JP2003064082A - Avermectin derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a controller which has excellent insect exterminating, acaricidal or insecticidal activity and is used against various disease damages caused by insects, parasites, etc., living in animals. SOLUTION: This avermectin derivative being a component for the controller is represented by general formula (1) [R<1> is an isopropyl group, a cyclohexyl group or the like; R<2> and R<3> are each a hydrogen atom, a 1-3C alkyl group or the like; R<4> is a hydrogen atom, a 1-4C alkoxyalkoxy group, a 1-4C alkylsulfonylamino group, a 1-4C alkoxycarbonylamino group, a saturated 5-membered or 6-membered heterocycle containing one nitrogen atom as a ring atom being a bonding linkage; dotted line is a single bond or double bond].

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a milbemycin derivative having a substituent 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;
No. 4-61198, etc.

[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.

As milbemycins having an ester bond at the 13-position, JP-A-61-180787 discloses 13-ester milbemycins of substituted or unsubstituted alkanoic acids. In addition, JP-A 1-1
JP-A-04078 describes 13-ester rubemycins having an alkyl side chain at the α-position of alkanoic acid. Furthermore, JP-A-5-25
In Japanese Patent No. 5343, 13-ester milbemycins characterized by having a heterocyclic functional group at the α-position of alkanoic acid, and in Japanese Patent Laid-Open No. 8-193805 have a dialkyl group at the α-position of alkanoic acid. 13-ester milbemycins characterized in that they are described. All of the compounds described in these patents have an acyloxy group coordination β, and no compound having an α-coordinate acyloxy group is known. In avermectin, the sugar substituent at the 13-position is α-coordinated, but the 13-α-form derivative of its aglycone, the 13-α-form, has the corresponding α-coordinate.
It has been reported that its biological activity is lower than that of the -β-type derivative (J. Med. Chem., 1989, 32, 375-381), 13-
Efforts have been made to convert α-type to 13-β-type (JP-A-61-200993, J. Org. Chem., Vol. 57, No11, 1992,
3248-3250).

[0006]

DISCLOSURE OF THE INVENTION The present inventors have conducted extensive studies to find a novel avermectin derivative having an excellent insecticidal activity against pests, especially fleas.

[0007]

As a result, the 13-ester avermectin derivative as shown below is
The present invention has been completed by discovering that, despite being α-type, it exhibits strong insecticidal activity against pests, especially fleas.
That is, the present invention has the following general formula (I)

[0008]

[Chemical 3]

[0009]

In the above formula, R ¹ represents an isopropyl group, a cyclohexyl group or a sec-butyl group, and R ² and R
³ is a hydrogen atom, a C ₁ -C ₃ alkyl group, or R ² , R ³
There together, show a base group form a ring of C ₃ -C ₆ together with the carbon atoms of these substituents, R ⁴ is a hydrogen atom, a halogen atom, a cyano group, a nitro group, C ₁ -C ₄ Alkyl group, C ₁ -C ₂ haloalkyl group, C ₁ -C ₄ alkoxy group, C ₁ -C ₄ alkoxyalkoxy group, formula NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ are hydrogen atoms or C ₁ A group represented by —C ₄ alkyl group), a formula NR ⁵ COR ⁷ (in the formula, R ⁵ has the same meaning as described above, and R ⁷ has a substituent selected from the following substituent group A: Optionally a C ₁ -C ₄ alkyl group,
A C ₃ -C ₆ cycloalkyl group, a phenyl group which may have a substituent selected from the following substituent group A, or a heterocycle having 1 to 3 hetero atoms is shown. ) Group,
A C ₁ -C ₄ alkylsulfonylamino group, a C ₁ -C ₄ alkoxycarbonylamino group, or a saturated 5-membered or 6-membered heterocycle containing one nitrogen atom as a bond as a ring atom is shown, and the dotted line is a single bond. Or a double bond and having a substituent group A
Is a halogen atom, cyano group, nitro group, hydroxyl group, amino group, mono (C ₁ -C ₄ alkyl) -substituted amino group, di (C
₁ -C ₄ alkyl) -substituted amino group, C ₁ -C ₄ alkoxy groups, C ₁ -C ₄ alkanoyloxy group, C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfonyl group, C ₁ -C ₄ alkanoyl Group, C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C
₄ alkanoylamino group, C ₆ -C ₁₀ arylcarbonyl group, C ₁ -C ₄ alkoxycarbonylamino group, C ₁ -C ₄
An alkylsulfonylamino group, a phenyl group, or a heterocycle having 1 to 3 heteroatoms is shown.

The active ingredient of the pest control agent of the present invention is an avermectin derivative having the general formula (I).

Further, the present invention provides an anthelmintic, acaricidal or insecticidal compound selected from the compound having the general formula (I) or a pharmaceutically or veterinary acceptable salt when forming a salt. .

In the above general formula (I), among the "isopropyl group", "cyclohexyl group" or "sec-butyl group" in the definition of R ¹ , isopropyl group or sec-butyl group is preferred, More preferably, sec-butyl group is mentioned.

The "C ₁ -C ₃ alkyl group" in the definition of R ² and R ³ is a linear or branched alkyl group having 1 to 3 carbon atoms, for example, methyl, ethyl, propyl, Or, isopropyl can be mentioned, and of these, a methyl, ethyl, or propyl group is preferable, and a methyl group can be more preferable.

In the definition of R ² and R ³ , "a group in which R ² and R ³ are taken together to form a C ₃ -C ₆ ring together with the carbon atom at the base of these substituents" means R ² and R 3. ³ shows that a cycloalkyl group is formed by containing the carbon atom at the base of ³ , and examples of these cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, and among these, preferred Examples thereof include a cyclopropyl group, cyclobutyl group, and cyclopentyl group, and more preferable examples include a cyclopentyl group.

"Halogen atom" in the definition of R ⁴ is
Examples thereof include fluorine, chlorine, bromine and iodine atoms, and fluorine atom is preferable.

The "C ₁ -C ₄ alkyl group" in the definition of R ⁴ is a linear or branched alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl and butyl. , Isobutyl, or ter
A t-butyl group may be mentioned, and preferably a methyl group may be mentioned.

The "C ₁ -C ₂ haloalkyl group" in the definition of R ⁴ is a group in which an alkyl group having 1 to 2 carbon atoms is substituted with one or more halogen atoms, for example, trifluoromethyl, Chloromethyl or pentafluoroethyl may be mentioned, and preferably a trifluoromethyl group may be mentioned.

The "C ₁ -C ₄ alkoxy group" in the definition of R ⁴ is a linear or branched alkoxy group having 1 to 4 carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, Butoxy, or tert-
A butyl group is mentioned, and a methoxy group is preferable.

The "C ₁ -C ₄ alkoxyalkoxy group" in the definition of R ⁴ is a group in which a linear or branched alkoxy group having 1 to 4 carbon atoms is connected through two oxygen atoms. Shown, for example, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxybutoxy,
Alternatively, an ethoxybutoxy group can be mentioned, and preferably a methoxymethoxy or methoxyethoxy group can be mentioned.

The "C ₁ -C ₄ alkylsulfonyl group" in the definition of R ⁴ is a group in which a linear or branched alkyl group having 1 to 4 carbon atoms is bonded to a sulfonyl group, and examples thereof include methane. Examples thereof include a sulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, and an isopropylsulfonyl group, preferably a methanesulfonyl group and an ethanesulfonyl group.

The "C ₁ -C ₄ alkoxycarbonyl group" in the definition of R ⁴ is a group in which a linear or branched alkoxy group having 1 to 4 carbon atoms is bonded to a carbonyl group, for example, methoxy. Carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s
An ec-butoxycarbonyl group or a tert-butoxycarbonyl group is mentioned, and a methoxycarbonyl group is preferable.

"Saturated 5- or 6-membered heterocycle containing one nitrogen atom as a bond as a ring atom" in the definition of R ⁴ is, for example, 1-pyrrolidinyl, piperidino, 2-
An oxo-1-pyrrolidinyl, 2-oxopiperidino, or 2-oxazolidinone-1-yl group is mentioned, and preferably a 2-oxo-1-pyrrolidinyl or 2-oxazolidinone-1-yl group is mentioned.

"C ₁ in the definition of R ⁵ , R ⁶ or R ⁷
The “-C ₄ alkyl group” is a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include a methyl, ethyl, propyl, isopropyl, butyl, or isobutyl group, and preferably Is a methyl or ethyl group.

The “C ₃ -C ₆ cycloalkyl group” in the definition of R ⁷ includes, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, preferably cyclopropyl, cyclobutyl or cyclopentyl. Groups.

The "heterocycle having 1 to 3 heteroatoms" in the definition of R ⁷ includes, for example, pyridyl, furyl, thienyl, pyrrolyl, or indolyl group, preferably pyridyl group. To be

The "halogen atom" in the definition of Substituent group A includes, for example, fluorine, chlorine, bromine, or iodine atom, and preferably fluorine atom.

In the definition of the substituent group A, "mono (C₁−
C_FourAlkyl) substituted amino group "," C ₁-C_FourAlkyl "
Is the above R^FourHas the same meaning as the definition of
Are, for example, methylamino, ethylamino, propyl
Group, such as ruamino or butylamino group, and preferably
A tylamino group may be mentioned.

In the definition of the substituent group A, "di (C ₁ -C ₄
Alkyl) substituted amino group "," C ₁ -C ₄ alkyl "
It has the same meaning as described above for the definition of R ⁴ , and examples of the group include dimethylamino, diethylamino, or
A dipropylamino group is shown, and a dimethylamino group is preferable.

The "C ₁ -C ₄ alkoxy group" in the definition of Substituent group A has the same meaning as described above for the definition of R ⁴ .

The "C ₁ -C ₄ alkanoyloxy group" in the definition of Substituent group A is a group in which a linear or branched alkyl group having 1 to 4 carbon atoms is bonded to a carbonyloxy group. Examples include acetoxy, propionyloxy, and butyryloxy groups, and acetoxy groups are preferred.

The "C ₁ -C ₄ alkylthio group" in the definition of the substituent group A is a group in which a linear or branched alkyl group having 1 to 4 carbon atoms is bonded to a sulfur atom,
For example, a methylthio, ethylthio, propylthio, isopropylthio, or butylthio group can be mentioned, and preferably a methylthio or ethylthio group can be mentioned.

The "C ₁ -C ₄ alkylsulfonyl group" in the definition of Substituent group A has the same meaning as described above for the definition of R ⁴ .

Examples of the "C ₁ -C ₄ alkanoyl group" in the definition of Substituent group A include formyl, acetyl,
A propionyl group or a butyryl group is mentioned, and an acetyl group is preferable.

The "C ₁ -C ₄ alkoxycarbonyl group" in the definition of Substituent group A is a group in which a linear or branched alkoxy group having 1 to 4 carbon atoms is bonded to a carbonyl group, Examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and a butoxycarbonyl group, and a methoxycarbonyl group and an ethoxycarbonyl group are preferable.

The "C ₁ -C ₄ alkanoylamino group" in the definition of Substituent group A is a group in which a linear or branched alkanoyl group having 1 to 4 carbon atoms is bonded to an amino group, For example, formylamino, acetylamino,
A propionylamino or butyrylamino group is mentioned, and a formylamino or acetylamino group is preferable.

The "C ₆ -C ₁₀ arylcarbonyl group" in the definition of Substituent group A is a group in which a carbonyl group is bonded to a phenyl group, and examples thereof include a benzoyl group and a naphthoyl group. Examples thereof include a benzoyl group.

The "C ₁ -C ₄ alkoxycarbonylamino group" in the definition of Substituent group A is a linear or branched alkoxy group having 1 to 4 carbon atoms bonded to a carbonyl group, and further an amino group. It represents a group bonded to a group, and examples thereof include a methoxycarbonylamino group, an ethoxycarbonylamino group, a propoxycarbonylamino group, and a butoxycarbonylamino group, and a methoxycarbonylamino group is preferable.

The "C ₁ -C ₄ alkylsulfonylamino group" in the definition of Substituent group A is a linear or branched alkyl group having 1 to 4 carbon atoms bonded to a sulfonyl group, and further includes an amino group. A group bonded to a group is shown, for example, methanesulfonylamino, ethanesulfonylamino,
Propane sulfonylamino group, and preferably,
A methanesulfonylamino group is mentioned.

The "heterocycle having 1 to 3 heteroatoms" in the definition of Substituent group A includes, for example, pyridyl, furyl, thienyl, pyrrolyl or indolyl group, preferably pyridyl group. Is mentioned.

The compounds of the general formula (I) according to the invention are
Also included are those which can be converted into the corresponding pharmaceutically or veterinary acceptable salts by treating with an acid according to a conventional method. The present invention also includes these salts.
For example, the compound (I) may be in a solvent (for example, ethers, esters or alcohols, preferably ethers such as diethyl ether or alcohols such as methanol) and a corresponding acid at room temperature for 1 minute to 30 minutes. It can be obtained by treating for minutes and filtering the precipitated crystals or distilling off the solvent under reduced pressure.

Examples of such salts include carbonates; minerals such as hydrofluoric acid salts, hydrochloric acid salts, hydrobromic acid salts, hydroiodic acid salts, nitrate salts, perchloric acid salts, sulfuric acid salts or phosphoric acid salts. Salts; sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate; acetate, propionate, butyrate, fumarate , Succinates, citrates, tartrates, oxalates or carboxylates such as maleates or benzoates; or amino acid salts such as glutamate or aspartate.

When the compound having the general formula (I) or a pharmaceutically acceptable salt thereof of the present invention has an asymmetric carbon atom in the molecule, it has stereoisomers of R coordination and S coordination. In some cases, each of them, or a compound containing them in any proportion is included in the present invention. Such stereoisomers are prepared, for example, by synthesizing the compound (I) using an optically resolved raw material compound or optically synthesizing the synthesized compound (I) by a conventional optical resolution or separation method. be able to.

When the compound having the general formula (I) of the present invention or a salt thereof absorbs water by adsorbing water or becomes a hydrate by being left in the air or recrystallized. The present invention also includes a compound containing the general formula (I) containing water or a pharmaceutically acceptable salt thereof.

Preferred compounds for the compound having the general formula (I) are listed below. (A) a compound in which R ¹ is an isopropyl group or a sec-butyl group, (B) a compound in which R ¹ is a sec-butyl group, (C)
A compound in which R ² is a methyl, ethyl or propyl group, (D) a compound in which R ² is a methyl group, (E) a compound in which R ³ is a methyl, ethyl or propyl group, (F)
A compound in which R ³ is a methyl group, (G) R ² and R ³ together, and a compound in which cyclopropyl, cyclobutyl or cyclopentyl group (H) R ² and R ³ together, A compound having a cyclopentyl group, (I) R
⁴ is an amino group, a formula NR ⁵ COR ⁷ (in the formula, R ⁵ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, and R ⁷ represents an optionally substituted C ₁ -C ₄ alkyl group ( The substituent is a halogen atom, cyano group, nitro group, hydroxyl group, amino group, mono (C
₁ -C ₄ alkyl) -substituted amino group, di (C ₁ -C ₄ alkyl) -substituted amino group, C ₁ -C ₄ alkoxy groups, C ₁ -C ₄ alkanoyloxy group, C ₁ -C ₄ alkylthio group, C ₁ −
C ₄ alkylsulfonyl group, C ₁ -C ₄ alkanoyl group, C
₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ alkanoylamino group, C ₆ -C ₁₀ arylcarbonyl group, C ₁ -C ₄
It may be substituted with an alkoxycarbonylamino group, a C ₁ -C ₄ alkylsulfonylamino group, a phenyl group, or a heterocycle having 1 to 3 heteroatoms. ), C
_3- C ₆ cycloalkyl group, a phenyl group which may have a substituent (the substituent is a halogen atom, a cyano group, a nitro group, a hydroxyl group, an amino group, a mono (C ₁ -C ₄ alkyl) -substituted amino group A di (C ₁ -C ₄ alkyl) -substituted amino group, C ₁
-C ₄ alkoxy groups, C ₁ -C ₄ alkanoyloxy group,
C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfonyl group, C ₁ -C ₄ alkanoyl group, C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ alkanoylamino group, C ₆ -C ₁₀
It may be substituted with an arylcarbonyl group, a C ₁ -C ₄ alkoxycarbonylamino group, a C ₁ -C ₄ alkylsulfonylamino group, a phenyl group, or a heterocycle having 1 to 3 heteroatoms. ), Or a heterocycle having 1 to 3 heteroatoms. ), A C ₁ -C ₄ alkylsulfonylamino group, a C ₁ -C ₄ alkoxycarbonylamino group, or a nitrogen atom as a bond is 1 as a ring atom.
A saturated 5- or 6-membered heterocyclic compound containing
(J) R ⁴ is an amino group, a formula NR ⁵ COR ⁷ (In the formula, R ⁵ is a hydrogen atom or a C ₁ -C ₄ alkyl group, and R ⁷ is a C ₁ -C which may have a substituent. ₄ alkyl group (the substituent is a halogen atom, a cyano group, a nitro group, a hydroxyl group, an amino group, a mono (C ₁ -C ₄ alkyl) -substituted amino group, a di (C ₁ -C ₄ alkyl) -substituted amino group, C ₁ -C ₄ alkoxy groups, C ₁ -
A C ₄ alkanoyloxy group, a C ₁ -C ₄ alkylthio group,
C ₁ -C ₄ alkylsulfonyl group, C ₁ -C ₄ alkanoyl group, C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ alkanoylamino group, C ₆ -C ₁₀ arylcarbonyl group, C ₁
It may be substituted with a -C ₄ alkoxycarbonylamino group, a C ₁ -C ₄ alkylsulfonylamino group, a phenyl group, or a heterocycle having 1 to 3 heteroatoms. ), A C ₃ -C ₆ cycloalkyl group, and a phenyl group which may have a substituent (the substituent is a halogen atom, a cyano group, a nitro group, a hydroxyl group, an amino group, a mono (C ₁ -C ₄ alkyl)). Substituted amino group, di (C ₁ -C ₄ alkyl) substituted amino group, C ₁ -C ₄ alkoxy group, C ₁ -C ₄ alkanoyloxy group, C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfonyl group , C ₁ -C ₄ alkanoyl group, C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ alkanoylamino group, C
_6- C ₁₀ arylcarbonyl group, C ₁ -C ₄ alkoxycarbonylamino group, C ₁ -C ₄ alkylsulfonylamino group, phenyl group, or even if substituted with a heterocycle having 1 to 3 heteroatoms Good. ), Or 1 to 3
Shown is a heterocycle having 3 heteroatoms. ), Or C ₁
A compound which is a -C ₄ alkylsulfonylamino group,
(K) a compound in which the substitution position of R ⁴ is the para position (4 position),
(L) In the structural formula of the general formula (I), a compound in which the dotted line is a single bond can be mentioned.

With respect to R ¹ , preferred ranks increase from (A) to (B), with respect to R ² preferred ranks from (C) to (D), and with respect to R ³ ,
In the order from (E) to (F), the preferred ranks increase, and R ² and R ³
And (G) together form a ring, (G) to (H)
The preferred rank increases in the order of, and with respect to R ⁴ , the suitable rank increases in the order of (I) to (J).

The compounds having the general formula (I) include (A)-(B), (C)-(D), (E)-
Select 5 to 6 from the group consisting of (F), (G)-(H), (I)-(J), (K), and (L), and list them in any combination. And a suitable combination thereof is, for example, (M)
(A), (C), (E), (I), (K), and
(L), (N) (B), (D), (F), (J),
(K) and (L), (O) (A), (G),
(I), (K), and (L), (P) (B),
(H), (J), (K), and (L) can be mentioned. Regarding the above, in the order of (M) to (N), and
The preferred rank increases from (O) to (P).

As the representative compounds of the present invention, for example, the compounds shown in the following table can be exemplified, but the present invention is not limited to these compounds.

[0049]

[Table 1] In the following table, abbreviations indicate the following groups or symbols.

[0050]         Bu ... Butyl Et ... Ethyl         Me ・ ・ ・ ・ ・ ・ Methyl Pen ・ ・ ・ Pentyl         Pr ··· Propyl Ph ···· Phenyl         i ... iso c ... cyclo         s ... Secondary

[0051]

[Chemical 4]

[0052] Number R1 R2 R3 = C R4 1 sBu cPen H 2 sBu cPen 4-F 3 sBu cPen 4-Cl 4 sBu cPen 4-Br 5 sBu cPen 4-I 6 sBu cPen 4-CN 7 sBu cPen 4-NO2 8 sBu cPen 4 -Me 9 sBu cPen 4-CF3 10 sBu cPen 4-OH 11 sBu cPen 4-OMe 12 sBu cPen 4-OEt 13 sBu cPen 4-OCH2OMe 14 sBu cPen 4-OCH2CH2OMe 15 sBu cPen 4-NH2 16 sBu cPen 4-NHMe 17 sBu cPen 4-NHEt 18 sBu cPen 4-NMe2 19 sBu cPen 4-NHCOMe 20 sBu cPen 4-NHCOCF3 21 sBu cPen 4-NHCOCH2CN 22 sBu cPen 4-NHCOCH2OH 23 sBu cPen 4-NHCOCH2NH2 24 sBu cPen 4-NHCOCH2 cPen 4-NHCOCH2N (Me) COMe 26 sBu cPen 4-NHCOCH2OMe 27 sBu cPen 4-NHCOCH2OEt 28 sBu cPen 4-NHCOCH2OCOMe 29 sBu cPen 4-NHCOCH2SMe 30 sBu cPen 4-NHCOCH2SEt 31 sBu cPen 32NHBuCHPEN 4-NHCOBu2COMe 33 sBu cPen 4-NHCOCH2COOEt 34 sBu cPen 4-NHCOcPr 35 sBu cPen 4-NHCOcBu 36 sBu cPen 4-NHCOcPen 37 sBu cPen 4-NHCOPh 38 sBu cPen 4-NHCOPh (4-MeO) 39 sBu cPen 4-NHCOPh (4- CN) 40 sBu cPen 4-NHCOPy (4-) 41 sBu cPen 4-NHCOPy (3-) 42 sBu cPen 4-NHCOPy (2-) 43 sBu cPen 4-NHCOOMe 44 sBu cPen 4-NHCOOEt 45 sBu cPen 4-NH SO2Me 46 sBu cPen 4-NHSO2Et 47 sBu cPen 4- (2-azetidinone-1-yl) 48 sBu cPen 4- (2-pyrrolidinone-1-yl) 49 sBu cPen 4- (2-oxazolidinone-1-yl) 50 sBu cPen 4- (2-piperidinone-1-yl) 51 sBu cBu H 52 sBu cBu 4-F 53 sBu cBu 4-Cl 54 sBu cBu 4-Br 55 sBu cBu 4-I 56 sBu cBu 4-CN 57 sBu cBu 4-NO2 58 sBu cBu 4-Me 59 sBu cBu 4-CF3 60 sBu cBu 4-OH 61 sBu cBu 4-OMe 62 sBu cBu 4-OEt 63 sBu cBu 4-OCH2OMe 64 sBu cBu 4-OCH2CH2OMe 65 sBu cBu 4- NH2 66 sBu cBu 4-NHMe 67 sBu cBu 4-NHEt 68 sBu cBu 4-NMe2 69 sBu cBu 4-NHCOMe 70 sBu cBu 4-NHCOCF3 71 sBu cBu 4-NHCOCH2CN 72 sBu cBu 4-NHCOCH2OH 73 sBu cBu 4-NHCOCH2NH2 74 sBu cBu 4-NHCOCH2NHCOMe 75 sBu cBu 4-NHCOCH2N (Me) COMe 76 sBu cBu 4-NHCOCH2OMe 77 sBu cBu 4-NHCOCH2OEt 78 sBu cBu 4-NHCOCH2OCOMe 79 sBu cBu 4-NHCOCH2SMe 80 sBu cBu 4-NHCOCHBuSEt 81 NHCOCH2COMe 82 sBu cBu 4-NHCOCH2COOMe 83 sBu cBu 4-NHCOCH2COOEt 84 sBu cBu 4-NHCOcPr 85 sBu cBu 4-NHCOcBu 86 sBu cBu 4-NHCOcPen 87 sBu cBu 4-NHCOPh 88 sBu cBu 4-NHCOPh (4-Me O) 89 sBu cBu 4-NHCOPh (4-CN) 90 sBu cBu 4-NHCOPy (4-) 91 sBu cBu 4-NHCOPy (3-) 92 sBu cBu 4-NHCOPy (2-) 93 sBu cBu 4-NHCOOMe 94 sBu cBu 4-NHCOOEt 95 sBu cBu 4-NHSO2Me 96 sBu cBu 4-NHSO2Et 97 sBu cBu 4- (2-azetidinone-1-yl) 98 sBu cBu 4- (2-pyrrolidinone-1-yl) 99 sBu cBu 4- (2-oxazolidinone-1-yl) 100 sBu cBu 4- (2-piperidinone-1-yl) 101 sBu cPr H 102 sBu cPr 4-F 103 sBu cPr 4-Cl 104 sBu cPr 4-Br 105 sBu cPr 4- I 106 sBu cPr 4-CN 107 sBu cPr 4-NO2 108 sBu cPr 4-Me 109 sBu cPr 4-CF3 110 sBu cPr 4-OH 111 sBu cPr 4-OMe 112 sBu cPr 4-OEt 113 sBu cPr 4-OCH2OMe 114 sBu cPr 4-OCH2CH2OMe 115 sBu cPr 4-NH2 116 sBu cPr 4-NHMe 117 sBu cPr 4-NHEt 118 sBu cPr 4-NMe2 119 sBu cPr 4-NHCOMe 120 sBu cPr 4-NHCOCF3 121 sBu cPr 4-NHCOCH2CN 122 sBu 4-NHCOCH2OH 123 sBu cPr 4-NHCOCH2NH2 124 sBu cPr 4-NHCOCH2NHCOMe 125 sBu cPr 4-NHCOCH2N (Me) COMe 126 sBu cPr 4-NHCOCH2OMe 127 sBu cPr 4-NHCOCH2OEt 128 sBu cPr 4-NH129CHCHCOCH2OCOMe sBu cPr 4-NHCOCH2SEt 1 31 sBu cPr 4-NHCOCH2COMe 132 sBu cPr 4-NHCOCH2COOMe 133 sBu cPr 4-NHCOCH2COOEt 134 sBu cPr 4-NHCOcPr 135 sBu cPr 4-NHCOcBu 136 sBu cPr 4-NHCOcPen 137 sBu cPr 4-NHCOPh 4NHCOBuh -MeO) 139 sBu cPr 4-NHCOPh (4-CN) 140 sBu cPr 4-NHCOPy (4-) 141 sBu cPr 4-NHCOPy (3-) 142 sBu cPr 4-NHCOPy (2-) 143 sBu cPr 4-NHCOOMe 144 sBu cPr 4-NHCOOEt 145 sBu cPr 4-NHSO2Me 146 sBu cPr 4-NHSO2Et 147 sBu cPr 4- (azetidinone-1-yl) 148 sBu cPr 4- (2-pyrrolidinone-1-yl) 149 sBu cPr 4- ( 2-oxazolidinone-1-yl) 150 sBu cPr 4- (2-piperidinone-1-yl) 151 sBu Me2C H 152 sBu Me2C 4-F 153 sBu Me2C 4-Cl 154 sBu Me2C 4-Br 155 sBu Me2C 4-I 156 sBu Me2C 4-CN 157 sBu Me2C 4-NO2 158 sBu Me2C 4-Me 159 sBu Me2C 4-CF3 160 sBu Me2C 4-OH 161 sBu Me2C 4-OMe 162 sBu Me2C 4-OEt 163 sBu Me2C 4-OCH2OMe 164 sBu Me2C 4-OCH2CH2OMe 165 sBu Me2C 4-NH2 166 sBu Me2C 4-NHMe 167 sBu Me2C 4-NHEt 168 sBu Me2C 4-NMe2 169 sBu Me2C 4-NHCOMe 170 sBu Me2C 4-NHCOCF3 171 sBu Me2C 4-NHCOCHBuCN 172 -NHCOCH2OH 173 sBu Me2C 4-NHCOCH2NH2 174 sBu Me2C 4-NHCOCH2NHCOMe 175 sBu Me2C 4-NHCOCH2N (Me) COMe 176 sBu Me2C 4-NHCOCH2OMe 177 sBu Me2C 4-NHCOCH2OEt 178 sBuMesCO2CH4COCH2OEt 178 sBu Me2C Me2C 4-NHCOCH2SEt 181 sBu Me2C 4-NHCOCH2COMe 182 sBu Me2C 4-NHCOCH2COOMe 183 sBu Me2C 4-NHCOCH2COOEt 184 sBu Me2C 4-NHCOcPr 185 sBu Me2C 4-NHCOcBu 186 sBu Me2C 4-NHCOcBu 186 sBu Me2C 4-NHCOcBu -NHCOPh (4-MeO) 189 sBu Me2C 4-NHCOPh (4-CN) 190 sBu Me2C 4-NHCOPy (4-) 191 sBu Me2C 4-NHCOPy (3-) 192 sBu Me2C 4-NHCOPy (2-) 193 sBu Me2C 4-NHCOOMe 194 sBu Me2C 4-NHCOOEt 195 sBu Me2C 4-NHSO2Me 196 sBu Me2C 4-NHSO2Et 197 sBu Me2C 4- (2-azetidinone-1-yl) 198 sBu Me2C 4- (2-pyrrolidinone-1-yl) 199 sBu Me2C 4- (2-oxazolidinone-1-yl) 200 sBu Me2C 4- (2-piperidinone-1-yl) 201 sBu Et2C H 202 sBu Et2C 4-F 203 sBu Et2C 4-Cl 204 sBu Et2C 4-Br 205 sBu Et2C 4-I 206 sBu Et2C 4-CN 207 sBu Et2C 4-NO2 208 sBu Et2C 4-Me 209 sBu Et2C 4-CF3 210 sBu Et2C 4- OH 211 sBu Et2C 4-OMe 212 sBu Et2C 4-OEt 213 sBu Et2C 4-OCH2OMe 214 sBu Et2C 4-OCH2CH2OMe 215 sBu Et2C 4-NH2 216 sBu Et2C 4-NHMe 217 sBu Et2C 4-NHEt 218 sBu Et2C 4-NMe4 sBu Et2C 4-NHCOMe 220 sBu Et2C 4-NHCOCF3 221 sBu Et2C 4-NHCOCH2CN 222 sBu Et2C 4-NHCOCH2OH 223 sBu Et2C 4-NHCOCH2NH2 224 sBu Et2C 4-NHCOCH2NHCOMe 225 sBu Et2C 4-NHCOCH2N (Me) NHCOCH2OMe 227 sBu Et2C 4-NHCOCH2OEt 228 sBu Et2C 4-NHCOCH2OCOMe 229 sBu Et2C 4-NHCOCH2SMe 230 sBu Et2C 4-NHCOCH2SEt 231 sBu Et2C 4-NHCOCH2CO2CH2CO2CH2CO2CH2CO2CH2CO2CH2CO2CH2CO2CH2CO2CH2CO2CH2CO2 sBu Et2C 4-NHCOcBu 236 sBu Et2C 4-NHCOcPen 237 sBu Et2C 4-NHCOPh 238 sBu Et2C 4-NHCOPh (4-MeO) 239 sBu Et2C 4-NHCOPh (4-CN) 240 sBu Et2C 4-NHCOPy (4-) 241 sBu Et2C 4-NHCOPy (3-) 242 sBu Et2C 4-NHCOPy (2-) 243 sBu Et2C 4-NHCOOMe 244 sBu Et2C 4-NHCOOEt 245 sBu Et2C 4-NHSO2Me 246 sBu Et2C 4-NHSO2Et 247 sBu Et2C 4- (2 -Azetidinone-1-yl) 248 sBu Et2C 4- (2-pyrrolidinone-1-yl) 249 sBu Et2C 4- (2-o Xazolidinone-1-yl) 250 sBu Et2C 4- (2-piperidinone-1-yl) 251 sBu H2C H 252 sBu H2C 4-F 253 sBu H2C 4-Cl 254 sBu H2C 4-Br 255 sBu H2C 4-I 256 sBu H2C 4-CN 257 sBu H2C 4-NO2 258 sBu H2C 4-Me 259 sBu H2C 4-CF3 260 sBu H2C 4-OH 261 sBu H2C 4-OMe 262 sBu H2C 4-OEt 263 sBu H2C 4-OCH2OMe 264 sBu H2C 4 -OCH2CH2OMe 265 sBu H2C 4-NH2 266 sBu H2C 4-NHMe 267 sBu H2C 4-NHEt 268 sBu H2C 4-NMe2 269 sBu H2C 4-NHCOMe 270 sBu H2C 4-NHCOCF3 271 sBu H2C 4-NHCOCH2CNBu2H 273 sBu H2C 4-NHCOCH2NH2 274 sBu H2C 4-NHCOCH2NHCOMe 275 sBu H2C 4-NHCOCH2N (Me) COMe 276 sBu H2C 4-NHCOCH2OMe 277 sBu H2C 4-NHCOCH2CO2SM2CH4CO2CH2COBu2 -NHCOCH2SEt 281 sBu H2C 4-NHCOCH2COMe 282 sBu H2C 4-NHCOCH2COOMe 283 sBu H2C 4-NHCOCH2COOEt 284 sBu H2C 4-NHCOcPr 285 sBu H2C 4-NHCOPBu2C 4-NHCOCPh2C 4-NHCOcPh2287 (4-MeO) 289 sBu H2C 4-NHCOPh (4-CN) 290 sBu H2C 4-NHCOPy (4-) 291 sBu H2C 4-NHCOPy (3-) 292 sBu H2C 4-NHCOPy ( 2-) 293 sBu H2C 4-NHCOOMe 294 sBu H2C 4-NHCOOEt 295 sBu H2C 4-NHSO2Me 296 sBu H2C 4-NHSO2Et 297 sBu H2C 4- (2-azetidinone-1-yl) 298 sBu H2C 4- (2-pyrrolidinone -1-yl 299 sBu H2C 4- (2-oxazolidinone-1-yl) 300 sBu H2C 4- (2-piperidinone-1-yl) 301 iPr cPen H 302 iPr cPen 4-F 303 iPr cPen 4-Cl 304 iPr cPen 4-Br 305 iPr cPen 4-I 306 iPr cPen 4-CN 307 iPr cPen 4-NO2 308 iPr cPen 4-Me 309 iPr cPen 4-CF3 310 iPr cPen 4-OH 311 iPr cPen 4-OMe 312 iPr cPen 4 -OEt 313 iPr cPen 4-OCH2OMe 314 iPr cPen 4-OCH2CH2OMe 315 iPr cPen 4-NH2 316 iPr cPen 4-NHMe 317 iPr cPen 4-NHEt 318 iPr cPen 4-NMe2 319 iPr cPen 4-NHCOMe 320 iPr cPen 321 iPr cPen 4-NHCOCH2CN 322 iPr cPen 4-NHCOCH2OH 323 iPr cPen 4-NHCOCH2NH2 324 iPr cPen 4-NHCOCH2NHCOMe 325 iPr cPen 4-NHCOCH2N (Me) COMe 326 iPr cPen 4-NHCOCH2PrCOPCHCOMP2 327 -NHCOCH2OCOMe 329 iPr cPen 4-NHCOCH2SMe 330 iPr cPen 4-NHCOCH2SEt 331 iPr cPen 4-NHCOCH2COMe 332 iPr cPen 4-NHCOCH2COOMe 333 iPr cPen 4-NHCOCH2COOEt 334 iPr cPen 4-NHCOcPr 335 iPr cPen 4-NHCOcBu 336 iPr cPen 4-NHCOcPen 337 iPr cPen 4-NHCOPh3 338 iPr cPen 4-NHCOPh (4-MeO) 339 iPr cPen 4-CNCOPh 340 iPr cPen 4-NHCOPy (4-) 341 iPr cPen 4-NHCOPy (3-) 342 iPr cPen 4-NHCOPy (2-) 343 iPr cPen 4-NHCOOMe 344 iPr cPen 4-NHCOOEt 345 iPr cPen 4-NHSO2Me 346 iPr cPen NHSO2Et 347 iPr cPen 4- (2-azetidinone-1-yl) 348 iPr cPen 4- (2-pyrrolidinone-1-yl) 349 iPr cPen 4- (2-oxazolidinone-1-yl) 350 iPr cPen 4- ( 2-piperidinone-1-yl) 351 iPr cBu H 352 iPr cBu 4-F 353 iPr cBu 4-Cl 354 iPr cBu 4-Br 355 iPr cBu 4-I 356 iPr cBu 4-CN 357 iPr cBu 4-NO2 358 iPr cBu 4-Me 359 iPr cBu 4-CF3 360 iPr cBu 4-OH 361 iPr cBu 4-OMe 362 iPr cBu 4-OEt 363 iPr cBu 4-OCH2OMe 364 iPr cBu 4-OCH2CH2OMe 365 iPr cBu 4-NH2 366 iPr cBu 4 -NHMe 367 iPr cBu 4-NHEt 368 iPr cBu 4-NMe2 369 iPr cBu 4-NHCOMe 370 iPr cBu 4-NHCOCF3 371 iPr cBu 4-NHCOCH2CN 372 iPr cBu 4-NHCOCH2OH 373 iPr cBu 4-NHCOCH2NH2 374 iPr cBu 4-NH 375 iPr cBu 4-NHCOCH2N (Me) COMe 376 iPr cBu 4-NHCOCH2OMe 377 iPr cBu 4-NHCOCH2OEt 378 iPr cBu 4-NHCOCH2OCOMe 379 iPr cBu 4-NHCOCH2SMe 380 iPr cBu 4-NHCOCH2SEt 382 iPrcBu 4-NHCOCH2SEt 382 iPrcBu -NHCOCH2COOMe 383 iPr cBu 4-NHCOCH2COOEt 384 iPr cBu 4-NHCOcPr 385 iPr cBu 4-NHCOcBu 386 iPr cBu 4-NHCOcPen 387 iPr cBu 4-NHCOPh 388 iPr cBu 4-NHCOPh (4-MeO) 4-389 iPr cBu 4-CN) 390 iPr cBu 4-NHCOPy (4-) 391 iPr cBu 4-NHCOPy (3-) 392 iPr cBu 4-NHCOPy (2-) 393 iPr cBu 4-NHCOOMe 394 iPr cBu 4-NHCOOEt 395 iPr cBu 4 -NHSO2Me 396 iPr cBu 4-NHSO2Et 397 iPr cBu 4- (2-azetidinone-1-yl) 398 iPr cBu 4- (2-pyrrolidinone-1-yl) 399 iPr cBu 4- (2-oxazolidinone-1-yl) 400 iPr cBu 4- (2-piperidinone-1-yl) 401 iPr cPr H 402 iPr cPr 4-F 403 iPr cPr 4-Cl 404 iPr cPr 4-Br 405 iPr cPr 4-I 406 iPr cPr 4-CN 407 iPr cPr 4-NO2 408 iPr cPr 4-Me 409 iPr cPr 4-CF3 410 iPr cPr 4-OH 411 iPr cPr 4-OMe 412 iPr cPr 4-OEt 413 iPr cPr 4-OCH2OMe 414 iPr cPr 4-OCH2CH2OMe 415 iPr cPr 4 -N H2 416 iPr cPr 4-NHMe 417 iPr cPr 4-NHEt 418 iPr cPr 4-NMe2 419 iPr cPr 4-NHCOMe 420 iPr cPr 4-NHCOCF3 421 iPr cPr 4-NHCOCH2CN 422 iPr cPr 4-NHCOCH2OH 423 iPr cPr 4-NHCOCH2OH 423 iPr cPr iPr cPr 4-NHCOCH2NHCOMe 425 iPr cPr 4-NHCOCH2N (Me) COMe 426 iPr cPr 4-NHCOCH2OMe 427 iPr cPr 4-NHCOCH2OEt 428 iPr cPr 4-NHCOCH2OCOMe 429 iPr cPr 4-NHCOCHPCOCHPSMCH4SMR 430P NHCOCH2COMe 432 iPr cPr 4-NHCOCH2COOMe 433 iPr cPr 4-NHCOCH2COOEt 434 iPr cPr 4-NHCOcPr 435 iPr cPr 4-NHCOcBu 436 iPr cPr 4-NHCOcPen 437 iPr cPr 4-NHCOPhPr 438 iPr c cPr 4-NHCOPh (4-CN) 440 iPr cPr 4-NHCOPy (4-) 441 iPr cPr 4-NHCOPy (3-) 442 iPr cPr 4-NHCOPy (2-) 443 iPr cPr 4-NHCOOMe 444 iPr cPr 4- NHCOOEt 445 iPr cPr 4-NHSO2Me 446 iPr cPr 4-NHSO2Et 447 iPr cPr 4- (2-azetidinone-1-yl) 448 iPr cPr 4- (2-pyrrolidinone-1-yl) 449 iPr cPr 4- (2-oxazolidinone -1-yl) 450 iPr cPr 4- (2-piperidinone-1-yl) 451 iPr Me2C H 452 iPr Me2C 4-F 453 iPr Me2C 4-Cl 454 iPr Me2C 4-Br 455 iPr Me2C 4-I 456 iPr Me2C 4-CN 457 iPr Me2C 4-NO2 458 iPr Me2C 4-Me 459 iPr Me2C 4-CF3 460 iPr Me2C 4-OH 461 iPr Me2C 4-OMe 462 iPr Me2C 4- OEt 463 iPr Me2C 4-OCH2OMe 464 iPr Me2C 4-OCH2CH2OMe 465 iPr Me2C 4-NH2 466 iPr Me2C 4-NHMe 467 iPr Me2C 4-NHEt 468 iPr Me2C 4-NMe2 469 iPr Me2C 4-NHCOMe 471 iPr Me2C iPr Me2C 4-NHCOCH2CN 472 iPr Me2C 4-NHCOCH2OH 473 iPr Me2C 4-NHCOCH2NH2 474 iPr Me2C 4-NHCOCH2NHCOMe 475 iPr Me2C 4-NHCOCH2N (Me) COMe 476 iPr Me2C 4-NHCOCH2OMr 477 iNHCH 477 iNH NHCOCH2OCOMe 479 iPr Me2C 4-NHCOCH2SMe 480 iPr Me2C 4-NHCOCH2SEt 481 iPr Me2C 4-NHCOCH2COMe 482 iPr Me2C 4-NHCOCH2COOMe 483 iPr Me2C 4-NHCOCH2COOEt 484 iPr Me2C 4-NH iCOr Me2C 4-NHCOCHPCOr iPr Me2C 4-NHCOPh 488 iPr Me2C 4-NHCOPh (4-MeO) 489 iPr Me2C 4-NHCOPh (4-CN) 490 iPr Me2C 4-NHCOPy (4-) 491 iPr Me2C 4-NHCOPy (3-) 492 iPr Me2C 4-NHCOPy (2-) 493 iPr Me2C 4-NHCOOMe 494 iPr Me2C 4-NHCOOEt 495 iPr Me2C 4-NHSO2Me 496 iPr Me2C 4-NHSO2Et 497 iPr Me2C 4- (2-azetidinone-1-yl) 498 iPr Me2C 4- (2-pyrrolidinone-1-yl) 499 iPr Me2C 4- (2-oxazolidinone-1-yl) 500 iPr Me2C 4- (2-piperidinone -1-yl) 501 iPr Et2C H 502 iPr Et2C 4-F 503 iPr Et2C 4-Cl 504 iPr Et2C 4-Br 505 iPr Et2C 4-I 506 iPr Et2C 4-CN 507 iPr Et2C 4-NO2 508 iPr Et2C 4- Me 509 iPr Et2C 4-CF3 510 iPr Et2C 4-OH 511 iPr Et2C 4-OMe 512 iPr Et2C 4-OEt 513 iPr Et2C 4-OCH2OMe 514 iPr Et2C 4-OCH2CH2OMe 515 iPr Et2C 4-NH2 516 iPr Et2C 4-NHMe 517 iPr Et2C 4-NHEt 518 iPr Et2C 4-NMe2 519 iPr Et2C 4-NHCOMe 520 iPr Et2C 4-NHCOCF3 521 iPr Et2C 4-NHCOCH2CN 522 iPr Et2C 4-NHCOCH2OH 523 iPr Et2C 4-NHCOCH2NH2C 524iPrCH Et 4-NHCOCH2N (Me) COMe 526 iPr Et2C 4-NHCOCH2OMe 527 iPr Et2C 4-NHCOCH2OEt 528 iPr Et2C 4-NHCOCH2OCOMe 529 iPr Et2C 4-NHCOCH2SMe 530 iPr Et2C 4-NHCOCH2SEt 531 iPrCO2CH2CO2CH2CO2CH4CO2CH2CO4 iPr Et2C 4-NHCOCH2COOEt 534 iPr Et2C 4-NHCOcPr 535 iPr Et2C 4-NHCOcBu 536 iPr Et2C 4-NHCOcPen 537 iPr Et2C 4-NHCOPh 538 iPr Et2C 4-NHCOPh (4-MeO) 539 iPr Et2C 4-NHCOPh (4-CN) 540 iPr Et2C 4-NHCOPy (4-) 541 iPr Et2C 4-NHCOPy (3-) 542 iPr Et2C 4-NCOPy (2-) 543 iPr Et2C 4-NHCOOMe 544 iPr Et2C 4-NHCOOEt 545 iPr Et2C 4-NHSO2Me 546 iPr Et2C 4-NHSO2Et 547 iPr Et2C 4- (2-azetidinone-1-yl) 548 iPr Et2C 4 -(2-pyrrolidinone-1-yl) 549 iPr Et2C 4- (2-oxazolidinone-1-yl) 550 iPr Et2C 4- (2-piperidinone-1-yl) 551 iPr H2C H 552 iPr H2C 4-F 553 iPr H2C 4-Cl 554 iPr H2C 4-Br 555 iPr H2C 4-I 556 iPr H2C 4-CN 557 iPr H2C 4-NO2 558 iPr H2C 4-Me 559 iPr H2C 4-CF3 560 iPr H2C 4-OH 561 iPr H2C 4 -OMe 562 iPr H2C 4-OEt 563 iPr H2C 4-OCH2OMe 564 iPr H2C 4-OCH2CH2OMe 565 iPr H2C 4-NH2 566 iPr H2C 4-NHMe 567 iPr H2C 4-NHEt 568 iPr H2C 4-NMe2 569 iPr He 570 iPr H2C 4-NHCOCF3 571 iPr H2C 4-NHCOCH2CN 572 iPr H2C 4-NHCOCH2OH 573 iPr H2C 4-NHCOCH2NH2 574 iPr H2C 4-NHCOCH2NHCOMe 575 iPr H2C 4-NHCOCH2N (Me) COMe 576iCOH2C4HCOC2 -NHCOCH2OEt 578 iPr H2C 4-NHCOCH2OCOMe 579 iPr H2C 4-NHCOCH2SMe 580 iPr H2C 4-NHCOCH2SEt 581 iPr H2C 4-NHCOCH2COMe 582 iPr H2C 4-NHCOCH2COOMe 583 iPr H2C 4-NHCOCH2COOEt 584 iPrH2C 4-NHCOCH2COOEt 584 iPrHP -NHCOcPen 587 iPr H2C 4-NHCOPh 588 iPr H2C 4-NHCOPh (4-MeO) 589 iPr H2C 4-NHCOPh (4-CN) 590 iPr H2C 4-NHCOPy (4-) 591 iPr H2C 4-NHCOPy (3-) 592 iPr H2C 4-NHCOPy (2-) 593 iPr H2C 4-NHCOOMe 594 iPr H2C 4-NHCOOEt 595 iPr H2C 4-NHSO2Me 596 iPr H2C 4-NHSO2Et 597 iPr H2C 4- (2-azetidinone-1-yl) 598 iPr H2C 4- (2-pyrrolidinone-1-yl) 599 iPr H2C 4- (2-oxazolidinone-1-yl) 600 iPr H2C 4- (2-piperidinone-1-yl) 601 sBu cPen 3-NH2 602 sBu cPen 3 -NHMe 603 sBu cPen 3-NHCOMe 604 sBu cPen 3-NHCOCF3 605 sBu cPen 3-NHCOCN 606 sBu cPen 3-NHCOCH2OMe 607 sBu cPen 3-NHCOOMe 608 sBu cPen 3-NHSO2Me 609 sBu cPen 3- (2-pyrrolidinone Yl) 610 sBu cPen 3- (2-oxazolidinone-1-yl) 611 sBu cBu 3-NH2 612 sBu cBu 3-NHMe 613 sBu cBu 3-NHCOMe 614 sBu cBu 3-NHCO CF3 615 sBu cBu 3-NHCOCN 616 sBu cBu 3-NHCOCH2OMe 617 sBu cBu 3-NHCOOMe 618 sBu cBu 3-NHSO2Me 619 sBu cBu 3- (2-pyrrolidinone-1-yl) 620 sBu cBu 3- (2-oxazolidinone-1 -Ill) 621 sBu Me2C 3-NH2 622 sBu Me2C 3-NHMe 623 sBu Me2C 3-NHCOMe 624 sBu Me2C 3-NHCOCF3 625 sBu Me2C 3-NHCOCN 626 sBu Me2C 3-NHCOCH2OMe 627 sBu Me2C 3-NHCOOMe 628 sBu Me2C NHSO2Me 629 sBu Me2C 3- (2-pyrrolidinone-1-yl) 630 sBu Me2C 3- (2-oxazolidinone-1-yl) Of the above compounds, Exemplified Compound No. 11 and 1 are preferable.
5, 16, 18, 19, 20, 21, 22, 23, 2
4, 25, 26, 28, 29, 34, 35, 37, 3
8, 39, 40, 41, 42, 43, 45, 47, 4
8, 49, 50, 61, 65, 68, 69, 70, 7
1, 72, 73, 74, 75, 76, 78, 79, 8
4, 85, 87, 88, 89, 90, 91, 92, 9
3, 95, 97, 98, 99, 100, 115, 11
9, 126, 145, 161, 165, 168, 16
9, 170, 171, 172, 173, 174, 17
5, 176, 178, 179, 184, 185, 18
7, 188, 189, 190, 191, 192, 19
3, 195, 197, 198, 199, 200, 21
5, 219, 226, 245, 265, 269, 27
6 or 295, and more preferably, Exemplified Compound Nos. 15, 19, 26, 45, 6
The compounds of 5, 69, 76, 95, 165, 169, 176, or 195 can be mentioned, and particularly preferably, the exemplified compound numbers 15, 19, 26, 45, 165,
169, 176, or 195 compounds can be mentioned.

[0053]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by formula (I) of the present invention can be produced by the following method.

[0054]

[Chemical 5]

[0055]

[Chemical 6]

A compound represented by the formula (III) which is a starting material of the present production method (in the formula, -Y: = O, -OSi (Me) ₂ tBu)
Are known compounds obtained by oxidizing or silylating manganese dioxide of known 22,23-dihydro-avermectin-aglycone or avermectin-aglycone (J. Org. Chem., 1989, Vol54). , 1756-1
757, see JP-A-4-352794).

Of the compounds represented by the following general formula (V), which is another starting material of this production method, the following (VIb)
The compound represented by can be produced as follows.

[0058]

[Chemical 7]

(In the above formula, R ² and R ³ have the same meanings as described above.) (VIb) can be produced by combining the known compound (VIa) with a known method. That is, the carboxylic acid moiety is esterified, then the nitro group is catalytically reduced to an amino group, and the resulting amino compound is acylated or sulfonylated with a suitable reagent in the presence of a base.
When the obtained amide is further reacted with an alkylating agent such as methyl iodide in the presence of sodium hydride, a compound having an alkyl group introduced into R ⁶ can be obtained. Further, a cyclized product can be obtained by causing intramolecular alkylation by causing sodium hydride to act on a compound having a leaving group such as halogen at a suitable position on the alkyl side chain of an acyl group or an alkanesulfonyl group. . Finally, the ester portion is converted into a carboxylic acid by a means such as hydrolysis to produce (VIb). Step A A method for producing a compound represented by the general formula (IV), which is strong against an avermectin derivative having an oxo group (Y: = O) at the 5-position among the compounds represented by the general formula (III). In the presence of trifluoromethanesulfonic acid which is an organic acid or its trimethylsilyl ether, a compound of the general formula (V) (wherein R ² and / or R ³ is an alkyl group or R
² and R ³ together represent a cycloalkyl group, and R ⁴ has the same meaning as described above. ) Is carried out by reacting with a carboxylic acid.

The amount of trifluoromethanesulphonic acid or its trimethylsilyl ether used is, in principle, a catalytic amount, one equivalent is not necessary, but can vary considerably depending on the reactivity of the carboxylic acid 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 more 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 some extent. Preferably, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, 1,2
-Halogenated hydrocarbons such as dichloroethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide Examples thereof include amides; sulfoxides such as dimethyl sulfoxide, and nitriles such as acetonitrile. Reaction temperature is -1
It is carried out at 0 ° 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.

In particular, when a carboxylic acid having no substituent at the α-position is used in this step, it can also be produced by the following method.

An acid of a carboxylic acid represented by the general formula (V) (wherein R ² and R ³ represent H) in the presence of a base in the compound represented by the general formula (III). It is also possible to directly acylate with chloride. In this case, in addition to the 5-position oxo group (Y: = O), the 5-position hydroxyl group is replaced by a general protective group such as t-butyldimethylsilyl group (Y: -OSi (Me) ₂ tBu). Protected avermectin derivatives can be used.

The amount of acid chloride used is 1 to 3 equivalents, and suitable bases include, for example, triethylamine, N, N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo [ 4.
Examples include organic bases such as 3.0] nonene-5 (DBN) or 1,8-diazabicyclo [5.4.0] undecene-7 (DBU).

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 some extent. Preferably, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, 1,2
-Halogenated hydrocarbons such as dichloroethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide Examples thereof include amides; sulfoxides such as dimethyl sulfoxide, and nitriles such as acetonitrile.

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

The reaction time varies depending mainly on the reaction temperature, the starting compound or the type of solvent used, but is usually 5 minutes to 6 hours, and preferably 10 minutes to 2 hours. Step B In the step B, Y of the compound represented by the general formula (IV) is replaced with OH.
Is a process of converting into.

The compound represented by the general formula (IV) is 5-
In the case of the oxo form (Y: = O), it is a step of reacting with a reducing agent such as sodium borohydride to convert the carbonyl group at the 5-position into a hydroxyl group.

In the reaction, a reducing agent known to reduce a carbonyl group to a hydroxyl group such as sodium borohydride or lithium borohydride can be widely 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, and examples thereof include lower alcohols such as methanol, ethanol and propanol, and ethers such as tetrahydrofuran and dimethoxyethane.

The reaction temperature is usually -50 ° C to 50 ° C, preferably -40 ° C to 0 ° C. The reaction time varies depending mainly on the reaction temperature, the starting compound or the type of solvent used, but is usually 10 minutes to 10 hours, and preferably 10 minutes to 30 minutes.

The compound represented by the general formula (IV) is t-
In the case of a butyldimethylsilyloxy group (Y: OSi (Me) ₂ tBu), a known method used for elimination of t-butyldimethylsilyl group (for example, Protecting Group in Organi
c Synthesis, Third Ed., p135 John Wieley & Sonc In
Although c.) can be widely used, it is preferably a method of treating with an acid in a solvent, for example, a method of treating with hydrochloric acid in methanol. The reaction is usually performed at 0 ° C to 50 ° C, preferably 0 ° C to 25 ° C. The reaction time varies depending on the reaction temperature and other reaction conditions, but is usually 10 minutes to 10 hours, and preferably 10 minutes to 2 hours.

The following steps C and D are represented by the general formula (I)
The method for producing the compound represented by the general formula (Ic) among the compounds represented by Step C Step C is the general formula (Ia) (wherein R ¹ has the same meaning as described above, and Y ′ represents OH or OSi (Me) ₂ tBu).
Is a step of reducing the nitro group of the compound represented by to produce a compound represented by the general formula (Ib) having an amino group.

For reduction of the nitro group, a commonly used method can be used. One of such examples is catalytic reduction using a noble metal catalyst. Suitable catalysts for the reaction include palladium-carbon, palladium-barium sulfate, platinum oxide and the like.

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 usually 10 ° C to 80 ° C,
It is preferably 10 ° C to 30 ° C. The reaction time varies depending mainly on the reaction temperature, the starting compound or the type of solvent used, but is usually 10 minutes to 5 hours, and preferably 1
It is from 0 minutes to 1 hour.

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

The reaction temperature is usually 0 ° C. to room temperature. The reaction time varies depending mainly on the reaction temperature, the starting compound or the type of solvent used, but is 30 minutes to 12 hours,
It is preferably 30 minutes to 1 hour.

As a more preferable reduction method, reduction with sodium borohydride in the presence of a nickel catalyst can be mentioned. As the nickel catalyst, nickel salts such as nickel chloride and nickel bromide can be used, but more preferred are triphenylphosphine complexes of these nickel salts.

Suitable solvents for use in the reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane.

The reaction temperature is usually 0 ° C. to room temperature. The reaction time varies depending mainly on the reaction temperature, the starting compound or the type of solvent used, but is usually 10 minutes to 120 minutes, and preferably 10 minutes to 30 minutes. Step D In Step D, the amino group of the compound represented by the general formula (Ib) is reacted with a reactive derivative to give a compound represented by the general formula (Ic) (in the formula,
R ¹ , R ² and R ³ have the same meanings as defined above, and R ⁸
Is a general formula: R ⁷ —CO (R ⁷ has the same meaning as described above), a C ₁ -C ₄ alkylsulfonyl group, or
Shows the C ₁ -C ₄ alkoxycarbonyl group. ) Is a step of producing a compound represented by

The reactive derivative used is, for example, acid halide (acid chloride, acid bromide, etc.), acid anhydride,
Examples include mixed acid anhydrides, active esters, active amides and the like, which are commonly used in condensation reactions.

When an acid halide is used in the reaction, it is preferably carried out in the presence of a base. Examples of suitable bases include triethylamine, N, N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1, 5-diazabicyclo [4.3.0] nonene-5 (DBN) or 1,8-diazabicyclo [5.4.0] undecene-7
Examples include organic bases such as (DBU).

The acid halide is usually used in 1 to 10 equivalents, and the base is usually used in 2 to 8 equivalents.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferably, hydrocarbons such as hexane, petroleum ether, benzene and toluene, 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 a mixture of these solvents and the like, 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 starting 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.

In the case of an acid represented by R ⁷ -COOH (wherein R ⁷ has the same meaning as described above), it can be used as a reactive derivative in the reaction system. In that case, For example, a dehydrating agent such as dicyclohexylcarbodiimide (DCC), 2-chloro-1-methylpyridinium iodide, p-toluenesulfonic acid or sulfuric acid is used, and preferably 2-chloro-1-methylpyridinium iodide is used. It
The amount used is relative to the acid represented by R ⁷ -COOH,
It is usually 1 to 5 equivalents, preferably 1 to 2 equivalents.

The reaction temperature, reaction time, and solvent used are the same as those when the above acid halide is used.

After completion of the reaction in the above step, if the 5-position hydroxyl group is protected, the protecting group is removed by the method described above.

General formula (I) obtained in step B and step D
The compounds represented by (Ic) and (Ic) are isolated from the reaction mixture by a known method and, if necessary, purified by a known means such as column chromatography.

The natural avermectins and their related compounds, which are the starting materials for the compound represented by the general formula (III), are fermentation products and may be either a single compound or a mixture thereof. Therefore, the general formula (I)
The compound represented by can also be manufactured as a single compound or a mixture.

The novel 13-substituted milbemycin derivatives of the present invention represented by the above general formula (I) have insecticidal or anthelmintic activity and are excellent control against various insects parasitic on animals and various diseases caused by parasites. Show the effect.

That is, the compound of the present invention exhibits an excellent insecticidal effect against fleas parasitic on pets and humans, and is extremely effective as a repellent for these. Examples of fleas include cat fleas (Ctenocephalides felis) and dog fleas (Ctenocephalides felis).
ocephalides canis) and the like.

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

Examples of insects include the fruit fly (Gastero)
philus spp.), sand flies (Stomoxys spp.), lice (Tr
ichodectes spp.), reed turtles (Rhodnius spp.) and the like. In addition, Ixodidae (Ix
odidae), the arachnid family (Dermanyssid-ae), and the mites family (Sarcoptidae).

Furthermore, the compounds of the present invention have excellent parasiticidal activity as anthelmintic agents for animals and humans, especially domestic animals such as pigs, sheep, goats, cows, horses, dogs, cats and chickens.
Effective against the following nematodes that infect poultry and pets: Haemonchus, Trichoslongilus (Tri
chostrongylus), Ostertagia, Nematodirus, Cooperi
a), Ascaris, and Bunostom
tomum), the genus Oesophagostomum (Oesophagostomum),
Chabertia, Triculis (Trichur
is), Stronongylus, Triconema
(Trichonema), Dictyocaulus genus (Dictyocaulus),
Capillaria, Heteraki
s), Toxocara, Ascadia (Asca)
ridia), Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parasca.
ris).

Certain species of Nematodillus, Cooperia and Esagogostomum attack the intestinal tract, while those of the genus Hemonx and Ostertergia parasitize the stomach and the parasites of the Tichtiocaurus genus 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 that parasitize the human digestive tract are the genus Ancylostoma and the genus Necatol.
(Necator), Ascaris (Asdaris), Strongyloides (Strongyloides), Trichinella (Trichinell)
a), Capillaria, Triculis (Tr
ichuris) 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 Deracunculus parasites of the family Dracunculidae (Deracunculidae), as well as the genus Strongyleutes and Trichinella in the special intestinal parasitism state of intestinal parasites.

When the avermectin derivative having the above-mentioned general formula (I) of the present invention or a pharmacologically acceptable salt thereof is used as an anthelmintic agent in animals or humans, for example, liquid beverage, dry solid unit use As a form, or dispersed in feed and administered orally, or dissolved or dispersed in a liquid carrier excipient for injection, or dissolved in a solvent and administered locally, parenterally It can be administered.

Beverages may include solutions, suspensions or dispersions, usually consisting of a suitable non-toxic solvent or water, with suspending agents such as bentonite and wetting agents or other excipients, If desired, a defoaming agent can be contained. Beverage formulations may include beverages containing from about 0.01 to 0.5% by weight (preferably 0.01 to 0.1% by weight) of active compound.

For oral administration in a dry solid unit dosage form, capsules, pills or tablets containing the desired amount of the active compound will usually be employed. These use forms are such that the active ingredient is homogeneous with suitable finely divided diluents, fillers, disintegrants and / or binders such as starch, lactose, talc, magnesium stearate or vegetable gums. It is manufactured by mixing with. Such unit-use formulation can appropriately change the weight and content of the anthelmintic agent depending on the type of host animal to be treated, the degree of infection, the type of parasite and the weight of the host.

When administered by animal feed, the compounds of the invention can be homogeneously dispersed in the feed, used as a top dressing or used in the form of pellets. Generally, the desired antiparasitic effect is obtained when the final feed contains 0.0001 to 0.02% of the compound of the present invention.

A solution or dispersion in a liquid carrier excipient can be parenterally administered to animals by intragastric, intramuscular, intratracheal or subcutaneous injection. For parenteral administration, the compounds of the present invention may be mixed with vegetable oils such as, for example, peanut oil or cottonseed oil. Generally, when the compound of the present invention is contained in an injection at 0.05 to 50% by weight, a desired antiparasitic effect is obtained.

When the drug is dissolved in a solvent and directly administered topically, the solvent used is known to enhance the transdermal absorbability, for example, ethanol, isopropanol, oleyl alcohol or benzyl alcohol. Such alcohols; carboxylic acids such as lauric acid or oleic acid; esters such as isopropyl myristate or propylene carbonate; sulfoxides such as dimethyl sulfoxide; amides such as N-methylpyrrolidone; Mention may be made of mixed solvents.

The optimum amount of the compound having the general formula (I) or a pharmaceutically acceptable salt thereof of the present invention for obtaining the best results depends on the kind of animal to be treated, the type and degree of parasitic infection. Normally, when administered orally, the amount is about 0.01 to 100 mg / kg of animal body weight (preferably,
0.5 to 50.0 mg) is preferably administered 1 to 6 times a day for 1 to 5 days depending on the symptoms.

[0109]

EXAMPLES The present invention will be described in detail below with reference to Examples and Test Examples.
However, the scope of the present invention is not limited to these.
is not.Example 1 13-O- [1- (4-methoxyacetylaminophenyl) siku
Lopentanecarbonyl] -22,23-dihydro-avermek
Chin B_1a-Aglycon (R¹: Sec-butyl, R², R ³: Shi
Clopentyl, R^Four: 4-methoxyacetylamino, eg
Compound number 26) (Step 1) 4-nitrophenyl cyclopentane carvone
Dissolve acid (2.25g) in dichloromethane (30ml)
And trimethylsilyl trifluoromethanesulfonate
Add stell (50 μl) and add 5-oxo-22,23-dihydride
B-Avermectin B_1aAglycon (1.40g) jiku
Lormethane (8 ml) solution was added dropwise at 40 ° C for 20 minutes.
It was stirred. Ethyl acetate and 4% sodium bicarbonate in the reaction mixture
Equivalent mixture of aqueous solution (10 ml) was added and stirred
Afterwards, extract with dichloromethane, 10% sodium hydrogen carbonate
Wash with aqueous solution, water, dry over anhydrous sodium sulfate, and depressurize
Evaporated to dryness below. Residue in methanol (30 ml)
Melt and bring to -40 ° C, then sodium borohydride
(99.5 mg) and boron trifluoride A
Add the telluride (catalyst amount) and stir at -40 ° C for 1 hour.
It was Ethyl acetate (50 ml) was added to the reaction mixture to dilute it,
4% sodium hydrogen carbonate solution, wash with water, anhydrous sodium sulfate
It was dried over triumnium and evaporated to dryness under reduced pressure. Empty the residue
Chromatography (ODS, 90% -100%
(Toluene gradient elution)
Gave a mixture (0.72 g) containing the desired compound.
It was

This mixture was mixed with dichloromethane (20 ml).
Dissolved in t-butyldimethylsilyl chloride (40
6.9 mg) and imidazole (367.6 mg) were added, and the mixture was stirred at room temperature for 4 hours. Dichloromethane (1
(0 ml) was added to dilute, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Column chromatography of the residue (silica gel, ethyl acetate / hexane =
5-O-t-
Butyldimethylsilyl-13-O- [1- (4-nitro) cyclopentanecarbonyl] -22,23-dihydro-avermectin B _1a aglycone (0.53g, 5-oxo-22,23-dihydro-avermectin B _1a aglycone Yield from 24.3
%)was gotten. (Step 2) 5-O-t-butyldimethylsilyl-13-O- [1- (4-nitro) cyclopentanecarbonyl] -22,23-dihydro-avermectin B _1a aglycone obtained in (Step 1) Was dissolved in methanol (3 ml), and bis (triphenylphosphine) nickel (II) chloride (7
5.9 mg) was added, and the mixture was ice-cooled, sodium borohydride (87.8 mg) was slowly added, and the mixture was stirred at 4 ° C. for 20 minutes. Ethyl acetate / water / acetic acid (10 ml / 0.
5 ml / 10 ml) and extracted with ethyl acetate, 4%
It was washed with sodium borohydride solution, water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was separated by column chromatography (silica gel, eluted with ethyl acetate / hexane = 1: 9) to give 5-O.
-T-Butyldimethylsilyl-13-O- [1- (4-amino)
Cyclopentanecarbonyl] -22,23-dihydro-avermectin B _1a aglycone (0.50 g, 97.1 yield)
%)was gotten. (Step 3) 5-O-t-butyldimethylsilyl-13-O- [1- (4-amino) cyclopentanecarbonyl] -22,23-dihydro-avermectin B _1a aglycone obtained in (Step 2) (88.8 mg) with dichloromethane (2 ml)
, Pyridine (8.9 μl) and methoxyacetyl chloride (10.0 μl) were added at 4 ° C., and the mixture was stirred for 1 hour. The reaction solution was diluted with dichloromethane (10 ml), washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was dissolved in methanol (2 ml), 1M-hydrochloric acid aqueous solution (0.3 ml) was added, and the mixture was stirred at room temperature for 4 hours.
Stir for hours. The reaction solution was diluted with ethyl acetate (10 ml), washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Column chromatography of the residue (silica gel, elution with ethyl acetate: hexane = 2: 8)
The target compound, 13-O- [1
-(4-Methoxyacetylaminophenyl) cyclopentanecarbonyl] -22,23-dihydro-avermectin B _1a
Aglycone (70.8 mg, yield 83.7%) was obtained as an amorphous solid.

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 8.27 (1H, s), 7.52 (2H, d, J = 8.6Hz), 7.40 (2H,
d, J = 8.6Hz), 5.85 (1H, dt, J = 11.2 & 2.1Hz), 5.67 (1H,
dd, J = 15.0 & 11.2Hz) 5.45 (1H, s), 5.37 (1H, dd, J = 1.0
& 10.0Hz) 5.26 (1H, m), 4.97 (1H, s) 4.76 (1H, m) 4.67
and 4.63 (2H, AB-q, J = 14.3Hz), 4.30 (1H, t, J = 6.9H
z), 4.26 (1H, s), 4.04 (2H, d, J = 6.8Hz), 3.96 (1H, d,
J = 6.3Hz), 3.58 (1H, m), 3.50 (3H, s) 3.25 (1H, m), 3.2
0 (1H, m), 2.30 (1H, d, J = 8.5Hz) 1.88 (3H, s), 1.29 (1
H, t, J = 11.7Hz), 1.01 (3H, t, J = 7.3Hz), 0.88 (3H, d,
J = 6.7Hz) 0.81 (3H, d, J = 5.4Hz), 0.64 (3H, d, J = 6.8H
z). Mass spectrum m / e: = 845 (M = C ₄₉ H ₆₇ NO ₁₁ ). Example 2 13-O- [1- (4-acetylaminophenyl) cyclopentanecarbonyl] -22,23-dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² , R ³ : cyclopentyl, R ⁴ : 4-acetylamino, Exemplified Compound No. 19) In Example 1, (Step 3), acetyl chloride was used instead of methoxyacetyl chloride. Was used to give the title compound as an amorphous solid (yield 83.2%).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.44 (2H, d, J = 8.6Hz), 7.38 (2H, d, J = 8.6Hz),
7.24 (1H, s) 5.82 (1H, m), 5.67 (1H, dd, J = 14.9 & 11.2Hz),
5.45 (1H, s), 5.36 (1H, dd, J = 14.9 & 10.0Hz), 5.29 (1
H, m), 4.98 (1H, s), 4.80 (1H, m), 4.67 and 4.63 (2H, AB
-q, J = 14.2Hz), 4.30 (1H, m), 4.22 (1H, s), 3.96 (1H,
d, J = 6.0Hz), 3.60 (1H, m), 3.26 (1H, m), 3.20 (1H,
m), 2.32 (1H, d, J = 8.2Hz) 2.17 (3H, s) 1.89 (3H, s),
1.31 (1H, t, J = 11.7Hz), 1.01 (3H, t, J = 7.3Hz), 0.88
(3H, d, J = 6.7Hz) 0.81 (3H, d, J = 5.1Hz), 0.62 (3H, d,
J = 6.9 Hz). Mass spectrum m / e: = 815 (M = C ₄₈ H ₆₅ NO ₁₀ ). Example 3 13-O- [1- (4-methanesulfonylaminophenyl) cyclopentanecarbonyl] -22,23 -Dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² , R ³ : cyclopentyl, R ⁴ : 4-methanesulfonylamino,
Exemplified Compound No. 45) The title compound was obtained as an amorphous solid by using methanesulfonyl chloride instead of methoxyacetyl chloride in (Step 3) of Example 1 (yield 10
0.0%) Nuclear magnetic resonance spectrum (400MHz) δ (ppm): 7.42 (2H,
d, J = 8.6Hz), 7.19 (2H, d, 8.6Hz), 6.51 (1H, s), 5.79
(1H, dt, J = 11.4 & 2.2Hz), 5.68 (1H, dd, J = 14.7 & 11.4H
z), 5.45 (1H, s), 5.40 ~ 5.30 (2H, m), 4.99 (1H, s),
4.89 (1H, m) 4.67and 4.62 (2H, AB-q, J = 14.3Hz), 4.30
(1H, m), 4.01 (1H, s), 3.96 (1H, d, J = 6.1Hz), 3.62 (1
H, m), 3.28 (1H, m), 3.21 (1H, m), 2.97 (3H, s), 2.34
(1H, d, J = 8.1Hz), 1.88 (3H, s), 1.33 (1H, t, J = 11.7H
z), 1.00 (3H, t, J = 7.3Hz), 0.88 (3H, d, J = 6.7Hz), 0.
56 (3H, d, J = 6.8Hz). Mass spectrum m / e: = 851 (M = C ₄₇ H ₆₅ NO ₁₁ S) Example 4 13-O- [1- (4-aminophenyl) cyclopentanecarbonyl ] -22,23-Dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² , R ³ : cyclopentyl,
R ^4: 4-methanesulfonyl amino, Compound No. 15) 5-O-t- butyl obtained in Example 1 (Step 2) dimethylsilyl -13-O - [1- (4- amino) cyclopentane Carbonyl] -22,23-dihydro-avermectin B _1a aglycone (250 mg) was dissolved in methanol (5 ml),
1M-hydrochloric acid aqueous solution (1.0 ml) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate (30 ml), washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was separated and purified by column chromatography (silica gel, eluted with ethyl acetate: hexane = 1: 1) to obtain 206.5 mg of the target compound as an amorphous solid (yield 95.3%).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.20 (2H, d, J = 8.6Hz), 6.65 (2H, d, 8.6Hz), 5.79
(1H, dt, J = 11.4 & 2.2Hz), 5.67 (1H, dd, J = 14.9 & 11.4H
z), 5.45 (1H, s), 5.41 ~ 5.32 (2H, m), 4.98 (1H, s),
4,85 (1H, m), 4.67 and 4.63 (2H, AB-q, J = 14.4Hz), 4.30
(1H, m), 3.97 (1H, d, J = 6.1Hz), 3.60 (1H, m), 3.28 (1
H, m), 3.21 (1H, m), 1.88 (3H, s), 1.33 (1H, t, J = 11.
7Hz), 1.01 (3H, t, J = 7.3Hz), 0.88 (3H, d, J = 6.6Hz),
0.81 (3H, d, J = 5.5Hz), 0.62 (3H, d, J = 6.9Hz). Mass spectrum m / e: = 773 (M = C ₄₆ H ₆₃ NO ₉ ). The compounds of Example 5 to Example 20 were obtained in the same manner as in 4. Example 5 13-O- [1- (4-methoxyacetylaminophenyl) cyclobutanecarbonyl] -22,23-dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² , R ³ : cyclobutyl, R ⁴ : 4-methoxyacetylamino, Exemplified Compound No. 76) In Example 1, (Step 1), the title compound was made amorphous by using 4-nitrophenylcyclobutanecarboxylic acid instead of 4-nitrophenylcyclopentanecarboxylic acid. Obtained as a solid (yield 84.2%: from amino compound).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 8.30 (1H, s), 7.54 (2H, d, J = 8.4Hz), 7.30 (2H,
d, J = 8.4Hz), 5.85 (1H, dt, J = 11.3 & 2.2Hz), 5.66 (1H,
dd, J = 15.0 & 11.3Hz), 5.45 (1H, s), 5.32 (1H, dd, J = 1
5.0 & 10.0Hz), 5.21 (1H, m), 5.00 (1H, s), 4.75 (1H,
m), 4.66 and 4.62 (2H, AB-q, J = 14.3Hz), 4.41 (1H,
s), 4.30 (1H, m), 3.96 (1H, d, J = 6.1Hz), 3.57 (1H,
m), 3.51 (3H, s) 3.24 (1H, m), 3.23 (1H, m), 2.30 (1H,
d, J = 8.5Hz), 1.88 (3H, s), 1.00 (3H, t, J = 7.3Hz), 0.
88 (3H, d, J = 6.6Hz), 0.81 (3H, d, J = 5.3Hz), 0.72 (3H,
d, J = 6.9 Hz). Mass spectrum m / e: = 831 (M = C ₄₈ H ₆₅ NO ₁₁ ). Example 6 13-O- [1- (4-acetylaminophenyl) cyclobutanecarbonyl] -22,23 -Dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² , R ³ : cyclobutyl,
R ^4: 4-acetylamino, in the illustrated compound No. 69) of Example 2 (step 1), the title compound by using 4-nitrophenyl cyclobutanecarboxylic acid instead of 4-nitrophenyl cyclopentanecarboxylic acid Amorphous It was obtained as a solid (yield 86.5%: from amino compound).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.45 (2H, d, J = 8.5Hz), 7.28 (2H, d, J = 8.5Hz),
5.82 (1H, m), 5.67 (1H, dd, J = 14.9 & 11.2Hz), 5.46 (1H,
s), 5.30 (1H, dd, J = 14.9 & 9.9Hz), 5.25 (1H, m), 5.00
(1H, s), 4.77 (1H, m), 4.66 and 4.63 (2H, AB-q, J = 1
4.3Hz), 4.34 (1H, s), 4.30 (1H, m) 3.96 (1H, d, J = 6.0H
z), 3.57 (1H, m), 3.27 (1H, m), 3.23 (1H, m), 2.32 (1H,
d, J = 10.3Hz), 1.89 (3H, s), 1.30 (1H, t, J = 11.7Hz),
1.00 (3H, t, J = 7.3Hz), 0.88 (3H, d, J = 6.7Hz), 0.81 (3
H, d, J = 7.3Hz), 0.69 (3H, d, J = 6.9Hz). Mass spectrum m / e: = 801 (M = C ₄₇ H ₆₃ NO ₁₀ ) Example 7 13-O- [1- (4-Methanesulfonylaminophenyl) cyclobutanecarbonyl] -22,23-dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² , R ³ : cyclobutyl, R ⁴ : 4-methanesulfonylamino, exemplified compound number 95) In (Step 1) of Example 3, the title compound was obtained as an amorphous solid by using 4-nitrophenylcyclobutanecarboxylic acid instead of 4-nitrophenylcyclopentanecarboxylic acid (yield 92.2%: (From the amino form).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.32 (2H, d, J = 8.5Hz), 7.23 (2H, d, J = 8.5Hz), 6.
63 (1H, s), 5.75 (1H, dt, J = 11.3 & 2.1Hz), 5.68 (1H, d
d, J = 14.4 & 11.3Hz), 5.45 (1H, s), 5.35 (1H.m), 5.27
(1H, dd, 14.4 & 10.1Hz), 5.03 (1H.s), 4.94 ~ 4.90 (1H,
 m), 4.67 and 4.62 (2H, AB-q, J = 14.4Hz), 4.30 (1H,
m), 4.04 (1H, s), 3.95 (1H, d, J = 6.1Hz), 3.66 ~ 3.60 (1
H, m), 3.28 (1H, m), 3.22 (1H, m), 2.99 (3H, s), 1.88
(3H, s), 1.34 (1H, t, J = 11.7Hz) 0.93 (3H, t, J = 7.4H
z), 0.88 (3H, d, J = 6.6Hz), 0.81 (3H, d, J = 5.1Hz), 0.
64 (3H, d, J = 7.0Hz). Mass spectrum m / e: = 837 (M = C₄₆H₆₃NO₁₁S)Example 8 13-O- [1- (4-aminophenyl) cyclobutane carbonate
]]-22,23-Dihydro-avermectin B_1aAglycon
(R¹: Sec-butyl, R², R³: Cyclobutyl, R ^Four: 4
-Amino, exemplified compound number 65) In (Step 1) of Example 4, 4-nitrophenyl
4-nitrophenyl instead of clopentanecarboxylic acid
The title compound by using cyclobutanecarboxylic acid
Was obtained as an amorphous solid (yield 93.4%: silyl ether
From the body).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.12 (2H, d, J = 8.5Hz), 6.69 (2H, d, 8.5Hz), 5.77
~ 5.74 (1H, m), 5.66 (1H, dd, J = 14.7 & 11.3Hz), 5.45 (1
H, s), 5.37 (1H, m), 5.27 (1H, dd, J = 14.7 & 10.1Hz), 5.
01 (1H, s), 4.90 (1H, m), 4.67 and 4.63 (2H, AB-q, J =
14.3Hz), 4.30 (1H, m), 3.97 (1H, d, J = 6.4Hz), 3.67 ~
3.60 (1H, m), 3.27 (1H, m), 3.21 (1H, m), 1.89 (3H, s),
1.34 (1H, t, J = 11.7Hz), 0.93 (3H, t, J = 7.3Hz), 0.88
(3H, d, J = 7.3Hz), 0.81 (3H, d, J = 5.3Hz), 0.68 (3H,
d, J = 7.0 Hz). Mass spectrum m / e: = 759 (M = C ₄₅ H ₆₁ NO ₉ ). Example 9 13-O- [1- (4-methoxyacetylaminophenyl) cyclopropanecarbonyl] -22 , 23-Dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² , R ³ : cyclopropyl, R ⁴ : 4-methoxyacetylamino, Exemplified Compound No. 126) In (Step 1) of Example 1, The title compound was obtained as an amorphous solid by using 4-nitrophenylcyclopropanecarboxylic acid instead of 4-nitrophenylcyclopentanecarboxylic acid (yield 63.8%: from amino form).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 8.47 (1H, s), 7.52 (2H, d, J = 8.6Hz), 7.36 (2H,
d, J = 8.6Hz), 5.69 ~ 5.58 (2H, m), 5.47 (1H, s), 5.19
(1H, m), 4.98 (1H, m), 4.91 (1H, dd, J = 14.2 & 10.0Hz),
4.67 (1H, s), 4.63 and 4.60 (2H, AB-q, J = 14.5Hz),
4.30 (1H, m), 4.15 & 4.04 (2H, ABq, J = 15.3Hz), 3.94 (1
H, d, J = 6.0Hz), 3.63 (1H, m), 3.50 (3H, s) 3.23 (2H,
m), 1.88 (3H, s), 1.04 (3H, t, J = 7.2Hz), 0.94 (3H, d,
J = 6.9Hz), 0.90 (3H, d, J = 6.3Hz), 0.82 (3H, d, J = 5.5H
z). Mass spectrum m / e: = 817 (M = C ₄₇ H ₆₃ NO ₁₁ ). Example 10 13-O- [1- (4-acetylaminophenyl) cyclopropanecarbonyl] -22,23-dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² , R ³ : cyclopropyl, R ⁴ : 4-acetylamino, exemplified compound number 11
9) The title compound was obtained as an amorphous solid by using 4-nitrophenylcyclopropanecarboxylic acid in place of 4-nitrophenylcyclopentanecarboxylic acid in (Step 1) of Example 2 (yield 88.4% : From the amino form).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.51 (1H, s), 7.43 (2H, d, J = 8.4Hz), 7.34 (2H,
d, J = 8.4Hz), 5.67 ~ 5.59 (2H, m), 5.47 (1H, s), 5.22
(1H, m), 4.98 (1H, s), 4.94 ~ 4.88 (1H, m), 4.78 ~ 4.76
(1H, m), 4.64 and 4.60 (2H, AB-q, J = 14.1Hz), 4.42 (1
H, s), 4.31 (1H, m), 3.93 (1H, d, J = 6.0Hz), 3.67 ~ 3.
61 (1H, m), 3.24 (2H, m), 2.19 (3H, s) 1.89 (3H, s), 1.
04 (3H, t, J = 7.3Hz), 0.93 (3H, d, J = 6.9Hz), 0.91 (3H,
d, J = 6.6Hz), 0.82 (3H, d, J = 5.4Hz). Mass spectrum m / e: = 787 (M = C ₄₆ H ₆₁ NO ₁₀ ). Example 11 13-O- [1- (4 - methanesulfonyl-aminophenyl) cyclopropanecarbonyl] -22,23-dihydro - avermectin B _1a aglycone (R ^1: sec-butyl, R ^2, R ^3: cyclopropyl, R ^4: 4-methanesulfonyl amino,
Exemplified Compound No. 145) In (Step 1) of Example 3, the title compound was obtained as an amorphous solid by using 4-nitrophenylcyclopropanecarboxylic acid in place of 4-nitrophenylcyclopentanecarboxylic acid (yield). 96.7% (from amino form).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.37 (2H, d, J = 8.3Hz), 7.28 (2H, d, 8.3Hz), 7.11
(1H, s), 5.62 (1H, dd, J = 14.9 & 11.2Hz), 5.53 to 5.48 (2
H, m), 5.35 (1H, m), 4.95 (1H, s), 4.85 ~ 4.82 (1H,
m), 4.78 (1H, dd, J = 14.9 & 9.9Hz), 4.64 and 4.59 (2H,
AB-q, J = 14.4Hz), 4.25 (1H, m), 4.15 (1H, s), 3.90 (1H,
d, J = 6.3Hz), 3.69 (1H, m), 3.27 (2H, m), 3.06 (3H,
s), 1.87 (3H, s), 1.02 (3H, t, J = 7.2Hz) 0.92 (3H, d, J
= 7.0Hz), 0.90 (3H, d, J = 6.5Hz), 0.82 (3H, d, J = 5.3H
z). Mass spectrum m / e: = 823 (M = C ₄₅ H ₆₁ NO ₁₁ S) Example 12 13-O- [1- (4-aminophenyl) cyclopropanecarbonyl] -22,23-dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² , R ³ : cyclopropyl,
R ⁴ : 4-amino, exemplified compound No. 115) In (Step 1) of Example 4, the title compound was amorphous by using 4-nitrophenylcyclopropanecarboxylic acid instead of 4-nitrophenylcyclopentanecarboxylic acid. It was obtained as a solid (yield 94.7%: from silyl ether form).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.16 (2H, d, J = 8.2Hz), 6.73 (2H, d, 8.2Hz), 5.59
(1H, dd, J = 14.5 & 11.1Hz), 5.52 (1H, dt, J = 11.1 & 2.1H
z), 5.47 (1H, s), 5.42 (1H, m), 4.89 (1H, s), 4.86 ~
4.84 (1H, m), 4.77 (1H, dd, J = 14.5 & 9.9Hz), 4.64 and
4.60 (2H, AB-q, J = 14.2Hz), 4.30 (1H, m), 3.95 (1H,
d, J = 6.4Hz), 3.74 (1H, m), 3.26 (2H, m), 1.89 (3H, s),
1.35 (1H, t, J = 11.8Hz), 1.02 (3H, t, J = 7.1Hz), 0.92
(3H, d, J = 6.8Hz), 0.91 (3H, d, J = 6.3Hz). 0.82 (3H,
d, J = 5.4Hz), 0.69 (3H, q, J = 11.8Hz). Mass spectrum m / e: = 745 (M = C ₄₄ H ₅₉ NO ₉ ). Example 13 13-O- [1- (4 -Methoxyacetylaminophenyl) -1-methylpropionyl] -22,23-dihydro-avermectin
B _1a aglycone (R ¹ : sec-butyl, R ² : methyl, R ³ :
Methyl, R ^4: 4-methoxy-acetylamino, in the illustrated compound No. 176) of Example 1 (step 1), 4-nitrophenyl instead of 1- (4-nitrophenyl cyclopentanecarboxylic acid) -1-methylpropionic The title compound was obtained as an amorphous solid by using an acid (yield 97.7%: from amino form).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 8.27 (1H, s), 7.54 (2H, d, J = 8.6Hz), 7.39 (2H,
d, J = 8.6Hz), 5.80 (1H, dt, J = 11.2 & 2.1Hz), 5.68 (1H,
dd, J = 14.8 & 11.2Hz), 5.44 (1H, s), 5.35 (1H, dd, J = 1
4.8 & 10.0Hz), 5.30 ~ 5.22 (1H, m), 5.04 (1H, m), 4.80
(1H, m), 4.66 and 4.62 (2H, AB-q, J = 14.3Hz), 4.29 (1
H, m), 4.19 (1H, s), 4.03 (2H, d, J = 4.4Hz), 3.95 (1H,
d, J = 6.3Hz), 3.56 (1H, m), 3.50 (3H, s) 3.25 (1H, m),
3.19 (1H, m), 2.31 (1H, d, J = 8.2Hz), 1.88 (3H, s), 1.
68 (3H, s), 1.63 (3H, s), 1.29 (1H, t, J = 11.7Hz), 0.9
9 (3H, t, J = 7.3Hz), 0.87 (3H, d, J = 6.8Hz), 0.80 (3H,
d, J = 5.3Hz), 0.76 (3H, d, J = 6.8Hz). Mass spectrum m / e: = 819 (M = C ₄₇ H ₆₅ NO ₁₁ ). Example 14 13-O- [1- (4 -Acetylaminophenyl) -1-methylpropionyl] -22,23-dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² : methyl, R ³ : methyl, R ⁴ : 4-acetylamino, exemplified compound Number 16
9) The title compound was obtained as an amorphous solid by substituting 1- (4-nitrophenyl) -1-methylpropionic acid for 4-nitrophenylcyclopentanecarboxylic acid in (Step 1) of Example 2. (Yield 80.9%: from amino compound).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.46 (2H, d, J = 8.7Hz), 7.37 (2H, d, J = 8.7Hz),
7.23 (1H, s) 5.80 ~ 5.77 (1H, m), 5.68 (1H, dd, J = 14.7 &
11.3Hz), 5.44 (1H, s), 5.33 (1H, dd, J = 14.7 & 10.1Hz),
5.31 ~ 5.24 (1H, m), 5.04 (1H, s), 4.82 (1H, m), 4.67
and 4.62 (2H, AB-q, J = 14.3Hz), 4.29 (1H, m), 4.14 (1
H, s), 3.95 (1H, d, J = 6.0Hz), 3.57 (1H, m), 3.25 (1H,
m), 3.18 (1H, m), 2.52 (1H, m), 2.32 (1H, d, J = 8.5H
z), 2.17 (3H, s) 1.88 (3H, s), 1.68 (3H, s), 1.62 (3H,
s), 1.31 (1H, t, J = 11.7Hz), 0.98 (3H, t, J = 7.4Hz),
0.87 (3H, d, J = 6.8Hz), 0.81 (3H, d, J = 5.4Hz), 0.74 (3
H, d, J = 7.0 Hz). Mass spectrum m / e: = 789 (M = C ₄₆ H ₆₃ NO ₁₀ ). Example 15 13-O- [1- (4-methanesulfonylaminophenyl) -1
-Methylpropionyl] -22,23-dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² : methyl,
R ³ : Methyl, R ⁴ : 4-methanesulfonylamino, Exemplified Compound No. 195) In (Step 1) of Example 3, 1- (4-nitrophenyl) -1 was used instead of 4-nitrophenylcyclopentanecarboxylic acid. By using methylpropionic acid, the title compound was obtained as an amorphous solid (yield 68.9%: from amino compound).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.41 (2H, d, J = 8.6Hz), 7.21 (2H, d, J = 8.6Hz), 6.
55 (1H, s), 5.75 (1H, dt, J = 11.2 & 2.0Hz), 5.69 (1H, d
d, J = 14.1 & 11.3Hz), 5.44 (1H, s), 5.37 ~ 5.28 (2H, m),
5.04 (1H, s), 4.86 (1H, m), 4.67 and 4.62 (2H, AB-q,
J = 14.3Hz), 4.29 (1H, m), 3.99 (1H, s), 3.95 (1H, d, J =
6.3Hz), 3.59 (1H, m), 3.27 (1H, m), 3.20 (1H, m), 2.99
(3H, s), 2.53 (1H, m), 2.34 (1H, d, J = 8.2Hz), 1.88 (3
H, s), 1.70 (3H, s), 1.63 (3H, s), 1.33 (1H, t, J = 11.7
Hz) 0.97 (3H, t, J = 7.4Hz), 0.87 (3H, d, J = 6.7Hz), 0.
81 (3H, d, J = 5.2Hz), 0.71 (3H, d, J = 6.8Hz). Mass spectrum m / e: = 825 (M = C ₄₅ H ₆₃ NO ₁₁ S) Example 16 13-O- [1- (4-Aminophenyl) -1-methylpropionyl] -22,23-dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² : methyl, R ³ : methyl, R ⁴ :
4-Amino, Exemplified Compound No. 165) In (Step 1) of Example 4, the title compound was obtained by using 1- (4-nitrophenyl) -1-methylpropionic acid instead of 4-nitrophenylcyclopentanecarboxylic acid. Was obtained as an amorphous solid (yield 72.7%: from silyl ether form).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.20 (2H, d, J = 8.7Hz), 6.67 (2H, d, 8.7Hz), 5.75
(1H, dt, J = 11.5 & 2.2Hz), 5.67 (1H, dd, J = 14.5 & 11.5H
z), 5.44 (1H, s), 5.39 ~ 5.28 (2H, m), 5.02 (1H, s),
4.83 (1H, m), 4.67 and 4.63 (2H, AB-q, J = 14.2Hz), 4.
30 (1H, broad s), 3.96 (1H, d, J = 6.4Hz), 3.60 (1H,
m), 3.27 (1H, m), 3.21 (1H, m), 2.51 (1H, m), 1.88 (3H,
s), 1.64 (3H, s), 1.60 (3H, s), 1.32 (1H, t, J = 11.7H
z), 0.99 (3H, t, J = 7.3Hz), 0.88 (3H, d, J = 6.6Hz), 0.8
1 (3H, d, J = 5.5Hz), 0.74 (3H, d, J = 7.0Hz) Mass spectrum m / e:. = 747 ( M = C 44 H 61 NO 9) Example 17 13-O- [ 1- (4-Methoxyacetylaminophenyl) -1-ethylbutyryl] -22,23-dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² : ethyl, R ³ : ethyl, R ⁴ : 4-methoxy Acetylamino, Exemplified Compound No. 226) In (Step 1) of Example 1, 1- (4-nitrophenyl) -1-ethylbutyric acid was used in place of 4-nitrophenylcyclopentanecarboxylic acid to give the title compound. Obtained as a crystalline solid (yield 94.7%: from amino compound).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 8.25 (1H, s), 7.54 (2H, d, J = 8.7Hz), 7.34 (2H,
d, J = 8.7Hz), 5.81 to 5.78 (1H, m), 5.67 (1H, dd, J = 1
4.8 & 11.4Hz), 5.43 (1H, s), 5.36 (1H, dd, J = 14.8 & 10.0
Hz), 5.32 ~ 5.25 (1H, m), 5.07 (1H, s), 4.83 (1H, m),
4.66 and 4.62 (2H, AB-q, J = 14.3Hz), 4.29 (1H, m),
4.11 (1H, s), 4.02 (2H, s), 3.95 (1H, d, J = 6.1Hz), 3.
57 (1H, m), 3.50 (3H, s) 3.25 (1H, m), 3.17 (1H, m), 2.
31 (1H, d, J = 8.3Hz), 1.88 (3H, s), 1.30 (1H, t, J = 11.
7Hz), 1.00 (3H, t , J = 7.4Hz), 0.87 (3H, d, J = 6.7Hz) Mass spectrum m / e:. = 848 ( M + H, M = C 49 H 69 NO 11) carried Example 18 13-O- [1- (4-acetylaminophenyl) -1-ethylbutyryl] -22,23-dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² : ethyl, R ³ : ethyl,
R ^4: 4-acetylamino, in the illustrated compound No. 219) of Example 2 (Step 1), 4 instead of nitrophenyl cyclopentanecarboxylic acid 1- (4-nitrophenyl) -1-using ethyl butyrate The title compound was obtained as an amorphous solid (yield 99.3%: from amino compound).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.46 (2H, d, J = 8.6Hz), 7.32 (2H, d, J = 8.6Hz),
7.20 (1H, s) 5.80 ~ 5.77 (1H, m), 5.67 (1H, dd, J = 14.8 &
11.2Hz), 5.44 (1H, s), 5.34 (1H, dd, J = 14.8 & 9.9Hz),
5.35 ~ 5.27 (1H, m), 5.07 (1H, s), 4.84 (1H, m), 4.6
7 and 4.62 (2H, AB-q, J = 14.3Hz), 4.29 (1H, m), 4.10
(1H, s), 3.95 (1H, d, J = 6.3Hz), 3.59 (1H, m), 3.26 (1
H, m), 3.18 (1H, m), 2.50 (1H, m), 2.32 (1H, d, J = 8.5H
z), 2.17 (3H, s) 1.88 (3H, s), 1.31 (1H, t, J = 11.7H
z), 1.00 (3H, t, J = 7.4Hz), 0.87 (3H, d, J = 6.7Hz), 0.
72 (3H, t, J = 7.6Hz), 0.69 (3H, d, J = 7.1Hz). Mass spectrum m / e: = 817 (M = C ₄₈ H ₆₇ NO ₁₀ ). Example 19 13-O- [ 1- (4-methanesulfonylaminophenyl) -1
-Ethylbutyryl] -22,23-dihydro-avermectin B
_1a aglycone (R ¹ : sec-butyl, R ² : ethyl, R ³ :
Ethyl, R ^4: 4- methanesulfonyl amino, in the illustrated compound No. 245) of Example 3 (Step 1), 4-nitrophenyl instead of 1- (4-nitrophenyl cyclopentanecarboxylic acid) -1-ethyl butyrate Was used to obtain the title compound as an amorphous solid (yield 87.6%: from amino compound).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.36 (2H, d, J = 8.7Hz), 7.19 (2H, d, J = 8.7Hz), 6.
47 (1H, s), 5.77 (1H, dt, J = 11.2 & 2.1Hz), 5.68 (1H, d
d, J = 14.6 & 11.2Hz), 5.44 (1H, s), 5.34 (1H, dd, J = 14.
6 & 10.0Hz), 5.07 (1H, s), 4.88 (1H, m), 4.67 and 4.62
(2H, AB-q, J = 14.3Hz), 4.29 (1H, m), 3.99 (1H, s), 3.9
5 (1H, d, J = 6.1Hz), 3.59 (1H, m), 3.27 (1H, m), 3.23 (1
H, m), 2.97 (3H, s), 2.51 (1H, m), 2.33 (1H, d, J = 8.2
Hz), 1.88 (3H, s), 1.33 (1H, t, J = 11.8Hz), 0.99 (3H,
t, J = 7.4Hz), 0.82 (3H, d, J = 6.0Hz), 0.72 (3H, t, J =
7.4Hz) 0.66 (3H, d, J = 6.8Hz). Mass spectrum m / e: = 853 (M = C ₄₇ H ₆₇ NO ₁₁ S) Example 20 13-O- [1- (4-aminophenyl) -1-Ethylbutyryl]
−22,23-Dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² : ethyl, R ³ : ethyl, R ⁴ :
4-Amino, Exemplified Compound No. 215) In (Step 1) of Example 4, the title compound was obtained by substituting 1- (4-nitrophenyl) -1-ethylbutyric acid for 4-nitrophenylcyclopentanecarboxylic acid. Obtained as an amorphous solid (yield 72.7%: from silyl ether form).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.14 (2H, d, J = 8.6Hz), 6.65 (2H, d, 8.6Hz), 5.79
~ 5.76 (1H, m), 5.66 (1H, dd, J = 14.8 & 11.2Hz), 5.43 (1
H, s), 5.37 (1H, dd, J = 14.8 & 10.0Hz), 5.06 (1H, s), 4.
81 (1H, m), 4.67 and 4.63 (2H, AB-q, J = 14.2Hz), 4.29
(1H, m), 3.96 (1H, d, J = 6.2Hz), 3.61 (3H, m), 3.26 (1
H, m), 3.20 (1H, m), 2.50 (1H, m), 2.33 (1H, d, J = 8.3H
z), 1.88 (3H, s), 1.32 (1H, t, J = 11.7H), 1.01 (3H, t,
J = 7.3Hz), 0.88 (3H, d, J = 6.6Hz), 0.74 (3H, t, J = 7.5H
z) 0.71 (3H, d, J = 7.0Hz) Mass spectrum m / e:. = 775 ( M = C 46 H 65 NO 9) Example 21 13-O- (4- methoxyacetyl aminophenyl) acetyl -22 Preparation of a, 23-dihydro-avermectin B _1a aglycone (R ¹ : sec-butyl, R ² : hydrogen atom, R ³ : hydrogen atom, R ⁴ : 4-methoxyacetylamino, Exemplified Compound No. 276) (Step 1) 4 -Nitrophenylacetic acid (1.45 g) was dissolved in thionyl chloride (16 ml), the mixture was stirred at room temperature for 1 hr, and the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane (5 ml) and treated with 5-Ot-butyldimethylsilyl-22,23-dihydro-avermectin B.
_1a aglycone (1.40g) and pyridine (808.8μ
A solution of l) in dichloromethane (10 ml) was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Ethyl acetate (30m
1) was added to dilute, washed with 4% sodium borohydride solution and water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Column chromatography of the residue (silica gel, elution with ethyl acetate: hexane = 2: 8)
By separating and purifying with 1., the mixture containing the target compound (1.
39 g) was obtained. This mixture was added to methanol (10 ml)
, Bis (triphenylphosphine) nickel (II) chloride (210.0 mg) was added, sodium borohydride (243.2 mg) was slowly added at 4 ° C., and the mixture was stirred for 40 minutes. The reaction mixture was poured into ethyl acetate / water / acetic acid (20 ml / 1 ml / 20 ml), extracted with ethyl acetate, washed with 4% sodium borohydride solution and water,
It was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.
The residue was separated and purified by column chromatography (silica gel, eluted with ethyl acetate: hexane = 1: 9) to give 5-Ot-butyldimethylsilyl-13-O- (4-
517.5 mg of aminophenyl) acetyl-22,23-dihydro-avermectin B _1a aglycone was obtained (yield 38.5
%). (Step 2) 5-O-t-butyldimethylsilyl-13-O- (4-aminophenyl) acetyl-22,23-dihydro-avermectin B _1a aglycone (1 obtained in Step 1)
60.0 mg) was dissolved in dichloromethane, pyridine (16.9 μl) and methoxyacetyl chloride (19.1 μl) were added at 4 ° C., and the mixture was stirred for 1 hour and 30 minutes. Ethyl acetate (10 ml) was added to the reaction solution to dilute it, and after washing with water,
It was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.
The residue was dissolved in methanol (2 ml), 1M-hydrochloric acid aqueous solution (0.3 ml) was added, and the mixture was stirred at room temperature for 3 hr. The reaction solution was diluted with ethyl acetate (10 ml), washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Column chromatography of the residue (silica gel,
By elution and separation with ethyl acetate: hexane = 1: 1), 138.4 mg of the target compound was obtained as an amorphous solid (yield 92.0%).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 8.30 (1H, s), 7.55 (2H, d, J = 8.5Hz), 7.29 (2H,
 d, J = 8.5Hz), 5.84 (1H, dt, J = 11.3 & 2.2Hz), 5.72 (1H,
 dd, J = 14.8 & 11.3Hz) 5.48 (1H, m), 5.44 (1H, s) 5.28 (1
H, m), 5.10 (1H, s) 4.87 (1H, m) 4.68 and 4.64 (2H, AB-
q, J = 14.3Hz), 4.32 (1H, s), 4.30 (1H, m), 4.04 (2H,
d, J = 5.5Hz), 3.97 (1H, d, J = 6.2Hz), 3.70 (2H, s), 3.
61 (1H, m), 3.51 (3H, s) 3.25 (1H, m), 3.20 (1H, m), 2.
32 (1H, d, J = 8.3Hz) 1.88 (3H, s), 1.31 (1H, t, J = 11.7
Hz), 1.00 (3H, t, J = 7.4Hz), 0.91 (3H, d, J = 6.9Hz) 0.
88 (3H, d, J = 6.6 Hz), 0.80 (3H, d, J = 5.3Hz). Mass spectrum m / e: = 791 (M = C₄₅H₆₁NO₁₁)Example 22 13-O- [1- (4-acetylaminophenyl) acetyl]-
22,23- Dihydro-avermectin B_1aAglycon (R¹:
sec-butyl, R²: Hydrogen atom, R³: Hydrogen atom, R ^Four: 4
-Acetylamino, exemplified compound number 269) Methoxyacetyl chloride in (Step 2) of Example 21
By using acetyl chloride instead of
The target compound was obtained as an amorphous solid (yield 81.5%:
(From the body).

Nuclear magnetic resonance spectrum (400MHz) δ (pp
m): 7.43 (2H, d, J = 8.3Hz), 7.27 (2H, d, J = 8.3Hz),
7.24 (1H, s) 5.83 (1H, m), 5.73 (1H, dd, J = 14.7 & 11.2Hz),
5.48 (1H, m), 5.44 (1H, s), 5.30 (1H, m), 5.10 (1H,
s), 4.90 (1H, m), 4.69 and 4.65 (2H, AB-q, J = 14.3Hz),
4.30 (1H, m), 4.26 (1H, s), 3.97 (1H, d, J = 6.0Hz),
3.69 (2H, s), 3.63 (1H, m), 3.26 (1H, m), 3.22 (1H,
m), 2.33 (1H, d, J = 8.2Hz) 2.18 (3H, s) 1.88 (3H, s),
1.32 (1H, t, J = 11.7Hz), 1.00 (3H, t, J = 7.4Hz), 0.90
(3H, d, J = 7.2Hz) 0.88 (3H, d, J = 6.8Hz). Mass spectrum m / e: = 761 (M = C ₄₄ H ₅₉ NO ₁₀ ) Test Example 1 Insecticidal test against cat fleas As artificial skin Prepare a test container that separates the flea living space from the bovine serum in the parafilm used.
The concentration of drug was added and the fleas were allowed to suck blood through Parafilm at 37 ° C. Using 20 fleas per group, 48 hours later, the flea-killing effect of the test drug was determined from the number of fleas that died. The mortality rate was corrected from the survival rate of the control group to which no drug was added.

[0132] Compound mortality rate (%) Example 1 72.0 Example 2 69.3 Example 3 68.7 Example 4 78.2 Example 5 83.8 Example 6 80.7 Example 7 80.7 Example 8 88.3 Example 13 72.2 Example 14 89.5 Example 15 89.5 Example 16 75.9 Ivermectin 19.0 (5 ppm)

[0133]

INDUSTRIAL APPLICABILITY The 13-ester avermectin derivative of the present invention exhibits excellent insecticidal activity against pests, especially fleas, even though it is of 13-α-type.

Front page continuation (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 33/14 A61P 33/14 F term (reference) 4C071 AA04 AA07 BB03 CC14 EE05 FF17 GG01 HH05 JJ06 LL01 4C086 AA01 AA02 AA03 BA17 MA01 MA01 MA04 NA14 ZB37 ZB39 ZC61 4H011 AC01 BA01 BB08 BC23 DA12 DC05 DD07

Claims (13)

[Claims] 1. A general formula: [Wherein R ¹ is an isopropyl group, a cyclohexyl group,
Or a sec-butyl group, R ² and R ³ are hydrogen atoms, C
₁ -C ₃ alkyl group, or, R ^2, R ³ are taken together, represents a group forming a ring of C ₃ -C ₆ together with the carbon atoms at the base of these substituents, R ⁴ is a hydrogen atom, halogen atom, a cyano group, a nitro group, C ₁ -C ₄ alkyl group, C ₁ -
C ₂ haloalkyl group, C ₁ -C ₄ alkoxy group, C ₁ -C ₄
Alkoxyalkoxy group, formula NR ⁵ R ⁶ (in the formula, R ⁵ , R ⁶
Is a hydrogen atom or a group represented by a C ₁ -C ₄ alkyl group), a formula NR ⁵ COR ⁷ (in the formula, R ⁵ has the same meaning as described above, and R ⁷ is the following substituent group A C ₁ -C ₄ alkyl group which may have a substituent selected from A, a C ₃ -C ₆ cycloalkyl group, a phenyl group which may have a substituent selected from the following substituent group A, or A heterocycle having 1 to 3 heteroatoms), a C ₁ -C ₄ alkylsulfonylamino group, a C ₁ -C ₄ alkoxycarbonylamino group, or a nitrogen atom as a bond. A saturated 5-membered or 6-membered heterocyclic ring containing one atom is shown, a dotted line shows a single bond or a double bond, and the substituent group A is a halogen atom, a cyano group, a nitro group, a hydroxyl group, an amino group, a mono ₁ -C ₄ alkyl) -substituted amino group, di (C ₁ -C ₄ alkyl) location Amino group, C ₁ -C ₄ alkoxy groups, C ₁ -C ₄
Alkanoyloxy group, C ₁ -C ₄ alkylthio group, C ₁
-C ₄ alkylsulfonyl group, C ₁ -C ₄ alkanoyl group,
C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ alkanoylamino group, C ₆ -C ₁₀ arylcarbonyl groups, C ₁ -C
_{4 represents an} alkoxycarbonylamino group, a C ₁ -C ₄ alkylsulfonylamino group, a phenyl group, or a heterocycle having 1 to 3 heteroatoms. ], Or a pharmaceutically or veterinary acceptable salt thereof. 2. The avermectin derivative according to claim 1, wherein R ¹ is an isopropyl group or a sec-butyl group, or a pharmaceutically or veterinary acceptable salt thereof. 3. The avermectin derivative according to claim 1, wherein R ¹ is a sec-butyl group, or a pharmaceutically or veterinary acceptable salt thereof. 4. The avermectin derivative according to claim 1, wherein R ² is a methyl, ethyl or propyl group, or a pharmaceutically or veterinary acceptable salt thereof. . 5. The avermectin derivative according to claim 1, wherein R ² is a methyl group, or a pharmaceutically or veterinary acceptable salt thereof. 6. The avermectin derivative according to claim 1, wherein R ³ is methyl, ethyl or propyl, or a pharmaceutically or veterinarily acceptable salt thereof. . 7. The avermectin derivative according to claim 1, wherein R ³ is a methyl group, or a pharmaceutically or veterinarily acceptable salt thereof. 8. An avermectin derivative in which R ² and R ³ together are a cyclopropyl, cyclobutyl or cyclopentyl group in one claim selected from claims 1 to 7 or a pharmaceutical thereof. A salt that is acceptable for the above or veterinary medicine. 9. In one claim selected from claims 1 to 7, R ² and R ³ together are an avermectin derivative which is a cyclopentyl group, or a pharmaceutically or veterinarily acceptable thereof. Ru salt. 10. In one claim selected from claims 1 to 9, R ⁴ is an amino group, a group of formula NR ⁵ COR ⁷ (wherein
R ⁵ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, and R ⁷ is
A C ₁ -C ₄ alkyl group which may have a substituent (the substituent is a halogen atom, a cyano group, a nitro group, a hydroxyl group, an amino group, a mono (C ₁ -C ₄ alkyl) substituted amino group, a di ( C
₁ -C ₄ alkyl) -substituted amino group, C ₁ -C ₄ alkoxy groups, C ₁ -C ₄ alkanoyloxy group, C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfonyl group, C ₁ -C ₄ alkanoyl Group, C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C
₄ alkanoylamino group, C ₆ -C ₁₀ arylcarbonyl group, C ₁ -C ₄ alkoxycarbonylamino group, C ₁ -C ₄
It may be substituted with an alkylsulfonylamino group, a phenyl group, or a heterocycle having 1 to 3 heteroatoms. ), A C ₃ -C ₆ cycloalkyl group, and a phenyl group which may have a substituent (the substituent is a halogen atom, a cyano group, a nitro group, a hydroxyl group, an amino group, a mono (C ₁ -C ₄ alkyl)). Substituted amino group, di (C ₁ -C ₄ alkyl) substituted amino group, C ₁ -C ₄ alkoxy group, C ₁ -C ₄ alkanoyloxy group, C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfonyl group , C ₁ -C ₄ alkanoyl group, C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ alkanoylamino group, C
_6- C ₁₀ arylcarbonyl group, C ₁ -C ₄ alkoxycarbonylamino group, C ₁ -C ₄ alkylsulfonylamino group, phenyl group, or even if substituted with a heterocycle having 1 to 3 heteroatoms Good. ), Or 1 to 3
Shown is a heterocycle having 3 heteroatoms. ), A C ₁ -C ₄ alkylsulfonylamino group, a C ₁ -C ₄ alkoxycarbonylamino group, or an avermectin derivative which is a saturated 5-membered or 6-membered heterocycle containing one nitrogen atom as a bond as a ring atom, Alternatively, a pharmaceutically or veterinary acceptable salt thereof. 11. In one claim selected from Claims 1 to 9, R ⁴ is an amino group and is of the formula NR ⁵ COR ⁷ (wherein
J) R ⁴ is an amino group, a formula NR ⁵ COR ⁷ (in the formula, R ⁵ is a hydrogen atom or a C ₁ -C ₄ alkyl group, and R ⁷ is a C ₁ -C ₄ which may have a substituent. Alkyl group (the substituent is a halogen atom, a cyano group, a nitro group, a hydroxyl group, an amino group, a mono (C ₁ -C ₄ alkyl) -substituted amino group, a di (C ₁ -C ₄ alkyl) -substituted amino group, C ₁ -C ₄ alkoxy groups, C ₁ -C ₄
Alkanoyloxy group, C ₁ -C ₄ alkylthio group, C ₁
-C ₄ alkylsulfonyl group, C ₁ -C ₄ alkanoyl group,
C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ alkanoylamino group, C ₆ -C ₁₀ arylcarbonyl groups, C ₁ -C
_It may be substituted with a ₄ alkoxycarbonylamino group, a C ₁ -C ₄ alkylsulfonylamino group, a phenyl group, or a heterocycle having 1 to 3 heteroatoms. ),
C ₃ -C ₆ cycloalkyl, substituents phenyl group (the substituent group which may have a represents a halogen atom, a cyano group, a nitro group, a hydroxyl group, an amino group, a mono (C ₁ -C ₄ alkyl) substituted amino Group, di (C ₁ -C ₄ alkyl) -substituted amino group, C ₁
-C ₄ alkoxy groups, C ₁ -C ₄ alkanoyloxy group,
C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfonyl group, C ₁ -C ₄ alkanoyl group, C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ alkanoylamino group, C ₆ -C ₁₀
It may be substituted with an arylcarbonyl group, a C ₁ -C ₄ alkoxycarbonylamino group, a C ₁ -C ₄ alkylsulfonylamino group, a phenyl group, or a heterocycle having 1 to 3 heteroatoms. ), Or a heterocycle having 1 to 3 heteroatoms. ), Or an avermectin derivative which is a C ₁ -C ₄ alkylsulfonylamino group,
Alternatively, a pharmaceutically or veterinary acceptable salt thereof. 12. An avermectin derivative according to claim 1, wherein the substitution position of R ⁴ is the para position (position 4), or a pharmaceutically or veterinarily acceptable thereof. salt. 13. The avermectin derivative according to claim 1, which is selected from claims 1 to 12, or a pharmaceutically or veterinary acceptable salt thereof.