JPS6345281A - 5-hydrazone derivative of 5-ketomilbemycin - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [Z represents H, OH or oxo; dotted line represents single or double bond, wherein the double bond occurs only when Z is H; R<1> represents 1-8C alkyl, 2-8C alkenyl, 1-4C alkoxy, etc.; X represents H, halogen atom, OH, etc.; R<2> represents H, lower alkyl or phenyl; R<3> represents H, lower alkyl, phenyl, -SO2R<5> (R<5> represents lower alkyl or phenyl), etc.]. EXAMPLE:13-Pivaloxyloxy-5-ketomilbemycin A45-semicarbazone. USE:An insecticidal, miticidal and anthelmintic agent. PREPARATION:5-Ketomilbemycins expressed by formula II are reacted with a hydrazine derivative expressed by formula III in the presence of a lower aliphatic carboxylic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION [Objective] The present invention relates to a 5-hydrazone derivative of 13-d-converted milbemycins and an acaricide, insecticide and anthelmintic agent containing the same as an active ingredient.

Milbemycin is a series of macrolide compounds, also called antibiotic B-41, and is disclosed in Japanese Patent Application Laid-open No. 50-2974.
2, No. 56-32481, etc., and is a compound represented by the following formula (2).

In the formula, X represents a hydrogen atom; range; 22.2 including the dotted line
The bond between the 3-positions represents a single bond, R1 represents a methyl, ethyl or inglovir group, and are designated as resolemilpemycin A3, milbemycin A4 and milbemycin D.

In addition, in the above formula (■), X is a hydrogen atom, and R' is s
Compounds with @a-tutyl group are disclosed in JP-A-54-1456.
Publication No. 99 Q! It is a milbemycin analog described in . X is 4'-(α-L-oleandrosyl)-α-L
-Oleandrosiloxy group and R is 1ee-butyl or inglovir group are compounds described as avermectins in JP-A-54-61198 and the like. In addition, in the above formula (g), X is a hydrogen atom, 2 is a hydrogen atom or a hydroxyl group, and R
1 is 1-methyl-1-7'ropenyl, 1-methyl-1-
Similar compounds that are butenyl or 1,3-dimethyl-1-butenyl groups are
This is a compound described in Publication No. 1-280496.

Further, in the above formula (6),
Similar compounds having a 1-butenyl group are disclosed in JP-A-61-28
It is described in Publication No. 0496. Furthermore, in the above formula (g), X is a hydrogen atom or a hydroxyl group, and R is an alpha-branched C5-a alkyl, alkenyl, alkynyl, alkoxyalkyl, or alkylthioalkyl group; C-C cycloalkylalkyl a: C3-C
, cycloalkyl or C5-08 cycloalkenyl group (also optionally substituted by dimethylene or one or more C,-C4 alkyl groups or halodane atoms); Similar compounds which are unsaturated 3- to 6-membered oxygen- or sulfur-containing heterocycles optionally substituted (by l or more C1-C4 alkyl groups or halodane atoms) are described in JP-A It is described in Publication No. 62-29590.

The present inventors have conducted extensive studies on the synthesis of derivatives of milbemycins and similar compounds modified at the 5- and 13-positions, and have discovered compounds with excellent acaricidal, insecticidal, anthelmintic, etc. Completed the invention.

〔composition〕

The novel compound of the present invention is represented by general formula (I).

In the above formula, 2 represents a hydrogen atom, a hydroxyl group or an oxy/group. Does the dotted line indicate a single bond or double bond between positions 22 and 23? and can be a double bond only when 2 is a hydrogen atom.

R1 is a C1-8 alkyl group, a C2-8 fluorenyl or alkynyl group, a Cl-4 alkoxy or alkylthio C1-4 alkyl group, a C3-8 cycloalkyl group;
1-5 alkyl group, C3-8 cycloalkyl or C
5-8 cycloalkenyl group (both optionally substituted with methylene or one or more Cl-4 alkyl or halodane), or a saturated or unsaturated 3- to 6-membered oxygen- or sulfur-containing hetero Indicates a ring (optionally substituted with one or more 01-4 alkyl or halodane).

X is a hydrogen atom, a halodane atom, a hydroxyl group, 4'-(α-
L-oleandrosyl)-α-L-oleandrosiloxy group or group R-(0)n-Coo-.

n represents 0 or l.

R4 is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, or a heterocyclic group containing at least one oxygen, sulfur or nitrogen atom and having 4 to 10 ring atoms; be. However, the above R4 group may contain at least one substituent, and when R4 is an alkyl group, the substituent is a cycloalkyl group; a lower alkoxy group; a lower alkoxycarbonyl group; a halodane atom; Aryloxy group or arylthio group that may be Mono- or di-lower alkylcarbamoyl group; mercapto group; lower alkylthio group; lower alkylsulfinyl group; lower alkylsulfonyl group; nitro group or 5- or 6-membered Fi heterocyclic group containing at least one oxygen, sulfur or nitrogen atom If R4 is an alkenyl group or an alkynyl group, it is an aryl group, or if R4 is an alkyl group, it is the above-mentioned substituent υ, and R4 is a cycloalkyl group, an aryl group, an aralkyl group, or at least In the case of a heterocyclic group containing one oxygen, sulfur or nitrogen atom and having a ring atom number of 4 to 10,
The substituent on the ring is a lower alkyl group, a lower alkoxy lower alkyl group, a lower haloalkyl group, a haloalkenyl group, or the above-mentioned substituents when R is an alkyl group.

R2 represents a hydrogen atom, a lower alkyl group or a phenyl group.

R3 is a hydrogen atom, a lower alkyl group, a phenyl group, a group-3
o2R5 or a group -C-R'.

R5 represents a lower alkyl group or a phenyl group.

86 B Amino group, mono- or di-lower alkylamino group, lower alkyl group, lower haloalkyl group, lower alkyl group substituted at the nitrogen atom of a group having a quaternary nitrogen atom with a counter ion, lower alkoxy group, phenyl a halophenyl group or a 5- or 6-membered heterocyclic group containing at least one oxygen, sulfur or nitrogen atom.

Y represents an oxygen atom or a sulfur atom.

In the compound of the present invention represented by the general formula (1), R is, for example, methyl, ethyl, isopropyl, 5e
e-butyl, 1-methyl-1-propenyl, l-methyl-1-butenyl, 1,3-di)f-1-butenyl, cyclointhyl, cyclobutyl, 3-cyclohexenyl,
Cyclohexyl, 1-methylthioethyl, 2-methylcyclopropyl, 2-pentyl, 2-methyl-5ec-butyl, 2-hexyl, 4-penten-2-yl, 2-hegetenyl, 1-cyclopropylethyl, cycloheptyl, 4.4-difluorohexyl, 4-methylenecyclohexyl, 3-methylcyclohexyl, 1-cyclopentenyl, 1-cyclohexenyl, 2-tetrahydrofuryl, 2-thienyl, 3-furyl, 2-chloro-4-thienyl, etc. Preferably, methyl,
Ethyl, isozorovir, 5ec-butyl, 1-methyl-
1-propenyl, 1-methyl-1-butenyl, 1,3-
Dimethyl-1-butenyl, cyclopentyl, cyclobutyl, 3-cyclohexenyl, cyclohexyl, 1-methylthioethyl, 2-methylcyclopropyl, and most preferably methyl, ethyl, isozolobyl,
! IeC-butyl, 1-methyl-1-propenyl, 1-
Methyl-1-butenyl and 1,3-dimethyl-1-butenyl.

When X is a halogen atom, it is, for example, chlorine, bromine, fluorine or iodine, preferably chlorine or fluorine.

When X is a group R'-(0)n-Coo-, and R4 has a substituent as defined above, and the substituent contains a carbon atom, the substituent preferably has from 1 to 6 carbon atoms.

Examples of the "alkyl group" in the definition of R4 include methyl, ethyl, propyl, isozolobyl, butyl, s@
e-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3
, 7-dimethyloctyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,
1-methyl 4-ntadecyl, 14-methylpentadecyl,
13.13-dimethyltetradecyl, heptadecyl, 1
5-methylhexadecyl, octadecyl, 1-methylhegetadecyl, nonadecyl, eicosyl, henaicosyl,
Mention may be made of straight-chain or branched-chain alkyl groups having 1 to 22 carbon atoms such as tocosyl, preferably C alkyl groups. In addition, in the following description, the term "lower alkyl group" refers to, for example, a C1-6, preferably C1,4, linear alkyl group.

Examples of the "cycloalkyl group" in the definition of R4 and its substituents include cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cyclohegetyl, cyclooctyl, cyclononyl, norbornane, bicyclo(2,2,1)hebutyl, adamantyl, cyclodecyl, cycloundecyl, cyclododecyl, which may have 3 to 12 carbon atoms and may be fused. Examples include cyclic alkyl groups, preferably 03-. . cycloalkyl group, more preferably cyclopropyl, cyclobutyl,
Cyclohexyl, adamantyl, etc.

The "alkenyl group" and "alkynyl group" in the definition of R4 may themselves be an alkenyl group or alkynyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, impropenyl, Examples include groups such as butenyl, imbutenyl, butadienyl, methylallyl, hexadecyl, ethynyl, and zolzenyl, preferably C2-4 alkenyl or arginyl groups, more preferably vinyl, allyl, etc. be.

Examples of the "aryl group" in the definition other than R4 and its substitution include aryl groups having 6 to 10 carbon atoms such as phenyl and naphthyl, with phenyl being preferred.

Examples of the "aralkyl group" in the definition of R4 include benzyl, α-methylbenzyl, α, α-dimethylbenzyl, α-methyl-α-ethylbenzyl, α-methyl-
Examples include groups in which the above-defined "aryl group" is substituted with a "lower alkyl group" such as α-fluoromethylpencyl, phenethyl, phenylpropyl, naphthylmethyl, and naphthylethyl, preferably a C 7-ralkyl group. 7 to 12, more preferably α-methylbenzyl, α,α-dimethylpencil, and the like.

Examples of the "heterocyclic group containing at least one oxygen, sulfur or nitrogen atom and having 4 to 10 ring atoms" in the definition of R4 include oxiranyl, oxetanyl,
oxynonyl, aziridinyl, azetidinyl, thiiranyl, cetanyl, (2,2-dimethyl)-1,3-dioxononyl, furyl, thienyl, pyrrolyl, bilisol, thiazolyl, inthiazolyl, oxasilyl, isoxasilyl, imidazolyl, pyrazolyl, ginonyl, pyrazinyl , pyridazinyl, pyrimidinyl, pennyl, naphthyridinyl, xanthenyl, tetrahydrofuranyl,
Unsaturated or partially or fully saturated, such as tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, imidazolidinyl, imidazolinyl, oxazolinyl, oxacylinonyl, bizo”)nonyl, piperazyl, tetrahydropyrimidinyl, dihydrohylida nonyl, morpholinyl, indolinyl, tetrahydroquinolyl Examples include oxiranyl, oxetanyl, aziridinyl, azetidinyl, furyl, thienyl, pyrrolyl, pyridyl, thiazolyl, inthiazolyl, oxasilyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, morpholinyl, benzofuranyl, pentthiophenyl, (2,2-dimethyl) -1
, 3-dioxononyl or quinolyl, and more preferably furyl, thienyl, pyridyl, oxetanyl and the like.

The "lower alkoxy group" in the definition of R6 and other than the substitution of R4 refers to a C1,6 alkoxy group in which the "lower alkyl group" defined above is bonded to an oxygen atom, and preferably a C1-6 alkoxy group such as methoxy or ethoxy. 2 alkoxy group.

"Lower alkoxycarbonyl group" other than R4 substitution
"lower alkoxy group" refers to a group in which a "lower alkoxy group" is bonded to a carbonyl group, preferably methoxycarbonyl or ethoxycarbonyl group. Nyl, propoxycarbyl, and t-butoxycar can be 02-7 alkyloxycarbonyl groups such as nyl, more preferably methoxyal&nyl. The "halogen atom" other than the substitution of R is defined in the above X, that is, preferably fluorine, chlorine, halogen, or iodine, and more preferably chlorine or fluorine. The term "aryloxy group or arylthio group which may be substituted with an atom" other than the substitution of R4 means an aryl ring in which the "atom" is an aryloxy group or an arylthio group, preferably indicates a group substituted on the benzene ring,
Suitable groups include phenoxy, phenylthio, chlorophenoxy, bromophenoxy, iodophenoxy, fluorophenoxy, dichlorophenoxy, chlorophenylthio, and bromophenylthio.

The protecting group for the "optionally protected hydroxy group" is not particularly limited as long as it is a normal hydroxy group protecting group, but preferably trimethylsilyl, triethylsilyl, inzolobildimethylsilyl, t-butyl Tri-lower alkylsilyl groups such as dimethylsilyl, methyldiisozolopylsilyl, methylsortatersilyl, triisozolopylsilyl; formyl, acetyl, chloroacetyl,
Lower aliphatic acyl groups such as nochloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, propionyl, n-butyryl, (tho)-2-methyl-2-butenoyl, isobutyryl, pentanoyl, piparoyl, or benzoyl 0+( can be an aromatic acyl group such as dibromomethyl)benzoyl, 0-(methoxyyl, p-aninyl, p-chlorobenzoyl, p-nitrobensoyl, 0-nitropensoyl, α-naphthoyl), with two or more hydroxyl groups; The group that simultaneously protects may be, for example, an alkylidene group such as impropylidene.The term "mono- or di-lower alkylamino group" in the definition of the substituent of R and R6 means that the lower alkyl group is amino Indicates a group substituted with one or two hydrogen atoms of the group, preferably mono- or non-C1 such as methylamine, ethylamino, propylamine, isobutylamino, dimethylamino, diethylamino, methylethylamino, methylbutylamino. , 6-alkylamino group, more preferably methylamine, ethylamino. "Acylamino group" means C1-6 aliphatic acyl group such as formyl, acetyl, propionyl, butyryl, hexanoyl, or benzoyl, naphthoyl. It refers to a group in which a hydrogen atom of an amino group is substituted with an aromatic acyl group such as, and preferred is a C2,4 aliphatic acylamino group such as acetylamino, propionylamino, or butyrylamino. '' refers to a group in which the lower alkyl group substitutes one or two hydrogen atoms of carbamoyl, preferably a mono- or di-C1-6 alkylcarpamoyl group such as methylcarbamoyl, dimethylcarbamoyl, noethylcarpamoyl. "Lower alkylthio group" refers to a group in which the lower alkyl group is bonded to a sulfur atom,
Preferably methylthio, ethylthio, propylthio, butylthio,! A C1,6 alkylthio group such as Iee-butylthio, more preferably methylthio. Similarly, "lower alkylsulfinyl group and lower alkylsulfonyl group" refer to a group in which the lower alkyl group is bonded to a sulfinyl group or a sulfonyl group, preferably C1, methylsulfinyl, ethylsulfinyl, etc.
, 6 alkylsulfinyl group or meta/sulfonyl,
Al in a C1-6 alkylsulfonyl group such as ethanesulfonyl.

The "lower alkoxy lower alkyl group" in the definition of the @ substituent for R4 indicates a group in which a "lower alkoxy group" is bonded to a "lower alkyl group", such as methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl. , 2-ethoxyethyl, 2-butoxyethyl, C alkyloxy C4,6 alkyl group such as 3-propoxyprobyl? 1 to 6, preferably C1,4 alkyloxyC
It is a 4-4 alkyl group, more preferably methoxymethyl. The "lower haloalkyl group" in the definition of the substituent of R4 and R6 refers to a group in which a "halogen atom" is bonded to a "lower alkyl group", and preferably chloromethyl, bromomethyl, iodomethyl, fluoromethyl, dichloromethyl. , trifluoromethyl, trichloromethyl, 2-chloroethyl, 2,3-dibromopropyl, 2,
2.2-) 1 to 4 halo-substituted C1-6 alkyl groups such as dichloroethyl, 1,2,2,2-tetrabromoethyl, more preferably chloromethyl, trifluoromethyl, etc. . Similarly, a "lower haloalkenyl group" refers to a group in which an "alkenyl group" is substituted with a "halogen atom", such as 2-chlorovinyl, 2-fluorovinyl, 2.2-difluorovinyl, 2.2-difluorovinyl, -1 to 4 such as cyfromovinyl, 2,2-dichlorovinyl
It can be a halor substituted C2,6 alkenyl group, preferably 2,2-dichlorovinyl, 2,2-difluorovinyl.

The "acyl group" at C2 of R4 is, for example, a C4 group such as acetyl, propionyl, butyryl, piparoyl, etc.
, 6 alkanoyl group, acryloyl, methacryloyl, C3,6 alkenoyl group, benzoyl, o-, m
-4L< can be an aromatic acyl group e6 such as p-chlorobenzoyl, preferably acetyl, piparoyl, benzoyl and the like.

Similarly, the "acyloxy group" in the definition of R4 is
The above-mentioned "acyl group" represents a group bonded to an oxygen atom, and preferable aK may be acetoxy, piparoyloxy, benzoyloxy, etc.

"5 or 6 negative rings containing at least one oxygen, sulfur or nitrogen atom" in the 4th conversion of R4 means the above-mentioned R
Among the heterolayers defined in 4., it may be a 5- or 6-membered ring, 2,2-methyl-1,3-dioxolane, etc., preferably morpholinyl, 2,2-dimethyl-1,3- It can be dioxolane, etc.

Suitable examples of the above B group include, for example, a hydrogen atom; a C alkyl group such as methyl, ethyl, isopropyl, butyl, pentyl, hegetyl, or pentadecyl;
C cycloal 3-12 which may be fused, such as cyclozolovir, Schiff 1-22 C7''yl, cyclohexyl, 1-methylcyclopropyl, 1-methylcyclohexyl, adamantyl; trifluoromethyl, iodomethyl, chloromethyl , bromomethyl, trichloromethyl, ) IJ 7
'lomomethyl, 2-chloroethyl, fluoromethyl, 2
-Fluoroethyl, 2-bromoethyl, 1.1-dichloroethyl, 1.1-dimethyl-2-chloroethyl, 2,
Halogenated 01-6 alkyl groups such as 2,2-trichloroethyl, 2,2,2-t-bromoether, 2,2,2-trifluoromethyl; methoxymethyl, ethoxymethyl, methoxyethyl, 2-methoxyethyl C4-4 alkoxy C1-4 alkyl group; Aryloxy C4-6 alkyl group whose ring may be halogenated such as phenoxymethyl, 4-fluorophenoxymethyl; 2-hydroxyethyl, hydroxymethyl, 2 ．．
optionally protected hydroxy C4-6 alkyl groups such as 3-dihydroxypropyl, acetoxymethyl, pivaloyloxymethyl; mercapto C4-6 alkyl groups such as 2-mercaptoethyl; C1, such as methylthiomethyl; 4 alkylthio C1-4 alkyl group; diC1,4 alkylamino C such as dimethylaminomethyl
1-4 alkyl group; alkenyl-substituted cycloalkyl group such as 2-inbutenyl-3,3-tumethylcyclopropyl: 2-(1,2,2,2-tetrabromoethyl)-3,3-dimethylcyclopropyl Halo C like
4-4 alkyl substituted cycloalkyl group; 2-(2,2-
dichlorovinyl) -haloalkenyl-substituted cyfuroa"l/'i;2- such as 3,3-trimethylcyclopropyl
Heterocycle C4,,6 such as furfuryl, imidazolylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 2,2-tmethyl-1,3-dioxolan-4-ylmethyl
Alkyl group; halogenated alkenyl group such as 2,2-dichlorovinyl; C2-4 alkenyl group such as vinyl, 1-propenyl, 1-inbutenyl; C2-4 alkynyl group such as 1-f ropynyl, ethynyl; C7~, aralkyl group such as benzyl, 7-enethyl, α-methylbenzyl, α, α-dimethylbenzyl; ary-A4 such as phenyl; 2-, 3-linked L<f14-chlorophenyl, 2-13- or 4-bromophenyl, 2
-23-E<tli-fluorophenyl, 2,4-dichlorophenyl, 2,5-dichloro-6-methoxyphenyl, 2,3,4,5.6-pentafluorophenyl,
2. Halogenated aryl groups such as 6-difluorophenyl, especially halophenyl groups; C4-4 alkoxyaryl groups, especially alkoxyphenyl groups, such as methoxyphenyl; Nitrophenyl group: 2-.

C1-4 alkylaryl groups such as 3- or 4-tolyl, 4-tert-butylphenyl, especially alkylphenyl groups; 2-. HaloC1,4-alkyl substituted aryl groups such as 3- or 4-trifluoromethylphenyl, 2,5-ditrifluoromethylphenyl, especially haloalkyl monosubstituted phenyl groups: protected such as 1-acetoxyphenyl Moyo 2- or 3-furyl, 2- or 3-thienyl, 1-inquinolyl, 2- or 4
- 5- or 6-membered heterocyclic groups having 1 or 2 heteroatoms, such as pyrinol.

When R6 is a lower alkyl group substituted on the nitrogen atom of a group having a quaternary nitrogen atom accompanied by a counter ion, the "group having a quaternary nitrogen" means, for example, trimethylammonium, triethylammonium, tributylammonium, Trialkylammonium groups such as cetyldimethylammonium, dialkylbenzylammoniums such as dimethylbenzylammonium, aromatic heterocyclic groups such as pyridinium, quinolinium, and saturated groups such as N-methylpiperidinium and N-methylmorpholinium. It can be a heterocyclic group, and examples of counterions include anions such as chlorine, bromine, iodine, and chlorate ions. Such U% lower alkyl group is preferably exemplified.

The "halophenyl group" in the definition of R6 refers to a group in which at least one "halogen atom" defined above is bonded to a phenyl group, for example, 2-23- or 4-
Chlorophenyl, 2-13- also L<H4-bromophenyl, 2-. 3-also L<1f4-fluorophenyl, 2-
13- or 4-iodophenyl, 2+3- + 2
+4- or 2,6-dichlorophenyl, 2,4- or 2,6-difluorophenyl, 2.3,4*5
+6-pentachlorophenyl, 2,3,4,5.6-pentafluorophenyl, etc., preferably 2-fluorophenyl, 2-chlorophenyl, etc.

When R6 is "a 5- or 6-negative ring group containing at least one oxygen, sulfur or nitrogen atom", it is a 5- or 6-membered heterocyclic group shown in R4 above.) Preferably, it is an aromatic heterocyclic group, such as furyl, thienyl, pyrrolyl, pyridyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, etc., and more preferably furyl, thienyl, pyrrolyl, These include pyridyl and thiazolyl.

The above R is preferably a hydrogen atom, and R is preferably a group -
C-R', D, r is preferably an oxygen atom, and R
is preferably an amine group.

The compound of the present invention represented by formula (1) above may have an α or β configuration with respect to the steric configuration at the 13th position. Therefore, although the present invention encompasses each isomer and mixtures thereof, most preferred are the β-coordinated compounds.

Specific examples of the compound having the general formula (1)' of the present invention include (1) the compounds listed in the following Table 1, (2) the compounds listed in Section 12, and 22°23
When there is no double bond at position 2 and 2 is a hydroxyl group or oxo group, or when there is a double bond at position 22 and 23, Z
Compounds in which R, R, R and X have the same meanings as those listed in Table 1 can be mentioned, but the present invention is not limited to these compounds.

In Table 1, position 22.23 is a single bond, Z represents a hydrogen atom, Me represents a methyl group i, and Et represents an ethyl i'1i-
1Pr is a zorobyl group, Bu is a butyl group, Ph is a phenyl group, and Ae is an acetyl group? Each is shown below.

As illustrated below, the compound of formula (1) according to the present invention is represented by formula (■)? It can be produced directly from a compound having formula (Ia), or it can be produced via a compound tid having formula (Ia), which is a part of the compounds of the present invention.

N-bi-R2 (In the formula, R1, R2, R' a Or compounds with hydroxyl group are registered in 1987-2473.
79 or U.S. Pat. No. 4,423,209, and in which X is a herro r7 atom-1 is a group R(0) nee coo-, a compound in which X is a hydroxyl group The compound can be easily obtained by reacting with a halogenating agent, an acid represented by the following formula (2), or a reactive bound conductor thereof.

R'-(0)-COOH(lIt) (In the formula, R4 and n have the same meanings as described above.) This reaction involves the reaction between the hydroxyl group at the 13th position of 13-hydroxy-5-ketomilbemycins and the halogenated Is it a halogenation reaction with a chemical agent, or is it a halogenation reaction with a chemical agent? The esterification reaction with phosphoric acid (t) is therefore carried out by known methods known per se as halogenation and esterification reactions. Examples of the halogenating agent include diethylaminosulfur trifluoride, thionyl chloride, and phosphorus tribromide. Examples of the reactive derivatives of the carboxylic acid of formula (g) include acid halides (acid chloride, acid bromide, acid iodite, etc.), acid anhydrides, mixed acid anhydrides, active esters (for example, p-nitrobenzyl ester), Examples include those commonly used for esterification, such as activated amides.

Step A is a step of producing a compound of formula (1) by reacting the 5-ketomilbemycins of 20) with a hydrazine derivative represented by the following formula ω in the presence of a lower aliphatic carboxylic acid.

(In the formula, R and R have the same meaning as described above.) Examples of the lower aliphatic carboxylic acid used in this step include formic acid, acetic acid, propionic acid, etc.
Examples of acids include acetic acid, preferably acetic acid. The amount thereof is usually 10 equivalents to a large excess relative to the compound of formula (n). This reaction is usually carried out in a solvent, and it is also possible to use the lower aliphatic carboxylic acid itself as a solvent for the reaction. Co-solvents may optionally be used. U, evahexane, benzene, toluene, methylene chloride, chloroform, diethyl ether,
There is no particular limitation as long as it does not participate in this reaction, such as tetrahydrofuran, dioxane, acetonitrile, and ethyl acetate. The reaction temperature is usually 0°C to 80°C, preferably 10°C to 40°C, and the time required for the reaction is usually 30 minutes to 6 hours, preferably Fi 1 to 3 hours. The hydrazine sieve conductor used in the reaction can be used as it is or as a mineral acid salt such as hydrochloric acid or sulfuric acid.
The amount used is usually 1 to 10 equivalents, preferably 1.5 to 6 equivalents, relative to the compound of formula Ql).

Step B is a step of producing a compound of formula (11) by reacting the compound of 201) with a compound of formula (7).

NH2NH-R2(v) (wherein R has the same meaning as above) In this reaction, as in the case of Step A, the presence of a lower aliphatic carboxylic acid is essential; The amount used is the same as in step A. The type of auxiliary solvent that may be used, reaction temperature, reaction time, etc. are also the same as in Step A.

Step C is a step of producing a compound of formula (1) by reacting a compound of formula (Im) with a compound of the following formula @ or υ or a reactive derivative thereof.

(In the formula, R, R and Y have the same meanings as defined above) This reaction is an amidation reaction between the amino group of the hydrazone at the 5-position of the compound @ (Im) and an acid (b) or an acid, It is therefore carried out by a conventional method known per se as the amidation reaction. Examples of acid (b) or reactive derivatives of acid (to) include acid halides (acid chlorides, acid chlorides,
Examples include those commonly used for esterification, such as acid bromide, acid iodite, etc.), acid anhydrides, mixed acid anhydrides, active esters (fc and tij' p-nitrobenzyl esters), and active amides.

The reaction is usually carried out in a solvent, such as hexane, benzene, toluene, methylene chloride, chloroform, diethyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, etc., which are not particularly limited as long as they do not participate in the reaction. It's not something you can do.

The reaction temperature is usually 0°C to 80°C, preferably 10°C to 30°C, and the time required for the reaction is usually 1 hour to 6 hours. Acid (b) or acid ■ used in the reaction
When used on the reactive derivative of acid (a), a dehydrating agent such as dicyclohexylcardiimide, p-toluenesulfonic acid, sulfuric acid, etc. is usually used. , pyridine, triethylamine, 4
- It is desirable to use an organic base such as dimethylaminopyridine or an inorganic base such as potassium carbonate or sodium carbonate as an aid for promoting the reaction.

After the reaction of each step is completed, the formula (1) is calculated using each target product.
The compounds of (Ia) and (Ia) are isolated from the reaction mixture by well-known methods and, if necessary, purified by known means such as column chromatography.

The natural milbemycins, which are the starting materials for the compound of formula (n), are fermentation products in which a large number of fractions are produced in various proportions, and each 72 fraction is isolated and then or as a mixture.

Therefore, a compound of formula (n) may be a single compound (e.g. R
(methyl, ethyl, impropyl or aeC-butyl compounds) or mixtures thereof. Therefore, the compound of formula (1) can also be produced as a single compound or a mixture.

〔effect〕

The compounds of the present invention are useful for adults and eggs of two-spotted spider mites (Tetranychus) that parasitize fruit trees, vegetables, and flowers, apple spider mites, citrus spider mites (Paponyehus), and rust mites, and Ixodids that parasitize animals.
ae) It is not an acaricide that has excellent acaricidal activity against Dermanyaalde and Sarcoptidae, but it has become a major problem in the United States in recent years as existing acaricides have become ineffective. It has excellent activity even against resistant mites, which is a major feature of the compound of the present invention.

The compounds of the present invention can be used in the eastern sheep fly (Oeatrus).
, Lucilim, Hypod
erma), horse par? -(Gautrophilus
), chisels, lice, and other animal and bird ectoparasites; cockroaches, house flies, and other sanitary pests; and other 81 agricultural and horticultural pests, such as aphids and lepidopteran larvae. Furthermore, root-knot nematodes (Msloldogyn) in the soil
, Bursaphelenchus
, Rhizoglyphus and the like.

The compounds of the present invention are also active against insects that harm plants, especially insects that attack plants by feeding on them.

Furthermore, the compounds of the invention have excellent parasiticidal activity as anthelmintics for animals and humans. It is particularly effective against the following nematodes that infect livestock, poultry and pets such as pigs, sheep, goats, cows, horses, dogs, cats and chickens.

Haemonchua, Trichostrongylu@, Oatertagim, Nematodirus, Ku4lia (
Cooperia), Agcaria, Bunoatomum, Oeaophagostmum, Chabertia, Trichuria, Strongylus m (Str
ongylus), Trichonem
a), Dictyocaurus spp.
s), Capillarim, Heteraklg, Toxocara
xocara), Ascaridim, Oxyuri@, Ancyloatoma, Uncinarim, Toxa♂cartm and NoJ? Genus Lascaris (
Parascaria).

Certain species of the genera Nematodeilus, Cooperia, and Esophagostomum are found in the intestinal tract, whereas parasites of the genera Hemonchus and Ostiltagia occur in the stomach, and parasites of the genus Dictyokaurus are found in the lungs. However, it also shows activity against these.

Additionally, parasites of the family Flarariidae and Setariidae are found in other tissues and organs of the body, such as the heart and blood vessels, subbuttal tissue, and Lin-9I tissue, and are active there as well. show.

It is also useful against parasites that infect humans.
c a tor), Ascaris 7 (Asca
rim).

Strongyloides
, Trichinella, Capillarim, Triculis! A(
Triehurim) and Enteropius (Ent.
erobius).

Other medically important parasites found outside the gastrointestinal tract in the blood or other tissues and in the fatty ducts
ugia), Onchocerca% (Onchoerc
a) and the Loa genus (Loa) and the Nematodae nematodae (
The genus Dracunculus (Draeunculidae)
It is also active against the genus Strongyloides and Trichinella in the special extraintestinal parasitic state of intestinal parasites.

When the compounds of the invention are used as anthelmintics in animals and humans, they can be administered orally as a liquid beverage. Beverages are usually solutions, suspensions or dispersions in a suitable non-toxic solvent or water with suspending and wetting agents such as bentonite or other excipients. Beverages generally also contain antifoaming agents. Beverage formulations generally contain about 0.01-0.5% by weight of active compound, preferably 0.01-0.
．． Contains 1% by weight.

If oral administration in a dry, solid unit dosage form is desired, capsules, pills or tablets containing the desired amount of active compound are usually employed.

These use forms involve homogeneously admixing the active ingredient with suitable finely divided diluents, fillers, disintegrants and/or binders such as starch, lactose, talc, magnesium stearate, vegetable gums, etc. Manufactured by Such unit use formulations can vary widely with respect to weight and content of anthelmintic agent depending on the type of host animal being treated, the degree of infection and the type of parasite and the weight of the host.

If it is administered by animal feed? It can be homogeneously dispersed in the feed, used as corn dressing or in the form of pellets. To achieve the desired antiparasitic effect, the final feed usually contains 0.0001-0.02% of active compound.

Also, those dissolved or dispersed in a liquid carrier excipient,
It can be administered to animals parenterally by injection into the proventriculus, intramuscularly, intratracheally or subcutaneously. For parenteral administration, the active compound is preferably mixed with a suitable vegetable oil, such as peanut oil, cottonseed oil. Such formulations generally contain from 0.05 to 50% by weight of active compound.

They may also be administered topically by mixing with a suitable carrier such as dimethyl sulfoxide or a hydrocarbon solvent. This formulation is applied directly to the external surface of the animal by spray or direct pressure.

The optimum amount of active compound to be used for best results will depend on the weight of the animal being treated and the type and extent of the parasitic infection, but will generally be about 0.01 kg/kg of animal body weight.
~100 μ, preferably 0.5 to 50.0 μ by oral administration.

Such usage may range from 1 to 1 at once or in divided stool doses.
It is given over a relatively short period of time, such as 5 days.

Next, the present invention will be explained in more detail with reference to Examples and Reference Examples. In the following examples, the steric configuration of the 13-substituent is all β-coordinated.

Reference Example 1 13-H)" Roxy 5-ketomilbemycin A4 (Formula 1, R': Et, X: OH, 5sorn9
) Diethylaminosulfur trifluoride (707Q) in methylene chloride solution (25m7) at -60°C!
dripped into. After the completion of the dropwise addition, the reaction solution was stirred for 15 minutes, poured into water, extracted with ethyl acetate, and the extract was dried over sodium sulfate. Residue after solvent distillation? Purified by silica gel column chromatography, the listed compound 320 m
I got a 9.

Mass spectrum (m/z): 559 (~r+) nuclear magnetic resonance (m) k (270 MHz) δ (CDC4
3) ppm: 3.88 (s, IH, C6H),
4.02 (a, LH+c, OH), 4.40 (d, d
tlH.

C13H) Reference Example 2 13-hydroxy-5-ketomilbemycin A4 (33
6rn9) in benzene solution (5 ml), add pyridine (0
, 38+aA trifluoro-2-trifluoromethylbenzoyl chloride (sooyy) was added thereto, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the same post-treatment as in Reference Example 1 was carried out to obtain 270 da of the described compound.

Infrared absorption spectrum νKBr: 3450 (br), 1
735.

ax 1680.1605.1585 cm-'Mass spectrum (Vz): 710 (M"-13), 610.520
Nuclear magnetic resonance spectrum δ (CDCl3) ppm: 5.
22 (d, LH.

J=10.6 Hz), 5.4-5.6 (m, 3
H), 5.85-5.95 (m.

2H), 6.55 (m, IH), 7.55~7
．． 85 (m, 4H) Reference Example 3 (2n, R, 1,3-dimethyl-1-butenyl.

LL-F 28249α(61,2Tv)k Acetone (
Activated manganese dioxide (0,64,9) dissolved in
was added and stirred vigorously for 30 minutes. The reaction solution was filtered through Celite, and the filtrate was then concentrated to obtain a crude product of the title compound.
I got 59.3 ■.

Mass spectrum (Vz): 610,592-574
Nuclear magnetic resonance spectrum δ (CDCl2) pprn:
3.78 (s, IH.

C70H) -3-84(a-IH,06H) Example 1 (Step A) (R1: Et, R, H, R, CONH2, X: 0CO
C(C)13) 3゜13-piparoyloxy-5-ketomilbemycin A4 (0.11 g) in acetic acid solution (5TI
Semicarbazide hydrochloride (0.15:l) was added to Lt) under water cooling.
The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with methylene chloride containing 10-thi-methanol.

The extract was washed with saturated brine and then dried over magnesium sulfate. The extract was concentrated and the residue was purified by silica column chromatography to give 0.085p (71.0%)
The described compound was obtained.

Mass spectrum (m/z); 654 (M"-45)
, 636,621 nuclear magnetic resonance spectrum δ(CDCl
2) pprn: 1.20 (s.

9H), 3.03 (d, t, IH, J = 3.10Hz)
, 3.29 (t, IH, J=2Hz), 3.56 (
d, t, IH, J=2.11Hz), 4.10(br,
s, IH), 4.21 (s, IH), 4.71 (
a, 2H), 4.91 (d, lH, J=10.6H
z), 5.3-5.5 (m, 3H), 5.75-5.
95 (m, 3H), 8.5 (s, IH) By similar experimental procedures, using the corresponding hydrazine derivative Crude product of F28249α (971n9
) in an acetic acid solution (2n/) of pyridine (0,064m/)
, add semicarbazide hydrochloride (89TI19) and stir at room temperature for 3 minutes.
Stir for hours. Reaction solution? The mixture was poured into water, extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium bicarbonate, water, and saturated brine.

After drying with sulfuric acid and distilling off the solvent, the residue was purified by silica glu column chromatography.
The target product 67■ (yield 65%) was obtained.

Nuclear magnetic resonance spectrum δ (CDCt,) ppm: 3
．． 47 (m, IHC2H), 3.75 (m, II,
C2,OH), 3.80 (m, IH,C,,)I
), 3.92 (d, IH, J=10.9Hz, C25H
), 3.97 (br, I, IH, C2, H) 4.10
(br, m, IH, C, OH), 4-36 (m −
I H, C6H), 4.87 (d.

2H, J = 2.0Hz, C, H), 5.12 (m,
IH, C15H), 5.38 (d, IH.

J=10.1 Hz, 03□H), 5.56 (d
d, IH, J=10.1, 14.5Hz.

C1, H), 5.91 (dd, IH, J=14.5
, 11.3Hz, C1°H), 6.02(q =
IH, J=6-2 Hz t C3H), 6.05 (
td*IH-J=11.3-2.0 Hz)6.
15 (br, s, IH, NH), 8.66 (s,
IH, NH) Mass spectrum (m/z): 624 (M
+-45), 606.591 Example 12 (Step B) i 3- (2,2,2-)! J Chlorethoxycarbonyloxy)-5-ketomilbemycin A4. (
To a mixed solution of acetic acid and chloroform (0,3d and 4 ml) of (0,26P) (mixture of 2,3:1) was added hydrazine hydrate (0,17m/) under water cooling, and further stirred at room temperature for 3
Stir for hours. The reaction solution was poured into water and extracted with diethyl ether. The extract was washed with water and saturated brine, and then dried over sodium sulfate. The extract was reduced in diameter and the residue was purified by silica gel chromatography to give a concentration of 0.2449 (92
, 1) were obtained.

Mass spectrum # (m/z): 744 (M”), 7
20.714.604゜KBr.

Infrared absorption spectrum ν, 3400.1760
°ax 1720, 1625 inverted-1 Nuclear magnetic resonance spectrum δ (CDCt3) ppm: 3.
04(d,t.

0.7 H, J=2.4, 9.3 Hz), 3.2
6 (d, q, 0.3H, J=3.4, 9.3Hz)
, 3.31 (t, IH, J=2.0Hz), 3.59
(m, IH), 3.95 (br, s, IH), 4.
33 (s, IH), 4.7 (d, IH, J=11
．． ~． 4.71 (s r 2H), 4.80 (d, 1
n, J=lo,, m, 4.84 (d, IH, J-
11,8), 5.3-5.6 (m.

3H), 5.61 (br, s, IH), 5.8-6.0
(m, 2H) In the same manner as in Example 12, the compounds of Examples 13 and 14 were prepared.

Z　　　　　H In both cases, the books are popular.

Example 15 (Step C) (R': mixture of Et and Me (3:1), R2
:H, R3: 13-hydroxy-5-ketomilbemycin A4 + 5-5-hydrazone (2,3:1 mixture) (
Pyridine (0,016 m) and acetyl chloride (0,0
13d) was added and stirred for 25 minutes. Reaction solution? Pour into water, extract with diethyl ether, extract liquid? Washed with water and saturated saline. After drying with sodium sulfate, concentrate the extract and leave a residue. Purified by silica dal chromatography,
The target product 94Tn9 (90 pieces) was obtained.

Mass hardness torque (rrV'z): 612 (M+),
594.580KBr.

Infrared absorption spectrum ν, 3350.1715
゜m&x 1680 cm-' Nuclear magnetic resonance spectrum δ(CDCl2) ppm: 2
．． 30 (a.

3H), 3.29 (t, IH, J=2.4Hz), 3.
73 (d, IH, J=9.87 Hz), 4.
10 (s, IH), 4.17 (s, IH), 5.
34 (br, s, IH), 9.19 (s, IH) By the same operation as in Example 15, the following Examples 16 to 23
of compounds were produced.

Example 23 Seed. After 11 days of inoculation, the inoculated leaves were injected with a solution 7r! containing the test compound at a concentration of 3 ppm! Lt at the Mizuho type distribution tower,
The amount of sprayed liquid was 35 m/α leaf area. 3
After a day, the viability of the adults was examined using a stereomicroscope. Each test compound was tested in duplicate, and the chemical solutions treated during the test were stored in a constant temperature room at 25°C. As a result of this test, each of the compounds of Examples 21, 22, and 23 showed a mite killing rate of 100.

Example 24 One group was fixed in a row on a polyvinyl chloride panel using double-sided adhesive. Note that one row includes 10 animals.

Example compounds were tested as follows.

Serial groups were treated by injection with 2μ or 0.0005μy to 5μg of test compound dissolved in 1 m vehicle of drug. The effect is IR. value, i.e. 30 after processing
The ratio is expressed as the concentration that inhibits mitotic reproduction by 90% after 1 day. IR,. According to Hani, the compound of Example 4 is 0.5μ
It was effective at a concentration of 9/group.

Example 25 Efficacy against sheep maggot fly 3rILl! Suspension of test compound in liquid medium of 1-
Freshly spawned sheep maggot flies (Lucilia aericata) were mixed and injected with 10 ppm or 100 ppm of compound r into test tubes.
eggs? Approximately 30 to 50 pieces were transferred to each group. The test tube was kept at 30°C for 4 days with a cotton stopper. Four days after treatment, the compound of Example 15 was at 10 ppm and each of Examples 17, 18, 19, 20, and 21 was at 10 ppm.
All showed 100% insecticidal efficacy at 0 ppm.

Claims (2)

[Claims] (1) Compounds having the following general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, Z represents a hydrogen atom, a hydroxyl group, or an oxo group. The dotted line indicates a single bond or a double bond between the 22nd and 23rd positions, and can be a double bond only when Z is a hydrogen atom. R^1 is C_1_-_8 alkyl group, C_2_-_8
alkenyl or alkynyl group, C_1_-_4 alkoxy or alkylthioC_1_-_4 alkyl group, C_3_-_8 cycloalkylC_1_-_5 alkyl group, C_3_-_8 cycloalkyl or C_5_
-_8 cycloalkenyl group (both optionally substituted with methylene or one or more C_1_-_4 alkyl or halogen), or a saturated or unsaturated 3- to 6-membered oxygen- or sulfur-containing heterocycle (optionally substituted with one or more C_1_-_4 alkyl or halogen). X is a hydrogen atom, a halogen atom, a hydroxyl group, 4'-(α-
L-oleandrosyl)-α-L-oleandrosiloxy group or group R^4-(O)_n-COO-. n represents 0 or 1. R^4 is a hydrogen atom, an alkyl group, a cycloalkyl group,
It is an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, or a heterocyclic group containing at least one oxygen, sulfur or nitrogen atom and having 4 to 10 ring atoms. However, the above R^4 group may have at least one substituent, and the substituent is, when R^4 is an alkyl group,
Cycloalkyl group; lower alkoxy group; lower alkoxycarbonyl group; halogen atom; optionally halogen-substituted aryloxy or arylthio group; acyl group; acyloxy group; optionally protected hydroxy group; carboxy group; amino group; mono- or di-lower alkylamino group; acylamino group; cyano group; carbamoyl group; mono- or di-lower alkylcarbamoyl group; mercapto group; lower alkylthio group; lower alkylsulfinyl group; lower alkylsulfonyl group; nitro group or at least one is a 5- or 6-membered heterocyclic group containing oxygen, sulfur or nitrogen atom, and when R^4 is an alkenyl group or an alkynyl group, it is an aryl group, or when R^4 is an alkyl group, it is an alkyl group. is a substituent, and when R^4 is a cycloalkyl group, aryl group, aralkyl group, or a heterocyclic group containing at least one oxygen, sulfur or nitrogen atom and having 4 to 10 ring atoms, The substituent on the ring is a lower alkyl group, a lower alkoxy lower alkyl group, a lower haloalkyl group, a haloalkenyl group, or the above-mentioned substituents when R^4 is an alkyl group. R^2 represents a hydrogen atom, a lower alkyl group or a phenyl group. R^3 is a hydrogen atom, a lower alkyl group, a phenyl group, a group -
SO_2R^5 or the group ▲There are mathematical formulas, chemical formulas, tables, etc.▼. R^5 represents a lower alkyl group or a phenyl group. R^6 is an amino group, a mono- or di-lower alkylamino group, a lower alkyl group, a lower haloalkyl group, a lower alkyl group or a lower alkoxy group substituted on the nitrogen atom of a group having a quaternary nitrogen atom with a counter ion. , a phenyl group, a halophenyl group, or a 5- or 6-membered heterocyclic group containing at least one oxygen, sulfur or nitrogen atom. Y represents an oxygen atom or a sulfur atom. ]. (2) Insecticides, acaricides, and anthelmintic agents containing compounds having the following general formula as active ingredients: ▲Mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, Z represents a hydrogen atom, a hydroxyl group, or an oxo group. The dotted line indicates a single bond or a double bond between the 22nd and 23rd positions, and can be a double bond only when Z is a hydrogen atom. R^1 is C_1_-_8 alkyl group, C_2_-_8
alkenyl or alkynyl group, C_1_-_4 alkoxy or alkylthioC_1_-_4 alkyl group, C_3_-_8 cycloalkylC_1_-_5 alkyl group, C_3_-_8 cycloalkyl or C_5_
-_8 cycloalkenyl group (both optionally substituted with methylene or one or more C_1_-_4 alkyl or halogen), or a saturated or unsaturated 3- to 6-membered oxygen- or sulfur-containing heterocycle (optionally substituted with one or more C_1_-_4 alkyl or halogen). X is a hydrogen atom, a halogen atom, a hydroxyl group, 4'-(α-
L-oleandrosyl)-α-L-oleandrosiloxy group or group R^4-(O)_n-COO-. n represents 0 or 1. R^4 is a hydrogen atom, an alkyl group, a cycloalkyl group,
It is an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, or a heterocyclic group containing at least one oxygen, sulfur or nitrogen atom and having 4 to 10 ring atoms. However, the above R^4 may have at least one substituent, and when R^4 is an alkyl group, the substituent is a cycloalkyl group; a lower alkoxy group; a lower alkoxycarbonyl group; a halogen atom. ; Aryloxy group or arylthio group that may be substituted with halogen; Acyl group; Acyloxy group; Hydroxy group that may be protected; Carboxy group; Amino group; Mono- or di-lower alkylamino group; Acylamino group; Cyano group ; Carbamoyl group; Mono- or di-lower alkylcarbamoyl group;
Mercapto group; lower alkylthio group; lower alkylsulfinyl group; lower alkylsulfonyl group; nitro group or 5 containing at least one oxygen, sulfur or nitrogen atom
or a 6-membered heterocyclic group, when R^4 is an alkenyl group or an alkynyl group, it is an aryl group, or when R^4 is an alkyl group, it is the above-mentioned substituent, and R^4 is , a cycloalkyl group, an aryl group, an aralkyl group, or a heterocyclic group containing at least one oxygen, sulfur or nitrogen atom and having 4 to 10 ring atoms, the substituents on the ring are lower alkyl group, lower alkoxy lower alkyl group, lower haloalkyl group, haloalkenyl group or R^4 is an alkyl group. R^2 represents a hydrogen atom, a lower alkyl group or a phenyl group. R^3 is a hydrogen atom, a lower alkyl group, a phenyl group, a group -
SO_2R^5 or the group ▲There are mathematical formulas, chemical formulas, tables, etc.▼. R^5 represents a lower alkyl group or a phenyl group. R^6 is an amino group, a mono- or di-lower alkylamino group, a lower alkyl group, a lower haloalkyl group, a lower alkyl group substituted at the nitrogen atom of a group having a quaternary nitrogen atom with a counter ion, or a lower alkoxy group , a phenyl group, a halophenyl group, or a 5- or 6-membered heterocyclic group containing at least one oxygen, sulfur or nitrogen atom. Y represents an oxygen atom or a sulfur atom. ].