JP2849389B2 - New macrolide compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Prior art]

The present invention relates to a series of novel macrolide compounds defined as milbemycin compounds having the formula (I): The new compounds have useful acaricidal, insecticidal and anthelmintic activities, which are generally referred to in the text as parasiticidal activity. The invention also relates to a process for the preparation of the novel milbemycin compounds and to a parasiticidal composition containing the compounds. The novel compounds provided by the present invention are macrolides chemically related to known milbemycins, avermectins and similar compounds. Several known compounds with a 16-shell macrolide structure can be obtained semisynthetically by fermentation of various microorganisms or by chemical induction from such natural fermentation products, and killing mites, insecticidal, anthelmintic and other parasitism Shows insect activity. Milbemycins and avermectins are examples of these two classes of known compounds, but there are also various other classes, identified by different names or code numbers. The names of these various macrolide compounds have generally been taken from the names or code numbers of the microorganisms that produce each class of natural product. And these names are further used for the same class of chemical derivatives, since there has been no standard systematic nomenclature commonly used for such compounds in the past. Natural milbemycins are defined by formula (A) as follows: For the avoidance of doubt, formula (A) also indicates the number of some of the carbon atoms most appropriate for the compounds of the present invention. The carbon atom of the methyl group at position 4 was numbered 26. Milbemycin A ₃ and A ₄ which are naturally produced along with those numerous other in Japanese Patent Publication 56-45890 and milbemycin D was published in JP-56-32481. Milbemycin was designated in these patents as "Compound B-41". In these compounds, a methyl group, an ethyl group or an isopropyl group is substituted at the 25-position in the above formula (A). Various derivatives of milbemycin were prepared and tested for their activity. For example, 5-position esterified milbemycins are disclosed in JP-A-54-61197, JP-A-54-145699, and JP-A-55-2079.
7, JP-A-57-18684, JP-A-58-59988, JP-A-61-22087,
JP-A-55-24165, JP-A-59-20285, JP-A-59-141582,
JP-A-61-85390, JP-A-61-130292, JP-A-57-120589
And JP-A-59-16894. 13-hydroxy-5-ketomylbemycin derivatives are disclosed in U.S. Pat. No. 4,423,209. Milbemycin 5-oxime derivatives were published in JP-A-60-14299 and JP-A-62-89685. JP 61-180787 discloses milbemycin derivatives having an esterified carboxy substituent at position 13 in combination with a hydroxy or esterified hydroxy substituent at position 5. Like milbemycins, avermectins also have a 16-membered ring macrolide structure. Avermecuns are, for example, Antimicrobial Agents C
hemotherapy 1979, 15 361 (1979) and Jr. Am. Chem. So
c., 1981, 103 , 4216. These compounds are represented by the above formula (A) except that the 13-position is substituted with a 4 '-(α-L-oleandrosyl) -α-L-oleandrosyloxy group. Position 25 is substituted with an isopropyl or sec -butyl group, and between positions 22 and 23 there is a carbon-carbon double bond or there is a hydroxyl group at position 23 and methyl is substituted at position 4. I have. Avermectins (which are referred to by the literature as CO76 compounds) are defined as follows. "db" indicates a double bond between positions 22 and 23, and "ab" indicates a single bond between positions 22 and 23. Avermectin A ₂ a, A
₂ b, if position 23-keto derivatives of B ₂ a and B ₂ b Sho 57-18684
Known from. The 22,23-position dihydroavermectins are obtained by reduction of the double bond between the 22-position and the 23-position and are disclosed in JP-A-54-61198. Further various derivatives are known from aglycone derivatives of avermectins which are analogs of milbemycin. For example,
54-61197 published derivatives in which the 13-position was substituted by a lower alkanoyl group. JP-A-58-59988 discloses avermectin compounds derived at the 4-position methyl group. Conversion of the 4-position methyl group to a hydroxymethyl group is acetyloxymethyl,
It has been described with the formation of various oxymethyl derivatives such as benzoyloxymethyl and other carbonyloxymethyl compounds. Japanese Patent Application Laid-Open No. 61-10589 discloses a specific compound which is collectively identified by the code number LL-F28249, produced by fermentation, and has biological activity. In some of them, position 23 is a hydroxyl group,
25-position is 1-methyl-1-propenyl, 1-methyl-
It has a 16-membered ring macrolide structure corresponding to the above formula (A) substituted with 1-butenyl or 1,3-dimethyl-1-butenyl. In these compounds, the hydroxyl group at the 5-position may be substituted by a methoxy group. The same or similar compound identified as S-541 is known from JP-A-61-118387. The 23-position keto derivative and 23-position deoxy derivative of S-541 are known from JP-A-61-280496. S-541 derivatives having a carbon-carbon double bond at the 22-position and the 23-position are disclosed in JP-A-62-67087. S-541 and the 26-position hydroxy and 26-position C _1-4 alkanoyloxy derivatives of the 23-position keto and 23-position deoxy derivatives of S-541 are known from JP-A-62-226984. JP-A-61-280496 has a hydroxyl group or a substituted hydroxyl group at the 5-position, a hydroxyl group, a substituted hydroxyl group or a keto group at the 23-position, and an α-branched alkenyl group at the 25-position. Another group of macrolide antibiotics has been published. JP-A-62-29590 discloses that the 5-position is a hydroxyl group, the 22- and 23-positions are double bonds, and the 25-position is a general alkyl or alkenyl group, an alkoxyalkyl group, an alkylthioalkyl group,
A cycloalkyl group, a cycloalkenyl group or a heterocyclic group, wherein the 13-position is α-L-oleandrosyloxy-α-
It was substituted with an L-oleandrosyloxy group. A group of compounds corresponding to the above formula (A) is disclosed. JP-A-63-57591 discloses that the 5-position is a hydroxyl group, a methoxy group,
A group of macrolide compounds having a hydroxyl group at the position and an α-branched alkenyl group at the 25 position and corresponding to the above formula (A) has been published. All of the above milbemycin related macrolide compounds are said to have one or more activities as an anthelmintic, ectoparasiticide, acaricide or other pesticide. However, there is a further need to provide compounds having improved activity against one or more web parasite pests.

[Problems to be solved by the invention]

Therefore, it is an object of the present invention to provide new milbemycin compounds having improved parasiticidal activity. It is another object of the present invention to provide a method for making such a compound. It is yet another object to provide a parasiticidal composition based on the present compounds.

Configuration of the Invention

 The activity of the milbemycin derivative is different from that of the 4-position methyl group.
Can be improved by converting the organic substituent of
I came out. The present invention relates to a compound having the formula (I) and a process for preparing the same.
It is about the law. Wherein: -XY- is -CH_Two−CH_Two-, -CH_Two−CH (O
H)-, -CH = CH-, -CH_Two-C (= O)-or -CH
(OH) -CH_TwoIndicates-. R¹Represents an alkyl group, an alkenyl group, an alkynyl group,
Coxyalkyl group, alkylthioalkyl group, cycloalkyl
A alkyl group, a cycloalkenyl group or a heterocyclic group,
R¹When is a cyclic group, the ring has a substituent
Is also good. R^TwoRepresents a hydrogen atom, a methyl group, a hydroxyl protecting group or
Indicates a carboxylic acid residue or carbonic acid residue that forms a stele.
You. R^ThreeIs a hydrogen atom, a halogen atom, a lower alkyl group or OR
^FourAnd R^FourIs lower alkyl group, phenyl group, ester
A carboxylic acid residue or a carbonic acid residue which forms
Sugar residue or oxacycloalkyl that forms tar
Represents a group. A is a lower alkyl group, a formyl group, an azidomethyl group,
A cyanomethyl group, or a formula CH_TwoOCOR^Five, CH_TwoOR⁶, CH_TwoS (CO)_nR
⁶, CH = NO (CO)_nR⁶, CH_TwoN (R⁷) (CO) n-R⁶Or CH_TwoO
SO_TwoR⁸Is shown. n represents 0 or 1, R^FiveIs an aralkyl group or at least one sulfur atom
Or a heterocyclic group containing an oxygen atom. R⁶Represents a hydrogen atom, an alkyl group, an alkenyl group,
Alkyl group, cycloalkenyl group, aryl group or heterocycle
Represents a group. Where R⁶Becomes a hydrogen atom only when n is 0
obtain. R⁷Represents a hydrogen atom, a lower alkyl group or a phenyl group
You. R⁸Represents a lower alkyl group, a phenyl group or a tolyl group
You. A excludes methyl and hydroxymethyl groups.
Good. The invention further relates to insecticides, acaricides, insecticides, etc.
An active parasiticidal composition is provided. The composition is
Pharmaceutical, pesticide, veterinary or garden containing a compound of formula (I)
Composition mixed with an art-acceptable carrier or diluent
Consists of R¹Is an alkyl, alkenyl or alkynyl group
If it is linear or branched, preferably C_1-8
An alkyl group such as methyl, ethyl,
Isopropyl, butyl,sec-Butyl, pentyl,
Isopentyl, hexyl,secHexyl, heptyl,
1-ethylhexyl, 1-propenyl, 1-methyl-1
-Propenyl, 1-methyl-1-butenyl, 1,3-dimethyl
It can be tyl-1-butenyl, ethynyl and the like. R¹Is an alkoxy or alkylthioalkyl group
If they are suitable, they are preferably alkoxy, alkylthio and
And the alkyl moiety is C_1-4For example, methoxymeth
, Methylthiomethyl, 1-methoxyethyl, 1-methyl
Luthioethyl, 1-methoxypropyl, 1-propylthio
Oethyl, butoxymethyl, 1-ethylthiobutyl, etc.
It is possible. R¹When is a cycloalkyl group, they are preferably
Is C_3-8Cycloalkyl C_1-5An alkyl group, for example,
Cyclopropylmethyl, cyclobutylmethyl, 1-cyclo
Lopentylethyl, cyclohexylmethyl, 1-1 cycle
It may be rohebutylbutyl, cyclooctylmethyl, etc.
You. R¹Is an optionally substituted cycloalkyl
When the groups are cycloalkenyl groups, they are preferred.
Suitably C_3-8Cycloalkyl or C_5-8Cycloalkenyl
For example, cyclopropyl, cyclobutyl,
2-methylcyclopropyl, cyclohexyl, 2-cyclo
Rohexenyl, 2,2-dichlorocyclopropyl, cyclo
Hebutyl, cyclooctyl, 2,5-cyclohexa-geni
And so on. R¹May be optionally substituted
If it is a heterocycle, it may be, for example, 3-thienyl, 3
-Frills and the like. R¹Preferable typical examples include methyl, ethyl and the like.
Isopropyl,sec-Butyl, 1-methyl-1-p
Lopenyl, 1-1-methyl-1-butenyl, 1,3-dimethyl
Tyl-1-butenyl and the like. R^TwoIf is a hydroxyl protecting group, it is
May be any of the protecting groups commonly used for example
If the protecting group is of the formula Si (R ') (R ") (R) (wherein
R ', R "and R are each C_1-4Alkyl group, benzyl
A phenyl group or a phenyl group. ) Shown by
It may be a radical. An example of a silyl group is trimethylsilyl.
, Triethylsilyl, tripropylsilyl, triiso
Propylsilyl, diisopropylmethylsilyl,t−
Tyldimethylsilyl, dimethylphenylsilyl,t−
Tyldiphenylsilyl, triphenylsilyl and tri
Contains a benzylsilyl group. Among these groups, trimethy
Lucyl, triethylsilyl andt-Butyldimethyl
Silyl groups are preferred. Protecting groups are also described separately
Carboxylic acid residues or carbonic acid residues that form esters
Group. R^TwoWhere is an acid residue, there are no particular restrictions on the nature of the acid.
No. The biological activity of the compound of formula (I) is -OR^TwoIs a hydroxyl group
Because of the formation of certain compounds,
You can choose from boric acid and carbonic acid. As mentioned above,
Known literature is for the formation of 5-position esterified milbemycin.
Numerous examples of suitable acids are described, such acids being
Can be easily picked up for compounds of the invention
You. Although not exhaustive, R^TwoForms an ester
When the residue is a carboxylic acid or a carbonic acid, the formula -CO- (O)_n
−R⁹Wherein n is 0 or 1, R⁹Is linear or branched
Branched chain C_1-18Alkyl group, C_3-7Cycloalkyl group, C
_7-9Aralkyl group, C_2-6Alkenyl or alkynyl
Group, C_6-10Allyl group or 5 to 10 ring atoms
At least one oxygen, sulfur or nitrogen atom
A monocyclyl group or a fused heterocyclyl group containing
Show. ). R^TenIs, for example, alkyl, alcohol
Xy, alkoxyalkyl, halogen, haloalkyl,
Alkoxycarbonyl, acyloxy, hydroxy,
Ruboxy, amino, mono- or cyalkylcarbamo
Yl, mercapto, alkylthio, alkylsulfini
, Alkylsulfonyl, nitro, phenoxy, haloff
Phenoxy, alkylsulfonyloxy, arylsulfo
Nyloxy, cyanothio and at least one oxygen, sulfur
5- or 6-membered heterocyclyl containing a yellow or nitrogen atom
Having one or more substituents, such as
Is also good. Substituent contains one or more carbon atoms
In this case, the number of carbon atoms is suitably from 1 to 9. R⁹Self
Is an alkyl, alkenyl or alkynyl group
Where the substituent is alkyl, alkoxyalkyl or halo
Not an alkyl group. Preferred R⁹Is ethyl. Specificity of acid residues suitable for use as hydroxy protecting groups
Examples include formyl, acetyl, chloroacetyl,
Loroacetyl, trichloroacetyl, trifluoroacetate
Tyl, methoxyacetyl, propionyl, n-butylyl
, (E) -2-methyl-2-butenoyl, isobutylyl
Lower aliphatics such as pentanoyl or pivaloyl
An acyl group; or benzoyl,o-(Dibromoethyl)
Benzoyl,o-(Methoxycarbonyl) benzoyl,p
-Phenylbenzoyl, 2,4,6-trimethylbenzoy
,p-Tolu oil,p-Anisoyl,p-Chlorobenzo
Il,p-Nitrobenzoyl,o-Nitrobenzoyl or
Has an aromatic acyl group such as α-naphthoyl. R^ThreeWhen is a halogen atom, it is, for example, chloro,
Flor, Brom. R^ThreeIs a lower alkyl group
When, for example, methyl, ethyl, propyl, isopropyl, etc.
And preferably methyl or ethyl. R^FourAre lower alkyl groups, they are C_1-4Alkyl group
And may be linear or branched, and in some cases
May be substituted with a phenyl group. Such a low grade
Examples of the alkyl group include methyl, ethyl, propyl,
Isopropyl, butyl,sec-Butyl,t-Butyl, ben
Jill, 2-phenylethyl or 1-phenylethyl
And the like. R^FourA carboxylic acid residue or carbonic acid which forms an ester
If it is a residue, examples are^TwoAs an acid residue
Group. Particularly preferred R⁹As a group corresponding to
Is, for example, ethyl, propyl, butyl, isopropyl,t
-Butyl, trifluoromethyl, trichloromethyl,
Nil,p-Aminophenyl,m-Aminophenyl,o-A
Minoaenyl, 2,6-difluorophenyl, 2,6-dimethyl
Phenyl, benzyl, α-methylbenzyl, α, α-di
Methylbenzyl,p-Amino-α-methylbenzyl, 2,6
-Dichlorobenzyl, 2,6-dichloro-α-methylben
Jill, α-naphthyl and the like. R^FourAcetal
A sugar residue or oxacycloalkyl group to be formed
In this case, for example, α-L-oleandrosyloxy-α-
L-oleandrosyl, α-L-oleandrosyl,
Lucosyl, ribosyl, 1-oxacyclopentyl, 1-
Oxacyclohexyl and the like. When A is a lower alkyl group, they are_2-6Archi
Represents a linear group or a branched group.
May be substituted with two phenyl groups. Such a
As the alkyl group, ethyl, propyl, butyl, 2-methyl
Butyl, 2-phenylethyl and the like, but preferred
Representative examples are ethyl, propyl or 2-methylbutyi.
Is given. R^FiveAre aralkyl groups, they have a substituent moiety.
You may. As the aralkyl group, for example, benzyl, α-
Methylbenzyl, α, α-dimethylbenzyl, α-methyl
Rouxp-Chlorobenzyl, α-methyl-2,6-difluorobe
Undil, α-methyl-p-Aminobenzyl and the like
You. R^FiveContains at least one sulfur or oxygen atom
In the case of a heterocyclic group, the ring is a sulfur atom or an oxygen atom
May contain a nitrogen atom in addition to the substituent
May be provided. Examples of such heterocyclic groups are
For example, 2-furyl, 2-thienyl, benzo-2-thiene
Nyl, 2-benzothiazolyl and the like. R⁶Is an alkyl or alkenyl group,
C_1-6Alkyl group or C_2-6Alkenyl group, straight chain
Or branched, and one or more
The above hydrogen atom is replaced with a halogen atom or a phenyl group.
It may be. For example, methyl, ethyl, propyl,
Isopropyl, butyl,sec-Butyl,t-Butyl, pen
Chill, hexyl, 2,2,2-trifluoroethyl, etheni
, Propenyl, 2-methylpropenyl, 1-methyl
Lopenyl, butenyl, 2-methylbutenyl, pentenyl
, 2-methylpentenyl, hexenyl, 2,2-dichloro
Loethenyl, 2-phenylethenyl, 2-chloroprope
Nyl and 2-phenylpropenyl. R⁶Are cycloalkyl groups._3-6Cycloal
A kill group, which is a halogen atom, a methyl group or
One or more phenyl groups may be substituted.
Such cycloalkyl groups include, for example, cyclopropyl
Ropyl, 1-methylcyclopropyl, 2-methylcyclo
Propyl, 2,2-dimethylcyclopropyl, 2,2-dichloro
Rocyclopropyl, 1-methyl-2,2-dichlorocyclo
Propyl, cyclobutyl, cyclopentyl, cyclohexyl
Sill and the like. R⁶Are cycloalkenyl groups, they are C_4-6Shiku
Loanikenyl groups, which are halogen atoms, methyl
Is substituted by one or more groups
Is also good. Such cycloalkenyl groups include
Lobutenyl, 2-methylcyclobutenyl, cyclopente
Nil, 2-methylcyclopentenyl, 2-bromocyclo
Hexenyl, cyclohexenyl, 2-methylcyclohexyl
Cenyl, 2-chlorocyclohexenyl, 2-phenyl
Clohexenyl and the like. R⁶Is a substituted phenyl group, the number and position of the substituents are limited.
Although not specified, examples of the substituent include fluoro, chloro,
Bromo, iodo, methyl, ethyl, propyl, isopro
Pill, trialolomethyl, trichloromethyl, methoxy
Ethoxy, methylthio, ethylthio, phenyl,
Enoxy, phenylthio, amino, dimethylamino, d
Toro, acetyl and the like. Preferred for substituted phenyl groups
A typical example isp-Fluorophenyl,p-Chloropheny
,m-Chlorophenyl,o-Chlorophenyl, 2,4-di
Chlorophenyl,p-Bromophenyl,p−Iodopheni
, 3,4-dichlorophenyl, 2,6-difluorophenyl,
p-Methoxyphenyl,p-Tolyl,p-Aminophen
,p-Nitrophenyl, 2-chloro-4-nitrophen
Nil and the like. R⁶Is a heterocyclic group, they are a pyridyl group, a substituted pyridyl group.
Or at least one sulfur or oxygen atom
Represents a heterocyclic group. R⁶Is a substituted pyridyl group, the preferred substituted pyridyl group
Representative examples include 2-chloro-3-pyridyl, 2
-Chloro-4-pyridyl, 2-chloro-5-pyridyl and the like
Is raised. R⁶Contains at least one sulfur or oxygen atom
In the case of a heterocyclic group, the ring is a sulfur atom or an oxygen atom
May contain a nitrogen atom in addition to the substituent
May be provided. Examples of such heterocyclic groups are
For example, 2-furyl, 2-thienyl, benzo-2-thiene
Nyl, 2-benzothiazolyl and the like. R⁷And R⁸Are linear when they are lower alkyl groups.
C_1-6Represents an alkyl group. Next, specific examples of the present invention are shown in the following table.
−, R¹, R^Two, R^ThreeAnd A are those shown in general formula (I)
Is the same as  In the above formula, each symbol has the following meaning. Me: methyl group Et: ethyl group Pr: propyl groupi Pr: isopropyl group Bu: butyl groupsec −Bu:sec-Butyl group TBDMS:t-Butyldimethylsilyl group The compound of the formula (I) of the present invention can be obtained by the following reaction scheme.
-Y-, n, and R¹To R⁸Is the same as above. B is the formula OC
OR^FiveOr OSO_TwoR⁸Is shown. E is fluorine, chlorine, iodine
Or expression OR⁶Is shown. D represents a lower alkyl group, an azide group,
Ano group or fluorine, chlorine, iodine or formula S (CO)_nR⁶,if
K is N (R⁷) − (CO)_n−R⁶Is shown. By the process shown in｝
Can be manufactured.  In the reaction diagram, step A is a 26-position methyl group,
The methyl group attached to the 4-position of the bemycin molecule can be selectively acidified
This is a step of converting to a 26-position hydroxymethyl group. this
The reaction is called "Sharpless reaction" or "Sharpless oxidation".
Selenium dioxide and t-butylhydro
Allyl oxidation using peroxide. Applies Sharpless reaction to macrolides of formula (II)
Is already known, and JP-A-58-59988 discloses
Referenced. In order to perform Step A, the amount of selenium dioxide catalyst
In the presence of the 4-methyl compound of formula (II)t-Butyl hydride
Oxidizes with peroxide.t-Butyl hydroperoxy
Sid is reduced selenium to further oxidize the molecule
The compound is oxidized back to selenium dioxide. Smell this way
Selenium dioxide requires very little catalyst
It is. The reaction is performed in an inert solvent that is not easily oxidized. Acetic acid
Also uses ethyl, tetrahydrofuran and other solvents
However, methylene chloride is preferred. reaction
The temperature is not particularly limited, but is, for example, 0 to 50 ° C.
Reaction at room temperature is preferred. Reaction is usually 1 to 48 hours
The reaction generally takes about 24 hours under suitable conditions
Complete in time. Step B is the formula R^FiveCOOH or R⁸SO_ThreeH (R^FiveAnd R⁸Is
The same as above) or a compound derived from its reactive derivative
The esterification of the hydroxyl group at the 26-position of (III)
It can be performed under known conditions. Examples of reactive derivatives include acid chloride, acid bromide
Acid halides, such as chloride or acid iodide; acid anhydrides;
Mixed acid anhydride; pentachlorophenyl ester or p
Active esters such as nitrophenyl esters; and
And active acid amides. Step B is preferably performed in the presence of a solvent,
The nature of the solvent is not particularly limited as long as there are no side effects in the reaction.
No. Examples of suitable solvents include hexane, petroleum ether,
Benzene, toluene, xylene, chloroform, chloride
Aliphatic or aromatic, such as tyl or chlorobenzene
And optionally halogenated hydrocarbons
Element: diethyl ether, tetrahydrofuran or geo
Ethers such as xanes; and methyl acetate or acetic acid
Includes esters such as ethyl. Reaction over a wide temperature range
The reaction may be carried out over a range of 0 ° C to 100 ° C.
It is convenient to be carried out at, more preferably 20 ℃ ~
The temperature is 50 ° C. The time it takes to respond depends on many factors.
Although 30 minutes to 3 hours are usually sufficient. Generally, 1 to 10 equivalents of the acid or its reactive derivative
Amount, more preferably 1.5 to 4 equivalents, of a compound of formula (III)
Used per mole of product. If the acid itself is used, the reaction is
Hexylcarbodiimide (DCC), polyethyl phosphate
Stell (PPE), mesitylenesulfonyl triazolide (M
ST), desulfurization such as p-toluenesulfonic acid or sulfuric acid.
It is carried out in the presence of a solution, more preferably DCC. Prolapse
The amount of the solution is usually 1 to 5 equivalents, preferably 1.5 equivalents.
It is 4 equivalents. If DCC is used, the reaction is
Bases such as gin or 4-pyrrolidino-pyridine
It is expedient to work in the presence of a medium volume. In step C, the hydroxyl group at the 26-position was alkylated with an alkyl halide.
This is a step of obtaining a compound of the formula (Ic) by telling. For etherification, the hydroxyl group at position 26 is usually converted to a metal alcoholate.
After that, by reacting with an alkyl halide, etc.
Be done. To make a metal alcoholate, for example,
Thorium, potassium hydride, alkyl lithium, green
For example, a silver reagent, silver oxide or silver carbonate is used.
Preferably, it is sodium hydride or silver oxide. Haloge
Although there is no particular limitation on the alkyl iodide, iodide
Desirably. Examples of haloalkyl and the like include:
Iodomethane, iodoethane, 2-iodopropane, 4
-Iodo-2-methyl-2-butene, 1-iodo-2,2
-Dimethylcyclopropane, benzyl bromide, ben iodide
Jill, iodobenzene and the like. Step C is preferably performed in the presence of a solvent.
The nature of the solvent is not particularly limited as long as it has no side effects on the reaction.
No. Examples of suitable solvents include hexane, petroleum ether,
Benzene, toluene, xylene, chloroform, chloride
Like Tylene, Dichloroethane or Chlorobenzene
It may be aliphatic or aromatic and may be halogenated.
Hydrocarbons which may be added; diethyl ether, tetrahi
Ethers such as drofuran or dioxane; and
Dimethylsulfoxide, dimethylformamide, etc.
No. The reaction may be performed over a wide range of temperatures,
Conveniently at a temperature of 100 ° C to 100 ° C,
More preferably, the temperature is from -70 ° C to 30 ° C. To the reaction
The time required depends on many factors, but can range from 30 minutes
Three hours is usually sufficient. Generally, 1 to 10 equivalents of a reactant such as a haloalkyl,
More preferably, 1.5 to 4 equivalents of the compound of formula (III)
Used per mole of Step D comprises oxidizing the hydroxyl group at the 26-position of compound (III) to give a compound of formula (I
This is the step of obtaining the compound of d). Hydroxyl group as oxidizing agent
There is no particular limitation as long as it is commonly used for the oxidation of
For example, chromium oxide pyridine (Collins reagent),
Tajinium dichromate (PDC), pyridinium chloro
Chromate (PCC), oxalyl chloride-triethylamido
-Dimethylsulfoxide (Swern oxidation), man dioxide
A gun or the like is used. Step D is preferably performed in the presence of a solvent,
The nature of the solvent is not particularly limited if there are no side effects in the reaction.
No. Examples of suitable solvents include hexane, petroleum ether,
Benzene, toluene, xylene, chloroform, chloride
Aliphatic or aromatic like Tylene or Chlorobenzene
Or a halogenated charcoal
Hydrogen; diethyl ether, tetrahydrofuran or
Ethers such as dioxane; and methyl acetate or
Includes esters such as ethyl acetate. The reaction is over a wide range of temperatures
The reaction may be carried out between 0 ° C and 100 ° C.
It is convenient to carry out at a temperature, more preferably at 20 ° C.
The temperature is 50 ° C. The time it takes to react depends on many factors
30 minutes to 3 hours are usually sufficient
You. Step E comprises the step of oxylating the formyl group at the 26-position of the compound of formula (Id).
This is a step of obtaining a compound (Ie). Hydroxylamine as the oximation agent,o-Al
Kill hydroxylamine,o-Alkenyl hydroxyl
Amine oro-Arylhydroxylamine, etc.
Are their hydrochlorides. Step E is preferably performed in the presence of a solvent,
The nature of the solvent is not particularly limited if there are no side effects in the reaction.
No. Examples of suitable solvents are water, ethanol or ethanol.
Protic solvents such as toluene; diethyl ether,
Ethers such as drofuran or dioxane; and
Dimethylformamide or dimethylsulfoxide, etc.
Alternatively, a mixed solvent thereof may be used. Reaction is extensive
The reaction may be carried out over a temperature of 0 ° C to 100 ° C.
It is expedient to carry out the reaction at a temperature of
The temperature is between 50 ° C and 50 ° C. The reaction takes a lot of time
Depending on the factors, usually 1 to 12 hours is enough
is there. Generally 1 to 10 equivalents of oximation agent, more preferred
Has 2 to 8 equivalents per mole of the compound of formula (Id)
used. Step F is based on the formula (Ib¹26) alkyl of the compound or
Arylsulfonyloxy groups can be converted to lower
Alkyl group, azide group, cyano group, fluorine, chlorine, iodine
Element or formula S (CO)_nR⁶Or R⁷-N- (CO)_nR⁶Convert with
This is the step of performing Examples of nucleophilic reagents include ammonia and alkylamido.
Amines such as amines and dialkylamines; Grignard reagents,
Organic gold such as lithium lithium and trialkyl aluminum
Genus compounds: potassium fluoride, cesium fluoride, sodium iodide
Metal halides such as thorium and lithium iodide;
Hydrogen hydride, hydrogen cyanide, mercaptan, thiol carb
Acid salts or metal salts such as monoacylamines
It is. Step F is preferably performed in the presence of a solvent,
The nature of the solvent is not particularly limited if there are no side effects in the reaction.
No. Examples of suitable solvents include hexane, petroleum ether,
Benzene, toluene, xylene, chloroform, chloride
Aliphatic or aromatic like Tylene or Chlorobenzene
Or a halogenated charcoal
Hydrogen; diethyl ether, tetrahydrofuran or
Ethers such as dioxane; methyl acetate or ethyl acetate
Esters such as tyl; dimethylformamide or di
Amides such as methylacetamide; and dimethyls
And the nature and reaction of nucleophilic reagents.
Those suitable for the temperature conditions are selected. The reaction may be performed over a wide range of temperatures
It is convenient to carry out at a temperature of
Preferably, the temperature is between -50 ° C and 30 ° C. Required for reaction
The time depends on many factors, but between 5 minutes and 8 o'clock
Usually between is enough. Generally, 1 to 10 equivalents of the nucleophile, more preferably
Two to six equivalents are of the formula (Ib¹) Per mole of compound
Used. Step G is based on the formula (If¹) To reduce the 26-position azide group
This is a process for converting to an amino group.
This is done in a known manner. However, reduction reaction
Damages other functional groups such as the olefin moiety.
It is necessary that zinc-acetic acid
The reduction is optimal. Step G is preferably performed in the presence of a solvent,
The nature of the solvent is not particularly limited if there are no side effects in the reaction.
No. Examples of suitable solvents include hexane, petroleum ether,
Benzene, toluene, xylene, chloroform, chloride
Aliphatic or aromatic like Tylene or Chlorobenzene
Which may be a group and may be halogenated
Hydrogen; diethyl ether, tetrahydrofuran or di
Ethers such as oxane; methyl acetate or ethyl acetate
Esters such as dimethylformamide or dimethylformamide
Amides such as tilacetamide; and methylsulfo
Oxide and the like. The reaction spans a wide range of temperatures
The reaction may be carried out at a temperature between 0 ° C. and 100 ° C.
It is convenient and more preferably between 20 ° C and 50 ° C.
Temperature. The time required for a reaction depends on many factors.
However, 30 minutes to 3 hours are usually sufficient. The amount of zinc and acetic acid used is determined by the compound (If¹) For
It is usually 5 to 20 equivalents, preferably 8 to 15 equivalents. In formula (Ie) obtained in each step, R⁶Is a compound of a hydrogen atom
And D in the formula (If) is a mercapto group or amino
The hydroxyl, mercapto and amino groups of the compound
Carboxylic acid ester or by the same method as in step b
It can be a carboxamide. Compounds obtained in steps B, C, D, E, f and G
The 5-position hydroxyl group of (I) is protected by a silyl protecting group
Deprotect the 5-position hydroxyl group to convert it to a hydroxyl group.
Can be Deprotection includes dilute acids such as dilute hydrochloric acid and dilute sulfuric acid;
Mechanical acid; p-toluenesulfonic acid / tetrabutylammonium
Using mufluoride or hydrogen fluoride / pyridine
Attained, preferably in diluted hydrochloric acid and hydrogen fluoride.
Pyridine. The acid is usually in excess and preferably
Is about 2 to 100 equivalents. The deprotection reaction is preferably performed in the presence of a solvent.
The nature of the solvent is not particularly limited as long as the reaction has no side effects.
No. Suitable solvents include, for example, hexane, petroleum
-Tel, benzene, toluene, chloroform, methyl chloride
Hydrocarbons such as ren, dichloroethane (aliphatic or
Is aromatic and may be halogenated);
Luether, tetrahydrofuran, dioxane, dimethoate
Ethers such as xyethane; methanol, ethanol
Alcohols such as acetonitrile, propioni
Nitriles such as tolyl; and mixtures of these solvents
Is raised. The reaction takes place over a wide range of temperatures, the temperature chosen
It is not limited to the present invention. However, the reaction
Is conveniently carried out at a temperature between -20 ° C and 70 ° C, but
More preferably, it is -10 ° C to 30 ° C. When it takes to react
The time depends on many factors, but can range from 30 minutes to 24 hours,
Preferably 30 minutes to 6 hours are generally sufficient. R^FiveIs a hydrogen atom of a carboxylic acid
Or esterified with carbonic acid or its reactive derivative
Thus, the compound is esterified at the 5-position. After completion of the reaction in each step, the product is mixed by a well-known method.
From the material and, if necessary, column chromatography
It is further purified by known means such as-. formula
The compound of (I) is sometimes a mixture of such compounds.
But they need not be separated from each other
There is no. The starting material of formula (II) is a known compound, or
It can be produced by the method described in the literature. for example
For example, JP-B-56-45890, JP-A-53-130695, JP-A-57-1
20589, Jr. Am. Chem. Soc., 1981,103, 4216, Tokiko 62-541
13, JP-A-54-61198, JP-A-57-18684, JP-A-61-11838
7, JP-A-61-10589, JP-A-62-67087, JP-A-61-28049
6, JP-A-54-145699. Milbemycin derivative of formula (III) as a starting compound
Among them, the compound in which the 13-position is a hydroxyl group is disclosed in JP-A-58-59988.
Wherein the 13-position of the formula (II) is a halogen atom
The compound is obtained by reacting a compound having a hydroxyl group at position 13 with a halogenating agent.
13th place OR⁹And R⁹Is es
Form a carboxylic acid residue or ester that forms a ter
Compounds having a carbonic acid residue include compounds having a hydroxyl group at position 13.
It is obtained by esterification with the desired acid. That is, in 13-hydroxylation, the 13-position is a hydrogen atom
Compound with selenium dioxide in presence of lower alkanoic acid catalyst
It is a method of oxidation. For 13-halogenation, the 13-position is a hydroxyl group
For example, dimethylaminosulfur trif
Fluoride, phosphorus trichloride, thionyl chloride, phosphorus tribromide,
Bromotrimethylsilane, chlorotrimethylsilane-iodine
React with a halogenating agent such as sodium halide. S
Tellation is a reaction of a compound with a hydroxyl group at position 13 with a desired acid.
By reacting the acidic derivative with ordinary esterification means.
Manufactured. R^ThreeIs a hydrogen atom.^ThreeThe purpose of which has other significance
Known methods can be used to convert the compound.
You. Such conversion is performed in Step A and Step B
It is preferably done before. Esterification of 5-position hydroxyl group with carboxylic acid or carbonic acid
Is performed using the technique described for step B above.
Can be. The starting material, which is a natural product, can be a single separated compound or separated
A mixture of two or more types used without being used is used. for example
For example, Milbemycin A_ThreeAnd A_FourMixture is easily obtained
They are easy to use and easy to use.
Each reaction can be used without separation. The compounds of formula (I) of the present invention are useful on fruit trees, vegetables and flowers.
Native spider mites (Tetranychus), apple spider mites,
Adults such as red mites (Panonychus) and rust mites and
Eggs, Ixodidae, Parasitoids Parasitizing Animals
(Dermanysside) and Sarcoptidae (Sarcoptidae)
Has excellent acaricidal activity against More sheep
Fly (Oestrus), Flies (Lucilia), Cowflies
(Hypoderma), flies (Gautrophilus), etc.
Ectoparasites of animals and birds, such as turtles and lice; cockroaches, houses
Hygiene pests such as flies; other aphids, moths, lepidoptera
Active against various plantation pests such as eye larvae. The compounds of the present invention can also be used for the root-knot nematodes (Me
loidogyne), pine wood nematode (Bursaphelenchu)
s), also active against spider mites (Phizoglyphus)
You. The compounds of the invention are effective against animal and human endoparasites.
It has excellent activity. Especially pigs, sheep, goats,
Livestock, poultry and pets such as cows, horses, dogs, cats and chickens.
In addition to nematodes that infect larvae, Filariidae
And Setariidae parasites, human digestive tract,
Against parasites found in blood or other tissues and organs
It is still effective. In order to use the compound of the present invention for agricultural and horticultural use, a carrier and
Mixed with other auxiliaries as needed and used as a pesticide
Dosage forms such as powders, wettable powders, emulsions and water
Or a composition such as an oily suspension or aerosol
used. The carrier referred to here is the
Helps reach the active ingredient compound,
Pesticides to facilitate storage, transport or handling
Synthetic or natural inorganic or organic substances mixed in
means. Suitable solid carriers include kaolinites,
Represented by lonite group or attapulgite group
Clay, talc, mica, phyllite, pumice, vermicul
Light, gypsum, calcium carbonate, dolomite, keiso
Rust, magnesium carbonate, apatite, zeolite, anhydrous
Inorganic substances such as silicic acid, synthetic calcium silicate, soy flour,
Tobacco flour, walnut flour, flour, wood flour, starch, crystal
Plant organic substances such as lulose, coumarone resin, petroleum tree
Fat, alkyd resin, polyvinyl chloride, polyalkylene
Recall, ketone resin, ester gum, copal gum,
Synthetic or natural polymer compounds such as dammar gum, cal
Waxes such as Nava wax and beeswax, or urea
I can do it. Suitable liquid carriers include kerosene, mineral oil, and spind
Oil, white oil, etc.
Hydrocarbons: benzene, toluene, xylene, ethyl
Aromatic hydrocarbons such as benzene, cumene and methylnaphthalene
Element: carbon tetrachloride, chloroform, trichloroethylene,
Monochlorobenzene,o-Chlorinated carbon such as chlorotoluene
Hydrogen; ane such as dioxane and tetrahydrofuran
Ters: acetone, methyl ethyl ketone, diisobutyl
Ketone, cyclohexanone, acetophenone, isophorone
Ketones such as ethylene; ethyl acetate, amyl acetate, ethylene glycol
Recall acetate, diethylene glycol acetate
, Dibutyl maleate, diethyl succinate, etc.
Compounds; methanol, n-hexanol, ethylene glycol
Tools, diethylene glycol, cyclohexanol,
Alcohols such as benzyl alcohol; ethylene glycol
Ethyl ether, ethylene glycol phenyl ether
, Diethylene glycol ethyl ether, diethylene
Ether alcohols such as glycol butyl ether;
Polarity such as dimethylformamide and dimethylsulfoxide
Examples thereof include a solvent and water. Also as a gas carrier
Gases like air, nitrogen, carbon dioxide, freon are good,
These can be mixed and injected. In addition, properties such as dispersion, emulsification, spreading, penetration,
Various surfactants, high molecular compounds, etc.
If necessary, add this drug to animals and plants,
It can increase the yield and increase the effect. Emulsification, dispersion, wetting, spreading, binding, disintegration control, active ingredient
Interface used for stabilization, fluidity improvement, rust prevention, etc.
Activators include non-ionic, anionic, cationic and
Any of the zwitterionics can be used, but usually
Nonionic and / or anionic are used
It is. Suitable nonionic surfactants include, for example,
Is lauryl alcohol, stearyl alcohol,
Ethylene oxide to higher alcohols such as yl alcohol
Polymerized, isooctylphenol, noni
Ethylene phenol to alkylphenols such as
Butyl naphthol, octyl
Ethylene oxide to alkyl naphthol such as naphthol
Polymerized, palmitic acid, stearic acid,
Polymerization of ethylene oxide on higher fatty acids such as oleic acid
Added, stearic phosphate, dilauryl phosphate, etc.
Ethylene oxide to mono- or di-alkyl phosphoric acid
Polymerized addition, dodecylamine, stearic acid
Polymerization of ethylene oxide with amines such as amide
Higher fatty acid esthetics of polyhydric alcohols such as sorbitan
Polymerized with ethylene oxide
Of ethylene oxide and propylene oxide
And the like. Suitable anionic surfactant
Examples of the agent include sodium lauryl sulfate and oleic acid.
Alkylsulfuric acid such as amine sulfates of alcoholic sulfate
Ester salt, dioctylsternatorium sulfosuccinate
Alcohol such as sodium 2-ethylhexenesulfonate
Kill sulfonic acid salt, isopropyl naphthalene sulfonic acid
Sodium, sodium methylenebisnaphthalenesulfonate
, Sodium ligninsulfonate, dodecylbenze
Aryl sulfonates such as sodium sulfonate
can give. Further, the composition of the present invention improves the properties of
Casein, gelatin, albumin
, Glue, sodium alginate, carboxymethyl cell
Loin, methylcellulose, hydroxyethyl cellulose
Polymers, polyvinyl alcohol, etc. and other auxiliary compounds
Agents can be used in combination. The above carriers and various adjuvants are used in the formulation
Considering aspects, etc., each individually or according to the purpose
They are used as appropriate in combination. Dusts are, for example, usually 1 to 25% by weight of the active ingredient compound.
And the balance is a solid carrier. The wettable powder is, for example, usually 10 to 90 times the active ingredient compound.
Of the solid carrier and the dispersing wetting agent.
Protective colloids, thixotropes, defoamers as needed
Etc. are added. Emulsions usually contain, for example, 5 to 50% by weight of an active ingredient compound.
About 5 to 20 parts by weight of the emulsifier.
Included, the remainder is a liquid carrier, if necessary, a rust inhibitor
Added. The oil agent may be, for example, usually 0.5 to 5 layers of the active ingredient compound.
And the balance is a liquid carrier such as kerosene. Aerosols, for example, usually contain no active ingredient compounds
5 parts by weight, optionally containing fragrances, the balance
Is an oily and / or liquid carrier, liquefied petroleum gas,
Propellants such as CFC gas and carbon dioxide gas are sealed.
You. The composition of the present invention thus prepared in various dosage forms
Objects in paddy fields, orchards or fields, for example
When sprayed on insects, spider mites parasitized crops or livestock
In this case, 0.5 to 100 ppm as active ingredient concentration is
Effective control by applying to leaves, soil or livestock
I can do it. The compounds of the present invention as anthelmintics in animals and humans
If used, administered orally as a liquid beverage
Can be. Beverages are usually made with suspending agents such as bentonite and
Suitable non-toxic solvents or wetting agents or other excipients
Is a solution, suspension or dispersion in water. Generally, beverages
It also contains an antifoaming agent. Beverage formulations generally contain the active compound
About 0.01-0.5% by weight, preferably 0.01-0.1% by weight
You. When administering the compound of the present invention by animal feed,
Disperse it homogeneously in the feed or top dressing
Used as or in the form of pellets
You. To achieve the normally desirable antiparasitic effect,
Contains 0.0001-0.02% of active compound in the final feed
You. Further, the compound of the present invention is dissolved or dissolved in a liquid carrier excipient.
Inject into the forestomach, intramuscularly, intratracheally or subcutaneously.
It can be administered to animals parenterally by injection. Non
For oral administration, the active compound is preferably a dropping oil, cotton.
Mix with a suitable vegetable oil, such as a real oil. Such a prescription
Contains generally from 0.05 to 50% by weight of active compound. The compounds of the present invention may also include dimethyl sulfoxide or charcoal.
By mixing with a suitable carrier such as a hydride solvent
It can be administered locally. This formulation can be sprayed or injected directly.
Applied directly to the external surface of the animal. The optimal amount of active compound used for best results is
Depending on the type of animal being treated and the type and extent of parasite infection
In general, about 0.01 to 100 mg per kg of animal weight,
Preferably obtained by oral administration of 0.5 to 50.0 mg.
It is. Such usage amounts may be used once or in divided
Given over a relatively short period of time, such as 1-5 days. Next, the present invention will be described in more detail with reference to examples. Example 1 (Step B) 26-methanesulfonyloxy-5-O−t-Butyl dime
Tilsilylmilpemycin A_Four(Compound No. 188) 26-hydroxy-5-O−t-Butyldimethylsilylmi
Rubemycin A_Four(1.42g) and triethylamine (0.32m
l) in dichloromethane (20 ml) solution at 0 ° C in methane chloride
Sulfonyl (0.64 ml) was added dropwise over 5 minutes. Reaction mixture
The mixture was stirred at the same temperature for 1 hour, and then saturated saline was added.
Extracted with ethyl acetate. Organic layer is anhydrous magnesium sulfate
And then concentrated. The obtained residue is applied to a silica gel column.
Purify by chromatography to obtain the target compound (1.1 g, yield 66).
%). Mass spectrum (EI method) (m / z): 750 (M⁺), 732,693,65
4,636,597. Nuclear magnetic resonance spectrum (270MHz) δ (CDCl_Three) Ppm: 3.01 (s, 3H, SO_TwoCH_Three), 3.07 (dt, 1H, J = 2.4Hz, J = 8.9Hz,
C_{twenty five}−H), 3.86 (d, 1H, J = 5.6Hz, C₆−H), 4.55−4.95
(M, 5H, C₂₆−H, C₂₆−H, C_Five-H). Example 2 (Step C) 26-methoxy-5O−t-Butyldimethylsilyl mill
Bemycin A_Four(Compound No. 44) 26-methoxy-5-O−t-Butyldimethylsilyl mill
Bemycin A_Four(67mg) in dichloroethane (5ml) solution
Silver oxide (232 mg) and methyl iodide (0.38 ml) at room temperature
Was added and stirred for 20 hours. After filtering the reaction mixture, the solution was concentrated.
Shrunk. The resulting residue is purified by preparative thin-layer chromatography.
Purification gave the desired product (50 mg, 73% yield). Mass spectrum (EI method) (m / z): 686 (M⁺), 668,654,62
9,579,536 Nuclear magnetic resonance spectrum (270MHz), δ (CDCl_Three) Ppm: 3.07 (dt, 1H, J = 2.7Hz, J = 9.3Hz, C₂₆−H), 3.31 (s, 3
H, OCH_Three), 3.80 (d, 1H, J = 12.5Hz, C₂₆−H), 4.16 (d, 1
H, J = 12.5Hz, C₃₆-H). Example 3 (Step D) 26-hydroxy-5-O−t-Butyldimethylsilylmi
Rubemycin A_Four(Compound No. 12) 26-hydroxy-5-O−t-Butyldimethylsilylmi
Rubemycin A_Four(67 mg) in dichloromethane at room temperature
Manganese dioxide (435 mg) was added and the mixture was stirred for 90 minutes. reaction
After the mixture was filtered, the solution was concentrated to obtain the target compound. Mass spectrum (EI method) (m / z); 670 (M⁺), 652,595,52
Example 4 (Step E) 26-oxo-5O−t-Butyldimethylsilylmilbe
Mycin A_FourOxime (Compound No. 149) Residue obtained in Example 3 and hydroxyamine hydrochloride (70 mg)
In water / methanol / dioxane (1: 2: 3v / v, 5ml)
Stir for 5 minutes at warm. Pour the reaction mixture into ice-cold water and add
Extracted with chill. After washing the organic layer with water, anhydrous sodium sulfate
And concentrated. The obtained residue is separated by preparative thin-layer chromatography.
Purify by luffy and purify the desired product (40 mg, 26-hydroxy-5-O
−t-Butylmethylsilylmilbemycin A_FourYield from 5
8%). Mass spectrum (EI method) (m / z): 685 (M⁺), 628,610,59
2,519. Nuclear magnetic resonance spectrum (270MHz) δ (CDCl_Three) Ppm: 3.08 (dT, 1H, J = 2.4Hz, J = 9.3Hz, C_{twenty five}−H), 7.73 (s, 1
H, CH = N). Example 5 (Step F) 26-methyl-5O−t-Butyldimethylsilylmilbe
Mycin A_Four(Compound No. 1) 26-methanesulfonyloxy-5-O−t-Butyl dime
Tilsilylmilbemycin A_Four(53.4mg) hexane (2m
l) Add 19% trimethylaluminum (hex
Solution, 0.36 ml) and the mixture was stirred at the same temperature for 15 minutes. reaction
Pour the mixture into ice-cold water, filter and extract the filtrate with ethyl acetate
did. The organic layer was washed with water and then with saturated saline, and then dried over anhydrous sulfur.
Dried over sodium acid and concentrated. Residues are nika gelka
Purification by column chromatography and the desired product (20 mg, yield 42)
%). Mass spectrum (EI method) (m / z): 670 (M⁺), 613,595,57
7,453,429,414. Nuclear magnetic resonance spectrum (270MHz) δ (CDCl_Three) Ppm: 0.130 (s, 3H, SiCH_Three), 0.133 (s, 3H, SiCH_Three), 0.92 (s, 9
H, C (CH_Three)_Three), 3.08 (dt, 1H, J = 2.4Hz, J = 11.3Hz, C_{twenty five}−
H), 3.39 (m, 1H, C_Two−H), 3.81 (d, 1H, J = 5.6Hz, C₆−
H), 4.48 (dm ,, 1H, J = 5.6Hz, C_Five−H), 4.58 (d, 1H, J =
14.1Hz, C₂₇−H), 4.65 (d, 1H, J = 14.1 Hz, C₂₇−H), 5.
29 (brs, 1H, C_Three-H). Example 6 (Step F) 26-azido-5O−t-Butyldimethylsilylmilbe
Mycin A_Four(Compound No. 18) 26-methanesulfonyloxy-5-O−t-Butyl dime
Tilsilylmilbemycin A_Four(224ml) tetrahydro
Sodium azide (46mg) in furan (4ml) solution at room temperature
Aqueous solution (0.2 ml) was added and stirred for 3 hours. Reaction mixture
Was poured into ice-cold water and extracted with sodium acetate. Organic layer with water
After washing, it was dried over anhydrous sodium sulfate. Reduce solvent at 15 ° C
The desired product and 3-azido-2,3-dihydro-
Δ4,26−5−O−t-Butyldimethylsilylmillbemashi
A_Four(Approximately 4: 1, 204 mg). Mass spectrum (EI method) (m / z): 697 (M⁺), 679,640,61
2,594,521. Example 7 (Step F) 26-cyano-5O−t-Butyldimethylsilylmilbe
Mycin A_Four(Compound No. 23) 26-methanesulfonyloxy-5-O−t-Butyl dime
Tilsilylmilbemycin A_Four(145mg) hexane (2m
l) 1.0 M of diethylaluminum cyanide in solution at 0 ° C
Toluene solution (1.54 ml) was added and stirred at room temperature for 5 hours.
Was. The reaction mixture was poured into ice-cold water and filtered, and the filtrate was washed with ethyl acetate.
Extracted. Wash the organic layer with water and then with saturated saline
Then, it was dried over anhydrous sodium sulfate and concentrated. Residue
Purified by Ricagel column chromatography
(13.5 mg, 10% yield) was obtained. Mass spectrum (EI method) (m / z): 681 (M⁺), 624,464,44
0,414,342. Nuclear magnetic resonance spectrum (270MHz) δ (CDCl_Three) Ppm: 0.15 (s, 3H, SiCH_Three), 0.16 (s, 3H, SiCH_Three), 0.93 (s, 9H, C
(CH_Three)_Three), 3.02-3.19 (m, 2H, C_{twenty five}−H, C₂₆−H), 3.28−
3.41 (m, 2H, C_Two−H, C₂₆−H), 3.84 (d, 1H, J = 5.2Hz, C₆
-H), 4.60 (dd, 1H, J = 1.6 Hz, J = 14.1 Hz, C₂₇−H), 4.
66 (dd, 1H, J = 2.0Hz, J = 14.1Hz, C₂₇−H), 5.77 (brs, 1
H, C_Five-H) Example 8 (Step F) 26-phenylthio-5-O−t-Butyldimethylsilyl
Milbemycin A_Four(Compound No. 93) To a suspension of 60% sodium hydride (11 mg) in THF (1 ml)
Add thiophenol (0.03 ml) at room temperature and stir for 5 minutes
Was. Here, at the same temperature, 26-methanesulfonyloxy-5-
O−t-Butyldimethylsilylmilbemycin A_Four(141m
g) in THF (2 ml) was added dropwise and stirred for 15 minutes. reaction
The mixture was poured into ice-cold water and extracted with ethyl acetate. Organic layer
After washing with water and then with a saturated saline solution, anhydrous sodium sulfate is used.
Dried and concentrated. The residue is purified by silica gel column chromatography.
Purification by luffy gave the desired product (78 mg, yield 54%). Mass spectrum (EI method) (m / z): 764 (M⁺), 707,699,65
5,637,579,414. Nuclear magnetic resonance spectrum (270MHz) δ (CDCl_Three) Ppm: 3.06 (dt, 1H, J = 2.4Hz, J = 9.3Hz, C₂₆−H), 3.54 (d, 1
H, J = 14.1Hz, C₂₆−H), 3.70 (d, 1H, J = 14.1Hz, C₂₆−
H), 4.80 (d, 1H, J = 4.8Hz, C_Five−H), 7.21 to 7.31 (m, 5
H, C₆H_Five). Example 9 (Step F) 26-dimethylamino-5O−t-Butyldimethylsilicone
Lumilbemycin A_Four(Compound No. 183) 26-methanesulfonyloxy-5-O−t-Butyl dime
Tilsilylmil bemacyin A_Four(230mg) tetrahydro
50% dimethylamine aqueous solution in furan (41 ml) solution at room temperature
(0.06 ml) was added and stirred for 2.5 hours. Ice water
And extracted with ethyl acetate. Organic layer is dried with anhydrous sodium sulfate
After drying with helium, the mixture was concentrated. The residue obtained is silica gel
Purified by column chromatography and the target compound (117 mg, yield
58%). Mass spectrum (EI method) (m / z): 699 (M⁺), 684,642,56
7,195. Nuclear magnetic resonance spectrum (270MHz) δ (CDCl_Three) Ppm: 0.31 (s, 3H, SiCH_Three), 0.14 (s, 3H, SiCH_Three), 0.92 (s, 9H, C
(CH_Three)_Three), 2.17 (s, 6H, N (CH_Three)_Two), 2.56 (d, 1H, J = 13.3H
z, C₂₆−H), 3.07 (dt, 1H, J = 2.4Hz, J = 9.3Hz, C_{twenty five}−
H), 3.26 (d, 1H, J = 13.3Hz, C₂₆-H). Example 10 (Step G) 26-amino-5O−t-Butyldimethylsilylmilbe
Mycin A_Four(Compound No. 170) The 26-azide form and the 3-azide form obtained in Example 6 (about
4: 1) mixture (204 mg) in dimethylformamide (51 m
l) Add water (0.2 ml), acetic acid (0.2 ml) and
Lead powder (202 mg) was added and stirred for 2 hours. To the reaction mixture
Add ethyl acetate / benzene (1: 1 v / v) and add saturated heavy water,
Then, it was washed with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate.
After washing with uranium, the mixture was concentrated. The residue obtained is silica gel
Purify by column chromatography and purify the target compound (99 mg, 26
-Yield from methanesulfonyloxy compound 49%) and 3
-Amino-2,3-dihydro-Δ^4.26−5-O−t-Butyl
Dimethylsilylmilbemycin A_Four(29 mg, same, yield 14
%). ○ Target compound Mass spectrum (EI method) (m / z): 671 (M⁺), 653,614,59
7 Nuclear magnetic resonance spectrum (270MHz) δ (CDCl_Three) Ppm: 3.07 (dt, 1H, J = 2.4Hz, J = 9.3Hz, C_{twenty five}−H), 3.30 (d, 1
H, J = 5.7Hz, C₂₆−H), 3.39 (brs, 1H, C_Two−H), 3.47
(D, 1H, J = 5.7Hz, C₂₆-H). ○ 3-amino, 2,3-dihydro-Δ^4.26−5-O−t-Buchi
Ledimethyllylmilbemycin A_Four Mass spectrum (EI method) (m / z): 671 (M⁺), 653, 614. Nuclear magnetic resonance spectrum (270MHz) δ (CDCl_Three) Ppm: 2.36 (d, 1H, J = 12.1Hz, C_Two−H), 3.07 (dt, 1H, J = 2.4H
z, J = 9.3Hz, C_{twenty five}−H), 3.71 (d, 1H, 12.1Hz, C_Five−H), 5.
16 (s, 1H, C₂₆−H), 5.38 (s, 1H, C₂₆-H). The following compounds were synthesized according to the methods of Examples 1 to 10.
Was made. The measurement method of the mass spectrum is the EI method. NM
R indicates a nuclear magnetic resonance spectrum (270 MHz),
Indicates δ (ppm) in form. Compound number 2 Mass spectrum: 556 (M⁺), 520,414,396 356,314,279,2
64,245 NMR spectrum: 3.07 (dt, 1H 9 J = 2.8 Hz, J = 9.3 Hz C_{twenty five}
−H), 3.32 (brs, 1H, C_Two−H), 3.96 (d, 1H, J = 6.0Hz, C
6-H), 4.36 (dd, J = 6.0Hz, J = 6.0Hz, C_Five−H), 4.70
(Brs, 2H, C₂₇-H). Compound number 5 Mass spectrum: 684 (M⁺), 609,534,467 443,414,396,3
45,314 NMR spectrum: 3.07 (dt, 1H, J = 2.8 Hz, J = 9.2 Hz, C_{twenty five}−
H), 3.33 (m, 1H, C_Two−H), 3.95 (d, 1H, J = 6.0Hz, C6−
H), 4.35 (dd, 1H, J = 6.0Hz, J = 6.0Hz, C_Five−H), 4.70
(Brs, 2H, C₂₇-H). Compound number 7 Mass spectrum: 712 (M⁺), 637,562,471,414 NMR spectrum: 3.08 (dt, 1H, J = 2.4 Hz, J = 9.3 Hz, C_{twenty five}−
H), 3.39 (t, 1H, J = 2.0Hz, C_Two−H), 5.26−5.32 (m, 3
H, C_Three−H, C₁₁−H, C₁₉-H). Compound number 24 Mass spectrum: 567 (M⁺), 414,396,356,314,285,245 NMR spectrum: 3.07 (dt, 1H, J = 2.0 Hz, J = 9.2 Hz, C₂₆−
H), 3.19 (brd, 1H, J = 18.9, C_{twenty five}−H), 3.27 (brd, 1H, C
_Two−H), 3.42 (brd, 1H, J = 18.9Hz, C₂₆−H), 4.00 (d, 1
H, J = 6.5Hz, C₆-H). Compound 31 Mass spectrum: 676 (M⁺), 640,522,414,396,356 NMR spectrum: 3.08 (dt, 1H, J = 2.4 Hz, J = 9.3 Hz, C_{twenty five}−
H), 3.67 (s, 2H, ArCH_Two), 4.70 (d, 1H, J = 13.3Hz, C₂₆−
H), 4.80 (d, 1H, J = 13.3Hz, C₂₆-H). Compound 32 Mass spectrum: 690 (M⁺), 245, 654, 522, 396, 276, NMR spectrum: 3.08 (dt, 1H, J = 2.4 Hz, J = 9.3 Hz C₂₆−
H), 4.69 (d, 1H, J = 14.1Hz, C₂₆−H), 4.78 (d, 1H, J =
14.1Hz, C₂₆-H), 7.27-7.34 (m, 5H, ArH). Compound 34 mass spectrum: 652 (M⁺), 616,522,414,396,314,264 NMR spectrum: 3.07 (dt, 1H, J = 2.4 Hz, J = 9.3 Hz, C_{twenty five}−
H), 4.91 (d, 1H, J = 13.3HZ, C₂₆−H), 5.01 (d, 1H, J =
13.3Hz, C₂₆-H), 6.50-7.6 (m, 3H, ArH). Compound 36 mass spectrum: 668 (M⁺), 632,522,414,396 NMR spectrum: 3.07 (dt, 1H, J = 2.4 Hz, J = 9.4 Hz, C_{twenty five}−
H), 4.93 (d, 1H, J = 13.3Hz, C₂₆−H), 4.98 (d, 1H, J =
13.3Hz, C₂₆-H) Compound 39 mass spectrum: 718 (M⁺), 700,530,522,414,396,344 NMR spectrum: 3.07 (dt, 1H, J = 2.8 Hz, J = 9.4 Hz, C_{twenty five}−
H), 3.37 (brs, 1H, C_Two−H), 4.04 (d, 1H, J = 6.5Hz, C₆
−H), 4.72 (brs, 2H, C₂₇−H), 4.99 (d, 1H, J = 13.3H
z, C₂₆−H), 5.06 (d, 1H, J = 13.3Hz, C₂₆-H). Compound 45 mass spectrum: 572 (M⁺), 540,414,396,356,314,264 NMR spectrum: 3.07 (dt, 1H, J = 2.4 Hz, J = 9.3 Hz, C_{twenty five}−
H), 3.36 (s, 3H, OCH_Three), 4.01 (d, 1H, J = 14.5Hz, C₂₆−
H), 4.13 (d, 1H, J = 14.5Hz, C₂₆-H). Compound 51 mass spectrum: 600 (M⁺), 540,414,396,356,314,303 NMR spectrum: 1.17 (d, 6H, J = 6.0 Hz, CH (CH_Three)_Two) .3.07
(Dt, 1H, J = 2.4Hz, J = 9.3Hz, C_{twenty five}−H), 3.63 (m, 1H, OC
H), 4.11 (m, 2H, C₂₆-H) Compound 59 Mass spectrum: 648 (M⁺), 612,540.414,396.356,314,2
64,195 NMR spectrum: 3.07 (dt, 1H, J = 2.8 Hz, J = 9.3 Hz, C_{twenty five}−
H), 3.35 (brs, 1H, C_Two−H), 4.00 (d, 1H, J = 6.5Hz, C₆
−H), 4.13 (d, 1H, J = 12.9Hz, C₂₆−H), 4.20 (d, 1H, J
= 12.9Hz, C₂₆-H, 4.54 (s, 2H, OCH2Ar). Compound 94 mass spectrum: 650 (M⁺), 632.612,541,522,195.167 NMR spectrum: 3.06 (dt, 1H, J = 24Hz, J = 9.3HZ, C₂₆−
H), 3.67 (d, 1H, J = 14.1Hz, C₂₆−H), 3.72 (d, J = 14.
1Hz, C₂₆-H)), 7.20-7.39 (m, 5H, ArH). Compound 103 mass spectrum: 730 (M⁺), 414,264,195,167 NMR spectrum: 2.32 (s, 3H, COCH_Three), 3.06 (dt, 1H, J = 2.
4Hz, J = 9.3Hz, C_{twenty five}−H), 3.62 (d, 1H, J = 14.1 Hz, C₂₆−
H), 3.72 (d, 1H, J = 14.1Hz, C₂₆-H). Compound 104 mass spectrum: 616 (M⁺), 522,414,264,195,167, NMR spectrum: 2.35 (s, 3H, COCH3), 3.07 (dt, 1H, J = 2.
4Hz, J = 9.3Hz, C_{twenty five}−H), 3.62 (d, 1H, J = 14.1 Hz, C₂₆−
H), 3.84 (d, 1H, J = 14.1Hz, C₂₆-H)). Compound 110 mass spectrum: 770 (M⁺), 725,707,655,597,414,323 NMR spectrum: 3.07 (brt, 1H, J = 8.9 Hz, C_{twenty five}−H), 3.38
(Brs, 1H, C_Two−H), 3.82 (d, 1H, J = 5.2Hz, C₆−H), 5.9
6 (brs, 1H, C_Three-H). Compound 112 mass spectrum: 656 (M⁺) 620,541,414,396,356,314,26
4,245 NMR spectrum: 3.07 (dt, 1H, J = 2.4 Hz, J = 8.9 Hz, C_{twenty five}−
H), 3.33 (brs, 1H, C_Two−H), 3.61 (d, 1H, J = 14.5Hz, C
₂₆−H)), 3.89 (d, 1H, J = 14.5Hz, C₂₆-H), 4.68 (br
s, 2H, C₂₇−H), 6.00 (brs, 1H, C_Three-H). Compound 158 Mass spectrum: 655 (M⁺), 637,619,575,519,356,312 NMR spectrum: 1.28 (s, 9H, C (CH_Three)_Three), 3.08 (dt, 1H, J =
2.4Hz, J = 9.3Hz, C_{twenty five}−H), 5.10 (d, 1H, J = 4.8Hz, C_Five−
H) .8.00 (s, 1H, C₂₆-H). Compound 164 mass spectrum: 711 (M⁺), 693, 675, 536, 517, 481, 417, NMR spectrum: 3.07 (dt, 1H, J = 2.4 Hz, J = 93 Hz C_{twenty five}−
H), 5.13 (d, 1H, J = 6.0Hz, C_Five−H), 7.00−7.53 (m, 3
H, ArH), 8.12 (s, 1H, C₂₆-H). Compound 177 Mass spectrum: 639 (M⁺), 621,603,414,264 NMR spectrum: 3.08 (dt, 1H, J = 2.8 Hz, J = 9.3 Hz, C_{twenty five}−
H), 3.79 (dd, 1H, J = 4.8 Hz, J = 15.3 Hz, C₂₆-H), 4.29
(Dd, 1H, J = 4.8, J = 15.3Hz, C₂₆−H), 5.58 (s, 1H, NHCO
CH). Compound 190 mass spectrum: 654 ｛(M-TsOH)⁺｝, 597,265,229,195,16
7,75 NMR spectrum: 2.45 (s, 3H, ArCH_Three) .3.07 (dt, 1H.J = 2.
4Hz, J = 9.3Hz, C_{twenty five}−H), 7.34 (d, 2H, J = 8.5 Hz, CH = C
−CH_Three), 7.78 (d, 2H, J = 8.5 Hz, CH = C-SO_Two). Example 11 Activity test: Adult tick: Individual compound of the present invention or a control compound (Japanese Unexamined Patent Publication No.
26-acetoxymilbemycin described in 29742
A_Four) Each containing 3ppm or 10ppm, to which 0.01% of spreading agent
The added drug solution was prepared. Cowpea (Vignasinensis Sav
i) In the primary leaves of the spider mites (T
etranychus urticae), And 1 day after inoculation, Mizuho formula
In the rotary stripping tower, 7 ml of the above chemical solution, the amount of the stripping liquid is 3.5 mg / c
m^TwoI removed it before it became a leaf. After dismantling, remove cowpea leaves at 25 ° C.
Stored in a constant temperature room, and 3 days later,
Life and death were examined, and the mortality (%) was calculated. The results are shown in the following table.
Shown in Thus, the novel milbemycin compounds of the present invention
It shows a high adulticidal mite effect at low concentrations of pm
It can be seen that they also have egg activity. The case compounds and example compounds shown here are
It does not limit the scope of the invention.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07H 17/08 C07H 17/08 (72) Inventor Kuki Kajino 1041 Yasu-cho, Yasu-cho, Yasu-gun, Shiga Prefecture Sankyo Co., Ltd. (72) Inventor Keiji Tanaka 1041 Yasu-cho, Yasu-cho, Yasu-gun, Shiga Pref. (56) References JP-A-59-141582 (JP, A) JP-A-58-59988 (JP, A) JP-A-62-226984 (JP, A) A) JP-A-63-57591 (JP, A) JP-A-1-157985 (JP, A) JP-A-2-138187 (JP, A) JP-A-2-22279 (JP, A) JP-A-1 -25706 (JP, A) US Patent 4,457,920 (US, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 493/22 C07H 17/08 A61K 31/35 A61K 31/71 C07F 9 / 6561 A01N 57/16 CA (STN) WPIDS (Derwent)

Claims (9)

(57) [Claims] (1) Expression A compound having the formula: [Wherein, -XY is -CH ₂ -CH _2- , -CH ₂ -CH (OH)
-, - CH = CH -, - CH 2 -C (= O) -, or -CH (O
H) -CH ₂ - shows the. R ¹ represents an alkyl group, an alkenyl group, an alkynyl group, an alkoxyalkyl group, an alkylthioalkyl group, a cycloalkyl group, cycloalkenyl group or a heterocyclic group, R ¹
When is a cyclic group, the ring may have a substituent. R ² represents a hydrogen atom, a methyl group, a hydroxyl protecting group or a carboxylic acid residue or a carbonic acid residue forming an ester. R ³ is a hydrogen atom, a halogen atom, a lower alkyl group or OR ⁴
And R ⁴ represents a lower alkyl group, a phenyl group, a carboxylic acid residue or a carbonate residue forming an ester, or a sugar residue or an oxacycloalkyl group forming an acetal. A represents a lower alkyl group, a formyl group, an azidomethyl group, a cyanomethyl group, or a group represented by the formula CH ₂ OCOR ⁵ , CH ₂ OR ⁶ , CH ₂ S (CO)
^{_{n R 6, CH = N-}} O (CO) n R 6, CH 2 N (R 7) (CO) nR 6 or CH ₂
OSO ₂ R ⁸ is shown. n represents 0 or 1, and R ⁵ represents an aralkyl group or a heterocyclic group containing at least one sulfur atom or oxygen atom. R ⁶ represents a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group or a heterocyclic group. However, R ⁶ can be a hydrogen atom only when n is 0. R ⁷ represents a hydrogen atom, a lower alkyl group or a phenyl group. R ⁸ represents a lower alkyl group, a phenyl group or a tolyl group. A excludes a methyl group and a hydroxymethyl group]. Wherein R ¹ is a methyl group, ethyl, isopropyl, se
c - butyl group or a group represented by the formula _{-C (CH 3) = CH-} R 9 indicates, R ⁹ is a methyl group, an ethyl group or Claims compound of the preceding claims is isopropyl group. Wherein -X-Y- is -CH ₂ -CH ₂ - is, R ¹ is methyl, ethyl or isopropyl group in which Claims compound of the preceding claims. 4. The method according to claim ³ , wherein R ³ is a hydrogen atom, a halogen atom or OR ⁴ and R ⁴ is a lower alkyl group, a phenyl group, a carboxylic acid residue or a carbonic acid residue forming an ester. Compound. (5) A is a compound represented by the formula CH ₂ OCOR ⁵ (R ⁵ is as defined in claim 1)
Same as described in section. 5. The compound according to claim 4, wherein the compound is: 6. R ³ is a hydrogen atom, and A is a lower alkyl group, formyl group, azidomethyl group, cyanomethyl group, CH
₂ OR ⁶ , CH ₂ S (CO) _n R ⁶ , CH = NO- (CO) _n -R ⁶ , CH ₂ N (R ⁷ )
(CO) _n -R ⁶ or ^{_{CH 2 SO 2 R 8 (R}} 6 and R ⁷ are the same. As described in paragraph 1 claims) a is proprietary compounds ranging second claim of claim. 7. A parasiticidal composition comprising the compound according to claim 1 as an active ingredient. 8. The composition according to claim 7, wherein the parasite is acaricidal. 9. The expression [Wherein -XY-, R ¹ , R ² and R ³ are the same as described in Claim 1], [Wherein -XY-, R ¹ , R ² , R ³ and A are the same as those described above].