JP2010037266A - Avermectin monoglycoside derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel avermectin derivative compound which shows superior insecticidal, acaricidal or anthelmintic activity against pest insects for agricultural and horticultural crops, particularly lepidopteral pests, Acari or animal parasites and has low toxicity and high safety. <P>SOLUTION: Provided is an avermectin monoglycoside represented by formula (I) or its salt and an insecticide or an anthelmintic comprising the avermectin monoglycoside or its salt as an active ingredient. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a cycloalkanecarbonyl group or a piperidine substituted with an amino group or an aminoalkyl group at the 4′-position hydroxyl group of a monomedeoleandrose glycoside of avermectins from which one oleandrose is eliminated from avermectins. The present invention relates to a novel avermectin monoglycoside derivative to which a -4-carbonyl group is added and a salt thereof, and a pest control agent containing the compound as an active ingredient. The pest control agent in the present invention refers to insecticides, acaricides and nematicides in the field of agriculture and horticulture, medicines or animal drugs in the fields of medicine, livestock and fisheries (mammals, birds and It means control agents for harmful organisms such as fish and other pesticidal agents, and insecticides in the hygiene field (household and commercial hygiene pests, unpleasant pest control agents).

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

The monoglycoside derivative of avermectins is a known compound represented by the following formula (III) (see Patent Document 2).

  The avermectins are known to have acaricidal, anthelmintic or insecticidal activity, and various substituents are introduced into their 4 "-position or the 4'-position hydroxyl group of the monooleandrose glycoside of avermectins. Numerous patents and papers have been reported on semisynthetic avermectins whose biological activity has been improved by some means (see Non-Patent Document 1, Patent Documents 3, 4, 5, 6, 7, 8, 9 and 10). .

  Among them, the 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 acid, benzoic acid or An avermectin derivative in which a substituted benzoic acid or the like is ester-bonded at the 4′-position of avermectins or the 4′-position hydroxyl group of a monooleandrose glycoside of avermectins is known (see Patent Document 11).

Examples of avermectins having an ester bond substituent at the 4′-hydroxyl group of monooleandrose glycosides of avermectins include substituted or unsubstituted lower alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl on the carbonyl carbon Also known is an avermectin derivative in which an organic acid substituted with an aromatic heterocycle or the like is ester-bonded to the 4′-position R-configured hydroxyl group of monooleandrose glycoside of avermectins (see Patent Document 12).
In addition, an avermectin derivative in which an aromatic heterocyclic carboxylic acid compound such as thiadiazole or cinnoline is ester-bonded to the 4′-position hydroxyl group of a monomeandrose glycoside of avermectins exhibits high acaricidal activity against various mites. It is known (see Patent Document 13).
In addition, semisynthetic avermectins in which various substituents are introduced into the 5-position hydroxyl group of avermectins have 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, an aromatic heterocyclic carboxylic acid derivative or the like is ester-bonded to the 5-position hydroxyl group are known (see Patent Document 14).
JP-A-52-151197 U.S. Pat. No. 4,206,205 American Chemical Society Symposium Series (ACS Symp. Ser.) 658, 220, 1997 JP 2005-530776 A JP-T-2006-515849 JP-T-2006-51658 Special table 2006-516585 gazette Special table 2006-516590 gazette JP-T-2006-527724 Special table 2007-504113 gazette Special table 2008-511564 gazette JP 54-61197 A WO2008 / 019784 WO2008 / 056608 Chinese Patent CN1302805

As described above, many reports have been made on avermectin derivatives. Cycloalkanecarboxylic acid derivatives substituted with an amino group or aminoalkyl group are present at the 4′-position hydroxyl group of monooleandrose glycosides of avermectins. An ester-linked avermectin derivative has not yet been reported. Patent Document 12 describes substituted or unsubstituted cycloalkyl as one of the substituents of the ester carbonyl group, but there is no specific description of the substituent of cycloalkyl, and there is no general formula or compound example.
In addition, an avermectin derivative in which a piperidine-4-carboxylic acid derivative is ester-bonded to the 4′-position hydroxyl group of a monooleandrose glycoside of avermectins has not yet been reported. In Patent Document 12, there is a description of piperidine as one of the substituents of the ester carbonyl group. Regarding the substitution position, only a general formula indicating 3-position substitution and an example of a 3-position substitution compound are described. There is no mention of positional substitution.
Further, these compounds described in the present specification have a very high insecticidal effect as a pest control agent, particularly against lepidopterous pests, and the insecticidal effect is much higher than the compound described in Patent Document 12, It is not known at all to be even more useful as an endo or ectoparasite control agent for mammals or birds.
Patent Document 13 is an aromatic heterocyclic compound ester-bonded, and exhibits a high acaricidal effect mainly on mites, but has a low insecticidal effect on lepidopterous pests.

  Avermectins have been put to practical use as anthelmintic, acaricidal or insecticidal agents, all of which are highly toxic and classified as poisonous equivalents or deleterious substances. In particular, avermectin B1a / B1b shows high acaricidal activity, but its use is limited because it itself is equivalent to a poison. The object of the present invention is to exhibit superior insecticidal, acaricidal or anthelmintic activity against pests of agricultural and horticultural crops, in particular lepidopterous pests, mites, or animal parasites, and has low toxicity and high safety. It is providing the novel avermectin derivative compound which has these.

  The present inventors have examined the effects of various avermectin derivative compounds in order to provide agricultural and horticultural insecticides, acaricides, and anthelmintic agents against animal parasites that meet the above-mentioned purpose. As a result, as represented by the following general formula (1) according to the present invention, a cycloalkanecarboxylic acid derivative substituted with an amino group or an aminoalkyl group and N-methylpiperidine-4-carboxylic acid are converted into monovalent avermectins. A novel avermectin derivative ester-linked to the 4′-position hydroxyl group of oleandrose glycoside exhibits excellent pest control activity as shown below, particularly strong insecticidal activity against lepidopterous insects, total lepidopterous insects, In addition, the inventors have found that it has low toxicity and high safety for mammals, and has completed the present invention.

  That is, the present invention relates to an avermectin monoglycoside represented by the following general formula (I) or a salt thereof, and an insecticide or an anthelmintic agent containing these as active ingredients.

ｍおよびｎは、それぞれ独立に０から３の整数を示し、Ｒ₁は、イソプロピル基またはｓｅｃ−ブチル基を示し、Ｒ₂は水素原子；Ｃ₁〜Ｃ₆アルキル基；Ｃ₂〜Ｃ₆ハロアルキル基；Ｃ₃〜Ｃ₆アルケニル基；Ｃ₃〜Ｃ₆アルキニル基；Ｃ₁〜Ｃ₄アルコキシＣ₁〜Ｃ₄アルキル基；Ｃ₁〜Ｃ₄アルキルチオＣ₁〜Ｃ₄アルキル基；Ｃ₁〜Ｃ₆アミノアルキル基；Ｃ₁〜Ｃ₄アルキルアミノＣ₁〜Ｃ₄アルキル基；Ｃ₂〜Ｃ₆ヒドロキシアルキル基；アミノカルボニルＣ₁〜Ｃ₄アルキル基；Ｃ₁〜Ｃ₄アルキルアミノカルボニルＣ₁〜Ｃ₄アルキル基；Ｃ₁〜Ｃ₄アルコキシカルボニルＣ₁〜Ｃ₄アルキル基；アミノ基；Ｃ₁〜Ｃ₆アルキルアミノ基；Ｃ₃〜Ｃ₇シクロアルキル基；Ｃ₃〜Ｃ₇シクロアルキルＣ₁〜Ｃ₄アルキル基；無置換もしくはＣ₁〜Ｃ₆アルキル基で置換されていてもよいヘテロシクリルＣ₁〜Ｃ₄アルキル基；無置換もしくはハロゲン原子、Ｃ₁〜Ｃ₆アルキル基、Ｃ₁〜Ｃ₆ハロアルキル基で置換されていても良いヘテロアリールＣ₁〜Ｃ₄アルキル基；または無置換もしくはハロゲン原子、Ｃ₁〜Ｃ₆アルキル基、Ｃ₁〜Ｃ₆ハロアルキル基、ベンジル基で置換されていても良いフェニルＣ₁〜Ｃ₄アルキル基を示し、Ｒ₃は、水素原子、Ｃ₁〜Ｃ₆アルキル基、ｔｅｒｔ−ブトキシカルボニル基またはトリフルオロアセチル基を示し、あるいは、−ＮＲ₂Ｒ₃は、窒素原子、Ｒ₂およびＲ₃が一緒になって環を形成し、１−ピペリジル基、４−モルホリノ基または４−メチル−１−ピペラジニル基を示してもよく、Ｒ₄は水素原子、Ｃ₁〜Ｃ₆アルキル基、ｔｅｒｔ−ブトキシカルボニル基またはトリフルオロアセチル基を示す。〕 [In the formula, A represents the following general formula (A-1) or (A-2),

m and n each independently represents an integer of 0 to 3, R ₁ represents an isopropyl group or a sec-butyl group, R ₂ represents a hydrogen atom; a C ₁ -C ₆ alkyl group; a C ₂ -C ₆ haloalkyl. C ₃ -C ₆ alkenyl group; C ₃ -C ₆ alkynyl group; C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl group; C ₁ -C ₄ alkylthio C ₁ -C ₄ alkyl group; C ₁ -C ₆ aminoalkyl group; C ₁ -C ₄ alkylamino C ₁ -C ₄ alkyl group; C ₂ -C ₆ hydroxyalkyl group; aminocarbonyl C ₁ -C ₄ alkyl group; C ₁ -C ₄ alkylaminocarbonyl C ₁ ~ C ₄ -alkyl group; C ₁ -C ₄ alkoxycarbonyl C ₁ -C ₄ alkyl group; amino group; C ₁ -C ₆ alkyl amino group; C ₃ -C ₇ cycloalkyl group; C ₃ -C ₇ cycloalkyl C ₁ -C ₄ alkyl group; unsubstituted or C ₁ Heterocyclyl optionally substituted with a C ₆ alkyl group C ₁ -C ₄ alkyl group; unsubstituted or hetero optionally substituted with a halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group aryl C ₁ -C ₄ alkyl group; or an unsubstituted or halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, a phenyl C ₁ -C ₄ alkyl group optionally substituted with a benzyl group R ₃ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a tert-butoxycarbonyl group or a trifluoroacetyl group, or —NR ₂ R ₃ represents a nitrogen atom, R ₂ and R ₃ together. is to form a ring, 1-piperidyl group, 4-morpholino group or a 4-methyl-1 may indicate piperazinyl group, R ₄ is a hydrogen atom, C ₁ -C ₆ alkyl group, tert- butoxide Sheet showing a carbonyl group or a trifluoroacetyl group. ]

In the present invention, preferably, in the general formulas (A-1) and (A-2), m represents 1 or 2, n represents 0 or 1, and when m is 1, R ₃ R The substitution position of ₂ N— (CH ₂ ) _n — is the 3-position, and when m is 2, the substitution position of R ₃ R ₂ N— (CH ₂ ) _n — is the 3-position or the 4-position, and R ₂ , R ₃ and R _{4 each} represent a hydrogen atom or a C ₁ -C ₆ alkyl group, an avermectin monoglycoside derivative, or a salt thereof, and an insecticide or an insecticide containing these as active ingredients It relates to the agent.

  A more preferred compound is an avermectin monoglycoside wherein A in the general formula (I) represents 4-dimethylaminocyclohexyl group, 3-dimethylaminocyclohexyl group or N-methyl-4-piperidyl group The present invention relates to a derivative or a salt thereof, and an insecticide or an anthelmintic containing these as active ingredients.

  The novel 4′-substituted avermectin monoglycoside derivative of the present invention represented by the general formula (I) has an insecticidal, acaricidal or anthelmintic activity, and is useful for harmful insects and mites in agricultural and horticultural settings. Excellent effect on various diseases caused by control or animal parasites. In particular, for lepidopterous pests and total lepidopterous pests, both avermectin and a commercially available pest species that are difficult to work with show excellent effects. In addition, the novel compound of the present invention provides an insecticide, acaricide or anthelmintic agent that has low toxicity, is classified as a normal product according to the classification based on the Poisonous and Deleterious Substances Control Law, and is highly safe for human livestock. can do.

ｍおよびｎは、それぞれ独立に０から３の整数を示し、Ｒ₁は、イソプロピル基またはｓｅｃ−ブチル基を示し、Ｒ₂は、水素原子；Ｃ₁〜Ｃ₆アルキル基；Ｃ₂〜Ｃ₆ハロアルキル基；Ｃ₃〜Ｃ₆アルケニル基；Ｃ₃〜Ｃ₆アルキニル基；Ｃ₁〜Ｃ₄アルコキシＣ₁〜Ｃ₄アルキル基；Ｃ₁〜Ｃ₄アルキルチオＣ₁〜Ｃ₄アルキル基；Ｃ₁〜Ｃ₆アミノアルキル基；Ｃ₁〜Ｃ₄アルキルアミノＣ₁〜Ｃ₄アルキル基；Ｃ₂〜Ｃ₆ヒドロキシアルキル基；アミノカルボニルＣ₁〜Ｃ₄アルキル基；Ｃ₁〜Ｃ₄アルキルアミノカルボニルＣ₁〜Ｃ₄アルキル基；Ｃ₁〜Ｃ₄アルコキシカルボニルＣ₁〜Ｃ₄アルキル基；アミノ基；Ｃ₁〜Ｃ₆アルキルアミノ基；Ｃ₃〜Ｃ₇シクロアルキル基；Ｃ₃〜Ｃ₇シクロアルキルＣ₁〜Ｃ₄アルキル基；無置換もしくはＣ₁〜Ｃ₆アルキル基で置換されていてもよいヘテロシクリルＣ₁〜Ｃ₄アルキル基；無置換もしくはハロゲン原子、Ｃ₁〜Ｃ₆アルキル基、Ｃ₁〜Ｃ₆ハロアルキル基で置換されていても良いヘテロアリールＣ₁〜Ｃ₄アルキル基；または無置換もしくはハロゲン原子、Ｃ₁〜Ｃ₆アルキル基、Ｃ₁〜Ｃ₆ハロアルキル基、ベンジル基で置換されていても良いフェニルＣ₁〜Ｃ₄アルキル基を示し、Ｒ₃は、水素原子、Ｃ₁〜Ｃ₆アルキル基、ｔｅｒｔ−ブトキシカルボニル基、トリフルオロアセチル基を示し、あるいは、−ＮＲ₂Ｒ₃は、窒素原子、Ｒ₂およびＲ₃が一緒になって環を形成し、１−ピペリジル基、４−モルホリノ基または４−メチル−１−ピペラジニル基を示してもよく、Ｒ₄は、水素原子、Ｃ₁〜Ｃ₆アルキル基、ｔｅｒｔ−ブトキシカルボニル基またはトリフルオロアセチル基を示す。 The compounds of the present invention are described in detail below.
In general formula (I), A represents the following general formula (A-1) or (A-2),

m and n each independently represents an integer of 0 to 3, R ₁ represents an isopropyl group or a sec-butyl group, R ₂ represents a hydrogen atom; a C ₁ -C ₆ alkyl group; C ₂ -C ₆ haloalkyl groups; C ₃ -C ₆ alkenyl group; C ₃ -C ₆ alkynyl; C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl group; C ₁ -C ₄ alkylthio C ₁ -C ₄ alkyl group; C ₁ ~ C ₆ aminoalkyl group; C ₁ -C ₄ alkylamino C ₁ -C ₄ alkyl group; C ₂ -C ₆ hydroxyalkyl group; aminocarbonyl C ₁ -C ₄ alkyl group; C ₁ -C ₄ alkylaminocarbonyl C ₁ -C ₄ alkyl group; C ₁ -C ₄ alkoxycarbonyl C ₁ -C ₄ alkyl group; an amino group; C ₁ -C ₆ alkylamino group; C ₃ -C ₇ cycloalkyl group; C ₃ -C ₇ cycloalkyl C ₁ -C ₄ alkyl group; unsubstituted or C ₁ -C heterocyclyl C ₁ may be substituted with _alkyl group -C ₄ alkyl group; unsubstituted or halogen atom, C ₁ -C ₆ alkyl group, may be substituted by C ₁ -C ₆ haloalkyl group heteroaryl C ₁ -C ₄ alkyl group; or an unsubstituted or halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, a phenyl C ₁ -C ₄ alkyl group optionally substituted with a benzyl group R ₃ represents a hydrogen atom, a C _{1 to} C ₆ alkyl group, a tert-butoxycarbonyl group or a trifluoroacetyl group, or —NR ₂ R ₃ represents a nitrogen atom, R ₂ and R ₃ together. is in the form a ring, 1-piperidyl group may indicate 4-morpholino group or a 4-methyl-1-piperazinyl group, R ₄ is a hydrogen atom, C ₁ -C ₆ alkyl group, tert- butoxide Sheet showing a carbonyl group or a trifluoroacetyl group.

The “C ₁ -C ₆ alkyl group” shown in the definition of R ₂ , R ₃ , R ₄ is a linear or branched alkyl group having 1 to 6 carbon atoms. As, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, neopentyl 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-dimethylbutyl group, 2-methyl-1-ethylpropyl group, 2,2-dimethylbutyl group, etc. Like Or a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

The “C ₂ -C ₆ haloalkyl group” shown in the definition of R ₂ is a straight chain having 2 to 6 carbon atoms in which at least one hydrogen atom in the alkyl group is substituted with a halogen atom, or Examples of the branched alkyl group include 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoro Ethyl group, 2-fluoropropyl group, 3-fluoropropyl group, 2-chloropropyl group, 3-chloropropyl group, 3-iodopropyl group, heptafluoroisopropyl group, 2-fluorobutyl group, 4-fluorobutyl group, Halogens such as fluorine, chlorine, bromine or iodine on alkyl groups such as 2-chlorobutyl, 5-fluoropentyl, 6-fluorohexyl, etc. An alkyl group to which atoms are bonded, preferably a 2,2-difluoroethyl group or a 2,2,2-trifluoroethyl group.

The “C ₃ -C ₆ alkenyl group” shown in the definition of R _{2 is} a linear or branched alkenyl group having 3 to 6 carbon atoms. Examples thereof include a 2-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 2-ethyl-2-propenyl group, 2-butenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-ethyl-2-butenyl group, 3-butenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 1,3-butadienyl group And a 2,4-pentadienyl group, preferably a 2-propenyl group, a 1-methyl-2-propenyl group, or a 2-butenyl group.

The “C ₃ -C ₆ alkynyl group” shown in the definition of R ₂ is a linear or branched alkynyl group having 3 to 6 carbon atoms, and examples thereof include a 2-propynyl group. 1-methyl-2-propynyl group, 2-butynyl group, 1-methyl-2-butynyl group, 1-ethyl-2-butynyl group, 3-butynyl group, 2-methyl-3-butynyl group, 2-pentynyl Group, 4-pentynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group or 5-hexynyl group, preferably 2-propynyl group, 1-methyl-2-propynyl group, 2-butynyl It is a group.

The “C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl group” shown in the definition of R ₂ is the number of carbon atoms substituted with a linear or branched alkoxy group having 1 to 4 carbon atoms. 1-4 linear or branched alkyl groups, examples of which include methoxymethyl group, ethoxymethyl group, n-propoxymethyl group, isopropoxymethyl group, n-butoxymethyl group, isobutoxymethyl Group, sec-butoxymethyl group, tert-butoxymethyl group, n-pentyloxymethyl group, isopentyloxymethyl group, 1-methoxyethyl group, 2-methoxyethyl group, 1-ethoxyethyl group, 2-ethoxyethyl group 1-n-propoxyethyl group, 2-n-propoxyethyl group, 1-isopropoxyethyl group, 2-isopropoxyethyl group, 1-n-butoxyethyl 2-n-butoxyethyl group, 1-isobutoxyethyl group, 2-isobutoxyethyl group, 1-sec-butoxyethyl group, 2-sec-butoxyethyl group, 1-tert-butoxyethyl group, 2-tert -Butoxyethyl group, 1-methoxypropyl group, 2-methoxypropyl group, 3-methoxypropyl group, 1-methoxy-1-methylethyl group, 2-methoxy-1-methylethyl group, 1-ethoxypropyl group, 2 -Ethoxypropyl group, 3-ethoxypropyl group, 1-ethoxy-1-methylethyl group, 2-ethoxy-1-methylethyl group, 1-n-propoxypropyl group, 2-n-propoxypropyl group, 3-n -Propoxypropyl group, 1-n-propoxy-1-methylethyl group, 2-n-propoxy-1-methylethyl group, 1-isopropyl Poxypropyl group, 2-isopropoxypropyl group, 3-isopropoxypropyl group, 1-isopropoxy-1-methylethyl group, 2-isopropoxy-1-methylethyl group, 1-methoxybutyl group, 2-methoxybutyl Group, 3-methoxybutyl group, 4-methoxybutyl group, 2-methoxy-1-methylpropyl group, 3-methoxy-1-methylpropyl group, 3-methoxy-2-methylpropyl group, 2-methoxy-1- Ethylethyl group, 1-ethoxybutyl group, 2-ethoxybutyl group, 3-ethoxybutyl group, 4-ethoxybutyl group, 2-ethoxy-1-methylpropyl group, 3-ethoxy-1-methylpropyl group, 3-ethoxy -2-methylpropyl group, 2-ethoxy-1-ethylethyl group, etc., preferably methoxymethyl group, 2-metho Xylethyl group, 2-ethoxyethyl group, 3-methoxypropyl group or 3-ethoxypropyl group.

The “C ₁ -C ₄ alkylthio C ₁ -C ₄ alkyl group” shown in the definition of R ₂ is a linear or branched alkylthio moiety having 1 to 4 carbon atoms, and the alkyl moiety has carbon atoms. 1-4 linear or branched alkylthioalkyl groups, examples of which include methylthiomethyl group, ethylthiomethyl group, n-propylthiomethyl group, isopropylthiomethyl group, n-butylthiomethyl group , Isobutylthiomethyl group, sec-butylthiomethyl group, tert-butylthiomethyl group, n-pentylthiomethyl group, isopentylthiomethyl group, 1-methylthioethyl group, 2-methylthioethyl group, 1-ethylthioethyl Group, 2-ethylthioethyl group, 1-n-propylthioethyl group, 2-n-propylthioethyl group, 1-isopropylthioethyl group, 2 Isopropylthioethyl group, 1-n-butylthioethyl group, 2-n-butylthioethyl group, 1-isobutylthioethyl group, 2-isobutylthioethyl group, 1-sec-butylthioethyl group, 2-sec- Butylthioethyl group, 1-tert-butylthioethyl group, 2-tert-butylthioethyl group, 1-methylthiopropyl group, 2-methylthiopropyl group, 3-methylthiopropyl group, 1-methylthio-1-methylethyl group 2-methylthio-1-methylethyl group, 1-ethylthiopropyl group, 2-ethylthiopropyl group, 3-ethylthiopropyl group, 1-ethylthio-1-methylethyl group, 2-ethylthio-1-methylethyl Group, 1-n-propylthiopropyl group, 2-n-propylthiopropyl group, 3-n-propylthiopropyl group 1-n-propylthio-1-methylethyl group, 2-n-propylthio-1-methylethyl group, 1-isopropylthiopropyl group, 2-isopropylthiopropyl group, 3-isopropylthiopropyl group, 1-isopropylthio- 1-methylethyl group, 2-isopropylthio-1-methylethyl group, 1-methylthiobutyl group, 2-methylthiobutyl group, 3-methylthiobutyl group, 4-methylthiobutyl group, 2-methylthio-1-methylpropyl group 3-methylthio-1-methylpropyl group, 3-methylthio-2-methylpropyl group, 2-methylthio-1-ethylethyl group, 1-ethylthiobutyl group, 2-ethylthiobutyl group, 3-ethylthiobutyl group 4-ethylthiobutyl group, 2-ethylthio-1-methylpropyl group, 3-ethylthio-1-me A propyl group, a 3-ethylthio-2-methylpropyl group, a 2-ethylthio-1-ethylethyl group, etc., preferably a methylthiomethyl group, a 2-methylthioethyl group, a 2-ethylthioethyl group or a 3-methylthiopropyl group It is.

The “C ₁ -C ₆ aminoalkyl group” shown in the definition of R ₂ is a straight chain having 1 to 6 carbon atoms in which at least one hydrogen atom in the alkyl group is substituted with an amino group. Or a branched alkyl group, and examples thereof include aminomethyl group, 1-aminoethyl group, 2-aminoethyl group, 1-aminopropyl group, 2-aminopropyl group, 3-aminopropyl group, 1-aminopropyl group, Amino-1-methylethyl group, 2-amino-1-methylethyl group, 1-aminobutyl group, 2-aminobutyl group, 3-aminobutyl group, 4-aminobutyl group, 1-amino-1-methylpropyl Group, 2-amino-1-methylpropyl group, 3-amino-1-methylpropyl group, 1-amino-2-methylpropyl group, 2-amino-2-methylpropyl group, 3-amino-2-methylpropyl group Group, 2- An amino-1-ethylethyl group, a 1-aminopentyl group, a 5-aminopentyl group, a 6-aminohexyl group, and the like, preferably a 2-aminoethyl group.

The “C ₁ -C ₄ alkylamino C ₁ -C ₄ alkyl group” shown in the definition of R ₂ is one or two linear or branched alkyl groups having 1 to 4 carbon atoms. A linear or branched alkyl group having 1 to 4 carbon atoms substituted with an alkylamino group bonded to a nitrogen atom, and when there are two alkyl groups bonded to the nitrogen atom of the alkylamino group, an alkyl group May be the same or different, and examples thereof include methylaminomethyl group, ethylaminomethyl group, n-propylaminomethyl group, isopropylaminomethyl group, n-butylaminomethyl group, isobutylaminomethyl group, sec- Butylaminomethyl group, tert-butylaminomethyl group, n-pentylaminomethyl group, isopentylaminomethyl group, 1-methylaminoethyl group, 2-methylamino Ethyl group, 1-ethylaminoethyl group, 2-ethylaminoethyl group, 1-n-propylaminoethyl group, 2-n-propylaminoethyl group, 1-isopropylaminoethyl group, 2-isopropylaminoethyl group, 1 -N-butylaminoethyl group, 2-n-butylaminoethyl group, 1-isobutylaminoethyl group, 2-isobutylaminoethyl group, 1-sec-butylaminoethyl group, 2-sec-butylaminoethyl group, 1 -Tert-butylaminoethyl group, 2-tert-butylaminoethyl group, 1-methylaminopropyl group, 2-methylaminopropyl group, 3-methylaminopropyl group, 1-methylamino-1-methylethyl group, 2 -Methylamino-1-methylethyl group, 1-ethylaminopropyl group, 2-ethylaminopropyl group 3-ethylaminopropyl group, 1-ethylamino-1-methylethyl group, 2-ethylamino-1-methylethyl group, 1-n-propylaminopropyl group, 2-n-propylaminopropyl group, 3-n -Propylaminopropyl group, 1-n-propylamino-1-methylethyl group, 2-n-propylamino-1-methylethyl group, 1-isopropylaminopropyl group, 2-isopropylaminopropyl group, 3-isopropylamino Propyl group, 1-isopropylamino-1-methylethyl group, 2-isopropylamino-1-methylethyl group, 1-methylaminobutyl group, 2-methylaminobutyl group, 3-methylaminobutyl group, 4-methylamino Butyl group, 2-methylamino-1-methylpropyl group, 3-methylamino-1-methylpropyl group 3-methylamino-2-methylpropyl group, 2-methylamino-1-ethylethyl group, 1-ethylaminobutyl group, 2-ethylaminobutyl group, 3-ethylaminobutyl group, 4-ethylaminobutyl group, 2-ethylamino-1-methylpropyl group, 3-ethylamino-1-methylpropyl group, 3-ethylamino-2-methylpropyl group, 2-ethylamino-1-ethylethyl group, dimethylaminomethyl group, diethylaminomethyl Group, di-n-propylaminomethyl group, diisopropylaminomethyl group, di-n-butylaminomethyl group, diisobutylaminomethyl group, di-sec-butylaminomethyl group, di-tert-butylaminomethyl group, di- n-pentylaminomethyl group, diisopentylaminomethyl group, 1-dimethylaminoethyl 2-dimethylaminoethyl group, 1-diethylaminoethyl group, 2-diethylaminoethyl group, 1-di-n-propylaminoethyl group, 2-di-n-propylaminoethyl group, 1-diisopropylaminoethyl group, 2 -Diisopropylaminoethyl group, 1-di-n-butylaminoethyl group, 2-di-n-butylaminoethyl group, 1-diisobutylaminoethyl group, 2-diisobutylaminoethyl group, 1-di-sec-butylamino Ethyl group, 2-di-sec-butylaminoethyl group, 1-di-tert-butylaminoethyl group, 2-di-tert-butylaminoethyl group, 1-dimethylaminopropyl group, 2-dimethylaminopropyl group, 3-dimethylaminopropyl group, 1-dimethylamino-1-methylethyl group, 2-dimethylamino- -Methylethyl group, 1-diethylaminopropyl group, 2-diethylaminopropyl group, 3-diethylaminopropyl group, 1-diethylamino-1-methylethyl group, 2-diethylamino-1-methylethyl group, 1-di-n-propyl Aminopropyl group, 2-di-n-propylaminopropyl group, 3-di-n-propylaminopropyl group, 1-di-n-propylamino-1-methylethyl group, 2-di-n-propylamino- 1-methylethyl group, 1-diisopropylaminopropyl group, 2-diisopropylaminopropyl group, 3-diisopropylaminopropyl group, 1-diisopropylamino-1-methylethyl group, 2-diisopropylamino-1-methylethyl group, 1 -Dimethylaminobutyl group, 2-dimethylaminobutyl group, 3-dimethyl Aminobutyl group, 4-meditylaminobutyl group, 2-dimethylamino-1-methylpropyl group, 3-dimethylamino-1-methylpropyl group, 3-dimethylamino-2-methylpropyl group, 2-dimethylamino- 1-ethylethyl group, 1-diethylaminobutyl group, 2-diethylaminobutyl group, 3-diethylaminobutyl group, 4-diethylaminobutyl group, 2-diethylamino-1-methylpropyl group, 3-diethylamino-1-methylpropyl group, 3 -Diethylamino-2-methylpropyl group, 2-diethylamino-1-ethylethyl group, 2- (ethylmethylamino) ethyl, 3- (ethylmethylamino) propyl, etc., preferably 2-methylaminoethyl group and 2 -A dimethylaminoethyl group.

The “C ₂ -C ₆ hydroxyalkyl group” shown in the definition of R ² is a straight chain having 2 to 6 carbon atoms in which at least one hydrogen atom in the alkyl group is substituted with a hydroxyl group, or Examples of the branched alkyl group include 2-hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxy-1-methylethyl group, 2-hydroxybutyl group, and 3-hydroxy. Butyl group, 4-hydroxybutyl group, 2-hydroxy-1-methylpropyl group, 3-hydroxy-1-methylpropyl group, 2-hydroxy-2-methylpropyl group, 3-hydroxy-2-methylpropyl group, 2 -Hydroxy-1-ethylethyl group, 5-hydroxypentyl group, 6-hydroxyhexyl group, etc., preferably 2-hydroxyethyl group And 2-hydroxy-1-ethylethyl group.

The “aminocarbonyl C ₁ -C ₄ alkyl group” shown in the definition of R ₂ is a straight chain having 1 to 4 carbon atoms in which at least one hydrogen atom in the alkyl group is substituted with an aminocarbonyl group. Examples of the chain-like or branched alkyl group include aminocarbonylmethyl group, 1-aminocarbonylethyl group, 2-aminocarbonylethyl group, 1-aminocarbonylpropyl group, 2-aminocarbonylpropyl group, 3 -Aminocarbonylpropyl group, 1-aminocarbonyl-1-methylethyl group, 2-aminocarbonyl-1-methylethyl group, 1-aminocarbonylbutyl group, 2-aminocarbonylbutyl group, 3-aminocarbonylbutyl group, 4 -Aminocarbonylbutyl group, 1-aminocarbonyl-1-methylpropyl group, 2-aminocarbonyl-1-me Tylpropyl group, 3-aminocarbonyl-1-methylpropyl group, 1-aminocarbonyl-2-methylpropyl group, 2-aminocarbonyl-2-methylpropyl group, 3-aminocarbonyl-2-methylpropyl group, 2-amino A carbonyl-1-ethylethyl group and the like, preferably an aminocarbonylmethyl group.

The “C ₁ -C ₄ alkylaminocarbonyl C ₁ -C ₄ alkyl group” shown in the definition of R ₂ is one or two linear or branched alkyl groups having 1 to 4 carbon atoms. A linear or branched alkyl group having 1 to 4 carbon atoms substituted with an alkylaminocarbonyl group bonded to the nitrogen atom of the aminocarbonyl group, and an alkyl group bonded to the nitrogen atom of the alkylaminocarbonyl group In the case of two, the alkyl groups may be the same or different, and examples thereof include methylaminocarbonylmethyl group, ethylaminocarbonylmethyl group, n-propylaminocarbonylmethyl group, isopropylaminocarbonylmethyl group, n-butyl. Aminocarbonylmethyl group, isobutylaminocarbonylmethyl group, sec-butylaminocarbonylmethyl group, tert Butylaminocarbonylmethyl group, n-pentylaminocarbonylmethyl group, isopentylaminocarbonylmethyl group, 1-methylaminoecarbonylyl group, 2-methylaminocarbonylethyl group, 1-ethylaminocarbonylethyl group, 2-ethylamino Carbonylethyl group, 1-n-propylaminocarbonylethyl group, 2-n-propylaminocarbonylethyl group, 1-isopropylaminocarbonylethyl group, 2-isopropylaminocarbonylethyl group, 1-n-butylaminocarbonylethyl group, 2-n-butylaminocarbonylethyl group, 1-isobutylaminocarbonylethyl group, 2-isobutylaminocarbonylethyl group, 1-sec-butylaminocarbonylethyl group, 2-sec-butylaminocarbonylethyl group 1-tert-butylaminocarbonylethyl group, 2-tert-butylaminocarbonylethyl group, 1-methylaminocarbonylpropyl group, 2-methylaminocarbonylpropyl group, 3-methylaminocarbonylpropyl group, 1-methylaminocarbonyl -1-methylethyl group, 2-methylaminocarbonyl-1-methylethyl group, 1-ethylaminocarbonylpropyl group, 2-ethylaminocarbonylpropyl group, 3-ethylaminocarbonylpropyl group, 1-ethylaminocarbonyl-1 -Methylethyl group, 2-ethylaminocarbonyl-1-methylethyl group, 1-n-propylaminocarbonylpropyl group, 2-n-propylaminocarbonylpropyl group, 3-n-propylaminocarbonylpropyl group, 1-n -Propylamino Nocarbonyl-1-methylethyl group, 2-n-propylaminocarbonyl-1-methylethyl group, 1-isopropylaminocarbonylpropyl group, 2-isopropylaminocarbonylpropyl group, 3-isopropylaminocarbonylpropyl group, 1-isopropyl Aminocarbonyl-1-methylethyl group, 2-isopropylaminocarbonyl-1-methylethyl group, 1-methylaminocarbonylbutyl group, 2-methylaminocarbonylbutyl group, 3-methylaminocarbonylbutyl group, 4-methylaminocarbonyl Butyl group, 2-methylaminocarbonyl-1-methylpropyl group, 3-methylaminocarbonyl-1-methylpropyl group, 3-methylaminocarbonyl-2-methylpropyl group, 2-methylaminocarbonyl-1-ethylethyl 1-ethylaminocarbonylbutyl group, 2-ethylaminocarbonylbutyl group, 3-ethylaminocarbonylbutyl group, 4-ethylaminocarbonylbutyl group, 2-ethylaminocarbonyl-1-methylpropyl group, 3-ethylaminocarbonyl -1-methylpropyl group, 3-ethylaminocarbonyl-2-methylpropyl group, 2-ethylaminocarbonyl-1-ethylethyl group, dimethylaminocarbonylmethyl group, diethylaminocarbonylmethyl group, di-n-propylaminocarbonylmethyl group Diisopropylaminocarbonylmethyl group, di-n-butylaminocarbonylmethyl group, diisobutylaminocarbonylmethyl group, di-sec-butylaminocarbonylmethyl group, di-tert-butylaminocarbonylmethyl group, di- n-pentylaminocarbonylmethyl group, diisopentylaminocarbonylmethyl group, 1-dimethylaminocarbonylethyl group, 2-dimethylaminocarbonylethyl group, 1-diethylaminocarbonylethyl group, 2-diethylaminocarbonylethyl group, 1-di- n-propylaminocarbonylethyl group, 2-di-n-propylaminocarbonylethyl group, 1-diisopropylaminocarbonylethyl group, 2-diisopropylaminocarbonylethyl group, 1-di-n-butylaminocarbonylethyl group, 2- Di-n-butylaminocarbonylethyl group, 1-diisobutylaminocarbonylethyl group, 2-diisobutylaminocarbonylethyl group, 1-di-sec-butylaminocarbonylethyl group, 2-di-sec-butylaminocarbonyl Ruethyl group, 1-di-tert-butylaminocarbonylethyl group, 2-di-tert-butylaminocarbonylethyl group, 1-dimethylaminocarbonylpropyl group, 2-dimethylaminocarbonylpropyl group, 3-dimethylaminocarbonylpropyl group 1-dimethylaminocarbonyl-1-methylethyl group, 2-dimethylaminocarbonyl-1-methylethyl group, 1-diethylaminocarbonylpropyl group, 2-diethylaminocarbonylpropyl group, 3-diethylaminocarbonylpropyl group, 1-diethylaminocarbonyl -1-methylethyl group, 2-diethylaminocarbonyl-1-methylethyl group, 1-di-n-propylaminocarbonylpropyl group, 2-di-n-propylaminocarbonylpropyl group, 3-di-n-propiyl Aminocarbonylpropyl group, 1-di-n-propylaminocarbonyl-1-methylethyl group, 2-di-n-propylaminocarbonyl-1-methylethyl group, 1-diisopropylaminocarbonylpropyl group, 2-diisopropylaminocarbonyl Propyl group, 3-diisopropylaminocarbonylpropyl group, 1-diisopropylaminocarbonyl-1-methylethyl group, 2-diisopropylaminocarbonyl-1-methylethyl group, 1-dimethylaminocarbonylbutyl group, 2-dimethylaminocarbonylbutyl group 3-dimethylaminocarbonylbutyl group, 4-mesitylaminocarbonylbutyl group, 2-dimethylaminocarbonyl-1-methylpropyl group, 3-dimethylaminocarbonyl-1-methylpropyl group, 3-dimethylamino Nocarbonyl-2-methylpropyl group, 2-dimethylaminocarbonyl-1-ethylethyl group, 1-diethylaminocarbonylbutyl group, 2-diethylaminocarbonylbutyl group, 3-diethylaminocarbonylbutyl group, 4-diethylaminocarbonylbutyl group, 2- Diethylaminocarbonyl-1-methylpropyl group, 3-diethylaminocarbonyl-1-methylpropyl group, 3-diethylaminocarbonyl-2-methylpropyl group, 2-diethylaminocarbonyl-1-ethylethyl group, 2- (ethylmethylaminocarbonyl) ethyl Group, 3- (ethylmethylaminocarbonyl) propyl group and the like, preferably methylaminocarbonylmethyl group and dimethylaminocarbonylmethyl group.

The “C ₁ -C ₄ alkoxycarbonyl C ₁ -C ₄ alkyl group” shown in the definition of R ₂ is substituted with a linear or branched alkoxycarbonyl group having 1 to 4 carbon atoms. A straight or branched alkyl group having 1 to 4 carbon atoms, examples of which include methoxycarbonylmethyl group, ethoxycarbonylmethyl group, n-propoxycarbonylmethyl group, isopropoxycarbonylmethyl group, n-butoxy Carbonylmethyl group, isobutoxycarbonylmethyl group, sec-butoxycarbonylmethyl group, tert-butoxycarbonylmethyl group, n-pentyloxycarbonylmethyl group, isopentyloxycarbonylmethyl group, 1-methoxycarbonylethyl group, 2-methoxycarbonyl Ethyl, 1-ethoxycarbonylethyl, 2-ethyl Xoxycarbonylethyl group, 1-n-propoxycarbonylethyl group, 2-n-propoxycarbonylethyl group, 1-isopropoxycarbonylethyl group, 2-isopropoxycarbonylethyl group, 1-n-butoxycarbonylethyl group, 2- n-butoxycarbonylethyl group, 1-isobutoxycarbonylethyl group, 2-isobutoxycarbonylethyl group, 1-sec-butoxycarbonylethyl group, 2-sec-butoxycarbonylethyl group, 1-tert-butoxycarbonylethyl group, 2-tert-butoxycarbonylethyl group, 1-methoxycarbonylpropyl group, 2-methoxycarbonylpropyl group, 3-methoxycarbonylpropyl group, 1-methoxycarbonyl-1-methylethyl group, 2-methoxycarbonyl-1-methyl Til group, 1-ethoxycarbonylpropyl group, 2-ethoxycarbonylpropyl group, 3-ethoxycarbonylpropyl group, 1-ethoxycarbonyl-1-methylethyl group, 2-ethoxycarbonyl-1-methylethyl group, 1-n- Propoxycarbonylpropyl group, 2-n-propoxycarbonylpropyl group, 3-n-propoxycarbonylpropyl group, 1-n-propoxycarbonyl-1-methylethyl group, 2-n-propoxycarbonyl-1-methylethyl group, 1 -Isopropoxycarbonylpropyl group, 2-isopropoxycarbonylpropyl group, 3-isopropoxycarbonylpropyl group, 1-isopropoxycarbonyl-1-methylethyl group, 2-isopropoxycarbonyl-1-methylethyl group, 1-methoxy Carbonyl butyl Group, 2-methoxycarbonylbutyl group, 3-methoxycarbonylbutyl group, 4-methoxycarbonylbutyl group, 2-methoxycarbonyl-1-methylpropyl group, 3-methoxycarbonyl-1-methylpropyl group, 3-methoxycarbonyl- 2-methylpropyl group, 2-methoxycarbonyl-1-ethylethyl group, 1-ethoxycarbonylbutyl group, 2-ethoxycarbonylbutyl group, 3-ethoxycarbonylbutyl group, 4-ethoxycarbonylbutyl group, 2-ethoxycarbonyl-1 -Methylpropyl group, 3-ethoxycarbonyl-1-methylpropyl group, 3-ethoxycarbonyl-2-methylpropyl group, 2-ethoxycarbonyl-1-ethylethyl group, etc., preferably methoxycarbonylmethyl group, ethoxycarbonyl Methyl And 2-methoxycarbonylethyl group.

The “C ₁ -C ₆ alkylamino group” shown in the definition of R ₂ is a linear or branched alkyl group having 1 to 6 carbon atoms bonded to a nitrogen atom. And when there are two alkyl groups, the alkyl groups may be the same or different. Examples thereof include methylamino group, dimethylamino group, ethylamino group, diethylamino group, n-propylamino group, di-n-propylamino group, isopropylamino group, n-butylamino group, di-n-butylamino. Group, isobutylamino group, sec-butylamino group, tert-butylamino group, n-pentylamino group, isopentylamino group, 2-methylbutylamino group, neopentylamino group, n-hexylamino group, 4-methyl Pentylamino group, 3-methylpentylamino group, 2-methylpentylamino group, 3,3-dimethylbutylamino group, 1,1-dimethylbutylamino group, 1,3-dimethylbutylamino group, 2,3-dimethyl Butylamino group, 1-ethylbutylamino group, 1-methyl-1-ethylpropylamino group, 1,2 A dimethylbutylamino group, a 2-methyl-1-ethylpropylamino group, a 2,2-dimethylbutylamino group, an ethylmethylamino group, an isopropylmethylamino group, etc., preferably a methylamino group and a dimethylamino group .

The “C ₃ -C ₇ cycloalkyl group” shown in the definition of R ₂ is a cyclic alkyl group having 3 to 7 carbon atoms, and may have a branched chain on the ring, Examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, 2-methylcyclopropyl group, 2-methylcyclopentyl group or 2-methylcyclohexyl group, preferably cyclopropyl group, cyclopentyl group and cyclohexyl. It is a group.

The “C ₃ -C ₇ cycloalkyl C ₁ -C ₄ alkyl group” shown in the definition of R ₂ has a cycloalkyl moiety having 3 to 7 carbon atoms and has a branched chain on the ring. A linear or branched alkyl group having 1 to 4 carbon atoms substituted by an optionally substituted cyclic alkyl group. Examples thereof include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, and cyclohexyl. Methyl group, 2-methylcyclopropylmethyl group, 2-methylcyclopentylmethyl group, 2-methylcyclohexylmethyl group, 1-cyclopropylethyl group, 1-cyclobutylethyl group, 1-cyclopentylethyl group, 1-cyclohexylethyl group 1- (2-methylcyclopropyl) ethyl group, 1- (2-methylcyclopentyl) ethyl group, 1- (2-methylcyclohexane) Syl) ethyl group, 2-cyclopropylethyl group, 2-cyclobutylethyl group, 2-cyclopentylethyl group, 2-cyclohexylethyl group, 2- (2-methylcyclopropyl) ethyl group, 2- (2-methylcyclopentyl) ) Ethyl group, 2- (2-methylcyclohexyl) ethyl group, 1-cyclopropylpropyl group, 1-cyclobutylpropyl group, 1-cyclopentylpropyl group, 1-cyclohexylpropyl group, 1- (2-methylcyclopropyl) Propyl group, 1- (2-methylcyclopentyl) propyl group, 1- (2-methylcyclohexyl) propyl group, 2-cyclopropylpropyl group, 2-cyclobutylpropyl group, 2-cyclopentylpropyl group, 2-cyclohexylpropyl group , 2- (2-methylcyclopropyl) propyl group, -(2-methylcyclopentyl) propyl group, 2- (2-methylcyclohexyl) propyl group, 3-cyclopropylpropyl group, 3-cyclobutylpropyl group, 3-cyclopentylpropyl group, 3-cyclohexylpropyl group, 3- ( 2-methylcyclopropyl) propyl group, 3- (2-methylcyclopentyl) propyl group, 3- (2-methylcyclohexyl) propyl group, 1-cyclopropyl-1-methylethyl group, 1-cyclobutyl-1-methylethyl Group, 1-cyclopentyl-1-methylethyl group, 1-cyclohexyl-1-methylethyl group, 1- (2-methylcyclopropyl) -1-methylethyl group, 1- (2-methylcyclopentyl) -1-methyl Ethyl group, 1- (2-methylcyclohexyl) -1-methylethyl group, 2-cyclo Propyl-1-methylethyl group, 2-cyclobutyl-1-methylethyl group, 2-cyclopentyl-1-methylethyl group, 2-cyclohexyl-1-methylethyl group, 2- (2-methylcyclopropyl) -1- Methylethyl group, 2- (2-methylcyclopentyl) -1-methylethyl group, 2- (2-methylcyclohexyl) -1-methylethyl group, 1-cyclopropylbutyl group, 1-cyclobutylbutyl group, 1- Cyclopentylbutyl group, 1-cyclohexylbutyl group, 1- (2-methylcyclopropyl) butyl group, 1- (2-methylcyclopentyl) butyl group, 1- (2-methylcyclohexyl) butyl group, 2-cyclopropylbutyl group 2-cyclobutylbutyl group, 2-cyclopentylbutyl group, 2-cyclohexylbutyl group, 2- (2- Tilcyclopropyl) butyl group, 2- (2-methylcyclopentyl) butyl group, 2- (2-methylcyclohexyl) butyl group, 3-cyclopropylbutyl group, 3-cyclobutylbutyl group, 3-cyclopentylbutyl group, 3 -Cyclohexylbutyl group, 3- (2-methylcyclopropyl) butyl group, 3- (2-methylcyclopentyl) butyl group, 3- (2-methylcyclohexyl) butyl group, 4-cyclopropylbutyl group, 4-cyclobutyl Butyl group, 4-cyclopentylbutyl group, 4-cyclohexylbutyl group, 4- (2-methylcyclopropyl) butyl group, 4- (2-methylcyclopentyl) butyl group, 4- (2-methylcyclohexyl) butyl group, 2 -Cyclopropyl-1-ethylethyl group, 2-cyclobutyl-1-ethylethyl group, -Cyclopentyl-1-ethylethyl group, 2-cyclohexyl-1-ethylethyl group, 2- (2-methylcyclopropyl) -1-ethylethyl group, 2- (2-methylcyclopentyl) -1-ethylethyl group, 2- (2 -Methylcyclohexyl) -1-ethylethyl group, 2-cyclopropyl-1-methylpropyl group, 2-cyclobutyl-1-methylpropyl group, 2-cyclopentyl-1-methylpropyl group, 2-cyclohexyl-1-methylpropyl group 2- (2-methylcyclopropyl) -1-methylpropyl group, 2- (2-methylcyclopentyl) -1-methylpropyl group, 2- (2-methylcyclohexyl) -1-methylpropyl group, 3-cyclo Propyl-1-methylpropyl group, 3-cyclobutyl-1-methylpropyl group, 3-cyclo Pentyl-1-methylpropyl group, 3-cyclohexyl-1-methylpropyl group, 3- (2-methylcyclopropyl) -1-methylpropyl group, 3- (2-methylcyclopentyl) -1-methylpropyl group, 3 -(2-methylcyclohexyl) -1-methylpropyl group, 3-cyclopropyl-2-methylpropyl group, 3-cyclobutyl-2-methylpropyl group, 3-cyclopentyl-2-methylpropyl group, 3-cyclohexyl-2 -Methylpropyl group, 3- (2-methylcyclopropyl) -2-methylpropyl group, 3- (2-methylcyclopentyl) -2-methylpropyl group or 3- (2-methylcyclohexyl) -2-methylpropyl group Preferably, cyclopropylmethyl group, cyclopentylmethyl group and cyclohexyl It is a methyl group.

The “heterocyclyl C ₁ -C ₄ alkyl group” shown in the definition of R ₂ has 1 carbon atom substituted with an alicyclic heterocycle containing one or more heteroatoms in a 5- to 6-membered ring. -4 linear or branched alkyl groups, such as 2-tetrahydrofuranylmethyl group, 3-tetrahydrofuranylmethyl group, 2-tetrahydrothienylmethyl group, 3-tetrahydrothienylmethyl group, 2 -Piperidylmethyl group, 3-piperidylmethyl group, 4-piperidylmethyl group, 2-morpholinylmethyl group, 3-morpholinylmethyl group, 2-piperazinylmethyl group, 3-piperazinylmethyl group, 1 -(2-tetrahydrofuranyl) ethyl group, 1- (3-tetrahydrofuranyl) ethyl group, 1- (2-tetrahydrothienyl) ethyl group, 1- (3-tetrahydro Thienyl) ethyl group, 1- (2-piperidyl) ethyl group, 1- (3-piperidyl) ethyl group, 1- (4-piperidyl) ethyl group, 2- (2-tetrahydrofuranyl) ethyl group, 2- (3 -Tetrahydrofuranyl) ethyl group, 2- (2-tetrahydrothienyl) ethyl group, 2- (3-tetrahydrothienyl) ethyl group, 2- (1-piperidyl) ethyl group, 2- (2-piperidyl) ethyl group, 2 -(3-piperidyl) ethyl group, 2- (4-piperidyl) ethyl group, 1- (2-tetrahydrofuranyl) propyl group, 1- (3-tetrahydrofuranyl) propyl group, 1- (2-tetrahydrothienyl) propyl Group, 1- (3-tetrahydrothienyl) propyl group, 1- (2-piperidyl) propyl group, 1- (3-piperidyl) propyl group, 1- (4- Peridyl) propyl group, 3- (2-tetrahydrofuranyl) propyl group, 3- (3-tetrahydrofuranyl) propyl group, 3- (2-tetrahydrothienyl) propyl group, 3- (3-tetrahydrothienyl) propyl group, 3 -(1-piperidyl) propyl group, 3- (2-piperidyl) propyl group, 3- (3-piperidyl) propyl group, 3- (4-piperidyl) propyl group, 4- (2-tetrahydrofuranyl) butyl group, 4- (3-tetrahydrofuranyl) butyl group or 4- (2-tetrahydrothienyl) butyl group, etc., preferably 2-tetrahydrofuranylmethyl group, 3-tetrahydrofuranylmethyl group, 2-tetrahydrothienylmethyl group and 3 -Tetrahydrothienylmethyl group.

The “heteroaryl C ₁ -C ₄ alkyl group” shown in the definition of R ₂ has ₁ to 6 carbon atoms substituted with a heteroaromatic ring containing one or more heteroatoms in a 5- to 6-membered ring. Examples of four linear or branched alkyl groups include 2-furanylmethyl group, 3-furanylmethyl group, 2-thienylmethyl group, 3-thienylmethyl group, 2-pyridylmethyl group, 3- Pyridylmethyl group, 4-pyridylmethyl group, 3-pyrazolemethyl group, 2-imidazolmethyl group, 2-oxazolemethyl group, 3-isoxazolemethyl group, 1- (2-furanyl) ethyl group, 1- (3- Furanyl) ethyl group, 1- (2-thienyl) ethyl group, 1-
(3-thienyl) ethyl group, 1- (2-pyridyl) ethyl group, 1- (3-pyridyl) ethyl group, 1- (4-pyridyl) ethyl group, 2- (2-furanyl) ethyl group, 2- (3-furanyl) ethyl group, 2- (2-thienyl) ethyl group, 2- (3-thienyl) ethyl group, 2- (2-pyridyl) ethyl group, 2- (3-pyridyl) ethyl group, 2- (4-pyridyl) ethyl group, 1- (2-furanyl) propyl group, 1- (3-furanyl) propyl group, 1- (2-thienyl) propyl group, 1- (3-thienyl) propyl group, 1- (2-pyridyl) propyl group, 1- (3-pyridyl) propyl group, 1- (4-pyridyl) propyl group, 3- (2-furanyl) propyl group, 3- (3-furanyl) propyl group, 3- (2-thienyl) propyl group, 3- (3-thienyl) Lopyl group, 3- (2-pyridyl) propyl group, 3- (3-pyridyl) propyl group, 3- (4-pyridyl) propyl group, 4- (2-furanyl) butyl group, 4- (3-furanyl) A butyl group or a 4- (2-thienyl) butyl group is preferable, and a 2-furanylmethyl group, a 3-furanylmethyl group, a 2-pyridylmethyl group, a 3-pyridylmethyl group, and a 4-pyridylmethyl group are preferable.

The “phenyl C ₁ -C ₄ alkyl group” shown in the definition of R ₂ is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a phenyl group. As benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group, 1-phenyl-1-methylethyl group, 2-phenyl- 1-methylethyl group, 1-phenylbutyl group, 2-phenylbutyl group, 3-phenylbutyl group, 4-phenylbutyl group, 1-phenyl-1-methylpropyl group, 2-phenyl-1-methylpropyl group, 3-phenyl-1-methylpropyl group, 1-phenyl-2-methylpropyl group, 2-phenyl-2-methylpropyl group, 3-phenyl-2-methylpropyl group, etc. Yes, preferably a benzyl group.

The "heterocyclyl C ₁ -C ₄ alkyl group", "heteroaryl C ₁ -C ₄ alkyl group" and is shown in the definition of the substituents on "phenyl C ₁ -C ₄ alkyl group", "C ₁ ~ The “C ₆ alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, Isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, neopentyl 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-ethylpro Group, 1,2-dimethylbutyl group, 2-methyl-1-ethylpropyl group, 2,2-dimethylbutyl group, etc., preferably methyl group, ethyl group, n-propyl group, isopropyl group. .

The “halogen atom” shown in the definition of the substituent on the above “heteroaryl C ₁ -C ₄ alkyl group” and “phenyl C ₁ -C ₄ alkyl group” includes fluorine, chlorine, bromine, iodine atom Can be illustrated.

The “C ₁ -C ₆ haloalkyl group” shown in the definition of the substituent on the above “heteroaryl C ₁ -C ₄ alkyl group” and “phenyl C ₁ -C ₄ alkyl group” 6 linear or branched haloalkyl groups, examples of which include trifluoromethyl group, fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, dichloromethyl group, trichloromethyl group 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 1-fluoroethyl group, 1,1-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 1-fluoro Propyl group, 3-fluoropropyl group, 2-chloropropyl group, 3-chloropropyl group, 3-iodopropyl group, heptafluoroisopropyl Fluorine, chlorine and the like in the alkyl group such as pill group, 1-fluorobutyl group, 4-fluorobutyl group, 1-chlorobutyl group, 5-fluoropentyl group, 6-fluorohexyl group, tridecafluorohexyl group, etc. , An alkyl group to which a halogen atom such as bromine or iodine is bonded, preferably a trifluoromethyl group or a difluoromethyl group.

In the present invention, the salt of the avermectin monoglycoside derivative represented by the general formula (I) is preferably a pharmacologically acceptable salt. Examples of such a salt include an organic acid or an inorganic acid. And the like.
Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, benzoic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, Examples thereof include salts with acidic amino acids such as benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid and glutamic acid, cinnamic acid, p-methoxycinnamic acid, ferulic acid and the like.
Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, sulfuric acid, phosphoric acid and the like.

Among the above-mentioned salts, a salt with an organic acid is preferable, and a salt with benzoic acid is more preferable as the salt with an organic acid.
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 1-1 to 1-3 below. However, the present invention is not limited to the compounds having the substituents exemplified in these tables.

  In Table 1-1 to Table 1-3, 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 (the column used, the eluent, the flow rate, etc.) will be described in detail in Examples described later.

[Method for Producing Compound According to the Present Invention]
The compound represented by the general formula (I) of the present invention can be produced by the methods shown in the following production steps 1 to 9.

（式中、ＡおよびＲ₁は前記と同じ意味を示し、Ｒ₅は、トリアルキルシリル基、トリアリールシリル基、ジアルキルアリールシリル基、ジアリールアルキルシリル基などの３置換シリル基であり、トリメチルシリル基、トリエチルシリル基、トリイソプロピルシリル基、ジメチルイソプロピルシリル基、ｔ−ブチルジメチルシリル基、ｔ−ブチルジフェニルシリル基、トリベンジルシリル基、トリ−ｐ−キシリルシリル基、トリフェニルシリル基、ジフェニルメチルシリル基、ジ−ｔ−ブチルメチルシリル基、ｔ−ブチルメトキシフェニルシリル基、ｔ−ブトキシジフェニルシリル基などが挙げられ、特に好ましくはｔ−ブチルジメチルシリル基が挙げられる。） The avermectin monoglycoside derivative of the general formula (I) according to the present invention can be produced, for example, by the method of production step 1 below.
Manufacturing process 1

Wherein A and R ₁ have the same meaning as described above, and R ₅ is a trisubstituted silyl group such as a trialkylsilyl group, a triarylsilyl group, a dialkylarylsilyl group, a diarylalkylsilyl group, and a trimethylsilyl group , Triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, tribenzylsilyl group, tri-p-xylylsilyl group, triphenylsilyl group, diphenylmethylsilyl group , Di-t-butylmethylsilyl group, t-butylmethoxyphenylsilyl group, t-butoxydiphenylsilyl group, etc., particularly preferably t-butyldimethylsilyl group.)

The production step (1) is a step of removing the protecting group at the 5-position from the avermectin monooleandrose glycoside derivative (II) by acid treatment.
Acids used include inorganic acids such as sulfuric acid, hydrochloric acid or hydrofluoric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, etc. Examples of the organic acid and other H ⁺ type strongly acidic or weakly acidic ion exchangers include p-toluenesulfonic acid. The amount of acid used can vary greatly depending on the type of acid and solvent used, but is usually 0.1 to 10 equivalents. It 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 carbonization such as benzene, toluene and xylene. Hydrogen; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dimethylformamide And amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide and nitriles such as acetonitrile. These mixed solvents may be used.
Moreover, you may add organic bases, such as ammonia, a triethylamine, a pyridine, and a tetrabutylamine, or crown ether to a reaction solvent as needed.

The reaction temperature is −10 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C. The reaction time varies depending mainly on the reaction temperature or the type of solvent used, but is usually 10 minutes to 50 hours. Preferably, it is 0.5 hours to 5 hours.
The compound of the general formula (II) can be easily synthesized according to the methods described in, for example, the production step (5), the production step (6), the production step (7) described later.

（式中、Ｒ₁は前記と同じ意味を示し、Ｒ₆、Ｒ₇は、水素原子またはアルキル基を示し、Ａ₁は下記一般式（Ａ−１−１）または（Ａ−２−１）を示し、Ａ₂は下記一般式（Ａ−１−２）または４−ピペリジル基を示す。

（式中、ｍ、ｎ、Ｒ₂は前記と同じ意味を示し、Ｒ₃ａ、Ｒ₄ａはＣ₁〜Ｃ₆アルキル基を示す。）） The avermectin monoglycoside derivative of the general formula (Ia) according to the present invention can also be produced, for example, by the method of production step 2 below.
Manufacturing process (2)

(In the formula, R ₁ represents the same meaning as described above, R ₆ and R ₇ represent a hydrogen atom or an alkyl group, and A ₁ represents the following general formula (A-1-1) or (A-2-1). A ₂ represents the following general formula (A-1-2) or 4-piperidyl group.

(In the formula, m, n and R ₂ have the same meaning as described above, and R ₃ a and R ₄ a represent a C _{1 to} C ₆ alkyl group.)

The production step (2) is a step of condensing and reducing a nitrogen atom in A ₂ on the avermectin monooleandrose glycoside derivative (Ib) with a carbonyl derivative represented by the general formula (III).
Examples of the reducing agent used include complex hydrogen compounds such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, diborane, titanium (IV) chloride, and the like. Further, reduction with sodium, sodium amalgam, zinc-acid, catalytic reduction, or electrolytic reduction with lead or platinum as a cathode may be used. Preferred is sodium cyanoborohydride. The amount of reducing agent used can vary greatly depending on the type of reducing agent and solvent used, but is usually 0.1 to 10 equivalents. It is preferably 0.5 to 2 equivalents.
Solvents used in the reaction include water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, alcohols such as 2-butanol and t-butanol, and aromatic carbonization such as benzene, toluene and xylene. Hydrogen; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dimethylformamide And amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide and nitriles such as acetonitrile. These mixed solvents may be used.
In addition, organic bases such as ammonia, triethylamine, pyridine, and tetrabutylamine, organic acids such as acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid, and inorganic acids such as sulfuric acid and hydrochloric acid may be added to the reaction solvent as necessary. good. Alternatively, salts of these acids and bases or crown ethers may be added.

The reaction temperature is −10 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C. The reaction time varies depending mainly on the reaction temperature or the type of solvent used, but is usually 10 minutes to 50 hours. Preferably, it is 0.5 hours to 5 hours.
The compound of general formula (Ib) can be easily synthesized according to the methods described in, for example, the production step (1), the production step (3) and the production step (4) described later.
The compound of the general formula (III) can be produced by a known method, or a commercially available product can be used.

（式中、Ｒ₁、Ａ₂は前記と同じ意味を示し、Ａ₃は下記一般式（Ａ−１−３）または（Ａ−２−２）を示す。

（式中、ｍ、ｎ、Ｒ₂は前記と同じ意味を示し、Ｒ₃ｂ、Ｒ₄ｂはトリフルオロアセチル基またはｔｅｒｔ−ブトキシカルボニル基を示す。）） The avermectin monoglycoside derivative of the general formula (Ib) according to the present invention can also be produced, for example, by the method of the following production step (3).
Manufacturing process (3)

(In formula, R < ₁ >, A < ₂ > shows the same meaning as the above, and A < ₃ > shows the following general formula (A-1-3) or (A-2-2).

(In the formula, m, n and R ₂ have the same meaning as described above, and R ₃ b and R ₄ b represent a trifluoroacetyl group or a tert-butoxycarbonyl group.)

The production step (3) is a step of removing the protecting group on the nitrogen atom in A ₃ on the avermectin monooleandrose glycoside derivative (Ic) by acid treatment.
Acids used include inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid or hydrofluoric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzene Examples include organic acids such as sulfonic acid, and other H ⁺ type strongly acidic or weakly acidic ion exchangers, with sulfuric acid being preferred. The amount of acid used can vary greatly depending on the type of acid and solvent used, but is usually 0.1-50 equivalents. The amount is preferably 1 to 15 equivalents.
Solvents used in the reaction include water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, alcohols such as 2-butanol and t-butanol, and aromatic carbonization such as benzene, toluene and xylene. Hydrogen; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dimethylformamide And amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide and nitriles such as acetonitrile. These mixed solvents may be used.

The reaction temperature is −10 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C. The reaction time varies depending mainly on the reaction temperature or the type of solvent used, but is usually 10 minutes to 100 hours. Preferably, it is 0.5 to 24 hours.
The compound of general formula (Ic) can be easily synthesized, for example, according to the method described in the above production step (1).

（式中、Ｒ₁、Ｒ₂、ｍ、ｎは前記と同じ意味を示し、Ｒ₃ｃは前記Ｒ₃の定義において、トリフルオロアセチル基およびｔｅｒｔ−ブトキシカルボニル基を除いた基を示し、Ｂはオキソシクロブチル基、オキソシクロペンチル基、オキソシクロヘキシル基、オキソシクロヘプチル基または下記一般式（Ｂ−１）を示す。

（オキソシクロアルキル基上のカルボニルはシクロアルカン環のどこについていてもよく、また、式中ｍは前記と同じ意味を示し、ｎ₁は０、１、２のいずれかを示す。）） The avermectin monoglycoside derivative of the general formula (Id) according to the present invention can also be produced, for example, by the method of the following production step (4).
Manufacturing process (4)

(Wherein R ₁ , R ₂ , m and n represent the same meaning as described above, R ₃ c represents a group excluding the trifluoroacetyl group and the tert-butoxycarbonyl group in the definition of R ₃ ; Represents an oxocyclobutyl group, an oxocyclopentyl group, an oxocyclohexyl group, an oxocycloheptyl group or the following general formula (B-1).

(The carbonyl on the oxocycloalkyl group may be located anywhere on the cycloalkane ring, and in the formula, m represents the same meaning as described above, and n ₁ represents 0, 1, or 2.)

The production step (4) is a step for condensing and reducing the carbonyl group on the avermectin monooleandrose glycoside derivative (IV) with an amine represented by the general formula (V).
Examples of the reducing agent used include complex hydrogen compounds such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, diborane, titanium (IV) chloride, and the like. Further, reduction with sodium, sodium amalgam, zinc-acid, catalytic reduction, or electrolytic reduction with lead or platinum as a cathode may be used. Preferred is sodium cyanoborohydride. The amount of reducing agent used can vary greatly depending on the type of reducing agent and solvent used, but is usually 0.1 to 10 equivalents. It 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 carbonization such as benzene, toluene and xylene. Hydrogens; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dimethylformamide And amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide and nitriles such as acetonitrile. These mixed solvents may be used.
In addition, an organic base such as ammonia, triethylamine, pyridine and tetrabutylamine, an organic acid such as acetic acid, trifluoroacetic acid and p-toluenesulfonic acid, an inorganic acid such as sulfuric acid and hydrochloric acid may be added to the reaction solvent as necessary. good. Alternatively, salts of these acids and bases or crown ethers may be added.

The reaction temperature is −10 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C. The reaction time varies depending mainly on the reaction temperature or the type of solvent used, but is usually 10 minutes to 50 hours. Preferably, it is 0.5 hours to 5 hours.
The compound of the general formula (IV) can be easily synthesized, for example, according to the method described in the production step (8) described later. The compound of the general formula (V) can be produced by a known method, or a commercially available product can be used.

（式中、Ｒ₁、Ｒ₅は前記と同じ意味を示し、Ｘはハロゲン原子、ホルミルオキシ基、アルキルカルボニルオキシ基、水酸基など、縮合反応に通常用いられるものを示し、Ｘが水酸基の場合は、（ＶＩＩ）はアルカリ金属、アルカリ土類金属との塩を形成しても良く、Ａ₄は下記一般式（Ａ−１−３）、（Ａ−２−１）、（Ａ−１−４）または（Ａ−２−２）を示す。

（式中、ｍ、ｎ、Ｒ₂、Ｒ₃ａ、Ｒ₃ｂ、Ｒ₄ａ、Ｒ₄ｂは前記と同じ意味を示し、Ｒ₂ａは上記Ｒ₂の定義において水素原子を除いた基を示す。）） The avermectin monoglycoside derivative of the general formula (II-a) according to the present invention can also be produced, for example, by the method of the following production step (5).
Manufacturing process (5)

(Wherein R ₁ and R ₅ have the same meaning as described above, X represents a halogen atom, a formyloxy group, an alkylcarbonyloxy group, a hydroxyl group, etc., which are usually used in condensation reactions, and when X is a hydroxyl group, , (VII) may form a salt with an alkali metal or alkaline earth metal, and A ₄ represents the following general formulas (A-1-3), (A-2-1), (A-1-4). ) Or (A-2-2).

(In the formula, m, n, R ₂ , R ₃ a, R ₃ b, R ₄ a and R ₄ b have the same meaning as described above, and R ₂ a is a group in which a hydrogen atom is excluded in the definition of R ₂ above. ))

The production step (5) is a step in which the acid represented by the general formula (VII) or a reactive derivative thereof is ester-linked to the 4 ′ position of the avermectin monooleandrose glycoside (VI) in which the 5-position is protected.
When the general formula (VII) is a carboxylic acid or a salt thereof, for example, dicyclohexylcarbodiimide (DCC), 2-chloro-1-methylpyridinium iodide, 2-chloro-1,3-dimethylimidazolinium chloride (DMC) , 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) hydrochloride, p-toluenesulfonic acid, sulfuric acid and the like are used. Preferable examples include 2-chloro-1,3-dimethylimidazolinium chloride. The carboxylic acid represented by the general formula (VII) or a salt thereof is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, and the amount of the dehydrating agent used is the acid represented by the general formula (VII). On the other hand, it is usually 1 to 5 equivalents, preferably 1 to 2 equivalents.
The reaction does not necessarily require a base, but may be carried out in the presence of a base. Examples of the base to be used include inorganic bases such as sodium bicarbonate, potassium carbonate, sodium hydroxide or sodium hydride, triethylamine, N, N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo. Organic bases such as [4.3.0] nonene-5 (DBN) or 1,8-diazabicyclo [5.4.0] undecene-7 (DBU) and the like. Suitable bases include, for example, triethylamine , Organic bases such as pyridine, 4-dimethylaminopyridine or 1,8-diazabicyclo [5.4.0] undecene-7 (DBU).
The solvent 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, chloroform, chloride Halogenated hydrocarbons such as methylene and 1,2-dichloroethane, ethers such as diethyl ether and tetrahydrofuran, sulfoxides such as dimethyl sulfoxide, nitriles such as acetonitrile, and mixtures of these solvents, etc. Particularly preferred is methylene chloride or 1,2-dichloroethane.

  The reaction temperature is usually −10 ° C. to 90 ° C., but preferably 0 ° C. to 60 ° C. While the reaction time mainly varies depending on the reaction temperature, the raw material compound, the reaction reagent or the kind of the solvent used, it is usually 15 minutes to 24 hours, preferably 30 minutes to 12 hours.

When the general formula (VII) is an acid halide or an acid anhydride, a base is not necessarily required, but the reaction may be performed in the presence of a base. Examples of the base to be used include inorganic bases such as sodium bicarbonate, potassium carbonate, sodium hydroxide or sodium hydride, triethylamine, N, N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo. Organic bases such as [4.3.0] nonene-5 (DBN) or 1,8-diazabicyclo [5.4.0] undecene-7 (DBU) and the like. Suitable bases include, for example, triethylamine , Organic bases such as pyridine, 4-dimethylaminopyridine or 1,8-diazabicyclo [5.4.0] undecene-7 (DBU).
The acid halide and acid anhydride represented by the general formula (VII) are usually 1 to 10 equivalents, preferably 1 to 5 equivalents, and the base is usually used 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 performed at 0 ° C. to 50 ° C., and the reaction time is 5 minutes to 12 hours.
Examples of solvents inert to the reaction used herein include aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane, aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene, methylene chloride, 1 Halogenated hydrocarbons such as 1,2-dichloroethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, ketones such as acetone, 3-pentanone and cyclohexanone, N, N-dimethylformamide Amides such as N, N-dimethylacetamide or N-methyl-2-pyrrolidone, esters such as methyl acetate or ethyl acetate, nitriles such as acetonitrile or propionitrile, dimethyl sulfoxide, Include, preferably toluene, acetonitrile, tetrahydrofuran and N, N- dimethylformamide and the like.

The compound of general formula (VI) is a well-known compound, for example, can be easily synthesize | combined according to the method described in the international publication patent WO08 / 056608 pamphlet etc.
The compound of the general formula (VII) can be produced by a known method, or a commercially available product can be used.

（式中、Ｒ₁、Ｒ₂、Ｒ₃ｃ、Ｒ₅、Ｂ、ｍ、ｎは前記と同じ意味を示す。） The avermectin monoglycoside derivative of the general formula (II-b) according to the present invention can also be produced, for example, by the method of the following production step (6).
Manufacturing process (6)

(In the formula, R ₁ , R ₂ , R ₃ c, R ₅ , B, m, and n have the same meaning as described above.)

The production step (6) is a step of condensing and reducing the carbonyl group on the avermectin monooleandrose glycoside derivative (VIII) with the amine represented by the general formula (V).
Examples of the reducing agent used include complex hydrogen compounds such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, diborane, titanium (IV) chloride, and the like. Further, reduction with sodium, sodium amalgam, zinc-acid, catalytic reduction, or electrolytic reduction with lead or platinum as a cathode may be used. Preferred is sodium cyanoborohydride. The amount of reducing agent used can vary greatly depending on the type of reducing agent and solvent used, but is usually 0.1 to 10 equivalents. It is preferably 0.5 to 2 equivalents.
Solvents used in the reaction include water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, alcohols such as 2-butanol and t-butanol, and aromatic carbonization such as benzene, toluene and xylene. Hydrogen; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dimethylformamide And amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide and nitriles such as acetonitrile. These mixed solvents may be used.
In addition, organic bases such as ammonia, triethylamine, pyridine, and tetrabutylamine, organic acids such as acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid, and inorganic acids such as sulfuric acid and hydrochloric acid may be added to the reaction solvent as necessary. good. Alternatively, salts of these acids and bases or crown ethers may be added.

The reaction temperature is −10 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C. The reaction time varies depending mainly on the reaction temperature or the type of solvent used, but is usually 10 minutes to 50 hours. Preferably, it is 0.5 hours to 5 hours.
The compound of the general formula (VIII) can be easily synthesized according to the method described in, for example, the production step (9) described later.
The compound of the general formula (V) can be produced by a known method, or a commercially available product can be used.

（式中、Ｒ₁、Ｒ₅、Ｒ₆、Ｒ₇、Ａ₁、Ａ₂は前記と同じ意味を示す。） The avermectin monoglycoside derivative of the general formula (II-c) according to the present invention can also be produced, for example, by the method of the following production step (7).
Manufacturing process (7)

(In the formula, R ₁ , R ₅ , R ₆ , R ₇ , A ₁ and A ₂ have the same meaning as described above.)

The production step (7) is a step of condensing and reducing the nitrogen atom in A ₂ on the avermectin monooleandrose glycoside derivative (II-d) with the carbonyl derivative represented by the general formula (III).
Examples of the reducing agent used include complex hydrogen compounds such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, diborane, titanium (IV) chloride, and the like. Further, reduction with sodium, sodium amalgam, zinc-acid, catalytic reduction, or electrolytic reduction with lead or platinum as a cathode may be used. Preferred is sodium cyanoborohydride. The amount of reducing agent used can vary greatly depending on the type of reducing agent and solvent used, but is usually 0.1 to 10 equivalents. It is preferably 0.5 to 2 equivalents.
Solvents used in the reaction include water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, alcohols such as 2-butanol and t-butanol, and aromatic carbonization such as benzene, toluene and xylene. Hydrogen; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dimethylformamide And amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide and nitriles such as acetonitrile. These mixed solvents may be used.
In addition, organic bases such as ammonia, triethylamine, pyridine, and tetrabutylamine, organic acids such as acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid, and inorganic acids such as sulfuric acid and hydrochloric acid may be added to the reaction solvent as necessary. good. Alternatively, salts of these acids and bases or crown ethers may be added.

The reaction temperature is −10 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C. The reaction time varies depending mainly on the reaction temperature or the type of solvent used, but is usually 10 minutes to 50 hours. Preferably, it is 0.5 hours to 5 hours.
The compound of the general formula (II-d) can be easily synthesized according to the method described in the above production step (6), for example.
The compound of the general formula (III) can be produced by a known method, or a commercially available product can be used.

（式中、Ｒ₁、Ｒ₅、Ｂは前記と同じ意味を示す。） The avermectin monoglycoside derivative of the general formula (IV) according to the present invention can be produced, for example, by the method of the following production step (8).
Manufacturing process (8)

(In the formula, R ₁ , R ₅ and B have the same meaning as described above.)

The production step (8) is a step of removing the protecting group at the 5-position from the avermectin monooleandrose glycoside derivative (VIII) by acid treatment.
Acids used include inorganic acids such as sulfuric acid, hydrochloric acid or hydrofluoric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, etc. Examples of the organic acid and other H ⁺ type strongly acidic or weakly acidic ion exchangers include p-toluenesulfonic acid. The amount of acid used can vary greatly depending on the type of acid and solvent used, but is usually 0.1 to 10 equivalents. It is preferably 0.5 to 2 equivalents.
Solvents used in the reaction include water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, alcohols such as 2-butanol and t-butanol, and aromatic carbonization such as benzene, toluene and xylene. Hydrogen; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dimethylformamide And amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide and nitriles such as acetonitrile. These mixed solvents may be used.
Moreover, you may add organic bases, such as ammonia, a triethylamine, a pyridine, a tetrabutylamine, or crown ether to a reaction solvent as needed.

The reaction temperature is −10 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C. The reaction time varies depending mainly on the reaction temperature or the type of solvent used, but is usually 10 minutes to 50 hours. Preferably, it is 0.5 hours to 5 hours.
The compound of the general formula (VIII) can be easily synthesized according to the method described in, for example, the production step (9) described later.

（式中、Ｒ₁、Ｒ₅、Ｘ、Ｂは前記と同じ意味を示す。） The avermectin monoglycoside derivative of the general formula (VIII) according to the present invention can also be produced, for example, by the method of the following production step (9).
Manufacturing process (9)

(In the formula, R ₁ , R ₅ , X, and B have the same meaning as described above.)

The production step (9) is a step of esterifying an acid represented by the general formula (IX) or a reactive derivative thereof at the 4 ′ position of the avermectin monooleandrose glycoside (VI) in which the 5-position is protected.
When the general formula (IX) is a carboxylic acid or a salt thereof, for example, dicyclohexylcarbodiimide (DCC), 2-chloro-1-methylpyridinium iodide, 2-chloro-1,3-dimethylimidazolinium chloride (DMC) , 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) hydrochloride, p-toluenesulfonic acid, sulfuric acid and the like are used. Preferable examples include 2-chloro-1,3-dimethylimidazolinium chloride.
The reaction does not necessarily require a base, but may be carried out in the presence of a base. Examples of the base used include inorganic bases such as sodium hydrogen carbonate, potassium carbonate, sodium hydroxide or sodium hydride, triethylamine, N, N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo Organic bases such as [4.3.0] nonene-5 (DBN) or 1,8-diazabicyclo [5.4.0] undecene-7 (DBU) and the like. Suitable bases include, for example, triethylamine , Organic bases such as pyridine, 4-dimethylaminopyridine or 1,8-diazabicyclo [5.4.0] undecene-7 (DBU). The carboxylic acid represented by the general formula (IX) or a salt thereof is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, and the amount of the dehydrating agent used is the acid represented by the general formula (IX). On the other hand, it is usually 1 to 5 equivalents, preferably 1 to 2 equivalents.
The solvent 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, chloroform, chloride Halogenated hydrocarbons such as methylene and 1,2-dichloroethane, ethers such as diethyl ether and tetrahydrofuran, sulfoxides such as dimethyl sulfoxide, nitriles such as acetonitrile, and mixtures of these solvents, etc. Particularly preferred is methylene chloride or 1,2-dichloroethane.

  The reaction temperature is usually −10 ° C. to 90 ° C., but preferably 0 ° C. to 60 ° C. While the reaction time mainly varies depending on the reaction temperature, the raw material compound, the reaction reagent or the kind of the solvent used, it is usually 15 minutes to 24 hours, preferably 30 minutes to 12 hours.

When general formula (IX) is an acid halide or an acid anhydride, a base is not necessarily required, but the reaction may be performed in the presence of a base. Examples of the base used include inorganic bases such as sodium hydrogen carbonate, potassium carbonate, sodium hydroxide or sodium hydride, triethylamine, N, N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo Organic bases such as [4.3.0] nonene-5 (DBN) or 1,8-diazabicyclo [5.4.0] undecene-7 (DBU) and the like. Suitable bases include, for example, triethylamine , Organic bases such as pyridine, 4-dimethylaminopyridine or 1,8-diazabicyclo [5.4.0] undecene-7 (DBU).
The acid halide and acid anhydride represented by the general formula (IX) are usually 1 to 10 equivalents, preferably 1 to 5 equivalents, and the base is usually used 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 performed at 0 ° C. to 50 ° C., and the reaction time is 5 minutes to 12 hours.
Examples of solvents inert to the reaction used herein include aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane, aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene, methylene chloride, 1 Halogenated hydrocarbons such as 1,2-dichloroethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, ketones such as acetone, 3-pentanone and cyclohexanone, N, N-dimethylformamide Amides such as N, N-dimethylacetamide or N-methyl-2-pyrrolidone, esters such as methyl acetate or ethyl acetate, nitriles such as acetonitrile or propionitrile, dimethyl sulfoxide There are, preferably toluene, acetonitrile, tetrahydrofuran and N, N- dimethylformamide and the like.

The compound of general formula (VI) is a well-known compound, for example, can be easily synthesize | combined according to the method described in the international publication patent WO08 / 056608 pamphlet etc.
The compound of the general formula (IX) can be produced by a known method, or a commercially available product can be used.

  After the completion of each reaction of the above production steps (1) to (9), the target reaction product compound is isolated from the reaction mixture by a well-known method and, if necessary, purified by a known means such as column chromatography. May be.

  The novel 4′-substituted avermectin monoglycoside derivative of the present invention represented by the above general formula (I) has a strong insecticidal, acaricidal or anthelmintic activity and is a pest, a tick that harms agricultural and horticultural crops and trees. Caused by the control of insects and nematodes, sanitary pests that have various adverse effects on the human living environment such as houses, domestic pests on clothing, stored pests that damage stored grains, or animal parasites It shows excellent effects against various diseases. Further, the novel compound of the present invention is classified as a normal product with low toxicity, and can provide an insecticide, acaricide or anthelmintic agent which is highly safe for human livestock.

  As a use in the insecticide scene of this invention compound, it can be used for the following pest control. 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 extermination of them.

  Examples of such pests include the following pests. However, the application of the insecticide of the present invention is not limited to these pests.

Among the insects, as Lepidoptera pests, for example, Phyllonocycter lingonella, Pterella xylostella, Adonophyes orana, von moth, u Cnaphalocrosis medinalis, Chilo supresalis, Ostrinia furnacalis, Masustra brassicae, Pseudeletia sparpato tera litura), rice beetle (Parnara guttata), white butterfly (Pieris rapae crucivora), heliotis (Heliothis spp.), moth moth (Agrotis ipsilon), myr (Carpocapsa pomonella) etc.
Thysanoptera pests include, for example, Scottotrips dorsalis, Thrips tabaci, Thrips palmi, and Thrips palmi.
As Hemiptera [Hemiptera] pests, for example, green rice leafhopper (Nephotettix cincticeps), Sejirounka (Sogatella furcifera), brown planthopper (Nilaparvata lugens), small brown planthopper (Laodelphax striatellus), bombardier helicopter bug (Piezodorus clavatus), southern green stink bug (Nezara viridula), Nashigumbai (Stephanitis nashi), Onishitsubira lice (Trialeurodes vaporariorum), Bedbug (Cimex lectularius), Cotton aphid (Aphis gossypi), Peach aphid (Myzus persalum) Aphis cracivoora, Ayrakisi (Acyrthiosiphon sp.), Yanaspi yanonensis, Pseudococcus comsto cki, etc.
As Coleoptera [Coleoptera] pests, for example, cupreous chafer (Anomala cuprea), Japanese beetle (Popillia japonica), rice weevil (Echinocnemus squameus), rice water weevil (Lissorhoptrus oryzophilus), Inedorooimushi (Oulema oryzae), varied carpet beetle (Anthrenus verbasci), red flour (Tenebroides mauritanicus ), Weevil (Sitophilus zeamais), Epilachna vigintioctopuncta, Azuki beetle (Callosobruchus chinensis), pine wolf Li (Monochamus alternatus), cucurbit leaf beetle (Aulacophora femoralis), such as Diabrotica (Diabrotica spp.).
As an insect pest [Orthooptera], for example, Kelly (Gryllotalpa)
spp.), locust migratory, Oxya yezoensis and the like.
Examples of the insects of the Dictyoptera are German cockroaches (Bla)
tera germanica), black cockroach (Periplaneta furiginosa), cockroach (Periplaneta japonica) and the like.
Diptera pests such as Culex pipiens fatigans, Aedes aegpti, Culex pipiens, Anopheles slnensis, Hyphadata sp. Fly fly (Delica platera), house fly (Musca domestica), sand fly (Dacus cucurbitae), rice fly (Agromyza oryzae), and fly fly (Lucilia sppp.).
Isoptera pests include, for example, Yamato termites (Reticulites perstus), termites (Coptothermes formosanus), and the like.
Hymenoptera pests include, for example, wasp (Athalia rosae ruficornis), rurichu range (Arge similis) and the like.
Examples of pests of the Aphaniptera include human fleas (Pulex irritans), Xenopsilla cheosis, and Cenocephalides canis.
As Phthiraptera [Anoplura] pests, for example, body louse (Pediculus humanus corporis), crab louse (Phthirius pubis), head lice (Pediculus humanus capitis), Inujirami (Linognathus setosus), Butajirami (Haematopinus suis), etc. wallaby lice (Heterodoxus longitarsus).
Examples of the insects of the order of Pscoptera include Trogium pulsatorium and Hiratakatate (Liposcelis bostrychophilus).

Further, in the veterinary medicine field, the novel compound of the present invention is effective when used against various harmful animal parasitic pests (internal and ectoparasites). Examples of such animal parasitic pests include the following pests. Insects include, for example, horse flies (Gastrophilus spp.), Flies (Stomoxys spp.), White lice (Trichodectes spp.), Red turtles (Rhodnius spp.), Dog fleas (Ctenocephalides canis) and the like.
In the present invention, a substance having an insecticidal action against insects including all of these is sometimes called an insecticide.

  The compounds of the present invention also have an excellent effect on the control of ticks. That is, it exerts an accurate control effect without causing phytotoxicity to adult plants and eggs of mites such as spider mites (Tetranychidae) and Eriophydae that parasitize fruit trees, vegetables, and flower buds without causing phytotoxicity to cultivated plants. In addition, it exerts an accurate control effect on host animals safely and without causing phytotoxicity to mites such as Ixodidae, Dermanyssidae, and Sarcoptidae that parasitize animals. This compound not only has acaricidal activity, but also has an excellent acaricidal effect against drug-resistant mites that have become problematic in recent years due to the ineffectiveness of existing acaricides. Yes.

The following mites can be illustrated as an example of such mites. However, the application of the acaricide of the present invention is not limited to these mites.
Spider mites include, for example, Tetanychus urticae, Tetanychus kanzawai, Ripe tick (Pan
for example, onychus citri), apple tick (Panonychus ulmi), chamomile mite (Polyphagotarsonemus latus), citrus mite (Aculops pelekassi) and the like. Boophilus microplus as animal parasitic mites (Boophilus microplus), longicornis (Haemaphysalis longicornis), house dust mite (Ornithonyssus bacoti), Adenophora chima tick (Haemaphysalis campanulata), Demodex (Demodex folliculorum), Dermatophagoides compound, red mite (Dermanyssus gallinae), red mites ( And Leptotrombidium akamushi) and Sarcoptes scabiei.

  The compounds of the present invention have an excellent effect on nematode control and can also be used as nematicides. Examples of such plant-parasitic nematodes include soil nematodes, Meloidogyne incognita, Pratylenchus spp., And soy cyst nematodes (Heterodera glycines) that are problematic in field crops, vegetables, and the like. Can be mentioned. It is also useful as a nematicide to control pinewood nematode (Bursaphelenchus xylophilus) that infests pine and causes pine wilt.

  Other harmful animals, unpleasant animals, sanitary pests and parasites include gastropods such as Pomacea canalicula, slugs (Inciliaria sp.), African maimai (Achatina fulica), armadillium sp. It can also be used to control bed bugs such as Isopoda such as mussel, centipede, lice (Trichodes spp.), Cimex spp.

Furthermore, the compounds of the present invention have excellent parasiticidal activity as antiparasitic agents against animal and human parasites.
It is particularly effective against the following nematodes that infect livestock, poultry and pets such as pigs, sheep, goats, cattle, horses, dogs, cats and chickens. Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Couperia, Ascaris, Bunostomum, Esphagostoumum Oesophagostomum), Chabertia, Trichuris, Storongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxacaris and Parascaris.
Certain species of Nematogillus, Couperia, and Esophagostoma attack the intestinal tract, while those of the genus Haemonx and Ostertagia parasitize the stomach and parasites of the genus Dioctiosaurus are found in the lungs However, the compounds of the present invention are also active against these. Parasites of the Filariidae and Setariidae families are also found in other tissues and organs such as the heart and blood vessels, subcutaneous and lymphoid tissues, but the compounds of the present invention are also active against these Indicates.

The compounds of the present invention are also useful against parasites that infect humans. For example, the most common parasites that infest the human digestive tract, the genus Anchylostoma, Necator, Ascaris, Strongyloides, Trichinella, The genus Capillaria, the genus Trichuris and the genus Enterobius.
Other medically important parasites found in blood or other tissues and organs outside the gastrointestinal tract, the genus Wuchereria, Brugia, Onchocerca and Lohr ( Loa) and parasites of the genus Dracunculidae of Dracunculidae, as well as Stromboloides and Trihinella in the special intestinal parasitism state of intestinal parasites .

  When the compound of the present invention is used as an anthelmintic agent in animals and humans, it can be administered orally as a liquid beverage. Beverages are usually prepared as solutions, suspensions or dispersions using a suitable non-toxic solvent or water together with a suspending and wetting agent such as bentonite or other excipients. Generally, when using as a drink form, an antifoamer is contained. 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.

  When oral administration in a dry solid unit dosage form is desired, it is preferred to use capsules, pills or tablets containing the desired amount of the compound of the invention. These uses consist of mixing the active ingredient homogeneously with suitable finely divided diluents, fillers, disintegrants and / or binders such as starch, lactose, talc, magnesium stearate, vegetable gums and the like. Manufactured by. Such unit use formulations can vary widely with respect to the weight and content of the anthelmintic, depending on the type of host animal to be treated, the degree of infection and the type of parasite and the body weight of the host.

When administered with animal feed, the compound of the present invention is uniformly dispersed in the feed, used as a top dressing, or used in the form of pellets. In order to achieve a desired antiparasitic effect, it is preferable to add 0.0001 to 0.02% by weight of the compound of the present invention in the final feed.
A compound in which the compound of the present invention is dissolved or dispersed in a suitable carrier or a liquid carrier such as water can be administered parenterally to animals by injection into the stomach, intramuscularly, intratracheally or subcutaneously. .
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 preferred to contain 0.05 to 50% by weight of the compound of the present invention.

  Moreover, it can also be set as the formulation which can be administered locally by mixing this invention compound with the appropriate simple substance like a dimethyl sulfoxide or a hydrocarbon solvent. 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 for best results depends on the type of animal being treated and the type and extent of parasitic infection, but is generally about 0.01-100 mg / kg animal body weight, preferably 0 It is preferable to administer 5 to 50.0 mg orally. The compound of the present invention is given over a relatively short period of time such as 1 to 5 days in such a single amount or in divided amounts.

  When the compound of the present invention is used as an agricultural or horticultural agent, it may be used alone, but it is preferably used after being formulated by a formulation commonly used in the art depending on the purpose. That is, the compound of general formula (I) or a salt thereof and an appropriate carrier, surfactant, and other pharmaceutical adjuvants can be blended to obtain a preparation generally used as an agrochemical preparation. For example, wet powder, granule 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, quartz sand, synthetic silicate, calcium carbonate, calcium phosphate, alumina, white carbon, ammonium sulfate, urea, starch , Crystalline cellulose, soybean powder, walnut shell powder, tobacco stem powder and the like.

  Examples of the liquid carrier include water, alcohols (eg, methanol, ethanol, isopropyl alcohol, ethylene glycol, glycerin, etc.), ethers (eg, dioxane, tetrahydrofuran, etc.), ketones (eg, acetone, methyl ethyl ketone, cyclohexanone, etc.), Esters (eg fatty acid glycerin esters, phthalate esters, etc.), sulfoxides (eg dimethyl sulfoxide etc.), aliphatic or alicyclic hydrocarbons (eg cyclohexane, paraffins etc.), aromatic hydrocarbons (For example, xylene mixtures, substituted naphthalene, etc.), polar solvents such as N-methyl-2-pyrrolidone and N, N-dimethylformamide, vegetable oils such as soybean oil and coconut oil.

  Use surfactants to obtain formulations with good emulsification, dispersion, and wettability, and use any type of surfactants that are nonionic, anionic, cationic, or zwitterionic for normal agricultural chemical formulations. You can also.

  Suitable nonionic surfactants include polyoxyethylene alkyl ethers, polyoxyethylene alkyl esters, polyoxyethylene alkyl aryl ethers, polyoxyethylene sorbitan alkyl esters, sorbitan alkyl esters, sugar fatty acid esters, glycerin and pentaerythritol. Fatty acid esters, pluronic type surfactants, acetylene alcohols and acetylene diols, surfactants obtained by adding ethylene oxide to these, silicone surfactants, alkylglycosides, and the like.

  Suitable anionic surfactants include alkylbenzene sulfonates, dialkyl sulfosuccinates, alkyl sulfates, acylmethyl taurine salts, and nonionic surfactants added with the above-mentioned ethylene oxide esterified with sulfuric acid or phosphoric acid, If necessary, an anionic surfactant neutralized with a suitable alkali, lignin sulfonate, alkylnaphthalene sulfonic acid and its condensate salt, phenol sulfonic acid and its condensate salt, acrylic acid, maleic acid, Various surfactants of polycarboxylic acid type and polysulfonic acid type polysoap consisting of salts of styrene sulfonic acid and condensate of vinyl group, starch-based surfactants such as starch or dextrin with addition of 2-octenoyl succinate, carboxymethyl cellulose Salt, high-grade fat Soaps, such as sodium, potassium salt, alpha-like olefin sulfonate can be exemplified.

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

  Surfactants obtained by substituting some or all of the hydrogen atoms of these various surfactants with fluorine atoms are also strong in reducing the surface tension and can be used effectively. Moreover, said various surfactant is used individually or in mixture according to a use.

The formulation adjuvants include physical property improvers, decomposition inhibitors, antifoaming agents, viscosity modifiers, binders and adhesives, and the like, alone or as a mixture, of the acaricide and insecticide of the present invention. Or an anthelmintic agent can be included. Examples of these formulation adjuvants include carboxymethyl cellulose (CMC), polyvinyl alcohol (PVA), gum arabic, gelatin, casein, sodium alginate, gum tragacanth, 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 it in the preparation within a range of 0.01 to 99%, preferably 0.1 to 95% (% by weight, hereinafter the same). 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 a concentrated form, it is generally diluted to 0.00001-0.01% (ie, 0.1-100 ppm) before use.

  The compound of the present invention is used in preparations and use forms prepared by the preparation in the form of other active compounds such as insecticides, baits, fungicides, acaricides, nematicides, fungicides, herbicides, avian repellents. It can be used as a mixture with plant growth regulators, fertilizers, soil conditioners and the like. And the applicability (application pest, usage method, use time, etc.) can be expanded by the 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, microorganism source insecticides, insect growth regulators, and the like.

  Furthermore, this invention compound can be used also as a mixing agent with a synergist. The synergist does not need to have activity per se, and may be a compound that functions to enhance the effect of the compound of the present invention such as acaricide, insecticide, or anthelmintice.

  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 adjuvants, and the addition amounts thereof in the following production examples and formulation examples of agricultural and horticultural insecticides. Further, in the following production examples and formulation examples, “part” means all parts by weight, and “%” means “% by weight” unless otherwise stated as “volume%”.

As a starting material of the compound of the present invention, it is produced by a known fermentation method, or a commercial product, for example, a product name of a vendor: Wako Pure Chemical Industries, Ltd. (manufacturer: LKT Lab. Inc.): An avermectin compound available as Abamectin can be preferably used. This is a mixture of avermectin B1a and avermectin B1b in which sec-butyl group and isopropyl group are respectively substituted at the 25th position of the avermectin skeleton, and the composition is about 96% of “B1a” component and about 4% of “B1b”. Contains ingredients. "B1b" compound is present only in a very small percentage in the Weight, also structural differences from that little effect on the reaction processes and biological activities, the separation of these very similar compounds is generally conducted Absent.

Therefore, also in this example, the avermectin monoglycoside B1a / B1b derivative was a mixture, and the substituent at position 25 was used as a mixture of a sec-butyl group and an isopropyl group without being separated into each of them. . As described above, since this family of compounds is a mixture, the melting point or the like is not used to express the 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 avermectin monoglycoside B1a / B1b were represented by 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 prepared avermectin monoglycoside B1a / B
The chemical structure of the 1b derivative was confirmed by ¹ H- and ¹³ C-nuclear magnetic resonance spectra and, if necessary, mass spectra.

HPLC analysis condition column: YMC-pack ODS-AQ, 5 μm (φ4.6 mm × 250 mm) manufactured by YMC Co., Ltd.
Mobile phase: A; 0.01% trifluoroacetic acid-70% by volume acetonitrile aqueous solution
B; 0.01% trifluoroacetic acid-acetonitrile Gradient conditions:

Column temperature: 40 ° C
Flow rate: 2 ml / min
Detection: Tosoh PD8020 multi-wavelength detector, chromatogram: 246 nm, spectrum: three-dimensional detection at 200-300 nm Especially determined as avermectin derivatives by 246 nm maximum absorption, 238 nm and 254 nm shoulder absorption specific to avermectin skeleton .

Example 1
Avermectin B1a / B1b monoglycoside 100 g of avermectin B1a / B1b (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, and the filtrate was concentrated to about 200 ml under reduced pressure to distill off isopropanol. To this solution were added 1000 ml of ethyl acetate and 500 ml of water, and the mixture was stirred and separated into two layers. The aqueous layer was further extracted twice with 1000 ml of ethyl acetate. The ethyl acetate extracts were combined, washed 4 times with distilled water, and once with saturated brine. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain 118 g of avermectin B1a / B1b monoglycoside crude extract. The crude extract was subjected to column chromatography using silica gel 60 (particle size: 0.063 to 0.2 mm, manufactured by Merck & Co., 996 g), and the ethyl acetate concentration in hexane was 5% by volume from 30% to 60% by volume. Elution was performed step by step. In this way, 72.9 g (process yield: 87%) of pure avermectin B1a / B1b monoglycoside (general formula III) was obtained.

Example 2
5- Ot -butyldimethylsilyl avermectin B1a / B1b monoglycoside 52.6 g of the avermectin B1a / B1b monoglycoside obtained in Example 1 and 68.1 g of imidazole were combined, and 421 ml of dehydrated dimethyl was added thereto. Formamide was added and completely dissolved. Next, 24 g of t-butyldimethylchlorosilane was dissolved in 100 ml of dehydrated dimethylformamide and added dropwise to the reaction solution over 10 minutes with stirring. 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 a saturated saline solution. The aqueous layer was extracted twice more with 1000 ml of ethyl acetate and treated similarly. 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 5-Ot-butyldimethylsilyl avermectin B1a / B1b monoglycoside. This crude extract was subjected to column chromatography using silica gel 60 (particle size: 0.063 to 0.2 mm, manufactured by Merck & Co., 683 g), and the ethyl acetate concentration in hexane was 5% by volume to 5% by volume to 40% by volume. Elution was performed step by step. In this way, 52.3 g (process yield: 86%) of pure 5-Ot-butyldimethylsilyl avermectin B1a / B1b monoglycoside (general formula IV) was obtained.

Example 3
5-Ot-butyldimethylsilyl-4′-O- (4-oxocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside dried eggplant-shaped flask was obtained in Example 2 with 758 mg of 4-cyclohexanonecarboxylic acid. The obtained 5-Ot-butyldimethylsilyl avermectin B1a / B1b monoglycoside (3.0 g), dehydrated pyridine (5 ml), and dimethylaminopyridine (100 mg) are added, and methylene chloride (30 ml) is added and completely dissolved. To this solution, 3.0 g of 2-chloro-1,3-dimethylimidazolinium chloride was added and stirred at room temperature for 16 hours. The reaction solution was poured into saturated sodium bicarbonate water and extracted with 500 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 200 ml of ethyl acetate and treated similarly. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give a 5-Ot-butyldimethylsilyl-4′-O- (4-oxocyclohexanecarbonyl) avermectin B1a / B1b monolayer. 4.39 g of a crude saccharide extract was obtained. This crude extract was subjected to column chromatography using silica gel 60 (spherical, particle size 0.040 to 0.050 mm, manufactured by Kanto Chemical Co., 200 g), and the ethyl acetate concentration in hexane was 10% to 20% by volume to 50% by volume. Elution was performed with the solvent gradually increased by volume%. In this way, 2.99 g (process yield: 87%) of pure 5-Ot-butyldimethylsilyl-4′-O- (4-oxocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside was obtained. .

Example 4
5-Ot-butyldimethylsilyl-4′-O- (4-N-methylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside 5-Ot-butyldimethylsilyl- obtained in Example 3 307 mg of 4′-O- (4-oxocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside and 291 mg of methylamine / acetate were placed in a flask and dissolved by adding 2 ml of methanol. To this reaction solution, a solution of sodium cyanoborohydride, 20.1 mg of methanol (1 ml) was added dropwise over 10 minutes with stirring, and the mixture was further stirred at room temperature for 60 minutes. 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 50 ml of ethyl acetate and treated similarly. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain 368 mg of a crude extract. This crude extract is purified by silica gel 60
(Particle size: 0.04 to 0.05 mm, manufactured by Kanto Chemical Co., Ltd., 83 g) Subjected to column chromatography, the concentration of ethyl acetate in a 1% diethylamine-hexane-ethyl acetate mixed solvent is 10% by volume from 20% to 50% by volume. Elution was performed stepwise. Thus pure 5-Ot-butyldimethylsilyl-4′-O- (4-cis-N-methylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside, 106 mg (process yield: 34%) ) And 153 mg (process yield: 49%) of 5-Ot-butyldimethylsilyl-4′-O- (4-trans-N-methylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside .

Example 5
4′-O- (4-trans-methylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside (compound No. 6)
5-Ot-butyldimethylsilyl-4′-O- (4-trans-methylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside obtained in Example 4 was dissolved in 2 ml of methanol and stirred. While cooling in an ice-water bath. 175 mg of p-toluenesulfonic acid monohydrate was dissolved in 1 ml of methanol, ice-cooled, added to the reaction solution, and stirred for 90 minutes under ice-cooling. 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 50 ml of ethyl acetate and treated similarly. This ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain 168 mg of a crude extract. This crude extract was subjected to silica gel 60 (particle size: 0.04 to 0.05 mm, manufactured by Kanto Chemical Co., Ltd., 10 g) column chromatography, and the methanol concentration in 1% -diethylamine-ethyl acetate was continuously increased from 0% to 10%. Elevated to elute. In this way, 140.4 mg (process yield: 91%) of pure 4′-O- (4-trans-methylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside (compound No. 6) was obtained.

Example 6
4′-O- (4-trans-dimethylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside (compound No. 9)
4'-O- (4-trans-methylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside obtained in Example 5 was dissolved in 136 ml of methanol, formaldehyde solution and 0.1 ml were added, Stir at room temperature for 1 hour. To this reaction solution, 15 mg of sodium cyanoborohydride solution dissolved in 0.1 ml of methanol was added dropwise over 10 minutes with stirring, and the mixture was further stirred at room temperature for 60 minutes. 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 50 ml of ethyl acetate and treated similarly. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain 148 mg of a crude extract. This crude extract was subjected to silica gel 60 (particle size: 0.04 to 0.05 mm, manufactured by Kanto Chemical Co., Ltd., 10 g) column chromatography, and the methanol concentration in 1% -diethylamine-ethyl acetate was continuously increased from 0% to 10%. Elevated to elute. In this way, 87.6 mg (process yield: 63%) of pure 4′-O- (4-trans-dimethylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside (compound No. 9) was obtained.
¹ H-nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ ) δ ppm: 0.86 (1H, m), 0.92 (3H, d, J = 6.8), 0.93 (3H, t, J = 7.5), 1.10 (2H, m) , 1.11 (3H, d, J = 7.0), 1.15 (3H, d, J = 6.2), 1.30 (2H, m), 1.49 (1H, m), 1.50 (3H, brs), 1.50 (4H, m) , 1.64 (1H, m), 1.70 (1H, m), 1.79 (1H, m), 1.88 (3H, brs), 2.01 (1H, m), 2.26 (1H, m), 2.27 (1H, m), 2.28 (1H, m), 2.30 (3H, m), 2.35 (6H, s), 2.53 (1H, brt, J = 6.8), 3.30 (1H, m), 3.40 (3H, s), 3.48 (1H, d, J = 9.5), 3.64 (2H, m), 3.90 (1H, m), 3.94 (2H, m), 3.97 (1H, d, J = 5.9), 4.30 (1H, bd, J = 5.7), Four
.66 (2H, ABq), 4.82 (1H, brd, J = 3.1), 4.99 (1H, brdd, J = 9.7,5.1), 5.40 (1H, m), 5.43 (1H, brs), 5.55 (1H, dd, J = 9.9,2.6), 5.73 (2H, m), 5.77 (1H, dd, J = 8.3,1.7), 5.88 (1H, m)
¹³ C-nuclear magnetic resonance spectrum (75 MHz, CDCl ₃ ) δ ppm: 12.02 (q), 12.95 (q), 15.11 (q), 16.37 (q), 17.40 (q), 19.95 (q), 20.19 (q), 27.53 (t), 27.64 (t), 28.14 (t), 30.60 (d), 34.26 (t), 34.77 (t), 35.19 (d), 36.69 (t), 39.76 (d), 40.50 (t), 41.39 (q), 43.01 (d), 45.72 (d), 57.12 (q), 63.01 (d), 66.53 (d), 67.71 (d), 68.32 (d), 68.36 (d), 68.48 (t), 74.98 (d), 75.77 (d), 75.96 (d), 79.11 (d), 80.40 (s), 82.01 (d), 95.05 (d), 95.78 (s), 118.03 (d), 118.48 (d), 120.40 (d), 124.86 (d), 127.77 (d), 135.00 (s),
136.29 (d), 137.86 (d), 138.05 (s), 139.81 (s), 173.79 (s), 174.84 (s)

Example 7
5-Ot-butyldimethylsilyl-4′-O- (3-dimethylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside 356 mg of 3-dimethylaminocyclohexanecarboxylic acid methyl ester was taken into a methanol flask Dissolved in 2 ml. The ester was decomposed | dissolved by melt | dissolving 56.11 mg of potassium hydroxide in 1 ml of methanol, adding to a reaction liquid, and stirring at room temperature. After 1 hour, methanol in this reaction solution was distilled off under reduced pressure, and toluene was added to redissolve it. In this, 250 mg of 5-Ot-butyldimethylsilyl avermectin B1a / B1b monoglycoside obtained in Example 2, 0.3 ml of dehydrated pyridine, and 10 mg of dimethylaminopyridine were added, respectively, and 3 ml of methylene chloride was added and completely added. Dissolved in. To this solution, 250 mg of 2-chloro-1,3-dimethylimidazolinium 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. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 5-Ot-butyldimethylsilyl-4′-O- (3-dimethylaminocyclohexanecarbonyl) avermectin B1a / B1b mono 275.3 mg of a crude glycoside extract was obtained.
This crude extract was subjected to column chromatography using silica gel 60 (spherical, particle size 0.040 to 0.050 mm, manufactured by Kanto Chemical Co., Ltd., 20 g), and the ethyl acetate concentration in hexane was 50% by volume to Elution was performed with a solvent that was gradually increased by 10% by volume up to 100% by volume, and a solvent with 1% diethylamine added to each. Thus, 240 mg (process yield: 80%) of pure 5-Ot-butyldimethylsilyl-4′-O- (3-dimethylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside was obtained.

Example 8
4′-O- (3-dimethylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside (compound No. 15)
240 mg of 5-Ot-butyldimethylsilyl-4′-O- (3-dimethylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside obtained in Example 7 was placed in a flask and dissolved in 2 ml of methanol. Cooled in an ice-water bath with stirring. 175 mg of p-toluenesulfonic acid monohydrate was dissolved in 1 ml of methanol, ice-cooled, added to the reaction solution, and stirred for 90 minutes under ice-cooling. 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 50 ml of ethyl acetate and treated similarly. This ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain 168 mg of a crude extract. This crude extract was subjected to silica gel 60 (particle size: 0.04 to 0.05 mm, manufactured by Kanto Chemical Co., Ltd., 10 g) column chromatography, and the methanol concentration in 1% -diethylamine-ethyl acetate was continuously increased from 0% to 10%. Elevated to elute. In this way, 170 mg (compound No. 15, process yield: 80%) of pure 4′-O- (3-dimethylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside was obtained.
¹ H-nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ ) δ ppm :: 0.86 (1H, m), 0.93 (3H, d, J = 8.8), 0.93 (3H, t, J = 7.3), 1.10 (2H, m ), 1.11 (3H, d, J = 6.9), 1.17 (3H, d, J = 7.0), 1.30 (2H, m), 1.49 (1H, m), 1.50 (3H, brs), 1.50 (4H, m ), 1.64 (1H, m), 1.70 (1H, m),
1.79 (1H, m), 1.87 (3H, brs), 2.01 (1H, m), 2.20 (6H, s), 2.26 (1H, m), 2.27 (1H, m),
2.28 (1H, m), 2.30 (6H, s), 2.30 (3H, m), 2.53 (1H, brt, J = 6.8), 3.30 (1H, m), 3.41 (3H, s),
3.49 (1H, d, J = 10.1), 3.65 (1H, m), 3.90 (1H, m), 3.94 (2H, m), 3.97 (1H, d, J = 6.2), 4.30 (1H, bd, J = 5.9), 4.66 (2H, ABq), 4.66 (1H, m), 4.82 (1H, brd, J = 3.1), 4.99 (1H, brdd, J = 9.7,5.1), 5.40 (1H, m), 5.42 (1H, brs), 5.55 (1H, dd, J = 9.9,2.6), 5.73 (2H, m), 5.77 (1H, dd, J = 8.3,1.7), 5.87 (1H, m)
¹³ C-nuclear magnetic resonance spectrum (75 MHz, CDCl ₃ ) δ ppm: 11.98 (q), 12.90 (q), 15.05 (q), 16.32 (q), 17.35 (q), 17.37 (q), 19.99 (q), 20.15 (q), 24.59 (t), 27.46 (t), 27.59 (t), 27.95 (t), 28.70 (t), 28.71 (t), 30.52 (d), 30.70 (t), 30.87 (t), 34.21 (t), 34.74 (t), 35.14 (d), 36.60 (t), 39.69 (d), 40.44 (t), 41.16 (q), 41.23 (q), 43.08 (d), 43.14 (d), 45.66 (d), 57.10 (q), 62.62 (d), 62.66 (d), 66.48 (d), 67.65 (d), 68.29 (d), 68.29 (d), 68.36 (t), 74.90 (d), 75.76 (d), 75.91 (d), 79.13 (d), 80.34 (s), 82.01 (d), 82.03 (d), 94.97 (d), 95.72 (s), 117.95 (d), 118.42 (d), 120.30 (d), 124.82 (d), 127.72 (d), 134.95 (s), 136.21 (d), 137.77 (d), 137.94 (s), 139.78 (s), 173.66 (s), 174.74 (s)

Example 9
5-O-t-butyldimethylsilyl-4'-O-in (trans-4-ethylamino cyclohexanecarbonyl) avermectin B1a / B1b mono- glycoside 20mL egg plant flask, 5-O-t obtained in Example 3 -Butyldimethylsilyl-4′-O- (4-oxocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside (101 mg), ethylamine acetate (216 mg, 2.07 mmol), methanol (1 mL), and triethylamine (10 μL) And stirred at room temperature for 1.5 hours. A methanol solution (1 mL) of sodium cyanoborohydride (11.2 mg, 0.18 mmol) was added dropwise thereto, and the mixture was further stirred for 1 hour. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate, and then washed in the order of distilled water and saturated brine. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 114.3 mg of residue. Further, the obtained residue was subjected to silica gel column chromatography (silica gel 60, particle size 0.04 to 0.05 mm, 40 g, manufactured by Kanto Chemical Co., Ltd.), and the composition of the elution solvent was hexane: ethyl acetate: diethylamine = 160: 40: 1 ( Elution / purification by increasing the solvent volume ratio of ethyl acetate by 10% starting from the solvent volume ratio) and changing to 100: 100: 1, to give 5-Ot-butyldimethylsilyl-4′-O— (Trans-4-ethylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside was obtained as 58.8 mg (57% yield) as a white solid.

Example 10
4′-O- (trans-4-ethylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside (Compound No. 32)
In a 20 mL eggplant flask, 5-Ot-butyldimethylsilyl-4′-O- (trans-4-ethylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside (58.8 mg) obtained in Example 9 was used. , Methanol (1 mL) was added and cooled in an ice bath. A methanol solution (0.5 mL) of p-toluenesulfonic acid monohydrate (58.8 mg, 0.31 mmol) was added dropwise thereto, and the mixture was stirred for 2 hours in an ice bath. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added in an ice bath, and the mixture was extracted with ethyl acetate, followed by washing with distilled water and saturated brine in this order. The organic layer was separated, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was further chromatographed using silica gel 60 (particle size 0.04 to 0.05 mm, manufactured by Kanto Chemical Co., Inc.). Purified by chromatography [developing solvent; starting from ethyl acetate: methanol: diethylamine = 100: 1: 1 (solvent volume ratio), increasing the solvent volume ratio of methanol by 1% to 100: 5: 1] 4 ′ -O- (trans-4-ethylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside (Compound No. 32) was obtained as a white solid (51.7 mg, yield 95%).

Example 11
4′-O- [trans-4- (N-methylethylamino) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside (Compound No. 57)
In a 20 mL eggplant flask, 4′-O- (trans-4-ethylaminocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside (13.4 mg) obtained in Example 10, 36% formaldehyde (12.8 μL) , Methanol (1 mL), and 10% triethylamine / acetate methanol solution (46.7 μL) were added, and the mixture was stirred at room temperature for 1.5 hours. A methanol solution (1 mL) of sodium cyanoborohydride (1.5 mg, 0.02 mmol) was added dropwise thereto, and the mixture was further stirred for 1 hour. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate, and then washed in the order of distilled water and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was further chromatographed using silica gel 60 (particle size 0.04 to 0.05 mm, manufactured by Kanto Chemical Co., Inc.). Purified by chromatography [developing solvent; starting from ethyl acetate: methanol: diethylamine = 100: 1: 1 (solvent volume ratio), increasing the solvent volume ratio of methanol by 1% to 100: 5: 1] 4 ′ -O- [trans-4- (N-methylethylamino) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside (Compound No. 57) was obtained as 11.9 mg (yield 87%) as a white solid.

Example 12
5-Ot-butyldimethylsilyl-4′-O- [trans-4- (2-methoxyethylamino) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside obtained in Example 3 in a 20 mL eggplant flask 5-Ot-butyldimethylsilyl-4′-O- (4-oxocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside (101 mg), methoxyethylamine acetate (150 mg, 1.10 mmol), methanol (1 mL) And triethylamine (10 μL) were added and stirred at room temperature for 1.5 hours. A methanol solution (1 mL) of sodium cyanoborohydride (7.5 mg, 0.12 mmol) was added dropwise thereto, and the mixture was further stirred for 1 hour. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate, and then washed in the order of distilled water and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was further chromatographed using silica gel 60 (particle size 0.04 to 0.05 mm, manufactured by Kanto Chemical Co., Inc.). Purify by chromatography [developing solvent; starting from hexane: ethyl acetate: diethylamine = 160: 40: 1 (solvent volume ratio), increasing the solvent volume ratio of ethyl acetate by 10% to 100: 100: 1] -Ot-butyldimethylsilyl-4'-O- [trans-4- (2-methoxyethylamino) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside as 51.4 mg (yield 48%) as a white solid Obtained.

Example 13
4′-O- [trans-4- (2-methoxyethylamino) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside (Compound No. 34)
In a 20 mL eggplant flask, 5-Ot-butyldimethylsilyl-4′-O- [trans-4- (2-methoxyethyl) aminocyclohexanecarbonyl] avermectin B1a / B1b monoglycoside obtained in Example 12 (51.4 mg) and methanol (1 mL) were added and cooled in an ice bath. A methanol solution (0.5 mL) of p-toluenesulfonic acid monohydrate (51.4 mg, 0.27 mmol) was added dropwise thereto, and the mixture was stirred for 2 hours in an ice bath. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added in an ice bath, and the mixture was extracted with ethyl acetate, followed by washing with distilled water and saturated brine in this order. The organic layer was separated, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was further chromatographed using silica gel 60 (particle size 0.04 to 0.05 mm, manufactured by Kanto Chemical Co., Inc.). Purified by chromatography [developing solvent; starting from ethyl acetate: methanol: diethylamine = 100: 1: 1 (solvent volume ratio), increasing the solvent volume ratio of methanol by 1% to 100: 5: 1] 4 ′ -O- [trans-4- (2-methoxyethylamino) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside (Compound No. 34) was obtained as 34.9 mg (yield 76%) as a white solid.

Example 14
5-Ot-butyldimethylsilyl-4′-O- [trans-4- (2-ethoxyethylamino) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside obtained in Example 3 in a 20 mL eggplant flask 5-Ot-butyldimethylsilyl-4′-O- (4-oxocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside (101 mg), 2-ethoxyethylamine acetate (0.26 g, 1.60 mmol), Methanol (1 mL) and triethylamine (10 μL) were added and stirred at room temperature for 1.5 hours. A methanol solution (1 mL) of sodium cyanoborohydride (11.2 mg, 0.18 mmol) was added dropwise thereto, and the mixture was further stirred for 1 hour. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate, and then washed in the order of distilled water and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was further chromatographed using silica gel 60 (particle size 0.04 to 0.05 mm, manufactured by Kanto Chemical Co., Inc.). Purify by chromatography [developing solvent; starting from hexane: ethyl acetate: diethylamine = 160: 40: 1 (solvent volume ratio), increasing the solvent volume ratio of ethyl acetate by 10% to 100: 100: 1] -O-t-butyldimethylsilyl-4'-O- [trans-4- (2-ethoxyethylamino) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside 78.4 mg (yield 49%) as a white solid Obtained.

Example 15
4′-O- [trans-4- (2-ethoxyethylamino) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside (Compound No. 49)
In a 20 mL eggplant flask, 5-Ot-butyldimethylsilyl-4′-O- [trans-4- (2-ethoxyethylamino) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside obtained in Example 14 (78.4 mg) and methanol (1 mL) were added and cooled in an ice bath. A methanol solution (0.5 mL) of p-toluenesulfonic acid monohydrate (51.4 mg, 0.27 mmol) was added dropwise thereto, and the mixture was stirred for 2 hours in an ice bath. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added in an ice bath, and the mixture was extracted with ethyl acetate, followed by washing with distilled water and saturated brine in this order. The organic layer was separated, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was further chromatographed using silica gel 60 (particle size 0.04 to 0.05 mm, manufactured by Kanto Chemical Co., Inc.). Purified by chromatography [developing solvent; starting from ethyl acetate: methanol: diethylamine = 100: 1: 1 (solvent volume ratio), increasing the solvent volume ratio of methanol by 1% to 100: 5: 1] 4 ′ -O- [trans-4- (2-ethoxyethylamino) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside (Compound No. 49) was obtained as 66.0 mg (yield 95%) as a white solid.

Example 16
5-Ot-butyldimethylsilyl-4′-O- [4- (4-methylpiperazin-1-yl) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside was added to a 1-methylpiperazine acetate salt in a dried flask. 40 mg of 100 mg of 5-Ot-butyldimethylsilyl-4′-O- (4-oxocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside obtained in Example 3 was added, and 3 ml of methanol was added to completely It was dissolved in. To this solution, 10 mg of sodium cyanoborohydride was added and stirred at room temperature for 5 hours. The reaction solution was poured into 10 ml of saturated sodium bicarbonate water, 5 ml of water was added, and the mixture was extracted with 50 ml of ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 5-Ot-butyldimethylsilyl-4′-O- [4- (4-methylpiperazin-1-yl) cyclohexane. Carbonyl] Avermectin B1a / B1b monoglycoside 120 mg (process yield: 110%) was obtained as a crude extract.

Example 17
4′-O- [4- (4-Methylpiperazin-1-yl) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside (Compound No. 53)
Crude extract of 5-Ot-butyldimethylsilyl-4′-O- [4- (4-methylpiperazin-1-yl) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside obtained in Example 16 120 mg was dissolved in 5 ml of methanol and cooled in an ice-water bath with stirring. 120 mg of p-toluenesulfonic acid monohydrate was added to this solution, and the mixture was further stirred for 2 hours under ice cooling. The reaction mixture was poured into 10 ml of saturated aqueous sodium bicarbonate, 20 ml of water was added, and the mixture was extracted with 50 ml of ethyl acetate. The ethyl acetate layer was washed with 20 ml of water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a crude extract. This crude extract was purified by column chromatography using silica gel 60 (particle size: 0.063 to 0.2 mm, Merck, 20 g) (developing solvent: chloroform: methanol = 30: 1), 4′-O—. 47 mg (process yield: 48%) of [4- (4-methylpiperazin-1-yl) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside was obtained.

Example 18
5-Ot-butyldimethylsilyl-4′-O- [4- (piperidin-1-yl) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside was dried in a flask with piperidine acetate 75 mg, as in Example 3. 100 mg of the obtained 5-Ot-butyldimethylsilyl-4′-O- (4-oxocyclohexanecarbonyl) avermectin B1a / B1b monoglycoside was added, respectively, and 5 ml of methanol was added to completely dissolve it. To this solution, 10 mg of sodium cyanoborohydride was added and stirred at room temperature for 3 hours. The reaction solution was poured into 10 ml of saturated sodium bicarbonate water, 5 ml of water was added, and the mixture was extracted with 50 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 5-Ot-butyldimethylsilyl-4′-O- [4- (piperidin-1-yl) cyclohexanecarbonyl] avermectin 130 mg of B1a / B1b monoglycoside (process yield: 121%) was obtained as a crude extract.

Example 19
4′-O- [4- (piperidin-1-yl) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside (Compound No. 54)
130 mg of a crude extract of 5-Ot-butyldimethylsilyl-4′-O- [4- (piperidin-1-yl) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside obtained in Example 18 was dissolved in methanol. Dissolved in 5 ml and cooled in an ice-water bath with stirring. 130 mg of p-toluenesulfonic acid monohydrate was added to this solution, and the mixture was further stirred for 2 hours under ice cooling. The reaction mixture was poured into 10 ml of saturated aqueous sodium bicarbonate, 20 ml of water was added, and the mixture was extracted with 50 ml of ethyl acetate. The ethyl acetate layer was washed with 20 ml of water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a crude extract. This crude extract was purified by column chromatography using silica gel 60 (particle size: 0.063 to 0.2 mm, Merck, 20 g) (developing solvent chloroform: methanol 50: 1), 4′-
43 mg (process yield: 45%) of O- [4- (piperidin-1-yl) cyclohexanecarbonyl] avermectin B1a / B1b monoglycoside was obtained.

Example 20
5-Ot-Butyldimethylsilyl-4′-O- (Nt-butoxycarbonylpiperidine-4-carbonyl) avermectin B1a / B1b monoglycoside was added to a dry flask with Nt-butoxycarbonylpiperidine-4- Add 220 mg of carboxylic acid, 200 mg of 5-Ot-butyldimethylsilyl avermectin B1a / B1b monoglycoside obtained in Example 2 and 10 mg of 4-dimethylaminopyridine, and add 10 ml of methylene chloride to completely dissolve them. It was. To this solution, 190 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added and stirred at room temperature for 5 hours. After completion of the reaction, 50 ml of dichloromethane was added to the reaction solution to extract the desired product. This dichloromethane solution was washed twice with 20 ml of saturated saline, and further washed once with 20 ml of distilled water. The dichloromethane solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain a crude extract. The crude extract was purified by chromatography using silica gel (developing solvent hexane: ethyl acetate 5: 1) and 5-Ot-butyldimethylsilyl-4′-O- (Nt-butoxycarbonylpiperidine. -4-Carbonyl) avermectin B1a / B1b monoglycoside (200 mg, yield: 80%) was obtained.

Example 21
4′-O- (Nt-butoxycarbonylpiperidine-4-carbonyl) avermectin B1a / B1b monoglycoside 5-Ot-butyldimethylsilyl-4′-O— (N 200 mg of tert-butoxycarbonylpiperidine-4-carbonyl) avermectin B1a / B1b monoglycoside was dissolved in 10 ml of methanol and cooled in an ice-water bath with stirring. 300 mg of p-toluenesulfonic acid monohydrate was dissolved in 1 ml of methanol, an ice-cooled solution was added to the reaction solution, and the mixture was further stirred under ice-cooling for 2 hours. The reaction solution was poured into saturated sodium bicarbonate water and extracted with 60 ml of ethyl acetate. The ethyl acetate layer was washed with 20 ml of saturated saline, and further washed with 20 ml of distilled water. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain a crude product. This crude product was purified by chromatography using silica gel (developing solvent hexane: ethyl acetate 2: 1), 4′-O- (Nt-butoxycarbonylpiperidine-4-carbonyl) avermectin B1a / B1b mono 150 mg (yield: 85%) of glycoside was obtained.

Example 22
4′-O- (piperidine-4-carbonyl) avermectin B1a / B1b monoglycoside (Compound No. 75)
150 mg of 4′-O- (Nt-butoxycarbonylpiperidine-4-carbonyl) avermectin B1a / B1b monoglycoside obtained in Example 21 was dissolved in 5 ml of 3% sulfuric acid-isopropanol, and 24 hours at room temperature. Reacted. After the completion of the reaction, the reaction solution was poured into ice water, saturated aqueous sodium hydrogen carbonate was added thereto to make it weakly alkaline, and then extracted twice with 50 ml of ethyl acetate. The ethyl acetate layers were combined, washed with 20 ml of saturated brine, and further washed with 20 ml of distilled water. The 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 using silica gel (developing solvent: chloroform: methanol 10: 1), 4′-O- (piperidine-4-carbonyl) avermectin B1a / B1b monoglycoside (Compound No. 1). 75) 100 mg (yield: 77%) was obtained.
¹ H-nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ ) δ ppm: 0.84 (1H, m), 0.88 (3H, d, J = 6.8), 0.90 (3H, t, J = 7.5), 1.13 (3H, d, J = 7.0), 1.20 (3H, d, J = 6.2), 1.43 (1H, m), 1.48 (3H, brs), 1.50 (2H, m), 1.60 (1H, m), 1.72 (1H, m) , 1.76 (1H, brdd, J = 12.7,3.9
), 1.84 (3H, brs), 1.99 (1H, brdd, J = 11.6,4.4), 2.18 (2H, m), 2.21 (1H, m), 2.28 (2H, m),
2.31 (1H, m), 2.37 (1H, d, J = 8.1), 2.51 (1H, brt, J = 6.8), 2.69 (1H, m), 3.08 (2H, m), 3.27 (1H, dd, J = 4.6,2.4), 3.38 (2H, m), 3.39 (3H, s), 3.45 (1H, d, J = 9.5), 3.64 (1H, m), 3.94 (1H, m), 3.84 (1H, m ), 3.97 (1H, d, J = 5.9), 4.20 (1H, dq, J = 9.9,6.4), 4.27 (1H, brt, J = 6.8), 4.66 (2H, m), 4.67 (1H, t, J = 9.5), 4.83 (1H, brd, J = 3.5), 4.98 (1H, m), 5.37 (1H, m), 5.42 (1H, brs), 5.56 (1H, dd, J = 9.9,2.4), 5.76 (3H, m),, 5.86 (1H, m)
¹³ C-nuclear magnetic resonance spectrum (75 MHz, CDCl ₃ ) δ ppm: 12.02 (q), 12.90 (q), 15.11 (q), 16.33 (q), 17.59 (q), 19.90 (q), 20.18 (q), 24.58 (t), 24.81 (t), 27.49 (t), 30.54 (d), 34.22 (t), 34.46 (t), 35.14 (d), 36.62 (t), 37.91 (d), 39.65 (d), 40.44 (t), 42.46 (t), 42.46 (t), 45.67 (d), 56.42 (q), 66.18 (d), 67.65 (d), 68.27 (d), 68.27 (d), 68.38 (t), 74.91 (d), 75.63 (d), 75.95 (d), 79.15 (d), 80.36 (s), 82.15 (d), 94.82 (d), 95.76 (s), 117.976 (d), 118.55 (d), 120.29 (d), 124.98 (d), 127.68 (d), 134.85 (s),
136.26 (d), 137.47 (d), 137.99 (s), 139.91 (s), 172.12 (s),, 173.63 (d)

Example 23
5-Ot-Butyldimethylsilyl-4'-O- (N-methylpiperidine-4-carbonyl) avermectin B1a / B1b monoglycoside 180 mg, sodium 1-methylisonipecotate 300 mg of 5-Ot-butyldimethylsilyl avermectin B1a / B1b monoglycoside obtained in Example 2 was added, and 300 mg of dehydrated pyridine and 3 ml of dehydrated methylene chloride were added and completely dissolved. To this solution, 300 mg of 2-chloro-1,3-dimethylimidazolinium chloride was added and stirred at room temperature for 5 hours. The reaction solution was poured into 10 ml of saturated sodium bicarbonate water, 5 ml of water was added, and the mixture was extracted with 50 ml of ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain 600 mg of a crude extract. This crude extract was purified by column chromatography using silica gel 60 (particle size: 0.063 to 0.2 mm, Merck, 20 g) (developing solvent: toluene: methanol 30: 1), and 5-Ot- 340 mg (process yield: 100%) of butyldimethylsilyl-4′-O- (N-methylpiperidine-4-carbonyl) avermectin B1a / B1b monoglycoside was obtained.

Example 24
4′-O- (N-methylpiperidine-4-carbonyl) avermectin B1a / B1b monoglycoside (Compound No. 76)
340 mg of 5-Ot-butyldimethylsilyl-4′-O- (N-methylpiperidine-4-carbonyl) avermectin B1a / B1b monoglycoside obtained in Example 23 was dissolved in 5 ml of methanol and stirred. While cooling in an ice-water bath. 160 mg of p-toluenesulfonic acid monohydrate was added to this solution, and the mixture was further stirred for 2 hours under ice cooling. The reaction mixture was poured into 10 ml of saturated aqueous sodium bicarbonate, 20 ml of water was added, and the mixture was extracted with 50 ml of ethyl acetate. The ethyl acetate layer was washed with 20 ml of water, 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 toluene: methanol 10: 1), 4′-O- (N-methylpiperidine-4-carbonyl) avermectin B1a / B1b monoglycoside (compound) No. 76) 200 mg (process yield: 67%) was obtained.
¹ H-nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ ) δ ppm: 0.86 (1H, m), 0.92 (3H, d, J = 6.8), 0.93 (3H, t, J = 7.5), 1.11 (3H, d, J = 7.0), 1.15 (3H, d, J = 6.2), 1.49 (1H, m), 1.50 (3H, brs), 1.50 (2H, m), 1.64 (1H, m), 1.70 (1H, m) , 1.79 (1H, m), 1.91 (4H, m), 1.88 (3H, brs), 1.99 (4H, m), 2.01 (1H, m), 2.26 (1H, m), 2.27 (3H, s), 2.27 (1H, m), 2.28 (1H, m), 2.31 (1H, m), 2.53 (1H, brt, J = 6.8), 2.83 (4H, brd, J = 11.2), 3.30 (1H, dt, J = 2.4,2.2), 3.40 (3H, s), 3.48 (1H, d, J = 9.5), 3.64 (1H, m), 3.90 (1H, m), 3.94 (2H, m), 3.97 (1H, d , J = 5.9), 4.29 (1H, bd, J = 5.7), 4.66 (2H, ABq), 4.82 (1H, brd, J = 3.1), 4.99 (1H, brdd, J
= 9.7,5.1), 5.40 (1H, m), 5.43 (1H, brs), 5.55 (1H, dd, J = 9.9,2.6), 5.73 (2H, m), 5.77 (1H, dd, J = 8.3, 1.7), 5.88 (1H, m)
¹³ C-nuclear magnetic resonance spectrum (75 MHz, CDCl ₃ ) δ ppm: 11.99 (q), 12.91 (q), 15.08 (q), 16.34 (q), 17.39 (q), 19.91 (q), 20.15 (q), 27.49 (t), 28.27 (t), 28.33 (t), 30.55 (d), 34.23 (t), 34.71 (t), 35.17 (d), 36.64 (t), 39.73 (d), 40.47 (t), 40.72 (d), 45.70 (d), 46.38 (q), 54.90 (t), 54.92 (t), 57.06 (q), 66.49 (d), 67.69 (d), 68.31 (d), 68.33 (d), 68.42 (t), 74.95 (d), 75.81 (d), 75.95 (d), 79.11 (d), 80.37 (s), 82.01 (d), 94.97 (d), 95.75 (s), 118.00 (d), 118.45 (d), 120.35 (d), 124.84 (d), 127.74 (d), 134.96 (s), 136.26 (d), 137.81 (d), 137.99 (s), 139.78 (s), 173.72 (s), 174.26 (s)

Example 25
4′-O- (N-methylpiperidine-4-carbonyl) avermectin B1a / B1b monoglycoside benzoate (Compound No. 78)
In a dried flask, 550 mg of 4′-O- (N-methylpiperidine-4-carbonyl) avermectin B1a / B1b monoglycoside obtained in Example 24 was placed, dissolved by adding 5 ml of toluene, and stirred at room temperature. Then, 80 mg of benzoic acid was dissolved in 5 ml of toluene and added dropwise. After stirring for 30 minutes at room temperature, 50 ml of hexane was added dropwise to precipitate crystals, and the mixture was further stirred for 30 minutes in an ice-water bath. After stirring, the precipitated crystals are collected by filtration, dried under reduced pressure, and the 4'-O- (N-methylpiperidine-4-carbonyl) avermectin B1a / B1b monoglycoside benzoate (Compound No. 78). 550 mg (process yield: 88%) was obtained.

Formulation Example 1 (powder)
2 parts of the compound No. 11 and 1 part of PAP (physical property improving agent) and 97 parts of clay were uniformly mixed and pulverized to obtain a powder containing 2% of the active ingredient.
Formulation Example 2 (wettable powder)
30 parts of the compound No. 12 in Table 1, 3 parts of sodium alkylbenzene sulfonate, 5 parts of polyoxyethylene nonylphenyl ether and 62 parts of clay are uniformly mixed and ground, and water containing 30% of active ingredient A balm was obtained.
Formulation Example 3 (Emulsion)
5 parts of the compound No. 78 in Table 1 above, 65 parts of methyl ethyl ketone and 30 parts of polyoxyethylene nonylphenyl ether were mixed and dissolved to obtain an emulsion containing 5% of the active ingredient.
Formulation Example 4 (Granule)
5 parts of the compound No. 77 in Table 1 above, 1.5 parts of lauryl sulfate, 1.5 parts of calcium lignin sulfonate, 25 parts of bentonite and 67 parts of clay were uniformly mixed, and 15 parts of water was added thereto. After kneading with a kneader, the mixture was granulated with a granulator and dried with a fluid dryer to obtain a granule containing 5% of the active ingredient.
Formulation Example 5 (Flowable)
40 parts of the compound No. 76 in Table 1 above, 2 parts of lauryl sulfate, 2 parts of sodium alkylnaphthalene sulfonate, 1 part of hydroxypropyl cellulose and 55 parts of water are uniformly mixed and flowable containing 40% of the active ingredient An agent was obtained.

Next, although each test example of the insecticidal activity and toxicity test for various plant pests of the compound of the present invention is shown, the scope of the present invention is not limited to the following examples.
Comparative compound 1 in Tables 3 and 4 below is avermectin B1a / B1b (content ratio of about 96: 4), and comparative compound 2 is avermectin B1a / B1b monoglycoside (content ratio of about 96: 4). It is a compound having the structure shown below. Comparative compounds 3 to 7 are avermectin B1a / B1b monoglycoside derivative compounds in which the A part of the general formula I has the partial structures shown in Table 3, respectively.

Test Example 1 (Insecticidal effect test against Lotus moth)
10 mg of the compound of the present invention is dissolved in a mixed solution of 6.2 ml of acetone, 2.5 ml of xylene and 1.3 ml of Solpol 700HD (manufactured by Toho Chemical Co., Ltd.), and this is diluted with ion-exchanged water. Was prepared at a concentration of 0.01 ppm. A cabbage leaf piece having a diameter of 8 cm was immersed in this reagent solution for about 30 seconds, allowed to air dry, and then put into a plastic cup, to which 10 third instar larvae were released. After the release, the specimen was placed in a constant temperature room at 25 ° C. (lighted for 16 hours), and the number of living and dead individuals was examined 5 days after the treatment. This test was carried out in two consecutive systems, and the mortality rate (%) was calculated by the following formula, and the average mortality rate was obtained. The results are shown in Table 4.

Test Example 2 (Insecticidal effect test on Japanese moth)
A cabbage leaf piece having a diameter of 8 cm is immersed in a reagent solution containing the compound of the present invention prepared in the same manner as in Test Example 1 at a concentration of 0.001 ppm for about 30 seconds and air-dried. Ten third-instar larvae were released. After the release, the specimen was placed in a constant temperature room at 25 ° C. (lighted for 16 hours), and the number of living and dead individuals was examined 5 days after the treatment. This test was conducted in a two-running manner, and as in Test Example 1, the mortality rate (%) was calculated according to Equation 1, and the average mortality rate was determined. The results are shown in Table 5.

Test Example 3 (Acute oral toxicity test on mice)
The dose for the acute oral toxicity test was 30 mg / kg body weight and 300 mg / kg body weight. Three male mice weighing 10 weeks and weighing approximately 30 g were used in each test group, and the test solution prepared so that the dosage was the above-mentioned predetermined amount for each mouse was administered by single oral gavage using a metal gastric sonde. . After administration, toxicity classification based on the Toxic and Deleterious Substances Control Law derived from the life and death and general condition of mice for 14 days was evaluated. The results are shown in Table 6 together with the LD ₅₀ value.

Claims (7)

Avermectin monoglycoside derivatives represented by the following general formula (I) or salts thereof

[In the formula, A represents the following general formula (A-1) or (A-2),

m and n each independently represent an integer of 0 to 3,
R ₁ represents an isopropyl or sec- butyl group,
R ₂ is hydrogen atom; C ₁ -C ₆ alkyl group; C ₂ -C ₆ haloalkyl group; C ₃ -C ₆ alkenyl group; C ₃ -C ₆ alkynyl group; C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl group; C ₁ -C ₄ alkylthio C ₁ -C ₄ alkyl group; C ₁ -C ₆ aminoalkyl group; C ₁ -C ₄ alkylamino C ₁ -C ₄ alkyl group; C ₂ -C ₆ hydroxyalkyl group; aminocarbonyl C ₁ -C ₄ alkyl group; C ₁ -C ₄ alkylaminocarbonyl C ₁ -C ₄ alkyl group; C ₁ -C ₄ alkoxycarbonyl C ₁ -C ₄ alkyl group; an amino group; C ₁ -C ₆ alkyl Amino group; C ₃ -C ₇ cycloalkyl group; C ₃ -C ₇ cycloalkyl C ₁ -C ₄ alkyl group; heterocyclyl C ₁ -C ₄ optionally substituted with an unsubstituted or C ₁ -C ₆ alkyl group Alkyl group; unsubstituted or halogen atom C ₁ -C ₆ alkyl group, C ₁ -C ₆ heteroaryl optionally substituted by haloalkyl group C ₁ -C ₄ alkyl group; or an unsubstituted or halogen atom, C ₁ -C ₆ alkyl group, C ₁ ~ A C ₆ haloalkyl group, a phenyl C ₁ -C ₄ alkyl group optionally substituted with a benzyl group,
R ₃ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a tert-butoxycarbonyl group or a trifluoroacetyl group, or —NR ₂ R ₃ represents a nitrogen atom, R ₂ and R ₃ together. Forming a ring, which may represent a 1-piperidyl group, a 4-morpholino group or a 4-methyl-1-piperazinyl group, and R ₄ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a tert-butoxycarbonyl group or a trimethyl group; A fluoroacetyl group; ] In the general formulas (A-1) and (A-2),
m represents 1 or 2, n represents 0 or 1,
When m is 1, the substitution position of R ₃ R ₂ N— (CH ₂ ) _n — is the 3-position, and when m is 2, the substitution position of R ₃ R ₂ N— (CH ₂ ) _n — is 3 Or 4th place,
R _2, R _3, R ₄ is characterized by a hydrogen atom or a C ₁ -C ₆ alkyl group, avermectin mono- glycoside derivative or salt thereof according to claim 1. The avermectin monoglycoside derivative or a salt thereof according to claim 1 or 2, wherein A in the general formula (I) represents a 4-dimethylaminocyclohexyl group. The avermectin monoglycoside derivative or a salt thereof according to claim 1 or 2, wherein A in the general formula (I) represents a 3-dimethylaminocyclohexyl group. The avermectin monoglycoside derivative or a salt thereof according to claim 1 or 2, wherein A in the general formula (I) represents an N-methyl-4-piperidyl group. An insecticide comprising the avermectin monoglycoside derivative compound according to any one of claims 1 to 5 as an active ingredient. An anthelmintic agent comprising the avermectin monoglycoside derivative compound according to any one of claims 1 to 5 as an active ingredient.