg xylene mixtures, substituted naphthalene, etc.), polar solvents such as N-methyl-2-pyrrolidone, N, N-dimethylformamide, soybean oil, coconut oil And vegetable oils.

[0062] A surfactant is used to obtain a preparation having good emulsification, dispersion, and wettability. Any type of nonionic, anionic, cationic, or zwitterionic surfactants used in agrochemical formulations can be used.

[0063] Suitable nonionic surfactants include polyoxyethylene alkyl ether, polyoxyethylene alkyl ester, polyoxyethylene alkyl aryl ether, poly fatty acid ester, fatty acid ester of glycerin and pentaerythritol, pull mouth nick Examples include surfactants of the type, acetylene alcohol, acetylene diol, surfactants obtained by adding ethylene oxide to these, silicone surfactants, alkyl glycosides' and the like.

[0064] Suitable anionic surfactants include alkylbenzene sulfonates, dialkyl sulfosuccinates, alkyl sulfates, salts of acyl methyl taurine, and nonionic surfactants to which the above ethylene oxide is added sulfuric acid or Anionic surfactants esterified with phosphoric acid and optionally neutralized with an appropriate alkali, lignin sulfonate, alkylnaphthalene sulfonic acid and its condensate salts, phenol sulfonic acid and its condensate salts Starches such as starches or dextrins with various polycarboxylic acid-type and polysulfonic acid-type polysoaps, 2-octenoyl succinates, consisting of salts of acrylic acid, maleic acid, styrene sulfonic acid and condensation of bur group Surface active agent, carboxymethylcellulose salt Sodium higher fatty acids, stone 鹼類 such as potassium salts, such as α- O reflex in sulfonate can be exemplified.

[0065] Suitable cationic surfactants include amine salt type, quaternary ammonium salt type, ethylene oxide adducts of higher aliphatic amines and aliphatic amides. Suitable zwitterionic surfactants include amino acid type or betaine type surfactants and lecithin.

[0066] Surface active agents obtained by substituting some or all of the hydrogen atoms of these various types of surfactants with fluorine atoms can also be used effectively because of their strong ability to reduce the surface tension. Further, the above various surfactants may be used alone or in combination depending on the application.

[0067] Formulation adjuvants include physical property improvers, decomposition inhibitors, antifoaming agents, viscosity modifiers, binders, and pressure-sensitive adhesives, which are used alone or as a mixture. Agent, killing Insecticides or anthelmintic agents can be included. Examples of these formulation adjuvants include, for example, carboxymethylcellulose (CMC), polybulal alcohol (PVA), gum arabic, gelatin, casein, sodium alginate, tragacanth gum, xanthan gum and the like.

[0068] The content of the compound of the present invention as an active ingredient in these preparations can be appropriately changed depending on conditions such as the form of the preparation and the application method. In general, it is desirable to use in the preparation in the range of 0.0;! To 99%, preferably 0 .;! To 95% (% by weight, the same applies hereinafter). The solid or liquid carrier can be included in the range of 1 to 99%, and the surfactant in the range of 0 to 25%. If the formulation is in concentrated form, it is generally diluted to 0.00001 -0.01% (ie, 0 · ;! to lOOppm) before use.

[0069] The compounds of the present invention are used in preparations and use forms prepared by the preparations! / And other active compounds such as insecticides, baits, fungicides, acaricides, nematicides, It can be used in combination with fungicides, herbicides, avian repellents, plant growth regulators, fertilizers, soil conditioners and the like. In addition, the applicability (applicable insect pests, usage method, use period, etc.) can be expanded by using this mixture. In some cases, a synergistic control effect can be expected by the synergistic action of each active ingredient. Here, examples of the insecticide include organic phosphorus insecticides, carbamate insecticides, pyrethroid insecticides, neonicotinoid insecticides, microbial source insecticides, insect growth regulators and the like.

[0070] Furthermore, the compound of the present invention can also be used as a mixture with a synergist. The synergist is a compound that functions to enhance the effect of the compound of the present invention, such as miticide, insecticide, or anthelmintic, which need not have activity by itself.

Example

[0071] Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto. That is, the present invention is not limited to the addition amount of active ingredients, the types of carriers and auxiliary agents, and the addition amounts thereof in the following production examples and formulation examples of agricultural and horticultural insecticides. In the following production examples and formulation examples, “parts” means all parts by weight, and “%” means “% by weight” unless otherwise indicated as “volume%”. [0072] As a starting material of the compound of the present invention, it is produced by a known fermentation method or is commercially available, for example, distributor: Wako Pure Chemical Industries, Ltd. (manufacturer: LKT Lab. Inc. ) Product name: An avermectin compound available as Abamectin can be preferably used. This is a mixture of avermectin Bla and avermectin Bib in which the sec-butyl group and isopropyl group are respectively substituted at the 25th position of the avermectin skeleton, and the composition is about 96% of the “Bla” component and about 4% of the “vermectin”. It contains a “Bib” component. Since “Bib” compounds are present in very small proportions by weight and structural differences have little effect on the reaction process and biological activity, the separation of these very similar compounds is generally performed. I will not.

[0073] Therefore, also in this example, the avermectin monoglycoside Bla / Blb derivative is a mixture, and the substituent at position 25 without being separated into each of these is a mixture of sec-butyl group and isopropyl group. Using. Thus, since this group of compounds is a mixture, the melting point or the like is not used to express physicochemical properties, and generally the retention time of high-performance liquid chromatography is used. Also in this example, the physicochemical characteristics of each derivative of the avermectin monoglycoside Bla / Blb were expressed by the retention time in high performance liquid chromatography. The measurement conditions in high performance liquid chromatography are as described in detail below, and each derivative was detected by spectral matching using an ultraviolet absorption multi-wavelength detector. The results are summarized in Table 1.

The chemical structure of the prepared avermectin monoglycoside Bla / Blb derivative was confirmed by ^: H- and ¹³ C-nuclear magnetic resonance spectra and, if necessary, mass spectra.

[0074] HPLC analysis conditions

Column: YMC-pack ODS-AQ, 5 01 (4.6 mm X 250 mm)

Mobile phase: A; 0.01% trifluoroacetic acid-70% by volume aqueous acetonitrile

B; 0.01% trifluoroacetic acid-acetonitrile

Gradient conditions:

[0075] [Table 2] Time% A% B Gradient

(min) curve

0 1 0 0 0

6 1 0 0 0 Straight line

1 6 0 1 0 0

1 8 1 0 0 0

2 0 1 0 0 0

[0076] Column temperature: 40 ° C

Flow rate: 2ml / min

Detection: Tosohichi PD8020 multi-wavelength detector, chromatogram: 246nm, spectrum: 200-300nm 3D detection

In particular, it was judged to be an avermectin derivative based on the maximum absorption at 246 nm and the shoulder absorption at 238 nm and 254 nm, which are characteristic of the avermectin skeleton.

[0077] Example 1

Avermectin BlaZBlb monoglycoside (Step 1)

100 g of avermectin Bla / Blb (general formula II) was dissolved in 1000 ml of isopropanol and cooled in an ice bath. To this solution, 5 g of concentrated sulfuric acid dissolved in 100 ml of isopropanol was added dropwise. After dropping, the temperature was returned to room temperature, and the mixture was stirred at room temperature (about 20 ° C) for 43 hours under a nitrogen stream. Saturated aqueous sodium bicarbonate was added to neutralize the reaction solution, and the reaction solution was suction filtered. The filtrate was concentrated to about 200 ml under reduced pressure to distill off isopropanol. To this solution, 1000 ml of ethyl acetate and 500 ml of water were added and separated into two layers after holding ft. The aqueous layer was extracted twice more with 1000 ml of ethyl acetate. The ethyl acetate extracts were combined, washed 4 times with distilled water, and once with saturated saline. This ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain 118 g of avermectin Bla / Blb monoglycoside crude extract. This crude product was subjected to column chromatography using Silica Genole 60 (particle size 0 · 063—0.2 mm, manufactured by Menolec Co., Ltd., 996 g), and the ethyl acetate concentration in hexane was 30% to 60% by volume. Elution was carried out stepwise up to 5% by volume up to volume%. In this way, 72.9 g (process yield: 87%) of pure avermectin Bla / Blb monoglycoside (general formula III) was obtained.

[0078] Example 2

5— O t butyldimethylsilyl avermectin B 1 a ZB lb monoglycoside (Step 2) Combine 5 · 6 g avermectin Bla / Blb monoglycoside with 68 · lg imidazonole, and add 421 ml of dehydrated dimethylformamide into this. In addition, it was completely dissolved. Next, 24 g of t-butyldimethylsilyl chloride was dissolved in 100 ml of dehydrated dimethylformamide and added dropwise to the reaction solution with stirring for 10 minutes. The reaction solution was stirred at room temperature for an additional 70 minutes. 2000 ml of ethyl acetate and distilled water were added to the reaction solution, and the mixture was stirred and separated into two layers. The ethyl acetate layer was further washed four times with a small amount of distilled water and then with saturated saline. The aqueous layer was further extracted twice with 1000 ml of ethyl acetate and treated in the same manner. This ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain 68.6 g of a crude extract of B- / Blb monoglycoside of 5-O-t-butyldimethylsilyl avermectin. This crude product was subjected to column chromatography using Silica Genole 60 (particle size 0 · 063-0.2 mm, manufactured by Menolec Co., Ltd., 683 g)! /, And the ethyl acetate concentration in hexane was 5% to 40% by volume. Elution was carried out stepwise by 5% by volume up to 5%. In this way, 52.3 g (process yield: 86%) of pure 5-O-t-propyldimethylsilyl avermectin Bla / Blb monoglycoside (general formula IV) was obtained.

[0079] Congress 3

5— O— t butyldimethylsilyl 4 O pyridazine 3-carbonyl avermectin BlaZBlb monoglycoside (step 3)

Place 100 mg of pyridazine monocarboxylic acid, 300 mg of 5-O-t-butyldimethylsilyl avermectin Bla / Blb monoglycoside, 2 ml of dehydrated pyridine and 10 mg of dimethylaminopyridine in a dry flask, and add 3 ml of dichloromethane to complete. Dissolve in. To this solution, 300 mg of 1,3 dimethylimidazoline chloride was added and stirred at room temperature for 16 hours. The reaction solution was poured into saturated sodium bicarbonate water and extracted with 100 ml of ethyl acetate. The ethyl acetate layer was further washed four times with a small amount of distilled water and then with a saturated saline solution. The aqueous layer was extracted twice more with 100 ml of ethyl acetate and treated similarly. This ethyl acetate ε '(9 · 6 = Γρ'Ηΐ) 9 ^ · ε''Ηε) 6ε · ε'Έ'9 · = ΓΡΡ'ΗΪ) ε '(8 · 9 = Γ ^' ΗΪ) Ϊ9Έ '(Ϊ 8 = Ι "'Ρ

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200 mg of 5-O butyldimethylsilyl 4 ′ O pyridine 3-carbonyl avermectin Bla / Blb monoglycoside was dissolved in 3 ml of methanol and cooled in an ice-water bath with stirring. A solution obtained by dissolving 200 mg of p-toluenesulfonic acid in 1 ml of methanol and cooling with ice was added to the reaction solution, and the mixture was further stirred for 2 hours under ice cooling. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with 15 ml of ethyl acetate. The ethyl acetate layer was further washed four times with a small amount of distilled water and then with saturated saline. The aqueous layer was further extracted twice with 10 ml of ethyl acetate and treated in the same manner. This ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain a crude extract. This crude extract was purified by chromatography on silica gel (developing solvent hexane: 2 propanol 3: 2) and 4'-O-pyridin 3 carbonyl avermectin B 1 a / B lb monoglycoside 140 mg ( Process yield: 80%) was obtained.

ifi Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 4.96 (t, 1H, J = 9.5), 7.43 (m, 1

H), 8.36 (dt, 1H, J = 1.8, 7.9), 8.80 (dd, 1H, J = 1.7, 4.8), 9.27 (d, 1H, J = 2.0)

5 O t butyldimethylsilyl 4 'O benzofuran 2 carbonyl avermectin B la ZB lb monoglycoside

In a dry flask, 190 mg of benzofuran-2-carboxylic acid, 5 O t-butyldimethylsilyl avermectin Bla / Blb monoglycoside 200 mg, 4 mg of 4 dimethylaminopyridin were added, and 3 ml of dehydrated pyridine was added and completely dissolved. . To this solution, 230 mg of 1-ethyl-3- (3-dimethylaminopropyl) carpositimide hydrochloride was added and stirred at room temperature for 3 hours. The reaction solution was poured into saturated sodium bicarbonate water and extracted with 15 ml of ethyl acetate. The ethyl acetate layer was further washed four times with a small amount of distilled water and then with saturated saline. The aqueous layer was further extracted twice with 10 ml of ethyl acetate and treated in the same manner. This ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain a crude extract. This crude extract was purified by chromatography on silica gel (developing solvent hexane: ethynole acetate 4: 1) and 5—O t butyldimethylsilinoleate 4 ′ O benzofuran-2 carbonyl avermectin Bla / Blb mono 200 mg of saccharide (process yield: 85%) was obtained. [0084] Example 8

4 'O Benzofuran 2 Carbonyl avermectin B 1 a ZB lb Monoglycoside (Compound No. 20)

200 mg of 5 O t butyldimethylsilyl mono 4′O benzofuran 2-carbonyl avermectin Bla / Blb monoglycoside was dissolved in 3 ml of methanol and cooled in an ice-water bath with stirring. 220 mg of p-toluenesulfonic acid was dissolved in 1 ml of methanol, and an ice-cooled solution was added to the reaction solution, followed by further stirring for 2 hours under ice-cooling. The reaction mixture was poured into saturated sodium bicarbonate water and extracted with 15 ml of ethyl acetate. The ethyl acetate layer was further washed four times with a small amount of distilled water and then with saturated saline. The aqueous layer was further extracted twice with 10 ml of ethyl acetate and treated in the same manner. This ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain a crude extract. This crude extract was purified by chromatography on silica gel (developing solvent starting from hexane: ethyl acetate 2: 1 (volume ratio) to 1: 1 (volume ratio)) and 4 'O benzofuran-2-carbonyl. 145 mg (process yield: 82%) of avermectin B 1 a / B 1 b monoglycoside was obtained.

ifi Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 4.96 (t, 1H, J = 9.5), 7.71—7.2

9 (m, 5H,)

[0085] From Example 9 to Example 27

The following compounds from Example 9 to Example 27 were produced according to the procedures described in Examples 1 to 8 above. In order to show these production methods more specifically, the ester bond method of the heterocyclic carboxylic acid used in production step 3 and the yield in each step were described after each compound number.

The method for bonding the heterocyclic ring is as follows.

Method A: Method using 2 chloro-1,3 dimethylimidazolium chloride (Example 3) Method B: Method using acid chloride of heterocyclic carboxylic acid (Example 5)

Method C: Method using 1-ethyl-3- (3-dimethylaminopropyl) carpositimide hydrochloride (Example 7)

[0086] Example 9

4'— O (cinno JJ 1 3-carbonyl) _ avermectin B laZBlb monoglycoside [compound Material No. 18: Method C, Process 3 (87%) → Process 4 (92%))

^ H Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 5.07 (t, 1H, J = 9.5), 7.93 (m, 1

H), 8.67 (m, 1H), 8.87 (m, 1H), 9.72 (s, 1H)

[0087] Example 10

4'— 0— (4 Methinole 1, 2, 5 Thiadiazole-3 Carboniniore) Avermectin B 1 a ZB lb monoglycoside “Compound No. 19: Method C, Step 3 (85%) → Step 4 (91 %))

Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 2.86 (s, 3H), 4.96 (t, 1H, J = 9.

5), 7.27 (s, 1H)

[0088] Example 11

4'-Q- (6-Hydroxypyridazine 1-3-Luporinole) Avermectin Bla / Blb Monoglycoside "Compound No. 21: Method A, Step 1 (85%) → Step 4 (92%)]

Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 4.85 (t, lH, J = 9.5), 6.95 (d, l

H, J = 9.9), 7.88 (d, lH, J = 9.9)

[0089] Example 12

4'-Q- (3-Hydroxypyridazine 4-4-Luporinole) avermectin Bla / Blb monoglycoside [Compound No. 22: Method A, step 1 (21%) → step 4 (91%)]

Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 4.83 (t, lH, J = 9.5), 7.46 (d, l

H, J = 4.0), 7.87 (d, lH, J = 4.0), 12.28 (brs, lH)

[0090] Example 13

4 '— O— (6-clopyrididane 1-carbonyl) avermectin BlaZBlb monoglycoside [Compound No. 23: Method A, step 1 (82%) → step 4 (92%)]

—Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 4.95 (t, lH, J = 9.5), 7.63 (d, l

H, J = 8.9), 8.13 (d, lH, J = 8.9)

[0091] Example 14

4'—O— (3-Clopyrididazine 4-carbonyl) avermectin BlaZBlb monoglycoside [Compound No. 24: Method A, step 1 (80%) → step 4 (92%)]

Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 4.91 (t, lH, J = 9.5), 7.78 (d, l

H, J = 4.9), 9.28 (d, lH, J = 4.9) [0092] Example 15

5— O t

Nil avermectin BlaZBlb monoglycoside

Place 1, 2, 3 thiadiazole 4 carboxylic acid 0.9 g, 5-Ot —butyldimethylsilyl avermectin Bla / Blb monoglycoside 2 · 0 g, 4 dimethylaminoviridine 30 mg, dehydrated pyridine 1 · Og in a dry flask. Add dehydrated dichloromethane (20 ml) and dissolve completely. To this solution, 1.8 g of 1-ethyl-3- (3 dimethylaminopropinole) carpositimide hydrochloride was added and stirred at room temperature for 2 hours. The reaction solution was poured into saturated sodium bicarbonate water and extracted with 100 ml of dichloromethane. The dichloromethane layer was further washed four times with a small amount of distilled water and then with a saturated saline solution. The aqueous layer was extracted twice more with 50 ml of dichloromethane and treated similarly. The dichloromethane solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain a crude extract. This crude extract was purified by chromatography using silica gel (developing solvent hexane: ethyl acetate 5: 1), 50 t-butyldimethylsilyl 4 '1, 2, 3 thiadiazole-4 carbonylabenomemectin Bla / Blb Monoglycoside 1 · 8 g (process yield: 79%) was obtained.

[0093] Example 16

4 '-Q- l. 2. 3 Thiadiazole 4 Carponyl avermectin Bla / Blb Mono West? (.. 30)

5 O t butyldimethylsilanolate 4'-〇-1, 2, 3 thiadiazole-4 norebonyl avermectin Bla / Blb monoglycoside 1. Dissolve 8 g in 20 ml of methanol and stir in an ice water bath. Cooled down. 1. A solution prepared by dissolving Og of p-toluenesulfonic acid in 3 ml of methanol and cooling with ice was added to the reaction mixture, and the mixture was further stirred for 1 hour under cooling with ice. The reaction mixture was poured into saturated sodium bicarbonate water and extracted with 100 ml of ethyl acetate. The ethyl acetate layer was further washed four times with a small amount of distilled water and then with saturated saline. The aqueous layer was further extracted twice with 50 ml of ethyl acetate and treated in the same manner. This ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain a crude extract. By washing this crude extract with hexane, 4'-O-1, 2, 3, thiadiazole-4 carbonyl avermectin Bla / Blb monoglycoside 1.6 g (process yield: 100%) Got. H Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 5.03 (t, 1H, J = 9.4), 9.34 (s, 1

H,)

[0094] Example 17

4 'O (thiophene 2-carbonyl) avermectin B 1 a ZB lb monoglycoside "compound Νο · 35: Method C, step 3 (82%) → step 4 (72%)]

—Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 4.86 (t, lH, J = 9.5), 7.13 (m, l

H), 7.59 (m, lH), 7.87 (m, lH)

[0095] Example 18

4 ′ O— (4-methylthiazole 5 carboninole) avermectin B 1 a ZB lb monoglycoside [Compound No. 38: Method C, step 3 (87%) → step 4 (99%)]

Nuclear magnetic resonance spectrum (300MHz, CDC1) 6 pm:2.81 (s, 3H), 5.01 (brs, 1H), 8.

82 (s, 1H)

[0096] Example 19

4'-Q- (1.2.5 thiadiazole 3 strength luponinole) avermectin Bla / Blb monoglycoside "Compound No. 42: Method C, step 3 (88%) → step 4 (99%)]

Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 4.98 (t, 1H, J = 9.5), 9.13 (s, 1

H)

[0097] Example 20

4'-Q- (2.1 Benzoisoxazole-3 strength luponinole) avermectin Bla / B lb monoglycoside "Compound No. 52: Method C, step 3 (95%) → step 4 (81%))

^ H Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 5.02 (t, 1H, J = 9.5), 7.27 (m, 1

H), 7.41 (m, 1H), 7.75 (m, 1H), 7.95 (m, 1H)

[0098] Example 21

4 ′ O (oxazole 4-carbonyl) avermectin B 1 a ZB lb monoglycoside “Compound No. 59: Method A, step 3 (92%) → step 4 (86%)]

—Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 4.91 (t, 1H, J = 9.5), 7.94 (d, lH,

J = 0.9), 8.32 (d, 1H, J = 0.9)

[0099] Example 22 4'—O (furan-3-carbonyl) avermectin B 1 a ZB lb monoglycoside [Compound No. 61: Method C, step 3 (84%) → step 4 (90%)]

—Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 4.86 (t, lH, J = 9.5), 6.79 (m, l

H), 7.45 (m, lH), 8.07 (m, lH)

[0100] Example 23

4'-Q- (1,3-Dimethylbiazole-5-Carboninole) avermectin BlaZBlb monoglycoside "Compound No. 63: Method C, step 3 (61%) → step 4 (81%)]

ifi Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 2.28 (s, 3H), 4.13 (s, 3H), 5.01

(brs, 1H), 6.67 (s, 1H)

[0101] Example 24

4'— 0— (4-Methinole 1.2.5—Oxaziazol 3—Strong Luponyl) Avermectin B 1 a ZB lb Monoglycoside “Compound No. 65: Method C, Step 3 (80%) → Step 4 (72%)] Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 2.62 (s, 3H), 4.94 (t, 1H, J = 9.

Five)

[0102] Example 25

4'-Q- (1.2.3 Benzothiadiazole 6-powered Luponinole) Avermectin Bla /

B lb monoglycoside “Compound No. 74: Method C, Step 3 (97%) → Step 4 (98%)]

ifi Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 5.01 (t, 1H, J = 9.3), 8.34 (dd, 1

H, J = 1.5, 8.8), 8.72 (d, 1H, J = 8.8), 8.86 (d, 1H, J = 1.5)

[0103] Example 26

4 'O— (1, 2 Benzisothiazole 3 Carboninole) avermectin Bla / Bib monoglycoside “Compound No. 80: Method C, step 3 (97%) → step 4 (98%)]

—Nuclear magnetic resonance spectrum (300MHz, CDC1) δ ppm: 5.07 (t, 1H, J = 9.7), 7.54-7.62

(m, 2H), 8.01 (d, 1H, J = 6.1), 8.82 (d, 1H, J = 6.1)

[0104] Example 27

4'-Q- (1, 3 Dimethyl-1, 2, 4 Triazole-5 Carboninole) Avermectin

BlaZBlb monoglycoside “Compound No. 94: Method A, Step 3 (18%) → Step 4 (77%)] ifi Nuclear magnetic resonance spectrum (300 MHz, CDC1) δ ppm: 2.45 (s, 3H), 4.20 ( s, 3H), 4.94 (t, lH, J = 9.5)

[0105] Formulation Example 1 (Dust)

2 parts of compound No. 1, 1 part of PAP (physical property improver) and 97 parts of clay are uniformly mixed and pulverized to obtain a powder containing 2% of the active ingredient.

Row 2 (7 Sleep D

Compound No. 14 (30 parts), alkyl benzene sulfonate (3 parts), polyoxyethylene nouryl phenyl ether (5 parts) and clay (62 parts) were uniformly mixed and ground to obtain a wettable powder containing 30% of the active ingredient. obtain.

3 agents in a row)

When 30 parts of the compound No. 19 compound, 55 parts of methyl ethyl ketone and 15 parts of polyoxyethylene phenyl phenyl ether are mixed and dissolved, an emulsion containing 30% of the active ingredient is obtained.

Row 4 (誦

Compound No. 24 No. 24 compound, lauryl sulfate 1.5 parts, lignin sulfonic acid strength Lucium 1.5 parts, bentonite 25 parts and clay 67 parts were mixed uniformly, and after adding 15 parts of water and kneading in a kneader, Granulate with a granulator and dry with a fluid dryer to obtain granules containing 5% of the active ingredient.

吝 II example 5 (floor pull agent)

Compound No. 30 (40 parts), lauryl sulfate (2 parts), alkylnaphthalene sodium sulfonate (2 parts), hydroxypropylcellulose (1 part) and water (55 parts) are uniformly mixed to obtain a flowable agent containing 40% of the active ingredient.

[0106] Next, each test example of the control or insecticidal activity and toxicity test for various plant pests (ticks, insects) and nematodes (C. elegans) of the compound of the present invention is shown. The scope of the present invention is as follows. It is not limited to examples.

In Tables 4, 6, 8 and 9 below, comparative compound 1 is avermectin Bla / Blb (content ratio of about 96: 4), and comparative compound 2 is avermectin Bla / Blb monoglycoside (containing The ratio is about 96: 4) .Comparative compound 3 is milbemectin A / A (content ratio about 3: 7).

3 4

The compound having the structure shown in FIG.

(Comparative Compound 3

Test Example 1 (Insecticidal effect test for Namihadai 1, Lee:

10 mg of each of the compounds of the present invention was dissolved in a mixture of 6.2 ml of acetone, 2.5 ml of xylene and Solbol 700 HD (manufactured by Toho Chemical Co., Ltd.) 1. 3 ml and diluted with ion-exchanged water. Reagent liquids containing inventive compounds at concentrations of Ippm and 0.1 ppm were prepared. . On the other hand, a glass petri dish (diameter 9 cm) was filled with an agar solution in which 2.5 g of agar was dissolved in 1 L of ion-exchanged water and allowed to cool. On this agar gel, two leaf discs 3 cm in diameter made from kidney bean true leaves were placed, and 10 adult females were released each. After 24 hours of release, the Nami-hada two adults are removed, and for the laid eggs, a reagent solution prepared at a concentration of lppm and 0.3 ppm is applied to a cylindrical automatic spraying device at a spray volume of 2.5 ml / Petri dish. Sprayed with. This leaf disc was placed in a constant temperature room at 25 ° C (16 hours illumination), and the number of living and dead individuals was examined under a stereomicroscope 8 days after the treatment. This test was carried out in two consecutive systems, the mortality rate (%) was calculated by the following formula, and the average mortality rate was obtained. This average mortality was converted into an evaluation value of mortality according to the criteria shown below. The results are shown in Table 4.

Country Death count

Death rate (%) = X 1 0 0

(Number of surviving individuals + number of dead individuals)

[Table 3] Evaluation of mortality rate Average mortality rate

5 9 5% or more

4 9 0 to less than 5%

3 7 0 to less than 90%

2 4 0 to less than 70%

1 4 Less than 0% [Table 4-1] Active ingredient concentration of treatment chemical (ppm) Test area Compound No. 1 0.3 Evaluation value of mortality rate Evaluation value of mortality rate

1 5 4

3 5 3

4 5 3

5 5 4

6 5 5

7 5 4

8 5 3

9 5 3

10 5 4

12 5 3

13 5 3

14 5 4

16 5 5

17 5 5

18 5 5

19 5 5

20 5 3

21 5 4

22 5 3

23 5 3

24 5 4

25 5 3

26 5 3 Invention Zone 27 5 3

28 5 3

29 5 5

30 5 5

31 5 4

32 5 5

35 5 5

36 5 5

37 5 5

38 5 5

39 5 4

40 5 4

41 5 5

42 5 5

43 5 5

44 5 5

46 5 5

47 5 4

50 5 4

51 5 5

52 5 5

53 5 4

54 5 5

56 5 5 [Table 4-2]

(Note) As Comparative Compound 3, a commercially available preparation was used.

Test Example 2 (Insecticidal effect on legumes)

Three adult aphids were released on broad bean seedlings grown in plastic cups (5.5 cm in diameter). Then, 24 hours later, this broad bean seedling was placed on a turntable, and a reagent solution having a concentration of 10 ppm of the compound of the present invention prepared in the same manner as in Test Example 1 was sprayed with a spray gun at a dose of 2.5 ml / cup. After the treatment, this broad bean was placed in a constant temperature room at 25 ° C (16-hour lighting), and the number of adult and larvae parasitizing 4 days after the treatment was investigated. This test was conducted in a two-unit system, and the control value (%) was calculated by the following formula, and the average control value was obtained. This average control value was converted into an evaluation value of the control value according to the following criteria. The results are shown in Table 6.

[Equation 2]

T b / T a

Control value (%) = X 0 0

C b / C a

C a: Number of insects before spraying in the non-spreading zone C b: Number of insects after spraying in the non-spraying zone T a: Number of insects before spraying in the spraying zone T b: Number of insects after spraying in the spraying zone

[Table 5]

Evaluation value of control value Average control value

5 9 5% or more

4 9◦ to less than 95%

3 7 0 to less than 90%

2 4 0 to less than 70% 1 less than 4 0% 6]

Concentration of active ingredient in chemical treatment (ppm) Test area Compound No. 10

Evaluation value of control value

5 5

6 5

7 5

10 5

28 4

29 5

32 5

33 5

35 4

37 4

38 5

39 4

40 4

Invention Zone 43 4

44 5

49 4

50 5

51 5

52 4

54 5

56 5

57 4

63 4

66 5

70 5

86 5

92 4

Comparative compound

Control zone 1 4

3 3 Test Example 3 (C. elegans nematicidal effect)

Grow soil nematode C. elegans at 20 ° C for 4 days in a petri dish of NGM medium where E. coli is grown. Wash this nematode with physiological saline and adjust the dilution to a nematode concentration of 100 / ml. 1 ml of this nematode dilution was taken in a glass petri dish (diameter 4 cm), a reagent solution was added to a concentration of 0 · lppm and 0. Olppm, and left in a constant temperature room at 25 ° C. After 24 hours, the number of living and dead individuals was examined under a stereomicroscope. This test was carried out in two consecutive systems, and the nematicidal rate was calculated from the following formula, and the average nematicidal rate was obtained. This average nematicidal rate was converted into an evaluation value of the nematicidal rate according to the following criteria. The results are shown in Table 8. It is.

[Number 3] Number of dead individuals

Nematicidal rate (%) X 1 0 0

(Surviving population + dead population)

[Table 7]

Evaluation value of nematicide rate Average nematode rate

5 95% or more 4 9◦ to less than 9% 3 7◦ to less than 90%

2 4 0 to less than 70%

4 Less than 0% [Table 8-1]

Active ingredient concentration in treatment chemical (ppm) Test group Compound number 0.1 0.01

Evaluation value of nematicide rate Evaluation value of nematicide rate

1 5 2

2 5 5

3 5 3

5 5 3

6 5 2

7 5 3

8 4 3

10 5 2

13 5 4

14 5 3

16 4 4

18 4 4

19 5 3

20 5 2

21 5 3

22 5 2

23 5 2

24 5 3

25 4 3

26 4 3

29 5 3

30 5 2

31 5 2 Invention Zone 33 5 2

34 5 4

35 5 4

36 5 5

37 5 3

38 5 4

39 5 4

40 5 4

41 5 4

42 5 2

43 5 3

44 5 3

45 5 3

46 5 5

47 5 5

49 5 4

50 5 5

51 5 4

52 5 5

53 5 5

54 5 3

55 5 4 [Table 8-2]

Test Example 4 (Acute oral toxicity test on mice)

The dose for acute oral toxicity studies should be 30 mg / kg body weight and 300 mg / kg body weight. It was. Three male mice, each 10 weeks old, weighing approximately 30 g, were used in each test group, and the test solution prepared so that the dose was the above-mentioned amount for each mouse was administered by single forced oral administration using a metal gastric sonde. did. Toxicity classification based on the Toxic and Deleterious Substances Control Law derived from life and death and general condition of mice for 14 days after administration was evaluated. The results are shown in Table 9 together with the LD values. [Table 9] Acute oral toxicity in mice

Test area Compound number

Toxicity classification

(mg / kg body weight)

1〉 3 0 0

2> 3 0 0

5> 3 0 0

Invention zone 8> 3 0 0

1 2> 3 0 0

1 4> 3 0 0

1 6> 3 0 0

1 8> 3 0 0 Normal

1 9> 3 0 0

2 0> 3 0 0

2 2> 3 0 0

2 3> 3 0 0

2 4> 3 0 0

2 8> 3 0 0

2 9> 3 0 0

3 0> 3 0 0

Control group Comparative compound

1 <5 0 Poisonous equivalent

2 5 0 <LD ₅₀ ≤ 3 0 0

3 ≥ 3 0 0 Equivalent to normal

Claims

(In the formula, R represents an isopropyl or sec-butyl group, A represents a heterocyclic ring,

1

A 5-membered ring, a 6-membered ring or a condensed ring containing one or more atoms selected from the group consisting of a child atom, a nitrogen atom and a sulfur atom, which are unsubstituted; Or a halogen atom, nitro group, cyano group, carboxyl group, C to C alkyl

1 6 group, c-c haloalkyl group, hydroxyl group, thiol group, amino group, c-c alkyl

1 6 1 6 Roxy group, C-C haloalkyloxy group, C-C alkylthio group, C-C alkyl

1 6 1 6 1 6 Nolesulphoxyl group, c-c alkylsulfonyl group, c-canolenoquinamino group, c-c

1 6 1 6 1 6 Alkylcarbonyl group, C-C alkyloxycarbonyl group, C-C alkanol

1 6 1 6

It may be substituted with the same or different 1 to 4 substituents selected from the mino group. When A contains a nitrogen atom as its ring constituent atom, the nitrogen atom is N- Xoxide may be formed. )

[2] In the general formula (I), A force S, thiadiazole, oxadiazole, thiophene, thiazole, isothiazole, isoxazonole, oxazonole, benzoisothiazole, cinnoline, pyridine, pyridazine, benzothiadiazole, benzo Xadiazole, furan, pyrrole, pyrazole, imidazole, triazole, tetrazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, benzofuran, benzothiphene, i Ndonole, indazonole, benzimidazole, benzotriazolole, benzoxazole, benzisoxazole, benzothiazole, pyrimidine, triazine, tetrazine, and virazine (the rings are unsubstituted or , Halogen atom, nitro group, cyano group, carboxyl group, c-canolenoquinole group, c-c haloalkyl group, hydroxyl group,

1 6 1 6

Thiol group, amino group, C-C alkyloxy group, C-C haloalkyloxy group, C

1 6 1 6 1

~ C alkylthio group, c ~ c alkylsulfoxyl group, c ~ c alkylsulfonyl

6 1 6 1 6

Group, C-C anolenoquinamino group, C-C alkylcarbonyl group, C-C alkyloxy group

1 6 1 6 1 6 Same or different selected from carbonyl group and c to c alkanoylamino group

1 6

When A, which may be substituted with 1 to 4 substituents, contains a nitrogen atom as the ring atom, the nitrogen atom may form an N-oxide. The avermectin monoglycoside derivative or a salt thereof according to claim 1, wherein

[3] The avermectin monoglycoside derivative or a salt thereof according to claim 1, wherein in the general formula (I), A is thiadiazole.

[4] The avenoremectin monoglycoside derivative or a salt thereof according to claim 1, wherein in the general formula (I), A is cinnoline.

[5] An acaricide or insecticide comprising the avermectin monoglycoside derivative compound according to any one of claims 1 to 4 as an active ingredient.

[6] An anthelmintic comprising the avermectin monoglycoside derivative compound according to any one of claims 1 to 4 as an active ingredient.