JPH09151188A - Milbemycin 5-oxide derivative substituted at 13-position - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new milbemycin derivative having insecticidal, acaricidal or elminthic activity, useful as an exterminator. SOLUTION: This compound is shown by formula I [Me is methyl; R<1> is methyl, ethyl, isopropyl or sec-butyl; X is carbonyl or methylene; Z is C=(R<2> )2 or C=(CH2 )m (R<2> is a 1-3C alkyl; (m) is 2-5); R<3> is nitro, a (1-4C alkyl-substituted) amino or a 1-4C alkoxy, etc.; (n) is 0 or 1] such as 13-[2-(4- cyanoacetylaminophenyl)-2-methyl-propionyloxy]-5-hydroxyiminomilbemycin A4 . The compound of formula I is obtained, for example, by reacting a compound of formula II with a compound of formula III (R<3a> is nitro, etc.) to give a compound of formula IV and reacting this compound with hydroxylamine hydrochloride in a solvent such as dioxane.

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, and a novel milbemycin compound having excellent insecticidal activity against harmful insects, especially fleas. Is related to the development of.

[0002]

2. Description of the Related Art Milbemycins and avermectins are a series of 16-membered macrolide compounds, and are disclosed in, for example, JP-A Nos. 50-29742, 56-32481 and 5;
The following known formula (II) [in the formula, Me represents a methyl group, which is described in, for example, JP-A No. 4-61198. ] It is a compound represented by these.

[0003]

Embedded image

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

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

Examples of milbemycins having an oxime group at the 5-position include, for example, JP-A-60-142991, JP-A-62-89685, JP-A-62-252788, and JP-A-63-. 10791
JP-A-63-264484, JP-A-1-
The description can be found in 1995991 and JP-A-2-19383.

[0007]

An object of the present invention is to develop a novel milbemycin compound having insecticidal, acaricidal or anthelmintic activity, which has excellent insecticidal activity against harmful insects, especially fleas. To develop a novel milbemycin compound having.

[0008]

As a result of searching for 13-substituted milbemycins showing stronger biological activity, the present inventors newly obtained a substituted derivative having an oxime group at the 5-position as shown below. , Found a strong flea-killing activity,
The present invention has been completed.

That is, the present invention provides a compound represented by the general formula (I):

[0010]

Embedded image

The present invention relates to a 13-substituted-5-hydroxyiminomilbemycin derivative represented by:

[In the formula, Me represents a methyl group.

R ¹ represents a methyl group; an ethyl group; an isopropyl group; or a sec-butyl group, X represents a carbonyl group; or a methylene group, and Z represents a formula: ═C = (R ² ) ₂ (i)
(In the formula, R ² represents a C ₁ -C ₃ alkyl group.); Or a formula: = C = (CH ₂ ) _m (ii) (in the formula, m represents 2 to 5). Group,
n represents 0 or 1, R ₃ is a nitro group; an amino group; C
₁ -C ₄ alkyl-substituted amino group; C ₂ -C ₈ dialkylamino-substituted amino group; C ₁ -C ₄ alkoxy group; C ₁ -C ₃ alkoxy C ₂ -C ₃ alkoxy group; formula: (ii
i),: (iv), (v),: (vi),: (vi
i),: (viii) and: (ix) are shown.

[0014]

[Chemical 6]

[0015] (wherein, R ⁴ is a hydrogen atom; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkyl group at least one perforated a substituent selected from substituent group A; C ₃ -C ₆ cycloalkyl C ₃ -C ₆ cycloalkyl group at least one have a selected from substituent group B substituents; alkyl C ₆ -C ₁₄
3 to 6-membered having oxygen, nitrogen, at least one atom selected from sulfur atom as ring atoms; an aryl group; C ₆ -C least one perforated a substituent selected from Substituent Group C ₁₄ aryl group Heterocyclic group; 3- to 6-membered heterocyclic group having at least one substituent selected from Substituent group C and having at least one atom selected from oxygen, nitrogen and sulfur atoms as a ring atom; oxygen A 3- to 6-membered heterocyclic thio group having at least one atom selected from nitrogen and sulfur atoms as a ring atom; having at least one substituent selected from Substituent group C, oxygen, nitrogen and sulfur A 3- to 6-membered heterocyclic thio group having at least one atom selected from the atoms as a ring atom, R ⁵ is a hydrogen atom; C ₁
Represents a -C ₄ alkyl group, R ⁶ represents a hydrogen atom; C ₁ -C ₆
Represents an alkyl group, R ⁷ is a C ₁ -C ₆ alkyl group; C ₃
-C ₆ cycloalkyl; C ₇ -C ₁₁ aralkyl group (C
₆ -C ₁₀ aryl + C ₁ -C ₄ alkyl); substituent group C
C ₇ -C having at least one substituent selected from
₁₁ aralkyl group (C ₆ -C ₁₀ aryl + C ₁ -C ₄ alkyl); C ₆ -C ₁₄ aryl group; a substituent selected from substituent group C shows a C ₆ -C ₁₄ aryl group at least one organic , Or R ⁶ and R ⁷ combine to form a 3- to 6-membered nitrogen-containing heterocyclic group, Y represents an oxygen atom; a sulfur atom, r
Represents an integer of 1, 2 or 3, Q represents a carbonyl group; or a methylene group, R ⁸ represents a C ₁ -C ₄ alkyl group; C ₆
-C ₁₀ aryl group; represents a C ₆ -C ₁₀ aryl group having at least one substituent selected from the substituent group C, and R
⁹ C ₁ -C ₆ alkyl group; C ₆ -C ₁₀ aryl group which at least one have a selected from substituent group C substituents; C ₃ -C ₆ cycloalkyl group; C ₆ -C ₁₀ aryl group;
C ₇ -C ₁₁ aralkyl group (C ₆ -C ₁₀ aryl + C ₁ -
C ₄ alkyl); C ₇ -C ₁₁ aralkyl group (C ₆ -C) having at least one substituent selected from the substituent group C.
₁₀ aryl + C ₁ -C ₄ alkyl) and R ¹⁰ is a 5- or 6-membered aromatic heterocyclic group having at least one atom selected from oxygen, nitrogen and sulfur atoms as a ring atom; A 5- or 6-membered aromatic heterocyclic group having at least one atom selected from oxygen, nitrogen and sulfur atoms having at least one selected substituent as a ring atom is shown, and R ¹¹ is C ₁ -C ₄ Indicates an alkyl group.

Substituent group A: halogen atom; cyano group; C
₁ -C ₄ alkoxy groups; C ₂ -C ₅ alkanoyl group; C
₂ -C ₅ alkanoyloxy group; C ₂ -C ₅ alkoxycarbonyl group; C ₆ -C ₁₀ aryloxy group; C ₁ -C
₄ alkylthio group; C ₆ -C ₁₀ arylthio group; C _1-
C ₄ alkylsulfonyl group; C ₆ -C ₁₀ arylsulfonyl group; an amino group; C ₂ -C ₅ alkanoylamino group;
C ₂ -C ₅ halo alkanoylamino group; N- (C ₂ -C
₅ alkanoyl) -N- (C ₁ -C ₃ alkyl) amino groups; C ₂ -C ₅ alkoxycarbonylamino group; C ₃ -
C ₅ halo alkoxycarbonylamino group; N- (C ₂ -
C ₅ alkoxycarbonyl) -N- (C ₁ -C ₃ alkyl) amino group; C ₆ -C ₁₀ aryl group which may have a substituent selected from the substituent group C; C ₇ -C ₁₁ arylcarbonyl Amino group (C ₆ -C ₁₀ aryl); C ₇ -C ₁₁
Aralkylamino group (C ₆ -C ₁₀ aryl + C ₁ -C ₄
Alkyl); at least one selected from oxygen, oxygen, and sulfur atoms which may have a substituent selected from the substituent group C
3 to 6-membered heterocyclic group having 4 atoms as ring atoms; at least one atom selected from oxygen, oxygen, and sulfur atoms which may have a substituent selected from Substituent group C is a ring atom. A 3- to 6-membered heterocyclic thio group having as; a C ₈ -C ₁₂ aralkyloxycarbonylamino group (C ₆ -C ₁₀ aryl + C ₁ -C ₄ alkyl) substituent group B: halogen atom; C ₁ -C ₄ alkoxy group ;
C ₂ -C ₅ alkanoyloxy group substituent group C: a halogen atom, a hydroxyl group, a cyano group, a nitro group, C ₁ -C ₄ alkyl group; C ₁ -C ₄ alkoxy group;
C ₂ -C ₅ alkoxycarbonyl group; oxo group substituent group D: amino group; C ₂ -C ₅ alkanoylamino group; C ₂ -C ₅ halo alkanoylamino group; C ₂ -C ₆
Alkoxycarbonylamino group] will be described in detail below.

Of the "methyl, ethyl, isopropyl or sec-butyl group" mentioned for R ¹ in the above general formula (I), a methyl group or an ethyl group is preferable,
More preferably, it is an ethyl group. X represents a methylene or carbonyl group, preferably a carbonyl group.

When Z represents the formula (i), the "C ₁ -C ₃ alkyl group" in R ² is, for example, methyl, ethyl,
It is an n-propyl or isopropyl group, preferably a methyl or ethyl group, and more preferably a methyl group.

When Z is of the formula (ii), m is, for example, when m = 2, cyclopropyl, m = 3, cyclobutyl, m = 4, cyclopentyl, m = 5, 13-position such as cyclohexyl group. Represents the carbon number of a spirocycloalkyl group formed by bonding the side chain of one methylene group in the carboxylic acid group substituted with, preferably 3 (cyclobutyl), 4 (cyclopentyl group), More preferably,
4 (cyclopentyl group).

Possible substitution positions of R ³ are 2-position, 3-position, 4-position.
Position is possible, but is preferably fourth.

The "C ₁ -C ₄ alkylamino group" for R ³ is _one such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino group. "C
A _{group 1} -C ₄ alkyl group "is bonded to the" amino group ", preferably a C ₁ -C ₂ alkylamino group, more preferably a methylamino group.

The "C ₂ -C ₈ dialkylamino group" for R ³ is, for example, dimethylamino, diethylamino,
Dipropylamino, diisopropylamino, dibutyl,
Two "C ₁ -C such as diisobutyl di tert-butyl
_A “ ₄ alkyl group” is a group formed by bonding with an “amino group”, and preferably a diC ₁ -C ₂ alkylamino group,
More preferably, it is a dimethylamino group.

"C ₁ -C ₄ alkoxy group" for R ³
Is, for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy group, preferably a methoxy group, an ethoxy group, and particularly preferably a methoxy group.

"C ₁ -C ₃ alkoxy C ₂ in R ³
“C ₃ alkoxy group” is, for example, methoxyethoxy,
Ethoxyethoxy, propoxyethoxy and butyloxyethoxy groups are preferred, and methoxyethoxy and ethoxyethoxy groups are preferred.

The "C ₁ -C ₆ alkyl group" in R ⁴ when R ³ represents the formula (iii) is, for example, methyl,
A linear or branched alkyl group such as ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, neohexyl groups And preferably a C ₁ -C ₄ alkyl group,
A C ₁ -C ₂ alkyl group is more preferred, and a methyl group is particularly preferred.

The "C ₁ -C ₆ alkyl group having at least one substituent selected from the substituent group A" in R ⁴ when R ³ has the formula (iii) is, for example, bromomethyl or chloromethyl. A C ₁ -C ₆ alkyl group substituted with a halogen atom such as methyl, trifluoromethyl, chloroethyl, trifluoroethyl, chlorobutyl, chloropentyl and chlorohexyl (hereinafter abbreviated as an alkyl group); a cyanomethyl 2-cyanoethyl group An alkyl group substituted with a cyano group; an alkyl group substituted with a C ₁ -C ₄ alkoxy group such as methoxymethyl, ethoxymethyl, methoxyethyl, propoxymethyl, butoxymethyl; methylthiomethyl, ethylthiomethyl, propylthiomethyl , C ₁ -C ₄ alkylthio group such as butyl thiomethyl-substituted Alkyl group; phenylthiomethyl, phenylthiopropyl, phenylthioethyl, phenylthiomethyl hexyl, as naphthyl Lucio methyl C ₆ -
Alkyl groups substituted with C ₁₀ arylthio groups; substituted with C ₂ -C ₅ alkanoyloxy groups such as acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, acetyloxybutyl, and acetyloxyhexyl Alkyl group; methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, tert-
An alkyl group substituted with a C ₂ -C ₅ alkoxycarbonyl group such as butoxycarbonylmethyl group; an alkyl group substituted with a C ₆ -C ₁₀ aryloxy group such as phenoxymethyl, phenoxyethyl, phenoxypropyl and naphthoxymethyl; C ₁ -C ₄ such as methylsulfonylmethyl, ethylsulfonylmethyl, propylsulfonylmethyl, butylsulfonylmethylmethylsulfonylpropyl, methylsulfonylbutyl, methylsulfonylhexyl.
An alkyl group substituted with an alkylsulfonyl group; an alkyl group substituted with a C ₆ -C ₁₀ arylsulfonyl group such as phenylsulfonylmethyl, phenylsulfonylethyl, phenylsulfonylpropyl and naphthylsulfonylmethyl; aminomethyl, 1-aminoethyl, 2-aminoethyl, aminopropyl, aminobutyl, aminopentyl,
An alkyl group substituted with an amino group such as amihexyl;
C ₂ such as acetylaminomethyl, acetylaminoethyl, acetylaminopropyl, acetylaminobutyl, acetylaminohexyl, propionylaminomethyl, propionylaminoethyl, propionylaminobutyl, propionylaminohexyl, butyrylaminomethyl, pentanoylaminomethyl -C ₅ Alkyl group substituted with alkanoylamino group; C ₂ such as trifluoroacetylaminomethyl, bromoacetylaminoethyl, chloroacetylaminopropyl, bromopropionylaminomethyl, bromobutyrylaminomethyl, chloropentanoylaminomethyl. -C ₅ haloalkanoyl alkyl group substituted by an amino group; N- acetyl -N- methylaminomethyl, N- propionyl -N- methylaminomethyl, N- butyryl -N-methylaminomethyl, N-
N-, like pentanoyl-N-methylaminomethyl
An alkyl group substituted with a (C ₂ -C ₅ alkanoyl) -N- (C ₁ -C ₃ alkyl) amino group; methoxycarbonylaminomethyl, methoxycarbonylaminoethyl,
Methoxycarbonylaminopropyl, methoxycarbonylaminobutyl, methoxycarbonylaminopentyl,
Methoxycarbonylaminohexyl, ethoxycarbonylaminomethyl, ethoxycarbonylaminoethyl, ethoxycarbonylaminopropyl, ethoxycarbonylaminobutyl, ethoxycarbonylaminohexyl, propoxycarbonylaminomethyl, propoxycarbonylaminoethyl, butoxycarbonylaminoethyl, te
C ₂ -C as rt- butoxycarbonylamino-methyl
Alkyl group substituted with ₅ alkoxycarbonylamino group; substituted with C ₃ -C ₅ haloalkoxycarbonylamino group such as chloroethoxycarbonylaminomethyl, bromopropoxycarbonylaminomethyl, dichlorobutoxycarbonylaminoethyl, trichloroethoxycarbonylaminomethyl Alkyl group; N-methoxycarbonyl-N-methylaminomethyl, N-methoxycarbonyl-N-methylaminoethyl, N-ethoxycarbonyl-N-methylaminomethyl, N-methoxycarbonyl-N-ethylaminomethyl, N - as methoxycarbonyl -N- ethylamino propyl, N- (C ₂ -C
₅ Alkoxycarbonyl) -N- (C ₁ -C ₃ alkyl) amino-substituted alkyl groups; substituted with C ₇ -C ₁₁ arylcarbonylamino groups such as benzoylaminomethyl, benzoylaminoethyl, naphthoylaminomethyl Alkyl group; C such as benzylaminomethyl, benzylaminoethyl, benzylaminopropyl, benzylaminopentyl, benzylaminohexyl, phenethylaminomethyl, naphthylmethylaminomethyl
₇ -C ₁₁ aralkyl (C ₆ -C ₁₀ aryl + C ₁ -C ₄
An alkyl group substituted with an (alkyl) amino group; an alkyl group substituted with a C ₆ -C ₁₀ aryl group such as phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, naphthylmethyl, and naphthylethyl. Selected from substituents C such as 4-chlorophenylmethyl, 4-fluorophenylethyl, 4-nitrophenylmethyl, 4-methoxyphenylbutyl, 4-methoxyphenylmethyl, 2-methylnaphthylmethyl, 4-chloronaphthylethyl An alkyl group substituted with a C ₆ -C ₁₀ aryl group having a group
An alkyl group substituted with a 3- to 6-membered heterocyclic group such as 2-pyrimidylmethyl, 2-pyridylmethyl and 2-thiazolidinylmethyl; 2-pyrimidylthiomethyl, 2-pyridylthiomethyl, 2-thiazolidinyl Like ruthiomethyl 3
To an alkyl group substituted with a 6-membered heterocyclic thio group; acetylmethyl, acetylethyl, propionylmethyl, butyrylmethyl, pentenoylmethyl, acetylpropyl,
C ₂ -C ₅ alkanoyl group group substituted as acetyl hexyl; benzyloxycarbonylaminomethyl, benzyloxycarbonylamino ethyl, benzyloxycarbonylamino-butyl, benzyloxycarbonylamino-hexyl, phenethyl aryloxycarbonylamino methyl, phenyl butyl oxycarbonyl aminomethyl, alkyl C ₈ -C ₁₂ aralkyloxycarbonyl amino group such as naphthyl methyloxy carbonyl aminomethyl group (C ₆ -C ₁₀ aryl + C ₁ -C ₄ alkyl) is substituted; thienyl-2-methyl (Tenyl),
3-Bromothienyl-2-methyl (thenyl), furyl-2
Substituent group C such as -methyl, 3-chlorofuryl-2-methyl, pyridazyl-3-methyl, pyridazyl-3-propyl, 4-chloropyridazyl-3-methyl, pyridazyl-3-butyl, pyridazyl-3-hexyl. An alkyl group substituted with a 3- to 6-membered heterocyclic group having as a ring atom at least one atom selected from oxygen, oxygen, and sulfur atoms which may have a substituent selected from the group; pyrimidylthiomethyl , Chloropyrimidylthiomethyl, methylpyrimidylthiomethyl, bromopyrimidylthiomethyl, pyrimidylthioethyl, pyrimidylthiobutyl, pyridylthiomethyl, pyridylthiohexyl, thiazolidinylthiomethyl, etc. At least one selected from oxygen, oxygen and sulfur atoms which may have a selected substituent
Examples thereof include an alkyl group substituted with a 3- to 6-membered heterocyclic thio group having 4 atoms as ring atoms, and preferably an alkyl group substituted with a C ₁ -C ₄ alkylthio group; C ₆ -C ₁₀ An alkyl group substituted with an arylthio group;
An alkyl group substituted with a C ₁ -C ₄ alkoxy group; an alkyl group substituted with a cyano group; an alkyl group substituted with a C ₂ -C ₅ alkanoyloxy group; an alkyl group substituted with a C ₂ -C ₅ alkanoylamino group; An alkyl group substituted with an amino group; an alkyl group substituted with a C ₂ -C ₅ alkoxycarbonylamino group; an oxygen group selected from the substituent group C, selected from oxygen, oxygen, and sulfur atoms Examples thereof include an alkyl group substituted with a 3- to 6-membered heterocyclic thio group having at least one atom as a ring atom, and particularly preferably, an alkyl group substituted with a C ₁ -C ₄ alkoxy group; a cyano group is substituted alkyl groups; substituted by C ₂ -C ₅ alkanoylamino group alkyl group;; C ₂ -C ₅ alkanoyloxy group is an alkyl group substituted C ₂ -C
₅ It is an alkyl group substituted with an alkoxycarbonylamino group.

The "C ₃ -C ₆ cycloalkyl group" in R ⁴ when R ³ represents the formula (iii) is, for example, a cyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. Of these, a cycloC ₄ -C ₆ alkyl group is preferable, and a cyclohexyl group is particularly preferable.

The "C ₃ -C ₆ cycloalkyl group having at least one substituent selected from the substituent group B" in R ⁴ when R ³ has the formula: (iii) is, for example,
Substituted cyclic alkyl groups such as chlorocyclopropyl, bromocyclobutyl, methoxycyclopentyl and acetylcyclohexyl groups are preferred, and methoxycyclobutyl group is preferred.

The "C ₂ -C ₆ alkenyl group" in R ⁴ when R ³ represents the formula (iii) is, for example, vinyl, allyl, propenyl, butenyl, isobutenyl,
A group having a double bond such as a pentenyl group and a hexenyl group, and preferably a propenyl group.

The "C ₂ -C ₆ alkynyl group" in R ⁴ when R ³ represents the formula (iii) is a group having a triple bond such as acetylenyl, propynyl, butynyl, pentynyl and hexynyl groups. And preferably an acetylenyl group.

The "C ₆ -C ₁₄ aryl group" in R ⁴ when R ³ represents the formula (iii) is, for example, phenyl, naphthyl or anthranyl group, preferably phenyl or naphthyl group, Particularly preferred is a phenyl group.

The "C ₆ -C ₁₄ aryl group having at least one substituent selected from the substituent group C" in R ⁴ when R ³ represents the formula (iii) is, for example, 2-hydroxyphenyl. , A hydroxyphenyl group such as 4-hydroxyphenyl; a cyanophenyl group such as 2-cyanophenyl; 2-acetylphenyl, 4-acetyl,
C ₂ -C ₅ alkanoyl phenyl group such as 4-propionylphenyl; 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, halogenated phenyl group such as 4-chlorophenyl; 4-methyl Phenyl, 4-ethylphenyl, 4-te
C ₁ -C ₄ alkylphenyl groups such as rt-butylphenyl; nitrophenyl groups such as 3-nitrophenyl, 4-nitro; such as 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl (C ₁ -C
₄ ) Alkoxyphenyl group; 2-methylnaphthyl, 4-
(C ₁ -C ₄ alkyl) naphthyl group such as methylnaphthyl; is 5-chloro anthracite group, preferably a halogenated phenyl group, particularly preferably a fluorophenyl group.

When R ³ has the formula: (iii), the “3- to 6-membered heterocyclic group having at least one atom selected from oxygen, nitrogen and sulfur atoms as a ring atom” in R ⁴ is, for example, , Aziridyl, azetidinyl, furyl,
Saturated or unsaturated heterocyclic groups such as thienyl, pyrrolidinyl, pyrrolyl, pyrazolyl, triazolyl, thiazolyl, thiazolidinyl, isoxazolyl, pyridyl, piperidyl, pyrimidyl, pyranyl, pyrazyl, pyridazyl, and preferably pyrrolidinyl and piperidyl groups. .

When R ³ has the formula: (iii), it has at least one substituent selected from the substituent group C in R ⁴ and at least one selected from oxygen, nitrogen and sulfur atoms. "A 3- to 6-membered heterocyclic group having an atom as a ring atom" is, for example, a halogenated heterocyclic group such as 3-chlorofuryl, 3-bromothienyl, 2-chlorothiazolyl, 4-bromoisoxazolyl; Methoxycarbonylpyrrolidinyl, 1-methoxycarbonylpiperidyl, 1
- methoxycarbonyl thiazolidinyl C ₂ -C such as Le
₅ alkoxycarbonylated heterocyclic group; C ₁ -C ₄ alkylated heterocyclic group such as 2-methylpyrazyl, preferably alkoxycarbonylated heterocyclic group, and particularly preferably 1-methoxycarbonylpyrrolyl group. R ³ which is a dinyl group has the formula: (iii),: (iv),: (vii) ,:
(Viii) ,: "C ₁ -C ₄ alkyl group" in R ⁵ when (iv) is, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, te.
It is a rt-butyl group, preferably a C ₁ -C ₂ alkyl group, and particularly preferably a methyl group.

The "C ₁ -C ₆ alkyl group" in R ⁶ and R ⁷ when R ³ has the formula (iv) has the same meaning as R ⁴ .

The "C ₃ -C ₆ cycloalkyl group" in R ⁷ when R ³ represents the formula (iv) has the same meaning as R ⁴ .

The "C ₇ -C ₁₁ aralkyl group" in R ⁷ when R ³ represents the formula (iv) is, for example, benzyl, phenethyl, phenylpropyl, phenylbutyl,
Groups such as naphthylmethyl and naphthylethyl groups,
The aryl portion is C ₆ -C ₁₀ aryl group, the alkyl group moiety is a C ₁ -C ₄ alkyl group, preferably a benzyl group.

The "C ₆ -C ₁₄ aryl group" in R ⁷ when R ³ has the formula (iv) has the same meaning as R ⁴ .

R ⁶ and R when R ³ represents the formula: (iv)
^The 3- to 6-membered nitrogen-containing heterocyclic group formed by combining ⁷ is, for example, an aziridyl, azetidyl, pyrrolidyl, or piperidyl group, which may have an oxo group as a substituent, and is preferably pyrrolidyl.

When R ³ has the formula (iv), Y represents an oxygen atom or a sulfur atom, and preferably an oxygen atom.

When R ³ represents the formula: (v), r is 1
(Indicates an azetidyl group), 2 (indicates a pyrrolidinyl group), 3 (indicates a piperidyl group), and is preferably 2 or 3.

When R ³ has the formula (v), q is a methylene group or a carbonyl group, preferably a carbonyl group.

When R ³ represents the formula: (vi), r is 2
(Shows an oxazoline group), 3 (shows an oxazine group), and is preferably 2.

The "C ₁ -C ₄ alkyl group" in R ⁸ when R ³ represents the formula (vi) has the same meaning as R ⁵ .

The "C ₁ -C ₄ alkyl group" in R ⁸ when R ³ represents the formula (vii) has the same meaning as R ⁵ .

[0046] R ³ has the formula: "C ₆ -C ₁₀ aryl group" and "C ₆ -C ₁₀ aryl which at least one have a substituent selected from substituent group C at R ⁸ when indicating the (vii) The “group” has the same meaning as the “C ₆ -C ₁₀ aryl” included in the “C ₆ -C ₁₄ aryl” for R ⁴ .

R ⁹ when R ³ represents the formula: (viii)
The “C ₁ -C ₆ alkyl group” has the same meaning as R ⁴ .

R ⁹ when R ³ represents the formula: (viii)
“C ₃ -C ₆ cycloalkyl group” has the same meaning as R ⁴ .

R ⁹ when R ³ represents the formula: (viii)
C ₆ -C ₁₀ for at least one have the "C ₆ -C ₁₀ aryl group" and "selected from substituent group C substituents in
The “aryl group” has the same meaning as the “C ₆ -C ₁₀ aryl” included in the “C ₆ -C ₁₄ aryl” for R ⁴ .

The "5- or 6-membered heterocyclic group having at least one atom selected from oxygen, nitrogen and sulfur atoms as a ring atom" in R ¹⁰ when R ³ represents the formula (ix) is It has the same meaning as R ⁴ .

The "C ₁ -C ₃ alkyl group" in R ¹¹ when R ³ represents the formula (ix) is, for example, a methyl, ethyl, propyl or isopropyl group, preferably C ₁
A -C ₂ alkyl group, more preferably a methyl group.

"Halogen atom" in the definition of Substituent group A is, for example, fluorine, chlorine, bromine or iodine atom, preferably bromine atom or fluorine atom.

A. The “C ₁ -C ₄ alkoxy group” has the same meaning as R ³ .

B. The “C ₁ -C ₄ alkylthio group” is, for example, a methylthio, ethylthio, propylthio, isopropylthio, butylthio or isobutylthio group, wherein the “C ₁ -C ₄ alkyl group” defined in the above R ⁵ is bonded to a sulfur atom. And a methylthio group or an ethylthio group.

C. The “C ₂ -C ₅ alkanoyl group” is, for example, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, sec-butyryl, tert-butyryl, pentynyl group, preferably acetyl, propionyl group, particularly preferably Is an acetyl group.

D. "C ₂ -C ₅ alkanoyloxy group"
Is, for example, acetoxy, propionyloxy, isopropionyl, butyryloxy, iso-butyryloxy, sec- butyryloxy, tert- butyryloxy, an oxygen atom to the "C ₂ -C ₅ alkanoyl group" as -pentynyloxy group bonded And a acetyloxy group, a propionyloxy group, and an isopropionyloxy group are preferable, and an acetyloxy group is particularly preferable.

E. “C ₂ -C ₅ alkoxycarbonyl group” is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, propoxycarbonyl,
A group formed by combining a “C ₁ -C ₄ alkoxy group” and a “carbonyl group” in the above definition of R ³ , such as butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl group, Preferably,
A methoxycarbonyl group and an ethoxycarbonyl group are preferred, and a methoxycarbonyl group is particularly preferred.

F. “C ₆ -C ₁₀ aryloxy group” is
For example, a group formed by combining an oxygen atom with a “C ₆ -C ₁₀ aryl group” having the same meaning as described in R ⁸ such as a phenoxy group and a naphthoxy group, and preferably a phenoxy group. .

G. The “C ₆ -C ₁₀ arylthio group” is a “C ₆ -C ₁₀ aryl group” having the same meaning as described in R ⁸ such as phenylthio and naphthylthio group.
And a sulfur-atom atom are bonded to each other, and preferably a phenylthio group.

H. "C ₆ -C ₁₀ arylsulfonyl group"
Is a group in which a sulfonyl group is bonded to a “C ₆ -C ₁₀ aryl group” having the same meaning as described in R ⁸ such as phenyl (benzene) sulfonyl and naphthylsulfonyl group, and is preferable. Is a phenylsulfonyl group.

I. "C ₂ -C ₅ alkanoylamino group"
For example, acetylamino, propionylamino, the "C ₂ -C ₅ alkanoyl group" and an amino group is bonded groups as butyrylamino group, preferably, acetylamino, a propionylamino group, especially Acetylamino group is preferred.

J. The “C ₂ -C ₅ haloalkanoylamino group” is, for example, C ₃ of the above “C ₂ -C ₅ alkanoylamino group” such as chloroacetylamino, trichloroacetylamino, bromoacetylamino, α-bromobutyrylamino group. a group -C ₅ alkanoyl group is substituted by a halogen atom, preferably, chloroacetyl amino, bromoacetyl amino group.

K. "N- (C ₂ -C ₅ alkanoyl) -
“N- (C ₁ -C ₃ alkyl) amino group” is, for example, N-
Acetyl-N-methylamino, N-propionyl-N-
Methylamino, N-butyryl-N-methylamino, N-
Valeryl -N- methylamino, N- acetyl -N- ethylamino, "C ₁ -C ₃ alkyl in the amino group of the above" C ₂ -C ₅ alkanoylamino group "as N- propionyl -N- ethylamino Is a group formed by bonding,
Preferred is an N-acetyl-N-methylamino group.

L. "C ₂ -C ₅ alkoxycarbonyl group" is, for example, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,
Iso propoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonyl amino, sec- butoxycarbonylamino, generated above as "C ₂ -C ₅ alkoxycarbonyl group", "amino group" bonds, such as tert- butoxycarbonylamino group Group, preferably a methoxycarbonylamino or ethoxycarbonylamino group, and particularly preferably a methoxycarbonylamino group.

M. The “C ₃ -C ₅ haloalkoxycarbonylamino group” is, for example, a “C ₃ -C ₅ alkoxycarbonylamino group” in which an alkoxy group is substituted with a halogen atom such as a trichloroethoxycarbonylamino group, and preferably, It is a trichloroethoxycarbonylamino group.

N. "N- (C ₂ -C ₅ alkoxycarbonyl) -N- (C ₁ -C ₃ alkyl) amino group", for example, N- methoxycarbonyl -N-methylamino, N-
Ethoxycarbonylmethyl -N-methylamino, N- propoxycarbonyl -N-methylamino, N- above as methoxycarbonyl -N ethylamino group to the amino group of the "C ₂ -C ₅ alkoxycarbonyl group", "C ₁ -C ₃ And a N-methoxycarbonyl-N-methylamino, N-ethoxycarbonyl-N-methylamino group, particularly preferably N-methoxycarbonyl-N-methylamino group. It is a base.

O. The “C ₆ -C ₁₀ aryl group” of the “C ₆ -C ₁₀ aryl group which may have a substituent selected from the substituent group C” has the same meaning as defined for R ⁴ .

P. The “C ₇ -C ₁₁ arylcarbonylamino group” is a group formed by combining the above “C ₆ -C ₁₀ aryl group” with a carbonyl group and an amino group, such as a benzoylamino group and a naphthoylamino group. A benzoylamino group is preferred.

Q. “C ₇ -C ₁₁ aralkylamino group (C
₆ -C ₁₀ aryl + C ₁ -C ₄ alkyl) "includes, for example, benzylamino, phenethylamino, phenylpropylamino, the" C as naphthyl methylamino group
₆ -C a ₁₀ aryl group "and" C ₁ -C ₄ alkyl group "and an amino group is bonded group, preferably a benzylamino group.

R. “C ₈ -C ₁₂ aralkyloxycarbonylamino group (C ₆ -C ₁₀ aryl + C ₁ -C ₄ alkyl)” is, for example, benzyloxycarbonylamino,
Phenethyloxycarbonyl carbonylamino, phenylpropyl oxycarbonyl, phenyl-butyloxycarbonylamino, The "C ₇ -C ₁₁ aralkyl group" is an oxygen atom and the carbonyl group and an amino group formed by bonding as naphthylmethyl aryloxycarbonylamino group Group, and preferably a benzyloxycarbonylamino group.

S. "3- to 6-membered heterocyclic group having at least one atom selected from oxygen, nitrogen and sulfur atoms which may have a substituent selected from the substituent group C as a ring atom" and "substituent group" At least one selected from oxygen, oxygen and sulfur atoms which may have a substituent selected from C
"3- to 6-membered heterocyclic thio group having 4 atoms as ring atoms", "3- to 6-membered heterocyclic group having at least one atom selected from oxygen, oxygen and sulfur atoms as ring atoms"
Have the same meanings as described for R ⁴ .

T. “A 3- to 6-membered heterocyclic thio group having as a ring atom at least one atom selected from an oxygen / nitrogen / sulfur atom which may have a substituent selected from the substituent group C” is, for example, A group formed by combining a sulfur atom with a 3- to 6-membered heterocyclic group having the same meaning as R ⁴ such as a pyrimidinylthio, pyridylthio, and thiazolidinylthio group, and preferably pyridylthio, pyrimidylthio, and thiazolidinyl. It is a ruthio group. In the definition of Substituent Group B: a. “Halogen atom” has the same meaning as defined for Substituent Group A.

B. The “C ₁ -C ₄ alkoxy group” has the same meaning as defined for R ³ .

C. "C ₂ -C ₅ alkanoyloxy group"
Has the same meaning as the definition in Substituent group A.

In the definition of Substituent Group C: a. “Halogen atom” has the same meaning as defined in Substituent group A.

B. The “C ₁ -C ₄ alkyl group” has the same meaning as defined in R ⁵ .

C. The “C ₁ -C ₄ alkoxy group” has the same meaning as defined in R ³ .

D. The “C ₂ -C ₅ alkoxycarbonyl group” has the same meaning as defined in Substituent group A.

In the definition of Substituent Group D: a. "C ₂ -C ₅ alkanoylamino group";"C ₂ -C
₅ halo alkanoylamino group ";" C ₂ -C ₅ alkoxycarbonyl group "represents a the same meanings as defined according to Substituent Group A.

The preferred compounds are shown below. General formula (I)
In (1) R ¹ represents a methyl group; an ethyl group, (2) X represents a carbonyl group; a methylene group, and (3) Z represents R ² in the formula: Represents a methyl group; an ethyl group, m in the formula (ii) represented by (4) Z represents 2 to 4, (5) n represents 0,
(6) R ₃ is a nitro group; an amino group; a C ₁ -C ₂ alkyl-substituted amino group; a C ₁ -C ₂ alkoxy group; a formula: (ii
i),: (iv),: (vi),: (vii),: (v
ii), represents a group represented by: (viii),

[0081]

Embedded image

R ⁴ , R ⁵ , R ⁶ , R ⁷ and R in the above formula
⁸ , R ⁹ ; (7) R ⁴ is a hydrogen atom; C ₁ -C ₄ alkyl group; C having at least one substituent selected from the substituent group A _1.
1 -C ₂ alkyl group; C ₄ -C ₆ cycloalkyl group; C ₄ having one a substituent selected from substituent group B ₁
-C ₆ cycloalkyl group; C ₆ -C ₁₀ aryl group; C ₆ -C ₁₀ for one perforated a substituent selected from substituent group C ₁
Aryl group; 5- or 6-membered heterocyclic group having at least one atom selected from oxygen, nitrogen and sulfur atoms as a ring atom; having at least one substituent selected from Substituent group C ₁ and oxygen , A 5- or 6-membered heterocyclic group having at least one atom selected from a nitrogen atom and a sulfur atom as a ring atom, (8) R ⁵ represents a hydrogen atom; a C ₁ -C ₂ alkyl group, (9) ) R ⁶ represents a hydrogen atom; a C ₁ -C ₄ alkyl group, (10) R ⁷ represents a C ₁ -C ₄ alkyl group; C ₄
-C ₆ cycloalkyl group; C ₇ -C ₁₁ aralkyl group; C ₆ -C ₁₀ aryl group; Substituent Group C ₇ -C ₁₁ aralkyl group which at least one perforated a substituent selected from substituent group C ₁ (11) Y represents a C ₆ -C ₁₀ aryl group having at least one substituent selected from C ₁ , or R ⁶ and R ⁷ combine to form a 5- to 6-membered nitrogen-containing heterocyclic group; Represents an oxygen atom; a sulfur atom, (12) r represents an integer of 2 or 3, (13) Q represents a carbonyl group, (14)
R ⁸ is a C ₁ -C ₂ alkyl group; a C ₆ -C ₁₀ aryl group;
C _6- having one substituent selected from the substituent group C _1.
Indicates C ₁₀ aryl group, (15) R ⁹ is C ₁ -C ₄ alkyl radical; a selected from substituent group C ₁ substituents; C ₄ -C ₆ cycloalkyl group; C ₆ -C ₁₀ aryl group A compound having a C ₇ -C ₁₁ aralkyl group having at least one C ₆ -C ₁₀ aryl group; a C ₇ -C ₁₁ aralkyl group; a C ₇ -C ₁₁ aralkyl group having at least one substituent selected from the substituent group C ₁ .

Substituent group A ₁ : Fluorine / chlorine / bromine atom;
Cyano group; C ₁ -C ₂ alkoxy groups; C ₂ -C ₃ alkanoyl; C ₂ -C ₃ alkanoyloxy group; C ₂ -C
₃ Alkoxycarbonyl group; Phenoxy group; C ₁ -C ₂
Alkylthio group; phenylthio group; C ₁ -C ₂ alkylsulfonyl group; phenylsulfonyl group; amino group; C ₂
-C ₃ alkanoylamino group; C ₂ -C ₃ halo alkanoylamino group; N- (C ₂ -C ₃ alkanoyl) -N-
(C ₁ -C ₂ alkyl) amino group; C ₂ -C ₃ alkoxycarbonylamino group; C ₃ -C ₄ halo alkoxycarbonylamino group; N- (C ₂ -C ₃ alkoxycarbonyl) -N- (C ₁ - A C ₂ alkyl) amino group; a phenyl group which may have a substituent selected from the substituent group C ₁ .
Benzoylamino group; benzylamino group; Substituent group C ₁
A 5- or 6-membered heterocyclic group having, as a ring atom, at least one atom selected from oxygen, oxygen, and sulfur atoms which may have a substituent selected from the following; Substitution selected from the substituent group C ₁ 5- or 6-membered heterocyclic thio group having at least one atom selected from oxygen, oxygen and sulfur atoms which may have a group as a ring atom; benzyloxycarbonylamino group Substituent group B ₁ : fluorine / chlorine・ Bromine atom; C ₁ -C ₂ alkoxy group; C ₂ -C ₃ alkanoyloxy group Substituent group C ₁ : Fluorine, chlorine, bromine atom; Hydroxyl group; Cyano group; Nitro group; C ₁ -C ₂ alkyl group; C ₁ -C ₂ alkoxy group; C ₂ -C ₃ alkoxycarbonyl group; preferred compounds from oxo group, (16) a compound wherein R ¹ represents an ethyl group.

Further preferred compounds are (17) compounds in which R ³ is substituted at the 4-position.

In the general formula (I), a more preferable compound is: (18) X represents a methylene group, (19) Z represents R ² in the formula (i) represents a methyl group, (2)
0) R ³ is methoxycarbonylglycylamino group; acetylglycylamino group; 1-methoxycarbonyl-2-
A compound exhibiting a pyrrolidylcarbonylamino group, particularly preferably, in the general formula (I), (21) X represents a carbonyl group, and (22) Z represents R ² in the formula (i); An ethyl group is represented by the formula represented by Z: (ii)
M in ₃ represents 3 or 4, and (23) R ₃ is an amino group; an acetylamino group; a cyanoacetylamino group; a benzoylamino group; a 2-fluorobenzoylamino group;
-Fluorobenzoylamino group; acetylglycylamino group; methoxycarbonylglycylamino group; N-methyl-N-methoxycarbonylaminoacetylamino (methoxycarbonylglycylamino) group; methoxycarbonyl group; phenylureido group; 2-oxo A compound showing an oxazolin-3-yl group; a trifluoroacetylamino group; an ethoxyacetylamino group; an acetoxyacetylamino group; a methylsulfonylamino group; an ethylsulfonylamino group.

The most suitable compound is (24) 13- [2- (4-cyanoacetylaminophenyl) -2-methylpropionyloxy] -5-hydroxyiminomilbemycin A ₄ (25) 13- {2- [4- (N-acetylglycyl)
Aminophenyl] -2-methylpropionyloxy}-
5-hydroxyimino milbemycin A ₄ (26) 13- {2- [4- (N-methoxycarbonylglycyl) methylaminophenyl] -2-methylpropionyloxy} -5-hydroxyimino milbemycin A ₄ (27) 13- [2- (4-Methoxycarbonylaminophenyl) -2-methylpropionyloxy] -5-hydroxyiminomilbemycin A ₄ (28) 13- {2- [4- (N-phenylcarbamoylamino) phenyl] -2-methyl Propionyloxy} -5-hydroxyiminomylbemycin A ₄ (29) 13- {2- [4- (2-oxooxazolin-3-yl) phenyl] -2-methylpropionyloxy} -5-hydroxyiminomylbemycin A ₄ ( 30) 13- [1- (4-aminophenyl) cyclopen Emissions carbonyloxy] -5-hydroxyimino milbemycin _{A 4 (31) 13- [1-} (4- acetylamino-phenyl) Shikurohe ° Ntankaruho Bu Niruokishi] -5 hydrate Loki CHILLY amino mill F Bu mycin _{A 4 (32) 13- [1-} (4 - acetoxyacetyl-aminophenyl) cyclopentane carbonyl oxy] -5-hydroxyimino milbemycin _{A 4 (33) 13- [1-} (4- methanesulfonylamino-phenyl) cyclopentane carbonyl oxy] -5-hydroxyimino milbemycin A ₄ (34 ) 13- [1- (4-acetylaminophenyl)
1-ethyl-butyryloxy] -5-hydroxyimino milbemycin _{A 4 (35) 13- [1-} (4- acetylamino-phenyl)
Cyclobutanecarbonyloxy] -5-hydroxyiminomylbemycin A ₄ Next, specific examples of the compound of the present invention are shown in Table 1.
R ¹ , R ³ , X, Z and n have the same meanings as shown in formula (I).

[0087]

[Table 1]

[0088]

Embedded image

[In the formula, Me represents a methyl group. ] In the table below, abbreviations indicate the following groups or symbols.

Ac ・ ・ ・ ・ Acetyl Azt ・ ・ ・ ・ ・ Azetidinyl Bz ・ ・ ・ ・ ・ ・ Benzyl Fur ・ ・ ・ ・ ・ ・ Fryl Bu ・ ・ ・ ・ ・ ・ Butyl Et ・ ・ ・ ・ ・ ・ Ethyl Hex ・ ・ ・ ・ ・ Hexyl Isox ・ ・ ・ Isoxazolyl Lac ・ ・ ・ Lactam Me ・ ・ ・ ・ ・ ・ Methyl Oxaz ・ ・ ・ ・ ・ Oxazoline Pen ・ ・ ・ Pentyl Ph ・ ・ ・ ・ ・ ・Phenyl Pip ・ ・ ・ ・ ・ Piperidinyl Pr ・ ・ ・ ・ ・ Propyl Pyrd ・ ・ ・ Pyrrolidinyl Pym ・ ・ ・ ・ ・ Pyrimidinyl Pyr ・ ・ ・ Pyridyl Thdn ・ ・ ・ ・ ・ Thiazolidinyl Thi ・ ・ ・ ・ ・Thienyl Thiz ・ ・ ・ ・ ・ thiazolyl i- ・ ・ ・ ・ ・ ・ iso c- ・ ・ ・ ・ ・ cyclo s- ・ ・ ・ ・ ・ ・ secondary t- ・ ・ ・ ・ ・ tertiary ──────── ───────────────────────────── Compound number No. R ¹ Z n X R ³ ________________________________________________________________________________ 1 Et = C (Me) ₂ 1 C = 0 4-NO ₂ 2 Et = C (Me) ₂₀ C = 0 4-NO ₂ 3 Et = C (Me) ₂₀ C = 0 3-NO ₂ 4 Et = C (Me) ₂ 0 C = 0 2-NO ₂ 5 Et = C (Me) ₂ 1 C = 0 4-NH ₂ 6 Et = C (Me) ₂ 0 C = 0 4-NH ₂ 7 Et = C (Me) ₂ 0 C = 0 3-NH ₂ 8 Et = C (Me) ₂ 0 C = 0 2-NH ₂ 9 Et = C (Me) ₂ 0 C = 0 4- NHMe 10 Et = C (Me) ₂ 0 C = 0 4-NHEt 11 Et = C (Me) ₂₀ C = 0 4-NHPr 12 Et = C (Me) ₂ 0 C = 0 4-NHBu 13 Et = C (Me) ₂ 0 C = 0 4-NMe ₂ 14 Et = C (Me) ₂ 0 C = 0 4-NEt ₂ 15 Et = C (Me) ₂ 1 C = 0 4-OMe 16 Et = C (Me) ₂₀ C = 0 4-OMe 17 Et = C (Me) ₂₀ C = 0 3-OMe 18 Et = C (Me) ₂₀ C = 0 2-OMe 19 Et = C (Me) ₂₀ C = 0 4-OEt 20 Et = C (Me) ₂ 0 C = 0 4-OPr 21 Et = C (Me) ₂₀ C = 0 2-Oi-Pr 22 Et = C (Me) ₂₀ C = 0 4-OBu _{23 Et = C (Me) 2} 0 C = 0 4-Oi-Bu 24 Et = C (Me) 2 0 C = 0 4-OCH 2 CH 2 OMe 25 Et = C (Me) 2 1 C = 0 4- NHAc 26 Et = C (Me) ₂₀ C = 0 4-NHAc 27 Me = C (Me) ₂₀ C = 0 4-NHAc 28 Et = C (Me) ₂₀ C = 0 4-N (Me) Ac 29 Et = C (Me) ₂₀ C = 0 4-N (Et) Ac 30 Et = C (Me) ₂₀ C = 0 4-N (Pr) Ac 31 Et = C (Me) ₂₀ C = 0 4-N (Bu) Ac 32 Et = C (Me) ₂ 0 C = 0 3-NHAc 33 E t = C (Me) ₂₀ C = 0 4-NHCOEt 34 Et = C (Me) ₂₀ C = 0 4-NHCOPr 35 Et = C (Me) ₂₀ C = 0 4-NHCOi-Pr 36 Et = C (Me) ₂ 0 C = 0 4-NHCOBu 37 Et = C (Me) ₂ 0 C = 0 4-NHCOi-Bu 38 Et = C (Me) ₂₀ C = 0 4-NHCOt-Bu 39 Et = C ( Me) ₂₀ C = 0 4-NHCOc-Pr 40 Et = C (Me) ₂₀ C = 0 4-NHCOc-Bu 41 Et = C (Me) ₂₀ C = 0 4-NHCOc-Pen 42 Et = C (Me) ₂ 0 C = 0 4-NHCOc-Hex 43 Et = C (Me) ₂₀ C = 0 4-NHCOCH ₂ Br 44 Et = C (Me) ₂ 0 C = 0 4-NHCOCF ₃ 45 Et = C (Me) ₂ 0 C = 0 4-NHCOCHF ₂ 46 Et = C (Me) ₂₀ C = 0 4-NHCOCH ₂ CN 47 Et = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ OMe 48 Et = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ OEt 49 Et = C (Me) ₂₀ C = 0 4-NHCOCH ₂ OAc 50 Et = C (Me) ₂₀ C = 0 4-NHCOCH ₂ OCOPr 51 Et = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ SMe 52 Et = C (Me) ₂₀ C = 0 4-NHCOCH ₂ SO ₂ Me 53 Et = C (Me) ₂₀ C = 0 4-NHCOCH ₂ SPh 54 Et = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ S (2-Pym) 55 Et = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ S (2-Pyr) 56 Et = C (Me ) ₂₀ C = 0 4-NHCOCH ₂ S (2-Thdn) 57 Et = C (Me) ₂₀ C = 0 4-NHCOCH ₂ CH ₂ COMe 58 Et = C (Me) ₂₀ C = 0 4-NHCOCH ₂ CH ₂ COOMe 59 Et = C (Me) ₂ 0 C = 0 4-NHCOCH = CHMe 60 Et = C (Me) ₂₀ C = 0 4-NHCOC ≡CH 61 Et = C (Me) ₂₀ C = 0 4-NHCOCH ₂ (4-NO ₂ Ph) 62 Et = C (Me) ₂₀ C = 0 4-NHCOCH ₂ (4-MeOPh) 63 Et = C (Me) ₂₀ C = 0 4-NHCOPh 64 Et = C (Me) ₂₀ C = 0 4-NHCO (2-FPh) 65 Et = C (Me) ₂₀ C = 0 4-NHCO (3-FPh) 66 Et = C (Me) ₂₀ C = 0 4-NHCO (4-FPh) 67 Et = C (Me) ₂₀ C = 0 4-NHCO (4-ClPh) 68 Et = C (Me) ₂₀ C = 0 4-NHCO (3-ClPh) 69 Et = C (Me) ₂₀ C = 0 4-NHCO (4-MeOPh) 70 Et = C (Me) ₂₀ C = 0 4-NHCO (3-MeOPh) 71 Et = C (Me) ₂₀ C = 0 4-NHCO (3,4-di-MeOPh) 72 Et = C (Me) ₂₀ C = 0 4-NHCO (4-t-BuPh) 73 Et = C (Me) ₂₀ C = 0 4- NHCO (4-NO ₂ Ph) 74 Et = C (Me) ₂₀ C = 0 4-NHCO (3-NO ₂ Ph) 75 Et = C (Me) ₂₀ C = 0 4-NHCO (3-Pyr) 76 Et = C (Me) ₂₀ C = 0 4-NHCO (4-Pyr) 77 Et = C (Me) ₂₀ C = 0 4-NHCO (2-Fur) 78 Et = C (Me) ₂₀ C = 0 4-NHCO (2-Thi) 79 Et = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ NH ₂ 80 Et = C (Me) ₂ 1 C = 0 4-NHCOCH ₂ NHCOOMe 81 Et = C ( Me) ₂ 0 C = 0 4-NHCOCH ₂ NHCOOMe 82 Et = C (Me) ₂₀ C = 0 3-NHCOCH ₂ NHCOOMe 83 Et = C (Me) ₂₀ C = 0 2-NHCOCH ₂ NHCOOMe 84 Me = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ NHCOOMe 85 i-Pr = C (Me) ₂₀ C = 0 4-NHCOCH ₂ NHCOOMe 86 s-Bu = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ NHCOOMe 87 Et = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ NHCOOEt 88 Et = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ NHCOOCH ₂ CCl ₃ 89 Et = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ NHCOOt-Bu 90 Et = C (Me) ₂₀ C = 0 4-NHCOCH ₂ NHCOOBz 91 Et = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ NHAc 92 Me = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ NHAc 93 Et = C (Me) ₂ 0 C = 0 3-NHCOCH ₂ NHAc 94 Et = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ NHCOPh 95 Et = C (Me) ₂ 0 C = 0 4-NHCOCH ₂ N (Me) COOMe 96 Et = C (Me) ₂ 0 C = 0 4-N (Me) COCH ₂ NHCOOMe 97 Et = C (Me) ₂₀ C = 0 4-NHCOCH (Me) NHCOOMe 98 Et = C (Me) ₂ 0 C = 0 4 -NHCOCH ₂ NHCOEt 99 Et = C (Me) ₂ 0 C = 0 4-NHCOCH (Me) NHCOOEt 100 Et = C (Me) ₂ 0 C = 0 4-NHCOCH (Et) NHCOOMe 101 Et = C (Me) ₂ 0 C = 0 4-NHCOCH (i-Pr) NHCOOMe 102 Et = C (Me) ₂ 0 C = 0 4-NHCOCH (i-Bu) NHCOOMe 103 Et = C (Me) ₂ 0 C = 0 4-NHCOCH ( t-Bu) NHCOOMe 104 Et = C (Me) ₂ 0 C = 0 4-NHCOCH (CH ₂ CH ₂ SMe) NHCOOMe 105 Et = C (Me) ₂ 0 C = 0 4-NHCOCH (CH ₂ SMe) NHCOOMe 106 Et = C (Me) ₂ 0 C = 0 4-NHCOCH (CH ₂ SEt) NHCOOMe 107 Et = C (Me) ₂ 0 C = 0 4-NHCOC (Me) ₂ NHCOOMe 108 Me = C (Me) ₂ 0 C = 0 4-NHCOC (Me) ₂ NHCOOMe 109 Et = C (Me) ₂₀ C = 0 4-NHCOCH ₂ CH ₂ NH ₂ 110 Et = C (Me) ₂₀ C = 0 4-NHCOCH ₂ CH ₂ NHCOOMe 111 Et = C (Me) ₂ 1 C = 0 4-NHCO (1-COOMe-2-Pyrd) 112 Et = C (Me) ₂₀ C = 0 4-NHCO (1-COOMe-2-Pyrd) 113 Me = C (Me) ₂ 0 C = 0 4-NHCO (1-COOMe-2-Pyrd) 114 Et = C (Me) ₂₀ C = 0 4-NHCO (1-COOEt-2-Pyrd) 115 Et = C ( Me) ₂ 0 C = 0 4-NHCO (1-COOMe-4-Pip) 116 Et = C (Me) ₂ 0 C = 0 4-NHCO (3-COOEt-4-Thdn) 117 Et = C (Me) ₂ 0 C = 0 4-NHCO (5-γ-Lac) 118 Et = C (Me) ₂₀ C = 0 4-NHCOC (= NOMe) (2-NHCOCH ₂ Cl-4-Thiz) 119 Et = C ( Me) ₂ 0 C = 0 4-NHCOC (= NOMe) (2-NHCOOMe-4-Thiz) 120 Et = C (Me) ₂ 0 C = 0 4-NHCOC (= NOMe) (2-Thi) 121 Et = C (Me) ₂ 0 C = 0 4-NHCOOMe 122 Me = C (Me) ₂₀ C = 0 4-NHCOOMe 123 Et = C (Me) ₂ 0 C = 0 4-N (Me) COOMe 124 Et = C (Me) ₂₀ C = 0 4-NHCOOEt 125 Et = C (Me) ₂₀ C = 0 4-NHCOOPr 126 Et = C (Me) ₂₀ C = 0 4-NHCOOi-Pr 127 Et = C (Me) ₂ 0 C = 0 4-NHCOOBu 128 Et = C (Me) ₂ 0 C = 0 4-NHCOOi-Bu 129 Et = C (Me) ₂ 0 C = 0 4-NHCOOc-Pr 130 Et = C (Me) ₂ 0 C = 0 4-NHCOOBn 131 Et = C (Me) ₂ 0 C = 0 4-NHCOOPh 132 Et = C (Me) ₂ 0 C = 0 4-NHCONHMe 133 Me = C (Me) ₂ 0 C = 0 4 -NHCONHMe 134 Et = C (Me) ₂ 0 C = 0 3-NHCONHMe 135 Et = C (Me) ₂₀ C = 0 4-NHCONHEt 136 Et = C (Me) ₂ 0 C = 0 4-NHCONHPr 137 Et = C ( Me) ₂ 0 C = 0 4-NHCONHi-Pr 138 Et = C (Me) ₂₀ C = 0 4-NHCONHBu 139 Et = C (Me) ₂ 0 C = 0 4-NHCONHt-Bu 140 Et = C (Me ) ₂ 0 C = 0 4-NHCONHc-Hex 141 Et = C (Me) ₂ 0 C = 0 4-NHCONHBz 142 Et = C (Me) ₂ 0 C = 0 4-NHCONMe ₂ 143 Et = C (Me) ₂ 0 C = 0 4-NHCO (1-Pyrd) 144 Et = C (Me) ₂ 0 C = 0 4-NHCONHPh 145 Et = C (Me) ₂ 0 C = 0 4-NHCSNHMe 146 Et = C (Me) ₂ 0 C = 0 4-NHCSNHEt 147 Et = C (Me) ₂ 1 C = 0 4-NHSO ₂ Me 148 Et = C (Me) ₂ 0 C = 0 4-NHSO ₂ Me 149 Me = C (Me) ₂ 0 C = 0 4-NHSO ₂ Me 150 Et = C (Me) ₂₀ C = 0 3-NHSO ₂ Me 151 Et = C (Me) ₂₀ C = 0 4-N (Me) SO ₂ Me 152 Et = C (Me) ₂ 0 C = 0 4-N (Et) SO ₂ Me 153 Et = C (Me) ₂₀ C = 0 4-N (Pr) SO ₂ Me 154 Et = C (Me) ₂₀ C = 0 4-N (Bu) SO ₂ Me 155 Et = C (Me) ₂₀ C = 0 4-NHSO ₂ Et 156 Et = C (Me) ₂₀ C = 0 4-NHSO ₂ Pr 157 Et = C (Me) ₂₀ C = 0 4-NHSO ₂ Bu 158 Et = C (Me) ₂₀ C = 0 4-NHSO ₂ Ph 159 Et = C (Me) ₂₀ C = 0 4-NHSO ₂ (4-MePh) 160 Et = C (Me) ₂ 0 C = 0 4- (2-oxo-1-Azt) 161 Et = C (Me) ₂₀ C = 0 4- (2-oxo-1-Pip) 162 Et = C (Me ) ₂₀ C = 0 4- (2,6-dioxo-1-Pip) 163 Et = C (Me) ₂ 0 C = 0 4- (2-oxo-1-Pyrd) 164 Et = C (Me) ₂ 0 C = 0 4- (2,5-dioxo-1-Pyrd) 165 Et = _{C (Me) 2 0 C =} 0 4- (2-oxo-1,3-Oxaz-3-yl) 166 Et = C (CH 2) 4 1 C = 0 4-NO 2 167 Et = C (CH 2 ) ₄ 0 C = 0 4-NO ₂ 168 Et = C (CH ₂ ) ₄₀ C = 0 3-NO ₂ 169 Et = C (CH ₂ ) ₄ 0 C = 0 2-NO ₂ 170 Et = C (CH ₂ ) ₄ 1 C = 0 4-NH ₂ 171 Et = C (CH ₂ ) ₄₀ C = 0 4-NH ₂ 172 Et = C (CH ₂ ) ₄₀ C = 0 2-NH ₂ 173 Et = C ( CH ₂ ) ₄ 0 C = 0 3-NH ₂ 174 Et = C (CH ₂ ) ₄₀ C = 0 4-NHMe 175 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHEt 176 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHPr 177 Et = C (CH ₂ ) ₄₀ C = 0 4-NHBu 178 Et = C (CH ₂ ) ₄ 0 C = 0 4-NMe ₂ 179 Et = C (CH ₂ ) ₄ 0 C = 0 4-NEt ₂ 180 Et = C (CH ₂ ) ₄ 1 C = 0 4-OMe 181 Et = C (CH ₂ ) ₄ 0 C = 0 4-OMe 182 Et = C (CH ₂ ) ₄ 0 C = 0 3-OMe 183 Et = C (CH ₂ ) ₄₀ C = 0 2-OMe 184 Et = C (CH ₂ ) ₄₀ C = 0 4-OEt 185 Et = C (CH ₂ ) ₄₀ C = 0 4-OPr 186 Et = C (CH ₂ ) ₄ 0 C = 0 2-Oi-Pr 187 Et = C (CH ₂ ) ₄₀ C = 0 4-OBu 188 Et = C (CH ₂ ) ₄₀ C = 0 4-Oi-Bu 189 Et = C (CH ₂ ) ₄ 0 C = 0 4-OCH ₂ CH ₂ OMe 190 Et = C (CH ₂ ) ₄ 1 C = 0 4-NHAc 191 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHAc 192 Me = C (CH ₂ ) ₄₀ C = 0 4-NHAc 193 Et = C (CH ₂ ) ₄ 0 C = 0 4-N (Me) Ac 194 Et = C (CH ₂ ) ₄₀ C = 0 4-N (Et) Ac 195 Et = C (CH ₂ ) ₄₀ C = 0 4-N (Pr) Ac 196 Et = C (CH ₂ ) ₄₀ C = 0 4-N (Bu) Ac 197 Et = C (CH ₂ ) ₄₀ C = 0 3-NHAc 198 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOEt 199 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOPr 200 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOi-Pr 201 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOBu 202 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOi-Bu 203 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOt-Bu 204 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOc-Pr 205 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOc-Bu 206 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOc -Pen 207 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOc-Hex 208 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOCH ₂ Br 209 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOCF ₃ 210 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCHF ₂ 211 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ CN 212 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOCH ₂ OMe 213 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOCH ₂ OEt 214 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOCH ₂ OAc 215 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ OCOPr 216 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOCH ₂ SMe 217 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ SO ₂ Ph 218 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ SPh 219 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOCH ₂ S (2-Pym) 220 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ S (2-Pyr) 221 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ S (2-Thdn) 222 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ CH ₂ COMe 223 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ CH ₂ COOMe 224 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH = CHMe 225 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOC ≡CH 226 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ Ph 227 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ (4-NO ₂ Ph) 228 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOPh 229 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCO (2-FPh) 230 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCO (3-FPh) 231 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCO (4 -FPh) 232 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCO (4-ClPh) 233 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCO (3-ClPh) 234 Et = C ( CH ₂ ) ₄ 0 C = 0 4-NHCO (4-MeOPh) 235 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCO (3-MeOPh) 236 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCO (3,4-di-MeOPh) 237 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCO (4-t-BuPh) 238 Et = C (CH ₂ ) ₄ 0 C = 0 4- NHCO (4-NO ₂ Ph) 239 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCO (3-NO ₂ Ph) 240 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCO (3- Pyr) 241 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCO (4-Pyr) 242 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCO (2-Fur) 243 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCO (2-Thi) 244 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOCH ₂ NH ₂ 245 Et = C (CH ₂ ) ₄ 1 C = 0 4-NHCOCH ₂ NHCOOMe 246 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ NHCOOMe 247 Et = C (CH ₂ ) ₄ 0 C = 0 3-NHCOCH ₂ NHCOOMe 248 Et = C (CH ₂ ) ₄₀ C = 0 2- NHCOCH ₂ NHCOOMe 249 Me = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ NHCOOMe 250 i-Pr = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ NHCOOMe 251 s-Bu = C (CH _{2 ) 4 0 C = 0 4-} NHCOCH 2 NHCOOMe 252 Et = C (CH 2) 4 0 C = 0 4-NHCOCH 2 NHCOOEt 253 Et = C (CH 2) 4 0 C = 0 4-NHCOCH 2 NHCOOCH 2 CCl 3 254 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ NHCOOt-Bu 255 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ NHCOOBz 256 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOCH ₂ NHAc 257 Me = C (CH ₂ ) ₄₀ C = 0 4-NHCOCH ₂ NHAc 258 Et = C (CH ₂ ) ₄₀ C = 0 3-NHCOCH ₂ NHAc 259 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ NHCOPh 260 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOCH ₂ N (Me) COOMe 261 Et = C (CH ₂ ) ₄₀ C = 0 4-N (Me ) COCH ₂ NHCOOMe 262 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH (Me) NHCOOMe 263 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ NHCOEt 264 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH (Me) NHCOOEt 265 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOCH (Et) NHCOOMe 266 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH (i -Pr) NHCOOMe 267 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH (i-Bu) NHCOOMe 268 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH (t-Bu) NHCOOMe 269 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOCH (CH ₂ CH ₂ SMe) NHCOOMe 270 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOCH (CH ₂ SMe) NHCOOMe 271 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH (CH ₂ SEt) NHCOOMe 272 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOC (Me) ₂ NHCOOMe 273 Me = C (CH ₂ ) ₄ 0 C = 0 4-NHCOC (Me) ₂ NHCOOMe 274 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ CH ₂ NH ₂ 275 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOCH ₂ CH ₂ NHCOOMe 276 Et = C (CH ₂ ) ₄ 1 C = 0 4-NHCO (1-COOMe-2-Pyrd) 277 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCO (1-COOMe-2-Pyrd) 278 Me = C (CH ₂ ) ₄₀ C = 0 4-NHCO (1-COOMe-2-Pyrd) 279 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCO (1-COOEt-2-Pyrd) 280 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCO (1-COOMe-4-Pip) 281 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCO (3-COOEt-4-Thdn) 282 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCO (5-γ-Lac) 283 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOC (= NOMe) (2-NHCOCH ₂ Cl-4-Thiz) 284 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOC (= NOMe) (2-NHCOOMe-4-Thiz) 285 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOC (= NOMe) (2-Thi) 286 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOOMe 287 Me = C (CH ₂ ) ₄₀ C = 0 4-NHCOOMe 288 Et = C (CH ₂ ) ₄ 0 C = 0 3-NHCOOMe 289 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOOEt 290 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOOPr 291 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOOi-Pr 292 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCOOBu 293 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOOi-Bu 294 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOOc-Pr 295 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOOBn 296 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCOOPh 297 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCONHMe 298 Me = C (CH ₂ ) ₄₀ C = 0 4-NHCONHMe 299 Et = C (CH ₂ ) ₄₀ C = 0 3-NHCONHMe 300 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCONHEt 301 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCONHPr 302 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCONHi-Pr 303 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCONHBu 304 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCONHi-Bu 305 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCONHc-Hex 306 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCONHBz 307 Et = C (CH ₂ ) ₄₀ C = 0 4-NHCONMe ₂ 308 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCO (1-Pyrd) 309 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCONHPh 310 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCSNHMe 311 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHCSNHEt 312 Et = C (CH ₂ ) ₄ 1 C = 0 4-NHSO ₂ Me 313 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHSO ₂ Me 314 Me = C (CH ₂ ) ₄₀ C = 0 4-NHSO ₂ Me 315 Et = C (CH ₂ ) ₄₀ C = 0 3-NHSO ₂ Me 316 Et = C (CH ₂ ) ₄ 0 C = 0 4-N (Me) SO ₂ Me 317 Et = C (CH ₂ ) ₄ 0 C = 0 4-N (Et) SO ₂ Me 318 Et = C (CH ₂ ) ₄₀ C = 0 4-N (Pr) SO ₂ Me 319 Et = C ( CH ₂ ) ₄₀ C = 0 4-N (Bu) SO ₂ Me 320 Et = C (CH ₂ ) ₄₀ C = 0 4-NHSO ₂ Et 321 Et = C (CH ₂ ) ₄₀ C = 0 4- NHSO ₂ Pr 322 Et = C (CH ₂ ) ₄ 0 C = 0 4-NHSO ₂ Bu 323 Et = C (CH ₂ ) ₄₀ C = 0 4-NHSO ₂ Ph 324 Et = C (CH ₂ ) ₄₀ C = 0 4-NHSO ₂ (4-MePh) 325 Et = C (CH ₂ ) ₄ 0 C = 0 4-4- (2-oxo-1-Azt) 326 Et = C (CH ₂ ) ₄ 0 C = 0 4- (2-oxo-1-Pip) 327 Et = C (CH ₂ ) ₄ 0 C = 0 4- (2,6-dioxo-1-Pip) 328 Et = C (CH ₂ ) ₄ 0 C = 0 4- (2-oxo-1-Pyrd) 329 Et = C (CH ₂ ) ₄ 0 C = 0 4- (2,5-dioxo-1-Pyrd) 330 Et = C (CH ₂ ) ₄ 0 C = 0 4- (2-oxo-1,3-Oxaz-3-yl) 331 Et = C (Me) ₂ 0 C = 0 4-NO ₂ 332 Et = C (Et) ₂₀ C = 0 4-NH ₂ 333 Et = C (Et) ₂ 0 C = 0 4-NHMe 334 Et = C (Et) ₂₀ C = 0 4-NMe ₂ 335 Et = C (Et) ₂₀ C = 0 4-OMe 336 Et = C ( Et) ₂₀ C = 0 4-NHAc 337 Et = C (Et) ₂₀ C = 0 4-N (Me) Ac 338 Et = C (Et) ₂₀ C = 0 3-NHAc 339 Et = C (Et ) ₂ 0 C = 0 4-NHCOEt 340 Et = C (Et) ₂₀ C = 0 4-NHCOPr 341 Et = C (Et) ₂ 0 C = 0 4-NHCOi-Pr 342 Et = C (Et) ₂₀ C = 0 4-NHCOBu 343 Et = C (Et) ₂₀ C = 0 4-NHCOc-Pr 344 Et = C (Et) ₂₀ C = 0 4-N HCOc-Bu 345 Et = C (Et) ₂₀ C = 0 4-NHCOc-Hex 346 Et = C (Et) ₂₀ C = 0 4-NHCOCF ₃ 347 Et = C (Et) ₂₀ C = 0 4- NHCOCH ₂ CN 348 Et = C (Et) ₂ 0 C = 0 4-NHCOCH ₂ OMe 349 Et = C (Et) ₂₀ C = 0 4-NHCOCH ₂ OEt 350 Et = C (Et) ₂₀ C = 0 4 -NHCOCH ₂ OAc 351 Et = C (Et) ₂ 0 C = 0 4-NHCOCH ₂ SMe 352 Et = C (Et) ₂ 0 C = 0 4-NHCOPh 353 Et = C (Et) ₂₀ C = 0 4- NHCO (2-FPh) 354 Et = C (Et) ₂ 0 C = 0 4-NHCO (3-FPh) 355 Et = C (Et) ₂ 0 C = 0 4-NHCO (4-FPh) 356 Et = C (Et) ₂ 0 C = 0 4-NHCO (4-ClPh) 357 Et = C (Et) ₂₀ C = 0 4-NHCO (3,4-di-MeOPh) 358 Et = C (Et) ₂ 0 C = 0 4-NHCO (3-Pyr) 359 Et = C (Et) ₂ 0 C = 0 4-NHCO (4-Pyr) 360 Et = C (Et) ₂ 0 C = 0 4-NHCO (2-Fur) 361 Et = C (Et) ₂ 0 C = 0 4-NHCO (2-Thi) 363 Et = C (Et) ₂ 0 C = 0 4-NHCOCH ₂ NHAc 364 Et = C (Et) ₂ 0 C = 0 4 -N (Me) COCH ₂ NHCOOMe 365 Et = C (Et) ₂ 0 C = 0 4-NHCOCH ₂ N (Me) Ac 366 Et = C (Et) ₂ 0 C = 0 4-NHCOC (Me) ₂ NHCOOMe 367 Et = C (Et) ₂ 0 C = 0 4-NHCOCH ₂ CH ₂ NHCOOMe 368 Et = C (Et) ₂ 0 C = 0 4-NHCO (1-COOMe-2-Pyrd) 369 Et = C (Et) ₂ 0 C = 0 4-NHCOOMe 370 Et = C (Et) ₂₀ C = 0 4-NHCOOEt 371 Et = C (Et) ₂₀ C = 0 4-NHCOOi-Bu 372 Et = C (Et) ₂₀ C = 0 4-NHCONHMe 373 Et = C (Et) ₂ 0 C = 0 4-NHCONHEt 374 Et = C (Et) ₂₀ C = 0 4-NHCONHPr 375 Et = C (Et) ₂₀ C = 0 4-NHCONHBu 376 Et = C (Et) ₂₀ C = 0 4-NHCONHt-Bu 377 Et = C (Et) ₂₀ C = 0 4-NHCONHc-Hex 378 Et = C (Et) ₂₀ C = 0 4-NHCONHPh 379 Et = C (Et) ₂ 0 C = 0 4-NHCSNHMe 380 Et = C (Et) ₂₀ C = 0 4-NHSO ₂ Me 381 Et = C (Et) ₂ 0 C = 0 4-N (Me) SO ₂ Me 382 Et = C (Et) ₂ 0 C = 0 4-NHSO ₂ (4-MePh) 383 Et = C (Et) ₂₀ C = 0 4- (2-oxo-1-Azt) 384 Et = C (Et ) ₂₀ C = 0 4- (2-oxo-1-Pip) 385 Et = C (Et) ₂₀ C = 0 4- (2-oxo-1-Pyrd) 386 Et = C (Et) ₂₀ C = 0 4- (2-oxo-1,3-Oxaz-3-yl) 387 Et = C (CH ₂ ) ₂ 0 C = 0 4-NO ₂ 388 Et = C (CH ₂ ) ₂ 0 C = 0 4 -NH ₂ 389 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHMe 390 Et = C (CH ₂ ) ₂₀ C = 0 4-NMe ₂ 392 Et = C (CH ₂ ) ₂ 0 C = 0 4 -NHAc 393 Et = C (CH ₂ ) ₂₀ C = 0 4-N (Me) Ac 394 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOEt 395 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOPr 396 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCOt-Bu 397 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCOc-Pr 398 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCOc-Bu 399 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOc-Hex 400 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOCF ₃ 401 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCOCH ₂ CN 402 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCOCH ₂ Br 403 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCOCH ₂ OEt 404 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCOCH ₂ OAc 405 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCOCH ₂ SMe 406 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCOCH ₂ S (2-Pym) 407 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOCH ₂ S (2-Pyr) 408 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOCH ₂ S (2-Thdn) 409 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOCH = CHMe 410 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOPh 411 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCO (2-FPh) 412 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCO (3-FPh) 413 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCO (4-FPh) 414 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCO (4-MeOPh) 415 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCO (3,4-di-MeOPh) 416 Et = C (CH ₂ ) ₂ 0 C = 0 4- NHCO (4-NO ₂ Ph) 417 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCOPh (4-t-Bu) 418 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCO (3- Pyr) 419 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCO (4-Pyr) 420 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCO (2-Fur) 421 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCO (2-Thi) 422 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOCH ₂ NHCOOMe 423 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCOCH ₂ NHAc 424 Et = C (CH ₂ ) ₂ 0 C = 0 4-N (Me) COCH ₂ NHCOOMe 425 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOCH ₂ N (Me) Ac 426 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOC (Me) ₂ NHCOOMe 427 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOCH ₂ CH ₂ NHCOOMe 428 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCO (1-COOMe-2-Pyrd) 429 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHCOOMe 430 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOOEt 431 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCOOi-Bu 432 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCONHMe 433 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCONHEt 434 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCONHPr 435 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCONHBu 436 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCONHc-Hex 437 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCO (1-Pyrd) 438 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCONHPh 439 Et = C (CH ₂ ) ₂₀ C = 0 4-NHCSNHMe 440 Et = C (CH ₂ ) ₂ 1 C = 0 4-NHSO ₂ Me 441 Et = C (CH ₂ ) ₂₀ C = 0 4-NHSO ₂ Me 442 Et = C (CH ₂ ) ₂ 0 C = 0 4- N (Me) SO ₂ Me 443 Et = C (CH ₂ ) ₂ 0 C = 0 4-N (Bu) SO ₂ Me 444 Et = C (CH ₂ ) ₂ 0 C = 0 4-NHSO ₂ (4-MePh ) 445 Et = C (CH ₂ ) ₂ 0 C = 0 4- (2-oxo-1-Azt) 446 Et = C (CH ₂ ) ₂₀ C = 0 4- (2-oxo-1-Pip) 447 Et = C (CH ₂ ) ₂₀ C = 0 4- (2,6-dioxo-1-Pip) 448 Et = C (CH ₂ ) ₂₀ C = 0 4- (2-oxo-1-Pyrd) 449 Et = C (CH ₂ ) ₂ 0 C = 0 4- (2,5-dioxo-1-Pyrd) 450 Et = C (CH ₂ ) ₂₀ C = 0 4- (2-oxo-1,3-Oxaz -3-yl) 451 Et = C (CH ₂ ) ₃ 0 C = 0 4-NO ₂ 452 Et = C (CH ₂ ) ₃₀ C = 0 4-NH ₂ 453 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHMe 454 Et = C (CH ₂ ) ₃ 0 C = 0 4-NMe ₂ 455 Et = C (CH ₂ ) ₃ 0 C = 0 4-OMe 456 Et = C (CH ₂ ) ₃ 0 C = 0 4-OEt 457 Et = C (CH ₂ ) ₃₀ C = 0 4-NHAc 458 Et = C (CH ₂ ) ₃₀ C = 0 4-N (Me) Ac 459 Et = C (CH ₂ ) ₃₀ C = 0 4- NHCOEt 460 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOPr 461 Et = C (CH ₂ ) ₃₀ C = 0 4-NHCOBu 462 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOt- Bu 463 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOc-Bu 464 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOc-Hex 465 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOCF ₃ 466 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOCH ₂ CN 467 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOCH ₂ OMe 468 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOCH ₂ OEt 469 Et = C (CH ₂ ) ₃₀ C = 0 4-NHCOCH ₂ OAc 470 Et = C (CH ₂ ) ₃₀ C = 0 4-NHCOCH ₂ SMe 471 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOCH = CHMe 472 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOPh 473 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCO (2-FPh) 474 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCO (3-FPh) 475 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCO (4-FPh) 476 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCO (4-MeOPh) 477 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCO (4-ClPh) 478 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCO (4-NO ₂ Ph) 479 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCO (4-t-BuPh) 480 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCO ( 3-Pyr) 481 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCO (4-Pyr) 482 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCO (2-Fur) 483 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCO (2-Thi) 484 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOCH ₂ NHCOOMe 485 Et = C (CH ₂ ) ₃ 0 C = 0 4- NHCOCH ₂ NHAc 486 Et = C (CH ₂ ) ₃ 0 C = 0 4-N (Me) COCH ₂ NHCOOMe 487 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOCH ₂ N (Me) Ac 488 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOC (Me) ₂ NHCOOMe 489 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOCH ₂ CH ₂ NHCOOMe 490 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCO (1-COOMe-2-Pyrd) 491 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOOMe 492 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCOOEt 493 Et = C ( CH ₂ ) ₃ 0 C = 0 4-NHCOOi-Bu 494 Et = C (CH ₂ ) ₃₀ C = 0 4-NHCONHMe 495 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCONHEt 496 Et = C ( CH ₂ ) ₃ 0 C = 0 4-NHCONHPr 497 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCONHBu 498 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCONHc-Hex 499 Et = C ( CH ₂ ) ₃ 0 C = 0 4-NHCO (1-Pyrd) 500 Et = C (CH ₂ ) ₃₀ C = 0 4-NHCONHPh 501 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHCSNHMe 502 Et = C (CH ₂ ) ₃ 1 C = 0 4-NHSO ₂ Me 503 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHSO ₂ Me 504 Et = C (CH ₂ ) ₃ 0 C = 0 4-N (Me) SO ₂ Me 505 Et = C (CH ₂ ) ₃ 0 C = 0 4-N (Bu) SO ₂ Me 506 Et = C (CH ₂ ) ₃ 0 C = 0 4-NHSO ₂ (4-MePh) 507 Et = C (CH ₂ ) ₃ 0 C = 0 4- (2-oxo-1-Azt) 508 Et = C ( CH ₂ ) ₃ 0 C = 0 4- (2-oxo-1-Pip) 509 Et = C (CH ₂ ) ₃ 0 C = 0 4- (2,6-dioxo-1-Pip) 510 Et = C ( CH ₂ ) ₃ 0 C = 0 4- (2-oxo-1-Pyrd) 511 Et = C (CH ₂ ) ₃ 0 C = 0 4- (2,5-dioxo-1-Pyrd) 512 Et = C ( CH ₂ ) ₃ 0 C = 0 (2-oxo-1,3-Oxaz-3-yl) 513 Et = C (Me) ₂₀ CH ₂ 4-NO ₂ 514 Et = C (Me) ₂₀ CH ₂ 4 -NH ₂ 515 Et = C (Me) ₂₀ CH ₂ 4-NHMe 516 Et = C (Me) ₂₀ CH ₂ 4-NMe ₂ 517 Et = C (Me) ₂₀ CH ₂ 4-OMe 518 Et = C (Me) ₂₀ CH ₂ 4-OEt 519 Et = C (Me) ₂₀ CH ₂ 4-NHAc 520 Et = C (Me) ₂₀ CH ₂ 4-N (Me) Ac 521 Et = C (Me) ₂ 0 CH ₂ 4-NHCOEt 522 Et = C (Me) ₂₀ CH ₂ 4-NHCOPr 523 Et = C (Me) ₂₀ CH ₂ 4-NHCOc-Pr 524 Et = C (Me) ₂₀ CH ₂ 4-NHCOc -Bu 525 Et = C (Me) ₂₀ CH ₂ 4-NHCOc-Pen 526 Et = C (Me) ₂₀ CH ₂ 4-NHCOCF ₃ 527 Et = C (Me) ₂₀ CH ₂ 4-NHCOCH ₂ CN 528 Et = C (Me) ₂ 0 CH ₂ 4-NHCOCH ₂ OMe 529 Et = C (Me) ₂₀ CH ₂ 4-NHCOCH ₂ OEt 530 Et = C (Me) ₂₀ CH ₂ 4-NHCOCH ₂ OAc 531 Et = C (Me) ₂₀ CH ₂ 4-NHCOCH ₂ OCOPr 532 Et = C (Me) ₂₀ CH ₂ 4-NHCOCH ₂ SMe 533 Et = C (Me) ₂₀ CH ₂ 4-NHCOCH = CHMe 534 Et = C (Me ) ₂₀ CH ₂ 4-NHCOPh 535 Et = C (Me) ₂₀ CH ₂ 4-NHCO (2-FPh) 536 Et = C (Me) ₂₀ CH ₂ 4-NHCO (3-FPh) 537 Et = C (Me) ₂₀ CH ₂ 4-NHCO (4-FPh) 538 Et = C (Me) ₂₀ CH ₂ 4-NHCO (4-MeOPh) 539 Et = C (Me) ₂₀ CH ₂ 4-NHCO (3 -MeOPh) 540 Et = C (Me) ₂ 0 CH ₂ 4-NHCO (3,4-di-MeOPh) 541 Et = C (Me) ₂₀ CH ₂ 4-NHCO (4-NO ₂ Ph) 542 Et = C (Me) ₂₀ CH ₂ 4-NHCOPh (3-NO ₂ ) 543 Et = C (Me) ₂₀ CH ₂ 4-NHCO (3-Pyr) 544 Et = C (Me) ₂₀ CH ₂ 4-NHCO (4-Pyr) 545 Et = C (Me) ₂ 0 CH ₂ 4-NHCO (2-Fur) 546 Et = C (Me) ₂ 0 CH ₂ 4-NHCO (2-Thi) 547 Et = C (Me) ₂₀ CH ₂ 4-NHCOCH ₂ NHCOOMe 548 Et = C (Me) ₂₀ CH ₂ 4-NHCOCH ₂ NHAc 549 Et = C (Me) ₂₀ CH ₂ 4-N (Me) COCH ₂ NHCOOMe 550 Et = C ( Me) ₂₀ CH ₂ 4-NHCOCH ₂ N (Me) COOMe 551 Et = C (Me) ₂₀ CH ₂ 4-NHCOC (Me) ₂ NHCOOMe 552 Et = C (Me) ₂₀ CH ₂ 4-NHCOCH ₂ CH ₂ NHCOOMe 553 Et = C (Me) ₂ 0 CH ₂ 4-NHCO (1-COOMe-2-Pyrd) 554 Et = C (Me) ₂ 0 CH ₂ 4-NHCOOMe 555 Et = C (Me) ₂₀ CH ₂ 4-NHCOOEt 556 Et = C (Me) ₂ 0 CH ₂ 4 -NHCOOi-Bu 557 Et = C (Me) ₂₀ CH ₂ 4-NHCOOPh 557 Et = C (Me) ₂₀ CH ₂ 4-NHCONHMe 559 Et = C (Me) ₂₀ CH ₂ 3-NHCONHMe 560 Et = C (Me) ₂₀ CH ₂ 4-NHCONHc-Hex 561 Et = C (Me) ₂₀ CH ₂ 4-NHCO (1-Pyrd) 562 Et = C (Me) ₂₀ CH ₂ 4-NHCONHPh 563 Et = C ( Me) ₂ 0 CH ₂ 4-NHCSNHMe 564 Et = C (Me) ₂ 1 CH ₂ 4-NHSO ₂ Me 565 Et = C (Me) ₂ 0 CH ₂ 4-NHSO ₂ Me 566 Et = C (Me) ₂ 0 CH ₂ 4-N (Me) SO ₂ Me 567 Et = C (Me) ₂₀ CH ₂ 4-N (Bu) SO ₂ Me 568 Et = C (Me) ₂₀ CH ₂ 4-NHSO ₂ (4-MePh ) 569 Et = C (Me) ₂₀ CH ₂ 4- (2-oxo-1-Azt) 570 Et = C (Me) ₂₀ CH ₂ 4- (2-oxo-1-Pip) 571 Et = C ( Me) ₂₀ CH ₂ 4- (2,6-dioxo-1-Pip) 572 Et = C (Me) ₂₀ CH ₂ 4- (2-oxo-1-Pyrd) 573 Et = C (Me) ₂₀ CH ₂ 4- (2,5-dioxo-1-Pyrd) 574 Et = C (Me) ₂₀ CH ₂ (2-oxo-1,3-Oxaz-3-yl) 575 Et = C (CH ₂ ) ₂ 0 CH ₂ 4-NO ₂ 576 Et = C (CH ₂ ) ₂₀ CH ₂ 4-NH ₂ 577 Et = C (CH ₂ ) ₂₀ CH ₂ 4-NHMe 578 Et = C (CH ₂ ) ₂₀ CH ₂ 4-OMe 579 Et = C (CH ₂ ) ₂₀ CH ₂ 4-NHAc 580 Et = C (CH ₂ ) ₂₀ CH ₂ 4-N (Me) Ac 581 Et = C (CH ₂ ) ₂ 0 CH ₂ 4 -NHCOEt 582 Et = C (CH ₂ ) ₂ 0 CH ₂ 4-NHCOCF ₃ 583 Et = C (CH ₂ ) ₂ 0 CH ₂ 4-NHCOCH ₂ CN 584 Et = C (CH ₂ ) ₂₀ CH ₂ 4-NHCOCH ₂ OMe 585 Et = C (CH ₂ ) ₂₀ CH ₂ 4-NHCOCH ₂ OAc 586 Et = C (CH ₂ ) ₂₀ CH ₂ 4-NHCO (4-FPh) 587 Et = C (CH ₂ ) ₂₀ CH ₂ 4-NHCOCH ₂ NHCOOMe 588 Et = C (CH ₂ ) ₂₀ CH ₂ 4-NHCO (1-COOMe-2-Pyrd) 589 Et = C (CH ₂ ) ₂₀ CH ₂ 4-NHCOOMe 590 Et = C (CH ₂ ) ₂₀ CH ₂ 4-NHCONHMe 591 Et = C (CH ₂ ) ₂₀ CH ₂ 4-NHSO ₂ Me 592 Et = C (CH ₂ ) ₃₀ CH ₂ 4-NO ₂ 593 Et = C (CH ₂ ) ₃₀ CH ₂ 4-NH ₂ 594 Et = C (CH ₂ ) ₃₀ CH ₂ 4-NHMe 595 Et = C (CH ₂ ) ₃₀ CH ₂ 4-OMe 596 Et = C (CH ₂ ) ₃₀ CH ₂ 4-NHAc 597 Et = C (CH ₂ ) ₃₀ CH ₂ 4-N (Me) Ac 598 Et = C (CH ₂ ) ₃₀ CH ₂ 4-NHCOEt 599 Et = C (CH ₂ ) ₃ 0 CH ₂ 4-NHCOCF ₃ 600 Et = C (CH ₂ ) ₃₀ CH ₂ 4-NHCOCH ₂ CN 601 Et = C (CH ₂ ) ₃ 0 CH ₂ 4 -NHCOCH ₂ OMe 602 Et = C (CH ₂ ) ₃ 0 CH ₂ 4-NHCOCH ₂ OAc 603 Et = C (CH ₂ ) ₃ 0 CH ₂ 4-NHCO (4-FPh) 604 Et = C (CH ₂ ) ₃ 0 CH ₂ 4-NHCOCH ₂ NHCOOMe 605 Et = C (CH ₂ ) ₃ 0 CH ₂ 4-NHCO (1-COOMe-2-Pyrd) 606 Et = C (CH ₂ ) ₃ 0 CH ₂ 4-NHCOOMe 607 Et = C (CH ₂ ) ₃ 0 CH ₂ 4-NHCONHMe 608 Et = C (CH ₂ ) ₃₀ CH ₂ 4-NHSO ₂ Me 609 Et = C (CH ₂ ) ₄ 0 CH ₂ 4-NO ₂ 610 Et = C (CH ₂ ) ₄₀ CH ₂ 4-NH ₂ 611 Et = C (CH ₂ ) ₄₀ CH ₂ 4-NHMe 612 Et = C (CH ₂ ) ₄₀ CH ₂ 4-OMe 613 Et = C (CH ₂ ) ₄₀ CH ₂ 4-NHAc 614 Et = C (CH ₂ ) ₄₀ CH ₂ 4-N (Me) Ac 615 Et = C (CH ₂ ) ₄₀ CH ₂ 4-NHCOEt 616 Et = C (CH ₂ ) ₄₀ CH ₂ 4-NHCOCF ₃ 617 Et = C (CH ₂ ) ₄₀ CH ₂ 4-NHCOCH ₂ CN 618 Et = C (CH ₂ ) ₄₀ CH ₂ 4-NHCOCH ₂ OMe 619 Et = C (CH ₂ ) ₄₀ CH ₂ 4-NHCOCH ₂ OAc 620 Et = C (CH ₂ ) ₄₀ CH ₂ 4-NHCO (4-FPh) 621 Et = C (CH ₂ ) ₄ 0 CH ₂ 4-NHCOCH ₂ NHCOOMe 622 Et = C (CH ₂ ) ₄ 0 CH ₂ 4-NHCO (1-COOMe-2-Pyrd) 623 Et = C (CH ₂ ) ₄₀ CH ₂ 4-NHCOOMe 624 Et = C (CH ₂ ) ₄₀ CH ₂ 4-NHCONHMe 625 Et = C (CH ₂ ) ₄ 0 CH ₂ 4-NHSO ₂ Me 626 Et = C (CH ₂ ) ₄ 0 C = O 4-NHCOCH ₂ (3-OH-4-Isox) 627 Et = C (CH ₂ ) ₄ 0 C = O 4-NHCOCH ₂ (3-OH-4-Isox) ──────────────────────────── ───────── Of the above compounds, preferred compounds are compound numbers 9 and 1.
6, 26, 28, 33, 34, 35, 36, 37, 3
8, 39, 40, 41, 42, 43, 44, 45, 4
6, 47, 48, 49, 51, 63, 64, 65, 6
6, 69, 74, 75, 76, 77, 78, 81, 8
9, 91, 95, 96, 107, 110, 112, 12
1, 132, 138, 139, 140, 144, 14
5, 148, 151, 160, 161, 164, 16
5, 171, 174, 181, 191, 193, 19
8, 199, 200, 201, 202, 205, 20
9, 211, 212, 213, 214, 218, 22
8, 229, 230, 231, 234, 240, 24
1, 242, 243, 246, 256, 272, 27
7, 286, 289, 297, 309, 310, 31
3, 316, 320, 325, 326, 329, 33
0, 332, 333, 335, 336, 337, 33
9, 346, 347, 348, 349, 350, 35
1, 352, 353, 354, 355, 362, 36
3, 366, 367, 369, 372, 380, 38
1, 392, 399, 429, 431, 452, 45
3, 455, 457, 458, 461, 465, 46
6, 467, 468, 469, 470, 472, 47
3, 474, 475, 476, 484, 485, 48
8, 489, 490, 491, 494, 500, 50
1, 503, 504, 547, 548, 551, 552
And 553, and more preferably compound numbers 9 and 2
6, 42, 46, 63, 64, 65, 91, 96, 12
1, 144, 165, 171, 191, 209, 21
3, 214, 313, 320, 336, 457, 54
7, 548 and 553.

[0091]

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

[0092]

Embedded image

[0093]

Embedded image

[0094]

Embedded image

In the above formula, R ¹ , X, Z and n are
Same meaning as above. Me represents a methyl group.

R ^3a represents an amino group or a group excluding a substituted amino group among the substituents defined by R ³ , and (Ia) represents R ^3a in the compound represented by the general formula (I). A compound having a substituent on the phenyl group is shown. (Ia1) represents a compound of the above (Ia) in which R ^3a is a nitro group.

R ^3b represents an amino group among the groups defined by R ³ , and (Ib) represents a compound represented by the general formula (I) having R ^3b on the phenyl group. .

R ^3c represents a substituted amino group among the groups defined by R ³ , and (Ic) represents a compound represented by the general formula (I) in which R ^3c is a substituent on the phenyl group. The compound having is shown.

R ¹² represents a trialkylsilyl group representing a C ₁ -C ₄ alkyl group having the same or different alkyl groups such as trimethylsilyl group, triethylsilyl group or dimethyl tert-butylsilyl group, and (Ibs _i ) is Among the compounds represented by the general formula (I), compounds having R ^3b as a substituent on a phenyl group and R ¹² as a protecting group for 5-position hydroxyimino are shown, and (Ics _i )
Represents a compound represented by the general formula (I), which has R ^3c as a substituent on the phenyl group and R ¹² as a protective group for the 5-position hydroxyimino group.

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

The compound represented by the general formula (V), which is another starting material of the present production method, has the above R ^3a as a substituent on the phenyl group and has the following general formula (Va): (V
b), (Vc), there are variations of the compounds represented as (Vd), which are obtained by combining known methods and using commercially available reagents as starting materials, and are summarized in (1) or (2) below. Show.

[0102]

Embedded image

[In the formula, X and Z have the same meanings as described above, and m ′ represents an integer of 0 to 3. ], (1) n = 1
In the presence of a base, an α-alkyl-α-halogenoalkanoic acid ester obtained by alkylation of α-position of a commercially available alkanoic acid ester with a base-alkyl halide, and then halogenation of the α-position or a commercially available product thereof is used. , Α- (phenoxy) -α-alkylalkanoic acid ester obtained by reacting with phenol, is hydrolyzed to give a compound represented by the general formula (V
A carboxylic acid represented by a) is obtained. If a dihaloalkane such as 1,2-dibromoethane, 1,3-dibromopropane, or 1,4-dibropentane is used as the alkyl halide used, the cycloalkanecarboxylic acid represented by the general formula (Vc) can be obtained. The obtained carboxylic acid is reduced with a metal hydride such as lithium aluminum hydride to obtain an alcohol represented by the general formula (Vb) or (Vd). (2) When n = 0, α-phenyl-α, α-dialkylacetic acid ester obtained by alkylation of α-position of a commercially available phenylacetic acid ester with a base-alkyl halide is hydrolyzed (VIIa). A carboxylic acid of
As the alkyl halide used, 1,2-dibromoethane,
If a dihaloalkane such as 1,3-dibromopropane or 1,4-dibropentane is used, the cycloalkanecarboxylic acid represented by the general formula (Vc) can be obtained. The obtained carboxylic acid is reduced with a metal hydride such as lithium aluminum hydride to obtain an alcohol represented by the general formula (Vb) or (Vd). Step A is a method for producing a compound represented by the general formula (IV), wherein the compound represented by the general formula (V is added to the compound represented by the general formula (III) in the presence of trifluoromethanesulfonic acid which is a strong organic acid. ) Is carried out by reacting a carboxylic acid or alcohol.

The amount of trifluoromethanesulphonic acid used is, in principle, a catalytic amount, one equivalent is not necessary, but can vary considerably depending on the different reactivity of the carboxylic acid used.

In addition, when an inorganic compound powder is added to the reaction system, the reaction may be promoted to give a good result. Examples of such an inorganic compound include copper trifluoromethanesulfonate, cuprous iodide, zinc iodide, cobalt iodide, metal salts such as nickel iodide, celite, silica gel, alumina, and the like. Are copper salts such as copper trifluoromethanesulfonate and cuprous iodide, and most preferably cuprous iodide.

The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to 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.
° 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 is a step of reacting the compound represented by the general formula (IV) with hydroxylamine to convert the carbonyl group at the 5-position into a hydroxylamino group to produce a compound represented by the general formula (Ia). Is.

Various salts of hydroxylamine can be used in the reaction. Examples of such salts include salts with inorganic acids such as hydrochloride and sulfate, and salts with organic acids such as acetate and oxalic acid. However, it is preferably a hydrochloride.

The reaction solvent can be used without particular limitation as long as it does not participate in the reaction, but it is freely mixed with water, such as lower alcohols such as methanol, ethanol and propanol, and ethers such as tetrahydrofuran and dioxane. The use of a mixture with water is particularly preferred.

The reaction is usually carried out at 0 ° C to 50 ° C,
The reaction time is 1 hour to 10 hours.

Step C is the step of reducing the nitro group of the compound represented by the general formula (Ia1) to give a compound of the general formula (Ia) having an amino group.
This is a step of producing a compound represented by b).

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. Palladium-carbon, palladium-barium sulfate, platinum oxide, and the like can be given as preferable examples of the catalyst used in the reaction.

Suitable examples of the solvent used in the reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and esters such as ethyl acetate.

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

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

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

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 examples of the solvent used in the reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane.

The reaction temperature is preferably 0 ° C. to room temperature,
The reaction time is usually about 10 to 120 minutes.

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. Palladium-carbon, palladium-barium sulfate, platinum oxide, and the like can be given as preferable examples of the catalyst used in the reaction.
Suitable examples of the solvent used in the reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and esters such as ethyl acetate.

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

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

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

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 are:
Alcohols such as methanol and ethanol;
Ethers such as tetrahydrofuran and dioxane can be mentioned.

The reaction temperature is preferably 0 ° C. to room temperature,
The reaction time is usually about 10 to 120 minutes.

In step D, the amino group of the compound represented by the general formula (Ib), an acid represented by the formula: A-OH (A is shown below) or a reactive derivative thereof, or the following general formula (x)
This is a step of producing a compound represented by the general formula (Ic) having R ^3C (substituted amino group) as a substituent on the phenyl group by reacting with an isocyanate represented by v).

A in the acid represented by the above formula: A-OH or a reactive derivative thereof is represented by the following formula: R ⁴ -C = O- (x), R ⁶ R ⁷ NC = Y- (R ⁶ ≠ ^{H) (xi), R 8} SO 2 - (xii), R 9 OC = O - (xiii), R 10 C (= NOR 11) shows a C = O- (xiv), a group represented by and The isocyanate is represented by the following formula R ⁷ N = C (= Y) (xv) (in the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ ,
R ¹¹ and Y are as defined above. ).

As the reactive derivative of the acid represented by the formula: A-OH, for example, acid halides (acid chloride, acid bromide, etc.), acid anhydrides, mixed acid anhydrides, active esters, active amides, etc. are subjected to condensation reaction. Those usually used in.

In manufacture, a. When the acid represented by the formula: A-OH is used, for example, dicyclohexylcarbodiimide (DCC), iodide 2
A dehydrating agent such as -chloro-1-methylpyridinium, p-toluenesulfonic acid or sulfuric acid is used, and 2-chloro-1-methylpyridinium iodide is preferable. The amount used is usually 1 to 5 with respect to the acid represented by the formula: A-OH.
It is an equivalent, preferably 1-2 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 mixtures of these solvents, more preferably dichloromethane,
It is 1,2-dichloroethane.

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

B. When the acid halide of the acid represented by the formula: A-OH is used, the reaction is carried out in a solvent, preferably in the presence of a base, and suitable bases include, for example, triethylamine and N, N-dimethylaniline. , Pyridine, 4-
Dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN) or 1,8-diazabicyclo [5.4.0] undecene-7 (DBU)
The organic bases such as

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

The solvent, reaction temperature, reaction time and the like used in the reaction are the same as those when the acid represented by A-OH is used,
The same applies to each.

The reaction is usually carried out at 0 ° C to 50 ° C,
The reaction time is between 5 minutes and 2 hours. c. When the isocyanate represented by the formula: (xv) is used, the reaction is carried out in a solvent.

The amount of isocyanate is usually 1 to 10 equivalents.

The solvent, reaction temperature, reaction time and the like used in the reaction are the same as those when the above acid represented by A-OH is used.

Step C ¹ is represented by the general formula (Ibs _i ) by protecting the 5-position hydroxyimino group of the compound represented by the general formula (Ia1) with a trialkylsilyl group and then reducing the nitro group. It is a step of producing a compound.

For the silylation of the 5-position hydroxyl group, a commonly used method can be used. That is, it is achieved by adding a trialkylsilyl halide to a compound represented by the general formula (Ia1) in a solvent in the presence of a dehydrohalogenating agent.

Examples of the dehydrohalogenating agent include imidazoles such as imidazole; pyridines such as pyridine and 4-dimethylaminopyridine; and tertiary amines such as triethylamine and tributylamine. , Imidazoles, and more preferably,
It is imidazole. The trialkylsilyl halide is trimethylsilyl chloride, triethylsilyl chloride or dimethyl tert-butyl silyl chloride, preferably dimethyl tert-butyl silyl chloride.

Suitable solvents for use include hydrocarbons such as hexane, petroleum ether, benzene, toluene; chloroform, methylene chloride, 1,2-
Examples thereof include halogenated hydrocarbons such as dichloroethane; ethers such as tetrahydrofuran and dioxane; or esters such as ethyl acetate, but preferably halogenated hydrocarbons, more preferably , Methylene chloride.

The reaction temperature is preferably 0 ° C. to 80 ° C., and the reaction time is usually 10 minutes to 5 hours.

The reduction of the nitro group is carried out under the same conditions as in step C. Step D ¹ comprises the amino group of the compound represented by the general formula (Ibs _i ), the acid represented by the above formula: A—OH or a reactive derivative thereof, or the isocyanate represented by the general formula (xv). R ^3C (substituted amino group) as a substituent on the phenyl group by reacting
And a hydroxyimino group at the 5-position is protected by R ¹² is a step of producing a compound represented by the general formula (Ics _i ).

The acylation reaction is carried out under the same conditions as in step C. In step D ² , the protecting group R ¹² for the hydroxyimino group at the 5-position of the compound represented by general formula (Ics _i ) is deprotected in the presence of an acid catalyst in a solvent to produce a compound represented by (Ic). It is a process to do.

The solvent used is, for example, alcohols such as methanol and ethanol; tetrahydrofuran,
Although ethers such as dioxane can be mentioned, alcohols are preferable, and methanol is more preferable.

Examples of the acid catalyst used include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as methanesulfonic acid and paratoluenesulfonic acid, but inorganic acids are more preferable. It is hydrochloric acid. After the reaction of each step,
Formulas (IV), (Ia), and (Ia1), which are the respective objectives,
The compounds (Ib) 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 milbemycins and their related compounds that are the starting materials for the compound of formula (III) are fermentation products and can be either a single compound or a mixture thereof. Therefore, the compound represented by the general formula (I) can also be produced as a single compound or a mixture.

When the compound of the present invention is used as an anthelmintic in animals and humans, it can be orally administered as a liquid beverage. The beverage is usually a solution, suspension or dispersion in a suitable non-toxic solvent or water with suspending agents such as bentonite and wetting agents or other excipients. Generally, beverages also contain an antifoam. Beverage formulations generally contain from about 0.01 to 0.5% by weight of active compound, preferably 0.01 to 0.1% by weight.

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

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

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

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

The optimum amount of the active compound used for the best result depends on the kind of animal to be treated and the type and degree of parasitic infection, but it is generally about 0.01 to 100 mg / kg of animal body weight, preferably Is 0.5 to 50.0
It is obtained by orally administering mg. Such dosages may be given in a single or divided dosage over a relatively short period of time, such as 1-5 days.

When the compound of the present invention is used for agriculture or horticulture, it is used in various formulations. For example, powder, coarse powder, water solution, fine granule, wettable powder, granule, dry flowable, tablet, emulsion, emulsion, aqueous or oily suspension, aqueous or oily liquid (suspension, liquid is directly sprayed. , And can also be diluted.), Aerosol or capsules in a polymer substance. The carrier used can be organic or inorganic, natural or synthetic, used to assist the active compound in reaching its point of action, and to facilitate storage, transport and handling of the active compound. You. Also, solid, liquid and gaseous carriers are selected according to well-known techniques for carriers.

The above-mentioned preparation is manufactured according to a conventional method. For example, the active compound is mixed well with a carrier, a diluent (solvent etc.) or a surfactant if necessary, and then pulverized, granulated, tableted, coated, absorbed, etc., to be prepared into a formulation. .

Powders, coarse powders, water solvents, fine granules, wettable powders,
Powders, dry flowables, carriers for preparing solid agents such as tablets include kaolinite and pyrophyllite clay, talc, calcium carbonate, montmorillonite clay such as bentonite and acid clay, attapulgite, sepiolite, diatomaceous earth, pumice stone. , Powders of natural minerals such as silica sand or their granules, hydrous or anhydrous synthetic amorphous silicon dioxide, fine powders of inorganic compounds such as calcium silicate, magnesium carbonate, sugars such as sugar, lactose and glucose,
Starch, dextrin, microcrystalline cellulose, wood powder, coffee bean powder, chaff powder, wheat flour, organic materials such as tab powder, sodium sulfate, sodium carbonate, sodium hydrogen carbonate, sodium phosphate, calcium sulfate, inorganic salts such as ammonium sulfate, Urea etc. can be mentioned.

Suitable solvents include: xylene, methylnaphthalene, alkylbenzene,
Aromatic high-boiling solvents such as phenylxylylethane, paraffin-based and naphthene-based high-boiling solvents, oleic acid, adipic acid, lauric acid, coconut oil fatty acid, maleic acid, esters of various carboxylic acids such as phthalic acid, various Phosphate esters, cyclohexanone, ketones such as methyl isobutyl ketone, N-alkylpyrrolidones, polar solvents such as dimethyl sulfoxide, ethylene glycol,
Glycols such as propylene glycol, butanediol, hexylene glycol and their polymers, ethers or esters of these various glycols, methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, hexyl alcohol, octyl alcohol, lauryl alcohol, etc. Alcohols and various esters of these alcohols and ethers, optionally epoxidized coconut oil, vegetable oils such as soybean oil; or water.

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

Can be used.

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

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

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

Suitable zwitterionic surfactants include:
Amino acid type or betaine type surfactants, lecithin and the like can be mentioned.

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

These surfactants may be used alone or as a mixture depending on the application.

The composition may also contain stabilizers, defoamers, viscosity modifiers, binders, adhesives or mixtures thereof, and in order to achieve a particular effect, a fertilization promoter,
Other active substances may be included.

Insecticidal and acaricidal compositions generally comprise the following ingredients, provided in% and by weight: active compound 0.01.
~ 99%, preferably 0.1-95%; solid or liquid additive 1-99.99%; surfactant 0-25%, preferably 0.1-25%, commercial product concentrated In the case of a form, the active ingredient concentration is generally 0.001 to 0.001 before use.
It is diluted to 0.0001% by weight (1-10 ppm).

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

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

[0172]

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

[0173]

Example 1 13- [2- (4-nitrophenyl) -2-methylpro
Pionyloxy] -5-hydroxyimino mybemesis
A ₄ (V: R ¹ = Et, X = CO, Z = = C (CH ₃ ) ₂ , R ³ = 4-NO
₂ , n = 0) (Exemplified compound number 21) . (Step A) 15-Hydroxy-5-oxomilbemycin A ₄ (188 mg, 0.34 mmol) and 2- (4-nitrophenyl) -2-methylpropionic acid (212 mg, 1.01 mmo
l) in dichloromethane solution (8 ml) under an argon stream while ice-cooling trifluoromethanesulfonic acid (15 μm).
l) was added and the mixture was stirred at room temperature for 30 minutes. After the completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. Wash the extract with 5% sodium bicarbonate water and saturated saline, dry over magnesium sulfate, and
The solvent was distilled off. The residue was purified by silica gel column chromatography to give 13- [2- (4-nitrophenyl) -2-methylpropionyloxy] -5-oxomilbemycin A ₄ (IV: R ¹ = Et, X = CO 2, Z = = C (CH ₃ )
₂ , R ³ = 4-NO ₂ , n = 0) 502 mg (58%) was obtained.

Nuclear magnetic resonance spectrum (270 MHz) δ (pp
m): 8.16 (2H, d, J = 9.8Hz), 6.54 (1H, t, J = 1.8Hz), 5.
69 ~ 5.91 (2H, m), 5.29 ~ 5.47 (3H, m), 4.91 (1H, d, J
= 10.5Hz), 4.70 (2H, br-s), 3.84 (1H, s), 1.63 (6H,
6H). (Step B) 5-oxo compound (186 mg, 0.2) obtained in Step A
5 mmol) was dissolved in dioxane (1.5 ml) and water (0.75 m
l), methanol (1.5 ml), and hydroxylamine hydrochloride (165 mg) were added, and the mixture was stirred at 40 ° C. for 3 hr.
After completion of the reaction, add ethyl acetate (20 ml) to the reaction mixture and
The extract was washed with water once, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 170 mg (89.2%) of the target compound.

Nuclear magnetic resonance spectrum (270MHz) δ (CDCl
3): 8.17 (2H, d, J = 8.7Hz), 8.00 (1H, br), 7.47 (2H,
d, J = 8.7Hz), 5.71 ~ 5.90 (3H, m), 5.27 ~ 5.48
(3H, m), 4.91 (1H, d, J = 10.
6 Hz), 4.70 and 4.68 (2H, A
Bq, J = 15.0 Hz, 4.65 (1H,
s), 3.97 (1H, s), 3.57 (1H,
m), 3.36 (1H, m), 3.04 (1H,
dt, J = 2.3 and 9.3 Hz), 1.9
3 (3H, s), 1.63 (3H, s), 1.
60 (3H, s), 1.29 (3H, s),
0.99 (3H, t, J = 7.3Hz), 0.8
2 (6H, d, J = 6.5 Hz). According to this method, the compounds of the following Examples 2 to 8 were synthesized. The yield represents the total value of steps A and B.

[0176]

Example 2 13- [2- (3-Nitrophenyl) -2-methylpro
Pionyloxy] -5-hydroxyimino mybemesis
A ₄ (V: R ¹ = Et, X = CO, Z = = C (CH ₃ ) ₂ , R ³ = 3-NO
₂ , n = 0) (Exemplified compound No. 3) Yield: 64.3% Nuclear magnetic resonance spectrum (270MHz) δ (ppm): 8.19 (1H, d
d, J = 1.9 and 1.9Hz), 8.12 (1H, dd, J = 1.9 and 7.9Hz),
7.63 (1H, dd, J = 1.9 and 7.9Hz), 7.49 (1H, dd, J = 7.9
and 7.9Hz), 5.70 ~ 5.90 (3H, m), 5.29 ~ 5.47 (3H, m),
4.92 (1H, d, J = 10.6Hz), 4.73 and 4.68 (2H, AB-q, J =
14.4Hz), 4.66 (1H, s), 3.97 (1H, s), 3.57 (1H, m), 3.3
6 (1H, m), 3.04 (1H, dt, J = 2.1 and 9.1Hz), 1.93 (3H,
s), 1.66 (3H, s), 1.61 (3H, s), 1.29 (3H, s), 0.96 (3
H, t, J = 7.3Hz), 0.84 (3H, d, J = 6.5Hz), 0.83 (3H, d, J
= 6.4Hz).

[0177]

Example 3 13- [2- (4-methoxyphenyl) -2-methylpropyl
Ropionyloxy] -5-hydroxyiminomilbemai
Syn A ₄ (V: R ¹ = Et, X = CO, Z = = C (CH ₃ ) ₂ R ³ = 4-MeO
, N = 0) (Exemplified Compound No. 16). Mass spectrum (FAB-MS) (m / z): 748 (M + H ⁺ , M = C ₄₃ H
₅₇ NO ₁₀ ). Nuclear magnetic resonance spectrum (270 MHz) δ (CDCl3) ：
7.95 (1H, br.s), 7.22 (2H,
d, J = 8.8 Hz), 6.83 (2H, d, J
= 8.8 Hz), 4.86 (1H, d, J = 1)
0.5 Hz), 4.73 and 4.68 (2H,
AB-q, J = 18.8 & 14.4 Hz),
4.65 (1H, s), 3.96 (1H, s),
3.79 (3H, s), 3.56 (1H,
m), 3.36 (1H, m), 3.04 (1H,
dd, J = 2.3 and 9.2 Hz), 1.
93 (3H, s), 1.56 (3H, s), 1.
53 (3H, s), 1.30 (3H, s),
0.98 (3H, t, J = 7.3Hz), 0.8
3 (3H, d, J = 6.4Hz), 0.82 (3
H, d, J = 6.5 Hz).

[0178]

Example 4 13- [1- (4-methoxyphenyl) cyclopentane
Carbonyloxy] -5-hydroxyiminomilbemai
Syn A ₄ (V: R ¹ = Et, X = CO, Z = = C (CH ₃ ) ₄ R ³ = 2-MeO
, N = 0) (Exemplified Compound No. 181) . Mass spectrum (FAB-MS) (m / z): 774 (M + H ⁺ , M = C ₄₅ H
₅₉ NO ₁₀ ). Nuclear magnetic resonance spectrum (270MHz) δ (CDCl3): 7.25 (2H,
d, J = 8.6Hz), 6.81 (2H, d, J = 8.6Hz), 4.80 (1H, d, J = 1
0.6Hz), 4.72 and 4.70 (2H, AB-q, J = 14.4Hz), 4.65 (1H,
s), 3.96 (1H, s), 3.78 (3H, s), 3.56 (1H, m), 3.36 (1
H, m), 3.02 (1H, dd, J = 2.2 and 9.2Hz), 2.66-2.54 (2
H, m), 1.93 (3H, s), 1.29 (3H, s), 0.97 (3H, t, J = 7.3
Hz), 0.82 (3H, d, J = 6.6Hz), 0.82 (3H, d, J = 6.6Hz),
0.77 (3H, d, J = 5.9Hz).

[0179]

Example 5 13- [2- (4-methoxyphenyl) -2-methylpropyl
Ropionyloxy] -5-hydroxyiminomilbemai
Syn A ₄ (V: R ¹ = Et, X = CO, Z = = C (CH ₃ ) ₂ R ³ = 4-NO ₂
, N = 0) (Exemplified Compound No. 23) . Yield: 41.6% Nuclear magnetic resonance spectrum (270 MHz) δ (CDCl3): 7.90 (1H,
br), 7.22 (2H, d, J = 8.7Hz), 6.83 (2H, d, J = 8.7Hz),
5.71 ~ 5.90 (3H, m), 5.29 ~ 5.49 (3H, m), 4.86 (1H, d,
J = 10.5Hz), 4.72 and 4.68 (2H, AB-q, J = 14.4Hz), 4.6
5 (1H, s), 3.96 (1H, s), 3.79 (3H, s), 3.57 (1H, m),
3.36 (1H, m), 3.04 (1H, dt, J = 2.2 and 9.2Hz), 1.93 (3
H, s), 1.58 (6H, s), 1.30 (3H, s), 0.98 (3H, t, J = 7.3
Hz), 0.83 (3H, d, J = 6.5Hz), 0.82 (3H, d, J = 6.5Hz).

[0180]

Example 6 13- [1- (4-nitrophenyl) cyclopropane car
Lubonyloxy] -5-hydroxyimino mybemesis
A ₄ (V: R ¹ = Et, X = CO, Z = = C = (CH ₂ ) ₂ , R ³ = 4-
NO ₂ , n = 0) (Exemplified compound number 387) . Yield: 60.7% Nuclear magnetic resonance spectrum (270MHz) δ (CDCl3): 8.18 (2H,
d, J = 8.7Hz), 7.51 (2H, d, J = 8.7Hz), 5.82 (1H, s),
5.71 ~ 5.90 (2H, m), 5.27 ~ 5.46 (3H, m), 4.91 (1H,
d, J = 10.6Hz), 4.72 and 4.66 (2H, AB-q, J = 14.4Hz),
4.65 (1H, s), 3.93 (1H, s), 3.55 (1H, m), 3.35 (1H, m),
3.03 (1H, dt, J = 2.2 and 9.2Hz), 1.93 (3H, s), 1.36
(3H, s), 0.97 (3H, t, J = 7.3Hz), 0.91 (3H, d, J = 6.5H
z), 0.82 (3H, d, J = 6.5Hz).

[0181]

Example 7 13- [1- (4-nitrophenyl) cyclobutanecar
Bonyloxy] -5-hydroxyiminomilbemycin
A ₄ (V: R ¹ = Et, X = CO, Z = = C = (CH ₂ ) ₃ , R ³ = 4-NO
_2, n = 0) (Compound No. 451) _Yield:. 66.1% Nuclear Magnetic Resonance Spectrum (270MHz) δ (CDCl3): 8.18 (2H,
d, J = 8.9Hz), 7.42 (2H, d, J = 8.9Hz), 5.72 ~ 5.89 (3H,
m), 5.27 ~ 5.46 (3H, m), 4.88 (1H, d, J = 10.5Hz), 4.
73 and 4.67 (2H, AB-q, J = 14.4Hz), 4.66 (1H, s), 3.95
(1H, s), 3.56 (1H, m), 3.36 (1H, m), 3.03 (1H, dt, J =
2.3 and 9.2Hz), 1.93 (3H, s), 1.35 (3H, s), 0.98 (3H,
t, J = 7.3Hz), 0.82 (3H, d, J = 6.4Hz), 0.78 (3H, d, J =
6.6Hz).

[0182]

Example 8 13- [2- (4-nitrophenyl) -2-methylpro
Pyroxy] -5-hydroxyiminomilbemycin
A ₄ (V: R ¹ = Et, X = CH ₂ , Z = = C (CH ₃ ) ₂ , R ³ = 4-NO ₂ , n
= 0) (Compound No. 513) Nuclear magnetic resonance spectrum (270MHz) δ (CDCl3): . 8.14 (2H,
d, J = 8.9Hz), 7.51 (2H, d, J = 8.9Hz), 5.71 ~ 5.90 (3H,
m), 5.27 ~ 5.46 (3H, m), 4.65 (1H, s), 3.94 (1H, s),
3.31 (1H, d, J = 9.0Hz), 3.13 (2H, d, J = 9.0Hz), 1.87
(6H, s). Yield: 65.3%

[0183]

Example 9 13- [2- (4-aminophenyl) -2-methylpro
Pionyloxy] -5-hydroxyimino mybemesis
A ₄ (VI: R ¹ = Et, X = CO, Z = = C (CH ₃ ) ₂ , R ³ = 4-N
H ₂ , n = O) (Exemplified Compound No. 6) _{. The} nitro compound (1.00 g, 1.31 mmol) obtained in Example 1 was dissolved in a mixed solution of methanol (13 ml) and tetrahydrofuran (7 ml), and nickel ( II) Addition of chloride triphenylphosphine complex (85 mg, 0.13 mmol), and sodium borohydride (100 mg, 2.6 mmol) under ice cooling.
Was added and stirred for 30 minutes. Ethyl acetate (70 m
l) was added, the mixture was washed 3 times with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography to give the desired compound (802 mg)
(83.8%) was obtained.

Nuclear magnetic resonance spectrum (270 MHz) δ (CDCl
3): 8.0 (1H, br), 7.09 (2H, d, J = 8.5Hz), 6.62 (2H,
d, J = 8.5Hz), 5.71 ~ 5.95 (3H, m), 5.25 ~ 5.50 (3H,
m), 4.86 (1H, d, J = 10.5Hz), 4.75 and 4.68 (2H, AB-q,
J = 15.0Hz), 4.66 (1H, s), 3.57 (1H, m), 3.36 (1H, m),
3.04 (1H, dt, J = 2.1 and 9.0Hz), 1.93 (3H, s), 1.54 (3
H, s), 1.51 (3H, s), 1.32 (3H, s), 0.98 (3H, t, J = 7.2
Hz), 0.82 (6H, d, J = 6.4Hz). According to this method, the following compounds of Example 10 to Example 13 were synthesized.

[0185]

Example 10 13- [2- (3-aminophenyl) -2-methylpro
Pionyloxy] -5-hydroxyimino mybemesis
A ₄ (V: R ¹ = Et, X = CO, Z = = C (CH ₃ ) ₂ , R ³ = 3-
NH _2, n = 0) (Compound No. 7) Nuclear magnetic resonance spectrum (270MHz) δ (ppm): . 7.42 (1H,
m), 7.21 (1H, m), 6.90 (1H, m), 5.70 ~ 5.90 (3H, m),
5.29 ~ 5.48 (3H, m), 4.89 (1H, d, J = 10.6Hz), 4.73 an
d 4.68 (2H, AB-q, J = 14.4Hz), 4.65 (1H, s), 3.97 (1H,
br-s), 3.57 (1H, m), 3.36 (1H, m), 3.04 (1H, m), 1.93
(3H, s), 1.65 (3H, s), 1.62 (3H, s), 1.29 (3H, s), 0.
97 (3H, t, J = 7.3Hz), 0.84 (3H, d, J = 6.5Hz), 0.83 (3H,
d, J = 6.4Hz).

[0186]

Example 11 13- [1- (4-aminophenyl) cyclopropanecar
Lubonyloxy] -5-hydroxyimino mybemesis
A ₄ (VI: R ¹ = Et, X = CO, Z = = C = (CH ₂ ) ₂ , R ³ = 4-
NH _2, n = 0) (Compound No. 388) Nuclear magnetic resonance spectrum (270MHz) δ (CDCl3): . 7.25 (2H,
d, J = 8.1Hz), 7.01 (2H, d, J = 8.1Hz), 5.86 (1H, s),
5.71 ~ 5.95 (2H, m), 5.25 ~ 5.50 (3H, m), 4.82 (1H,
d, J = 10.5Hz), 4.75 and 4.68 (2H, AB-q, J = 16.2Hz),
4.66 (1H, s), 3.56 (1H, m), 3.36 (1H, m), 3.03 (1H, dt,
J = 2.2 and 9.2Hz), 1.96 (3H, s), 1.40 (3H, s), 0.98
(3H, t, J = 7.2Hz), 0.90 (3H, d, J = 6.5Hz), 0.83 (3H,
d, J = 6.4Hz).

[0187]

Example 12 13- [1- (4-aminophenyl) cyclobutanecar
Bonyloxy] -5-hydroxyiminomilbemycin
A ₄ (VI: R ¹ = Et, X = CO, Z = = C = (CH ₂ ) ₃ , R ³ = 4-NH
_2, n = 0) (Compound No. 452) Nuclear magnetic resonance spectrum (270MHz) δ (CDCl3): . 7.19 (2H,
d, J = 8.1Hz), 7.01 (2H, d, J = 8.1Hz), 5.71 ~ 5.95 (3H,
m), 5.25 ~ 5.50 (3H, m), 4.82 (1H, d, J = 10.5Hz), 4.
66 (1H, s), 3.57 (1H, m), 3.36 (1H, m), 3.03 (1H, dt, J
= 2.2 and 9.2Hz), 1.96 (3H, s), 1.40 (3H, s), 0.98 (3
H, t, J = 7.2Hz), 0.89 (3H, d, J = 6.5Hz), 0.82 (3H, d, J
= 6.5Hz).

[0188]

Example 13 13- [2- (4-aminophenyl) -2-methylpro
Pyroxy] -5-hydroxyiminomilbemycin
A ₄ (V: R ¹ = Et, X = CH ₂ , Z = = C (CH ₃ ) ₂ , R ³ = 4-NH ₂ , n
= 0) (Compound No. 514) Nuclear magnetic resonance spectrum (270MHz) δ (CDCl3): . 7.14 (2H,
d, J = 8.5Hz), 6.63 (2H, d, J = 8.5Hz), 5.71 ~ 5.90 (3H,
m), 5.27 ~ 5.46 (3H, m), 4.65 (1H, s), 3.94 (1H, s),
3.22 (1H, d, J = 8.9.0Hz).

[0189]

Example 14 13- [2- (4-methoxycarbonylaminoacetyl
Aminophenyl) -2-methylpropionyloxy]-
5-hydroxyimino milbemycin A ₄ (I: R ¹ = E
t, X = CO, Z = = C (CH ₃ ) ₂ , R ³ = 4-NHCOCH ₂ NHCOOMe, n =
0) (Exemplified Compound No. 81) . N-methoxycarbonylglycine (2.0g, 15.0 mmol)
In methylene chloride solution (20 ml) of 13- [2- (4-
Aminophenyl) -2-methylpropionyloxy] milbemycin A ₄ (3.61 g, 5.0 mmol), triethylamine (1.012 g, 10.0 mmol) and 2-chloro-1 iodide.
-Methylpyridinium (2.56 g, 10.0 mmol) was sequentially added, and then the mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The extract was dried (MgSO4), concentrated, and the residue was purified by silica gel column chromatography to give 3.53 g (84.4%).
Was obtained.

Nuclear magnetic resonance spectrum (270 MHz) δ (CDCl
3): 8.30 (1H, br-s), 7.96 (1H, br-s), 7.45 (2H, d, J
= 8.5Hz), 7.24 (2H, d, J = 8.5Hz), 5.71 ~ 5.89 (3H,
m), 5.26 ~ 5.51 (4H, m), 4.86 (1H, d, J = 10.8Hz), 4.6
5 and 4.73 (2H, AB-q, J = 15.0Hz), 3.99 (1H, d, J = 5.6H
z), 3.97 (3H, s), 3.75 (3H, s). 13-obtained in Example 13 according to the method described above.
The compounds of Examples 15 and 16 below were synthesized from [2- (4-aminophenyl) -2-methylpropyloxy] -5-hydroxyiminomylbemycin 4.

[0191]

Example 15 13- [2- (4-methoxycarbonylaminoacetyl
Aminophenyl) -2-methylpropyloxy] -5-
Hydroxyimino milbemycin A ₄ (I: R ¹ = Et,
X = CH ₂ , Z = = C (CH ₃ ) ₂ , R ³ = 4-NHCOCH ₂ NHCOOMe, n = 0)
(Exemplified Compound No. 547) . Mass spectrum (FAB-MS) (m / z): 983 (M + H ⁺ + triethanolamine = 833 + 1 + 149). Nuclear magnetic resonance spectrum (270MHz) δ (CDCl3): 7.88 (1H,
br), 7.80 (1H, br), 7.42 (2H, d, J = 8.9Hz), 7.31 (2H,
d, J = 8.9Hz), 5.69 ~ 5.85 (3H, m), 5.26 ~ 5.45 (3H,
m), 5.12 (1H, m), 4.70 (2H, m), 4.66 (1H, s), 3.98 (2
H, d, J = 5.9Hz), 3.90 (1H, s), 3.74 (3H, s), 3.57 (1H,
br), 3.36 (1H, t, J = 2.4Hz), 3.25 (1H, d, J = 8.9Hz), 3.
04〜3.13 (3H, m).

[0192]

Example 16 13- [2- (4- (1-methoxycarbonylpyrrolididiene
2-Carbonylamino) phenyl) -2-methyl group
Ropyroxy] -5-hydroxyiminomilbemycin
A ₄ (I: R ¹ = Et, X = CH ₂ , Z = = C (CH ₃ ) ₂ , R ³ = 4-NH
COCH ₂ NHCOOMe, n = 0) (Exemplified Compound No. 553) Mass spectrum (FAB-MS) (m / z): 1023 (M + H ⁺ + triethanolamine = 873 + 1 + 149). Nuclear magnetic resonance spectrum ( 270MHz) δ (CDCl3): 7.89 (1H,
br), 7.44 (2H, d, J = 8.5Hz), 7.30 (2H, d, J = 8.5Hz),
5.69 ~ 5.85 (3H, m), 5.27 ~ 5.44 (3H, m), 5.14 (1H,
m), 4.75 (2H, m), 4.66 (1H, s), 4.47 (1H, bs), 3.91 (1
H, s), 3.77 (3H, s), 3.57 (1H, br), 3.38 ~ 3.73 (4H,
m), 3.37 (1H, t, J = 2.4Hz), 3.25 (1H, d, J = 8.7Hz), 3.
04 to 3.14 (3H, m).

[0193]

Example 17 13- [1- (4-acetylaminophenyl) cyclop
Lopancarbonyloxy] -5-hydroxyiminomil
Bemycin A ₄ (VI: R ¹ = Et, X = CO, Z = = C = (C
^{_{H 2) 2, R 3 =}} 4-AcNH, n = 0) ( Compound No. 392). 13- [1- (4-aminophenyl) cyclopropanecarbonyloxy] -5-hydroxyiminomilbemycin A ₄ obtained in Example 11 (98.0 mg, 0.134 mmol)
Was dissolved in dichloromethane (1.0 ml) and pyridine (0.0121 ml, 0.15 mmol) was dissolved in dichloromethane under ice cooling (1.0 ml).
A solution and a solution of acetic anhydride (0.0142 ml, 0.15 mmol) in dichloromethane (1.0 ml) were added, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 10 minutes. Ethyl acetate (15
ml) was added, the mixture was washed 3 times with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography to give the desired compound 70.0 m
Obtained g (67.6%).

Nuclear magnetic resonance spectrum (270MHz) δ (CDCl
3): 7.41 (2H, d, J = 8.4Hz), 7.34 (2H, d, J = 8.4Hz),
5.83 (1H, s), 5.73 ~ 5.90 (2H, m), 5.27 ~ 5.44 (3H,
m), 4.90 (1H, d, J = 10.4Hz), 4.70 (2H, m), 4.66 (1H,
s), 3.93 (1H, s), 3.56 (1H, m), 3.35 (1H, m), 3.04 (1H,
dt, J = 2.2 and 9.2Hz), 2.13 (3H, s), 1.93 (3H, s),
1.38 (3H, s), 0.97 (3H, t, J = 7.2Hz), 0.93 (3H, d, J =
6.6Hz), 0.83 (3H, d, J = 6.5Hz).

[0195]

Example 18 13- [2- (4-Methanesulfonylaminophenyl)
-2-Methylpropionyloxy] -5-hydroxyl
Minomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (M
e) ₂ , R ³ = 4-NHSO ₂ Me, n = 0) (Compound No. 148) Step A 13- [2- (4-Nitrophenyl) -2-methylpropionyloxy] -5 in dichloromethane (25 ml) −
Hydroxyimino milbemycin A ₄ (2.289 g,
To a solution of 3.0 mmol, prepared as described in Example 1), imidazole (245 mg, 3.6 mmol), t-butyldimethylsilyl chloride (543 mg, 3.6 mmol) and 4-dimethylaminopyridine (20 mg). ) Was added and the mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed successively with 0.2M citric acid, water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate / hexane = 1: 9), 13- [2- (4-nitrophenyl) -2-methylpropionyloxy] -5-t-butyldimethylsilyloxyimino. Milbemycin A ₄
(2.542 g, 96.6%) was obtained as an amorphous solid.

Step B Silyl derivative (2.45 g, 2.71 mmol, Step A above)
Was dissolved in methanol (15 ml) and bis (triphenylphosphine) -nickel (II) chloride (253 mg) was added. Sodium borohydride was added to the resulting solution within 10 minutes with stirring and stirring was continued for another 7 minutes. The reaction mixture was poured into 1% acetic acid (200 ml),
It was extracted with ethyl acetate (200 ml, 50 ml). The extract was washed successively with water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate / hexane = 3: 7), and 13- [2- (4-
Aminophenyl) -2-methylpropionyloxy]-
5-t-Butyldimethylsilyloxyiminomilbemycin A ₄ (2.101 g, 91.5%) was obtained as an amorphous solid.

Step C Amino derivative (169) in dichloromethane (2.0 ml)
To a solution of mg, 0.20 mmol, obtained in step B above) was added pyridine (0.177 ml, 2.20 mmol) and methanesulfonyl chloride (252 mg, 2.20 mmol) and the resulting mixture was at room temperature for 2 hours. It was stirred. The reaction mixture was diluted with ethyl acetate (20 ml), 0.2M citric acid, water, 4
Washed sequentially with% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was dissolved in methanol (3.0 ml) and 1M hydrochloric acid (0.3 ml) was added to this solution. After stirring the mixture at room temperature for 20 minutes, the reaction mixture was diluted with ethyl acetate (20 ml),
It was washed successively with water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate / hexane = 6: 4) to give the title compound (717
mg, 94.5%) was obtained as an amorphous solid.

Mass spectrum (FAB-MS) m / z: 811 (M + H
⁺ , M = C ₄₃ H ₅₈ N ₁ O ₁₁ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.14 (1H, wide
s), 7.26 (2H, d, J = 8.6Hz), 7.20 (2H, d, J = 8.6Hz),
6.35 (1H, br-s), 4.87 (1H, d, J = 9.9Hz), 4.71 and 4.6
9 (2H, ABq, J = 14.5Hz), 4.65 (1H, s), 3.95 (1H, s), 3.
56 (1H, m), 3.36 (1H, m), 3.04 (1H, m), 2.98 (3H, s),
1.93 (3H, s), 1.58 (3H, s), 1.55 (3H, s), 1.31 (3H, s),
0.98 (3H, t, J = 7.3Hz), 0.84-0.80 (6H, m). Examples 19-56 Using a procedure similar to that in Example 18, the compounds of Examples 19-56 were prepared.

[0199]

Example 19 13- [2- (4-benzoylaminophenyl) -2-
Methylpropionyloxy] -5-hydroxyiminomi
Rubemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Me) ₂ ,
R ³ = 4-NHCOPh, n = 0) (Compound No. 63) Mass spectrum (FAB-MS) m / z: 837 (M + H ⁺ , M = C ₄₉ H
₆₀ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.89-7.31 (2H,
m), 7.77 (1H, wide s), 7.60-7.47 (5H, m), 7.31 (2H,
d, J = 8.6Hz), 4.89 (1H, d, J = 10.6Hz), 4.71 and 4.
69 (2H, ABq, J = 15.2Hz), 4.
65 (1H, s), 3.95 (1H, s),
3.56 (1H, m), 3.36 (1H, m),
3.04 (1H, m), 1.93 (3H, s),
1.59 (3H, s), 1.56 (3H, s)
s), 1.33 (3H, s), 0.98 (3H,
t, J = 7.3 Hz), 0.85-0.82 (6
H, m).

[0200]

Example 20 13- [2- (4-methoxycarbonylaminophenenyl)
) -2-Methylpropionyloxy] -5-hydroxy
Siimino milbemycin A ₄ (I: R ¹ = E
t, X = CO, Z = = C (Me) ₂ , R
³ = 4-NHCOOMe, n = 0) (compound
No. 121) Mass spectrum (FAB-MS) m / z: 791 (M + H ⁺ , M = C ₄₄ H
₅₈ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.82 (1H, wide
s), 7.31 (2H, d, J = 8.6Hz), 7.23 (2H, d, J = 8.6Hz), 6.
56 (1H, wide s), 4.87 (1H, d, J = 10.6Hz), 4.71 and 4.6
9 (2H, ABq, J = 14.5Hz), 4.65 (1H, s), 3.96 (1H, s), 3.
78 (3H, s), 3.56 (1H, m), 3.36 (1H, m), 3.04 (1H, dt,
J = 2.6 and 9.2Hz), 1.93 (3H, s), 1.56 (3H, s), 1.53 (3
H, s), 1.30 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.84-0.8
1 (6H, m).

[0201]

Example 21 13- [2- (4-acetylaminophenyl) -2-me
Cylpropionyloxy] -5-hydroxyiminomil
Bemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Me) ₂ , R ³
= 4-NHCOCH ₃ , n = 0) (Compound No. 26 ) Mass spectrum (FAB-MS) m / z: 775 (M + H ⁺ , M = C ₄₄ H
₅₈ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.83 (1H, wide
s), 7.42 (2H, d, J = 8.6Hz), 7.25 (2H, d, J = 8.6Hz), 7.
11 (1H, wide s), 4.87 (1H, d, J = 10.6Hz), 4.71 and 4.6
9 (2H, ABq, J = 14.5Hz), 4.65 (1H, s), 3.95 (1H, s), 3.
56 (1H, m), 3.36 (1H, m), 3.04 (1H, dt, J = 2.3 and 9.2
Hz), 2.18 (3H, s), 1.93 (3H, s), 1.57 (3H, s), 1.53 (3
H, s), 1.30 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.84-0.8
0 (6H, m).

[0202]

Example 22 13- [2- (4-phenoxycarbonylaminophenyi
) -2-Methylpropionyloxy] -5-hydroxy
Siimino milbemycin A ₄ (I: R ¹ = Et, X = CO, Z =
= C (Me) ₂ , R ³ = 4-NHCOOPh, n = 0) (Compound No. 13
1) Mass spectrum (FAB-MS) m / z: 853 (M + H ⁺ , M = C ₄₉ H
₆₀ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.89 (1H, wide
s), 7.43-7.37 (4H, m), 7.29-7.24 (2H, m), 7.19 (2H, d,
J = 7.3Hz), 6.91 (1H, wide s), 4.88 (1H, d, J = 10.6H
z), 4.72 and 4.69 (2H, ABq, J = 14.5Hz), 4.65 (1H, s),
3.96 (1H, s), 3.56 (1H, m), 3.36 (1H, m), 3.04 (1H,
m), 1.93 (3H, s), 1.57 (3H, s), 1.55 (3H, s), 1.31 (3H,
s), 0.98 (3H, t, J = 7.3Hz), 0.83 (6H, d, J = 6.6Hz).

[0203]

Example 23 13- [2- (4-crotonylaminophenyl) -2-
Methylpropionyloxy] -5-hydroxyiminomi
Rubemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Me) ₂ ,
R ³ = 4-NHCOCH = CHMe (trans), n = 0) (Compound number
59) Mass spectrum (FAB-MS) m / z: 801 (M + H ⁺ , M = C ₄₆ H
₆₀ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.16 (1H, s), 7.
48 (2H, d, J = 8.5 Hz), 7.26 (2H, d, J = 8.5 Hz), 7.11 (1
H, s), 7.00 (1H, m), 5.93 (1H, dd, J = 1.4 and 15.2Hz),
5.84 (1H, ddd, J = 2.0, 2.0 and 11.5Hz), 4.87 (1H, d,
J = 10.6Hz), 4.73 and 4.66 (2H, d-ABq, J = 1.9Hz and 1
4.6Hz), 4.65 (1H, s), 3.97 (1H, s), 3.56 (1H, m), 3.3
6 (1H, m), 3.04 (1H, dt, J = 2.0 and 9.4Hz), 1.93 (3H,
s), 1.57 (3H, s), 1.54 (3H, s), 1.30 (3H, s), 0.98 (3
H, t, J = 7.3Hz), 0.83 (3H, d, J = 6.3Hz), 0.81 (3H, d,
J = 6.3Hz).

[0204]

Example 24 13- {2- [4- (2,2-dimethylpropionyl)
Aminophenyl] -2-methylpropionyloxy}-
5-hydroxyimino milbemycin A ₄ (I: R ¹ = Et,
X = CO, Z = = C (Me) ₂ , R ³ = 4-NHCOBu (t-), n = 0)
(Compound number 38) Mass spectrum (FAB-MS) m / z: 817 (M + H ⁺ , M = C ₄₇ H
₆₄ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.81 (1H, s), 4.
88 (1H, d, J = 10.6Hz), 4.72 and 4.69 (2H, ABq, J = 13.9
Hz), 4.65 (1H, s), 3.96 (1H, s), 3.56 (1H, m), 3.36 (1
H, m), 3.04 (1H, dt, J = 2.6 and 9.2 Hz), 1.
93 (3H, s), 1.57 (3H, s),
1.53 (3H, s), 1.32 (12H,
s), 0.98 (3H, t, J = 7.3 Hz),
0.83 (6H, d, J = 6.3Hz).

[0205]

Example 25 13- [2- (4-valerylaminophenyl) -2-me
Cylpropionyloxy] -5-hydroxyiminomil
Bemycin A ₄ (I: R ¹ = Et, X =
_{CO, Z = = C (Me} ) 2, R 3 = 4-
NHCOBu, n = 0) (Compound No. 36) Mass spectrum (FAB-MS) m / z: 817 (M + H ⁺ , M = C ₄₇ H
₆₄ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.90 (1H, wide
s), 7.44 (2H, d, J = 8.6Hz), 7.24 (2H, d, J = 8.6 Hz),
7.08 (1H, s), 4.87 (1H, d, J = 10.6Hz), 4.72 and 4.69
(2H, ABq, J = 15.8Hz), 4.65 (1H, s), 3.96 (1H, s), 3.5
6 (1H, m), 3.36 (1H, m), 3.04 (1H, m), 1.93 (3H, s), 1.
57 (3H, s), 1.53 (3H, s), 1.31 (3H, s), 0.98 (3H, t, J
= 7.3Hz), 0.95 (3H, t, J = 7.6Hz), 0.84-0.81 (6H, m).

[0206]

Example 26 13- {2- [4- (3-fluorobenzoyl) amino
Phenyl] -2-methylpropionyloxy} -5-hi
Droxyimino milbemycin A ₄ (I: R ¹ = Et, X = C
O, Z = = C (Me) ₂ , R ³ = 4-NHCOPh (3-F), n = 0) (Compound
No. 65) Mass spectrum (FAB-MS) m / z: 855 (M + H ⁺ , M = C ₄₉ H
₅₉ FN ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 9.05 (1H, wide
s), 7.97 (1H, s), 7.65-7.56 (2H, m), 7.57 (2H, d, J =
8.6Hz), 7.32-7.20 (1H, m), 7.29 (2H, d, J = 8.6Hz), 4.
88 (1H, d, J = 10.5Hz), 4.70 and 4.68 (2H, ABq, J = 15.2H
z), 4.65 (1H, s), 4.00 (1H, s), 3.56 (1H, m), 3.36 (1H,
m), 3.05 (1H, m), 1.91 (3H, s), 1.58 (3H, s), 1.56 (3
H, s), 1.33 (3H, s), 0.98 (3H, t, J = 7.2Hz), 0.83 (6H,
d, J = 6.6Hz).

[0207]

Example 27 13- [2- (4-methylthioacetylaminophenyi
) -2-Methylpropionyloxy] -5-hydroxy
Shiminomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z =
= C (Me) ₂ , R ³ = 4-NHCOCH ₂ SMe, n = 0) (Compound No. 5
1) Mass spectrum (FAB-MS) m / z: 821
(M + H ⁺ , M = C ₄₅ H ₆₀ N ₂ O
₁₀ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.67 (1
H, s), 8.30 (1H, wide s), 7.50 (2H, d, J = 8.6Hz), 7.2
8 (2H, d, J = 8.6Hz), 4.88 (1H, d, J = 10.5Hz), 4.72 and 4.69 (2H, ABq, J = 14.6Hz), 4.66 (1H, s), 3.97 (1H,
s), 3.56 (1H, m), 3.36 (1H, m), 3.35 (2H, s), 3.04 (1
H, m), 2.05 (3H, s), 1.93 (3H, s), 1.57 (3H, s), 1.55
(3H, s), 1.32 (3H, s), 0.98 (3H, t, J = 7.2Hz), 0.83 (6
H, d, J = 6.4Hz).

[0208]

Example 28 13- [2- (4-methoxyacetylaminophenyl)
-2-Methylpropionyloxy] -5-hydroxyl
Minomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (M
e) ₂ , R ³ = 4-NHCOCH ₂ OMe, n = 0) (Compound No. 47) Mass spectrum (FAB-MS) m / z: 805 (M + H ⁺ , M = C ₄₅ H
₆₀ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 9.01 (1H, wide
s), 8.24 (1H, s), 7.51 (2H, d, J = 8.6Hz), 7.28 (2H, d,
J = 8.6Hz), 4.87 (1H, d, J = 10.5Hz), 4.71 and 4.68 (2H,
ABq, J = 15.2Hz), 4.66 (1H, s), 3.97 (3H, s), 3.58 (1
H, m), 3.51 (3H, S), 3.36 (1H, m), 3.04 (1H, m), 1.92
(3H, s), 1.57 (3H, s), 1.54 (3H, s), 1.30 (3H, s), 0.
98 (3H, t, J = 7.2Hz), 0.83 (3H, d, J = 6.4Hz), 0.82 (3H,
d, J = 6.4Hz).

[0209]

Example 29 13- [2- (4-cyclopropylcarbonylaminophine
2) Methyl propionyloxy] -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (Me) ₂ , R ³ = 4-NHCOPr (cyclo-), n = 0) (Compound
No. 39) Mass spectrum (FAB-MS) m / z: 801 (M + H ⁺ , M = C ₄₆ H
₆₀ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.80 (1H, wide
s), 7.49 (1H, s), 7.44 (2H, d, J = 8.6 Hz), 7.24 (2H,
d, J = 8.6 Hz), 4.87 (1H, d, J = 10.6 Hz), 4.72 and 4.
69 (2H, ABq, J = 14.8Hz), 4.
66 (1H, s), 3.57 (1H, m),
3.36 (1H, m), 3.04 (1H, m),
1.92 (3H, s), 1.56 (3H, s),
1.53 (3H, s), 1.30 (3H,
s), 1.09 (2H, m), 0.98 (3H,
t, J = 7.3 Hz), 0.83 (3H, d,
J = 6.3 Hz), 0.82 (3H, d, J =
6.5 Hz).

[0210]

Example 30 13- [2- (4-Cyclohexanecarbonylaminophosphine
2) Methyl propionyloxy] -5-hydr
Roxiiminomilbemycin A ₄ (I: R ¹ =
Et, X = CO, Z = = C (Me) ₂ ,
R ³ = 4-NHCOcHex (cyclo-), n = 0)
(Compound No. 40) Mass spectrum (FAB-MS) m / z: 843 (M + H ⁺ , M = C ₄₉ H
₆₆ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.99 (1H, wide
s), 7.45 (2H, d, J = 8.6Hz), 7.24 (2H, d, J = 8.6Hz), 7.
10 (1H, wide s), 4.87 (1H, d, J = 10.6Hz), 4.72 and 4.7
0 (2H, ABq, J = 14.5Hz), 4.65 (1H, s), 3.96 (1H, s), 3.
57 (1H, m), 3.36 (1H, m), 3.04 (1H, m), 1.93 (3H, s),
1.56 (3H, s), 1.53 (3H, s), 1.31 (3H, s), 0.98 (3H, t,
J = 7.3Hz), 0.83 (3H, d, J = 6.3Hz), 0.82 (3H, d, J = 6.5
Hz).

[0211]

Example 31 13- {2- [4- (4-methoxyphenyl) acetyl
Aminophenyl] -2-methylpropionyloxy}-
5-hydroxyimino milbemycin A ₄ (I: R ¹ = Et,
X = CO, Z = = C (Me) ₂ , R ³ = 4-NHCOCH ₂ Ph (4-MeO), n =
0) (Compound No. 62) mass spectrum (FAB-MS) m / z: 881 (M + H ⁺ , M = C ₅₁ H
₆₄ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.91 (1H, wide
s), 7.34 (2H, d, J = 8.6Hz), 7.25 (2H, d, J = 8.6Hz), 7.
21 (2H, d, J = 8.6Hz), 7.01 (1H, wide s), 6.94 (2H,
d, J = 8.6Hz), 4.86 (1H, d, J = 10.5Hz), 4.72 and 4.70
(2H, ABq, J = 14.3Hz), 4.66 (1H, s), 3.96 (1H, s), 3.8
4 (3H, s), 3.69 (2H, s), 3.58 (1H, m), 3.36 (1H, m), 3.
04 (1H, m), 1.94 (3H, s), 1.54 (3H, s), 1.51 (3H, s),
1.29 (3H, s), 0.98 (3H, t, J = 7.2Hz), 0.82 (6H, d, J = 6.
6Hz).

[0212]

Example 32 13- {2- [4- (4-nitrobenzoyl) aminoph
[Ethyl] -2-methylpropionyloxy} -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (Me) ₂ , R ³ = 4-NHCOPh (4-NO ₂ ), n = 0) (Compound
No. 73) Mass spectrum (FAB-MS) m / z: 882 (M + H ⁺ , M = C ₄₉ H
₆₀ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 9.10 (1H, wide
s), 8.35 (2H, d, J = 8.6Hz), 8.05 (2H, d, J = 8.6Hz), 7.
82 (1H, s), 7.58 (2H, d, J = 8.6Hz), 7.34 (2H, d, J = 8.6H
z), 4.89 (1H, d, J = 10.6Hz), 4.74 and 4.66 (2H, ABq, J
= 15.0Hz), 4.65 (1H, s), 3.97 (1H, s), 3.57 (1H, m),
3.35 (1H, m), 3.04 (1H, m), 1.93 (3H, s), 1.60 (3H, s),
1.57 (3H, s), 1.33 (3H, s), 0.98 (3H, t, J = 7.3Hz),
0.90-0.80 (4H, m).

[0213]

Example 33 13- {2- [4- (2-Furoyl) aminophenyl]
-2-Methylpropionyloxy} -5-hydroxyl
Minomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (M
e) ₂ , R ³ = 4-NHCOFur (2-), n = 0) (Compound No. 77) Mass spectrum (FAB-MS) m / z: 827 (M + H ⁺ , M = C ₄₇ H
₅₈ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.08 (1H, s), 7.
59 (2H, d, J = 8.6Hz), 7.51 (1H, d, J = 2.0Hz), 7.30 (2
H, d, J = 8.6Hz), 7.26 (1H, d, J = 3.7Hz), 6.56 (1H, dd,
J = 2.0 and 3.7Hz), 4.88 (1H, d, J = 10.5Hz), 4.71 and 4.68 (2H, ABq, J = 14.3Hz), 4.66 (1H, s), 3.97 (1H,
s), 3.57 (1H, m), 3.36 (1H, m), 3.04 (1H, m), 1.92 (3
H, s), 1.58 (3H, s), 1.56 (3H, s), 1.31 (3H, s), 0.98
(3H, t, J = 7.3Hz), 0.83 (6H, d, J = 6.4Hz).

[0214]

Example 34 13- [2- (4-propioroylaminophenyl)-
2-Methylpropionyloxy] -5-hydroxyimi
Nomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Me)
₂ , R ³ = 4-NHCOC≡CH, n = 0) (Compound No. 60) Mass spectrum (FAB-MS) m / z: 785 (M + H ⁺ , M = C ₄₅ H
₅₆ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.61 (1H, wide
s), 7.62 (1H, s), 7.45 (2H, d, J = 8.6Hz), 7.27 (2H,
d, J = 8.6Hz), 4.87 (1H, d, J = 10.5Hz), 4.71 and 4.69
(2H, ABq, J = 14.4Hz), 4.66 (1H, s), 3.98 (1H, wide
s), 3.57 (1H, m), 3.36 (1H, m), 3.04 (1H, m), 2.93 (1
H, s), 1.92 (3H, s), 1.57 (3H, s), 1.54 (3H, s), 1.30
(3H, s), 0.98 (3H, t, J = 7.3Hz), 0.84 (3H, d, J = 6.4H
z), 0.83 (3H, d, J = 6.5Hz).

[0215]

Example 35 13- {2- [4- (4-nitrophenyl) acetylacetate
Minophenyl] -2-methylpropionyloxy} -5
-Hydroxyiminomilbemycin A ₄ (I: R ¹ = Et, X
= CO, Z = = C (Me) ₂ , R ³ = 4-NHCOCH ₂ Ph (4-NO ₂ ), n = 0)
(Compound No. 61) mass spectrum (FAB-MS) m / z: 896 (M + H ⁺ , M = C ₅₀ H
₆₁ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.25 (2H, d, J =
8.6Hz), 7.80 (1H, wide s), 7.54 (2H, d, J = 8.6Hz),
7.39 (2H, d, J = 8.6Hz), 7.24 (2H, d, J = 8.6Hz), 7.11 (1
H, wide s), 4.87 (1H, d, J = 10.6Hz), 4.71 and 4.69 (2
H, ABq, J = 14.1Hz), 4.65 (1H, s), 3.96 (1H, s), 3.82 (2
H, s), 3.58 (1H, m), 3.36 (1H, m), 3.03 (1H, dt, J = 2.2
And 7.1Hz), 1.93 (3H, s), 1.56 (3H, s), 1.52 (3H,
s), 1.29 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.84-0.80 (6
H, m).

[0216]

Example 36 13- {2- [4- (4-methoxybenzoyl) amino
Phenyl] -2-methylpropionyloxy} -5-hi
Droxyimino milbemycin A ₄ (I: R ¹ = Et, X = C
O, Z = = C (Me) ₂ , R ³ = 4-NHCOPh (4-MeO), n = 0) (Compound
No. 69) Mass spectrum (FAB-MS) m / z: 867 (M + H ⁺ , M = C ₅₀ H
₆₂ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.85 (2H, d, J =
8.8Hz), 7.70 (1H, wide s), 7.57 (2H, d, J = 8.7Hz),
7.30 (2H, d, J = 8.7Hz), 6.98 (2H, d, J = 8.8Hz), 4.88 (1
H, d, J = 10.4Hz), 4.72 and 4.70 (2H, ABq, J = 14.6Hz),
4.65 (1H, s), 3.96 (1H, s), 3.88 (3H, s), 3.57 (1H,
m), 3.35 (1H, m), 3.04 (1H, dt, J = 2.4 and 9.1H
z), 1.93 (3H, s), 1.59 (3H, s)
s), 1.56 (3H, s), 1.32 (3
H, s), 0.98 (3H, t, J = 7.3H
z), 0.83 (6H, d, J = 6.3 Hz).

[0219]

Example 37 13- {2- [4- (4-t-butylbenzoyl) ami
Nophenyl] -2-methylpropionyloxy} -5-
Hydroxyimino milbemycin A ₄ (I: R ¹
= Et, X = CO, Z == C (M
e) ₂ , R ³ = 4-NHCOPh (4-t-B
u), n = 0) (Compound No. 72) Mass spectrum (FAB-MS) m / z: 893 (M + H ⁺ , M = C ₅₃ H
₆₈ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.81 (2H, d, J =
8.4Hz), 7.76 (1H, wide s), 7.58 (2H, d, J = 8.6Hz),
7.51 (2H, d, J = 8.4Hz), 7.31 (2H, d, J = 8.6Hz), 4.89 (1
H, d, J = 10.4Hz), 4.72 and 4.70 (2H, ABq, J = 14.8Hz),
4.65 (1H, s), 3.97 (1H, s), 3.56 (1H, m), 3.35 (1H,
m), 3.04 (1H, m), 1.93 (3H, s), 1.58 (3H, s), 1.56 (3
H, s), 1.36 (9H, s), 1.33 (3H, s), 0.99 (3H, t, J = 7.2
Hz), 0.78 (6H, d, J = 6.3Hz).

[0218]

Example 38 13- {2- [4- (4-chlorobenzoyl) aminophen
[Ethyl] -2-methylpropionyloxy} -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (Me) ₂ , R ³ = 4-NHCOPh (4-Cl), n = 0) (Compound
No. 67) Mass spectrum (FAB-MS) m / z: 871 (M + H ⁺ , M = C ₄₉ H
₅₉ ClN ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.94 (1H, wide
s), 7.83 (2H, d, J = 8.5Hz), 7.74 (1H, wide s), 7.57
(2H, d, J = 8.6Hz), 7.48 (2H, d, J = 8.5Hz), 7.32 (2H,
d, J = 8.6Hz), 4.89 (1H, d, J = 10.5Hz), 4.72 and 4.69
(2H, ABq, J = 14.4Hz), 4.65 (1H, s), 3.97 (1H, s), 3.5
6 (1H, m), 3.35 (1H, m), 3.04 (1H, m), 1.93 (3H, s),
1.59 (3H, s), 1.56 (3H, s), 1.32 (3H, s), 0.99 (3H, t,
J = 7.3Hz), 0.83 (6H, d, J = 6.4Hz).

[0219]

Example 39 13- [2- (4-Cyclobutanecarbonylaminophen
Nyl) -2-methylpropionyloxy] -5-hydro
Xiiminomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z
= = C (Me) ₂ , R ³ = 4-NHCOcBu, n = 0) (Compound No. 4
0) Mass spectrum (FAB-MS) m / z: 815 (M + H ⁺ , M = C ₄₇ H
₆₂ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 9.24 (1H, wide
s), 7.46 (2H, d, J = 8.6Hz), 7.24 (2H, d, J = 8.6Hz), 7.
20 (1H, s), 4.87 (1H, d, J = 9.9Hz), 4.71 and 4.67 (2H,
ABq, J = 14.9Hz), 4.66 (1H, s), 3.99 (1H, wide s), 3.
57 (1H, m), 3.36 (1H, m), 3.15 (1H, m), 3.04 (1H, m),
1.91 (3H, s), 1.56 (3H, s), 1.53 (3H, s), 1.30 (3H, s),
0.98 (3H, t, J = 7.3Hz), 0.83 (3H, d, J = 6.3Hz), 0.82
(3H, d, J = 6.4Hz).

[0220]

Example 40 13- [2- (4-Cyclopentanecarbonylaminophosphine
2) Methyl propionyloxy] -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (Me) ₂ , R ³ = 4-NHCOcPen, n = 0) (Compound number
41) Mass spectrum (FAB-MS) m / z: 829 (M + H ⁺ , M = C ₄₈ H
₆₄ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.46 (2H, d, J =
8.6Hz), 7.24 (2H, d, J = 8.6Hz), 7.21 (1H, s), 4.87 (1
H, d, J = 10.5Hz), 4.72 and 4.69 (2H, ABq, J = 15.3Hz),
4.66 (1H, s), 3.57 (1H, m), 3.36 (1H, m), 3.04 (1H,
m), 2.67 (1H, m), 1.92 (3H, s), 1.56 (3H, s), 1.53 (3
H, s), 1.31 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.83 (3H,
d, J = 6.3Hz), 0.82 (3H, d, J = 6.5Hz).

[0221]

Example 41 13- [2- (4-propionylaminophenyl) -2
-Methylpropionyloxy] -5-hydroxyimino
Milbemycin A ₄ (I: R ¹ = Et, X = CO, Z == C (Me) ₂ ,
R ³ = 4-NHCOEt, n = 0) (Compound No. 33) Mass spectrum (FAB-MS) m / z: 789 (M + H ⁺ , M = C ₄₅ H
₆₀ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 9.09 (1H, wide
s), 7.45 (2H, d, J = 8.6Hz), 7.24 (2H, d, J = 8.6Hz), 4.
87 (1H, d, J = 10.6Hz), 4.71 and 4.69 (2H, ABq, J = 14.5H
z), 4.66 (1H, s), 3.98 (1H, wide s), 3.57 (1H, m), 3.
36 (1H, m), 3.04 (1H, m), 2.38 (1H, q, J = 7.6Hz), 1.92
(3H, s), 1.56 (3H, s), 1.53 (3H, s), 1.30 (3H, s), 0.
98 (3H, t, J = 7.3Hz), 0.83 (3H, d, J = 6.4Hz), 0.82 (3H,
d, J = 6.5Hz).

[0222]

Example 42 13- [2- (4-isovalerylaminophenyl) -2
-Methylpropionyloxy] -5-hydroxyimino
Milbemycin A ₄ (I: R ¹ = Et, X = CO, Z == C (Me) ₂ ,
R ³ = 4-NHCOCH ₂ iPr, n = 0) (Compound No. 37) Mass spectrum (FAB-MS) m / z: 817 (M + H ⁺ , M = C ₄₇ H
₆₄ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.70 (1H, wide
s), 7.45 (2H, d, J = 8.6Hz), 7.25 (2H, d, J = 8.6Hz), 7.
16 (1H, s), 4.87 (1H, d, J = 10.5Hz), 4.71 and 4.68 (2H,
ABq, J = 15.0Hz), 4.66 (1H, s), 3.88 (1H, wide s), 3.
57 (1H, m), 3.36 (1H, m), 3.04 (1H, m), 2.21 (2H, d, J
= 2.3Hz), 1.92 (3H, s), 1.56 (3H, s), 1.53 (3H, s), 1.
31 (3H, s), 1.02-0.92 (9H, m), 0.83 (3H, d, J = 6.6Hz),
0.82 (3H, d, J = 6.3Hz).

[0223]

Example 43 13- [2- (4-isobutyrylaminophenyl) -2
-Methylpropionyloxy] -5-hydroxyimino
Milbemycin A ₄ (I: R ¹ = Et, X = CO, Z == C (Me) ₂ ,
R ³ = 4-NHCOiPr, n = 0) (Compound No. 35) Mass spectrum (FAB-MS) m / z: 803 (M + H ⁺ , M = C ₄₆ H
₆₂ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 9.20 (1H, wide
s), 7.45 (2H, d, J = 8.6Hz), 7.31 (1H, s), 7.24 (2H, d,
J = 8.6Hz), 4.87 (1H, d, J = 10.5Hz), 4.71 and 4.69 (2H,
ABq, J = 15.3Hz), 4.66 (1H, s), 4.01 (1H, wide s), 3.
57 (1H, m), 3.36 (1H, m), 3.04 (1H, m), 2.33 (1H, m),
1.92 (3H, s), 1.56 (3H, s), 1.53 (3H, s), 1.31 (3H, s),
1.03-0.95 (9H, m), 0.83 (3H, d, J = 6.2Hz), 0.82 (3H,
d, J = 6.4Hz).

[0224]

Example 44 13- [2- (4-butyrylaminophenyl) -2-me
Cylpropionyloxy] -5-hydroxyiminomil
Bemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Me) ₂ , R ³
= 4-NHCOPr, n = 0) (Compound No. 34) Mass spectrum (FAB-MS) m / z: 803 (M + H ⁺ , M = C ₄₆ H
₆₂ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 9.35 (1H, wide
s), 7.45 (2H, d, J = 8.6Hz), 7.35 (1H, s), 7.24 (2H, d,
J = 8.6Hz), 4.87 (1H, d, J = 10.5Hz), 4.72 and 4.69 (2H,
ABq, J = 15.0Hz), 4.66 (1H, s), 3.99 (1H, wide s), 3.
57 (1H, m), 3.36 (1H, m), 3.04 (1H, m), 2.51 (1H, t, J
= 6.8Hz), 1.91 (3H, s), 1.56 (3H, s), 1.53 (3H, s), 1.
31 (3H, s), 0.98 (3H, t, J = 7.2Hz), 0.83 (3H, d, J = 6.3
Hz), 0.82 (3H, d, J = 6.5Hz).

[0225]

Example 45 13- [2- (4-Bromoacetylaminophenyl)-
2-Methylpropionyloxy] -5-hydroxyimi
Nomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Me)
₂ , R ³ = 4-NHCOCH ₂ Br, n = 0) (Compound No. 43) Mass spectrum (FAB-MS) m / z: 853 (M + H ⁺ , M = C ₄₄ H
₅₇ BrN ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.09 (1H, wide
s), 7.47 (2H, d, J = 8.6Hz), 7.30 (2H, d, J = 8.6Hz), 4.
88 (1H, d, J = 10.7Hz), 4.72 and 4.69 (2H, ABq, J = 14.6H
z), 4.65 (1H, s), 4.03 (2H, s), 3.56 (1H, m), 3.37 (1
H, m), 3.04 (1H, dt, J = 2.0 and 8.9Hz), 1.93 (3H, s),
1.58 (3H, s), 1.56 (3H, s), 1.31 (3H, s), 0.98 (3H, t,
J = 7.2Hz), 0.83-0.74 (6H, m).

[0226]

Example 46 13- [2- (4-cyanoacetylaminophenyl)-
2-Methylpropionyloxy] -5-hydroxyimi
Nomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Me)
₂ , R ³ = 4-NHCOCH ₂ CN, n = 0) (Compound No. 43) Mass spectrum (FAB-MS) m / z: 853 (M + H ⁺ , M = C ₄₅ H
₅₇ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.69 (1H, wide
s), 7.44 (2H, d, J = 8.6Hz), 7.30 (2H, d, J = 8.6Hz), 4.
88 (1H, d, J = 10.5Hz), 4.72 and 4.70 (2H, ABq, J = 14.8H
z), 4.66 (1H, s), 3.57 (1H, m), 3.56 (2H, s), 3.36 (1
H, m), 3.04 (1H, m), 1.93 (3H, s), 1.58 (3H, s), 1.55
(3H, s), 1.31 (3H, s), 0.98 (3H, t, J = 7.2Hz), 0.84-
0.74 (6H, m).

[0227]

Example 47 13- {2- [4- (3-nitrobenzoyl) aminoph
[Ethyl] -2-methylpropionyloxy} -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (Me) ₂ , R ³ = 4-NHCOPh (3-NO ₂ ), n = 0) (Compound
No. 74) Mass spectrum (FAB-MS) m / z: 871 (M + H ⁺ , M = C ₄₉ H
₅₉ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.71 (1H, s), 8.
43 (1H, dd, J = 1.4 and 8.0Hz), 8.27 (1H, d, J = 8.0Hz),
7.88 (1H, wide s), 7.73 (1H, dd, J = 8.0 and 8.0Hz), 7.
60 (2H, d, J = 8.6Hz), 7.35 (2H, d, J = 8.6Hz), 4.90 (1H,
d, J = 10.5Hz), 4.72 and 4.69 (2H, ABq, J = 14.4Hz),
4.65 (1H, s), 3.56 (1H, m), 3.36 (1H, m), 3.04 (1H, dt,
J = 2.2 and 9.7Hz), 1.93 (3H, s), 1.60 (3H, s), 1.57 (3
H, s), 1.33 (3H, s), 0.99 (3H, t, J = 7.2Hz), 0.88-0.7
9 (6H, m).

[0228]

Example 48 13- {2- [4- (3-chlorobenzoyl) aminoph
[Ethyl] -2-methylpropionyloxy} -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (Me) ₂ , R ³ = 4-NHCOPh (3-Cl), n = 0) (Compound
No. 68) Mass spectrum (FAB-MS) m / z: 871 (M + H ⁺ , M = C ₄₉ H
₅₉ ClN ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.87-7.85 (1H,
m), 7.76-7.70 (2H, m), 7.57 (2H, d, J = 8.6Hz), 7.44 (1
H, dd, J = 7.8 and 7.8Hz), 7.32 (2H, d, J = 8.6Hz), 4.8
9 (1H, d, J = 10.5Hz), 4.71 and 4.69 (2H, ABq, J = 14.2H
z), 4.65 (1H, s), 3.56 (1H, m), 3.36 (1H, m), 3.04 (1H,
m), 1.93 (3H, s), 1.59 (3H, s), 1.56 (3H, s), 1.32 (3
H, s), 0.98 (3H, t, J = 7.3Hz), 0.84-0.77 (6H, m).

[0229]

Example 49 13- {2- [4- (4-fluorobenzoyl) amino
Phenyl] -2-methylpropionyloxy} -5-hi
Droxyimino milbemycin A ₄ (I: R ¹ = Et, X = C
O, Z = = C (Me) ₂ , R ³ = 4-NHCOPh (4-F), n = 0) (Compound
No. 66) Mass spectrum (FAB-MS) m / z: 855 (M + H ⁺ , M = C ₄₉ H
₅₉ FN ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.90 (2H, d, J =
8.5Hz), 7.72 (1H, wide s), 7.57 (2H, d, J = 8.6Hz),
7.32 (1H, d, J = 7.6Hz), 7.18 (2H, d, J = 8.5Hz), 4.89 (1
H, d, J = 10.5Hz), 4.72 and 4.69 (2H, ABq, J = 14.4Hz),
4.65 (1H, s), 3.56 (1H, m), 3.36 (1H, m), 3.04 (1H, d
t, J = 1.9 and 8.9Hz), 1.93 (3H, s), 1.59 (3H, s), 1.56
(3H, s), 1.32 (3H, s), 0.98 (3H, t, J = 7.2Hz), 0.83 (6
H, d, J = 6.3Hz).

[0230]

Example 50 13- {2- [4- (2-fluorobenzoyl) amino
Phenyl] -2-methylpropionyloxy} -5-hi
Droxyimino milbemycin A ₄ (I: R ¹ = Et, X = C
O, Z = = C (Me) ₂ , R ³ = 4-NHCOPh (2-F), n = 0) (Compound
No. 64) Mass spectrum (FAB-MS) m / z: 855 (M + H ⁺ , M = C ₄₉ H
₅₉ FN ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.61 (2H, d, J =
8.6Hz), 7.31 (1H, d, J = 7.6Hz), 4.89 (1H, d, J = 10.5H
z), 4.72 and 4.69 (2H, ABq, J = 14.4Hz), 4.65 (1H, s),
3.56 (1H, m), 3.36 (1H, m), 3.04 (1H, m), 1.93 (3H,
s), 1.59 (3H, s), 1.56 (3H, s), 1.32 (3H, s), 0.98 (3
H, t, J = 7.3Hz), 0.83 (6H, d, J = 6.3Hz).

[0231]

Example 51 13- [2- (4-trifluoroacetylaminophenenyl
) -2-Methylpropionyloxy] -5-hydroxy
Siimino milbemycin A ₄ (I: R ¹ = Et, X = CO, Z =
= C (Me) ₂ , R ³ = 4-NHCOCF ₃ , n = 0) (Compound No. 44) Mass spectrum (FAB-MS) m / z: 829 (M + H ⁺ , M = C ₄₄ H
₅₅ F ₃ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.81 (1H, wide
s), 8.03 (1H, s), 7.51 (2H, d, J = 8.7Hz), 7.33 (2H, d,
J = 8.7Hz), 4.88 (1H, d, J = 10.5Hz), 4.71 and 4.68 (2H,
ABq, J = 14.2Hz), 4.65 (1H, s), 3.98 (1H, wide s),
3.57 (1H, m), 3.36 (1H, m)
m), 3.04 (1H, m), 1.92 (3H,
s), 1.58 (3H, s), 1.56 (3
H, s), 1.31 (3H, s), 0.98 (3
H, t, J = 7.3 Hz, 0.83 (6H,
d, J = 6.4 Hz).

[0232]

Example 52 13- [2- (4-difluoroacetylaminopheny
) -2-Methylpropionyloxy] -5-hydroxy
Siimino milbemycin A ₄ (I: R ¹ = E
t, X = CO, Z = = C (Me) ₂ , R
³ = 4-NHCOCHF ₂ , n = 0)
Compound number 45) Mass spectrum (FAB-MS) m / z: 811 (M + H ⁺ , M = C ₄₄ H
₅₆ F ₂ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.72 (1H, wide
s), 7.93 (1H, s), 7.52 (2H, d, J = 8.7Hz), 7.31 (2H, d,
J = 8.7Hz), 6.02 (1H, t, J = 54.6Hz), 4.88 (1H, d, J = 1
0.5Hz), 4.71 and 4.69 (2H, ABq, J = 15.2Hz), 4.65 (1H,
s), 3.98 (1H, wide s), 3.57 (1H, m), 3.36 (1H, m),
3.04 (1H, m), 1.92 (3H, s), 1.58 (3H, s), 1.55 (3H,
s), 1.30 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.83 (3H, d,
J = 6.4Hz), 0.82 (3H, d, J = 6.5Hz).

[0233]

Example 53 13- {2- [4- (3-methoxybenzoyl) amino
Phenyl] -2-methylpropionyloxy} -5-hi
Droxyimino milbemycin A ₄ (I: R ¹ = Et, X = C
O, Z = = C (Me) ₂ , R ³ = 4-NHCOPh (3-MeO), n = 0) (Compound
No. 70) Mass spectrum (FAB-MS) m / z: 867 (M + H ⁺ , M = C ₅₀ H
₆₂ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.05 (1H, wide
s), 7.78 (1H, s), 7.58 (2H, d, J = 8.6Hz), 7.44 (1H, d,
J = 1.4Hz), 7.34-7.41 (2H, m), 7.31 (2H, d, J = 8.6Hz),
7.09 (1H, m), 4.88 (1H, d, J = 10.5Hz), 4.72 and 4.69
(2H, ABq, J = 14.5Hz), 4.65 (1H, s), 3.96 (1H, s), 3.8
8 (3H, s), 3.57 (1H, m), 3.35 (1H, m), 3.04 (1H, dt, J
= 2.0 and 9.3Hz), 1.93 (3H, s), 1.59 (3H, s), 1.56 (3H,
s), 1.32 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.83 (6H,
d, J = 5.8Hz).

[0234]

Example 54 13- [2- (4-thenoylaminophenyl) -2-me
Cylpropionyloxy] -5-hydroxyiminomil
Bemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Me) ₂ , R ³
= 4-NHCOThi (2-), n = 0) (Compound No. 78) Mass spectrum (FAB-MS) m / z: 843 (M + H ⁺ , M = C ₄₇ H
₅₈ N ₂ O ₁₀ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.09 (1H, s), 7.
66 (1H, s), 7.62 (1H, m), 7.55 (2H, d, J = 8.7Hz), 7.55
(1H, dd, J = 2.0 and 4.2Hz), 7.30 (2H, d, J = 8.7Hz), 7.
14 (1H, dd, J = 4.2 and 4.2Hz), 5.84 (1H, ddd, J = 2.1,
2.1, and 11.5Hz), 5.78 (1H, m), 4.88 (1H, d, J = 10.4H
z), 4.73 and 4.67 (2H, d-ABq, J = 2.0 and 14.5Hz), 4.
65 (1H, s), 3.97 (1H, s), 3.56 (1H, m), 3.36 (1H, m),
3.04 (1H, dt, J = 2.3 and 9.3Hz), 1.93 (3H, d, J = 1.4H
z), 1.59 (3H, s), 1.56 (3H, s), 1.31 (3H, s), 0.98 (3
H, t, J = 7.2Hz), 0.83 (6H, d, J = 6.5Hz).

[0235]

Example 55 13- [2- (4-nicotinoylaminophenyl) -2
-Methylpropionyloxy] -5-hydroxyimino
Milbemycin A ₄ (I: R ¹ = Et, X = CO, Z == C (Me) ₂ ,
R ³ = 4-NHCOPyr (3-), n = 0) (Compound No. 75) Mass spectrum (FAB-MS) m / z: 838 (M + H ⁺ , M = C ₄₈ H
₅₉ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 9.09 (1H, s), 8.
78 (1H, d, J = 4.8Hz), 8.61 (1H, s), 8.23 (1H, d, J = 7.9
Hz), 7.91 (1H, s), 7.58 (2H, d, J = 8.6Hz), 7.46 (1H, d
d, J = 4.8 and 7.9Hz), 7.33 (2H, d, J = 8.6Hz), 4.89 (1H,
d, J = 10.6Hz), 4.73 and 4.67 (2H, d-ABq, J = 2.0 and
14.7Hz), 4.66 (1H, s), 4.02 (1H, s), 3.57 (1H, m), 3.
36 (1H, m), 3.04 (1H, dt, J = 2.2 and 9.3Hz), 1.92 (3H,
d, J = 1.5Hz), 1.59 (3H, s), 1.56 (3H, s), 1.33 (3H,
s), 0.98 (3H, t, J = 7.3Hz), 0.83 (6H, d, J = 6.6Hz).

[0236]

Example 56 13- [2- (4-isonicotinoylaminophenyl)
-2-Methylpropionyloxy] -5-hydroxyl
Minomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (M
e) ₂ , R ³ = 4-NHCOPyr (4-), n = 0) (Compound No. 76) Mass spectrum (FAB-MS) m / z: 838 (M + H ⁺ , M = C ₄₈ H
₅₉ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.81 (2H, d, J =
5.7Hz), 8.52 (1H, s), 7.88 (1H, s), 7.72 (2H, d, J = 5.
7Hz), 7.58 (2H, d, J = 8.6Hz), 7.33 (2H, d, J = 8.6Hz),
4.89 (1H, d, J = 10.5Hz), 4.73 and 4.67 (2H, d-ABq, J =
2.0 and 13.5Hz), 4.66 (1H, s), 3.99 (1H, s), 3.57 (1
H, m), 3.36 (1H, m), 3.04 (1H, dt, J = 2.2 and 9.3Hz),
1.93 (3H, s), 1.59 (3H, s), 1.57 (3H, s), 1.32 (3H,
s), 0.98 (3H, t, J = 7.3Hz), 0.83 (6H, d, J = 6.5Hz).

[0237]

Example 57 13- [1- (4-aminophenyl) cyclopentaneca
Lubonyloxy] -5-hydroxyimino mybemesis
A ₄ (I: R ¹ = Et, X = CO, Z = = C (CH ₂ ) ₄ , R ³ = 4-NH
₂ , n = 0) (Compound No. 171) Step A 15-Hydroxy-5- in dichloromethane (50 ml)
Oxomilbemycin A ₄ (1.95g, 3.50mmo
1- (4-nitrophenyl) cyclopentanecarboxylic acid (4.11 g, 17.5 mmol), cupric anhydride (2.0 g) and trifluoromethanesulfonic acid (8 drops) were added to the solution of l), The resulting mixture was stirred at room temperature for 20 minutes under a nitrogen atmosphere. The reaction mixture was filtered to remove insoluble materials, and the filtrate was poured into a mixture of 4% sodium hydrogen carbonate and ethyl acetate with stirring. The ethyl acetate layer was separated from the mixture and the aqueous layer was extracted with a small amount of ethyl acetate. The ethyl acetate solution was collected, washed with 4% sodium hydrogen carbonate, then water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was used in the next step without further purification.

Step B The crude 5-oxo derivative (obtained in Step A above) was dissolved in dioxane (20 ml) and to this solution water (10 ml), methanol (20 ml) and hydroxylamine hydrochloride (3.0 ml).
g) was added. The mixture was stirred at 55 ° C. for 1 hour, then diluted with ethyl acetate, washed twice with water and evaporated under reduced pressure. The residue was used in the next step without further purification.

Step C To a solution of the crude 5-hydroxyimino derivative (obtained in Step B) in dichloromethane (30 ml) was added imidazole (28
6 mg, 4.2 mmol), t-butyldimethylsilyl chloride (634 mg, 4.2 mmol) and 4-dimethylaminopyridine (20 mg) were added and the mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (200 ml), washed successively with 0.2M citric acid, water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate,
Evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate / hexane = 1: 9), 13-1- (4-nitrophenyl) cyclopentanecarbonyloxy] -5-t-butyldimethylsilyloxyiminomilbemycin A ₄ (2.327 g, 73.
6%) as an amorphous solid.

Step D The silyl derivative (obtained in Step C above) was treated with methanol (15
ml) and bis (triphenylphosphine)-
Nickel (II) chloride (327 mg) was added. Sodium borohydride (230 mg) was added to the resulting solution within 10 minutes with stirring and stirring was continued for another 7 minutes. The reaction mixture was poured into 1% acetic acid (200 ml) and washed with ethyl acetate (20 ml).
It was extracted with 0 ml, 50 ml). The extract was washed successively with water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography (silica gel, ethyl acetate / hexane =
3: 7), 13-1- (4-aminophenyl)
Cyclopentanecarbonyloxy] -5-t-butyldimethylsilyloxyiminomilbemycin A ₄ (1.8
34 g, 81.5%) was obtained as an amorphous solid.

Step E To a solution of 873 mg (1.0 mmol) of the amino derivative (obtained in Step D above) in methanol (20 ml) was added 1M hydrochloric acid (2.0 ml) and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate (20 ml), water,
It was washed successively with 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue
Column chromatography (silica gel, ethyl acetate /
Purified with hexane = 6: 4, the title compound (717 mg,
94.5%) as an amorphous solid.

Mass spectrum (FAB-MS) m / z: 759 (M + H
⁺ , M = C ₄₄ H ₅₈ N ₂ O ₉ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.59 (1H, wide
s), 7.11 (2H, d, J = 8.5Hz), 6.60 (2H, d, J = 8.5Hz), 4.
80 (1H, d, J = 10.5Hz), 4.65 (1H, s), 3.90 (2H, wide
s), 3.55 (1H, m), 3.36 (1H, m), 3.02 (1H, dt, J = 2.1 and 9.3Hz), 2.60 (2H, m), 1.93 (3H, s), 1.31 (3H, s ), 0.
97 (3H, t, J = 7.3Hz), 0.82 (3H, d, J = 6.4Hz), 0.77 (3H,
d, J = 6.5Hz).

[0243]

Example 58 13- [2- (4-methylaminophenyl) -2-methyi
Lepropionyloxy] -5-hydroxyiminomylvay
Mycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Me) ₂ , R ³ =
4-NHMe, n = 0) (Compound No. 174) 2- [4- (N- (4-nitrobenzyloxycarbonyl) methylaminophenyl] -2 in place of 1- (4-nitrophenyl) cyclopentanecarboxylic acid The title compound was prepared in the same manner as in Example 57 except that -methylpropionic acid was used.

Mass spectrum (FAB-MS) m / z: 747 (M + H
⁺ , M = C ₄₃ H ₅₈ N ₂ O ₉ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.13 (1H, wide
s), 7.12 (2H, d, J = 8.6Hz), 7.54 (2H, d, J = 8.6 Hz),
5.86 (1H, ddd, J = 2.1, 2.1 and 11.2Hz), 5.79 (1H, m),
5.77 (1H, dd, J = 11.2 and 14.0Hz), 4.86 (1H, d, J = 10.
4Hz), 4.74 and 4.71 (2H, d-ABq, 2.1 and 14.5Hz), 4.6
5 (1H, s), 3.97 (1H, wide s), 3.57 (1H, m), 3.36 (1H,
m), 3.04 (1H, dt, J = 2.3 and 9.4Hz), 2.82 (3H, s), 1.9
3 (3H, d, J = 1.4Hz), 1.54 (3H, s), 1.51 (3H, s), 1.32
(3H, s), 0.98 (3H, t, J = 7.2Hz), 0.83 (6H, d, J = 6.5H
z).

[0245]

Example 59 13- [1- (4-acetylaminophenyl) cyclope
Tantocarbonyloxy] -5-hydroxyiminomil
Bemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (CH ₂ ) ₄ , R
³ = 4-NHCOMe, n = 0) (Compound No. 191 ) 13- [1- (4-Aminophenyl) cyclopentanecarbonyl] -5-t-butyldimethylsilyloxyiminomilbemycin A _{4 in} dichloromethane (15 ml)
To a solution of (1.31 g, 1.50 mmol, prepared by the method described in Example 57, Step C) pyridine (0.137 m
l, 1.70 mmol) and acetic anhydride (0.161 ml, 1.
70 mmol) was added and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate (100 ml),
It was washed successively with 0.2 M citric acid, water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was dissolved in methanol (30 ml) and 1M hydrochloric acid (3.0 ml) was added to this solution. After stirring the mixture at room temperature for 20 minutes, the reaction mixture was diluted with ethyl acetate, washed successively with water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate / hexane = 6: 4) to give the title compound (717 mg, 94.5%) as an amorphous solid.

Mass spectrum (FAB-MS) m / z: 801 (M + H
⁺ , M = C ₄₆ H ₆₀ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.34 (1H, s), 7.
41 (2H, d, J = 8.5Hz), 7.28 (2H, d, J = 8.5Hz), 7.17 (1H,
s), 5.83 (1H, m), 5.78 (1H, m), 5.77 (1H, m), 4.80 (1
H, d, J = 10.5Hz), 4.74 and 4.60 (2H, d-ABq, J = 1.9 and 14.6Hz), 4.65 (1H, s), 3.97 (1H, s), 3.54 (1H, m),
3.36 (1H, m), 3.02 (1H, dt, J = 2.2 and 9.3Hz), 2.61 (2
H, m), 2.17 (3H, s), 1.93 (3H, s), 1.29 (3H, s), 0.97
(3H, t, J = 7.3Hz), 0.82 (3H, d, J = 6.5Hz), 0.76 (3H,
d, J = 6.5 Hz). Examples 60-71 Using procedures similar to Example 59, the compounds of Examples 60-71 were prepared.

[0247]

Example 60 13- [1- (4-methanesulfonylaminophenyl)
Cyclopentanecarbonyloxy] -5-hydroxyl
Minomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (C
H ₂ ) ₄ , R ³ = 4-NHSO ₂ Me, n = 0) (Compound No. 313) Mass spectrum (FAB-MS) m / z: 837 (M + H ⁺ , M = C ₄₅ H
₆₀ N ₂ O ₁₁ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.74 (1H, wide
s), 7.32 (2H, d, J = 8.6Hz), 7.14 (2H, d, J = 8.6Hz), 6.
72 (1H, wide s), 4.80 (1H, d, J = 10.6Hz), 4.73 and 4.6
0 (2H, ABq, J = 14.5Hz), 4.65 (1H, s), 3.99 (1H, s), 3.
54 (1H, m), 3.36 (1H, m), 3.01 (1H, dt, J = 2.2 and 9.3
Hz), 2.96 (3H, s), 2.61 (2H, m), 1.91 (3H, s), 1.28 (3
H, s), 0.96 (3H, t, J = 7.2Hz), 0.81 (3H, d, J = 6.3Hz),
0.74 (3H, d, J = 6.5Hz).

[0248]

Example 61 13- {1- [4- (2,2-dimethylpropionyl)
Aminophenyl] cyclopentanecarbonyloxy}-
5-hydroxyimino milbemycin A ₄ (I: R ¹ = Et,
X = CO, Z = = C (CH ₂ ) ₄ , R ³ = 4-NHCOBu (t-), n = 0)
(Compound No. 203) Mass spectrum (FAB-MS) m / z: 843 (M + H ⁺ , M = C ₄₉ H
₆₆ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.50 (1H, wide
s), 7.44 (2H, d, J = 8.7Hz), 7.20-7.30 (3H, m), 4.81 (1
H, d, J = 10.5Hz), 4.75 and 4.67 (2H, ABq, J = 14.5Hz),
4.65 (1H, s), 3.96 (1H, wide s), 3.55 (1H, m), 3.36
(1H, m), 2.59 (2H, m), 1.92 (3H, s), 1.31 (3H, s), 1.1
4 (3H, d, J = 5.9Hz), 1.02 (3H, d, J = 6.4Hz), 0.82 (3H,
d, J = 6.4Hz).

[0249]

Example 62 13- [1- (4-cyclohexanecarbonylaminoph
) Phenyl) cyclopentanecarbonyloxy] -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (CH ₂ ) ₄ , R ³ = 4-NHCO-c-Hex (cyclo-), n = 0)
(Compound No. 207) Mass spectrum (FAB-MS) m / z: 869 (M + H ⁺ , M = C ₅₁ H
₆₈ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.75 (1H, wide
s), 7.44 (2H, d, J = 8.6Hz), 7.27 (2H, d, J = 8.6Hz), 7.
17 (1H, s), 4.81 (1H, d, J = 10.6Hz), 4.74 and 4.66 (2H,
ABq, J = 15.2Hz), 4.66 (1H, s), 4.00 (1H, wide s), 3.
55 (1H, m), 3.36 (1H, m), 3.02 (1H, m), 2.59 (2H, m),
1.92 (3H, s), 1.30 (3H, s), 0.97 (3H, t, J = 7.3Hz), 0.8
2 (3H, d, J = 6.4Hz), 0.76 (3H, d, J = 6.5Hz).

[0250]

Example 63 13- [1- (4-valerylaminophenyl) cyclope
Tantocarbonyloxy] -5-hydroxyiminomil
Bemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (CH ₂ ) ₄ , R
³ = 4-NHCOn-Bu, n = 0) (Compound No. 201) Mass spectrum (FAB-MS) m / z: 843 (M + H ⁺ , M = C ₄₉ H
₆₆ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.30 (1H, wide
s), 7.43 (2H, d, J = 8.5Hz), 7.27 (2H, d, J = 8.5Hz), 7.
08 (1H, s), 4.81 (1H, d, J = 10.6Hz), 4.75 and 4.67 (2H,
ABq, J = 15.0Hz), 4.66 (1H, s), 3.95 (1H, wide s), 3.
55 (1H, m), 3.36 (1H, m), 3.02 (1H, m), 2.60 (2H, m),
1.93 (3H, s), 1.31 (3H, s), 1.00-0.90 (4H, m), 0.82 (3
H, d, J = 6.4Hz), 0.76 (3H, d, J = 6.5Hz).

[0251]

Example 64 13- [1- (4-propionylaminophenyl) sik
Lopentanecarbonyloxy] -5-hydroxyimino
Milbemycin A ₄ (I: R ¹ = Et, X = CO, Z == C (C
H ₂ ) ₄ , R ³ = 4-NHCOEt, n = 0) (Compound No. 198) Mass spectrum (FAB-MS) m / z: 815 (M + H ⁺ , M = C ₄₇ H
₆₂ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.50 (1H, wide
s), 7.43 (2H, d, J = 8.5Hz), 7.27 (2H, d, J = 8.5Hz), 7.
12 (1H, wide s), 4.81 (1H, d, J = 10.5Hz), 4.74 and 4.6
6 (2H, ABq, J = 15.2Hz), 4.65 (1H, s), 3.95 (1H, wide
s), 3.55 (1H, m), 3.36 (1H, m), 3.02 (1H, m), 2.60 (2H,
m), 1.92 (3H, s), 1.30 (3H, s), 0.97 (3H, t, J = 7.2H
z), 0.82 (3H, d, J = 6.3Hz), 0.76 (3H, d, J = 6.5Hz).

[0252]

Example 65 13- [1- (4-cyclopropanecarbonylaminophosphine
) Phenyl) cyclopentanecarbonyloxy] -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (CH ₂ ) ₄ , R ³ = 4-NHCOc-Pr (cyclo-), n = 0)
(Compound No. 204) Mass spectrum (FAB-MS) m / z: 827 (M + H ⁺ , M = C ₄₈ H
₆₂ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.11 (1H, wide
s), 7.52-7.28 (5H, m), 4.80 (1H, d, J = 10.4Hz), 4.75
And 4.68 (2H, d-ABq, J = 1.8 and 14.9Hz), 4.65 (1H,
s), 3.97 (1H, wide s), 3.55 (1H, m), 3.36 (1H, m), 3.
03 (1H, m), 2.62 (2H, m), 1.93 (3H, s), 1.29 (3H, s),
0.97 (3H, t, J = 7.2Hz), 0.82 (3H, d, J = 6.4Hz), 0.76 (3
H, d, J = 6.5Hz).

[0253]

Example 66 13- {1- [4- (cyclobutanecarbonylamino)
Phenyl] cyclopentanecarbonyloxy} -5-hi
Droxyimino milbemycin A ₄ (I: R ¹ = Et, X = C
O, Z = = C (CH ₂ ) ₄ , R ³ = 4-NHCOc-Bu (cyclo-), n = 0)
(Compound No. 205) Mass spectrum (FAB-MS) m / z: 843 (M + H ⁺ , M = C ₄₉ H
₆₄ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.13 (1H, s), 7.
44 (2H, d, J = 8.7Hz), 7.27 (2H, d, J = 8.7Hz), 6.97 (1H,
s), 4.81 (1H, d, J = 10.4Hz), 4.74 and 4.68 (2H, ABq, J
= 14.4Hz), 4.65 (1H, s), 3.97 (1H, s), 3.55 (1H, m),
3.36 (1H, m), 3.02 (1H, m), 2.58 (2H, m), 1.93 (3H,
s), 1.30 (3H, s), 0.97 (3H, t, J = 7.2Hz), 0.82 (3H, d,
J = 6.4Hz), 0.76 (3H, d, J = 6.5Hz).

[0254]

Example 67 13- [1- (4-cyanoacetylaminophenyl) si
Clopentanecarbonyloxy] -5-hydroxyimi
Nomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (C
H ₂ ) ₄ , R ³ = 4-NHCOCH ₂ CN, n = 0) (Compound No. 21
1) Mass spectrum (FAB-MS) m / z: 826 (M + H ⁺ , M = C ₄₇ H
₅₉ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.07 (1H, s), 7.
70 (1H, s), 7.42 (2H, d, J = 8.7Hz), 7.33 (2H, d, J = 8.7H
z), 4.81 (1H, d, J = 10.4Hz), 4.74 and 4.68 (2H, ABq, J =
14.4Hz), 4.65 (1H, s), 3.97 (1H, s), 3.55 (2H, s), 3.
54 (1H, m), 3.36 (1H, m), 3.02 (1H, m), 2.61 (2H, m),
1.93 (3H, d, J = 1.6Hz), 1.30 (3H, s), 0.97 (3H, t, J =
7.2Hz), 0.82 (3H, d, J = 6.5Hz), 0.76 (3H, d, J = 6.5H
z).

[0255]

Example 68 13- [1- (4-butyrylaminophenyl) cyclope
Tantocarbonyloxy] -5-hydroxyiminomil
Bemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (CH ₂ ) ₄ , R
³ = 4-NHCOn-Pr, n = 0) (Compound No. 199) Mass spectrum (FAB-MS) m / z: 829 (M + H ⁺ , M = C ₄₈ H
₆₄ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.12 (1H, s), 7.
43 (2H, d, J = 8.6Hz), 7.28 (2H, d, J = 8.6Hz), 7.09 (1H,
s), 4.81 (1H, d, J = 10.4Hz), 4.74 and 4.67 (2H, d-ABq,
J = 2.0 and 14.4Hz), 4.65 (1H, s), 3.97 (1H, s), 3.54
(1H, m), 3.36 (1H, m), 3.02 (1H, m), 2.61 (2H, m), 1.
93 (3H, d, J = 1.6Hz), 1.30 (3H, s), 1.03-0.95 (6H,
m), 0.82 (3H, d, J = 6.4Hz), 0.76 (3H, d, J = 6.4Hz).

[0256]

Example 69 13- [1- (4-isobutyrylaminophenyl) siku
Lopentanecarbonyloxy] -5-hydroxyimino
Milbemycin A ₄ (I: R ¹ = Et, X = CO, Z == C (C
H ₂ ) ₄ , R ³ = 4-NHCOiPr, n = 0) (Compound No. 200) Mass spectrum (FAB-MS) m / z: 829 (M + H ⁺ , M = C ₄₈ H
₆₄ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.11 (1H, s), 7.
44 (2H, d, J = 8.6Hz), 7.28 (2H, d, J = 8.6Hz), 7.10 (1H,
s), 4.81 (1H, d, J = 10.4Hz), 4.75 and 4.68 (2H, d-ABq,
J = 2.0 and 14.4Hz), 4.65 (1H, s), 3.97 (1H, s), 3.54
(1H, m), 3.36 (1H, m), 3.02 (1H, m), 2.60 (2H, m), 1.
93 (3H, d, J = 1.6Hz), 1.30 (3H, s), 1.26 (6H, d, J = 6.8
Hz), 0.97 (3H, t, J = 7.2Hz), 0.82 (3H, d, J = 6.4Hz),
0.77 (3H, d, J = 6.4Hz).

[0257]

Example 70 13- [1- (4-isovalerylaminophenyl) sik
Lopentanecarbonyloxy] -5-hydroxyimino
Milbemycin A ₄ (I: R ¹ = Et, X = CO, Z == C (C
H ₂ ) ₄ , R ³ = 4-NHCOiBu, n = 0) (Compound No. 202) Mass spectrum (FAB-MS) m / z: 843 (M + H ⁺ , M = C ₄₉ H
₆₆ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.14 (1H, wide
s), 7.43 (2H, d, J = 8.6Hz), 7.28 (2H, d, J = 8.6 Hz),
7.07 (1H, s), 4.81 (1H, d, J = 10.4Hz), 4.74 and 4.68
(2H, d-ABq, J = 1.8 and 14.2Hz), 4.65 (1H, s), 3.97 (1
H, s), 3.54 (1H, m), 3.36 (1H, m), 3.02 (1H, m), 2.60
(2H, m), 1.93 (3H, d, J = 1.4Hz), 1.30 (3H, s), 1.02 (6
H, d, J = 7.2Hz), 0.97 (3H, t, J = 7.2Hz), 0.82 (3H, d,
J = 6.4Hz), 0.76 (3H, d, J = 6.4Hz).

[0258]

Example 71 13- {1- [4- (cyclopentanecarbonylamido
No) phenyl] cyclopentanecarbonyloxy} -5
-Hydroxyiminomilbemycin A ₄ (I: R ¹ = Et, X
= CO, Z = = C (CH ₂ ) ₄ , R ³ = 4-NHCOc-Pen, n = 0)
Compound number 206) Mass spectrum (FAB-MS) m / z: 855 (M + H ⁺ , M = C ₅₀ H
₆₆ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.16 (1H, wide
s), 7.44 (2H, d, J = 8.4Hz), 7.27 (2H, d, J = 8.4Hz), 7.
12 (1H, s), 4.81 (1H, d, J = 10.8Hz), 4.74 and 4.68 (2H,
d-ABq, J = 1.8 and 14.2Hz), 4.65 (1H, s), 3.97 (1H,
s), 3.54 (1H, m), 3.36 (1H, m), 3.03 (1H, m), 2.66 (1H,
m), 2.61 (2H, m), 1.93 (3H, d, J = 1.4Hz), 1.30 (3H,
s), 0.97 (3H, t, J = 7.3Hz), 0.82 (3H, d, J = 6.4Hz), 0.
76 (3H, d, J = 6.4Hz).

[0259]

Example 72 13- {2- [4- (N-methyl-methanesulphonyl)
Mino) phenyl] -2-methylpropionyloxy}-
5-hydroxyimino milbemycin A ₄ (I: R ¹ = Et,
X = CO, Z = = C (Me) ₂ , R ³ = 4-N (Me) SO ₂ Me, n = 0)
(Compound No. 151) Mass spectrum (FAB-MS) m / z: 825 (M + H ⁺ , M = C ₄₄ H
₆₀ N ₂ O ₁₁ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.05 (1H, s), 7.
31 (4H, s), 4.87 (1H, d, J = 10.7Hz), 4.73 and 4.67 (2H,
d-ABq, J = 2.0 and 14.3Hz), 4.65 (1H, s), 3.96 (1H,
s), 3.57 (1H, m), 3.36 (1H, m), 3.30 (3H, s), 3.03 (1
H, dd, J = 2.3 and 9.3Hz), 2.81 (3H, s), 1.93 (3H, s),
1.59 (3H.s), 1.56 (3H, s), 1.29 (3H, s), 0.98 (3H, t,
J = 7.3Hz), 0.83 (3H, d, J = 6.6Hz), 0.81 (3H, d, J = 6.6
Hz).

[0260]

Example 73 13- {2- [4- (N-methyl-methoxycarbonyl
Amino) phenyl] -2-methylpropionyloxy}
-5-hydroxyimino milbemycin A ₄ (I: R ¹ = E
t, X = CO, Z = = C (Me) ₂ , R ³ = 4-N (Me) COOMe, n = 0)
(Compound number 123) Mass spectrum (FAB-MS) m / z: 805 (M + H ⁺ , M = C ₄₅ H
₆₀ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.10 (1H, s), 7.
27 (2H, d, J = 8.5Hz), 7.16 (2H, d, J = 8.5Hz), 4.87 (1H,
d, J = 10.6Hz), 4.73 and 4.67 (2H, d-ABq, J = 2.0 and
14.5Hz), 4.65 (1H, s), 3.97 (1H, s), 3.71 (3H, s), 3.
57 (1H, m), 3.36 (1H, m), 3.27 (3H, s), 3.03 (1H, dd,
J = 2.2 and 9.3Hz), 1.93 (3H, s), 1.59 (3H.s), 1.56 (3
H, s), 1.29 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.83 (3H,
d, J = 6.5 Hz), 0.81 (3H, d, J = 6.5 Hz). Examples 74 to 83 Using the same procedure as in Example 18, 13- [1- (4-
Nitrophenyl) cyclobutanecarbonyloxy] -5
- were prepared compounds of Examples 74 to 83 from the hydroxyimino milbemycin A ₄ (prepared by the method described in Example 7).

[0261]

Example 74 13- [1- (4-acetylaminophenyl) cyclobute
Tancarbonyloxy] -5-hydroxyiminomylv
Mycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (CH ₂ ) ₃ , R ³
= 4-NHCOMe, n = 0) (Compound No. 457) Mass spectrum (FAB-MS) m / z: 787 (M + H ⁺ , M = C ₄₅ H
₅₈ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.34 (1H, s), 7.
41 (2H, d, J = 8.5Hz), 7.28 (2H, d, J = 8.5Hz), 7.17 (1H,
s), 5.83 (1H, m), 5.78 (1H, m), 5.77 (1H, m), 4.80 (1
H, d, J = 10.5Hz), 4.74 and 4.60 (2H, d-ABq, J = 1.9 and 14.6Hz), 4.65 (1H, s), 3.97 (1H, s), 3.54 (1H, m),
3.36 (1H, m), 3.02 (1H, dt, J = 2.2 and 9.3Hz), 2.61 (2
H, m), 2.17 (3H, s), 1.93 (3H, s), 1.29 (3H, s), 0.97
(3H, t, J = 7.3Hz), 0.82 (3H, d, J = 6.5Hz), 0.76 (3H,
d, J = 6.5Hz).

[0262]

Example 75 13- [1- (4-methoxycarbonylaminophenenyl
) Cyclobutanecarbonyloxy] -5-hydroxy
Iminomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C
(CH ₂ ) ₃ , R ³ = 4-NHCOOMe, n = 0) (Compound No. 49
1) Mass spectrum (FAB-MS) m / z: 803 (M + H ⁺ , M = C ₄₅ H
₅₈ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.82 (1H, wide
s), 7.32 (2H, d, J = 8.6Hz), 7.21 (2H, d, J = 8.6Hz), 6.
57 (1H, wide s), 4.84 (1H, d, J = 10.6Hz), 4.72 and 4.7
0 (2H, ABq, J = 14.5Hz), 4.65 (1H, s), 3.95 (1H, s), 3.
78 (3H, s), 3.54 (1H, m), 3.36 (1H, m), 3.03 (1H, dt,
J = 2.3 and 9.2Hz), 2.86-2.70 (2H, m), 2.52-2.41 (3H,
m), 1.93 (3H, s), 1.34 (3H, s), 0.98 (3H, t, J = 7.3H
z), 0.82 (3H, d, J = 6.6Hz), 0.76 (3H, d, J = 6.6Hz).

[0263]

Example 76 13- [1- (4-methanesulfonylaminophenyl)
Cyclobutanecarbonyloxy] -5-hydroxyimi
Nomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (C
H ₂ ) ₃ , R ³ = 4-NHSO ₂ Me, n = 0) (Compound No. 503) Mass spectrum (FAB-MS) m / z: 823 (M + H ⁺ , M = C ₄₄ H
₅₈ N ₂ O ₁₁ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.85 (1H, wide
s), 7.27 (2H, d, J = 8.6Hz), 7.17 (2H, d, J = 8.6Hz), 6.
35 (1H, wide s), 4.85 (1H, d, J = 10.6Hz), 4.73 and 4.70 (2H, ABq, J = 14.5Hz),
4.66 (1H, s), 3.96 (1H, s),
3.54 (1H, m), 3.36 (1H, m
m), 3.03 (1H, m), 2.98 (3H,
s), 2.88-2.73 (2H, m), 2.
53-2.42 (3H, m), 1.93 (3H,
s), 1.34 (3H, s), 0.97 (3H, s)
t, J = 7.3 Hz), 0.82 (3H, d,
J = 6.4 Hz), 0.76 (3H, d, J =
6.6 Hz).

[0264]

Example 77 13- {1- [4- (4-nitrobenzoylamino) phenyl
[Ethyl] cyclobutanecarbonyloxy} -5-hydro
Xiiminomilbemycin A ₄ (I: R ¹ =
Et, X = CO, Z == C (CH ₂ ) ₃ ,
_{^{R 3 = 4-NHCOPh (4}} -NO 2), n =
0) (Compound No. 478) Mass spectrum (FAB-MS) m / z: 894 (M + H ⁺ , M = C ₅₀ H
₅₉ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.60 (1H, wide
s), 8.35 (2H, d, J = 8.8Hz), 8.05 (2H, d, J = 8.4Hz), 7.8
5 (1H, s), 7.59 (2H, d, J = 8.4Hz), 7.31 (2H, d, J = 8.8H
z), 4.87 (1H, d, J = 10.4Hz), 4.74 and 4.68 (2H, d-AB
q, J = 1.6 and 14.4Hz), 4.65 (1H, s), 3.96 (1H, s), 3.
54 (1H, m), 3.36 (1H, m), 3.03 (1H, m), 2.88-2.75 (2H,
m), 1.93 (3H, s), 1.36 (3H, s), 0.98 (3H, t, J = 7.3H
z), 0.82 (3H, d, J = 6.4Hz), 0.79 (3H, d, J = 6.4Hz).

[0265]

Example 78 13- {1- [4- (4-t-butylbenzoylamido)
No) phenyl] cyclobutanecarbonyloxy} -5-
Hydroxyimino milbemycin A ₄ (I: R ¹ = Et, X =
CO, Z = = C (CH ₂ ) ₃ , R ³ = 4-NHCO (4-t-BuPh), n = 0)
(Compound No. 479) Mass spectrum (FAB-MS) m / z: 905 (M + H ⁺ , M = C ₅₄ H
₆₈ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.02 (1H, wide
s), 7.81 (2H, d, J = 8.4Hz), 7.77 (1H, s), 7.59 (2H,
d, J = 8.4Hz), 7.50 (2H, d, J = 8.4 Hz), 7.29 (1H, s), 4.
86 (1H, d, J = 10.4Hz), 4.75 and 4.68 (2H, ABq, J = 14.7
Hz), 4.66 (1H, s), 3.95 (1H, s), 3.55 (1H, m), 3.36 (1
H, m), 3.03 (1H, m), 2.87-2.74 (2H, m), 1.93 (3H, s),
1.36 (12H, m), 0.98 (3H, t, J = 7.4Hz), 0.82 (3H, d, J =
6.4Hz), 0.78 (3H, d, J = 6.8Hz).

[0266]

Example 79 13- {1- [4- (4-methoxybenzoylamino)
Phenyl] cyclobutanecarbonyloxy} -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (CH ₂ ) ₃ , R ³ = 4-NHCO (4-MeOPh), n = 0) (Compound
No. 476) Mass spectrum (FAB-MS) m / z: 867 (M + H ⁺ , M = C ₅₀ H
₆₂ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.23 (1H, wide
s), 7.85 (2H, d, J = 8.8Hz), 7.73 (1H, s), 7.58 (2H, d,
J = 8.6Hz), 7.28 (1H, s), 6.98 (2H, d, J = 8.8Hz), 4.86
(1H, d, J = 10.4Hz), 4.75 and 4.68 (2H, d-ABq, J = 1.8
And 14.6Hz), 4.66 (1H, s), 3.95 (1H, s), 3.88 (3H,
s), 3.54 (1H, m), 3.36 (1H, m), 3.03 (1H, m), 2.87-2.
74 (2H, m), 1.93 (3H, s), 1.36 (3H, m), 0.98 (3H, t, J
= 7.4Hz), 0.82 (3H, d, J = 6.6Hz), 0.78 (3H, d, J = 6.4H
z).

[0267]

Example 80 13- {1- [4- (4-chlorobenzoylamino) phenyl
[Ethyl] cyclobutanecarbonyloxy} -5-hydro
Xiiminomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z
= = C (CH ₂ ) ₃ , R ³ = 4-NHCO (4-ClPh), n = 0) (Compound number
No. 477) Mass spectrum (FAB-MS) m / z: 883 (M + H ⁺ , M = C ₅₀ H
₅₉ ClN ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.04 (1H, wide
s), 7.82 (2H, d, J = 8.8Hz), 7.76 (1H, s), 7.57 (2H, d,
J = 8.4Hz), 7.47 (2H, d, J = 8.4Hz), 7.28 (2H, d, J = 8.8H
z), 4.86 (1H, d, J = 10.4Hz), 4.75 and 4.68 (2H, d-ABq,
J = 1.8 and 14.6Hz), 4.66 (1H, s), 3.96 (1H, s), 3.54
(1H, m), 3.36 (1H, m), 3.03 (1H, m), 2.87-2.74 (2H,
m), 1.93 (3H, s), 1.36 (3H, s), 0.98 (3H, t, J = 7.2H
z), 0.82 (3H, d, J = 6.4Hz), 0.78 (3H, d, J = 6.4Hz).

[0268]

Example 81 13- [1- (4-valerylaminophenyl) cyclobu
Tancarbonyloxy] -5-hydroxyiminomylv
Mycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (CH ₂ ) ₃ , R ³
= 4-NHCOBu, n = 0) (Compound No. 461) Mass spectrum (FAB-MS) m / z: 829 (M + H ⁺ , M = C ₄₈ H
₆₄ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.48 (1H, wide
s), 7.46 (2H, d, J = 8.6Hz), 7.22 (2H, d, J = 8.6Hz), 7.
11 (1H, s), 4.85 (1H, d, J = 10.4Hz), 4.75 and 4.68 (2H,
d-ABq, J = 1.6 and 14.4Hz), 4.66 (1H, s), 3.96 (1H,
s), 3.54 (1H, m), 3.36 (1H, m), 3.03 (1H, m), 2.84-2.7
2 (2H, m), 1.93 (3H, s), 1.34 (3H, s), 0.99-0.93 (6H,
m), 0.82 (3H, d, J = 6.4Hz), 0.77 (3H, d, J = 6.4Hz).

[0269]

Example 82 13- {1- [4- (2,2-dimethylpropionylurea
Mino) phenyl] cyclobutanecarbonyloxy} -5
-Hydroxyiminomilbemycin A ₄ (I: R ¹ = Et, X
= CO, Z = = C (CH ₂ ) ₃ , R ³ = 4-NHCOt-Bu, n = 0) (Compound
No. 462) Mass spectrum (FAB-MS) m / z: 829 (M + H ⁺ , M = C ₄₈ H
₆₄ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.09 (1H, wide
s), 7.47 (2H, d, J = 8.8Hz), 7.29 (1H, s), 7.23 (2H,
d, J = 8.8Hz), 4.85 (1H, d, J = 10.8Hz), 4.75 and 4.68 (2
H, d-ABq, J = 1.8 and 14.2Hz), 4.66 (1H, s), 3.95 (1H,
s), 3.54 (1H, m), 3.36 (1H, m), 3.03 (1H, m), 2.85-
2.72 (2H, m), 1.93 (3H, s), 1.34 (3H, s), 1.32 (9H, s),
0.98 (3H, t, J = 7.4Hz), 0.82 (3H, d, J = 6.8Hz), 0.78
(3H, d, J = 6.4Hz).

[0270]

Example 83 13- {1- [4- (cyclohexanecarbonylamido
No) phenyl] cyclobutanecarbonyloxy} -5-
Hydroxyimino milbemycin A ₄ (I: R ¹ = Et, X =
CO, Z = = C (CH ₂ ) ₃ , R ³ = 4-NHCOc-Hex, n = 0) (Compound
No. 464) Mass spectrum (FAB-MS) m / z: 855 (M + H ⁺ , M = C ₅₀ H
₆₆ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.20 (1H, wide
s), 7.47 (2H, d, J = 8.6Hz), 7.22 (2H, d, J = 8.6Hz), 7.
12 (1H, s), 4.85 (1H, d, J = 10.4Hz), 4.75 and 4.68 (2H,
d-ABq, J = 1.8 and 14.2Hz), 4.66 (1H, s), 3.95 (1H,
s), 3.54 (1H, m), 3.36 (1H, m), 3.05 (1H, m), 2.85-2.7
1 (2H, m), 1.93 (3H, s), 1.34 (3H, s), 0.97 (3H, t, J
= 7.2Hz), 0.82 (3H, d, J = 6.4Hz), 0.77 (3H, d, J = 6.4H
z).

[0271]

Example 84 13- [1- (4-aminophenyl) -1-ethylbuty
Ryloxy] -5-hydroxyiminomilbemycin A
₄ (I: R ¹ = Et, X = CO, Z = = C (Et) ₂ , R ³ = 4-NH ₂ , n
= 0) (Compound No. 332) Step A 15-Hydroxy-5-oxomilbemycin is treated with 1- (4-nitrophenyl) -1-ethylbutyric acid under the conditions described in Example 57, Step A to give Example 57
In the same manner as in (Steps B, C and D), 13-
[1- (4-Aminophenyl) -1-ethylbutyryloxy] -5-t-butyldimethylsilyloxyiminomilbemycin A ₄ (46.9%) was obtained as an amorphous solid.

Step B Using a procedure similar to Example 57, Step E, the title compound was prepared from the amino derivative (obtained in Step A).

Mass spectrum (FAB-MS) m / z: 761 (M + H
⁺ , M = C ₄₄ H ₆₀ N ₂ O ₉ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.84 (1H, s), 6.
99 (2H, d, J = 8.6Hz), 6.61 (2H, d, J = 8.6Hz), 4.88 (1H,
d, J = 10.7Hz), 4.73 and 4.67 (2H, d-ABq, J = 2.2 and
14.4Hz), 4.65 (1H, s), 3.99 (1H, s), 3.65-3.50 (3H,
m), 3.36 (1H, m), 3.04 (1H, dd, J = 2.2 and 9.4Hz), 1.93
(3H, d, J = 1.8Hz), 1.27 (3H, s), 0.98 (3H, t, J = 7.3H
z), 0.83 (3H, d, J = 6.1Hz), 0.82 (3H, d, J = 6.4Hz), 0.
72 (3H, t, J = 7.4Hz), 0.67 (3H, t, J = 7.4Hz).

[0274]

Example 85 13- [1- (4-acetylaminophenyl) -1-e
Cylbutyryloxy] -5-hydroxyiminomilbema
Ishin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Et) ₂ , R ³ = 4
-NHCOMe, n = 0) (Compound No. 336) 13-1- (4-aminophenyl) -1-ethylbutyryloxy] -5-t- in dichloromethane (2.0 ml).
Butyldimethylsilyloxyiminomilbemycin A ₄
To a solution of (172 mg, 0.20 mmol, prepared as described in Example 84, Step A) was added pyridine (0.01
8 ml, 0.22 mmol) and acetic anhydride (0.021 ml,
0.22 mmol) was added and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate (20 ml),
It was washed successively with 0.2 M citric acid, water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was dissolved in methanol (4.0 ml) and 1M hydrochloric acid (0.4 ml) was added. After stirring the mixture at room temperature for 20 minutes, the reaction mixture was diluted with ethyl acetate (2
0 ml), washed successively with water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate / hexane = 6: 4) to give the title compound (149 mg, 92.7%) as an amorphous solid.

Mass spectrum (FAB-MS) m / z: 803 (M + H
⁺ , M = C ₄₆ H ₆₂ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.30 (1H, s), 7.
42 (2H, d, J = 8.6Hz), 7.17 (2H, d, J = 8.6Hz), 7.15 (1H,
Wide s), 4.89 (1H, d, J = 10.6Hz), 4.73 and 4.65 (2H,
ABq, J = 14.3Hz), 4.65 (1H, s), 3.99 (1H, s), 3.58 (1
H, m), 3.37 (1H, m), 3.03 (1H, m), 2.17 (3H, s), 1.93
(3H, s), 1.25 (3H, s), 0.98 (3H, t, J = 7.1Hz), 0.84-
0.79 (6H, m), 0.72-0.65 (6H, m). Using a procedure similar to Example 85, the compounds of Examples 86-89 were prepared.

[0276]

Example 86 13- [1- (4-methanesulfonylaminophenyl)
-1-Ethylbutyryloxy] -5-hydroxyimino
Milbemycin A ₄ (I: R ¹ = Et, X = CO, Z == = C (Et)
₂ , R ³ = 4-NHSO ₂ Me, n = 0) (Compound No. 380) Mass spectrum (FAB-MS) m / z: 839 (M + H ⁺ , M = C ₄₅ H ₆₂
N ₂ O ₁₁ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.15 (1H, s), 7.
23 (2H, d, J = 8.6Hz), 7.14 (2H, d, J = 8.6Hz), 6.43 (1
H, s), 4.89 (1H, d, J = 10.6Hz), 4.73 and 4.65
(2H, ABq, J = 15.4Hz), 4.65
(1H, s), 4.00 (1H, s), 3.5
7 (1H, m), 3.36 (1H, m), 3.
04 (1H, m), 2.98 (3H, s),
1.93 (3H, s), 1.27 (3H, s),
0.98 (3H, t, J = 7.3Hz), 0.8
3 (3H, d, J = 6.6Hz), 0.79 (3
H, d, J = 6.0 Hz), 0.75-0.66
(6H, m).

[0277]

Example 87 13- {1- [4- (4-chlorobenzoylamino) phenyl
[Ethyl] -1-ethylbutyryloxy} -5-hydroxy
Siimino milbemycin A ₄ (I: R ¹ = E
t, X = CO, Z == C (Et) ₂ , R ³
= 4-NHCOPh (4-Cl), n = 0)
(Compound No. 356) Mass spectrum (FAB-MS) m / z: 899 (M + H ⁺ , M = C ₅₁ H ₆₄
ClN ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.65 (1H, s), 7.
82 (2H, d, J = 8.5Hz), 7.73 (1H, s), 7.56 (2H, d, J = 8.6
Hz), 7.48 (2H, d, J = 8.5Hz), 7.24 (2H, d, J = 8.7Hz),
4.91 (1H, d, J = 10.5Hz), 4.74 and 4.66 (2H, ABq, J = 1
4.4Hz), 4.65 (1H, s), 4.00 (1H, s), 3.58 (1H, m), 3.35
(1H, m), 3.05 (1H, m), 1.93 (3H, s), 1.28 (3H, s), 0.
99 (3H, t, J = 7.3Hz), 0.81-0.84 (6H, m), 0.76-0.66 (6
H, m).

[0278]

Example 88 13- [1- (4-valerylaminophenyl) -1-e
Cylbutyryloxy] -5-hydroxyiminomilbema
Ishin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Et) ₂ , R ³ = 4
-NHCOBu, n = 0) (Compound No. 342) Mass spectrum (FAB-MS) m / z: 845 (M + H ⁺ , M = C ₄₉ H ₆₈
N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.34 (1H, wide
s), 7.43 (2H, d, J = 8.6Hz), 7.17 (2H, d, J = 8.6Hz), 7.
09 (1H, s), 4.90 (1H, d, J = 10.8Hz), 4.73 and 4.65 (2H,
d-ABq, J = 2.2 and 14.6Hz), 4.65 (1H, s), 3.99 (1H,
s), 3.57 (1H, m), 3.36 (1H, m), 3.04 (1H, m), 2.20 (1H,
dd, J = 11.6 and 24.0Hz), 1.93 (3H, s), 1.26 (3H, s),
1.00-0.88 (6H, m), 0.86-0.77 (6H, m), 0.73-0.66 (6H,
m).

[0279]

Example 89 13- {1- [4- (cyclohexanecarbonylamido
No) phenyl] -1-ethylbutyryloxy} -5-hi
Droxyimino milbemycin A ₄ (I: R ¹ = Et, X = C
O, Z = = C (Et) ₂ , R ³ = 4-NHCOcHex, n = 0) (Compound number
No. 345) mass spectrum (FAB-MS) m / z: 871 (M + H ⁺ , M = C ₅₁ H ₇₀
N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.05 (1H, wide
s), 7.45 (2H, d, J = 8.6Hz), 7.16 (2H, d, J = 8.6Hz), 7.
11 (1H, s), 4.90 (1H, d, J = 10.8Hz), 4.73 and 4.65 (2H,
d-ABq, J = 2.0 and 14.4Hz), 4.65 (1H, s), 3.99 (1H,
s), 3.57 (1H, m), 3.36 (1H, m), 3.04 (1H, m), 1.93 (3H,
s), 1.27 (3H, s), 0.98 (3H, t, J = 7.2Hz), 0.84-0.80
(6H, m), 0.73-0.67 (6H, m). Examples 90-97 Using the same procedure as in Example 18, 13- [1- (4-
Nitrophenyl) cyclopropanecarbonyloxy]-
The compounds of Examples 90-97 were prepared from 5-hydroxyimino milbemycin A ₄ (prepared as described in Example 6).

[0280]

Example 90 13- [1- (4-methanesulfonylaminophenyl)
Cyclopropanecarbonyloxy] -5-hydroxyl
Minomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (C
H ₂ ) ₂ , R ³ = 4-NHSO ₂ Me, n = 0) (Compound No. 441) Mass spectrum (FAB-MS) m / z: 809 (M + H ⁺ , M = C ₄₃ H
₅₆ N ₂ O ₁₁ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.13 (1H, s), 7.
32 (2H, d, J = 8.5Hz), 7.15 (2H, d, J = 8.5Hz), 6.50 (1H,
s), 4.88 (1H, d, J = 10.4Hz), 4.73 and 4.70 (2H, d-ABq,
J = 2.0 and 14.5Hz), 4.65 (1H, s), 3.93 (1H, s), 3.55
(1H, m), 3.36 (1H, m), 3.03 (1H, m), 3.01 (3H, s), 1.
93 (3H, d, J = 1.4Hz), 1.38 (3H, s), 1.17 (2H. M), 0.97
(3H, t, J = 7.3Hz), 0.92 (3H, d, J = 6.5Hz), 0.82 (3H,
d, J = 6.5Hz).

[0281]

Example 91 13- [1- (4-methoxycarbonylaminophenenyl
) Cyclopropanecarbonyloxy] -5-hydroxy
Shiminomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z =
= C (CH ₂ ) ₂ , R ³ = 4-NHCOOMe, n = 0) (Compound No. 42
9) Mass spectrum (FAB-MS) m / z: 789 (M + H ⁺ , M = C ₄₄ H
₅₆ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.11 (1H, s), 7.
31 (2H, d, J = 8.4Hz), 7.26 (2H, d, J = 8.4Hz), 6.61 (1H,
s), 4.86 (1H, d, J = 10.4Hz), 4.73 and 4.65 (2H, d-ABq,
J = 2.1 and 14.5Hz), 4.65 (1H, s), 3.92 (1H, s), 3.78
(3H, s), 3.55 (1H, m), 3.36 (1H, m), 3.03 (1H, dt, J =
2.2 and 9.3Hz), 1.93 (3H, s), 1.37 (3H, s), 1.15 (2H.
m), 0.97 (3H, t, J = 7.3Hz), 0.91 (3H, d, J = 6.5Hz), 0.
82 (3H, d, J = 6.5Hz).

[0282]

Example 92 13- [1- (4-bromoacetylaminophenyl) si
Clopropanecarbonyloxy] -5-hydroxyimi
Nomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (C
H ₂ ) ₂ , R ³ = 4-NHCOCH ₂ Br, n = 0) (Compound No. 40
2) Mass spectrum (FAB-MS) m / z: 851 (M + H ⁺ , M = C ₄₄ H
₅₅ BrN ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.14 (1H, s), 8.
13 (1H, s), 7.47 (2H, d, J = 8.4Hz), 7.32 (2H, d, J = 8.4H
z), 4.87 (1H, d, J = 10.5Hz), 4.73 and 4.66 (2H, d-ABq,
J = 2.0 and 15.3Hz), 4.65 (1H, s), 4.04 (2H, s), 3.93
(1H, s), 3.55 (1H, m), 3.36 (1H, m), 3.03 (1H, dt, J =
2.2 and 9.4Hz), 1.93 (3H, dd, J = 1.5 and 1.5Hz), 1.37
(3H, s), 1.15 (2H. M), 0.97 (3H, t, J = 7.3Hz), 0.91 (3
H, d, J = 6.5Hz), 0.83 (3H, d, J = 6.5Hz).

[0283]

Example 93 13- [1- (4-isobutyloxycarbonylamino)
(Phenyl) cyclopropanecarbonyloxy] -5-hi
Droxyimino milbemycin A ₄ (I: R ¹ = Et, X = C
O, Z = = C (CH ₂ ) ₂ , R ³ = 4-NHCOOiBu, n = 0) (Compound number
No. 431) Mass spectrum (FAB-MS) m / z: 831 (M + H ⁺ , M = C ₄₇ H
₆₂ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.01 (1H, s), 7.
32 (2H, d, J = 8.6Hz), 7.26 (2H, d, J = 8.6Hz), 6.60 (1H,
s), 4.86 (1H, d, J = 10.5Hz), 4.73 and 4.67 (2H, d-ABq,
J = 2.0 and 14.6Hz), 4.65 (1H, s), 3.96 (2H, d, J = 6.7
Hz), 3.92 (1H, s), 3.55 (1H, m), 3.36 (1H, m), 3.03 (1
H, dt, J = 2.2 and 9.4 Hz), 1.93 (3H,
s), 1.37 (3H, s), 1.15 (2H.s).
m), 0.97 (6H, d, J = 6.9H
z), 0.97 (3H, t, J = 7.2 Hz),
0.91 (3H, d, J = 6.5Hz), 0.
83 (3H, d, J = 6.5 Hz).

[0284]

Example 94 13- [1- (4-cyanoacetylaminophenyl) si
Clopropanecarbonyloxy] -5-hydroxyimi
Nomilbemycin A ₄ (I: R ¹ = Et,
_{X = CO, Z = = C} (CH 2) 2, R 3 =
4-NHCOCH ₂ CN, n = 0) (Compound
No. 401) Mass spectrum (FAB-MS) m / z: 798 (M + H ⁺ , M = C ₄₅ H
₅₅ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.24 (1H, s), 7.
80 (1H, s), 7.42 (2H, d, J = 8.6Hz), 7.32 (2H, d, J = 8.6H
z), 4.88 (1H, d, J = 10.5Hz), 4.73 and 4.67 (2H, d-ABq,
J = 1.9 and 14.6Hz), 4.65 (1H, s), 3.94 (1H, s), 3.55
(1H, m), 3.54 (2H, s), 3.36 (1H, m), 3.03 (1H, dt, J =
2.1 and 9.5Hz), 1.93 (3H, d, J = 1.5Hz), 1.38 (3H, s),
1.18 (2H.m), 0.97 (3H, t, J = 7.3Hz), 0.92 (3H, d, J =
6.6Hz), 0.83 (3H, d, J = 6.5Hz).

[0285]

Example 95 13- {1- [4- (4-nitrobenzoylamino) phenyl
[Ethyl] cyclopropanecarbonyloxy} -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (CH ₂ ) ₂ , R ³ = 4-NHCOPh (4-NO ₂ ), n = 0) (Compound
No. 416) Mass spectrum (FAB-MS) m / z: 880 (M + H ⁺ , M = C ₄₉ H
₅₈ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ³ ) δppm: 8.35 (2H, d, J =
8.8Hz), 8.07 (1H, s), 8.05 (2H, d, J = 8.8Hz), 7.88 (1
H, s), 7.58 (2H, d, J = 8.4Hz), 7.37 (2H, d, J = 8.4Hz),
4.90 (1H, d, J = 10.4Hz), 4.73 and 4.66 (2H, d-ABq, J =
1.9 and 14.4Hz), 4.64 (1H, s), 3.94 (1H, s), 3.55 (1
H, m), 3.54 (2H, s), 3.36 (1H, m), 3.03 (1H, m), 1.93
(3H, s), 1.39 (3H, s), 1.18 (2H. M), 0.97 (3H, t, J =
7.2Hz), 0.93 (3H, d, J = 6.4Hz), 0.83 (3H, d, J = 6.4H
z).

[0286]

Example 96 13- {1- [4- (4-t-butylbenzoylamido
No) phenyl] cyclopropanecarbonyloxy} -5
-Hydroxyiminomilbemycin A ₄ (I: R ¹ = Et, X
= CO, Z = = C (CH ₂ ) ₂ , R ³ = 4-NHCOPh (4-t-Bu), n = 0)
(Compound No. 417 ) Mass spectrum (FAB-MS) m / z: 913 (M + Na ⁺ , M = C ₅₃ H
₆₇ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.08 (1H, wide
s), 7.81 (2H, d, J = 8.8Hz), 7.79 (1H, s), 7.58 (2H,
d, J = 8.4Hz), 7.51 (2H, d, J = 8.8Hz), 7.33 (2H, d, J =
8.4Hz), 4.88 (1H, d, J = 10.4Hz), 4.73 and 4.66 (2H, d
-ABq, J = 1.9 and 14.6Hz), 4.65 (1H, s), 3.92 (1H,
s), 3.55 (1H, m), 3.36 (1H, m), 3.03 (1H, m), 1.93 (3H,
s), 1.38 (3H, s), 1.18 (2H. m), 0.97 (3H, t, J = 7.2H
z), 0.92 (3H, d, J = 6.4Hz), 0.83 (3H, d, J = 6.4Hz).

[0287]

Example 97 13- {1- [4- (3,4-dimethoxybenzoylurea
Mino) phenyl] cyclopropanecarbonyloxy}-
5-hydroxyimino milbemycin A ₄ (I: R ¹ = Et,
X = CO, Z = = C (CH ₂ ) ₂ , R ³ = 4-NHCOPh (3,4-di-MeO),
(n = 0) (Compound No. 415) Mass spectrum (FAB-MS) m / z: 895 (M + H ⁺ , M = C ₅₁ H
₆₂ N ₂ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.76 (1H, d, J =
7.5Hz), 7.59 (1H, s), 7.11 (2H, d, J = 7.9Hz), 6.91 (1
H, d, J = 8.6 Hz), 6.63 (2H, d, J = 8.6 Hz), 4.85 (1H,
d, J = 10.8Hz), 4.78-4.64 (2H, m), 4.68 (1H, s), 3.96
(3H, s), 3.95 (3H, s), 3.55 (1H, m), 3.37 (1H, m), 3.
03 (1H, m), 1.95 (3H, s), 1.39 (3H, s), 1.18 (2H. M),
1.00-0.92 (6H, m), 0.83 (3H, d, J = 6.6Hz).

[0288]

Example 98 13- {2- [4- (3-methoxycarbonylaminop
Ropionyl) aminophenyl] -2-methylpropioni
Luoxy} -5-hydroxyiminomilbemycin A ₄
(I: R ¹ = Et, X = CO, Z = = C (Me) ₂ , R ³ = 4-NHCOCH ₂ CH
₂ NHCOOMe, n = 0) (Compound No. 427 ) To a solution of 3-methoxycarbonylaminopropionic acid (44 mg, 0.30 mmol) in dichloromethane (2.0 ml) triethylamine (0.032 ml, 0.30 mmol).
And isobutyl chloroformate (41 mg, 0.30 mm
ol) was added at 4 ° C. and the resulting mixture was stirred for 5 minutes.
13- [2- (4-Aminophenyl) -2-methylpropionyloxy] -5-t-butyldimethylsilyloxyiminomilbemycin A ₄ (101 mg, 0.12 mmo
(prepared as described in Example 18, Steps A, B) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (20 ml), washed successively with 0.2 M citric acid, water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was dissolved in methanol (2.0 ml) and 1M hydrochloric acid (0.2 ml) was added. After stirring this mixture for 20 minutes at room temperature, the reaction mixture was diluted with ethyl acetate (20 ml), washed successively with water, 4% sodium hydrogen carbonate and water,
It was dried over anhydrous sodium sulfate and evaporated under reduced pressure.
The residue was purified by column chromatography (silica gel, ethyl acetate / hexane = 6: 4) to give the title compound (9
6 mg, 92.8%) was obtained as an amorphous solid.

Mass spectrum (FAB-MS) m / z: 862 (M + H
⁺ , M = C ₄₇ H ₆₃ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.39 (1H, s), 7.
50 (1H, s), 7.44 (2H, d, J = 8.6Hz), 7.26 (2H, d, J = 8.6H
z), 4.87 (1H, d, J = 10.6Hz), 4.73 and 4.67 (2H, d-AB
q, J = 2.0 and 14.7Hz), 4.66 (1H, s), 3.98 (1H, s), 3.
78 (3H, s), 3.55 (1H, m), 3.36 (1H, m), 3.04 (1H, dt,
J = 2.2 and 9.3Hz), 1.93 (3H, s), 1.56 (3H, s), 1.54 (3
H, s), 1.31 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.83 (3H,
d, J = 6.0 Hz) 0.82 (3H, d, J = 6.3 Hz). Examples 99-109 Using the same procedure as Example 98, Examples 99-109.
Was prepared.

[0290]

Example 99 13- {2- [4- (N-methyl-N-methoxycarbo
Nylglycyl) aminophenyl] -2-methylpropio
Nyloxy} -5-hydroxyiminomilbemycin A
₄ (I: R ¹ = Et, X = CO, Z = = C (Me) ₂ , R ³ = 4-NHCOCH ₂
N (Me) COOMe, n = 0 (Compound No. 95) mass spectrum (FAB-MS) m / z: 862
(M + H ⁺ , M = C ₄₇ H ₆₃ N
₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.22 (1
H, s), 7.45 (2H, d, J = 8.6Hz), 7.26 (2H, d, J = 8.6Hz),
4.87 (1H, d, J = 10.4Hz), 4.74 and 4.67 (2H, d-ABq, J
= 2.0 and 14.5Hz), 4.66 (1H, s), 4.03 (2H, s), 3.97 (1
H, s), 3.78 (3H, s), 3.57 (1H, m), 3.36 (1H, m), 3.06
(3H, s), 3.04 (1H, dt, J = 2.3 and 9.4Hz), 1.93 (3H, d,
J = 1.4Hz), 1.56 (3H, s), 1.53 (3H, s), 1.31 (3H, s),
0.98 (3H, t, J = 7.3Hz), 0.83 (3H, d, J = 6.5Hz) 0.82 (3
H, d, J = 6.5Hz).

[0291]

Example 100 13- {2- [4- (N-methoxycarbonylprolyl
A) Aminophenyl] -2-methylpropionyloxy
Ci} -5-hydroxyiminomilbemycin A ₄ (I: R ¹
= Et, X = CO, Z = = C (Me) ₂ , R ³ = 4-NH Prolyl (NC
OOMe), n = 0) (of compound No. 112) Mass spectrum (FAB-MS) m / z : 888 (M + H +, M = C 49 H
₆₅ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.13 (1H, s), 7.
46 (2H, d, J = 8.6Hz), 7.24 (2H, d, J = 8.6Hz), 4.88 (1H,
d, J = 10.6Hz), 4.74 and 4.68 (2H, d-ABq, J = 2.0 and
14.4Hz), 4.66 (1H, s), 3.97 (1H, s), 3.78 (3H, s), 3.
73 (1H, m), 3.57 (1H, m), 3.36 (1H, m), 3.04 (1H, dt,
J = 2.3 and 9.3Hz), 1.93 (3H, d, J = 1.5Hz), 1.56 (3H,
s), 1.53 (3H, s), 1.32 (3H, s), 0.98 (3H, t, J = 7.3H
z), 0.83 (6H, d, J = 6.5Hz).

[0292]

Example 101 13- {2- [4- (N-methoxycarbonylglycy
L) Methylaminophenyl] -2-methylpropionyl
Oxy} -5-hydroxyiminomilbemycin A ₄ (I:
R ¹ = Et, X = CO, Z = = C (Me) ₂ , R ³ = 4-N (Me) COCH ₂ NH
COOMe, n = 0) (Compound No. 96) Mass spectrum (FAB-MS) m / z: 862 (M + H ⁺ , M = C ₄₇ H
₆₃ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.12 (1H, s), 7.
38 (2H, d, J = 8.5Hz), 7.14 (2H, d, J = 8.5Hz), 4.88 (1H,
d, J = 10.4Hz), 4.73 and 4.68 (2H, d-ABq, J = 1.9 and
14.7Hz), 4.65 (1H, s), 3.97 (1H, s), 3.64 (3H, s), 3.
57 (1H, m), 3.36 (1H, m), 3.23 (3H, s), 3.04 (1H, dt,
J = 2.2 and 9.4Hz), 1.93 (3H, d, J = 1.5Hz), 1.61 (3H,
s), 1.58 (3H, s), 1.31 (3H, s), 0.98 (3H, t, J = 7.2H
z), 0.83 (3H, d, J = 6.4Hz) 0.82 (3H, d, J = 6.3Hz).

[0293]

Example 102 13- {2- [4- (Nt-butyloxycarbonyl)
Glycyl) aminophenyl] -2-methylpropionyl
Oxy} -5-hydroxyiminomilbemycin A ₄
(I: R ¹ = Et, X = CO, Z = = C (Me) ₂ , R ³ = 4-NHCOCH ₂ NH
COOtBu, n = 0) (Compound No. 89) Mass spectrum (FAB-MS) m / z: 890 (M + H ⁺ , M = C ₄₉ H
₆₇ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.19 (1H, s), 8.
07 (1H, wide s), 7.36 (2H, d, J = 8.4Hz), 7.26 (2H, d,
J = 8.4Hz), 4.87 (1H, d, J = 10.4Hz), 4.74 and 4.67 (2H,
d-ABq, J = 1.7 and 14.6Hz), 4.65 (1H, s), 3.97 (1H,
s), 3.92 (2H, d, J = 6.0Hz), 3.57 (1H, m), 3.36 (1H,
m), 3.04 (1H, m), 1.93 (3H, s), 1.60 (3H, s), 1.56 (3
H, s), 1.53 (3H, s), 1.48 (9H, s), 0.98 (3H, t, J = 7.4
Hz), 0.83 (6H, d, J = 6.5Hz).

[0294]

Example 103 13- {2- [4- (N-methoxycarbonyl-2,2
-Dimethylglycyl) aminophenyl] -2-methyl group
Ropionyloxy} -5-hydroxyiminomilbemai
Thin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Me) ₂ , R ³ = 4-N
HCOC (Me) ₂ NHCOOMe, n = 0) (Compound No. 107) Mass spectrum (FAB-MS) m / z: 874 (M + H ⁺ , M = C ₄₈ H
₆₃ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.67 (1H, wide
s), 8.17 (1H, s), 7.47 (2H, d, J = 8.6Hz), 7.28 (2H, d,
J = 8.6Hz), 5.13 (1H, s), 4.87 (1H, d, J = 10.4Hz), 4.7
4 and 4.67 (2H, d-ABq, J = 1.8 and 14.6Hz),
4.65 (1H, s), 3.92 (1H, s),
3.71 (3H, s), 3.56 (1H, m),
3.36 (1H, m), 3.04 (1H, m
m), 1.93 (3H, s), 1.61 (6H,
s), 1.38 (3H s), 0.98 (3H,
t, J = 7.4 Hz), 0.83 (6H, d,
J = 6.5 Hz).

[0295]

Example 104 13- {1- [4- (N-methoxycarbonylglycy
Le) Aminophenyl] cyclopropanecarbonyl
Ci} -5-Hydroxyiminomilbemycin A ₄
(I : R ¹ = Et, X = CO, Z =
^{_{= C (CH 2) 2,}} R 3 = 4-NHCOCH 2 N
HCOOMe, n = 0) (Compound No. 422) Mass spectrum (FAB-MS) m / z: 846 (M + H +, M = C ₄₆ H
₅₉ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.43 (1H, s), 8.
00 (1H, wide s), 7.46 (2H, d, J = 8.5Hz), 7.29 (2H, d,
J = 8.5 Hz), 4.87 (1H, d, J = 10.4Hz), 4.73 and 4.67 (2H,
d-ABq, J = 2.0 and 14.7Hz), 4.66 (1H, s), 4.00 (2H,
d, J = 5.9Hz), 3.94 (1H, s), 3.75 (3H, s), 3.55 (1H,
m), 3.36 (1H, m), 3.03 (1H, dt, J = 2.0 and 9.3Hz), 1.9
3 (3H, d, J = 1.6Hz), 1.36 (3H, s), 1.15 (2H, m), 0.97
(3H, t, J = 7.2Hz), 0.91 (3H, d, J = 6.5Hz) 0.83 (3H, d,
J = 6.4Hz).

[0296]

Example 105 13- {1- [4- (N-methoxycarbonylglycy
Le) Aminophenyl] cyclobutanecarbonyloxy}
-5-hydroxyimino milbemycin A ₄ (I: R ¹ = E
t, X = CO, Z = = C (CH ₂ ) ₃ , R ³ = 4-NHCOCH ₂ NHCOOMe, n
= 0) (Compound No. 484) Mass spectrum (FAB-MS) m / z: 860 (M + H ⁺ , M = C ₄₇ H
₆₁ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.23 (1H, s), 7.
94 (1H, wide s), 7.46 (2H, d, J = 8.4Hz), 7.23 (2H, d,
J = 8.4 Hz), 5.47 (1H, m), 4.84 (1H, d, J = 10.4Hz), 4.7
5 and 4.68 (2H, d-ABq, J = 1.9 and 14.6Hz), 4.66 (1H,
s), 4.00 (2H, d, J = 6.0Hz), 3.96 (1H, s), 3.75 (3H, s),
3.55 (1H, m), 3.36 (1H, m), 3.03 (1H, m), 2.84-2.73
(2H, m), 1.93 (3H, s), 1.33 (3H, s), 0.97 (3H, t, J =
7.2Hz), 0.82 (3H, d, J = 6.4Hz), 0.77 (3H, d, J = 6.4H
z).

[0297]

Example 106 13- {1- [4- (N-methoxycarbonylglycy
A) Aminophenyl] cyclopentanecarbonyl
Ci} -5-hydroxyiminomilbemycin A ₄ (I: R ¹
= Et, X = CO, Z = = C (CH ₂ ) ₄ , R ³ = 4-NHCOCH ₂ NHCOOM
e, n = 0) (Compound No. 246) Mass spectrum (FAB-MS) m / z: 874 (M + H ⁺ , M = C ₄₈ H
₆₃ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.34 (1H, s), 7.
96 (1H, wide s), 7.43 (2H, d, J = 8.4Hz), 7.29 (2H, d,
J = 8.4 Hz), 5.50 (1H, wide s), 4.81 (1H, d, J = 10.4H
z), 4.74 and 4.67 (2H, d-ABq, J = 1.8 and 14.4Hz), 4.
66 (1H, s), 3.99 (2H, d, J = 6.0Hz), 3.98 (1H, s), 3.75
(3H, s), 3.55 (1H, m), 3.36 (1H, m), 3.03 (1H, m), 2.
64-2.56 (2H, m), 2.17 (1H, dd, J = 11.6 and 24.0Hz), 1.
93 (3H, s), 1.29 (3H, s), 0.97 (3H, t, J = 7.2Hz), 0.82
(3H, d, J = 6.4Hz), 0.76 (3H, d, J = 6.4Hz).

[0298]

Example 107 13- {1- [4- (N-methoxycarbonyl-2,2
-Dimethylglycyl) aminophenyl] cyclopentane
Carbonyloxy} -5-hydroxyiminomilbemai
Syn A ₄ (I: R ¹ = Et, X = CO, Z = = C (CH ₂ ) ₄ , R ³ = 4-
NHCOC (Me) ₂ NHCOOMe, n = 0) (Compound No. 272) Mass spectrum (FAB-MS) m / z: 902 (M + H ⁺ , M = C ₅₀ H
₆₇ N ₃ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.64 (1H, wide
s), 7.45 (2H, d, J = 8.4Hz), 7.28 (2H, d, J = 8.4 Hz),
5.20 (1H, wide s), 4.82 (1H, d, J = 10.4Hz), 4.75 and 4.68 (2H, d-ABq, J = 1.8 and 14.2Hz), 4.66 (1H, s),
3.67 (3H, s), 3.55 (1H, m), 3.36 (1H, m), 3.03 (1H,
m), 2.65-2.52 (2H, m), 2.18 (1H, dd, J = 11.6 and 24.0H
z), 1.93 (3H, s), 1.60 (3H, s), 1.58 (3H, s), 1.32 (3
H, s), 0.97 (3H, t, J = 7.2Hz), 0.82 (3H, d, J = 6.4Hz),
0.78 (3H, d, J = 6.4Hz).

[0299]

Example 108 13- {1- [4- (N-acetylglycyl) aminoph
[Ethyl] cyclopentanecarbonyloxy} -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (CH ₂ ) ₄ , R ³ = 4-NHCOCH ₂ NHCOMe, n = 0) (Compound
No. 256) Mass spectrum (FAB-MS) m / z: 858 (M + H ⁺ , M = C ₄₈ H
₆₃ N ₃ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.50 (1H, s), 8.
45 (1H, wide s), 7.45 (2H, d, J = 8.6Hz), 7.28 (2H, d,
J = 8.6 Hz), 6.56 (1H, m), 4.80 (1H, d, J = 10.4Hz), 4.7
4 and 4.67 (2H, d-ABq, J = 1.8 and 14.6Hz), 4.10 (2H,
d, J = 5.2Hz), 4.00 (1H, s), 3.55 (1H, m), 3.36 (1H,
m), 3.03 (1H, m), 2.64-2.56 (2H, m), 2.17 (1H, dd, J =
11.6 and 24.0Hz), 2.09 (3H, s), 1.93 (3H, s), 1.29 (3
H, s), 0.97 (3H, t, J = 7.4Hz), 0.82 (3H, d, J = 6.4Hz),
0.75 (3H, d, J = 6.4Hz).

[0300]

Example 109 13- {2- [4- (N-acetylglycyl) aminoph
[Ethyl] -2-methylpropionyloxy} -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (Me) ₂ , R ³ = 4-NHCOCH ₂ NHCOMe, n = 0) (Compound
No. 91) mass spectrum (FAB-MS) m / z: 832 (M + H ⁺ , M = C ₄₆ H
₆₁ N ₃ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.34 (1H, wide
s), 7.46 (2H, d, J = 8.4Hz), 7.26 (2H, d, J = 8.4Hz), 6.
48 (1H, wide s), 4.87 (1H, d, J = 10.5Hz), 4.72 and 4.7
0 (2H, ABq, J = 14.4Hz), 4.66 (1H, s), 4.09 (2H, d, J =
4.4Hz), 3.55 (1H, m), 3.36 (1H, m), 3.04 (1H, dt, J = 2.
1 and 8.9Hz), 2.10 (3H, s), 1.93 (3H, s), 1.57 (3H,
s), 1.54 (3H, s), 1.30 (3H, s), 0.98 (3H, t, J = 7.3H
z), 0.84-0.76 (6H, m).

[0301]

Example 110 13- [1- (4-acetoxyacetylaminophenyi
And cyclopentanecarbonyloxy] -5-hydroxy
Shiminomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z =
= C (CH ₂ ) ₄ , R ³ = 4-NHCOCH ₂ OCOMe, n = 0) (Compound number
214) 13- [2- (4-aminophenyl) -2-methylpropionyloxy] -5 in dichloromethane (2.0 ml)
To a solution of -t-butyldimethylsilyloxyiminomilbemycin A ₄ (87.3 mg, 0.10 mmol, prepared as described in Example 57, Steps AD), 3-acetoxyacetic acid (47.2 mg, 0.40 mmol), triethylamine (0.028 ml, 0.20 mmol) and iodide 2
-Chloro-1-methylpyridinium (51.1 mg, 0.
20 mmol) was added and the resulting mixture was stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and diluted to 0.
It was washed successively with 2M citric acid, water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. Dissolve the residue in methanol (2.0 ml),
1M hydrochloric acid (0.2 ml) was added. This mixture is left at room temperature for 2 hours.
After stirring for 0 minutes, the reaction mixture was diluted with ethyl acetate (20 ml).
Diluted with water, washed successively with water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography (silica gel, EtOH / dichloromethane = 3: 97),
The title compound (66.4 mg, 77.4%) was obtained as an amorphous solid.

Mass spectrum (FAB-MS) m / z: 859 (M + H
⁺ , M = C ₄₈ H ₆₂ N ₂ O ₁₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.00 (1H, s), 7.
74 (1H, s), 7.46 (2H, d, J = 8.6Hz), 7.31 (2H, d, J = 8.6H
z), 4.81 (1H, d, J = 10.4Hz), 4.74 and 4.68 (2H, d-AB
q, J = 1.9 and 14.6Hz), 4.69 (2H, s), 4.65 (1H, s), 3.9
7 (1H, s), 3.55 (1H, m), 3.36 (1H, m), 3.03 (1H, dt,
J = 2.2 and 9.3Hz), 2.62 (2H, m), 2.25 (3H, s), 1.93 (3
H, s), 1.29 (3H, s), 0.97 (3H, t, J = 7.4Hz), 0.82 (3H,
d, J = 6.4 Hz) 0.77 (3H, d, J = 6.4 Hz). Examples 111 to 113 Using the same procedure as in Example 110, Examples 111 to 1
Thirteen compounds were prepared.

[0303]

Example 111 13- [1- (4-ethyloxyacetylaminophenenyl
And cyclopentanecarbonyloxy] -5-hydroxy
Siimino milbemycin A ₄ (I: R ¹ = Et, X = CO, Z =
= C (CH ₂ ) ₄ , R ³ = 4-NHCOCH ₂ OEt, n = 0) (Compound No. 2
13) Mass spectrum (FAB-MS) m / z: 845 (M + H ⁺ , M = C ₄₈ H
₆₄ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.27 (1H, s), 8.
13 (1H, s), 7.49 (2H, d, J = 8.4Hz), 7.30 (2H, d, J = 8.4H
z), 4.81 (1H, d, J = 10.4Hz), 4.74 and 4.67 (2H, d-AB
q, J = 1.8 and 14.6Hz), 4.65 (1H, s), 4.05 (2H, s), 3.9
7 (1H, s), 3.66 (2H, q, J = 7.2Hz), 3.54 (1H, m), 3.36
(1H, m), 3.02 (1H, dt, J = 2.1 and 9.4Hz), 2.61 (2H,
m), 1.93 (3H, s), 1.31 (3H, t, J = 7.2Hz), 1.29 (3H,
s), 0.97 (3H, t, J = 7.4Hz), 0.82 (3H, d, J = 6.4Hz) 0.76
(3H, d, J = 6.4Hz).

[0304]

Example 112 13- [1- (4-phenylthioacetylaminophenenyl)
) Cyclopentanecarbonyloxy] -5-hydroxy
Siimino milbemycin A ₄ (I: R ¹ = Et, X = CO, Z =
= C (CH ₂ ) ₄ , R ³ = 4-NHCOCH ₂ SPh, n = 0) (Compound No. 2
18) Mass spectrum (FAB-MS) m / z: 909 (M + H ⁺ , M = C ₅₂ H
₆₄ N ₂ O ₁₀ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.54 (1H, s), 8.
09 (1H, s), 7.40-7.21 (9H, m), 4.80 (1H, d, J = 10.4H
z), 4.75 and 4.68 (2H, d-ABq, J = 1.8 and 14.6Hz), 4.66
(1H, s), 3.97 (1H, s), 3.77 (2H, s), 3.54 (1H, m),
3.36 (1H, m), 3.02 (1H, dt, J = 2.2 and 9.3Hz), 2.60 (2
H, m), 1.93 (3H, d, J = 1.4Hz), 1.29 (3H, s), 0.97 (3H,
t, J = 7.2Hz), 0.82 (3H, d, J = 6.5Hz) 0.76 (3H, d, J =
6.4 Hz).

[0305]

Example 113 13- [1- (4-benzenesulfonylacetylamino
(Phenyl) cyclopentanecarbonyloxy] -5-hi
Droxyimino milbemycin A ₄ (I: R ¹ = Et, X = C
O, Z = = C (CH ₂ ) ₄ , R ³ = 4-NHCOCH ₂ SO ₂ Ph, n = 0) (Compound
No. 217) Mass spectrum (FAB-MS) m / z: 941 (M + H ⁺ , M = C ₅₂ H
₆₄ N ₂ O ₁₂ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.46 (1H, s), 8.
06 (1H, s), 7.92 (2H, d, J = 7.3Hz), 7.70 (1H, dd, J = 7.4
And 7.4Hz), 7.58 (2H, dd, J = 7.3 and 7.4Hz), 7.42
(2H, d, J = 8.7Hz), 7.31 (2H, d, J = 8.7Hz), 4.82 (1H,
d, J = 10.5Hz), 4.75 and 4.68 (2H, d-ABq, J = 1.8 and 1
4.5Hz), 4.65 (1H, s), 4.15 (2H, s) 3.97 (1H, s), 3.5
5 (1H, m), 3.36 (1H, m), 3.02 (1H, dt, J = 2.2 and 9.
4Hz), 2.62 (2H, m), 1.93 (3
H, d, J = 1.6 Hz), 1.31 (3H,
s), 0.97 (3H, t, J = 7.3 Hz),
0.82 (3H, d, J = 6.5Hz) 0.7
6 (3H, d, J = 6.5 Hz).

[0306]

Example 114 13- {2- [4- (N-methylcarbamoylamino)
Phenyl] -2-methylpropionyloxy} -5-hi
Droxyimino milbemycin A ₄ (I: R ¹
= Et, X = CO, Z = = C (M
e) ₂ , R ³ = 4-NHCONHMe, n =
0) (Compound No. 132) 13- [2- (4-aminophenyl) -2-methylpyropionyloxy] -5 in dichloromethane (2.0 ml)
-T- butyldimethylsilyloxy imino milbemycin A ₄ To a solution of (101 mg, 0.12 mmol, Example 18, Step A, was prepared as described in B), methyl isocyanate (11.4 mg, 0.20 mmol) And add
The resulting mixture was stirred for 5 hours. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in methanol (2.0 ml) and 1M hydrochloric acid (0.2 ml) was added to this solution. After stirring the mixture for 20 minutes at room temperature, the reaction mixture was diluted with ethyl acetate (20 ml), washed successively with water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate / hexane = 6: 4) to give the title compound (87 mg, 91%) as an amorphous solid.

Mass spectrum (FAB-MS) m / z: 790 (M + H
⁺ , M = C ₄₄ H ₅₉ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.14 (1H, wide
s), 7.26 (2H, d, J = 8.6Hz), 7.20 (2H, d, J = 8.6Hz),
6.27 (1H, wide s), 4.87 (1H, d, J = 10.6Hz), 4.72 and 4.69 (2H, ABq, J = 15.2Hz), 4.66 (1H, s), 3.95 (1H,
s), 3.55 (1H, m), 3.36 (1H, m), 3.04 (1H, m), 2.84 (3
H, d, J = 4.7Hz), 1.93 (3H, s), 1.58 (3H, s), 1.54 (3H,
s), 1.31 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.83-0.81 (6
H, m). Examples 115-119 Using a procedure similar to Example 114, Examples 115-1
Nineteen compounds were prepared.

[0308]

Example 115 13- {2- [4- (N-phenylcarbamoylamido
No) phenyl] -2-methylpropionyloxy} -5
-Hydroxyiminomilbemycin A ₄ (I: R ¹ = Et, X
= CO, Z = = C (Me) ₂ , R ³ = 4-NHCONHPh, n = 0) (Compound
No. 144) Mass spectrum (FAB-MS) m / z: 852 (M + H ⁺ , M = C ₄₉ H
₆₁ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.22 (1H, wide
s), 6.69 (1H, wide s), 6.64 (1H, wide s), 4.87 (1H, d,
J = 10.6Hz), 4.72 and 4.70 (2H, ABq, J = 14.5Hz), 4.66
(1H, s), 3.95 (1H, s), 3.55 (1H, m), 3.36 (1H, m), 3.
04 (1H, m), 1.92 (3H, s), 1.58 (3H, s), 1.54 (3H, s),
1.32 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.83 (6H, d, J =
6.6Hz).

[0309]

Example 116 13- {2- [4- (N-methylthiocarbamoylami ]
No) phenyl] -2-methylpropionyloxy} -5
-Hydroxyiminomilbemycin A ₄ (I: R ¹ = Et, X
= CO, Z = = C (Me) ₂ , R ³ = 4-NHCSNHMe, n = 0) (Compound
No. 145) mass spectrum (FAB-MS) m / z: 806 (M + H ⁺ , M = C ₄₄ H
₅₉ N ₃ O ₉ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.94 (1H, wide
s), 7.61 (1H, wide s), 7.37 (2H, d, J = 8.6Hz), 7.14 (2
H, d, J = 8.6 Hz), 5.97 (1H, wide s), 4.89 (1H, d, J = 1
0.6Hz), 4.72 and 4.70 (2H, ABq, J = 14.5Hz), 4.66 (1H,
s), 3.96 (1H, s), 3.55 (1H, m), 3.36 (1H, m), 3.14 (3
H, d, J = 4.6Hz), 3.03 (1H, dd, J = 2.0 and 9.2Hz), 1.9
3 (3H, s), 1.59 (3H, s), 1.57 (3H, s), 1.34 (3H, s),
0.98 (3H, t, J = 7.3Hz), 0.83 (6H, d, J = 6.5Hz).

[0310]

Example 117 13- {1- [4- (N-methylcarbamoylamino)
Phenyl] cyclobutanecarbonyloxy} -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (CH ₂ ) ₃ , R ³ = 4-NHCONHMe, n = 0) (Compound number
494) Mass spectrum (FAB-MS) m / z: 802 (M + H ⁺ , M = C ₄₅ H
₅₉ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.30 (1H, wide
s), 7.22 (4H, s), 6.31 (1H, wide s), 4.85 (1H, d, J =
10.6Hz), 4.73 and 4.70 (2H, ABq, J = 14.5Hz), 4.66 (1
H, s), 3.95 (1H, s), 3.55 (1H, m), 3.36 (1H, m), 3.03
(1H, dd, J = 2.3 and 9.2Hz), 2.84 (3H, d, J = 4.6Hz),
2.53-2.42 (3H, m), 1.93 (3H, s), 1.35 (3H, s), 0.97 (3
H, t, J = 7.3Hz), 0.82 (3H, d, J = 6.6Hz), 0.77 (3H, d,
J = 6.3Hz).

[0311]

Example 118 13- {1- [4- (N-phenylcarbamoylamido
No) phenyl] cyclobutanecarbonyloxy} -5-
Hydroxyimino milbemycin A ₄ (I: R ¹ = Et, X =
CO, Z = = C (CH ₂ ) ₃ , R ³ = 4-NHCONHPh, n = 0) (Compound
No. 500) Mass spectrum (FAB-MS) m / z: 864 (M + H ⁺ , M = C ₅₀ H
₆₁ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.56 (1H, s), 7.
35-7.30 (4H, m), 7.25-7.19 (4H, m), 7.15-7.10 (1H,
m), 6.89 (1H, s), 6.75 (1H, s), 4.86 (1H, d, J = 10.4H
z), 4.75 and 4.68 (2H, d-ABq, J = 1.6 and 14.8Hz), 4.
67 (1H, s), 3.95 (1H, s), 3.55 (1H, m), 3.36 (1H, m),
3.04 (1H, m), 2.84-2.72 (2H, m), 1.91 (3H, s), 1.36 (3
H, s), 0.96 (3H, t, J = 7.4Hz), 0.82 (3H, d, J = 6.5Hz),
0.79 (3H, d, J = 6.5Hz).

[0312]

Example 119 13- {1- [4- (N-phenylcarbamoylamido
No) phenyl] cyclopentanecarbonyloxy} -5
-Hydroxyiminomilbemycin A ₄ (I: R ¹ = Et, X
= CO, Z = = C (CH ₂ ) ₄ , R ³ = 4-NHCONHPh, n = 0) (Compound
No. 309) mass spectrum (FAB-MS) m / z: 878 (M + H ⁺ , M = C ₅₁ H
₆₃ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.80 (1H, wide
s), 7.40-7.00 (10H, m), 4.86 (1H, d, J = 10.3Hz), 4.74
And 4.66 (2H, ABq, J = 15.5Hz), 4.66 (1H, s), 3.95 (1H,
s), 3.53 (1H, m), 3.36 (1H, m), 3.01 (1H, m), 2.60 (2
H, m), 1.88 (3H, s), 1.34 (3H, s), 0.95 (3H, t, J = 7.2H
z), 0.81 (3H, d, J = 6.3Hz), 0.76 (3H, d, J = 6.4Hz).

[0313]

Example 120 13- {1- [4- (N-methylcarbamoylamino)
Phenyl] cyclopropanecarbonyloxy} -5-hi
Droxyimino milbemycin A ₄ (I: R ¹ = Et, X = C
O, Z = = C (CH ₂ ) ₂ , R ³ = 4-NHCONHMe, n = 0) (Compound number
No. 432) Step A Using a procedure similar to Example 18, Steps A and B, 13
13- [1- (4-nitrophenyl) -cyclopropanecarbonyloxy] -5-hydroxyiminomylmbemycin A ₄ (prepared as described in Example 6)
[1- (4-Aminophenyl) -cyclopropanecarbonyloxy] -5-t-butyldimethylsilyloxyiminomilbemycin A ₄ was converted. Amino derivative (8
45 mg, 1.0 mmol) was dissolved in dichloromethane (10 ml) and the resulting solution was pyridine (0.081 ml, 1.
0 mmol) and 2-chloroformyl-1,2,4-triazolo [4,3-a] pyridin-3-one (198 mg,
1.0 mmol) was added at 4 ° C. This mixture at room temperature for 20
After stirring for 1 min, the reaction mixture was ethyl acetate (100 ml)
It was diluted with, washed successively with 0.2M citric acid, water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Column chromatography of the residue (silica gel, ethyl acetate / hexane = 1: 1)
13- {1- [4- (1,2,4-triazolo [4,3-a] pyridin-3-one-2-carbonyl) aminophenyl] -cyclopropanecarbonyloxy} -5-t. - give butyldimethylsilyl oximino milbemycin a ₄ (995mg, 97.4%) as an amorphous solid.

Step B 13- {1- in N-methylpyrrolidone (1.0 ml)
[4- (1,2,4-Triazolo [4,3-a] pyridin-3-one-2-carbonyl) aminophenyl] -cyclopropanecarbonyloxy} -5-t-butyldimethylsilyloxyiminomilbemycin A ₄ (153m
g, 0.15 mmol, in the solution of step A) obtained above, 40
% Methylamine (in H ₂ O, 19.4 mg, 0.25 mmo
l) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 ml), water, 0.2M
It was washed successively with citric acid, water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was dissolved in methanol (2.0 ml), and 1M hydrochloric acid (0.2 ml) was added to this solution. After stirring this mixture for 20 minutes at room temperature, the reaction mixture was diluted with ethyl acetate (20 ml), washed successively with water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. . The residue was subjected to column chromatography (silica gel, ethanol / dichloromethane = 5: 9).
Purification in 5) gave the title compound (109 mg, 92.4%) as an amorphous solid.

Mass spectrum (FAB-MS) m / z: 788 (M + H
⁺ , M = C ₄₄ H ₅₇ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.86 (1H, s), 7.
27 (2H, d, J = 8.4Hz), 7.21 (2H, d, J = 8.4Hz), 6.53 (1H,
s), 4.87 (1H, d, J = 10.4Hz), 4.81 (1H, m), 4.73 and
4.67 (2H, d-ABq, J = 1.8 and 14.6Hz), 4.67 (1H, s), 3.
93 (1H, s), 3.55 (1H, m), 3.36 (1H, m), 3.03 (1H, dd,
J = 2.1 and 9.4Hz), 2.83 (3H, d, J = 4.9Hz), 1.93 (3H,
s), 1.38 (3H, s), 1.16 (2H, m), 0.97 (3H, t, J = 7.3H
z), 0.92 (3H, d, J = 6.5Hz), 0.82 (3H, d, J = 6.5Hz). Examples 121 to 124 Examples 121 to 1 using the same procedure as in Example 120.
Twenty-four compounds were prepared.

[0316]

Example 121 13- {1- [4- (1-pyrrolidinylcarbonylamido
No) phenyl] cyclopropanecarbonyloxy} -5
-Hydroxyiminomilbemycin A ₄ (I: R ¹ = Et, X
= CO, Z = = C (CH ₂ ) ₂ , R ³ = 4-NHCO (1-Pyrd), n = 0)
(Compound No. 437) Mass spectrum (FAB-MS) m / z: 828 (M + H ⁺ , M = C ₄₇ H
₆₁ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.37 (1H, s), 7.
35 (2H, d, J = 8.6Hz), 7.23 (2H, d, J = 8.6Hz), 6.15 (1H,
s), 4.86 (1H, d, J = 10.4Hz), 4.73 and 4.67 (2H, d-ABq,
J = 1.9 and 14.7Hz), 4.66 (1H, s), 3.92 (1H, s), 3.55
(1H, m), 3.47 (4H, m), 3.36 (1H, m), 3.03 (1H, dd, J =
2.2 and 9.4 Hz), 1.98 (4H, m),
1.93 (3H, d, J = 1.5Hz), 1.36
(3H, s), 1.15 (2H, m), 0.9
7 (3H, t, J = 7.3Hz), 0.90 (3
H, d, J = 6.5 Hz), 0.83 (3H,
d, J = 6.5 Hz).

[0317]

Example 122 13- {1- [4- (N-butylcarbamoylamino)
Phenyl] cyclopropanecarbonyloxy} -5-hi
Droxyimino milbemycin A ₄ (I: R ¹
= Et, X = CO, Z = = C (M
e) ₂ , R ³ = 4-NHCONHBu, n =
0) (Compound No. 138) mass spectrum (FAB-MS) m / z: 832 (M + H ⁺ , M = C ₄₇ H
₆₅ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.24 (1H, wide
s), 7.25 (2H, d, J = 8.6Hz), 7.20 (2H, d, J = 8.6 Hz),
6.28 (1H, wide s), 4.87 (1H, d, J = 10.6Hz), 4.72 and 4.69 (2H, ABq, J = 14.5Hz), 4.66 (1H, s), 3.95 (1H,
s), 3.56 (1H, m), 3.36 (1H, m), 3.25 (2H, q, J = 6.6H
z), 3.03 (1H, m), 1.93 (3H, s), 1.57 (3H, s), 1.54 (3H,
s), 1.31 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.84-0.81
(6H, m).

[0318]

Example 123 13- {1- [4- (Nt-butylcarbamoylamido)
No) phenyl] cyclopropanecarbonyloxy} -5
-Hydroxyiminomilbemycin A ₄ (I: R ¹ = Et, X
= CO, Z = = C (Me) ₂ , R ³ = 4-NHCONHt-Bu, n = 0)
Compound number 139) Mass spectrum (FAB-MS) m / z: 832 (M + H ⁺ , M = C ₄₇ H
₆₅ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.22 (1H, wide
s), 7.23 (2H, d, J = 8.6Hz), 7.17 (2H, d, J = 8.6 Hz),
6.13 (1H, wide s), 4.87 (1H, d, J = 10.6Hz), 4.72 and 4.69 (2H, ABq, J = 14.5Hz), 4.66 (1H, s), 3.95 (1H,
s), 3.56 (1H, m), 3.36 (1H, m), 3.03 (1H, dt, J = 1.7
And 8.9Hz), 1.93 (3H, s), 1.56 (3H, s), 1.53 (3H, s),
1.37 (9H, s), 1.32 (3H, s), 0.98 (3H, t, J = 7.3Hz),
0.84-0.80 (6H, m).

[0319]

Example 124 13- {1- [4- (N-cyclohexylcarbamoyl
Amino) phenyl] cyclopropanecarbonyloxy}
-5-hydroxyimino milbemycin A ₄ (I: R ¹ = E
t, X = CO, Z = = C (Me) ₂ , R ³ = 4-NHCONHcHex, n = 0)
(Compound No. 140) Mass spectrum (FAB-MS) m / z: 858 (M + H ⁺ , M = C ₄₉ H
₆₇ N ₃ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.17 (1H, wide
s), 7.25 (2H, d, J = 8.6Hz), 7.19 (2H, d, J = 8.6Hz),
6.18 (1H, wide s), 4.87 (1H, d, J = 10.5Hz), 4.72 and 4.69 (2H, ABq, J = 14.5Hz), 4.66 (1H, s), 3.95 (1H,
s), 3.56 (1H, m), 3.36 (1H, m), 3.04 (1H, dt, J = 1.9
And 9.2Hz), 1.93 (3H, s), 1.57 (3H, s), 1.54 (3H, s),
1.31 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.84-0.81 (6H,
m).

[0320]

Example 125 13- {1- [4- (pyrimidin-2-ylthioacetyl
Luamino) phenyl] cyclopropanecarbonyl
Ci} -5-hydroxyiminomilbemycin A ₄ (I: R ¹
= Et, X = CO, Z = = C (CH ₂ ) ₂ , R ³ = 4-NHCOCH ₂ S (2-Py
m), n = 0) (Compound No. 406) Using the same procedure as in Example 18, 13- [1- (4-
Nitrophenyl) -cyclopropanecarbonyloxy]
-5-hydroxyimino milbemycin A ₄ (Example 6
Was prepared as described in 1.) was converted to 13- [1- (4-bromoacetylaminophenyl) -cyclopropanecarbonyloxy] -5-t-butyldimethylsilyloxyiminomilbemycin A ₄ . The bromoacetyl derivative (115 mg, 0.12 mmol) was dissolved in N-methylpyrrolidone (2.0 ml) and the resulting solution was treated with 2-mercaptopyrimidine (22.4 mg, 0.20 mmol) and sodium hydride (55%, 6.5 mg, 0.15 mmol) was added. After stirring this mixture for 30 minutes at room temperature, the reaction mixture was diluted with ethyl acetate (20 ml) and washed successively with 0.2M citric acid, water, 4% sodium hydrogen carbonate and water,
It was dried over anhydrous sodium sulfate and evaporated under reduced pressure.
The residue was dissolved in methanol (2.0 ml), and 1M hydrochloric acid (0.2 ml) was added to this solution. Mix the mixture at room temperature for 20 minutes.
After stirring for 1 min, the reaction mixture was diluted with ethyl acetate (20 ml), washed successively with water, 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was subjected to column chromatography (silica gel,
Purification with ethanol / dichloromethane = 2.5: 97.5) gave the title compound (105 mg, 99.1%) as an amorphous solid.

Mass spectrum (FAB-MS) m / z: 883 (M + H
⁺ , M = C ₄₈ H ₅₈ N ₄ O ₁₀ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 9.13 (1H, s), 8.
63 (2H, d, J = 5.1Hz), 8.28 (1H, s), 7.40 (2H, d, J = 8.4
Hz), 7.25 (2H, d, J = 8.4Hz), 7.13 (1H, t, J = 5.1Hz),
4.85 (1H, d, J = 10.5Hz), 4.73 and 4.66 (2H, d-ABq, J =
2.0 and 14.5Hz), 4.65 (1H, s), 3.93 (3H, s), 3.54 (1
H, m), 3.36 (1H, m), 3.02 (1H, dd, J = 2.2 and 9.4Hz),
1.93 (3H, d, J = 1.5Hz), 1.36 (3H, s), 1.13 (2H, m),
0.97 (3H, t, J = 7.3Hz), 0.89 (3H, d, J = 6.5Hz), 0.82 (3
H, d, J = 6.5 Hz). Examples 126-127 Using the same procedure as Example 125, Examples 126-1.
Twenty-seven compounds were prepared.

[0322]

Example 126 13- {1- [4- (thiazolidin-2-ylthioacetate
Cylamino) phenyl] cyclopropanecarbonyloxy
Ci} -5-hydroxyiminomilbemycin A ₄ (I: R ¹
= Et, X = CO, Z = = C (CH ₂ ) ₂ , R ³ = 4-NHCOCH ₂ S (2-Thd
n), n = 0) (Compound No. 408) Mass spectrum (FAB-MS) m / z: 890 (M + H ⁺ , M = C ₄₇ H
₅₉ N ₃ O ₁₀ S ₂ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.21 (1H, s), 7.
41 (2H, d, J = 8.5Hz), 7.27 (2H, d, J = 8.5Hz), 4.87 (1H,
d, J = 10.5Hz), 4.73 and 4.66 (2H, d-ABq, J = 2.0 and
14.5Hz), 4.65 (1H, s), 4.31 (2H, t, J = 8.0Hz), 3.92 (3
H, s), 3.79 (2H, s), 3.56 (1H, m), 3.54 (2H, t, J = 8.0H
z), 3.36 (1H, m), 3.03 (1H, dd, J = 2.2 and 9.4Hz), 1.9
3 (3H, d, J = 1.4Hz), 1.37 (3H, s), 1.14 (2H, m), 0.97
(3H, t, J = 7.3Hz), 0.91 (3H, d, J = 6.5Hz), 0.82 (3H,
d, J = 6.5Hz).

[0323]

Example 127 13- {1- [4- (pyridin-2-ylthioacetyl
Amino) phenyl] cyclopropanecarbonyloxy}
-5-hydroxyimino milbemycin A ₄ (I: R ¹ = E
t, X = CO, Z = = C (CH ₂ ) ₂ , R ³ = 4-NHCOCH ₂ S (2-Pyr), n
= 0) (Compound No. 407) Mass spectrum (FAB-MS) m / z: 882 (M + H ⁺ , M = C ₄₉ H
₅₉ N ₃ O ₁₀ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.55 (1H, d, J =
5.2Hz), 8.18 (1H, s), 7.60 (1H, m), 7.42 (2H, d, J = 8.
6Hz), 7.32 (1H, d, J = 8.0Hz), 7.25 (2H, d, J = 8.6Hz),
7.16 (1H, dd, J = 5.2 and 7.2Hz), 4.85 (1H, d, J = 10.5H
z), 4.73 and 4.66 (2H, d-ABq, J = 2.0 and 14.6Hz), 4.
65 (1H, s), 3.92 (1H, s), 3.89 (2H, s), 3.54 (1H, m),
3.36 (1H, m), 3.03 (1H, dd, J = 2.2 and 9.4Hz), 1.93 (3
H, m), 1.36 (3H, s), 1.13 (2H, m), 0.97 (3H, t, J = 7.3
Hz), 0.89 (3H, d, J = 6.4Hz), 0.82 (3H, d, J = 6.5Hz). Examples 128 to 137 Using the same procedure as in Example 1, Examples 128 to 137.
Was prepared.

[0324]

Example 128 13- {1- [4- (N-methyl-acetylamino) phenyl
[Ethyl] cyclopentanecarbonyloxy} -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (CH ₂ ) ₄ , R ³ = 4-N (Me) COMe, n = 0) (Compound number
193) Mass spectrum (FAB-MS) m / z: 815 (M + H ⁺ , M = C ₄₇ H
₆₂ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.70 (1H, wide
s), 7.38 (2H, d, J = 8.3Hz), 7.11 (2H, d, J = 8.3Hz), 4.
81 (1H, d, J = 10.5Hz), 4.74 and 4.66 (2H, ABq, J = 14.9H
z), 4.65 (1H, s), 3.95 (1H, wide s), 3.55 (1H, m), 3.
35 (1H, m), 3.23 (3H, s), 3.02 (1H, m), 2.65 (2H, m),
1.92 (3H, s), 1.84 (3H, s), 1.30 (3H, s), 0.97 (3H, t,
J = 7.2Hz), 0.82 (3H, d, J = 6.3Hz), 0.76 (3H, d, J = 6.5
Hz).

[0325]

Example 129 13- {1- [4- (N-butyl-acetylamino) phenyl
[Ethyl] cyclopentanecarbonyloxy} -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (CH ₂ ) ₄ , R ³ = 4-N (Bu) COMe, n = 0) (Compound number
196) Mass spectrum (FAB-MS) m / z: 857
(M + H ⁺ , M = C ₅₀ H ₆₈ N
₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.11 (1
H, s), 7.38 (2H, d, J = 8.6Hz), 7.07 (2H, d, J = 8.6Hz),
4.80 (1H, d, J = 10.4Hz), 4.74 and 4.67 (2H, ABq, J = 1
4.4Hz), 4.65 (1H, s), 3.97 (1H, s), 3.66 ((2H, t, J =
7.6Hz), 3.55 (1H, m), 3.36 (1H, m), 3.03 (1H, m), 2.6
5 (2H, m), 1.93 (3H, s), 1.78 (3H, s), 1.28 (3H, s), 0.
97 (3H, t, J = 7.3Hz), 0.87 (3H, t, J = 7.2Hz), 0.82 (3H,
d, J = 6.4Hz), 0.72 (3H, d, J = 6.4Hz).

[0326]

Example 130 13- {1- [4- (N-methyl-methanesulphonyl)
Mino) phenyl] cyclopentanecarbonyloxy}-
5-hydroxyimino milbemycin A ₄ (I: R ¹ = Et,
X = CO, Z = = C (CH ₂ ) ₄ , R ³ = 4-N (Me) SO ₂ Me, n = 0)
(Compound No. 316) Mass spectrum (FAB-MS) m / z: 851 (M + H ⁺ , M = C ₄₆ H
₆₂ N ₂ O ₁₁ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.13 (1H, s), 7.
35 (2H, d, J = 8.7Hz), 7.29 (2H, d, J = 8.7Hz), 4.80 (1H,
d, J = 10.4Hz), 4.74 and 4.67 (2H, d-ABq, J = 1.8 and
14.2Hz), 4.65 (1H, s), 3.97 (1H, s), 3.55 (1H, m), 3.
36 (1H, m), 3.29 (3H, s), 3.02 (1H, m), 2.80 (3H, s),
2.62 (2H, m), 1.93 (3H, s), 1.27 (3H, s), 0.97 (3H, t,
J = 7.2Hz), 0.82 (3H, d, J = 6.4Hz), 0.75 (3H, d, J = 6.4H
z).

[0327]

Example 131 13- {1- [4- (N-butyl-methanesulfonyl chloride
Mino) phenyl] cyclopentanecarbonyloxy}-
5-hydroxyimino milbemycin A ₄ (I: R ¹ = Et,
X = CO, Z = = C (CH ₂ ) ₄ , R ³ = 4-N (Bu) SO ₂ Me, n = 0)
(Compound No. 319) Mass spectrum (FAB-MS) m / z: 893 (M + H ⁺ , M = C ₄₉ H
₆₈ N ₂ O ₁₁ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.03 (1H, s), 7.
36 (2H, d, J = 8.7Hz), 7.25 (2H, d, J = 8.7Hz), 4.79 (1H,
d, J = 10.8Hz), 4.74 and 4.67 (2H, d-ABq, J = 1.8 and
14.6Hz), 4.65 (1H, s), 3.97 (1H, s), 3.64 (2H, t, J =
6.8Hz), 3.55 (1H, m), 3.36 (1H, m), 3.03 (1H, m), 2.83
(3H, s), 2.65 (2H, m), 1.93 (3H, s), 1.27 (3H, s), 0.
97 (3H, t, J = 7.3Hz), 0.86 (3H, t, J = 7.2Hz), 0.82 (3H,
d, J = 6.4Hz), 0.72 (3H, d, J = 6.4Hz).

[0328]

Example 132 13- {2- [4- (2-oxopiperidino) phenyi
]]-2-Methylpropionyloxy} -5-hydroxy
Shiminomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z =
= C (Me) ₂ , R ³ = 4- (2-oxo-1-Pip), n = 0) (Compound number
No. 161) Mass spectrum (FAB-MS) m / z: 815 (M + H ⁺ , M = C ₄₇ H
₆₂ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.18 (1H, s), 7.
31 (2H, d, J = 8.5Hz), 7.18 (2H, d, J = 8.5Hz), 4.87 (1H,
d, J = 10.8Hz), 4.73 and 4.66 (2H, d-ABq, J = 1.8 and
14.6Hz), 4.65 (1H, s), 3.96 (1H, wide s), 3.62-3.52
(3H, m), 3.36 (1H, m), 3.03 (1H, m), 2.57 (2H, m), 1.9
2 (3H, s), 1.58 (3H, s), 1.55 (3H, s), 1.29 (3H, s),
0.98 (3H, t, J = 7.4Hz), 0.84-0.82 (6H, m).

[0329]

Example 133 13- {2- [4- (2-oxo-1-pyrrolidinyl)
Phenyl] -2-methylpropionyloxy} -5-hi
Droxyimino milbemycin A ₄ (I: R ¹ = Et, X = C
O, Z = = C (Me) ₂ , R ³ = 4- (2-oxo-1-Pyrd), n = 0)
(Compound No. 163) Mass spectrum (FAB-MS) m / z: 801 (M + H ⁺ , M = C ₄₆ H
₆₀ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.80 (1H, wide
s), 7.55 (2H, d, J = 8.6Hz), 7.30 (2H, d, J = 8.6 Hz),
4.88 (1H, d, J = 10.6Hz), 4.74 and 4.65 (2H, ABq, J = 14.5
Hz), 4.65 (1H, s), 3.96 (1H, s), 3.71 (2H, s), 3.57 (1
H, m), 3.38 (1H, m), 3.04 (1H, m), 2.62 (2H, t, J = 8.2H
z), 2.17 (2H, t, J = 7.5Hz), 1.93 (3H, s), 1.57 (3H,
s), 1.54 (3H, s), 1.32 (3H, s), 0.98 (3H, t, J = 7.2H
z), 0.85-0.82 (6H, m).

[0330]

Example 134 13- {2- [4- (2-oxoazetidine-1-i
Lu) phenyl] -2-methylpropionyloxy} -5
-Hydroxyiminomilbemycin A ₄ (I: R ¹ = Et, X
= CO, Z = = C (Me) ₂ , R ³ = 4- (2-oxo-1-Azt), n = 0)
(Compound No. 160) mass spectrum (FAB-MS) m / z: 787 (M + H ⁺ , M = C ₄₅ H
₅₈ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.99 (1H, s), 7.
28-7.26 (4H, m), 4.87 (1H, d, J = 10.8Hz), 4.74 and 4.
67 (2H, d-ABq, J = 2.0 and 14.4Hz), 4.66 (1H, s), 3.97
(1H, s), 3.63-3.60 (2H, m), 3.57 (1H, m), 3.38 (1H,
m), 3.13-3.10 (2H, m), 3.03 (1H, m), 1.93 (3H, s), 1.5
8 (3H, s), 1.54 (3H, s), 1.32 (3H, s), 0.98 (3H, t, J =
7.2Hz), 0.84-0.81 (6H, m).

[0331]

Example 135 13- {2- [4- (2,6-dioxopiperidino) fu
[Ethyl] -2-methylpropionyloxy} -5-hydr
Roxiimino milbemycin A ₄ (I: R ¹ = Et, X = CO,
Z = = C (Me) ₂ , R ³ = 4- (2,6-dioxo-1-Pip), n = 0)
Compound No. 162) mass spectrum (FAB-MS) m / z: 829 (M + H ⁺ , M = C ₄₇ H
₆₀ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.12 (1H, s), 7.
36 (2H, d, J = 8.6Hz), 7.01 (2H, d, J = 8.6Hz), 4.86 (1H,
d, J = 10.4Hz), 4.72 and 4.66 (2H, d-ABq, J = 2.1 and
14.5Hz), 4.65 (1H, s), 3.96 (1H, s), 3.56 (1H, m), 3.
35 (1H, m), 3.04 (1H, m), 2.81 (4H, t, J = 6.6Hz), 2.11
(2H, m), 1.93 (3H, s), 1.61 (3H, s), 1.56 (3H, s), 1.
23 (3H, s), 0.98 (3H, t, J = 7.2Hz), 0.84 (3H, d, J = 6.5
Hz), 0.83 (3H, d, J = 6.4Hz).

[0332]

Example 136 13- {2- [4- (2,5-dioxo-1-pyrrolidi
Nyl) phenyl] -2-methylpropionyloxy}-
5-hydroxyimino milbemycin A ₄ (I: R ¹ = Et,
X = CO, Z = = C (Me) ₂ , R ³ = 4- (2,5-dioxo-1-Pyrd), n
= 0) (Compound No. 164) mass spectrum (FAB-MS) m / z: 815
(M + H ⁺ , M = C ₄₆ H ₅₈ N
₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.25 (1
H, s), 7.39 (2H, d, J = 8.5Hz), 7.23 (2H, d, J = 8.5Hz),
4.88 (1H, d, J = 10.6Hz), 4.73 and 4.67 (2H, d-ABq, J
= 2.0 and 14.5Hz), 4.65 (1H, s), 3.97 (1H, s), 3.56 (1
H, m), 3.36 (1H, m), 3.04 (1H, dd, J = 2.2 and 9.5Hz),
2.90 (4H, s), 1.93 (3H, d, J = 1.5Hz), 1.60 (3H, s),
1.56 (3H, s), 1.27 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.
84 (3H, d, J = 6.5Hz), 0.83 (3H, d, J = 8.5Hz).

[0333]

Example 137 13- {2- [4- (2-oxooxazoline-3-i
Lu) phenyl] -2-methylpropionyloxy} -5
-Hydroxyiminomilbemycin A ₄ (I: R ¹ = Et, X
= CO, Z = = C (Me) ₂ , R ³ = 4- (2-oxo-3-Oxaz), n = 0)
(Compound No. 165) Mass spectrum (FAB-MS) m / z: 803 (M + H ⁺ , M = C ₄₅ H
₅₈ N ₂ O ₁₁ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.19 (1H, wide
s), 7.48 (2H, d, J = 9.0Hz), 7.30 (2H, d, J = 9.0Hz), 4.
88 (1H, d, J = 10.5Hz), 4.74 and 4.66 (2H, d-ABq, J = 2.
0 and 14.5Hz), 4.65 (1H, s), 4.49 (2H, m), 4.05 (2H,
m), 3.97 (1H, s), 3.57 (1H, m), 3.36 (1H, m), 3.04 (1H,
dd, J = 2.2 and 9.4Hz), 1.93 (3H, d, J = 1.4Hz), 1.58
(3H, s), 1.55 (3H, s), 1.32 (3H, s), 0.98 (3H, t, J =
7.3Hz), 0.83 (3H, d, J = 6.5Hz), 0.82 (3H, d, J = 6.5H
z). Examples 138-139 Using a procedure similar to that of Example 18, 13- [2- (3-
Nitrophenyl) -2-methylpropionyloxy]-
5-Hydroxyiminomilbemycin A ₄ (prepared as described in Example 2) to Examples 138-139
Was prepared.

[0334]

Example 138 13- [2- (3-acetylaminophenyl) -2-me
Cylpropionyloxy] -5-hydroxyiminomil
Bemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Me) ₂ , R ³
= 3-NHCOMe, n = 0) (Compound No. 32) Mass spectrum (FAB-MS) m / z: 775 (M + H ⁺ , M = C ₄₄ H
₅₈ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.87 (1H, wide
s), 7.50 (1H, d, J = 8.6Hz), 7.39 (1H, s), 7.22 (1H, d,
J = 7.9Hz), 7.10 (1H, wide s), 7.02 (1H, d, J = 7.9H
z), 4.87 (1H, d, J = 10.6Hz), 4.71 and 4.69 (2H, ABq,
J = 13.9Hz), 4.65 (1H, s), 3.95 (1H, s), 3.57 (1H, m),
3.36 (1H, m), 3.04 (1H, m), 2.18 (3H, s), 1.93 (3H,
s), 1.57 (3H, s), 1.54 (3H, s), 1.28 (3H, s), 0.98 (3
H, t, J = 7.3Hz), 0.84-0.81 (6H, m).

[0335]

Example 139 13- [2- (3-methanesulfonylaminophenyl)
-2-Methylpropionyloxy] -5-hydroxyl
Minomilbemycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (M
e) ₂ , R ³ = 3-NHSO ₂ Me, n = 0) (Compound No. 150) Mass spectrum (FAB-MS) m / z: 711 (M + H ⁺ , M = C ₄₃ H
₅₈ N ₂ O ₁₁ S). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 7.76 (1H, wide
s), 7.50-7.10 (24, m), 6.33 (1H, wide s), 4.88 (1H, d,
J = 10.6Hz), 4.71 and 4.70 (2H, ABq, J = 14.5Hz), 4.65
(1H, s), 3.94 (1H, s), 3.57 (1H, m), 3.36 (1H, m), 3.
04 (1H, m), 2.99 (3H, s), 1.93 (3H, s), 1.58 (3H, s),
1.56 (3H, s), 1.31 (3H, s), 0.98 (3H, t, J = 7.3Hz), 0.8
4-0.81 (6H, m).

[0336]

Example 140 13- [1- (4-acetylaminophenyl) cyclope
Tantocarbonyloxy] -5-hydroxyiminomil
Bemycin A ₃ (I: R ¹ = Me, X = CO, Z = = C (CH ₂ ) ₄ , R
_{^{3 = 4-NHCOCH 3, n}} = 0) ( using the same method as Compound No. 23) Example 57 and 59 The title compound was prepared from 15-hydroxy-5-oxo-milbemycin A _3.

Mass spectrum (FAB-MS) m / z: 787 (M + H
⁺ , M = C ₄₅ H ₅₈ N ₂ O ₁₀ ). Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.11 (1H, s), 7.
41 (2H, d, J = 8.6Hz), 7.28 (2H, d, J = 8.6Hz), 7.13 (1H,
s), 4.81 (1H, d, J = 10.4Hz), 4.75 and 4.69 (2H, ABq, J
= 14.7Hz), 4.65 (1H, s), 3.97 (1H, s), 3.52 (1H, m),
3.36 (1H, m), 3.21 (1H, m), 2.61 (2H, m), 2.17 (3H,
s), 1.93 (3H, s), 1.29 (3H, s), 1.14 (3H, d, J = 6.4H
z), 0.83 (3H, d, J = 6.5Hz), 0.75 (3H, d, J = 6.5Hz).

[0338]

Example 141 13- {2- [4- (1-methoxycarbonylpyrrolididiene
2-Carbonylamino) phenyloxy] -2-me
Cylpropynyloxy} -5-hydroxyiminomylvay
Mycin A ₄ (I: R ¹ = Et, X = CO, Z = = C (Me) ₂ , R ³ =
4-NHCO (1-COOMe-Pyrd), n = 1) (Compound No. 111) Using a method similar to Examples 57 and 110 , the title compound was prepared from 15-hydroxy-5-oxomilbemycin A ₄ .

Mass spectrum (FAB-MS) m / z: 1053 (M +
H ⁺ + triethanolamine = 903 + 1 + 149) Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.63 (1H, br.s),
7.34 (2H, d, J = 8.8Hz), 6.74 (2H, d, J = 8.8Hz), 5.86-
5.79 (3H, m), 5.45-5.30 (3H, m,), 5.02 (1H, d, J = 10.9H
z), 4.79- 4.68 (2H, ABq, J = 14.5Hz), 4.67 (1H, s), 4.
45 (1H, br.s), 4.00 (1H, s), 3.77 (3H, s), 3.73-3.38 (5
H, m), 3.65-3.42 (3H, m), 3.37 (1H, m), 3.06 (1H, m)

[0340]

Example 142 13- {2- [4- (1-methoxycarbonylglycyl
Amino) phenyloxy] -2-methylpropynyloxy
Ci} -5-hydroxyiminomilbemycin A ₄ (I: R ¹
= Et, X = CO, Z = = C (Me) ₂ , R ³ = 4-NHCONHCOOMe), n
= 1) (Compound No. 80) Using a method similar to that in Examples 57 and 110, the title compound was prepared from 15-hydroxy-5-oxomilbemycin A ₄ .

Mass spectrum (FAB-MS) m / z: 1013 (M +
H ⁺ + triethanolamine = 863 + 1 +149) Nuclear magnetic resonance spectrum (CDCl ₃ ) δppm: 8.27 (1H, br.s),
7.83 (1H, br.s), 7.31 (2H, d, J = 8.9Hz), 6.74 (2H, d,
J = 8.9Hz), 5.90-5.82 (3H, m), 5.50-5.31 (4H, m,), 5.00
(1H, d, J = 10.4Hz), 4.73- 4.67 (2H, ABq, J = 14.4Hz),
4.66 (1H, s), 3.97 (1H, s), 3.74 (3H, s), 3.66-3.55 (1H,
m), 3.37 (1H, m), 3.05 (1H, m).

[0342]

[Test Example] Next, a biological test example will be given to specifically show the effect.

Comparative compound 1 in Table 2 below is disclosed in
5-hydroxyimino milbemycin A ₄ (milbemycin A ₄ oxime) described in Examples of JP-A 60-142991, and Comparative Compound 2 is a compound described in Examples of JP-A-5-255343. Comparative Compound 3 is the compound described in Examples in JP-A-63-10791,
It is a compound having the structure shown below. [In the formula, Me is
Indicates a methyl group. ]

[0344]

Embedded image

[0345]

[Test example]

Insecticidal test against cat fleas Prepare a test container in which flea living space and bovine serum are isolated with parafilm used as artificial skin, and 1 ppm of bovine serum is prepared.
The concentration of drug is added and the fleas are 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. Table 2 shows the results.

[0346]

[Table 2] ──────────────────────────────────── Example Compound No. (Exemplified Compound No.) Mortality rate (%) ----------------------- Example Compound No. .3 (16) 97.5 Example compound No. 14 (81) 97.5 Example compound No. 15 (547) 92.6 Example compound No. 16 (553) 100.0 Example compound No. 17 (392) 90.2 Example compound No. 19 (63) 90.0 Example compound No. 20 (121) 94.6 Example compound No. 21 (26) 92.7 Example compound No. 24 (38 ) 92.5 Example compound No. 25 (36) 97.5 Example compound No. 26 (65) 90.0 Example compound No. 27 (51) 97.6 Example compound No. 28 (47) 94 .7 Example compound No. 30 (42) 97.5 Example compound No. 39 (4 ) Example compound No. 40 (41) 97.5 Example compound No. 42 (37) 90.2 Example compound No. 43 (35) 95.3 Example compound No. 44 (34) 90 .5 Example compound No. 46 (46) 97.5 Example compound No. 47 (74) 97.4 Example compound No. 49 (66) 97.5 Example compound No. 50 (64) 92.3 Example compound No. 55 (75) 92.1 Example compound No. 57 (171) 97.5 Example compound No. 58 (174) 95.0 Example compound No. 59 (191) 100.0 Example Compound No. 60 (313) 100.0 Example compound No. 64 (198) 90.2 Example compound No. 66 (205) 95.0 Example compound No. 67 (211) 90.0 Example compound No .68 (199) 5.0 Example compound No. 70 (202) 97.5 Example compound No. 74 (457) 90.0 Example compound No. 85 (336) 100.0 Example compound No. 91 (429) 97. 5 Example compound No. 93 (431) 90.0 Example compound No. 101 (96) 97.5 Example compound No. 105 (484) 95.2 Example compound No. 109 (91) 100.0 Example compound No. 110 (214) 100.0 Example compound No. 111 (213) 91.1 Example compound No. 112 (218) 95.5 Example compound No. 114 (132) 94.7 Example compound No. 115 (144) 92.3 Example compound No. 116 (145) 97.3 Example compound No. 118 (500) 95.1 Example compound No. 123 (139) 95.0 Example compound No. 124 (140) 97.3 Example compound No. 130 (316) 100.0 Example compound No. 137 (165) 97.4 --- --- --- --- Comparative Compound 1 20.9 Comparative Compound 2 31.4 Comparative Compound 3 26.8 ───────────────────────── ───────────────────────

[0347]

INDUSTRIAL APPLICABILITY The novel 13-substituted milbemycin 5-oxime derivative of the present invention represented by the general formula (I) has insecticidal, acaricidal or anthelmintic activity, and particularly to fleas parasitic on pets and humans. On the other hand, it shows an excellent insecticidal effect, and is extremely effective as a pesticide for these.

Examples of fleas include cat fleas (Cteno).
cephalides felis), dog flea (Ctenocephalides cani
s) etc. can be mentioned.

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

[0350] 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, it has an excellent acaricidal activity against ticks (Ixodidae), lacqueridae (Dermanyssid-ae), and mites (Sarcoptidae) which parasitize animals.

Further, the novel 13-substituted milbemycin derivatives of the present invention show an excellent control effect against various diseases caused by agricultural and horticultural pests.

That is, the compound of the present invention has not only acaricidal activity against adults such as spider mites (Tetranychidae) and spider mites (Eriophyidae), which are parasitic on fruit trees, vegetables and flowers, and eggs. Rather, it has excellent activity against resistant mites which have become a big problem in recent years because existing acaricides have become ineffective.

Furthermore, root-knot nematodes (Meloidogyne) and pinewood nematodes (Bursapholench) in soil and in the trunk and bark of the tree
us), ticks (Phizoglyphus) and the like.

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

Examples of such pests include the following pests. As insects, Coleoptera pests, for example, Azuki weevil (Callosobruchus chin)
ensis), Sitophilus zeamais, Tribolium castaneum, Epilachna vigitioctomaculata, Agriores fuscicollis, Anoma
la rufocuprea), Colorado potato beetle (Leptinotars
a decemkineata), diabloteica (Diabrotica spp.)
, Pine beetle (Monochamus alternatus),
Rice water weevil (Lissorhoptrus oryzophilus), Flying bark beetle (Lyctusbruneus), Lepidoptera, for example, Gypsy moth (Lymantria dispar), Sea worm (Malacosoma
neustria), Caterpillar (Pieris rapae), Lotus cutworm
(Spodoptera litura), armyworm (Mamestra brassica)
e), Japanese squirrel (Chilosuppressalis), Awaneniga (Pyrausta nubilalis),
cautella), kamakumamakimaki (Adoxophyes orana), codling moth (Carpocapsa pomonella), kaburayaga (Agrotis
fucosa), Honey Beetle (Galleria mellonella), Diamondback moth
(Plutella mylostella), mandarin orange moth (phenyl
yllocnistis citrella); Hemiptera, such as leafhopper (Nephotettix cincticeps), brown planthopper (Nil
aparvata lugens), Pseudodococcu
scomstocki), Unaspis yanonensi
s), peach aphid (Myzus persicae), apple aphid (Aphis pomi), cotton aphid (Aphis gossypi
i), radish aphid (Rhopalosiphum pseudobra
ssicas), Stephanitis nashi, Green stink bug (Nazara spp.), Bed bug (Cimex lectulariu)
s), Whitefly (Trialeurodes vaporariorum)
, Psyllid (Psylla spp.), Orthoptera, for example, German cockroach (Blatella germanica), American cockroach (P
eriplaneta americana), Kera (Gryllotalpa african
a), grasshoppers (Locusta migratoria migratoriodes); Isoptera, for example, Yamato termite (Deucotermes speratu)
s), house termites (Coptotermes formosamus); Diptera, such as house dust (Musca domestica), Aedes aegypti, rice fly (Hylemia platura),
Culex pipiens, Culex pipiens, Anophele
s sinensis), Culex tritaeniorhync
hus) and the like.

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

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

Certain species of Nematodillus, Cooperia and Esagogostomum attack the intestinal tract, while those of the genus Hemonx and Ostertagia parasitize the stomach and the parasites of the Tichtiocaurus parasite. It is found in the lungs, but it also shows activity. In addition, Filaria family (Filar
iidae) and Setariidae parasites are found in and are 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 of the human digestive tract are the genus Ancylostoma and the genus Necator.
, Asdaris, Strongyroides
(Strongyloides), genus Trichinella, genus Capillaria, genus Trichuris
And the genus Enterobius.

Other medically important parasites found in the blood or other tissues and organs outside the gastrointestinal tract, the genus Wuchereria, the genus Buchsia (Bucheria)
rugia), Onchoceca and Loa
(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.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical display location A61K 31/365 AEC A61K 31/365 AEC 31/38 AFJ 31/38 AFJ 31/395 31/395 31 / 40 31/40 31/42 31/42 31/425 31/425 31/44 31/44 31/445 31/445 31/505 31/505

Claims (18)

[Claims] 1. A milbemici represented by the following general formula (I):
Derivatives. Embedded image[In the formula, Me represents a methyl group. R¹ Is a methyl group;
A tyl group; an isopropyl group; or a sec-butyl group, X represents a carbonyl group; or a methylene group, and Z represents the formula: = C = (R^Two )_Two (I) (where R is^Two Is C
₁ -C_Three Shows an alkyl group. ); Or the formula: = C = (CH_Two )_m (Ii) represents a group represented by the formula (wherein m represents 2 to 5),
n represents 0 or 1, R_Three Is a nitro group; an amino group; C₁ -C_Four Alkyl substitution
Amino group; C_Two -C₈Dialkyl-substituted amino group; C₁ −
C_Four Alkoxy group; C₁ -C_Three Alkoxy C_Two-C_Three A
Lucoxy group; the following formulas: (iii) ,: (iv), (i
v) ,: (vi) ,: (vii) ,: (viii) ,:
The group represented by (ix) is shown. Embedded image(Where R^Four Is a hydrogen atom; C₁ -C₆ Alkyl group; Substitution
C having at least one substituent selected from the group A
₁ -C₆ Alkyl group; C_Three -C₆ Cycloalkyl group;
Have at least one substituent selected from the substituent group B
C_Three -C₆ Cycloalkyl group; C_Two -C₆ Alkenyl
Group; C_Two -C₆ Alkynyl group; C₆ -C₁₄Aryl group;
Have at least one substituent selected from the substituent group C
C₆ -C₁₄Aryl group; selected from oxygen, nitrogen and sulfur atoms
Having at least one selected atom as a ring atom 3
To 6-membered heterocyclic group; a substituent selected from Substituent group C
It has at least one and is selected from oxygen, nitrogen and sulfur atoms.
3 to 3 having at least one selected atom as a ring atom
A 6-membered heterocyclic group, R^Five Is a hydrogen atom; C₁ -C_Four Represents an alkyl group, R⁶ Is a hydrogen atom; C₁ -C₆ Represents an alkyl group, R⁷ Is C₁ -C₆ Alkyl group; C_Three -C₆ Cycloalkyl
R group; C₇ -C₁₁Aralkyl group (C₆ -C_TenAryl +
C₁ -C_Four Alkyl); Substitutions selected from Substituent group C
C having at least one group₇ -C₁₁Aralkyl group (C
₆ -C_TenAryl + C₁ -C_Four Alkyl); C₆ -C₁₄
Aryl group; Fewer substituents selected from Substituent group C
Both have one C₆ -C₁₄Represents an aryl group, or R⁶ 
And R⁷ Are combined to form a 3- to 6-membered nitrogen-containing heterocyclic group, Y is an oxygen atom; a sulfur atom, r is an integer of 1, 2 or 3, Q is a carbonyl group; or a methylene group, R⁸ Is C₁ -C_Four Alkyl group; C₆ -C_TenAryl group;
Have at least one substituent selected from the substituent group C
C₆ -C_TenRepresents an aryl group, R⁹ Is C₁ -C₆ Alkyl group; C_Three -C₆ Cycloalkyl
R group; C₆ -C_TenAryl group; selected from Substituent group C
C having at least one substituent₆ -C_TenAryl
Group; C₇ -C₁₁Aralkyl group (C₆ -C_TenAryl + C
₁ -C_Four Alkyl); Substituent selected from Substituent group C
C having at least one₇ -C₁₁Aralkyl group (C₆ 
-C_TenAryl + C₁ -C_Four Alkyl), R^TenIs at least selected from oxygen, nitrogen and sulfur atoms
5- or 6-membered aromatic heterocycle having one atom as a ring atom
A cyclic group; at least one substituent selected from the substituent group D
At least one selected from oxygen, nitrogen and sulfur atoms
Is a 5- or 6-membered aromatic compound having one atom as a ring atom.
Indicates a ring group, R¹¹Is C₁ -C_Four Shows an alkyl group. Substituent group A: halogen atom; cyano group; C₁ -C_Four Al
Coxy group; C_Two -C_Five Alkanoyl group; C_Two -C_Five Al
Canoyloxy group; C_Two -C_Five Alkoxycarbonyl
Group; C₆ -C_TenAryloxy group; C₁ -C_Four Alkyl
Thio group; C₆ -C_TenArylthio group; C₁ -C_Four Archi
Lesulfonyl group; C₆ -C_TenArylsulfonyl group; a
Mino group; C_Two -C_Five Alkanoylamino group; C_Two -C_Five 
Haloalkanoylamino group; N- (C_Two -C_Five Alkano
Il) -N- (C₁ -C_Three Alkyl) amino group; C_Two −
C_Five Alkoxycarbonylamino group; C_Two -C_Five Haloa
Lucoxycarbonylamino group; N- (C_Two -C_Five Arco
Xycarbonyl) -N- (C₁ -C_Three Alkyl) amino
Group; C which may have a substituent selected from Substituent group C
₆ -C_TenAryl group; C₇ -C₁₁Aryl carbonyl
Mino group (C₆ -C_TenAryl); C ₇ -C₁₁Aralkyl
Amino group (C₆ -C_TenAryl + C₁ -C_Four Archi
May have a substituent selected from the substituent group C.
At least one selected from oxygen, nitrogen and sulfur atoms
3- to 6-membered heterocyclic group having atoms as ring atoms; substituents
Oxygen, nitrogen, which may have a substituent selected from Group C,
At least one atom selected from sulfur atoms is a ring atom.
A 3- to 6-membered heterocyclic thio group having as; C₈ -C₁₂Ara
Lucyloxycarbonylamino group (C₆ -C_TenAryl
+ C₁ -C_Four Alkyl) Substituent group B: halogen atom; C₁ -C_Four An alkoxy group;
C_Two -C_Five Alkanoyloxy group Substituent group C: halogen atom; hydroxyl group; cyano group; nitro
Group; C₁ -C_Four Alkyl group; C₁ -C_Four An alkoxy group;
C_Two -C_Five Alkoxycarbonyl group; Oxo group Substituent group D: Amino group; C_Two -C_Five Alkanoylamino
Group; C_Two -C_Five Haloalkanoylamino group; C_Two -C₆ 
Alkoxycarbonylamino group] 2. In the general formula (I), R ¹ represents a methyl group; an ethyl group, X represents a carbonyl group; or a methylene group, and R ² in the formula (i) represented by Z is C _1-. Represents a C ₂ alkyl group, m in the formula (ii) represents 2 to 4, n represents 0, R ₃ represents a cyano group; a nitro group; an amino group; a C ₁ -C ₂ alkyl-substituted amino group ; C ₂ -C ₄ dialkyl substituted amino group; C ₁ -C ₂ alkoxy group, the following formula: (iii) ,:
(Iv),: (vi),: (vii) and: (vii
The compound according to claim 1, which represents a group represented by i). Embedded image (In the formula, R ⁴ is a hydrogen atom; C ₁ -C ₄ alkyl group; C ₁ -C ₂ alkyl group having at least one substituent selected from the substituent group A ₁ ; C ₄ -C ₆ cycloalkyl group ;
C having one substituent selected from the substituent group B _1
4 -C ₆ cycloalkyl group; C ₆ -C ₁₀ aryl group; C ₆ -C be one perforated a substituent selected from substituent group C _1
10 aryl groups; 5- or 6-membered heterocyclic groups having at least one atom selected from oxygen, nitrogen, and sulfur atoms as ring atoms; having at least one substituent selected from Substituent group C ₁ . Represents a 5- or 6-membered heterocyclic group having at least one atom selected from oxygen, nitrogen, and sulfur atoms as a ring atom, R ⁵ represents a hydrogen atom; a C ₁ -C ₂ alkyl group, and R ⁶ represents hydrogen. atom; C ₁ -C ₄ represents an alkyl group, R ⁷ is C ₁ -C ₄ alkyl group; C ₄ -C ₆ cycloalkyl; C ₇ -C ₁₀ aralkyl group (C ₆ aryl + C ₁ -
C ₄ alkyl); at least one perforated a substituent selected from substituent group C ₁ C ₇ -C ₁₀ aralkyl group (C ₆ aryl + C ₁ -C ₄ alkyl); C ₆ -C ₁₀ aryl group; substituents at least a substituent selected from the group C ₁ 1
C ₆ -C ₁₀ aryl group having one or R ⁶ and R ⁷
Form a 5- to 6-membered nitrogen-containing heterocyclic group, Y represents an oxygen atom; a sulfur atom, r represents an integer of 2 or 3, Q represents a carbonyl group, and R ⁸ represents C _1-. C ₂ alkyl group; C ₆ -C ₁₀ aryl group;
C _6- having one substituent selected from the substituent group C _1.
A C ₁₀ aryl group, R ⁹ represents a C ₁ -C ₄ alkyl group; a C ₄ -C ₆ cycloalkyl group; a C ₆ -C ₁₀ aryl group; at least one substituent selected from the substituent group C _1. C ₆ -C ₁₀ aryl group having; C ₇ -C ₁₀ aralkyl group (C ₆ aryl + C ₁ -C
₄ alkyl); indicating the selected from substituent group C ₁ substituents at least one have the C ₇ -C ₁₀ aralkyl group (C ₆ aryl + C ₁ -C ₄ alkyl). ) Substituent group A ₁ : Fluorine / chlorine / bromine atom; cyano group; C
₁ -C ₂ alkoxy groups; C ₂ -C ₃ alkanoyl; C
₂ -C ₃ alkanoyloxy group; C ₂ -C ₃ alkoxycarbonyl group; a phenoxy group; C ₁ -C ₂ alkylthio group; a phenylthio group; C ₁ -C ₂ alkylsulfonyl group; a phenylsulfonyl group; amino group; C ₂ - C ₃ alkanoylamino group; C ₂ -C ₃ haloalkanoylamino group; N- (C ₂ -C ₃ alkanoyl) -N- (C ₁ -C
₂ alkyl) amino group; C ₂ -C ₃ alkoxycarbonylamino group; C ₃ -C ₄ haloalkoxycarbonylamino group; N- (C ₂ -C ₃ alkoxycarbonyl) -N-
(C ₁ -C ₂ alkyl) amino group; phenyl group which may have a substituent selected from the substituent group C ₁ ; benzoylamino group; C ₇ -C ₁₀ aralkylamino group (C ₆ aryl + C _1-) C ₄ alkyl); 5- or 6-membered heterocyclic group having as a ring atom at least one atom selected from oxygen, oxygen and sulfur atoms which may have a substituent selected from the substituent group C ₁ . A 5- or 6-membered heterocyclic thio group having as a ring atom at least one atom selected from oxygen, oxygen and sulfur atoms which may have a substituent selected from the substituent group C ₁ ; C ₈ -C ₁₂ Aralkyloxycarbonylamino group (C ₆ aryl + C ₁ -C ₄ alkyl) Substituent group B ₁ : Fluorine / chlorine / bromine atom; C ₁ -C ₂ alkoxy group; C ₂ -C ₃ alkanoyloxy group Substituent group C ₁ : Fluorine, chlorine, bromine atom; hydroxyl group A cyano group; a nitro group; a C ₁ -C ₂ alkyl group; a C ₁ -C ₂ alkoxy group; a C ₂ -C ₃ alkoxycarbonyl group; an oxo group 3. The milbemycin derivative according to claim 2, wherein in the general formula (I), R ¹ represents an ethyl group. 4. The milbemycin derivative according to claim ³ , wherein R ³ is substituted at the 4-position in the general formula (I). 5. The general formula (I), X represents a methylene group, formula shown Z is: R ² in (i) represents a methyl group, R ³ is methoxycarbonylamino acetylamino group (hereinafter, underline The compound may be referred to as glycyl in some cases.); Acetylglycylamino group; 1-methoxycarbonyl-2-pyrrolidylcarbonylamino group; 6. In the general formula (I), X represents a carbonyl group, R ² in the formula (i) represented by Z represents a methyl group; or ethyl group, and m in the formula (ii) represented by Z. Represents 3 or 4, and R ₃ is an amino group; an acetylamino group; a cyanoacetylamino group; a benzoylamino group; a 2-fluorobenzoylamino group; a 3-fluorobenzoylamino group; a acetylglycylamino group; a methoxycarbonylglycol group. Sylamino group; N-methyl-N-methoxycarbonylaminoacetylamino (methoxycarbonylglycylamino) group;
Methoxycarbonylamino group; phenylcarbamoylamino group; 2-oxooxazolin-3-yl group; trifluoroacetylamino group; ethoxyacetylamino group;
An acetoxyacetylamino group; a methylsulfonylamino group; an ethylsulfonylamino group [claim 4]
The compound according to the above. . 7. 13- [2- (4-Cyanoacetylaminophenyl) -2-methylpropionyloxy] -5-hydroxyiminomilbemycin A ₄ 8. 13- {2- [4- (N-acetylglycyl) aminophenyl] -2-methylpropionyloxy} -5-hydroxyiminomilbemycin A ₄ 9. A 13- {2- [4- (N-methoxycarbonylglycyl) methylaminophenyl] -2-methylpropionyloxy} -5-hydroxyiminomilbemycin A ₄ 10. 13- [2- (4-Methoxycarbonylaminophenyl) -2-methylpropionyloxy]-
5-hydroxyimino milbemycin A ₄ 11. 13- {2- [4- (N-phenylcarbamoylamino) phenyl] -2-methylpropionyloxy} -5-hydroxyiminomilbemycin A ₄ 12. A 13- {2- [4- (2-oxooxazolin-3-yl) phenyl] -2-methylpropionyloxy} -5-hydroxyiminomilbemycin A.
_Four 13. 13- [1- (4-Aminophenyl) cyclopentanecarbonyloxy] -5-hydroxyiminomilbemycin A ₄ 14. 13- [1- (4-Acetylaminophenyl) cyclopentanecarbonyloxy] -5-hydroxyiminomilbemycin A ₄ 15. 13- [1- (4-acetoxyacetylaminophenyl) cyclopentanecarbonyloxy]-
5-hydroxyimino milbemycin A ₄ 16. 13- [1- (4-Methanesulfonylaminophenyl) cyclopentanecarbonyloxy] -5
-Hydroxyimino milbemycin A ₄ 17. 13- [1- (4-Acetylaminophenyl) -1-ethylbutyryloxy] -5-hydroxyiminomilbemycin A ₄ 18. A 13- [1- (4-acetylaminophenyl) cyclobutanecarbonyloxy] -5-hydroxyiminomilbemycin A ₄