WO2008056608A1 - Dérivés de monoglycoside d'avermectine - Google Patents

Dérivés de monoglycoside d'avermectine Download PDF

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Publication number
WO2008056608A1
WO2008056608A1 PCT/JP2007/071398 JP2007071398W WO2008056608A1 WO 2008056608 A1 WO2008056608 A1 WO 2008056608A1 JP 2007071398 W JP2007071398 W JP 2007071398W WO 2008056608 A1 WO2008056608 A1 WO 2008056608A1
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group
avermectin
monoglycoside
acid
compound
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PCT/JP2007/071398
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English (en)
Japanese (ja)
Inventor
Satoru Kondo
Hiroyuki Okita
Daigo Okamura
Shuji Itakura
Jun Suzuki
Katsuhiko Iwasaki
Hideyuki Murakami
Tsunehiro Kido
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Hokko Chemical Industry Co., Ltd.
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Publication of WO2008056608A1 publication Critical patent/WO2008056608A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system

Definitions

  • 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.
  • Avermectins are a series of 16-membered ring macrolide compounds, which are known compounds represented by the following formula (II) (see Patent Document 1).
  • Monoglycoside derivatives of avermectins are known compounds represented by the following formula (III) (see Patent Document 2).
  • 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.
  • 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).
  • 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
  • Avermectins have been put into practical use as acaricide, anthelmintic or insecticide! /, And are all classified as poisonous or deleterious substances with high toxicity.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, tetraz
  • Halogen atom nitro group, cyano group, canolepoxinole group, c
  • 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.
  • 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.
  • the present invention also relates to an acaricidal method, an insecticidal method, or an anthelmintic method, wherein the general formula (
  • 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.
  • 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.
  • 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.
  • 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!
  • 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.
  • 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.
  • 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
  • halogen atom included in the heterocyclic substituent group include fluorine, chlorine, bromine and iodine atoms.
  • C C alkyl group included as one of the substituent groups of the heterocyclic ring has carbon number
  • 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.
  • the "C C haloalkyl group” included as one of the substituent groups of the heterocyclic ring has a carbon number of 1 to
  • 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 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.
  • 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,
  • 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.
  • 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.
  • ⁇ C alkylthio group '' is a straight or branched alkyl group having 6 to 6 carbon atoms
  • 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-ethylprop
  • the “C alkylsulfoxyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • 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.
  • ⁇ C alkylsulfonyl group '' is a straight or branched alkyl group having 1 to 6 carbon atoms.
  • 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.
  • Examples thereof include 2-dimethylbutylsulfonyl group.
  • ⁇ C alkylamino group '' is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • 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-dimethylbuty
  • 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.
  • 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.
  • C C alkanoylamino group included as one of the substituent groups of the heterocyclic ring is, 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.
  • a pharmacologically acceptable salt is preferable.
  • salts with acids, inorganic acids, organic bases or inorganic bases are preferable.
  • 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.
  • the salt with inorganic acid include salts with hydrochloric acid, sulfuric acid, phosphoric acid and the like.
  • 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.
  • 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.
  • salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • salts with basic amino acid include salts with arginine, lysine, ornithine and the like.
  • salts with organic acids or organic bases are preferred.
  • salts with organic acids salts with acetic acid, benzoic acid, etc. are preferred.
  • salts with organic bases include triethylamine. I like the salt!
  • the salt in this invention is not limited to said salt at all.
  • 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.
  • the measurement conditions (column used, eluent, flow rate, etc.) will be described in detail in the examples described later.
  • the compound represented by the general formula (I) of the present invention can be produced by the method shown in the following process diagram.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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 !!
  • Avermectin monooleandrose glycoside is dissolved in an aprotic solvent such as dimethylformamide, and imidazole is added as a base.
  • an aprotic solvent such as dimethylformamide
  • imidazole is added as a base.
  • 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.
  • 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.
  • 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.
  • DMC dimethylimidazoline
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carpositimide
  • 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.
  • 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.
  • an acid halide represented by the general formula (V) When an acid halide represented by the general formula (V) is used, the reaction is carried out in the presence of a base.
  • suitable bases include triethylamine, N, N-dimethylaniline, pyridine, 4-dimethylamine.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • animal parasitic insects are effective for use against various harmful animal parasitic insects (internal and external parasites).
  • 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.
  • the compound of the present invention has excellent parasiticidal activity as an anthelmintic against animal and human parasites.
  • nematodes that infect livestock, poultry and pets such as pigs, hidges, goats, horses, horses, dogs, cats and chickens.
  • the force S, the compounds of the present invention also show activity against these.
  • 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.
  • the compounds of the present invention are also useful against parasites that infect humans.
  • 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
  • the compound of the present invention when 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.
  • suspending agents such as bentonite and wetting agents or other excipients.
  • an antifoaming agent is included.
  • 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.
  • the compound of the present invention 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;
  • 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.
  • the compound of the present invention is preferably used by mixing with an appropriate vegetable oil such as peanut oil or cottonseed oil.
  • an appropriate vegetable oil such as peanut oil or cottonseed oil.
  • 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.
  • 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.
  • the compound of the present invention when 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.
  • 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.
  • 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.
  • Liquid carriers include water, alcohols (eg, methanol, ethanol, isopropyl alcohol, ethylene glycol, glycerin, etc.), ethers (eg, dioxane, tetrahydrofuran, etc.), ketones (eg, acetone, methyl ester).
  • alcohols eg, methanol, ethanol, isopropyl alcohol, ethylene glycol, glycerin, etc.
  • ethers eg, dioxane, tetrahydrofuran, etc.
  • ketones eg, acetone, methyl ester
  • Tilketone, cyclohexanone, etc. 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.
  • esters eg, glycerin esters of fatty acids, phthalate esters, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • aliphatic or alicyclic hydrocarbons eg, cyclohexane
  • 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.
  • 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
  • surfactants of the type include surfactants of the type, acetylene alcohol, acetylene diol, surfactants obtained by adding ethylene oxide to these, silicone surfactants, alkyl glycosides' and the like.
  • 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 ⁇ such as potassium
  • 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.
  • 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.
  • formulation adjuvants include, for example, carboxymethylcellulose (CMC), polybulal alcohol (PVA), gum arabic, gelatin, casein, sodium alginate, tragacanth gum, xanthan gum and the like.
  • 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.
  • 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.
  • the applicability (applicable insect pests, usage method, use period, etc.) can be expanded by using this mixture.
  • a synergistic control effect can be expected by the synergistic action of each active ingredient.
  • examples of the insecticide include organic phosphorus insecticides, carbamate insecticides, pyrethroid insecticides, neonicotinoid insecticides, microbial source insecticides, insect growth regulators and the like.
  • 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.
  • 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.
  • “parts” means all parts by weight
  • “%” means “% by weight” unless otherwise indicated as “volume%”.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Detection Tosohichi PD8020 multi-wavelength detector, chromatogram: 246nm, spectrum: 200-300nm 3D detection
  • 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.
  • Step 2 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)
  • 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.
  • 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%)]
  • 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).
  • Control value (%) X 0 0
  • 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
  • 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

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Abstract

L'invention a pour but de proposer de nouveaux dérivés de monoglycoside d'avermectine substitués en position 4', qui ont d'excellentes activités acaricide, insecticide ou antiparasitaire et exercent une excellente activité de lutte contre les acariens ou d'excellents effets contre divers dégâts dus à des maladies provoqués par des parasites animaux. L'invention concerne des dérivés de monoglycoside d'avermectine représentés par la formule générale (I) ou des sels de ceux-ci; et des acaricides, insecticides ou antiparasitaires contenant ceux-ci comme ingrédient actif : [dans laquelle R1 représente isopropyle ou sec.-butyle; et A est un noyau à cinq ou six chaînons ou fusionné contenant un ou plusieurs atomes qui sont choisis dans le groupe constitué par l'oxygène, l'azote et le soufre et peuvent être identiques ou différents avec les conditions que le noyau peut être non substitué ou substitué par un ou deux substituants et que, lorsque A est un noyau contenant de l'azote, un N-oxyde peut être formé].
PCT/JP2007/071398 2006-11-07 2007-11-02 Dérivés de monoglycoside d'avermectine WO2008056608A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023204124A1 (fr) * 2022-04-20 2023-10-26 日本曹達株式会社 Composé pyridazinone, germicide agricole et horticole, nématicide et agent antifongique médical et vétérinaire

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3001218B1 (fr) * 2013-01-24 2015-04-10 Pf Medicament Macrolides utiles comme agents anticancereux

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5461197A (en) * 1977-10-03 1979-05-17 Merck & Co Inc Vermifuge cc076 derivative
WO2005021569A1 (fr) * 2003-08-28 2005-03-10 Syngenta Participations Ag Avermectines et monosaccharides d'avermectine substitues aux positions 4' et 4 , possedant des proprietes pesticides
JP2006515849A (ja) * 2002-12-20 2006-06-08 シンジェンタ パーティシペーションズ アクチェンゲゼルシャフト アベルメクチンｂ１及び４”位又は４’−位にアルコキシメチル置換基を有するアベルメクチンｂ１モノサッカライド誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5461197A (en) * 1977-10-03 1979-05-17 Merck & Co Inc Vermifuge cc076 derivative
JP2006515849A (ja) * 2002-12-20 2006-06-08 シンジェンタ パーティシペーションズ アクチェンゲゼルシャフト アベルメクチンｂ１及び４”位又は４’−位にアルコキシメチル置換基を有するアベルメクチンｂ１モノサッカライド誘導体
WO2005021569A1 (fr) * 2003-08-28 2005-03-10 Syngenta Participations Ag Avermectines et monosaccharides d'avermectine substitues aux positions 4' et 4 , possedant des proprietes pesticides

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023204124A1 (fr) * 2022-04-20 2023-10-26 日本曹達株式会社 Composé pyridazinone, germicide agricole et horticole, nématicide et agent antifongique médical et vétérinaire

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