JP3499037B2 - Insecticidal milbemycin derivative having a substituent containing an oxime group at position 13 - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a 13-substituted milbemycin derivative having a substituent containing an oxime group at the 13-position, which exhibits insecticidal, acaricidal or anthelmintic activity.

[0002]

BACKGROUND OF THE INVENTION Milbemycins and avermectins are a series of 16-membered macrolide compounds, and are disclosed, for example, in JP-A Nos. 50-29742, 56-32481 and 5;
It is a known compound represented by the following formula (II) described in JP-A-4-61198.

[0003]

[Chemical 2]

It is known that the above-mentioned milbemycins and avermectins have insecticidal, acaricidal or anthelmintic activities, and the semisynthetic milbemycins having various substituents introduced at the 13-position thereof also have the above biological activity. Have been reported to have. Milbemycins having an ester bond at the 13-position are described in JP-A-61-1807.
87, 1 of substituted or unsubstituted alkanoic acids.
3-ester milbemycins have been described. Further, in Japanese Patent Application Laid-Open No. 1-104078, an alkanoic acid has an alkyl side chain at the α-position.
3-ester milbemycins have been described. Furthermore, in JP-A-5-255343, an alkanoic acid has a heterocyclic functional group at the α-position.
3-ester milbemycins have been described.

Further, as milbemycins having an ether bond at the 13-position, there are, for example, JP-A-2-174780.
In the publication, 13-ether milbemycins having a 2-phenylethoxy group at the 13-position are described.

Further, milbemycins having oximes as a substituent include, for example, JP-A-57-206.
No. 462, JP-A-60-142991 or JP-A-63-10791 describe 5-oxime milbemycins having an oxime group at the 5-position. Further, in JP-A-63-142991, 23-oxime milbemycins having an oxime group at the 23-position are described. Furthermore, EP165029
No. WO 931804 and EP 341972 describe 13-oxime milbemycins having an oxime group at the 13-position.

However, milbemycin 13-position esters and 13-position ethers containing an oxime group in the 13-position substituent have not been reported yet.

[0008]

The object of the present invention is to develop a novel milbemycin compound having excellent acaricidal, insecticidal or anthelmintic activity against mites, plant pests or animal parasites.

[0009]

In order to search for 13-esters and 13-ether milbemycins showing stronger biological activity, the present inventors newly found the 13-position showing strong biological activity as shown below. The present invention was completed by finding a 13-substituted milbemycin derivative having a substituent containing an oxime group.

That is, the present invention has the general formula (I)

[0011]

[Chemical 3]

[Wherein R ¹ represents a methyl, ethyl, isopropyl or sec-butyl group, and R ² represents a hydrogen atom or C ₁
-C ₄ represents an alkyl group, A is a heterocyclic group or a C ₆ -
It represents a C ₁₀ aryl group, and may be substituted with the same or different 1 or 2 groups selected from the following (Substituent group A). m and n each independently represent 0 or 1, and are not 0 at the same time.

(Substituent group A) halogen atom; nitro group;
Hydroxyl; C ₁ -C ₄ alkoxy group; C ₇ -C ₁₁ aralkyloxy group; an amino group; C ₁ -C ₄ alkanoylamino group; C ₂ -C ₄ halo alkanoylamino group; C ₁ -C ₃
Alkylsulfonylamino group; C ₂ -C ₅ alkoxycarbonylamino group; C ₃ -C ₅ halo alkoxycarbonylamino group; an amino C ₂ -C ₇ amino amino C ₂ -C ₇ alkanoyl group within alkanoylamino group (said group The group may be substituted with the same or different 1 or 2 substituents selected from the following (Substituent Group B), and the alkanoyl group is substituted with a phenyl group or a C ₁ -C ₃ alkylthio group. A saturated 5- or 6-membered heterocyclic carbonyl group containing one nitrogen atom as a ring atom (wherein the nitrogen atom is substituted with a substituent selected from the following (Substituent group B)) the carbonyl group may be also replaced in addition to the nitrogen atom), (substituent group B) C ₁ -C ₃ alkyl group;.. C ₂ -C ₃ alkanoyl; C ₂ -C ₄ Haroarukanoi Groups; C ₂ -C
₅ alkoxycarbonyl group; C ₃ -C ₅ haloalkoxycarbonyl group; C ₇ -C ₁₁ arylcarbonyl group; C ₈
[C ₁₀ aralkyloxycarbonyl group] 1
The present invention relates to a milbemycin derivative having a substituent containing an oxime group at the 3-position. The details will be described below.

In the above general formula (I), "methyl, ethyl, isopropyl or sec-butyl group) for R ¹ "
Of these, a methyl group or an ethyl group is preferable, and an ethyl group is more preferable.

"C ₁ -C ₄ alkyl group" for R ²
Are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and isobutyl groups, preferably methyl and ethyl groups, and more preferably methyl group.

The "heterocyclic group" in A is selected from nitrogen, oxygen or sulfur atoms such as furyl group, thienyl group, oxazolyl group, thiazolyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group or pyridyl group. A 5- or 6-membered heterocyclic group having 1 or 2 atoms as a ring atom, preferably a furyl group, a thienyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, a pyrimidinyl group, and more preferably A furyl group, a thienyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, and more preferably a 3-furyl group, a 2-thienyl group, a 4-oxazolyl group, a 4-thiazolyl group, a 2-pyridyl group,
Particularly preferred is a 4-thiazolyl group.

The "C ₆ -C ₁₀ aryl group" in A is
A phenyl group or a naphthyl group, particularly preferably a phenyl group. "Halogen atom" in Substituent group A
Is a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom as a substituent on the phenyl group or the 5- or 6-membered aromatic heterocyclic group.

The "C ₁ -C ₄ alkoxy group" in the substituent group A is, for example, methoxy, ethoxy, propoxy,
A group in which an alkyl group having 1 to 4 carbon atoms such as an isopropoxy, butoxy, isobutoxy, sec-butoxy group is bonded to an oxygen atom, and a methoxy group and an ethoxy group are preferable. More preferably, it is an ethoxy group.

[0019] "C ₇ -C ₁₁ aralkyloxy group" in substituent group A is, for example, binding benzyloxy, phenethyloxy, is C ₇ -C ₁₁ aralkyl such as phenylpropyloxy or naphthylmethyl group and an oxygen atom And is preferably a benzyloxy group or a phenethyloxy group.

"C ₁ -C ₄ alkanoylamino group" in Substituent group A, for example, an alkanoyl group having 1 to 4 carbon atoms such as formylamino, acetylamino, propionylamino, butyrylamino group bonded to an amino group. It is a group formed, and is preferably an acetylamino group.

In the "C ₂ -C ₄ haloalkanoylamino group" in the substituent group A, the above "halogen atom" has 2 carbon atoms in the above "C ₁ -C ₄ alkanoylamino group".
To 4 alkanoylamino groups substituted by 1 to 3 groups, for example, monochloroacetylamino, monobromoacetylamino, trifluoroacetylamino, 2,3-dichloropropionylamino, α-bromoisobutyryl. A group such as an amino group, preferably a monochloroacetylamino or monobromoacetylamino group.

The "C ₁ -C ₃ alkylsulfonylamino group" in the definition of Substituent group A is, for example, a methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or isopropylsulfonylamino group having 1 to 3 carbon atoms. Is a group formed by combining an alkylsulfonyl group with an amino group, preferably a methylsulfonylamino or ethylsulfonylamino group, and particularly preferably a methylsulfonylamino group.

In the substituent group A and the substituent group B, "C ₂
“—C ₅ alkoxycarbonyl group” is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
Isobutoxycarbonyl, sec-butoxycarbonyl, te
As in the rt-butoxycarbonyl group, the above-mentioned “C ₁ -C ₄
Alkoxy group "and a carbonyl group formed by bonding group, preferably a C ₂ -C ₃ alkoxycarbonyl group, particularly preferably a methoxycarbonyl group. The “C ₃ -C ₅ haloalkoxycarbonyl group” in Substituent group A and Substituent group B is, for example, 2-fluoroethoxycarbonyl, 3,3,3-trichloroethoxycarbonyl, 3-bromopropoxycarbonyl, 4-chloro. Like a butoxycarbonyl group, the "halogen atom" is 1
A group in which a linear or branched alkoxy group having 2 to 4 carbon atoms substituted with 3 to 3 and a carbonyl group are bonded to each other,
Preferably a C ₃ -C ₄ haloalkoxycarbonyl group, more preferably a 3,3,3-trichloroethoxycarbonyl group.

"Amino C ₂ -C ₇ alkanoylamino group in the substituent group A (the amino group of the amino C ₂ -C ₇ alkanoyl group in the group is the same or different selected from the following (substituent group B)" 1 or 2 substituents, and the alkanoyl group may be substituted with a phenyl group or a C ₁ -C ₃ alkylthio group.) ”Is, for example, aminoacetylamino, 2 -Aminopropionylamino, 3-aminopropionylamino, 2-aminobutyrylamino, 3-aminobutyrylamino, 4-aminobutyrylamino, 3-amino-3-methylpropionylamino, 2-amino-2-methylpropionyl Amino, 2-aminopentanoylamino, 3-
Aminopentanoylamino, 4-aminopentanoylamino, 5-aminopentanoylamino, 2-amino-3
-Methylbutyrylamino, 2-amino-2-methylbutyrylamino, 1-amino-cyclobutane-1-carbonylamino, 2-aminohexanoylamino, 3-aminohexanoylamino, 4-aminohexanoylamino, 5 -Aminohexanoylamino, 2-amino-3-
Methylpentanoylamino, 2-amino-4-methylpentanoylamino, 2-amino-3,3-dimethylbutyrylamino, 1-aminocyclopentane-1-carbonylamino, 2-aminoheptanoylamino, 1-amino Cyclohexyl-1-carbonylamino, α-aminophenylacetylamino, 2-amino-3-phenylpropionylamino, 2-amino-4-phenylbutyrylamino, 2-amino-3-methylthiopropionylamino, 2-amino-3 -Ethylthiopropionylamino,
2-amino-3-propylthiopropionylamino, 2
-Amino-3-isopropylthiopropionylamino,
2-amino-4-methylthiobutyrylamino, 2-amino-4-ethylthiobutyrylamino, 2-amino-4-
As in propylthiobutyrylamino and 2-amino-4-isopropylthiobutyrylamino group, “amino C ₂ -C ₇ alkanoyl” formed by substituting the alkyl group of “C ₂ -C ₇ alkanoyl” with an amino group. The "group" is a group formed by further amide bond with an amino group. In addition, “C ₂ −
A phenyl group or C is added to the alkyl portion of "C ₇ alkanoyl".
May be substituted with ₁ -C ₃ alkylthio group, wherein "C ₁ -C ₃ alkylthio group", for example, methyl, ethyl, straight-chain or branched having 1 to 3 carbon atoms, such as propyl or isopropyl group A branched alkyl group is bonded to a sulfur atom, preferably a methylthio group.

Of the above-mentioned "amino C ₂ -C ₇ alkanoylamino groups", aminoacetylamino and 2 are preferred.
-Aminopropionylamino, 3-aminopropionylamino, 2-amino-2-methylpropionylamino,
2-amino-3-methylbutyrylamino, 2-amino-
3,3-dimethylbutyrylamino, 2-amino-4-methylpentanoylamino, 1-aminocyclohexyl-
1-carbonylamino, α-aminophenylacetylamino, 2-amino-4-methylthiobutyrylamino, more preferably aminoacetylamino, 2-aminopropionylamino, 3-aminopropionylamino,
2-amino-2-methylpropionylamino, 2-amino-3-methylbutyrylamino, 1-aminocyclohexyl-1-carbonylamino group, particularly preferably,
Aminoacetylamino, 2-aminopropionylamino and 3-aminopropionylamino groups.

In the substituent group A, "a saturated 5- or 6-membered heterocyclic carbonyl group containing one nitrogen atom as a ring atom (the nitrogen atom is substituted with a substituent selected from the following (substituent group B)) Further, the carbonyl group is substituted in addition to the nitrogen atom.) "" Saturated 5- or 6-membered heterocyclic carbonyl group containing one nitrogen atom as a ring atom "
Is, for example, pyrrolidine-2-carbonyl, pyrrolidine-
3-carbonyl, piperidine-2-carbonyl, piperidine-4-carbonyl, preferably pyrrolidine-
It is a 2-carbonyl group.

The "C ₁ -C ₃ alkyl group" in Substituent group B is, for example, methyl, ethyl, propyl or isopropyl group, preferably methyl or ethyl group, more preferably methyl group. Is.

The "C ₂ -C ₃ alkanoyl group" in Substituent group B is, for example, an alkanoyl group having 2 to 3 carbon atoms such as acetyl and propionyl group, and preferably acetyl group.

The “C ₂ -C ₄ haloalkanoyl group” in Substituent group B is a group formed by substituting 1 to 3 alkanoyl groups having 2 to 4 carbon atoms with the above “halogen atom”, For example, it is a group such as a monochloroacetyl, monobromoacetyl, trifluoroacetyl, 2,3-dichloropropionyl, or α-bromoisobutyryl group, and is preferably a monochloroacetyl or monobromoacetyl group.

The “C ₆ -C ₁₀ arylcarbonyl group” in Substituent group B is a group in which an aryl group having 6 to 10 carbon atoms such as a benzoyl group or a naphthoyl group and a carbonyl group are bonded. And preferably a benzoyl group. The “C ₇ -C ₉ aralkyloxycarbonyl group” in Substituent group B is, for example, a carbonyl group bonded to the above aralkyl group having 7 to 9 carbon atoms such as benzyloxycarbonyl, phenylethoxycarbonyl, and phenylpropoxycarbonyl group. And is preferably a benzyloxycarbonyl group.

Since the 13-position substituent compound of the milbemycin derivative which is the starting material of the present invention has an oxime group,
There may be two isomers in the syn or anti coordination. Substituent compound (ester derivative or alcohol)
When two oxime compounds were obtained by column chromatography by separation, the milbemycin derivative formed by combining with the less polar oxime compound was temporarily changed to isomer A and formed by combining with the more polar oxime compound. The milbemycin derivative was tentatively designated as isomer B.

Next, suitable compounds will be listed.

In the general formula (I), (1) R ¹ and R
² is a compound having a methyl or ethyl group, (2) A is
A compound which is a furyl, thienyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl or phenyl group, which may be substituted with one or two substituents selected from the following (Substituent A ₁ group), (Substituent group A ₁ ) Fluorine atom; chlorine atom; bromine atom; nitro group; hydroxyl group; C ₁ -C ₃ alkoxy group; C ₇ -C ₁₀ aralkyloxy group; amino group;
C ₁ -C ₂ alkanoylamino group; fluorine, chlorine or bromine atom substituted C ₂ -C ₃ alkanoylamino group; C ₁ -C
₃ alkylsulfonylamino group; C ₂ -C ₃ alkoxycarbonylamino group; fluorine, chlorine or bromine atom substituted C
₃ -C ₄ alkoxycarbonylamino group; an amino C ₂ -
C ₅ alkanoylamino group (the amino group of the amino C ₂ -C ₅ alkanoyl group may be substituted with the same or different 1 or 2 substituents selected from the following (Substituent group B ₁ ). Further, the alkanoyl group of the amino C ₂ -C ₅ alkanoyl group may be substituted with a phenyl group or a C ₁ -C ₂ alkylthio group.); A saturated 5- or 6-membered heterocycle containing one nitrogen atom as a ring atom. Carbonyl group (the nitrogen atom may be substituted with a substituent selected from the following (Substituent group B ₁ ). The carbonyl group is substituted with a nitrogen atom.) (Substituent group B ₁ ) C ₁ -C ₂ alkyl group; formyl group;
C ₂ -C ₃ alkanoyl group optionally substituted by 1 to 3 fluorine, chlorine or bromine atoms; C ₂ -C ₃ alkoxycarbonyl group; benzoyl group; benzyloxycarbonyl group, more preferably (3) R ¹ is a compound having a methyl or ethyl group, (4) R ² is a compound having a methyl group, (5) A is a furyl group, thienyl, thiazolyl group or a phenyl group, and the following (substituent group A ₂ ) Compounds which may be substituted with 1 or 2 substituents selected from (Substituent group A ₂ ) fluorine atom; chlorine atom; bromine atom; hydroxyl group; C ₁ -C ₂ alkoxy group; benzyloxy group; an amino group; an acetylamino group; monochloroacetyl acetylamino group; mono- bromoacetyl amino group; trifluoroacetylamino group; C ₁ -C ₂ alkylsulfonyl group; an amino C ₂ -C ₃ A Kanoiruamino group (an amino group of the amino C ₂ -C ₃ alkanoyl group is substituted with substituents selected from the following substituent group B _2.); Pyrrolidine carbonyl group (the nitrogen atom, the following substituent group . B ₂ may be substituted with a substituent selected from also the carbonyl group is replaced in addition to the nitrogen atom) (substituent group B ₂₎ methyl;. C ₂ -C ₃ alkanoyl group; More preferably, (6) R ¹ is a compound having an ethyl group, (7) A is a phenyl group or a phenyl group having a substituent at the para-position, more preferably a C ₂ -C ₃ alkoxycarbonyl group, (8) a compound in which m is 0 and n is 1,
Particularly preferably, (9) A has a phenyl group; a 4- (methylsulfonylamino) phenyl group; or a 4- (methoxycarbonylaminoacetylamino) phenyl group.

The novel insecticidal milbemycin derivative having a substituent containing an oxime group at the 13-position of the present invention is shown below.

[0035]

[Chemical 4]

In the table below, the abbreviations indicate the following groups or symbols.

Ac ・ ・ ・ ・ Acetyl AcNH ・ ・ ・ Acetylamino BAc ・ ・ ・ ・ Bromoacetyl Bu ・ ・ ・ ・ ・ ・ Butyl BuO ・ ・ ・ Butoxy BzO ・ ・ ・ ・ ・ Benzyloxy BAcNH ・ ・ ・ ・ Bromoacetylamino CAc ・ ・ ・ ・ Chloroacetyl CAcNH ・ ・ ・ ・ Chloroacetylamino Et ・ ・ ・ ・ ・ ・ ・ Ethyl EtO ・ ・ ・ Ethoxy Fo ・ ・ ・ ・ ・ ・ Formyl Fu ・ ・・ ・ ・ ・ Furryl Hex ・ ・ ・ ・ ・ ・ Hexyl Me ・ ・ ・ ・ ・ ・ Methyl MeO ・ ・ ・ Methoxy Oxa ・ ・ ・ ・ ・ Oxazolyl Pen ・ ・ ・ Pentyl Ph ・ ・ ・ ・ ・ ・ Phenyl PhenO ··· Phenethyloxy Pip ··· Piperidyl Pr ··· Propyl PrO ··· Propoxy Pro ··· Propionyl ProNH ··· Propionylamino Py ···· Pyridyl Pyrd ... Pyrroli Le TfAcNH · · · · trifluoroacetylamino Thi · · · · · thienyl Thiz · · · · · thiazolyl i · · · · · · iso s · · · · · · · Secondary c - · · · · · cyclo t -...

[0038]

[Table 1] ─────────────────────────────────── Compound No. R ¹ R ² A-(CH ₂ ) _m- (C = O) _n -────────────────────────────────── 1 Me H Ph-CH _{2 - 2 Me Me Ph - CH} 2 - 3 Me Me 2-Cl-Ph - CH 2 - 4 Me Me 3-F-Ph - CH 2 - 5 Me Me 3-Cl-Ph - CH 2 - 6 Me Me 3 _{-Fu - CH 2 - 7 Me Me} 2-Thi - CH 2 - 8 Me Me 4- (2-NH 2 -Thiz) - CH 2 - 9 Me Me 4- (2-CAcNH-Thiz) - CH 2 - 10 _{Me Me 4-AcNHCH 2 CONH-} Ph - CH 2 - 11 Me Me 4-MeOCONHCH 2 CONH-Ph - CH 2 - 12 Me Me 4-MeSO 2 NH-Ph - CH 2 - 13 Et H Ph - CH 2 - 14 _{Et Me Ph - CH 2 - 15} Et Me 2-Cl-Ph - CH 2 - 16 Et Me 3-F-Ph - CH 2 - 17 Et Me 3-Cl-Ph - CH 2 - 18 Et Me 3-Fu - _{CH 2 - 19 Et Me 2-} Thi - CH 2 - 20 Et Me 4- (2-NH 2 -Thiz) - CH 2 - 21 Et Me 4- (2-CAcNH-Thiz) - CH 2 - 22 Et Me 4 _{-MeOCONH-Ph - CH 2 - 23} Et Me 4-EtOCONH-Ph - CH 2 - 24 Et Me 4-Cl 3 CH 2 OCONH-Ph - CH 2 - 25 Et Me 4-t-BuOCONH-Ph - CH 2 - 26 Et Me 4-FoNHCH _{2 CONH-Ph - CH 2 -} 27 Et Me 4-AcNHCH 2 CONH-Ph - CH 2 - 28 Et Me 4-ProNHCH 2 CONH-Ph - CH 2 - 29 Et Me 4-BAcNHCH 2 CONH-Ph - CH 2 - _{30 Et Me 4-CAcNHCH 2 CONH} -Ph - CH 2 - 31 Et Me 4-MeOCONHCH 2 CONH-Ph - CH 2 - 32 Et Me 4-MeSO 2 NH-Ph - CH 2 - 33 Et Me 4-EtSO 2 NH _{-Ph - CH 2 - 34 i -Pr} H Ph - CH 2 - 35 i -Pr Me Ph - CH 2 - 36 i -Pr Me 2-Cl-Ph - CH 2 - 37 i -Pr Me 3-F-Ph _{- CH 2 - 38 i -Pr Me} 3-Cl-Ph - CH 2 - 39 i -Pr Me 3-Fu - CH 2 - 40 i -Pr Me 2-Thi - CH 2 - 41 i -Pr Me 4- ( _{2-NH 2 -Thiz) - CH} 2 - 42 i -Pr Me 4- (2-CAcNH-Thiz) - CH 2 - 43 i -Pr Me 4-AcNHCH 2 CONH-Ph - CH 2 - 44 i -Pr Me _{4-MeSO 2 NH-Ph -} CH 2 - 45 s -Bu H Ph - CH 2 - 46 s -Bu Me Ph - CH 2 - 47 s -Bu Me 2-Cl-Ph - CH 2 - 48 s -Bu Me _{3-F-Ph - CH 2} - 49 s -Bu Me 3-Cl-Ph - CH 2 - 50 s -Bu Me 3-Fu - CH 2 - 51 s -Bu Me 2-Thi - CH 2 - 52 s - _{Bu Me 4- (2-NH 2} -Thiz) - CH 2 - 53 s -Bu Me 4- (2-CAcNH-Thiz) - CH 2 - 54 s -Bu Me 4-AcNHCH 2 CONH-Ph - CH 2 - _{55 s -Bu Me 4-MeSO 2} NH-Ph - CH 2 - 56 Me H Ph - CO - 57 Me Me Ph - CO - 58 Me Me 2- Cl-Ph-CO-59 Me Me 3-F-Ph-CO-60 Me Me 3-Cl-Ph-CO-61 Me Me 4-Cl-Ph-CO-62 Me Me 2,4-Cl ₂ -Ph -CO-63 Me Me 4-NO ₂ -Ph-CO-64 Me Me 4-NH ₂ -Ph-CO-65 Me Me 4-AcNH-Ph-CO-66 Me Me 4-ProNH-Ph-CO-67 Me Me 4-CAcNH-Ph-CO-68 Me Me 4-BAcNH-Ph-CO-69 Me Me 4-TfAcNH-Ph-CO-70 Me Me 4-FoNH-Ph-CO-71 Me Me 4-OH- Ph-CO-72 Me Me 2-MeO-Ph-CO-73 Me Me 2-EtO-Ph-CO-74 Me Me 4- i -PrO-Ph-CO-75 Me Me 4- s -BuO-Ph- CO-76 Me Me 2-BzO-Ph-CO-77 Me Me 3-PhenO-Ph-CO-78 Me Me 3-Fu-CO-79 Me Me 2- (5-Br-Fu)-CO-80 Me Me 2-Thi-CO-81 Me Me 2- (5-Br-Thi)-CO-82 Me Me 4-Thiz-CO-83 Me Me 4- (2-NH ₂ -Thiz)-CO-84 Me Me 4- (2-AcNH ₂ -Thiz)-CO-85 Me Me 4- (2-CAcNH-Thiz)-CO-86 Me Me 4- (2-BAcNH-Thiz)-CO-87 Me Me 4- (2 -FoNH-Thiz)-CO-88 Me Me 2-Py-CO-89 Me Me 2- (5-Cl-Py)-CO-90 Me H 4-MeSO ₂ NH-Ph-CO-91 Me Me 4- MeSO ₂ NH-Ph-CO-92 Me Me 4-EtSO ₂ NH-Ph-CO-93 Me Me 4-MeOCONH-Ph-CO-94 Me Me 4-AcNHCH ₂ CONH-Ph- CO-95 Me Me 2-MeOCONHCH ₂ CONH-Ph-CO-96 Me Me 3-MeOCONHCH ₂ CONH-Ph-CO-97 Me Me 4-MeOCONHCH ₂ CONH-Ph-CO-98 Me Me 4-MeOCONHCH (Me) CONH-Ph-CO-99 Me Me 4-MeOCONHC (Me) ₂ CONH-Ph-CO-101 Me Me 4- [1- (MeOCO) Pyrd-2-CONH-] Ph-CO-102 Me Me 4- ( 2-MeOCONHCH ₂ CONH-Thiz)-CO-103 Et H Ph-CO-104 Et H 2-Cl-Ph-CO-105 Et Me Ph (Isomer A)-CO-106 Et Me Ph (Isomer B) -CO-107 Et Me 2-Cl-Ph-CO-108 Et Me 3-F-Ph-CO-109 Et Me 3-Cl-Ph-CO-110 Et Me 4-Cl-Ph (Isomer A)- CO-111 Et Me 4-Cl-Ph (Isomer B)-CO-112 Et Et 4-Cl-Ph (Isomer A)-CO-113 Et Et 4-Cl-Ph (Isomer B)-CO- 114 Et Me 4-NO ₂ -Ph-CO-115 Et Me 4-NH ₂ -Ph-CO-116 Et Me 4-AcNH-Ph-CO-117 Et Me 4-ProNH-Ph-CO-118 Et Me 4 -CAcNH-Ph-CO-119 Et Me 4-BrAcNH-Ph-CO-120 Et Me 4-TfAcNH-Ph-CO-121 Et Me 4-FoNH-Ph-CO-122 Et Me 2-OH-Ph-CO -123 Et Me 2-MeO-Ph (Isomer A)-CO-124 Et Me 2-MeO-Ph (Isomer B)-CO-125 Et Me 2-EtO-Ph (Isomer A)-CO-126 Et Me 2-EtO-Ph (Isomer B)-CO-127 Et Me 4- i PrO-Ph (Isomer A)-CO-128 Et Me 4- i PrO-Ph (Isomer B)-CO-129 Et Me 4- s BuO-Ph (Isomer A)-CO-130 Et Me 4- s BuO-Ph (Isomer B)-CO-131 Et Me 3-BzO-Ph-CO-132 Et Me 3-PhenO-Ph -CO-133 Et Me 3-Fu-CO-134 Et Me 2- (5-Br-Fu)-CO-135 Et Me 2-Thi-CO-136 Et Me 2- (5-Br-Thi)-CO - 137 Et Me 4-Ox - CO - 138 Et Me 4- (2-NH 2 -Ox) - CO - 139 Et Me 4-Thiz - CO - 140 Et Me 4- (2-NH 2 -Thiz) - CO -141 Et Me 4- (2-AcNH ₂ -Thiz)-CO-142 Et Me 4- (2-CAcNH-Thiz)-CO-143 Et Me 4- (2-BAcNH-Thiz)-CO-144 Et Me 4- (2-FoNH-Thiz)-CO-145 Et Me 2-Py-CO-146 Et Me 2- (5-Cl-Py)-CO-147 Et Me 2-MeSO ₂ NH-Ph-CO-148 Et Me 3-MeSO ₂ NH-Ph-CO-149 Et Me 4-MeSO ₂ NH-Ph-CO-150 Et Et 4-MeSO ₂ NH-Ph-CO-151 Et Me 4-EtSO ₂ NH-Ph-CO -152 Et Me 4-PrSO ₂ NH-Ph-CO-153 Et Me 4- i -PrSO ₂ NH-Ph-CO-154 Et Me 4-MeOCONH-Ph-CO-155 Et Me 4-EtOCONH-Ph-CO -156 Et Me 4-Cl ₃ CH ₂ OCONH-Ph-CO-157 Et Me 4- i -Pr OCONH-Ph-CO-158 Et Me 4- t -BuOCONH-Ph-CO-159 Et Me 4-H ₂ NCH ₂ CONH-Ph-CO-160 Et Me 4-FoNHCH ₂ CONH-Ph-CO-161 Et Me 2-AcNHCH ₂ CONH-Ph-CO-162 Et Me 3-AcNHCH ₂ CONH-Ph-CO-163 Et Me 4-AcNHCH ₂ CONH-Ph-CO-164 Et Me 4-CAcNHCH ₂ CONH-Ph-CO-165 Et Me 4-BAcNHCH ₂ CONH-Ph-CO-166 Et Me 4-ProNHCH ₂ CONH-Ph-CO-167 Et H 4-MeOCONHCH ₂ CONH-Ph-CO-168 Et Me 2-MeOCONHCH ₂ CONH-Ph-CO -169 Et Me 3-MeOCONHCH ₂ CONH-Ph-CO-170 Et Me 4-MeOCONHCH ₂ CONH-Ph-CO-171 Et Et 4-MeOCONHCH ₂ CONH-Ph-CO-172 Et Pr 4-MeOCONHCH ₂ CONH-Ph -CO-173 Et i -Pr 4-MeOCONHCH ₂ CONH-Ph-CO-174 Et H 4-EtOCONHCH ₂ CONH-Ph-CO-175 Et Me 4-EtOCONHCH ₂ CONH-Ph-CO-176 Et Me 4-Cl ₃ CH ₂ OCONHCH ₂ CONH-Ph-CO-177 Et Me 4-PrOCONHCH ₂ CONH-Ph-CO-178 Et Me 4- i -PrOCONHCH ₂ CONH-Ph-CO-179 Et Me 4- t -BuOCONHCH ₂ CONH- Ph-CO-180 Et Me 4-BnOCONHCH ₂ CONH-Ph-CO-181 Et Me 4-PhenOCONHCH ₂ CONH-Ph-CO-182 Et Me 4-PhCONHCH ₂ CONH-Ph-CO-183 Et Me 4-MeOC ON (Me) CH ₂ CONH-Ph-CO-184 Et Me 4-EtOCON (Me) CH ₂ CONH-Ph-CO-185 Et Me 4-MeOCONHCH ₂ CH ₂ CONH-Ph-CO-186 Et Me 4-EtOCONHCH ₂ CH ₂ CONH-Ph-CO-187 Et Me 4-MeOCONHCH (Me) CONH-Ph-CO-188 Et Me 4-MeOCONHCH (Et) CONH-Ph-CO-189 Et Me 4-MeOCONHC (Me) ₂ CONH -Ph-CO-190 Et Me 4-MeOCONHCH ( i -Pr) CONH-Ph-CO-191 Et Me 4-MeOCONHCH (Bu) CONH-Ph-CO-192 Et Me 4-MeOCONHCH ( i -Bu) CONH- Ph-CO-193 Et Me 4-MeOCONHCH (t-Bu) CONH-Ph-CO-194 Et Me 4-MeOCONHCH (Ph) CONH-Ph-CO-195 Et Me 4-MeOCONHCH (Bn) CONH-Ph-CO -196 Et Me 4-MeOCONHCH (CH ₂ CH ₂ SMe) CONH-Ph-CO-197 Et Me 4-MeOCONHCH (CH ₂ SMe) CONH-Ph-CO-198 Et Me 4-MeOCONHCH (CH ₂ SEt) CONH- Ph-CO-199 Et Me 4- [1- (MeOCONH) c-Pen-1-CO-NH] Ph-CO-200 Et Me 4- [1- (MeOCONH) c-Hex-1-CO-NH] Ph-CO-201 Et Me 4- [1- (MeOCO) Pyrd-2-CONH-] Ph-CO-202 Et Me 4- (1-AcPyrd-2-CONH-] Ph-CO-203 Et Me 4- [1- (MeOCO) Pip-2-CONH-] Ph-CO-204 Et Me 4- (2-MeSO ₂ NH-Thiz)-CO-205 Et Me 4- (2-MeOCONH-Thiz)-CO-206 Et Me 4- (2-EtOCONH-Thiz)- CO-207 Et Me 4- (2-Cl ₃ CH ₂ OCONH-Thiz)-CO-208 Et Me 4- (2-AcNHCH ₂ CONH-Thiz)-CO-209 Et Me 4- (2-MeOCONHCH ₂ CONH- Thiz)-CO-210 Et Me 4- (2-EtOCONHCH ₂ CONH-Thiz)-CO-211 Et Me 4- (2- i -PrOCONH-Thiz)-CO-212 Et Me 4- [2- (2- (1-MeOCOPyrd) CO} NH-Thiz]-CO-213 i -Pr H Ph-CO-214 i -Pr Me Ph-CO-215 i -Pr Me 2-Cl-Ph-CO-216 i -Pr Me 3-F-Ph-CO-217 i -Pr Me 3-Cl-Ph-CO-218 i -Pr Me 4-Cl-Ph-CO-219 i -Pr Me 4-Cl-Ph-CO-220 i- Pr Me 4-NO ₂ -Ph-CO-221 i -Pr Me 4-NH ₂ -Ph-CO-222 i -Pr Me 4-AcNH-Ph-CO-223 i -Pr Me 4-ProNH-Ph-CO -224 i -Pr Me 4-CAcNH-Ph-CO-225 i -Pr Me 4-BrAcNH-Ph-CO-226 i -Pr Me 4-TfAcNH-Ph-CO-227 i -Pr Me 4-FoNH-Ph -CO-228 i -Pr Me 4-OH-Ph-CO-229 i -Pr Me 2-MeO-Ph-CO-230 i -Pr Me 2-EtO-Ph-CO-231 i -Pr Me 4- i -PrO-Ph-CO-232 i -Pr Me 4- s -BuO-Ph-CO-233 i -Pr Me 2-BzO-Ph-CO-234 i -Pr Me 3-PhenO-Ph-CO-235 i -Pr Me 2-Fu-CO-236 i -Pr Me 2- (5-Br-Fu)-CO-237 i -Pr Me 2-Thi-CO-2 38 i -Pr Me 2- (5-Br-Thi)-CO-239 i -Pr Me 4-Thiz-CO-240 i -Pr Me 4- (2-NH ₂ -Thiz)-CO-241 i -Pr Me 4- (2-CAcNH-Thiz)-CO-242 i -Pr Me 4- (2-BAcNH-Thiz)-CO-243 i -Pr Me 4- (2-FoNH-Thiz)-CO-244 i- Pr Me 2-Py-CO-245 i -Pr Me 2- (5-Cl-Py)-CO-246 i -Pr Me 4-MeSO ₂ NH-Ph-CO-247 i -Pr Me 4-MeOCONHCH ₂ CONH -Ph-CO-248 s -Bu H Ph-CO-249 s -Bu Me Ph-CO-250 s -Bu Me 2-Cl-Ph-CO-251 s -Bu Me 3-F-Ph-CO-252 s -Bu Me 3-Cl-Ph-CO-253 s -Bu Me 4-Cl-Ph-CO-254 s -Bu Et 4-Cl-Ph-CO-255 s -Bu Me 4-NO ₂ -Ph- CO-256 s -Bu Me 4-NH ₂ -Ph-CO-257 s -Bu Me 4-AcNH-Ph-CO-258 s -Bu Me 4-ProNH-Ph-CO-259 s -Bu Me 4-CAcNH -Ph-CO-260 s -Bu Me 4-BrAcNH-Ph-CO-261 s -Bu Me 4-TfAcNH-Ph-CO-262 s -Bu Me 4-FoNH-Ph-CO-263 s -Bu Me 4 -OH-Ph-CO-264 s -Bu Me 2-MeO-Ph-CO-265 s -Bu Me 2-EtO-Ph-CO-266 s -Bu Me 4- i -PrO-Ph-CO-267 s -Bu Me 4- s BuO-Ph-CO-268 s -Bu Me 2-BzO-Ph-CO-269 s -Bu Me 3-PhenO-Ph-CO-270 s -Bu Me 3-Fu -CO-271 s -Bu Me 2- (5-Br-Fu)-CO-272 s -Bu Me 2-Thi-CO-273 s -Bu Me 2- (5-Br-Thi)-CO-274 s -Bu Me 4-Thiz-CO-275 s -Bu Me 4- (2-NH ₂ -Thiz)-CO-276 s -Bu Me 4- (2-CAcNH-Thiz)-CO-277 s -Bu Me 4 -(2-BAcNH-Thiz)-CO-278 s -Bu Me 4- (2-FoNH-Thiz)-CO-279 s -Bu Me 2-Py-CO-280 s -Bu Me 2- (5-Cl -Py)-CO-281 s -Bu Me 4-MeSO ₂ NH-Ph-CO-282 s -Bu Me 4-MeOCONHCH ₂ CONH-Ph-CO-283 Me H Ph-CH ₂ -CO-284 Me Me Ph -CH ₂ -CO-285 Me Me 3-Fu-CH ₂ -CO-286 Me Me 2-Thi-CH ₂ -CO-287 Me Me 4- (2-NH ₂ -Thiz)-CH ₂ -CO-288 Me Me 2-Py-CH ₂ -CO-289 Me Me 4-MeSO ₂ NH-Ph-CH ₂ -CO-290 Me Me 4-AcNHCH ₂ CONH-Ph-CH ₂ -CO-291 Me Me 4-MeOCONHCH ₂ CONH-Ph-CH ₂ -CO-292 Et H Ph-CH ₂ -CO-293 Et Me Ph-CH ₂ -CO-294 Et Me 3-Fu-CH ₂ -CO-295 Et Me 2-Thi-CH ₂ -CO-296 Et Me 4- (2-NH ₂ -Thiz)-CH ₂ -CO-297 Et Me 2-Py-CH ₂ -CO-298 Et Me 4-MeSO ₂ NH-Ph-CH ₂ -CO- 299 Et Me 4-AcNHCH ₂ CONH-Ph-CH ₂ -CO-300 Et Me 4-MeOCONH CH ₂ CONH-Ph-CH ₂ -CO-301 i -Pr H Ph-CH ₂ -CO-302 i -Pr Me Ph-CH ₂ -CO-303 i -Pr Me 3-Fu-CH ₂ -CO-304 i -Pr Me 2-Thi-CH ₂ -CO-305 i -Pr Me 4- (2-NH ₂ -Thiz)-CH ₂ -CO-306 i -Pr Me 2-Py-CH ₂ -CO-307 i -Pr Me 4-MeSO ₂ NH-Ph-CH ₂ -CO-308 i -Pr Me 4-AcNHCH ₂ CONH-Ph-CH ₂ -CO-309 i -Pr Me 4-MeOCONHCH ₂ CONH-Ph-CH _2- CO-310 s -Bu H Ph-CH ₂ -CO-311 s -Bu Me Ph-CH ₂ -CO-312 s -Bu Me 3-Fu-CH ₂ -CO-313 s -Bu Me 2-Thi-CH ₂ -CO-314 s -Bu Me 4- (2-NH ₂ -Thiz)-CH ₂ -CO-315 s -Bu Me 2-Py-CH ₂ -CO-316 s -Bu Me 4-MeSO ₂ NH- Ph-CH ₂ -CO-317 s -Bu Me 4-AcNHCH ₂ CONH-Ph-CH ₂ -CO-318 s -Bu Me 4-MeOCONHCH ₂ CONH-Ph-CH ₂ -CO-──────── ──────────────────────────── Of the above compounds, preferably, compound numbers 14 and 15,
26, 27, 28, 32, 57, 105, 106, 10
7, 108, 110, 111, 112, 113, 11
4, 116, 122, 123, 124, 125, 12
6, 131, 133, 135, 140, 145, 14
9, 150, 151, 159, 160, 163, 97,
170, 171, 180, 182, 183, 184, 1
85, 187, 188, 189, 201, 202, 21
4, 249 or 293, more preferably compound Nos. 27, 57, 97, 105, 106, 1
10, 111, 112, 113, 122, 125, 12
6, 131, 149, 163, or 170, particularly preferably compound No. 105 or 106.

The compound represented by the formula (I) of the present invention can be produced by 4 methods shown in the following process drawings.

[0040]

[Chemical formula 5]

[0041]

[Chemical 6]

[0042]

[Chemical 7]

[0043]

[Chemical formula 8]

[Wherein R ¹ , R ² , m and n have the same meanings as described above, A ¹ is an amino group; an acyl-substituted amino group (however, a formylamino group; a monochloroacetylamino group; Monobromoacetylamino group; 3,3,3-
Trichloroethoxycarbonylamino group; excluding tert-butoxycarbonylamino group. ); Or a heterocyclic group which may be substituted with 1 or 2 substituents selected from the substituent group A excluding the C ₁ -C ₃ alkylsulfonylamino group or the same as the substituent of the heterocyclic group. Represents a C ₆ -C ₁₀ aryl group which may be substituted with one or two substituents.
A ¹¹ is a heterocyclic group substituted with 1 or 2 nitro groups or C ₆ -C substituted with 1 or 2 nitro groups
₁₀ aryl group, A ² represents a heterocyclic group substituted with 1 or 2 amino groups or a C ₆ -C ₁₀ aryl group substituted with 1 or 2 amino groups, and A ¹² Is substituted with 1 or 2 substituents selected from formylamino group; monochloroacetylamino group; monobromoacetylamino group; 3,3,3-trichloroethoxycarbonylamino group; tert-butoxycarbonylamino group. 1 or 2 which is the same as the heterocyclic group or the substituent of the heterocyclic group
Shows a C ₆ -C ₁₀ aryl group substituted with one substituent.

A ³ is an acyl-substituted amino group (excluding formylamino group; monochloroacetylamino group; monobromoacetylamino group; 3,3,3-trichloroethoxycarbonylamino group; tert-butoxycarbonylamino group). Or a heterocyclic group substituted with 1 or 2 substituents selected from a C ₁ -C ₃ alkylsulfonylamino group or substituted with 1 or 2 substituents identical to the substituents of the heterocyclic group Is a C ₆ -C ₁₀ aryl group.

[0046] However, the acylamino group, of (substituent group A), C ₁ -C ₄ alkanoylamino group; C ₂ -
It refers to an amino C ₂ -C ₇ alkanoylamino group; C ₄ halo alkanoylamino group; C ₂ -C ₅ alkoxycarbonylamino group; C ₃ -C ₅ halo alkoxycarbonylamino group.

The 15-hydroxymilbemycin derivative represented by the formula (III), which is the starting material of this production method, is produced according to the method described in JP-A-60-158191.

Further, the side chain compound represented by the general formula (IV), which is another starting material in this production method, may be a carboxylic acid or ethanol as shown below.

A ^1- (C = N-OR ² )-(CH ₂ ) _m- (C = O) _n -OH (IV) (In the formula, A ¹ , R ² , m and n are the same as those described above. In the compound represented by the general formula (IV), in the case of (1) an α-alkoxyiminophenylacetic acid derivative in which m = 0 and n = 1, α-alkoxyiminophenylacetic acid is described in JP-A-48. According to the publication No. 4487, it was produced using commercially available ethyl phenylglyoxylate as a starting material. α-Alkoxyimino-3-furylacetic acid is commercially available 3-
Using furylcarboxylic acid as a starting material, JP-A-53-316
It was manufactured according to Japanese Patent Publication No. 93. α-alkoxyimino-
2-Thienylacetic acid was produced using commercially available 2-thienylglyoxydylic acid as a starting material and commercially available ethyl phenylglyoxylate as a starting material according to JP-A-48-4487. α-alkoxyimino- (2-amino-4-
Thiazolyl) acetic acid and its derivatives are commercially available 2-amino-4
-Using thiazolyl glyoxidyl acid as a starting material
It was manufactured in accordance with JP-A-8-4487.

The α-alkoxyimino-substituted phenyl acetic acid is a 2-substituted phenyl-1 described in Journal of Medicinal Chemistry, Vol. 24, p. 1360 [J. Med. Chem., 24, 1360 (1981)]. , 2-ethanediol as a starting material to lead to the dimethyl ter-butylsilyl-2-oxo substituted phenethyl ether described in Chemistry Letter, p. 1359 (1985) [Chem.lett., 1359 (1985)], 2-Alkoxyimino-2-substituted phenylethanol was obtained by reacting O-alkoxyhydroxylamine by a conventional method. It was produced by oxidizing this by a conventional method.

For example, 2-alkoxyimino-2- (4
-Nitrophenyl) acetic acid is described in Journal of Medicinal Chemistry, Vol. 24, p. 1360 [J.Med.Che.
m., 24, 1360 (1981)], 2- (4
-Nitrophenyl) -1,2-ethanediol to tetr-
Butyldimethylsilyl-2-oxo-2- (4-nitrophenethyl) ether [This reaction is described in Chemistry Letter, No. 1359 (1985). ] 2-alkoxyimino-2- (4- obtained by reacting with O-alkoxyhydroxylamine
It is obtained by oxidizing nitrophenyl) ethanol by a conventional method.

Further, 2-alkoxyimino-2- (4-
Nitrophenyl) acetic acid is an alternative method [synthesis,
Page 850 (1990)]. That is, it is obtained by reacting ethyl 4-nitrophenylglyoxydylate with O-alkoxyhydroxylamine and then hydrolyzing it.

Further, 2-hydroxyimino-2- (4-
Nitrophenyl) acetic acid has been obtained by substituting hydroxylamine for O-alkoxyhydroxylamine in the above method.

(2) 2-alkoxyimino-2-substituted or unsubstituted phenylethanol derivative in which m = 1 and n = 0, 2-alkoxyimino-2- (2-furyl) ethanol derivative, 2-alkoxyimino- 2- (2-thienyl) ethanol derivative and 2-alkoxyimino-2-
The (2-amino-4-thiazolyl) ethanol derivative is
It was produced as an intermediate for producing the above α-alkoxyiminoacetic acid derivative.

(3) 3-alkoxyimino-3-substituted or unsubstituted phenylpropionic acid derivatives in which m = 1 and n = 1 are commercially available ethyl benzoyl acetate or ethyl substituted benzoyl acetate prepared by a known method. Used as a substance, it was produced according to the production method of α-alkoxyiminophenylacetic acid. 3-alkoxyimino-3- (3-furyl) propionic acid derivative, 3-alkoxyimino-3- (2-thienyl) propionic acid derivative and 3-alkoxyimino-3- (2-amino-4-)
The thiazolyl) propionic acid derivative was also produced according to the method for producing a 3-alkoxyimino-3-substituted phenylpropionic acid derivative.

The natural milbemycins and their related compounds, which are the starting materials for the compounds of the general formula (V), are fermentation products and may be either single compounds or a mixture thereof. In addition, since the 13-position side chain contains an oxime group, two syn- or anti-coordinated isomers may exist. Accordingly, the compounds of formula (I) may be prepared as single compounds or mixtures.

1) Method A Method A is a method for producing a compound (Ia) in which A has a group represented by A ¹ in the general formula (I).

(Step 1) is a method for producing the compound represented by the general formula (V), which is represented by the general formula (III).
This is achieved by reacting the 5-hydroxymilbemycin derivative with a carboxylic acid or alcohol represented by the general formula (IV) in the presence of a strong acid.

The strong acid used may be an inorganic acid such as sulfuric acid or hydrochloric acid or an organic acid such as trifluoroacetic acid, trifluoromethanesulfonic acid, benzenesulfonic acid or parachlorobenzenesulfonic acid. Is trifluoromethanesulfonic acid.

The amount of acid used is, in principle, a catalytic amount and does not require one equivalent, but it can vary greatly depending on the reactivity of the carboxylic acid or alcohol used.

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

The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent, but the carboxylic acid represented by the general formula (IV) or the alcohol itself It can also be used in combination. Preferably, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform; esters such as ethyl acetate and propyl acetate; diethyl ether. , Ethers such as tetrahydrofuran, dioxane, dimethoxyethane, amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide, and nitriles such as acetonitrile. .

The reaction temperature is -10 ° C to 100 ° C, preferably 0 ° C to 50 ° C.

The reaction time is usually 5 minutes to 6 hours, preferably 10 minutes to 2 hours, varying mainly depending on the reaction temperature, the kind of the raw material compound or the solvent used.

(Step 2) is a step for producing the compound represented by the general formula (Ia). This is achieved by reacting the compound represented by the general formula (V) obtained in step 1 above with a reducing agent to reduce the carbonyl group at the 5-position to a hydroxyl group.

The reagent used for reducing the 5-position carbonyl group to a hydroxyl group is not particularly limited as long as it can reduce the carbonyl group and does not affect other functional groups of the compound (V). Can be used for As such a reducing agent, a reducing agent using a hydrogen anion such as sodium borohydride or diborane can be used, but sodium borohydride is preferable.

The reaction solvent may be used without particular limitation as long as it does not participate in the reaction, but when sodium borohydride is used as the reducing agent, use of a lower alcohol such as methanol, ethanol or propanol is particularly preferred. Is.

The reaction is usually carried out at 0 ° C to 50 ° C,
The reaction time is 5 minutes to 2 hours. After completion of the reaction in each step, the desired compounds of formulas (Ia) and (V) are isolated from the reaction mixture by a well-known method and, if necessary, purified by a known means such as column chromatography. It

2) Method B This method is a method for producing a compound (Ib) in which A has a group represented by A ² in the general formula (I), and A in the general formula (I) is the above. This can be achieved by treating the compound (Ia1) having a group represented by A ¹¹ with a reducing agent to reduce the nitro group in the compound.

For the reduction of the nitro group in this step, a commonly used method can be used.

One example of such a case is catalytic reduction using a noble metal catalyst. Palladium-carbon, palladium-barium sulfate, platinum oxide, and the like can be given as preferable examples of the catalyst used in the reaction,
Preferred is palladium-carbon. Suitable examples of the solvent used in the reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and esters such as ethyl acetate.

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

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

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

After the completion of the reaction in this step, the desired compound represented by the general formula (Ib) is isolated from the reaction mixture by a well-known method and, if necessary, purified by a well-known means such as column chromatography. It

3) Method C This method is a method for producing a compound (Ib) having the group represented by A ² in the general formula (I), wherein A is the above A
^This is accomplished by treating the compound (Ia2) having the group represented by ¹² with various catalysts or reagents to carry out deacylation.

The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and preferably aromatic hydrocarbons such as benzene, toluene and xylene. Methylene chloride, 1,2
-Halogenated hydrocarbons such as dichloroethane, chloroform; esters such as ethyl acetate, propyl acetate; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide Examples thereof include amides; sulfoxides such as dimethyl sulfoxide, and nitriles such as acetonitrile. As the reagent, for example, in the case of a deformyl group, an organic acid or an inorganic acid such as formic acid or hydrochloric acid is used, in the case of a dehaloacetyl group, thiourea is used, and in the case of a dealkoxycarbonyl group, cadmium is used. A fine metal powder is used.

The reaction temperature is -10 ° C to 100 ° C, preferably 0 ° C to 50 ° C.

The reaction time is usually 5 minutes to 6 hours, preferably 10 minutes to 2 hours, varying mainly depending on the reaction temperature, the starting compound or the type of solvent used.

After the completion of the reaction in this step, the desired compound represented by the general formula (Ib) is isolated from the reaction mixture by a well-known method as in the method B, and if necessary, known by a ram chromatography or the like. It is purified by the means of.

4) Method D This method is a method for producing a compound (Ic) in which A has a group represented by A ³ in the general formula (I).
The amino group of the compound represented by b) has the formula: E-OH
[E is C ₁ -C ₄ alkanoyl group; C ₂ -C ₄ haloalkanoyl group; C ₁ -C ₃ alkylsulfonyl group; C ₂ -
C ₅ alkoxycarbonyl group; C ₃ -C ₅ haloalkoxycarbonyl group; amino C ₂ -C ₇ alkanoyl group (the amino group in the group is the same or different 1 or 2 selected from (Substituent group B)) The alkanoyl group may be substituted with a phenyl group or C _1-.
It may be substituted with a C ₃ alkylthio group. ); A saturated 5- or 6-membered heterocyclic carbonyl group containing one nitrogen atom as a ring atom (the nitrogen atom may be substituted with a substituent selected from (Substituent group B). , Other than a nitrogen atom.)]] Or a reactive derivative thereof.

Examples of the reactive derivative of the acid represented by the formula: E-OH include acid halides (acid chloride, acid bromide, etc.), acid anhydrides, mixed acid anhydrides, active esters, active amides, etc. Those usually used in.

When the acid represented by the formula: E-OH is used, for example, dicyclohexylcarbodiimide (DC
C), 2-chloro-1-methylpyridinium iodide, p
-A dehydrating agent such as toluene sulfonic acid or sulfuric acid is used, preferably 2-chloro-1-methylpyridinium iodide. The amount used is usually 1 to 5 equivalents, and preferably 1 to 2 equivalents, relative to the acid represented by the formula: E-OH.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but hydrocarbons such as hexane, petroleum ether, benzene and toluene are preferable, Chloroform, methylene chloride, halogenated hydrocarbons such as 1,2-dichloroethane, ethers such as ethyl ether, tetrahydroplan, amides such as N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide, and Nitriles such as acetonitrile and mixtures of these solvents, more preferably dichloromethane,
It is 1,2-dichloroethane.

The reaction temperature is usually -70 to 90 ° C, preferably 0 to 60 ° C. The reaction time varies depending mainly on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 15 minutes to 24 hours, and preferably 30 minutes to 6 hours.

When an acid halide of an acid of the formula E-OH is used, the reaction is preferably carried out in the presence of a base,
Suitable bases include, for example, triethylamine,
N, N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0]
Mention may be made of organic bases such as nonene-5 (DBN) or 1,8-diazabicyclo [5.4.0] undecene-7 (DBU).

The acid halide of the acid represented by the formula: E-OH is usually used in 1 to 10 equivalents, and the base is usually used in 2 to 8 equivalents.

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

The reaction is usually carried out at 0 ° C to 50 ° C,
The reaction time is 5 minutes to 2 hours. After the reaction of the process ends,
The target compound of the general formula (Ic) is isolated from the reaction mixture by a well-known method and, if necessary, purified by a known means such as column chromatography.

[0090]

INDUSTRIAL APPLICABILITY The novel 13-substituted milbemycin derivative of the present invention represented by the above general formula (I) has acaricidal, insecticidal or anthelmintic activity, and is caused by various mites, plant pests or animal parasites. It has an excellent control effect against diseases.

That is, the compound of the present invention is a member of the family Tetranychidae and the family Acaridae, which parasitize fruit trees, vegetables and flowers.
(Eriophyidae) adults and eggs of spider mites, such as ticks parasitic on animals (Ixodidae), Arachnidae (Dermanyssidae), and Acarinae (Sarcoptidae), etc. It also has excellent activity against resistant mites, which have become a big problem in recent years because the acaricides have not been effective.

The compounds according to the invention also show a strong insecticidal action. Therefore, they can be used as insecticides. Then, the active compound of the present invention exerts a proper controlling effect against harmful insects without giving any phytotoxicity to cultivated plants. Further, the compound of the present invention can be used for controlling a wide variety of pests, harmful sucking insects, masticatory insects and other plant parasitic pests, storage pests, sanitary pests, etc., and can be applied for eradication and eradication thereof. .

Examples of such pests include the following pests. As insects, pests of the order Coleoptera, for example, Callosobruchus chin
ensis), weevil (Sitophilus zeamais), stag beetle (Tribolium castaneum), rainbow tramp beetle (Epilachna vigitioctomaculata), red squirrel (Agriores fuscicollis), small beetle (Anoma)
la rufocuprea), Colorado potato beetle (Leptinotars)
a decemkineata), Diablotheca (Diabrotica spp.)
, Matsunomadara beetle (Monochamus alternatus),
Rice weevil (Lissorhoptrus oryzophilus), flat beetle (Lyctus bruneus), Lepidoptera, for example, gypsy moth (Lymantria dispar), plum bug (Malacosoma)
neustria), caterpillars (Pieris rapae), Spodoptera litura
(Spodoptera litura), Spodoptera litura (Mamestra brassica)
e), Nikameichu (Chilosuppressalis), Awanomeiga (Pyrausta nubilalis), Ephemeria (Ephestia)
cautella), Red-faced Piscine (Adoxophyes orana), Codling moth (Carpocapsa pomonella), Kaburagaga (Agrotis)
fucosa), Honey honey (Galleria mellonella), Diamondback moth
(Plutella mylostella), mandarin orange moth (phenyl
yllocnistis citrella); Hemiptera, such as leafhopper (Nephotettix cincticeps), brown planthopper (Nil
aparvata lugens), Pseudococcu
scomstocki), the scale bug (Unaspis yanonensi)
s), green peach aphid (Myzus persicae), apple aphid (Aphis pomi), cotton aphid (Aphis gossypi)
i), Rhopalosiphum pseudobra
ssicas), nasi gumbai (Stephanitis nashi), blue bug (Nazara spp.), bed bug (Cimex lectulariu)
s), Whitefly (Trialeurodes vaporariorum)
, White lice (Psylla spp.), Orthoptera, for example, German cockroach (Blatella germanica), American cockroach (P
eriplaneta americana), Kera (Gryllotalpa african
a), grasshoppers (Locusta migratoria migratoriodes); Isoptera, for example, the termite (Deucotermes speratu)
s), house termite (Coptotermes formosamus); Diptera, such as, for example, house dust (Musca domestica), Aedes aegypti (Aedes aegypti), fly (Hylemia platura),
Culex pipiens, Culex pipiens, Anophel
es slnensis), Culex tritaeniorhyn
chus) and the like.

Furthermore, in the field of veterinary medicine, the novel compounds of the present invention are effective for use against various harmful animal parasites (internal and ectoparasites), such as insects and helminths. . Examples of such animal parasites include the following pests.

Examples of insects include horsefly (Gastrop)
hilus spp.), sand flies (Stomoxys spp.), and lice (Tr
ichodectes spp.), reed 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 them is sometimes called an insecticide.

Furthermore, the compounds of the present invention have excellent parasiticidal activity as animal and human anthelmintic agents.

It is particularly effective against the following nematodes which infect domestic animals such as pigs, sheep, goats, cattle, horses, dogs, cats and chickens, poultry and pets. Haemonchus, Trichostrongylus, Ostertergia
Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Esphagostomum
ophagostomum), Chabertia (Chabertia), Trichuris (Storongylu)
s), genus Tricononema (Trichonema), genus Dichtyocaulus, genus Capillaria, genus Heterakis, genus Toxocara, genus Ascaridia, genus Oxyuris
, Ancylostoma, Uncinaria, Toxascaris and Parascaris.

Some of the genera Nematodillus, Cooperia and Esagogostomum attack the intestinal tract, while those of the genus Hemonx and Ostertergia parasitize the stomach and the parasites of the dictiocaurs are It is found in the lungs, but it also shows activity. In addition,
Parasites of the family iidae) and Setariidae are found in and active in other tissues and organs such as heart and blood vessels, subcutaneous and lymphatic tissues.

It is also useful against parasites that infect humans, and the most common parasites in the human digestive tract are the genus Ancylostoma and the genus Necator.
, Ascaris, Strongyroides
(Strongyloides), genus Trichinella, genus Capillaria, genus Trichuris
And the genus Enterobius.

Other medically important parasites found in the blood or other tissues and organs outside the gastrointestinal tract, butterflies of the family Filaria, Wuchereria, Brusia (B
rugia), the genus Onchoceca and the genus Roa
(Loa) and Dracunculidae (Dracunculidae) parasites of the genus Dracunculus (Dracunculus), intestinal parasites are also active in the special intestinal parasitism states of the genus Strongiroides and Trichinella.

When the compound of the present invention is used as an anthelmintic agent in animals and humans, it can be orally administered as a liquid beverage. Beverages are usually solutions, suspensions or dispersions in suitable non-toxic solvents or water with suspending agents such as bentonite and wetting agents or other excipients. Beverages also generally contain an antifoaming agent. Beverage formulations generally contain from about 0.01 to 0.5% by weight of active compound, preferably 0.01 to 0.1% by weight.

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

When administered by animal feed, it is dispersed homogeneously in the feed, used as a top dressing or used in the form of pellets.
Usually, 0.0001-0.02% of the active compound is included in the final feed in order to achieve the desired antiparasitic effect.

Further, the substance dissolved or dispersed in a liquid carrier excipient can be parenterally administered to animals by injection in the forestomach, intramuscularly, intratracheally or subcutaneously. For parenteral administration, the active compounds are preferably mixed with suitable vegetable oils such as peanut oil, cottonseed oil. Such formulations generally contain from 0.05 to 50% by weight of active compound.

It may also be administered topically by admixing it 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 spraying or direct pouring.

The optimum amount of the active compound used for best results depends on the kind of animal to be treated and on the type and degree of parasite infection, but is generally about 0.01 to 100 mg / kg of animal body weight, preferably Is 0.5 to 50.0
Obtained by oral administration of mg. Such doses may be given in single or divided doses over a relatively short period of time, such as 1-5 days.

When the compound of the present invention is used for agriculture or horticulture, it is used in various formulations. For example, powders, coarse powders, water solvents, fine granules, ultrafine granules, wettable powders, emulsions, emulsions, aqueous or oily suspensions, aqueous or oily liquids (suspensions, liquids can be directly sprayed and diluted. .), Capsules in aerosols or polymeric substances. The carrier used may be an organic or inorganic natural or synthetic product and is used to help reach the point of action of the active compound and to facilitate the storage, transport and handling of the active compound. It Also, solid, liquid and gaseous carriers are selected according to well known techniques for carriers.

The above-mentioned preparation is manufactured according to a conventional method. For example, it is produced by mixing the active compound with a carrier, a diluent (solvent etc.) or a surfactant if necessary, and pulverizing if necessary.

Suitable solvents include: aromatic hydrocarbons, especially C _{8 to} C ₁₂ petroleum distillates such as xylene mixtures or substituted naphthalenes; phthalic acids such as dibutyl phthalate or dioctyl. Esters; Aliphatic or alicyclic hydrocarbons such as cyclohexane and paraffins; Alcohols such as ethanol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycols or their ethers; cyclohexanone Ketones such as; N-methyl-2-pyrrolidone,
Polar solvents such as dimethyl sulfoxide, N, N-dimethylformamide; optionally epoxidized coconut oil, vegetable oils such as soybean oil; or water.

Examples of the carrier to be used include, for powders for powder or suspension, natural minerals such as calcite, talc, kaolin, montmorillonite and attapulgite. Highly disperse silicic acid or polymeric adsorbents can also be added to improve the physical properties of the composition. As a suitable granular carrier having absorbency,
Mention may be made of porous materials such as pumice, brick, sepiolite, bentonite or non-porous materials such as calcite and sand. Also, a wide range of organic and inorganic pre-granulates such as dolomite
e), plant residues, etc. are used.

The surfactant is used in order to obtain a preparation having good emulsification, dispersion and wettability, and nonionic, anionic, cationic and zwitterionic surfactants which are used in usual agricultural chemical preparations can be used.

Suitable nonionic activators include polyoxyethylene alkyl ethers, polyoxyethylene alkyl esters, polyoxyethylene alkyl aryl ethers, polyoxyethylene aryl aryl ethers, polyoxyethylene sorbitan alkyl esters,
Sorbitan alkyl ester, fatty acid ester of sugar,
Fatty acid esters of glycerin and pentaerythritol,
Pluronic type surfactants, acetylene alcohol and acetylene diol, and surfactants obtained by adding ethylene oxide to these, silicon-based surfactants,
Alkyl glucoside etc. can be mentioned.

Suitable anionic surfactants include alkylbenzene sulfonates, dialkylsulfosuccinates, salts of alkyl sulfates, salts of alkylmethyl taurides, and the above-mentioned nonionic surfactants with ethylene oxide added to sulfuric acid or phosphorus. Anionic surfactant, which is esterified with an acid and, if necessary, neutralized with a suitable alkali, ligninsulfonic acid salt, (alkyl) naphthalenesulfonic acid and its condensate salt, phenolsulfonic acid and its condensate salt, Various polycarboxylic acid type and polysulfonic acid type polysoaps consisting of salts of condensates of acrylic acid, maleic acid, styrene sulfonic acid, and vinyl groups, and starch to which 1- (2-octenoyl) -sodium succinate is added Or a starch-based surfactant such as dextrin Salts of carboxymethyl cellulose, sodium higher fatty acids, soaps such as potassium salts, and α- olefin sulfonate and the like.

Suitable cationic surfactants include amine salt type, quaternary ammonium salt type, higher aliphatic amine and ethylene oxide adducts of fatty acid amides.

Suitable zwitterionic surfactants include:
Examples thereof include amino acid type or betaine type surfactants, lecithin and the like.

Surfactants in which some or all of the hydrogen atoms of these various surfactants are replaced with fluorine atoms are also
It has a strong effect of lowering the surface tension and can be effectively used.

These surfactants may be used alone or in combination depending on the application.

Further, the composition may contain a stabilizer, an antifoaming agent, a viscosity modifier, a binder, an adhesive or a mixture thereof, and in order to achieve a special effect, a fertilization accelerator,
It may also contain other active substances.

Insecticidal and acaricidal compositions generally comprise the following components, where% is by weight: active compound 0.01.
~ 99%, preferably 0.1-95%; solid or liquid additive 1-99.99%; surfactant 0-25%, preferably 0.1-25%, sold When in the form, it is generally diluted to 0.001-0.0001% by weight (1-10 ppm) before use.

The compounds according to the invention are in their commercially useful formulations and the use forms prepared according to these formulations, other active compounds such as insecticides, baits, fungicides,
It can also be present as a mixture with acaricides, nematicides, fungicides, growth regulators or herbicides. Here, examples of the insecticide include organic phosphorus agents, carbamate agents, carboxylate agents, chlorinated hydrocarbon agents, and insecticidal substances produced by microorganisms.

Furthermore, the compound of the present invention can be present as a mixture with a synergist, and such preparations and forms of use include those which are commercially useful. The synergist is a compound which amplifies the action of the active compound, which need not be active in and of itself.

[0123]

EXAMPLES Next, the present invention will be specifically described with reference to examples.

[0124]

Example 1 (Method A) 13- (α-methoxyiminophenylacetoxy )
Si) Milbemycin A ₄ (isomer A) [Compound No. 10
5] (Step 1) 13- (α-methoxyiminophenylaceto )
Xy) -5-ketomilbemycin A ₄ 15-hydroxy-5-ketomilbemycin A ₄ (10
0 mg, 0.18 mmol) and the less polar isomer of α-methoxyiminophenylacetic acid (64.5 mg,
0.36 mmol) and copper (I) iodide (68 mg) in dichloromethane (5 ml) were added trifluoromethanesulfonic acid (one drop) under an argon stream under ice cooling,
Stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with 5% aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated.

The residue was purified by silica gel column chromatography to obtain 53 mg (41%) of the desired product. Elution was performed with a stepwise gradient of a mixed solution of n-hexane-ethyl acetate (ethyl acetate was added to 10-% in n-hexane).
Up to 50%) was used.

Mass spectrum (m / z): 717
(M ⁺ ), 659,539,520,502 Nuclear magnetic resonance spectrum (200 MHz) δ (CDCl ₃ ) ppm:
7.46-7.54 (m, 2H), 7.31-7.41 (m.3H), 6.55 (s, 1H), 5.78-5.
93 (m.2H), 5.38-5.57 (m, 3H), 5.20 (d, 1H, J = 10.9Hz), 3.99
(s, 3H), 3.86 (S, 1H). (Step 2) 13- (α-methoxyiminophenylacetate
Xy) milbemycin A ₄ (isomer A) 13- (α-methoxyiminophenylacetoxy) -5
-Ketomylbemycin A ₄ (43.2 mg, 0.06 m
mol) in a methanol solution (4 ml) under ice cooling, sodium borohydride (3.0 mg, 0.08 mmol)
Was added and stirred at 0 ° C. for 30 minutes. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated.
The residue was purified by silica gel column chromatography to obtain 38 mg (64%) of the desired product. Elution is n-
Stepwise gradient of hexane-ethyl acetate mixed solution (25-50% ethyl acetate in n-hexane)
Increase).

Mass spectrum (m / z): 719
(M ⁺ ), 591, 540, 412, 394, 279. Nuclear magnetic resonance spectrum (270 MHz) δ (CDC
l ₃ ) ppm: 7.48-7.54 (m, 2H), 7.31-7.42 (m, 3H), 5.78
-5.87 (m, 2H), 5.51 (dd, 1H, J = 8.0,12.0Hz), 5.31-5.47 (m, 3
H), 5.20 (d, 1H, J = 10.9Hz), 3.99 (s, 3H), 3.98 (S, 1H). Example 2 to Example 28 Compounds of Example 2 to Example 28 shown below Was prepared according to the procedure described in Example 1 above. In order to show the production methods thereof more specifically, the yield (%) in each step is described after each compound number. In the yield column, (*) indicates that the product was not isolated in the step and the crude product was left as it was, and the product proceeded to the next step.

[0128]

Example 2 (Method A) 13- (2-methoxyimino-2-phenylene)
Toxyl) milbemycin A ₄ [Compound No. 14: Step 1
(*) → step 2 (48%)] mass spectrum (m / z): 705 (M ⁺ ), 687,
656,554,540,504. Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.60-7.69 (m, 2H), 7.28-7.39 (m, 3H), 5.63
-5.81 (m, 2H), 5.13-5.46 (m, 4H), 4.45 (s, 2H), 3.98 (S, 3H),
3.21-3.30 (m, 2H).

[0129]

Example 3 (Method A) 13- [2-methoxyimino-2- (2-chloro )
Rophenyl) ethoxy] milbemycin A ₄ [Compound No.
No. 15: Step 1 (*) → Step 2 (74%)] Mass spectrum (m / z): 739 (M ⁺ ), 721,
690, 540, 460 Nuclear magnetic resonance spectrum (200 MHz) δ (CDC
l ₃ ) ppm: 7.25-7.40 (m, 4H), 5.57-5.78 (m, 2H), 5.14
-5.42 (m, 4H), 4.37and4.54 (ABq, 2H, J = 15.7Hz), 3.96 (m, 3
H), 3.16 (d, 1H, J = 9.9Hz).

[0130]

Example 4 (Method A) 13- [2-methoxyimino-2- (3-fur
Orophenyl) ethoxy] milbemycin A ₄ [Compound
No. 16: Step 1 (*) → Step 2 (55%)] Mass spectrum (m / z): 723 (M ⁺ ), 674
572, 540, 444, 414. Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.28-7.46 (m, 3H), 6.99-7.07 (m, 1H), 5.67
-5.81 (m, 2H), 5.14-5.46 (m, 4H), 3.98 (s, 3H).

[0131]

Example 5 (Method A) 13- [2-methoxyimino-2- (3-chloro )
Rophenyl) ethoxy] milbemycin A ₄ [Compound No.
No. 17: Step 1 (*) → Step 2 (61%)] Mass spectrum (m / z): 739 (M ⁺ ), 690,
611, 540, 460 Nuclear magnetic resonance spectrum (200 MHz) δ (CDC
l ₃ ) ppm: 7.65 (s, 1H), 7.52-7.58 (m.1H), 7.25-7.36
(m, 2H), 5.65-5.80 (m, 2H), 5.15-5.45 (m, 4H), 4.42 (s, 2H),
3.98 (s, 3H).

[0132]

Example 6 (Method A) 13- (α-methoxyiminophenylacetoxy )
Si) Milbemycin A ₄ (isomer B) [Compound No. 10
6: Step 1 (*) → Step 2 (55%)] Mass spectrum (m / z): 719 (M ⁺ ), 591,
540, 458, 412, 394. Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.30-7.46 (m, 5H), 5.70-5.89 (m.2H), 5.29
-5.48 (m, 4H), 5.10 (d, 1H, J = 10.5Hz), 4.04 (s, 3H).

[0133]

Example 7 (Method A) 13- (α-methoxyiminophenylacetoxy )
Shi) Milbemycin A ₃ [Compound No. 57: Step 1 (7
8%) → Step 2 (75%)] Mass spectrum (m / z): 705 (M ⁺ ), 577,
526, 398, 380 Nuclear magnetic resonance spectrum (200 MHz) δ (CDC
_{l 3) ppm: 7.45-7.55 (m} , 2H), 7.
28-7.40 (m.3H), 5.71-5.91.
(M, 2H), 5.29-5.60 (m, 4H), 5.
19 (d, 1H, J = 10.6 Hz), 3.98 (s,
3H).

[0134]

Example 8 (Method A) 13- (α-methoxyimino-2-chlorophe
Nylacetoxy) milbemycin A ₄ [Compound No. 1
07: Step 1 (*) → Step 2 (20%)] Mass spectrum (m / z): 753 (M ⁺ ), 625
540. Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.55-7.60 (m, 2H), 7.25-7.41 (m, 3H), 5.78
-5.91 (m, 2H), 5.28-5.52 (m, 4H), 5.12 (d, 1H, J = 10.5Hz), 4.
04 (s, 3H).

[0135]

Example 9 (Method A) 13- (α-methoxyimino-3-fluorophenyl)
Phenylacetoxy) milbemycin A ₄ [Compound No. 1
08: Step 1 (*) → Step 2 (60%)] Mass spectrum (m / z): 737 (M ⁺ ), 680,
609, 552, 522 Nuclear magnetic resonance spectrum (200 MHz) δ (CDC
l ₃ ) ppm: 5.77-5.98 (m, 2H), 5.30-5.61 (m.4H), 5.20
(d, 1H, J = 10.6Hz), 4.00 (s, 3H).

[0136]

Example 10 (Method A) 13- (α-methoxyimino-3-chlorophe
Nylacetoxy) milbemycin A ₄ [Compound No. 10
9: Step 1 (*) → Step 2 (55%)] Mass spectrum (m / z): 753 (M ⁺ ), 625
540, 456, 412, 394. Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.25-7.55 (m, 4H), 5.72-5.87 (m, 2H), 5.30
-5.49 (m, 4H), 5.20 (d, 1H, J = 10.4Hz), 4.01 (s, 3H).

[0137]

[Embodiment 11] (A method)13- (α-methoxyimino-4-chlorophene
Nylacetoxy) milbemycin A ₄ (isomer A)
Compound number 110: Step 1 (*) → Step 2 (34.0)
%)] Mass spectrum (m / z): 753 (M⁺), 625,
522, 456, 412 Nuclear magnetic resonance spectrum (270 MHz) δ (CDC
l₃) Ppm: 7.42-7.46 (m, 2H), 7.31-7.36 (m, 2H), 5.82
-5.90 (m, 2H), 5.34-5.54 (m, 4H), 5.19 (d, 1H, J = 10.5Hz), 3.
99 (s, 3H), 3.97 (d, 1H, J = 6.0Hz).

[0138]

[Example 12] (A method)13- (α-methoxyimino-4-chlorophene
Nylacetoxy) milbemycin A ₄ (isomer B)
Compound number 111: Step 1 (55.8%) → Step 2 (7
0.8%)] Mass spectrum (m / z): 753 (M⁺), 625,
522, 444, 412 Nuclear magnetic resonance spectrum (270 MHz) δ (CDC
l₃) Ppm: 7.32-7.40 (m, 4H), 5.77-5.88 (m, 2H), 5.33
-5.47 (m, 4H), 5.10 (d, 1H, J = 10.5Hz), 4.05 (s, 3H), 3.96 (d,
1H, J = 6.5Hz).

[0139]

Example 13 (A method)13- (α-ethoxyimino-4-chlorophene
Nylacetoxy) milbemycin A ₄ (isomer A)
Compound number 112: Step 1 (45%) → Step 2 (44
%)] Mass spectrum (m / z): 767 (M⁺), 639,
554, 522, 412. Nuclear magnetic resonance spectrum (270 MHz) δ (CDC
l₃) Ppm: 7.43-7.48 (m, 2H), 7.30-7.37 (m, 2H), 5.79
-5.90 (m, 2H), 5.34-5.54 (m, 4H), 5.20 (d, 1H, J = 10.5Hz), 4.
24 (q, 2H, J = 5.2Hz), 3.96 (d, 1H, J = 6.4Hz), 1.28 (t, 3H, J = 7.
3Hz).

[0140]

Example 14 (A method)13- (α-ethoxyimino-4-chlorophene
Nylacetoxy) milbemycin A ₄ (isomer B)
Compound number 113: Step 1 (33%) → Step 2 (65
%)] Mass spectrum (m / z): 767 (M⁺), 639,
540, 444, 412 Nuclear magnetic resonance spectrum (270 MHz) δ (CDC
l₃) Ppm: 7.32-7.44 (m, 4H), 5.75-5.88 (m, 2H), 5.30
-5.46 (m, 4H), 5.09 (d, 1H, J = 10.9Hz), 4.31 (q, 2H, J = 7.1H
z), 3.96 (d, 1H, J = 6.5Hz), 1.30 (t, 3H, J = 7.1Hz).

[0141]

Example 15 (Method A) 13- (α-methoxyimino-4-nitrophe)
Nylacetoxy) milbemycin A ₄ [Compound No. 11
4: Step 1 (*) → Step 2 (40%)] 13- (α-methoxyimino-4-nitrophenylacetoxy) -5-ketomylbemycin A ₄ (337 mg,
0.44 mmol) in a methanol solution (40 ml),
Under ice cooling, sodium borohydride (87 mg, 0.44
mmol) was added and the mixture was stirred at 0 ° C. for 30 minutes. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over magnesium sulfate,
Concentrated. The residue was purified by silica gel column chromatography to obtain 332 mg (98%) of the desired product.

Mass spectrum (m / z): 764
(M ⁺ ), 540, 504. Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 8.27 (d, 2H, J = 8.6Hz), 7.56 (d, 2H, J = 8.6H
z), 5.72-5.90 (m, 2H), 5.26-5.51 (m, 4H), 5.11 (d, 1H, J = 10.
7Hz), 4.08 (s, 3H).

[0143]

Example 16 (Method A) 13- (α-methoxyimino-2-hydroxy)
Phenylacetoxy) milbemycin A ₄ [Compound number
122: Step 1 (*) → Step 2 (24%)] Mass spectrum (m / z): 735 (M ⁺ ), 703,
634, 556, 540 Nuclear magnetic resonance spectrum (270 MHz) δ (CDC
l ₃ ) ppm: 9.96 (s, 1H), 7.38-7.48 (m, 1H), 6.91-7.18
(M, 3H), 5.90-6.03 (m, 2H), 5.63-5.71 (m, 1H), 5.40-5.58
(m, 3H), 5.34 (d, 1H, J = 10.0Hz), 4.12 (s, 3H).

[0144]

Example 17 (A method)13- (α-methoxyimino-2-methoxyphosphine
Phenylacetoxy) milbemycin A ₄ (isomer A)
[Compound No. 123: Step 1 (*) → Step 2 (20
%)] Mass spectrum (m / z): 749 (M⁺), 634,
600, 558, 506, 472, 412. Nuclear magnetic resonance spectrum (270 MHz) δ (CDC
l₃) Ppm: 7.82 (dd, 1H, J = 1.7,7.6Hz), 7.46 (dt, 1H, J
= 1.7,7.6Hz), 7.06 (t, 1H, J = 7.6Hz), 6.95 (d, 1H, J = 7.6Hz),
5.85-5.99 (m, 2H), 5.41-5.64 (m, 4H), 5.25 (d, 1H, J = 10.4H
z), 4.08 (s, 3H), 3.76 (s, 3H).

[0145]

Example 18 (A method)13- (α-methoxyimino-2-methoxyphosphine
Phenylacetoxy) milbemycin A ₄ (isomer B)
[Compound No. 124: step 1 (*) → step 2 (15
%)] Mass spectrum (m / z): 749 (M⁺), 621,
522, 412, 394, 355. Nuclear magnetic resonance spectrum (270 MHz) δ (CDC
l₃) Ppm: 7.27-7.42 (m, 1H), 7.08 (d, 1H, J = 8.1Hz),
6.87-7.01 (m, 1H), 6.78 (d, 1H, J = 8.1Hz), 5.74-5.89 (m, 2
H), 5.23-5.45 (m, 4H), 5.09 (d, 1H, J = 10.4Hz), 4.03 (s, 3H),
3.72 (s, 3H).

[0146]

Example 19 (A method)13- (α-methoxyimino-2-ethoxyphenol
Phenylacetoxy) milbemycin A ₄ (isomer A)
[Compound No. 125: step 1 (*) → step 2 (15
%)] Mass spectrum (m / z): 763 (M⁺), 586
540 Nuclear magnetic resonance spectrum (270 MHz) δ (CDC
l₃) Ppm: 7.64 (dd, 1H, J = 1.7,
7.5 Hz), 7.34 (dt, 1H, J = 1.7,
7.5 Hz), 6.96 (t, 1H, J = 7.5H)
z), 6.85 (d, 1H, J = 7.5 Hz), 5.7
1,5.90 (m, 2H), 5.31-5.53 (m,
4H), 5.10 (d, 1H, J = 10.4Hz),
3.99 (s, 3H), 3.90-4.05 (m, 3
H).

[0147]

Example 20 (A method)13- (α-methoxyimino-2-ethoxyphenol
Phenylacetoxy) milbemycin A ₄ (isomer B)
[Compound No. 126: step 1 (*) → step 2 (12
%)] Mass spectrum (m / z): 763 (M⁺), 634,
540, 506, 442, 412. Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l₃) Ppm: 7.25-7.39 (m, 1H), 6.72-7.14 (m, 3H), 5.70
-5.90 (m, 2H), 5.28-5.50 (m, 4H), 5.08 (d, 1H, J = 10.7Hz), 4.
03 (s, 3H), 3.89-4.11 (m, 3H).

[0148]

Example 21 (Method A) 13- (α-methoxyimino-2-benzylo)
Xyphenylacetoxy) milbemycin A ₄ [Compound
No. 131: Step 1 (*) → Step 2 (15%)] Mass spectrum (m / z): 825 (M ⁺ ), 697,
630, 540, 522, 412. Nuclear magnetic resonance spectrum (270 MHz) δ (CDC
l ₃ ) ppm: 7.67-7.71 (m, 1H), 7.23-7.35 (m, 6H), 6.75
-6.94 (m, 2H), 5.72-5.88 (m, 2H), 5.29-5.42 (m, 4H), 5.22
(d, 1H, J = 10.3Hz), 5.01-5.09 (m, 2H), 4.00 (s, 3H).

[0149]

Example 22 (A method)13- [α-methoxyimino- (2-pyridy
Le) acetoxy] milbemycin A ₄ [Compound No. 14
5: Step 1 (15%) → Step 2 (78%)] Mass spectrum (m / z): 720 (M⁺), 702,
540, 522, 412 Nuclear magnetic resonance spectrum (270 MHz) δ (CDC
l₃) Ppm: 8.66-8.68 (d, 1H, J =
4.8 Hz), 7.73-7.79 (m, 1H), 7.
59-7.62 (d, 1H, J = 8.1 Hz), 7.2
8-7.33 (m, 1H), 5.74-5.85 (m,
2H), 5.20-5.44 (m, 4H), 5.11.
(D, 1H, J = 10.5 Hz), 4.06 (s, 1
H), 3.96 (d, 1H, J = 6.0 Hz).

[0150]

Example 23 (Method A) 13- (3-Methoxyimino-3-phenylphenol)
Ropionyloxy) milbemycin A ₄ [Compound No.
293: Step 1 (61%) → Step 2 (74%)] Mass spectrum (m / z): 733 (M ⁺ ), 702
605, 586, 572, 554, 540, 522. Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.68-7.77 (m, 2H), 7.41-7.50 (m, 3H), 5.84
-5.91 (m, 2H), 5.39-5.51 (m, 4H), 5.03 (d, 1H, J = 10.5Hz), 4.
07 (s, 3H), 3.83 (br.s, 2H).

[0151]

Example 24 (Method A) 13- (α-hydroxyiminophenylacetate
Xy) milbemycin A ₄ [Compound No. 103: Step 1
(61%) → step 2 (41%)] mass spectrum (m / z): 705 (M ⁺ ), 577,
540, 522, 504, 412, 394, 279. Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 9.45 (br.s, 1H), 5.71-5.90 (m, 2H), 5.21-
5.51 (m, 4H), 5.12 (d, 1H, J = 10.5Hz), 4.68 (br.s, 2H), 4.30
(t, 1H, J = 7.4Hz), 4.10 (s, 1H), 3.97 (d, 1H, J = 6.2Hz).

[0152]

Example 25 (Method A) 13- (α-methoxyimino-2-cenylia)
Cetoxy) milbemycin A ₄ [Compound No. 135: step 1 (*) → step 2 (93%)] mass spectrum: 725 (M ⁺ ), 597, 554, 522 nuclear magnetic resonance spectrum (200 MHz), δ (CDCl ₃ ). ppm; 7.32
~ 7.38 (m, 1H), 6.95 ~ 7.04 (m, 4H), 5.74 ~ 5.92 (m, 2H),
5.27 ~ 5.58 (m, 4H), 5.18 (d, 1H, J = 10.5Hz) 4.69 (br.s, 2
H), 4.30 (m, 1H), 4.09 (s, 1H), 3.96 (br.s, 4H).

[0153]

Example 26 (Method A) 13- [α-methoxyimino- (2-chloroa
Cetylaminothiazol-4-yl) acetoxy] mil
Bemycin A ₄ [Compound No. 142: step 1 (*) → step 2 (60%)] mass spectrum (FAB-MS); 967 (M ⁺ + 150, C ₄₀ H ₅₂ ClN _3).
O ₁₁ S + triethanolamine + H) Nuclear magnetic resonance spectrum (200MHz), δ (CDCl ₃ ) ppm; 9.85 (b
rs, 1H), 7.07 (s, 1H), 5.76 ~ 5.93 (m, 2H), 5.28 ~ 5.69
(m, 4H), 5.18 (d, 1H, J = 10.4Hz) 4.69 (br.s, 2H), 4.29 (br.
s, 3H), 4.09 (s, 1H), 4.03 (s, 2H), 3.97 (d, 1H, J = 6.2Hz).

[0154]

Example 27 (Method A) 13- (α-methoxyimino-3-furanylua
Cetoxy) milbemycin A ₄ [Compound No. 133: Step 1 (*) → Step 2 (64%)] Nuclear magnetic resonance spectrum (200 MHz), δ (CDCl ₃ ) ppm; 7.50
(d, 1H, J = 1.8Hz), 6.45 ~ 6.53 (m, 2H), 5.78 ~ 5.92 (m, 2
H), 5.29 ~ 5.54 (m, 4H), 5.16 (d, 1H, J = 10.6Hz), 4.69 (br.
s, 2H), 4.30 (m, 1H), 4.08 (s, 1H), 3.99 (br.s, 4H).

[0155]

Example 28 13- [α-methoxyimino- (2- (2,2,2-to
Lichloroethoxycarbonylamino) thiazole-4-
Il) acetoxy] milbemycin A ₄ [Compound No. 2
07: Step A (*) → Step B (65%)] Mass spectrum (FAB-MS); 1065 ( M + + 150, C 41 H 52 Cl
₃ N ₃ O ₁₂ S + triethanolamine + H) Nuclear magnetic resonance spectrum (200MHz), δ (CDCl ₃ ) ppm; 7.07
(s, 1H), 5.77 ~ 5.92 (m, 2H), 5.28 ~ 5.49 (m, 4H), 5.17
(d, 1H, J = 10.5Hz), 4.88 (s, 2H), 4.69 (br.s, 2H), 4.31 (m, 1
H), 4.00 (br.s, 4H).

[0156]

Example 29 (Method B) 13- (α-methoxyimino-4-aminophen)
Nylacetoxy) milbemycin A ₄ [Compound No. 11
5] 13- (α-methoxyimino-4 obtained in Example 15)
-Nitrophenylacetoxy) milbemycin A ₄ (1.
98g, 2.59mmol) in acetic acid solution (20ml) at room temperature with zinc dust (1.1g).
9 g) was added and the mixture was stirred for 2 hours. After completion of the reaction, ethyl acetate was added to the reaction solution and the insoluble material was filtered off. Add water to the filtrate,
It was extracted with ethyl acetate, the extract was washed with 4% aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography,
789 mg (41%) of the desired product was obtained. Nuclear magnetic resonance spectrum (200MHz), δ (CDCl ₃ ) ppm; 7.30
(d, 2H, J = 7.1Hz), 6.61 (d, 2H, J = 7.1Hz), 5.78-5.88 (m, 2
H), 5.28 ~ 5.54 (m, 4H), 5.17 (d, 1H, J = 10.6Hz), 4.66 and
4.70 (ABq, 2H, J = 15.5Hz), 4.30 (t, 1H, J = 7.0Hz), 3.93 (s, 3
H).

[0157]

Example 30 (Method C) 13- [α-methoxyimino)-(2-amino
Thiazol-4-yl) acetoxy] milbemycin A
₄ [Compound No. 140] 13- [α-methoxyimino-obtained in Example 28
(2- (2,2,2-Trichloroethoxycarbonylamino) thiazolin-4-yl) acetoxy] milbemycin A ₄ (92 mg, 0.1 mmol) in dimethylformamide (1 ml)
-Cadmium powder (340 mg) was added to an acetic acid (1 ml) solution at room temperature, and the mixture was stirred for 2 hours. After completion of the reaction, ethyl acetate was added to the reaction solution and the insoluble material was filtered off. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was washed with 4% aqueous sodium hydrogen carbonate and saturated brine,
It was dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to give 33.2.
Obtained mg (45%) of the desired product.

Mass spectrum (FAB-MS): 891 (M ⁺⁺ 15)
0, C ₃₈ H ₅₁ N ₃ O ₁₀ S + triethanolamine + H) Nuclear magnetic resonance spectrum (200MHz), δ (CDCl ₃ ) ppm; 6.56
(s, 1H), 5.73 ~ 5.90 (m, 2H), 5.29 ~ 5.55 (m, 4H), 5.20
(s, 2H), 5.15 (d, 1H, J = 10.6Hz), 4.69 (br.s, 2H), 4.29 (m, 1
H), 4.09 (s, 1H), 3.99 (br.s, 4H).

[0159]

Example 31 (D method)13- [α-methoxyimino- (4-methoxy
Carbonylaminoacetylaminophenyl) acetoxy
Shi] Milbemycin A ₄ [Compound No. 170] Of N-methoxycarbonylglycine (0.815g, 6.12mmol)
Add 13- (α-methoxyimidin) to a methylene chloride solution (10 ml).
No-4-aminophenylacetoxy) milbemycin A
_Four (1.50g, 2.04mmol), triethylamine (0.597ml, 4.28m
mol) and 2-chloro-2-methylpyridinium iodide (1.0
(95 g, 4.28 mmol) in that order and then stirred at room temperature for 1.5 hours.
I stirred. After the reaction is completed, the reaction solution is poured into water and washed with ethyl acetate.
Extracted. The extract was dried (MgSO 4_Four), Concentrate and remove the residue.
Purified by silica gel column chromatography, 268mg
(92%) of the desired product was obtained. Elution is with n-hexane-acetic acid
Stepwise gradient of ethyl mixed solution (ethyl acetate
Increase in 10-50% in n-hexane)
used.

Mass spectrum (FAB-MS): 999 (M ⁺ +150,
C ₄₅ H ₅₉ N ₃ O ₁₃ + triethanolamine + H) Nuclear magnetic resonance spectrum (200MHz), δ (CDCl ₃ ) ppm; 8.13〜
8.25 (br.s, 1H), 7.55 (d, 2H, J = 8.7Hz), 7.47 (d, 2H, J = 8.7H
z), 5.75 to 5.92 (m, 2H), 5.27 to 5.69 (m, 4H), 5.19 (d, 1H, J
= 10.4Hz), 4.69 (br.s, 2H), 4.50 (m, 1H), 4.11 (s, 1H), 3.97
(br.s, 3H), 3.76 (s, 3H).

Examples 32 to 41 The compounds of Examples 2 to 41 shown below were prepared according to the procedure described in Example 31 above. In order to show the production methods thereof more specifically, the yield (%) in the step after each compound number is described.

[0162]

Example 32 (Method D) 13- (α-methoxyimino-4-acetylacea)
Minophenylacetoxy) milbemycin A ₄ [Compound No. 116: (70%)] Mass spectrum (m / z); 776 (M ⁺ ), 758, 522 Nuclear magnetic resonance spectrum (200 MHz), δ (CDCl ₃ ) ppm; 7.42 ~
7.59 (m, 4H), 7.29 (s, 1H),

[0163]

Example 33 (Method D) 13- [2-methoxyimino-2- (4-acetate
Cylaminoacetylaminophenyl) ethoxy] milbe
Mycin A ₄ [Compound No. 27: (65%)] mass spectrum (FAB-MS); 912 (M ⁺ + 150, C ₄₃ H ₅₈ N ₂ O
₁₀ + triethanolamine + H) Nuclear magnetic resonance spectrum (200MHz), δ (CDCl ₃ ) ppm; 7.62
(d, 2H, J = 8.8Hz), 7.50 (d, 2H, J = 8.8Hz), 5.64 ~ 5.80 (m, 2
H), 5.18 ~ 5.43 (m, 4H), 4.66 (br.s, 2H), 4.42 (br.s, 2H),
4.28 (m, 1H), 3.99 (s, 1H), 3.96 (br.s4H).

[0164]

Example 34 (Method D) 13- [2-Methoxyimino-2- (4-meta)
Sulfonylaminophenyl) ethoxy] milbemishi
A ₄ [Compound No. 32: (70%)] mass spectrum (FAB-MS); 948 (M ⁺ + 150, C ₄₂ H ₅₈ N ₂ O
₁₁ S + triethanolamine + H) Nuclear magnetic resonance spectrum (200MHz), δ (CDCl ₃ ) ppm; 7.65
(d, 2H, J = 8.7Hz), 7.21 (d, 2H, J = 8.7Hz) .6.83 (s, 1H), 5.64
~ 5.82 (m, 2H), 5.17 ~ 5.43 (m, 4H), 4.66 (br.s, 2H), 4.43
(br.s, 2H), 4.30 (br.s, 1H), 3.97 (s, 3H), 3.92 (d, 1H, J = 3.8
Hz)

[0165]

Example 35 (Method D) 13- [α-methoxyimino- (4-methane)
Rufonylaminophenyl) acetoxy] milbemycin
A ₄ [Compound No. 149: (75%)] Mass spectrum (m / z); 812 (M ⁺ ), 522 Nuclear magnetic resonance spectrum (200 MHz), δ (CDCl ₃ ) ppm; 7.51
(d, 2H, J = 8.6Hz), 7.12 (d, 2H, J = 8.6Hz) .6.67 (s, 1H), 5.77
~ 5.94 (m, 2H), 5.28 ~ 5.59 (m, 4H), 5.20 (d.1H, J = 10.7H
z), 4.69 (br.s, 2H), 4.30 (d, 1H, J = 6.2Hz), 3.98 (br.s, 4H)

[0166]

Example 36 (Method D) 13- [α-methoxyimino- (4-acetyl)
Aminoacetylaminophenyl) acetoxy] milbema
Isin A ₄ [Compound No. 163: (45%)] mass spectrum (FAB-MS); 983 (M ⁺ + 150, C ₄₅ H ₅₉ N ₃ O
₁₂ + triethanolamine + H) Nuclear magnetic resonance spectrum (200MHz), δ (CDCl ₃ ) ppm; 8.77
(s, 1H), 7.56 (d, 2H, J = 8.8Hz), 7.47 (d, 2H, J = 8.8Hz), 6.43
(t, 1H, J = 5.1Hz), 5.76 ~ 5.92 (m, 2H), 5.28 ~ 5.59 (m, 4H),
5.19 (d, 1H, J = 10.7Hz), 4.69 (br.s, 2H), 4.30 (m, 1H), 4.12
(br.s, 3H), 3.98 (br.s, 4H).

[0167]

Example 37 (D method)13- [α-methoxyimino- (4-methoxy
Carbonylaminoacetylaminophenyl) acetoxy
Shi] Milbemycin A ₃ [Compound No. 97: (85
%)] Nuclear magnetic resonance spectrum (200MHz), δ (CDCl₃) ppm ； 8.14 (b
r.s, 1H), 7.55 (d, 2H, J = 8.8Hz), 7.47 (d, 2H, J = 8.8Hz), 5.72
~ 5.91 (m, 2H), 5.27 ~ 5.59 (m, 4H), 5.20 (d, 1H, J = 10.4H
z), 4.69 (br.s, 2H), 4.30 (m, 1H), 3.85-4.12 (m, 4H), 3.97
(s, 3H).

[0168]

Example 38 (Method D) 13- [α-methoxyimino- (2-methoxy
Carbonylaminothiazol-4-yl) acetoxy]
Milbemycin A ₄ [Compound No. 205: (50%)] mass spectrum (FAB-MS); 949 (M ⁺ + 150, C ₄₀ H ₅₃ N ₃ O
₁₂ S + triethanolamine + H) Nuclear magnetic resonance spectrum (200 MHz), δ (CDCl ₃ ) ppm; 8.39 (b
rs, 1H), 6.96 (s, 1H), 5.76 to 5.91 (m, 2H), 5.27 to 5.58
(m, 4H), 5.17 (d, 1H, J = 10.4Hz), 4.69 (br.s, 2H), 4.30 (m, 1
H), 4.09 (s, 1H), 4.00 (br.s, 4H).

[0169]

Example 39 (Method D) 13- [α-methoxyimino- (2-ethoxy)
Carbonylaminothiazol-4-yl) acetoxy]
Milbemycin A ₄ [Compound No. 206: (55%)] Mass spectrum (FAB-MS); 963 ( M + + 150, C 41 H 55 N 3 O
₁₂ S + triethanolamine + H) Nuclear magnetic resonance spectrum (200MHz), δ (CDCl ₃ ) ppm; 8.24 (b
rs, 1H), 6.98 (s, 1H), 5.76 ~ 5.91 (m, 2H), 5.28 ~ 5.57
(m, 4H), 5.17 (d, 1H, J = 10.4Hz), 4.69 (br.s, 2H), 4.32 (q, 3
H, J = 7.0Hz), 4.09 (s, 1H), 4.00 (s, 3H), 3.97 (d, 1H, J = 6.7H
z).

[0170]

Example 40 (Method D) 13- [α-methoxyimino- (2-isopro
Poxycarbonylaminothiazol-A-yl) aceto
[ Xy] milbemycin A ₄ [Compound No. 211: (60
%)] Mass spectrum (FAB-MS); 977 (M ⁺ + 150, C ₄₂ H ₅₇ N ₃ O
₁₂ S + triethanolamine + H) Nuclear magnetic resonance spectrum (200MHz), δ (CDCl ₃ ) ppm; 8.31 (b
r.1H), 6.98 (s, 1H), 5.76 ~ 5.92 (m, 2H), 5.28 ~ 5.58 (m, 4
H), 5.17 (d, 1H, J = 10.4Hz), 5.08 (mJ = 6.3Hz), 4.69 (br.s, 2
H), 4.31 (t, 1H, J = 6.2Hz), 4.10 (s, 1H), 4.00 (s, 3H), 3.98
(d, 1H, J = 6Hz).

[0171]

Example 41 (D method)13- [α-methoxyimino- (2-methoxy
Carbonylaminoacetylaminothiazole-A-I
Le) acetoxy] milbemycin A ₄ [Compound No. 20
9: (45%)] Mass spectrum (FAB-MS); 1006 (M⁺+ 150, C₄₂H₅₆N_Four
O₁₃S + triethanolamine + H) Nuclear magnetic resonance spectrum (200MHz), δ (CDCl₃) ppm ； 9.8 (b
r.s, 1H), 7.03 (s, 1H), 5.76 ~ 5.91 (m, 2H), 5.27 ~ 5.66 (m,
4H), 5.17 (d, 1H, J = 10.6Hz), 4.69 (br.s, 2H), 4.30 (m, 1H),
4.12 (s, 1H), 4.09 (s, 2H), 4.00 (br.s, 4H), 3.77 (s, 3H).

[0172]

Reference Example 1 α-Methoxyiminophenylacetic acid (a) α-Methoxyiminophenylacetic acid ethyl ester Phenylglyoxylic acid ethyl ester (0.50 g,
To a DMF solution of 2.8 mmol), O-methylhydroxylamine hydrochloride (1.4 g, 16.8 mmol) and potassium carbonate (1.16 g, 8.4 mmol) were added, and the temperature was 90 ° C.
It was stirred for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain 0.47 g (67%) of one isomer of the less polar target compound.
%), 0.13 g of the other, more polar isomer
(19%) was obtained.

[0173]

[Small polar isomer]

Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.55-7.64 (m, 2H), 7.32-7.46 (m, 3H), 4.43
(q, 2H, J = 7.2Hz), 4.02 (s, 3H), 1.38 (t, 3H, J = 7.2Hz).

[0174]

[Highly polar isomer]

Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.42 (s, 5H), 4.37 (q, 2H, J = 7.1Hz), 4.06
(s, 3H), 1.36 (t, 3H, J = 7.1Hz). (b) α-methoxyiminophenylacetic acid ethyl α-methoxyiminophenylacetic acid ethyl ester (small polar isomer) (0 isomer) obtained by the above method. .47 g, 2.
Water and sodium hydroxide (0.90 g, 22.6 mmol) were added to a methanol solution of 3 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was poured into 1N hydrochloric acid water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The obtained residue was a crude product of the desired product, and was used in the next reaction shown in Examples without further purification.

Nuclear magnetic resonance spectrum (200 MHz) δ
(CDCl ₃ ) ppm: 10.3 (br.s, 1H), 7.60-7.72 (m, 2
H), 7.32-7.45 (m, 3H), 4.03 (s, 3H).

[0176]

Reference Example 2 α-Methoxyimino-2-chlorophenyl
Acetic acid (a) 1- (2-chlorophenyl) -1,2-ethanedi
All-2-O-tert-butyldimethylsilylate
In a DMF solution of terl- (2-chlorophenyl) -1,2-ethanediol (3.45 g, 20 mol) under ice cooling,
Imidazole (1.63 g, 20.0 mmol) and te
rt-butyldimethylsilyl chloride (1.63 g,
24 mmol) was sequentially added and the mixture was stirred at room temperature for 20 minutes.
After completion of the reaction, the reaction solution was poured into water and extracted with 50 cc of ethyl acetate three times. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound (3.5).
8 g (63%) was obtained.

Nuclear magnetic resonance spectrum (200 MHz) δ
(CDCl ₃ ) ppm: 7.58-7.66 (m, 1H), 7.16-7.35 (m,
3H), 5.16 (dt, 1H, Jd = 8.0Hz, Jt = 3.0Hz), 3.94 (dd, 1H, J = 10.
2,3.0Hz), 3.46 (dd, 1H, J = 8.0,3.0Hz), 3.06 (d, 1H, J = 3.0
Hz), 0.91 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H). (B) 2'-chloro-2-tert-butyldimethylsilyl
Oxyacetophenone 1- (2-chlorophenyl) -1,2-ethanediol-2-O-tert-butyldimethylsilyl ether (3.
5 g, 12.3 mol) and manganese dioxide (70.0 g) in a methylene chloride solution were added, and the mixture was stirred at room temperature for 4 hours.
After completion of the reaction, the reaction solution was filtered through Celite, the filtrate was concentrated, and 3.05 g (87%) of a crude product of 2'-chloro-2-tert-butyldimethylsilyloxyacetophenone was obtained.
Obtained.

Nuclear magnetic resonance spectrum (200 MHz) δ
(CDCl ₃ ) ppm: 7.25-7.48 (m, 4H), 4.75 (1s, 2H),
0.87 (s, 9H), 0.1 (s, 6H). (C) 2'-chloro-2-hydroxyacetophenone
O-methyl oxime 2′-chloro-2-ter-butyldimethylsilyloxyacetophenone (3.05 g) obtained above in methanol,
O-Methylhydroxylamine hydrochloride (1.78 g) was added to a mixed solution of water and 1,4-dioxane, and the mixture was stirred at room temperature for 1 hour.
Stir for 4 hours. After the reaction is completed, the reaction solution is poured into water, and 50
cc. It was extracted 3 times with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography,
691 m of one isomer of the less polar target compound
g (32.4%), 370 mg (17.3%) of the other, more polar isomer was obtained.

[0179]

[Small polar isomer]

Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.29-7.46 (m, 4H), 4.69 (d, 2H, J = 7.2Hz),
4.02 (s, 3H).

[0180]

[Highly polar isomer]

Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.41-7.47 (m, 1H), 7.29-7.38 (m, 1H), 7.14
-7.20 (m, 1H), 4.45 (d, 2H, J = 5.5Hz), 3.89 (s, 3H). (D) α-methoxyimino-2-chlorophenylacetic acid 2′-chloro-2-obtained above Hydroxyacetophenone-O-methyloxime (small polar isomer, 0.4
0 g) in acetone solution, Jones reagent (10 ml)
Was added and the mixture was stirred at room temperature for 1 hour. Isopropanol (10 ml) was added under ice cooling and then poured into 100 ml of water, 1
Extract 3 times with 0 cc of ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated to give 320 mg (75%) of the desired composition.

Nuclear magnetic resonance spectrum (200 MHz) δ
(CDCl ₃ ) ppm: 7.28-7.50 (m, 4H), 5.25 (br.s, 1
H), 4.14 (s, 3H).

[0182]

[Reference Example 3] 2-hydroxyacetophenone O-al
A 2-hydroxyacetophenone O-alkyl oxime having a substituent on the phenyl group as shown below according to the method for producing 2′-chloro-2-hydroxyacetophenone O-methyl oxime described in the Kiroxime derivative [Reference Example 2]. The derivative was prepared. (1) 2-hydroxyacetophenone O-methyloxy
Arm nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.60-7.69 (m, 2H), 7.34-7.43 (m, 3H), 4.69
(d, 2H, J = 7.0Hz), 4.04 (s, 3H), 2.73 (t, 1H, J = 7.0Hz). (2) 3'-Fluoro-2-hydroxyacetophenone
O-methyl oxime Nuclear magnetic resonance spectrum (200 MHz) δ (CDC
l ₃ ) ppm: 7.30-7.45 (m, 3H), 7.01-7.12 (m, 1H), 4.68
(d, 2H, J = 6.9Hz), 4.04 (s, 3H), 2.65 (t, 1H, J = 6.9Hz). (3) 3'-chloro-2-hydroxyacetophenone O
-Methyloxime Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.67 (m, 1H), 7.49-7.56 (m, 1H), 7.31-7.40
(m, 2H), 4.66 (d, 1H, J = 6.9Hz), 4.05 (s, 3H), 2.60 (t, 1H, J =
6.9 Hz).

[0183]

Reference Example 4 α-Methoxyimino-2-chlorophenyl
According to the method for producing α-methoxyimino-2-chlorophenylacetic acid described in the acetic acid derivative [Reference Example 2], as shown below,
An α-methoxyiminophenylacetic acid derivative having a substituent on the phenyl group was produced.

(1) α-Methoxyimino-3-fluorofuran
N-acetic acid Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 9.40 (br.s, 1H), 7.76-7.97 (m, 1H), 7.15-
7.58 (m, 3H), 4.07 (s, 3H), 3.89 (s, 3H). (2) α-Methoxyimino-3-chlorophenylacetic acid Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.94-8.10 (m, 1H), 7.25-7.70 (m, 3H), 4.09
(s, 3H). (3) α-Methoxyimino-4-chlorophenylacetic acid (small polar isomer) Nuclear magnetic resonance spectrum (200 MHz) δ (CDC
l ₃ ) ppm: 7.59 (d, 2H, J = 8.71Hz), 7.38 (d, 2H, J = 8.71)
Hz), 4.10 (s, 3H). (Isomer with large polarity) Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.50 (d, 2H, J = 8.91Hz), 7.42 (d, 2H, J = 8.91)
Hz), 4.12 (s, 3H). (4) α-Ethoxyimino-4-chlorophenylacetic acid (isomer with a small polarity) Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.69 (d, 2H, J = 9.0H
z), 7.39 (d, 2H, J = 9.0 Hz), 4.3
6 (q, 2H, J = 7.6 Hz), 1.38 (t, 3
H, J = 7.6 Hz). (Isomer with large polarity) Nuclear magnetic resonance spectrum (200 MHz) δ (CDCl
₃ ) ppm: 7.54 (d, 2H, J = 6.6Hz), 7.47 (d, 2H, J = 6.6H
z), 4.37 (q, 2H, J = 7.0Hz), 1.37 (t, 3H, J = 7.0Hz). (5) α-methoxyimino-2-methoxyphenylacetic acid Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.65 (dd, 1H, J = 1.6,7.7Hz), 7.41 (tt, 1H, J
= 1.6,8.0Hz), 6.80-7.05 (m, 2H), 4.07 (s, 3H), 3.82 (s, 3H). (6) α-methoxyimino-2-ethoxyphenylacetic acid (small polar isomer) Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.62 (dd, 1H, J = 1.7,7.7Hz), 7.39 (dt, 1H, J
= 1.0,7.0Hz), 6.85-8.01 (m, 2H), 4.08 (s, 3H), 4.0-4.13 (m,
2H), 1.40 (t, 3H, J = 7.0Hz). (Highly polar isomer) Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 7.25-7.40 (m2H), 6.88-7.05 (m, 2H), 4.08
(s, 3H), 4.0-4.13 (m, 2H), 1.33 (t, 3H, J = 7.0Hz). (7) α -Methoxyimino -2-benzyloxyphenyl
Acetic acid Nuclear magnetic resonance spectrum (200MHz) δ (CDC
l ₃ ) ppm: 8.70 (br.s, 1H), 7.25-7.42 (m, 7H), 7.06
(d, 2H, J = 8.3Hz), 6.99 (d, 2H, J = 8.3, Hz), 5.08 (s, 2H), 4.04
(s, 3H).

[0185]

[Reference Example 5] 3-methoxyimino-3-phenylpropyi
On-acid According to the method for producing α-methoxyiminophenylacetic acid described in [Reference Example 1], the title derivative was produced using ethylbenzoyl acetate as a starting material.

Nuclear magnetic resonance spectrum (200 MHz) δ
(CDCl ₃ ) ppm: 7.60-7.71 (m, 2H), 7.34-7.45 (m,
3H), 4.03 (s, 3H), 3.81 (s, 2H).

[0187]

Reference Example 6 α-Methoxyimino-2-hydroxyphene
According to the method for producing α-methoxyiminophenylacetic acid described in nilacetic acid [Reference Example 1], 2-hydroxyphenylglyoxylic acid ethyl ester was used as a starting material to produce the title derivative.

Nuclear magnetic resonance spectrum (200 MHz) δ
(CDCl ₃ ) ppm: 7.17-7.38 (m, 2H), 6.81-7.08 (m,
2H), 4.08 (s, 3H).

[0189]

Reference Example 7 α-Methoxyimino-2-pyridylacetic acid According to the method for producing α-methoxyiminophenylacetic acid described in [Reference Example 1], the title derivative was produced using commercially available 2-pyridylglyoxylic acid ethyl ester as a starting material. .

Nuclear magnetic resonance spectrum (200 MHz) δ
(CDCl ₃ ) ppm: 8.50 (d, 1H, J = 4.9Hz), 7.75 (dt, 1
H, Jd = 1.6Hz, Jt = 7.7Hz), 7.61 (dt, 1H, Jd = 7.7Hz, Jt = 1.6H
z), 7.28 (t, 1H, Jd = 7.7Hz), 4.38 (br.s, 1H), 3.97 (s, 3H).

[0191]

Reference Example 8 α-Methoxyimino-4-nitrophenyl
Acetic acid (a) α-methoxyimino-4-nitrophenylacetic acid
Methyl (3 ml) -dioxane (3 ml) -water (2 ml) of 4-nitrophenylglyoxylic acid ethyl ester (1.18 g, 5.7 mmol) prepared by the method described in chill ester synthesis (p. 850, 1990). O-methylhydroxylamine hydrochloride (0.9
5 g, 11.4 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue is purified by silica gel column chromatography to give 0.40 g of the desired compound.
(30%) obtained.

Nuclear magnetic resonance spectrum (200 MHz) δ
(CDCl ₃ ) ppm: 8.28 (d, 2H, J = 9.
0 Hz), 7.58 (d, 2H, J = 9.0 Hz),
4.38 (q, 2H, J = 7.1 Hz), 4.09
(S, 3H), 1.37 (t, 3H, J = 7.1H
z). (B) α- Methoxyimino-4-nitrophenylacetic acid α-methoxyimino-4-nitrophenylacetic acid ethyl ester (1.28 g, 5.07 mmo) obtained by the above method
1) in methanol solution, 2N-sodium hydroxide (5
(ml, 10 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into 1N hydrochloric acid water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The resulting residue is a crude product of 1.0 g (88%) of the desired product,
Used without further purification in the next reaction shown in the examples.

Nuclear magnetic resonance spectrum (200 MHz) δ
(CDCl ₃ ) ppm: 8.13 (d, 2H, J = 9.0Hz), 7.48 (d,
2H, J = 9.0Hz), 3.95 (s, 3H).

[0194]

[Reference Example 9] 4'-nitro-2-hydroxyacetophe
Non-O-methyloxime (a) 4-nitrophenylglyoxylic acid 4-nitrophenylglyoxylic acid ethyl ester (6
51 mg, 2.92 mmol) in methanol solution, 2
N sodium hydroxide (3 ml, 6 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into a 2N aqueous hydrochloric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated to give 0.8 g (quantitative) of a crude product of 4-nitrophenylglyoxylic acid.

(B) 1- ( 4-nitrophenyl) -1,
2-Ethanediol In a tetrahydrofuran (THF) solution of the crude product of 4-nitrophenylglyoxylic acid obtained above (0.5 g), a diborane / tetrahydrofuran complex (7 ml, 1M-THF solution) was added at 0 ° C. under a nitrogen stream. ) Was added and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated to give 1- (4-nitrophenyl) -1,2.
0.56 g (quantitative) of crude product of ethanediol was obtained.

(C) 1- (4-nitrophenyl) -1,
2-ethanediol-2-O-tert-butyl dimethyl
Rusilyl ether 1- (4-nitrophenyl) -1,2-ethanediol (0.56 g) in a dimethylformamide (DMF) solution, under ice cooling, with imidazole (0.23 g) and tert-.
Butyldimethylsilyl chloride (0.50 g) was sequentially added, and the mixture was stirred at room temperature for 20 minutes. After completion of the reaction, the reaction solution was poured into water and extracted with 50 cc of ethyl acetate three times. The extract was washed with saturated saline and dried over magnesium sulfate,
Concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.58 g, 63%).

Nuclear magnetic resonance spectrum (200 MHz) δ
(CDCl ₃ ) ppm: 8.22 (d, 2H, J = 8.7Hz), 4.84 (m, 1
H), 3.82 (dd, 1H, J = 3.9,10,1Hz)), 3.54 (dd, 1H, J = 7.9,10,1
Hz)), 3.06 (d, 1H, J = 2.9Hz), 0.91 (s, 9H), 0.07 (s, 6H), 0.05
(s, 6H). (d) 4'-nitrophenyl-2-tert-butyl dimethyl
Rusilyloxyacetophenone 1- (4-nitrophenyl) -1,2-ethanediol-2-O-tert-butyldimethylsilyl ether (0.
Manganese dioxide (3.5 g) was added to a methylene chloride solution (41 g, 1.36 mol), and the mixture was stirred at room temperature for 4 hours.
After completion of the reaction, the reaction solution was filtered through Celite, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 0.16 g (40% of 4'-nitro-2-tert-butyldimethylsilyloxyacetophenone).
%)Obtained.

Nuclear magnetic resonance spectrum (200 MHz) δ
(CDCl ₃ ) ppm: 8.32 (d, 2H, J = 9.0Hz), 8.11 (d, 2
H, J = 9.0Hz), 4.88 (s, 2H), 0.91 (s, 9H), 0.12 (s, 6H) (e) 4'-nitrophenyl-2-hydroxyacetoph
Enone O-methyl oxime 4′-nitro-2-ter-butyldimethylsilyloxyacetophenone obtained above (120 mg, 0.41 mmo
O-methylhydroxylamine hydrochloride (69 mg) was added to a mixed solution of 1) of methanol (1.2 ml), water (2.0 ml) and 1,4-dioxane (2.0 ml),
The mixture was stirred at 80 ° C for 1.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (58 mg, 67%).

[0199]

Reference Example 10 13- [2-methoxyimino-2- (4-phenyl) e
Toxyl] -5-keto-milbemycin A ₄ (Step 1) 13- [2-methoxyimino-2- (4-phenyl )
Phenyl) ethoxy] -5-keto-milbemycin A ₄ 15-hydroxy-5-keto-milbemycin A ₄ (82
1 mg, 1.5 mmol) and α-methoxyimino-2-
(4-nitrophenyl ethanol (1.08 g, 5.1
To a dichloromethane solution (10 ml) of 6 mmol) and copper (I) iodide (571 mg), trifluoromethanesulfonic acid (0.13 ml) was added under ice cooling under an argon stream, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with 5% aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated to give 824 mg of the crude title product, which was used in the next step without further purification.

(Step 2) 13- [2-methoxyimino-
2- (4-nitrophenyl) ethoxy] milbemycin
A ₄ 13- [2- methoxyimino-2- (4-nitrophenyl) ethoxy] -5-keto milbemycin A ₄ (824
mg, 1.01 mmol) in methanol (40 m
1) under ice cooling, sodium borohydride (200.0
mg, 1.01 mmol) was added and the mixture was stirred at 0 ° C. for 30 minutes. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated to give 720 mg of the crude title product, which was used in the next step without further purification.

(Step 3) 13- [2-methoxyimino-
2- (4-aminophenyl) ethoxy] milbemycin
A ₄ 13- [2- methoxyimino-2- (4-nitrophenyl) ethoxy] milbemycin A ₄ (150mg, 0.
Zinc dust (130 mg) was added to an acetic acid solution (40 ml) of 20 mmol) at room temperature, and the mixture was stirred for 30 minutes. After completion of the reaction, ethyl acetate was added to the reaction solution and the insoluble material was filtered off. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was washed with 4% aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. After distilling off the solvent, the residue was subjected to high performance liquid chromatography [column YMC ODS (10 μm), 20 × 20 mm I
D: Elution solvent methanol-water (6: 1), 10 ml / m
in; UV] to give 40 mg (28%) of the desired product.

Nuclear magnetic resonance spectrum (200MHz), δ (CDC
l ₃ ) ppm; 7.48 (d, 2H, J = 8.7Hz), 6.64 (d, 2H, J = 8.7Hz), 5.78
~ 5.88 (m, 2H), 5.15 ~ 5.44 (m, 4H), 4.68 (s, 2H), 4.40 (s,
2H), 4.29 (t, 1H, J = 5.7Hz), 3.98 (d, 1H, J = 5.7Hz), 3.94 (s, 3
H) Using the product obtained in this step as a starting material, Example 33 (Compound No. 27) and Example 34 (Compound No. 3)
The compound of 2) was prepared.

[0203]

Reference Example 11 13- (α-methoxyimino-4-nitrophenylacetate
Toxyl) -5-ketomylbemycin A ₄ 15-hydroxy-5-ketomylbemycin A ₄ (84
3 mg, 1.52 mmol) and α-methoxyimino-4
-Nitrophenylacetic acid (694 mg, 3.03 mmo
l) and copper (I) iodide (289 mg) in a dichloromethane solution (5 ml) were added trifluoromethanesulfonic acid (1 drop) under ice cooling under an argon stream and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with 5% aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated.

The residue was purified by silica gel column chromatography to obtain 663 mg (57%) of the desired product.

Nuclear magnetic resonance spectrum (200 MHz) δ
(CDCl ₃ ) ppm: 8.27 (d, 2H, J = 9.0Hz), 7.56 (d, 2
H, J = 9.0Hz), 6.54 (m, 1H), 5.74-5.94 (m, 2H), 5.32-5.54 (m,
3H), 5.12 (d, 1H, J = 10.5Hz), 4.74 (br.s, 2H), 4.08 (s, 3H),
4.01 (s, 1H), 3.86 (s, 1H). When the compound of the present invention is used as an agricultural and horticultural agent,
For example, it can be prepared and used as in the following formulation examples.

[0206]

[Formulation Example 1] (Wettable powder) 10% of compound No. 105, 2.5% of sodium dodecylbenzenesulfonate, 2.5% of sodium ligninsulfonate and 85% of diatomaceous earth are well pulverized and mixed to obtain a wettable powder. To get

[0207]

[Formulation Example 2] (Emulsion) Compound No. 105, compound 5%, emulsifier Solpol S
M100 (manufactured by Toho Chemical Co., Ltd.) 10% and xylene 8
Mix well with 5% to obtain an emulsion.

[0208]

[Formulation Example 3] (Granule) Compound No. 105, compound 3%, white carbon 1
%, Sodium lignin sulfonate 5% and clay 91
% Is well pulverized and mixed, water is added and kneaded well, and then granulated and dried to obtain granules.

[0209] Next, a biological test example will be given to concretely show its effect.

The comparative compounds 1, 2, 3 and 4 in Tables 2, 3 and 4 below are all disclosed in JP-A-1-10407.
Comparative compound 5 is the compound described in JP-A-2-174780, and Comparative compound 6 is the compound described in JP-A-63-10791. It is a compound having the structure shown in.

[0211]

[Chemical 9]

[0212]

[Chemical 10]

Test Example 1 Insecticidal test against diamondback moth Emulsion prepared according to the method of Preparation Example 2 above and containing 1% of the active ingredient compound was diluted with water so that the concentration of the active ingredient was 1 ppm. 10 cabbage leaves in the liquid
It was dipped for 2 seconds, air-dried and then placed in a polyethylene cup having a diameter of 8 cm. Ten third-instar larvae of Plutella xylostella were placed therein and the lid was covered. Then, it was placed in a constant temperature room at 25 ° C., and after 3 days, the mortality rate (including agony) was investigated. The test was conducted in two consecutive cycles.
The results are shown in Table 2.

[0214]

[Table 2] Test Example 2 Insecticidal test against Spodoptera litura Emulsion prepared according to the method of Preparation Example 2 above and containing 1% of the active ingredient compound was diluted with water so that the active ingredient concentration was 10 ppm. 5 g of artificial feed (Insector L) was immersed in the chemical solution for 20 seconds, air-dried, and then put in a polyethylene cup having a diameter of 8 cm. Ten third-instar larvae of Spodoptera litura were placed in it and the lid was closed. Then, it was placed in a constant temperature room at 25 ° C., and after 3 days, the mortality rate (including agony) was investigated. The test was conducted in two consecutive cycles. The results are shown in Table 3.

[0215]

[Table 3] Test Example 3 Insecticidal test against Scutellaria baicalensis Emulsion prepared according to the method of Formulation Example 2 above and containing 1% of the active ingredient compound was diluted with water so that the active ingredient concentration was 10 ppm. 5 g of artificial feed (Insector L) was immersed in the chemical solution for 20 seconds, air-dried, and then put in a polyethylene cup having a diameter of 8 cm. Ten fourth-instar larvae of Chacococca japonicus were put in it and the lid was covered. Then, it was placed in a constant temperature room at 25 ° C., and after 3 days, the mortality rate (including agony) was investigated. The test was conducted in two consecutive cycles. The results are shown in Table 4.

[0216]

[Table 4]

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification FI A61K 31/425 A61K 31/425 31/44 31/44 31/445 31/445 A61P 33/00 171 A61P 33/00 171 33 / 10 33/10 (C07D 493/22 C07D 307: 83 307: 83 309: 04 309: 04 309: 10 309: 10 313: 00 313: 00) (72) Inventor Shinji Yokoi Yasu, Yasu-cho, Yasu-gun, Shiga Prefecture 1041 Sankyo Stock Company (72) Inventor Reiji Ichinose Yasu, Yasu-cho, Yasu-gun, Shiga 1041 Sankyo Stock Company (72) Inventor Kinji Tanizawa Kinji 1041 Yasu-cho, Yasu-gun, Shiga Prefecture Company (56) References Special Kaihei 4-211087 (JP, A) JP 4-305579 (JP, A) JP 2-174780 (JP, A) JP 2-62882 (JP, A) JP 63-10791 ( JP, a) (58) investigated the field (Int.Cl. ^7, DB name) C07D 493/22 CAO D (STN) CAPLUS (STN) REGISTRY (STN)

Claims (8)

(57) [Claims] 1. A milbemycin derivative represented by the following general formula (I). [Chemical 1] [Wherein R ¹ is methyl, ethyl, isopropyl or sec
A butyl group, R ² represents a hydrogen atom or a C ₁ -C ₄ alkyl group, A represents a heterocyclic group or a C ₆ -C ₁₀ aryl group, and is selected from the following (Substituent group A) It may be substituted with the same or different 1 or 2 groups. m and n
Each independently represent 0 or 1, and are not 0 at the same time. (Substituent group A) a halogen atom; a nitro group; a hydroxyl group; C ₁ -C ₄ alkoxy group; C ₇ -C ₁₁ aralkyloxy group; an amino group; C ₁ -C
₄ alkanoylamino group; C ₂ -C ₄ haloalkanoylamino group; C ₁ -C ₃ alkylsulfonylamino group; C _2-
C ₅ alkoxycarbonylamino group; C ₃ -C ₅ haloalkoxycarbonylamino group; amino C ₂ -C ₇ alkanoylamino group (the amino group of the amino C ₂ -C ₇ alkanoyl group in the group is as follows (substituent group It may be substituted with the same or different 1 or 2 substituents selected from B), and the alkanoyl group may be substituted with a phenyl group or a C ₁ -C ₃ alkylthio group), (substituent group B) C ₁ -C ₃ alkyl groups; C ₂ -C ₃ alkanoyl; C ₂ -
C ₄ haloalkanoyl group; C ₂ -C ₅ alkoxycarbonyl group; C ₃ -C ₅ haloalkoxycarbonyl group; C ₇ -C
₁₁ arylcarbonyl group; C ₈ -C ₁₀ aralkyloxycarbonyl group] 2. In the general formula (I), R ¹ and R ² represent a methyl or ethyl group, A represents a furyl, thienyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl or phenyl group, and the following (substituent The milbemycin derivative according to claim 1, which may be substituted with 1 or 2 groups selected from A ₁ group). (Substituent Group A ₁ ) Fluorine atom; Chlorine atom; Bromine atom; Nitro group; Hydroxyl group;
C ₁ -C ₃ alkoxy group; C ₇ -C ₁₀ aralkyloxy group; amino group; C ₁ -C ₂ alkanoylamino group; fluorine, chlorine or bromine atom-substituted C ₂ -C ₃ alkanoylamino group; C ₁ -C ₃ alkylsulfonylamino group; C ₂ -C ₃ alkoxycarbonylamino group; fluorine, chlorine or bromine atom substituted C ₃ -C ₄ alkoxycarbonylamino group; an amino C ₂ -C ₅ alkanoylamino group (amino C ₂ -C ₅ alkanoyl group _May be substituted with the same or different 1 or 2 substituents selected from the following (Substituent group B ₁ ). Further, the alkanoyl group of the amino C ₂ -C ₅ alkanoyl group is a phenyl group or a C ₁ -C ₂ alkylthio group may be substituted) (substituent group B ₁₎ C ₁ -C ₂ alkyl group;. a formyl group; 1 to 3 fluorine, chlorine C is optionally substituted with a bromine atom ₂ -C ₃
Alkanoyl; C ₂ -C ₃ alkoxycarbonyl group; a benzoyl group; a benzyloxycarbonyl group 3. In the general formula (I), R ¹ represents a methyl or ethyl group, R ² represents a methyl group, A represents a furyl group, thienyl, thiazolyl group or a phenyl group. The milbemycin derivative according to claim 2, which may be substituted with 1 or 2 groups selected from the substituent group A ₂ ). (Substituent group A ₂ ) Fluorine atom; chlorine atom; bromine atom; hydroxyl group; C ₁ -C ₂ alkoxy group; benzyloxy group; amino group; acetylamino group; monochloroacetylamino group; monobromoacetylamino group; trifluoro Acetylamino group; C ₁ −
C ₂ alkylsulfonyl group; amino C ₂ -C ₃ alkanoylamino group (the amino group of the amino C ₂ -C ₃ alkanoyl group is substituted with a substituent selected from the following substituent group B ₂ ) ( substituent group B ₂₎ methyl; C ₂ -C ₃ alkanoyl; C ₂ -C ₃ alkoxycarbonyl group 4. The milbemycin derivative according to claim 3, wherein in the general formula (I), R ¹ represents an ethyl group. 5. The milbemycin derivative according to claim 4, wherein in the general formula (I), A represents a phenyl group or a phenyl group having a substituent at the para position. 6. In the general formula (I), m represents 0 and n
The milbemycin derivative according to claim 5, wherein 1 represents 1. 7. In the general formula (I), A is a phenyl group;
4- (methylsulfonylamino) phenyl group; or 4-
The milbemycin derivative according to claim 6, which represents a (methoxycarbonylaminoacetylamino) phenyl group. 8. A 13- {α-methoxyimino- [4- (1
-Methoxycarbonyl-2-pyrrolidinylcarbonylamino) phenyl] acetoxy} milbemycin A3; 13- {α-methoxyimino- [4- (1-methoxycarbonyl-2-pyrrolidinylcarbonylamino) phenyl] acetoxy} milbemycin A4 13- {α-methoxyimino- [4- (1-acetyl-
2-pyrrolidinylcarbonylamino) phenyl] acetoxy} milbemycin A4; 13- {α-methoxyimino- [4- (1-methoxycarbonyl-2-piperidylcarbonylamino) phenyl] acetoxy} milbemycin A4; or 13- {α. A milbemycin derivative which is -methoxyimino- [2- (1-methoxycarbonyl-2-pyrrolidinylcarbonylamino) thiazol-4-yl] acetoxy} milbemycin A4.