ZA200106491B

ZA200106491B - Avermectin derivatives.

Info

Publication number: ZA200106491B
Application number: ZA200106491A
Authority: ZA
Inventors: Satoshi Omura; Toshiaki Sunazuka; Andreas Turberg; Georg Von Samson-Himmelstjerna; Olaf Hansen
Original assignee: Kitasato Inst
Priority date: 1999-02-09
Filing date: 2001-08-07
Publication date: 2002-09-16

Description

SPECIFICATION

Avermectin Derivatives

Technical Field

The present invention relates to avermectin derivatives having antiparasitic

Background Art

Avermectins are antiparasitic antibiotics produced by Streptomyces avermitilis. Four main ingredients (Ala, A2a, Bla and B2a) have been known, and among them, avermectin Bla is known to have potent activity (Japanese Patent

Unexamined Publication (KOKAI) No. (Hei) 3-254678/1991).

Various derivatives have been synthesized so far to provide avermectin derivatives having higher activity. However, these derivatives fail to have fully satisfactory antiparasitic activity.

Disclosure of the Invention

An object of the present invention is to provide avermectin derivatives having antiparasitic activity.

In order to find avermectin derivatives having higher antiparasitic activity, the inventors of the present invention synthesized various derivatives using avermectins Bla and B2a as starting materials. As a result, we succeeded in . obtaining derivatives represented by the following general formula (I) which have high antiparasitic activity. The present invention was achieved on the basis of the findings.

The present invention thus provides compounds represented by the general formula (I) or salts thereof:

OCH;

RX

H,c~ O07 To. 4 CHs A _.-CH3

H,C™ 07 0... A. 0 (2

H.C | CH,CHj 0) 0 ow

Oo (1)

CH;

R2 wherein -X----Y- represents -CH=CH-, -CH2-C(=0)-, -CH2-CHz-, or -CH:-CH(R13)-; a line ---- between R1 and a carbon atom at the 4”-position represents a single or double bond; a line ---- between R2 and a carbon atom at the 5-position represents a single or double bond; 1) when -X----Y- represents -CH=CH-, the line ---- between R! and a carbon atom at the 4”-position represents a double bond;

R1 represents (R11)(R12)C [wherein R!! represents a substituted or unsubstituted lower alkyl group; a formy! group; a lower alkoxylcarbonyl group, the alkyl moiety of the said lower alkoxylcarbonyl group may be substituted with a heterocyclic group; -CH=N-OR2 wherein R3 represents a hydrogen atom or a lower alkyl group; a lower alkenyloxycarbonyl group; -CH=N-NH-CONHz3; a cyano group; -COR* wherein R4 represents a hydroxyl group or N(R5)(R6) wherein RS and Rf form a nitrogen containing heterocyclic group together with the adjacent nitrogen atom; a vinyl group substituted with a lower alkenyloxycarbonyl group; -CO-S-CHz-CH2-NH-CO-R= wherein R= represents a lower alkyl group; or -CH=CH-COOH; and R!? represents a hydrogen atom, or when R1! represents a cyano group, R!2 represents a hydrogen atom or a lower alkyl group]; when the line ---- between R? and a carbon atom at the 5-position represents a single bond, R2 represents a hydroxyl group, a lower alkoxyl group, or a trilower alkyl)silyloxy group; or when the line =--- between R2 and a carbon atom at the 5-position represents a double bond, R2 forms a carbonyl group or a hydroxime group {-C(=NOH)}, together with the carbon atom at the 5-position; 2) when -X----Y- represents -CH2-C(=0)-, the line ---- between R! and a carbon atom at the 4”-position represents a double bond;

R1 represents (R12)(R122)C [wherein R1!2 represents a lower alkoxycarbonyl group, the alkyl moiety of the said lower alkoxycarbonyl group may be substituted with a heterocyclic group, or -COOCH2CH=CHz; and R122 represents a hydrogen atom]; the line ---- between R2 and a carbon atom at the 5-position represents a single bond; and

R2 represents a hydroxyl group, a lower alkoxyl group, or a tri(lower alkyl)silyloxy group; 3) when -X----Y- represents -CHz-CHz-,

R11 represents (R1p)(R12p)C [wherein R11 represents a cyano group, a carboxyl group, or a lower alkenyloxycarbonyl group; and R12b represents a hydrogen atom]; or when the line ---- between R! and a carbon atom at the 4”-position represents a single bond,

Rl! may represent a carboxymethyl group or a cyanomethyl group; the line ---- between R2 and a carbon atom at the 5-position represents a single bond; and R2 represents a hydroxyl group, a lower alkoxyl group, or a trilower alkyl)silyloxy group; 4) when -X----Y- represents -CHz-CH(R13)-, the line ---- between R! and a carbon atom at the 4”-position represents a double bond;

Rl represents (R11¢)(R12¢)C [wherein Rll represents a cyano group, a carboxyl group, a lower alkoxycarbonyl group or a lower alkenyloxycarbonyl group; and R12¢ represents a hydrogen atom]; R13 represents a hydroxyl group or a lower alkylcabonyloxy group; the line ---- between R2 and a carbon atom at the 5-position represents a single bond; and R2 represents a hydroxyl group, a lower alkoxyl group or a trilower alkyl)silyloxy group.

Among the compounds of the general formula (I) according to the present invention, those wherein -X----Y- is -CH=CH- or the salts thereof are preferred.

Among the compounds of the general formula (I) according to the present invention, those wherein -X----Y- represents -CH=CH-, and R!! represents a substituted or unsubstituted lower alkyl group, a cyano group, or -COR4 wherein R4 has the same meaning as that defined above, or the salts thereof are also preferred.

Among the compounds of the general formula (I) according to the present invention, those wherein R2 is a hydroxyl group or a tri(lower alkyl)silyloxy group or the salts thereof are preferred. ‘ Among the compounds of the general formula (I) according to the present invention, those wherein -X----Y- represents -CHz-CHz- or the salts thereof are preferred. Among them,those wherein R11b represents a cyano group or a carboxyl group or the salts thereof are preferred.

According to another aspect of the present invention, there are provided medicaments which comprise as an active ingredient the compound represented by the aforementioned general formula (I) or the physiologically acceptable salt thereof.

The medicaments can be administered as antiparasitics to a mammal including a human.

According to further aspects of the present invention, there are provided a use of the compound represented by the aforementioned general formula (I) or the physiologically acceptable salt thereof for the manufacture of the aforementioned medicament; and a method for therapeutic treatment of parasitosis which comprises the step of administering a therapeutically effective amount of the compound represented by the aforementioned general formula (I) or the physiologically acceptable salt thereof to a mammal including a human.

Best Mode for Carrying Out the Invention

Hereinafter the compounds represented by the general formula (I) are referred to as the compounds (I). The compounds of other formula numbers are abbreviated in a similar manner.

In the compounds (I) of the present invention, -X----Y- represents -CH=CH-, -CH2-C(=0)-, -CH2-CHz2-, or -CH:-CH(R!3)- (in each formula, the carbon atom on the left side corresponds to X.).

In the compounds (I) of the present invention, the compounds, wherein R2is a hydroxyl group or a tri(lower alkyl)silyloxy group when -X----Y- represents -CH=CH- and the line ---- between RZ and a carbon atom at the 5-position represents a single bond, are referred to as the compounds (Ia), and those wherein -X----Y- represents -CH=CH- and R2 forms a carbonyl group or a hydroxime group together with the carbon atom at the 5-position are referred to as the compounds (Ic).

In the compounds (I) of the present invention, the compounds wherein -X----Y- represents -CHz-C(=0)-, the line ---- between R2 and a carbon atom at the 5-position represents a single bond, and R2 represents a hydroxyl group or a tri(lower alkyl)silyloxy group are referred to as the compounds (Ib).

In the compounds (I) of the present invention, the compounds wherein -X----Y- represents -CHz2-CHz-, the line ---- between R2? and a carbon atom at the 5-position represents a single bond, and R2 represents a hydroxyl group or a tri(lower alkyl)silyloxy group are sometimes referred to particularly as “ivermectin derivatives.” “Avermectin derivatives" referred to in the specification include the aforementioned ivermectin derivatives.

In the compounds (I) of the present invention, the compounds wherein -X----Y- represents -CHz-CH(R13)- wherein R12 represents a hydroxyl group or a lower alkylecarbonyloxy group, the line ---- between R2 and a carbon atom at the 5-position represents a single bond, and R2 represents a hydroxyl group or a tri(lower alkyl)silyloxy group are sometimes referred to as the compounds (Id).

In the definition of each group in the compounds (I), the lower alkyl group may be any of C1-Cs linear, branched, and cyclic alkyl groups or a combination thereof, preferably a Ci1-Cs linear or branched alkyl group. The lower alkyl group includes, for example, a methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclopropylmethyl group, cyclobutyl group, pentyl group, hexyl group, heptyl group, octyl group, and the like. A lower alkyl moiety in functional groups having the lower alkyl moiety, such as the lower alkoxycarbonyl group, lower alkoxyl group, lower alkylcarbonyloxy group and tri(lower alkyl)silyloxy group has the same meaning as that defined in the aforementioned lower alkyl group unless otherwise specifically mentioned. The lower alkyl moieties in the tri(lower alkyl)silyloxy group may be the ~/

same or different.

Examples of a lower alkenyl moiety in the lower alkenyloxycarbonyl group include C2-Cs straight and branched alkenyl groups, for example, a vinyl group, allyl group, methacryl group, butenyl group, pentenyl group, hexenyl group, and the like.

The number of double bonds present in the alkenyl group is not particularly limited, and preferably one.

The heterocyclic group may be either an aromatic or aliphatic heterocyclic oo group. Examples of the aromatic heterocyclic group include, for example, a 5- or 6-membered monocyclic aromatic heterocyclic group which contains at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur atoms.

More specifically, examples include a pyridyl group, pyrrolyl group, furyl group, thieny! group, thiazolyl group, pyrazinyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, and oxazolyl group. Examples of the aliphatic heterocyclic group include, for example, a 5- or 6-membered monocyclic aliphatic heterocyclic group which contains at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur atoms. More specifically, examples include a pyrrolidinyl group, tetrahydrofuryl group, and tetrahydropyranyl group.

The nitrogen containing heterocyclic group formed together with the adjacent nitrogen atom includes a morpholino group, thiomorpholino group, piperidino group, 1-piperazinyl group, and 1-pyrrolidinyl group.

The type and number of the substituent of the substituted alkyl group are not particularly limited. Preferably, the number of the substituent is from 1 to 3, and examples include a hydroxyl group, a halogen atom (“a halogen atom” used herein may be any of fluorine, chlorine, bromine, and iodine atoms), an amino group, a hydroxyamino group, a mono(lower alkyl)amino group, a mono(lower alkoxy)amino group, an alkanoylamino group, an azide group, a heterocyclic group (examples include those exemplified for the aforementioned heterocyclic group and the nitrogen containing heterocyclic group formed together with the adjacent nitrogen atom), a lower alkanoyloxy group, a heterocyclic carbonyloxy group(i.e., heterocycle-C(=0)-O wherein the heterocyclic moiety has the same meaning as that defined in the aforementioned heterocyclic group and the heterocyclic moiety may be substituted with a halogen atom or a lower alkoxycarbonyl group), and a heterocyclic oxy group such as tetrahydropyranyloxy group.

In the definition of the substituent of the substituted lower alkyl group, a lower alkyl moiety of the mono(lower alkyl)amino group, mono(lower alkoxy)amino group, alkanoylamino group, lower alkanoyloxy group and lower alkoxycarbonyl group has the same meaning as that defined in the aforementioned lower alkyl group.

Examples of the salt of the compounds (I) include acid-addition salts, metal salts, ammonium salts, and organic amine-addition salts. Examples of the oo acid-addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates and phosphates, and organic acid salts such as acetates, maleates, fumarates and citrates. Examples of the metal salts include alkali metal salts such as sodium salts and potassium salts, alkaline-earth metal salts such as magnesium salts and calcium salts, aluminium salts, and zinc salts. Examples of the ammonium salts include ammonium salts and tetramethylammonium salts, and examples of the organic amine-addition salts include salts with morpholine and piperidine. When a salt of the compound (I) is used as an active ingredient of the medicament of the present invention, a physiologically acceptable salt is preferably used.

Preparations of the compounds (I) will be explained below.

Avermectins Bla and B2a, which are used as starting materials for the avermectin derivatives disclosed in the present invention, are isolated from the culture of Streptomyces avermitilis, and they are known compounds (Japanese Patent

Unexamined Publication (KOKAI) Nos. (Hei) 3-74397/1991 and 3-254678/1991, and

USP 5,206,155 and the like).

In the present invention, 5-O-tri(lower alkyl)silyl-4”-oxoavermectin Bla (the compounds (ITa)), which are starting materials for the preparation of the compounds (Ia), can be synthesized by using avermectin Bla as a starting material according to the method disclosed in Japanese Patent Examined Publication (KOKOKU) No. (Hei) 6-33273/1994 or a similar method thereto. Specifically, the compounds (IIa) used as the starting material can be obtained by subjecting the hydroxyl group at the 5-position of avermectin Bla to tri(lower alkyl)silylation, and then oxidizing the hydroxyl group at the 4”-position. Examples of oxidations other than the method disclosed in Japanese Patent Examined Publication (KOKOKU) No. (Hei) 6-33273/1994 include oxidation with phenyl dichlorophosphate

(PhOPOCly) triethylamine (TEA)/dimethylsulfoxide (DMSO) in isopropyl acetate, oxidation with tetrapropylammonium perruthenate (PrsNRuO4)/4-methylmorpholine

N-oxide (NMO) in the presence of Molecular Sieves 4A (MS4A) in methylene chloride, and oxidation with sulfur trioxide/pyridine complex in dimethylsulfoxide (DMSO). 5-0-Tri(lower alkyl)silyl-4”,23-dioxoavermectin B2a (the compounds (IIb)), which are starting materials for the preparation of the compounds (Ib), can be obtained by using avermectin B2a asa starting material according to the method disclosed in Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 3-74397/1991 or a similar method thereto, which method comprises the step of producing 5-O-tri(lower alkylsilylavermectin B2a and the following oxidation at the 23- and 4”-positions.

In the following preparations, when a defined group is changed under conditions for a method to be applied, or the group is unsuitable for carrying out the method, desired compounds can be obtained by employing introduction and elimination of a protective group conventionally used in synthetic organic chemistry [see, for example, Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons Inc. (1981)].

Preparation 1

Among the compounds (I), the compound wherein -X----Y- is -CH=CH- or : -CH2-C(=0)-, Rl is a lower alkoxycarbonylmethylidene group optionally substituted with a heterocyclic group, a lower alkenyloxycarbonylmethylidene group, or a cyanomethylidene group, and R? is a tri(lower alkyl)silyloxy group (the compounds (I1Ia) and (IIIb)) can be prepared by the process set out below:

OCH oO 4 OCH;

H,c~ S07 To. 4 CH 05 CH;

H,C™ TOT 70... 0. |?

HyC™ | CH,CH, 0) 0) oH (I1a)or (I1b) O CH,

R23

R' OCH,

ANN

H,C~ ~O a 4 CH, NY _.-CHs

Hee” 07 To. 0% 1, 13 “0 CH

HyC™” | CH,CHj 0) 0 ow 0

CH3 (I11a)or (I11b) R28 (In the scheme, R12 represents a lower alkoxycarbonyl group optionally substituted with a heterocyclic group, a lower alkenyloxycarbonyl group, or a cyano group among the definition of R11; R22 represents a tri(lower alkyl)silyloxy group among the definition of R2; and -X!----Y1!- represents -CH=CH- or -CH2-C(=0)-.)

The compound (ITIa) or (IIIb) can be obtained by reacting the compound (Ila)

or (IIb) with 1 to 10 equivalents of a compound (IV) represented by the formula: (RO)2P(O)CH2R2 wherein R represents a lower alkyl group having the same meaning as that defined above and R112 has the same meaning as that defined above, in the presence of 1 to 10 equivalents of a base in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used for 1 minute to 24 hours.

As the inert solvent, tetrahydrofuran, ether, benzene, toluene, and the like can be used alone or as a mixture thereof. Examples of the base include potassium ] tert-butoxide, sodium hydride, potassium hydride, lithium hexamethyldisilazane, and lithium diisopropylamide.

The compound (I1la) wherein -X----Y- is -CH=CH-, R! is a lower alkoxycarbonyl group optionally substituted with a heterocyclic group and R2 is a tri(lower alkyl)silyloxy group can also be obtained using as a starting material the compound (VIIa) wherein -X----Y- is ~-CH=CH-, R!! is a carboxyl group and R2 is a tri(lower alkyl)silyloxy group which is obtained in Preparation 4 explained below. ~The reaction can be carried out by reacting the compound (VIIa) with a corresponding lower alcohol optionally substituted with a heterocyclic group or an ester of a corresponding lower alcohol optionally substituted with a heterocyclic group in the presence or absence of a base in an inert solvent at a temperature ranging from 0°C to a boiling point of a solvent used for one minute to 3 days to prepare the desired compounds.

As the inert solvent, lower alcohols such as methanol, ethanol, propanol and tert-butanol, tetrahydrofuran, ether, chloroform, methylene chloride, 1,2-dichloroethane, and the like may be used. The corresponding lower alcohol optionally substituted with a heterocyclic group or the ester of the corresponding lower alcohol optionally substituted with a heterocyclic group, per se, may be used as the inert solvent.

As the base, N-ethyl diisopropylamine, triethylamine, pyridine, 4-dimethyl- aminopyridine, and the like may be used.

Preparation 2

Among the compounds (I), the compound wherein -X----Y- is -CH=CH-, Rl is a hydroxymethyl group, and R2 is a tri(lower alkyl)silyloxy group (the compound (Va))

can be prepared by the process set out below:

AN

4 OCH;

HC oo AN 4 CH, ia _.-CH3

H,C™ O07 Oo... A. 0 13 o CH,

HC | CH,CHj 0] 0 oH ( IT Tai ) 0)

CH,

R22

HO

OCH;

NN

4"

OCHj3

H,c~ ~0~ To. 4 CH A CH, - X15 23

H,C 0] O.._ \ 0 13 0 CHs

H,C™” | CH,CH, 0 0 oH 0

CH, (Va) R22 (In the scheme, R121 represents a lower alkoxycarbonyl group optionally substituted with a heterocyclic group, or a lower alkenyloxycarbonyl group among the definition of Rla; -X1a--_-Yta- represents -CH=CH-, and R22 has the same meaning as that defined

® above.)

The compound (Va) can be obtained by treating the compound wherein R112 is a lower alkoxycarbonyl group optionally substituted with a heterocyclic group, or a lower alkenyloxycarbonyl group, and -Xt----Y1- is -CH=CH- (compound (IIIal)) among the compounds obtained in Preparation 1 with an equivalent to an excess amount of a reducing agent in an inert solvent at a temperature ranging from -78°C to a boiling point ofa solvent used for 1 minute to 24 hours. oo

As the inert solvent, methanol, ethanol, water, tetrahydrofuran, ether, benzene, toluene, pyridine, hexane, methylene chloride, chloroform, 1,2-dichloroethane, and the like may be used alone or as a mixture thereof.

Examples of the reducing agent include sodium borohydride, lithium aluminium hydride, and diisobutylaluminium hydride.

The compounds wherein R1! is a halomethyl group can be prepared by treating the compound obtained above wherein R!! is a hydroxymethyl group with a halogenating agent in the presence or absence of a base in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used for 1 minute to 24 hours.

As the inert solvent, methylene chloride, chloroform, 1,2-dichloroethane, benzene, ether, tetrahydrofuran, and the like may be used alone or as a mixture thereof. As the halogenating agent, p-toluenesulfonyl chloride, thionyl chloride, thionyl bromide, and the like may be used. As the base, N-ethyl diisopropylamine, triethylamine, pyridine, 4-dimethylaminopyridine, and the like may be used.

The compounds wherein Rl! is an aminomethyl group can also be prepared by reacting the compound wherein R!! is a halomethyl group with an azide-formation agent in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used for 1 minute to 24 hours and carrying out reduction in a conventional manner.

Sodium azide, potassium azide, and the like may be used as the azide- formation agent.

As the inert solvent, ether, tetrahydrofuran, and the like may be used alone or as a mixture thereof.

Preparation 3

Among the compounds (I), the compound wherein -X----Y- is -CH=CH-, R11 is a formyl group, and R2 is a tri(lower alkyl)silyloxy group (the compound (VIa)) can be prepared by the process set out below:

HO

- a: OCH; :

ANN

4"

OCH,

H,C~ “07 TO. 4 CH, tal CH; ~. 29 23

H3C Oo O.. NN Oo 13 o CH3

HiC™ | CH,CH, 0) 0) oH (Va) 0

CH, } R22

CHO OCH,

NN

4"

OCH,

H,C~ “07 TO. 4 1 _ CHj IPN CH;

H4C (@] O. NN Oo |%2 i 13 CH 0

H,C™” | CH,CHj

Oo 0 ow (VI1a) 0

CH

R22

® (In the scheme, R22 and -X12----Y12- have the same meanings as those defined above.)

The compound (VIa) can be obtained by treating the compound (Va) obtained in Preparation 2 with an equivalent to an excess amount of an oxidizing agent in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used for 1 minute to 24 hours.

As the inert solvent, water, tetrahydrofuran, ether, benzene, hexane, oo methylene chloride, chloroform, 1,2-dichloroethane, tert-butanol, and the like may be used alone or as a mixture thereof. Examples of the oxidizing agent include pyridinium chlorochromate, pyridinium dichromate, manganese dioxide, and potassium permanganate.

The compound (VIa) wherein the lower alkoxycarbonyl group optionally substituted with a heterocyclic group or the lower alkenyloxycarbonyl group is converted into a formyl group can also be obtained by controlling reaction conditions for reduction of the lower alkoxycarbonyl group optionally substituted with a heterocyclic group or the lower alkenyloxycarbonyl group of the compound (I1Ial) which is used as a starting material in Preparation 2. Examples of the reaction solvent, the reducing agent, equivalents of the reducing agent, the reaction time and the reaction temperature for the reduction of the compound (11Ial) to obtain the compound (VIa) include those exemplified in Preparation 2.

The compound wherein R11 is a vinyl group or a substituted vinyl group (e.g.,

Rl is -CH=CH-COOH) can be prepared by subjecting the compound obtained above wherein R!! is a formyl group to the Wittig reaction.

Examples of the solvent, the reaction temperature, equivalents of the reagent, the reaction time and the like for the Wittig reaction are similar to those described in

Preparation 1.

Preparation 4 ‘ Among the compounds (I), the compound wherein -X----Y- is -CH=CH-, R11 is a carboxyl group, and R? is a tri(lower alkyl)silyloxy group (the compound (VIIa)) can be prepared by the process set out below:

® (Va) ’ (VI1a) (111a)

HOOC OCH; oo

ANS

H,C~ “07 TO. 4 CH, ON __-CHj

H5C 0 O._ NN ONE 13 on

HsC™ | CH,CH; 0) 0 ow

Oo

CH, (VIIa) R22 (In the scheme, R22 and -X!a----Y1a- have the same meanings as those defined above.)

The compound (VIIa) can be obtained by treating the compound (Va) obtained in Preparation 2 with an equivalent to an excess amount of an oxidizing agent in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used for 1 minute to 24 hours. As the inert solvent, water, tetrahydrofuran, ether, benzene, hexane, chloroform, methylene chloride, 1,2-dichloroethane, tert-butanol, and the like may be used alone or as a mixture thereof. Examples of the oxidizing agent include pyridinium dichromate, pyridinium chlorochromate, Jones reagent, chromium trioxide, and potassium permanganate.

The compound (VIIa) can also be obtained by oxidizing the formyl group of the compound (VIa) obtained in Preparation 3 according to the method for preparing the compound (VIIa) from the compound (Va).

The compound (VIIa) can also be obtained by hydrolyzing the compound (IIIa)

® obtained in Preparation 1 in the presence of an equivalent to an excess amount of an acid or a base in an inert solvent. Examples of the inert solvent include methanol, ethanol, water, tetrahydrofuran, ether, and acetonitrile. Examples of the acid include hydrochloric acid, sulfuric acid, and nitric acid, and examples of the base include sodium hydroxide, potassium hydroxide, and lithium hydroxide.

The compound (VIIa) can also be obtained by treating the compound wherein

Rite is a lower alkenyloxycarbonyl group among the compound (IIIa) obtained in

Preparation 1 with an equivalent to an excess amount of a reducing agent in the presence of a palladium catalyst in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used for 1 minute to 24 hours. Examples of the inert solvent include methanol and ethanol, and examples of the reducing agent include sodium borohydride, formic acid and hydrazine. Examples of the palladium catalyst include tetrakis(triphenylphosphono)palladium.

The compound wherein R1! is -CO-S-CHz-CH2-NH-CO-Rx (Rx has the same meaning as that defined above) can be prepared by further reacting the compound obtained above wherein R!! is a carboxyl group with HS-CH2-CH:z-NH-CO-R= (Rx has the same meaning as that defined above).

For the preparation of the compound wherein R!! is -CO-S-CH2-CH2-NH-CO-Rx (Rx has the same meaning as that defined above) from the compound wherein R11 is a carboxyl group, reaction is generally carried out in the presence of a condensing agent and a base.

Examples of the solvent and the base used in the preparation of the compound wherein R! is -CO-S-CHz-CH2-NH-CO-Rx (Rx has the same meaning as that defined above) from the compound wherein R!! is a carboxyl group include the inert solvents and the bases used in the reaction of the compounds (VIIa) and (XV) in

Preparation 9 explained below.

As the condensing agent, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate and the like, as well as the condensing agents used in the reaction of the compounds (VIIa) and (XV) in Preparation 9 explained below, may be used.

Examples of the reaction time, the reaction temperature, equivalents of the reagent, and the like for the preparation of the compound wherein R1 is

_ -CO-S-CH:-CH2-NH-CO-R= (Rx has the same meaning as that defined above) from the compound wherein R1! is a carboxyl group are similar to those used in the reaction of the compounds (VIIa) and (XV) in Preparation 9 explained below.

Preparation 5

Among the compounds (I), the compound wherein -X----Y- is -CH=CH-, Rl is a lower alkanoyloxymethyl group, ora heterocyclic carbonyloxymethyl group: heterocycle-C(=0)-O-CHz- wherein the heterocyclic moiety has the same meaning as that defined in the aforementioned heterocyclic group and may be substituted with a halogen atom or a lower alkoxycarbonyl group, and R2 is a tri(lower alkyl)silyloxy group (the compound (IXa)) can be obtained by the following method.

HO

OCH, xn 4"

OCH;4

H,c~ “07 TO. 4 1

CH, slam CH;

H,C™ ~07 TO. A. NK 13 0 CH .

HC” | CH,CHj 0] 0 oH : 0

CH, (v a ) R22

R'CO0O

OCH;

NS

4"

OCHj

H,C~ O07 TO. 4 1 . CH, xia 5 CH;

H.C 0 O. NS 0) : Ta CH @]

HC” ’ | CH,CH; 0] 0 oH 0

CH, ( I X a) R22 (In the scheme, R7 represents a lower alkyl group or a heterocyclic group which may be substituted with a halogen atom or a lower alkoxycarbonyl group; R22 and

@ -X1a.---Y1a. have the same meanings as those defined above. The lower alkyl group, heterocyclic group, halogen atom and lower alkoxycarbonyl group in the definition of

R7 have the same meanings as those defined above, respectively.)

The compound (IXa) can be obtained by reacting the compound (Va) obtained in Preparation 2 with an equivalent to an excess amount of the compound (VIIIa) represented by the formula: R7"COCI] wherein R7 has the same meaning as that defined above, in the presence or absence of an equivalent to an excess amount of a base in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used for 1 minute to 24 hours. Examples of the inert solvent include chloroform, methylene chloride, 1,2-dichloroethane and pyridine, and examples of the base include triethylamine, diisopropylethylamine, pyridine, and dimethylaminopyridine.

The desired compound (I1Xa) can also be obtained by reacting the compound (Va) with an equivalent to an excess amount of the compound (VIIIb) represented by the formula: (R7CO)20 wherein R7 has the same meaning as that defined above, in the presence or absence of an equivalent to an excess amount of a base in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used for 1 minute to 24 hours. Examples of the inert solvent and the base used include those used in the reaction of the compounds (Va) and (VIIIa).

The desired compound (IXa) can alternatively be obtained by reacting the compound (Va) with an equivalent to an excess amount of the compound (VIIIc) represented by the formula: R7TCOOH wherein R7 has the same meaning as that defined above, for 1 minute to 24 hours in the presence or absence of an equivalent to an excess amount of a base and in the presence of an equivalent to an excess amount : of a condensing agent in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used. Examples of the inert solvent and the base used include those used in the reaction of the compounds (Va) and (VIIa). Examples of the condensing agent include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCI) hydrochloride and 1,3-dicyclocarbodiimide.

Preparation 6

Among the compounds (I), the compound wherein -X----Y- is -CH=CH-, R11 is

—CH=N-OR3 wherein R3 has the same meaning as that defined above, or —CH=N-NH-CONHzg, and R2? is a tri(lower alkyl)silyloxy group (the compound (XIa)) can be obtained by using the compound (VIa) obtained in Preparation 3 as a starting material by the following method.

CHO OCH;

ANN

OCH;

H,c™ “07 TO. 4' 1

CH, TPZ AN _-CHs

H,C™ ~07 0... A. Oo |2

EE oo . - --143 - NE ™ 0) Zl NE CHj3 - - - I

H,C™ | CH,CH, 0 0 ow 0]

CH, (VIa) R2a : .

RC -

N_

NN OCHj4

NS

4"

OCH,

H,C~ “O07 TO.. * CH, 1a No CHa

HC” 07 0. A oO |? ch 13 0 3

H.C” | CH,CH,4

Oo 0 ow : Oo

CH; (X I a) R23 (In the scheme, R? represents OR3 wherein R23 has the same meaning as that defined above, or NH-CONHz, and R22 and -X12----Y1a- have the same meanings as those defined above.)

The compound (XIa) can be obtained by reacting the compound (VIa) with an equivalent to an excess amount of the compound (X) represented by the formula:

HoN-OR3 wherein R2 has the same meaning as that defined above or a salt thereof (examples thereof include acid addition salts having the same meaning as that - defined above), or an equivalent to an excess amount of a semicarbazide or a salt thereof (examples thereof include acid addition salts having the same meaning as . that defined above) for 1 minute to 24 hours in the presence or absence of an equivalent to an excess amount of a base in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used. Examples of the inert solvent include methanol and ethanol.. Examples of the base include pyridine, triethylamine, and dimethylaminopyridine.

The compound wherein Ri! is -CH,-NH-OR?® can be prepared by reducing the : - compound obtained above wherein R'is ~-CH=N-OR2. The reduction can be carried out, for example, using a reducing reagent such as diisobutylaluminium hydride in an inert solvent such as dichloromethane, chloroform and tetrahydrofuran. :

Preparation 7

Among the compounds (I), the compound wherein -X----Y- is -CH=CH-, R11 is a tetrahydropyranyloxymethyl group, and R? is a tri(lower alkyl)silyloxy group (the . compound (XIIa)) can be obtained by using the compound (Va) obtained in

Preparation 2 by the following method.

CORRECTED

} SHEET oo 09/10/2002

HO

OCH3j

NS

4"

OCH;

H,C~ “07 O._ 4 1 . THs NE CH

H3C 0] O. J ONES — < coli cat) << —CH3— 13 0 3

HsC™” | CH,CH, 0) 0) oH 0)

CH; (Va) p28 ¢ 0

OCH;

NS

4"

OCH;

H,C~ “O07 To. 4' 1 . CH, xia _.-CH3

H.C 0] O.. J. 0 i 13 CHa 0

H,C™ | CH,CH; 0) 0) oH 0

CHs (XI1a) R22 (In the scheme, R22 and -X1a----Y!a- have the same meanings as those defined above.)

The compound (XIIa) can be obtained by reacting the compound (Va) obtained

® in Preparation 2 with an equivalent to an excess amount of dihydropyran in the presence of an acid catalyst in an inert solvent. Examples of the acid catalyst include hydrochloric acid, p-toluenesulfonic acid, and pyridinium p-toluenesulfonate.

Examples of the inert solvent include chloroform and methylene chloride. _ .. Preparation8 oo

Among the compounds (I), the compound wherein -X----Y- is -CH=CH-, R!! is an aminomethyl group or a methylaminomethyl group, and R2 is a tri(lower alkyl)silyloxy group (the compound (XIIIa)) can be prepared by using the compound (VIa) obtained in Preparation 3 as a starting material by the following method.

®

CHO OCH,

NS

H,c~ S07 TO. 4 CH, aX CHs

H,C~ ~07 0. A. NK

HC” | CH,CH,3 0) 0] oH

Oo

CH, (VI1a) | R28

R'°HN

OCH,

Se

H,C~ “07 TO. 4 CH io Yl CH; p 2

HC Oo O._ - Jn 0 Jon

HC” | CH,CH,4 0 Oo oH

Oo (X111a) 2 “Hs

R22 (In the scheme, R10 represents a hydrogen atom or a methyl group, and R22 and -X1a.---Y1a- have the same meanings as those defined above.)

The compound (XIIIa) wherein R10 is a hydrogen atom can be obtained by

® reacting the compound (VIa) with an equivalent to an excess amount of hexamethyldisilazane in the presence of a catalytic amount to an excess amount of a metal salt in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used for 1 minute to 24 hours, and then adding an equivalent to an excess amount of a reducing agent.

Examples of the inert solvent include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, methanol and ethanol. Examples of the metal salt include zinc chloride, and examples of the reducing agent include sodium borohydride, formic acid, hydrogen gas, and lithium aluminium hydride.

In Preparation 8 explained above, the compound (XIIla) wherein R10 is a methyl group can be obtained by using heptamethyldisilazane instead of hexamethyldisilazane.

Preparation 9 :

Among the compounds (I), the compound wherein -X----Y- is -CH=CH-, R!! is

CONRS5RS wherein R5 and R8 have the same meanings as those defined above, and R2 is a tri(lower alkyl)silyloxy group (the compound (XIVa)) can be prepared by using the compound (VIIa) obtained in Preparation 4 as a starting material by the method set out below.

HOOC OCH,

ANN

OCH;

H,C~ ~O~ TO. 4 CHs a ACH;

H,C™ ~07 0. AN. 0 |2 13 { No CH; :

H,C™ | CH,CH4

Oo 0 ow (VIIa) 0

CH,

R22

R¥0oc OCH;

NN

4"

OCH;

H,c~ “O07 TO. 4' 1a . CH, ahs _.-CH3

HiC 0) 0. NN Oo. |? ° Ret CH 0

HyC™ | CH,CH4 0 0] ow (XIVa) 0)

CH3

R22 (In the scheme, R3! represents NR5R6 wherein R5 and R® have the same meanings as those defined above, respectively, and R22 and -X!2----Y1a- have the same meanings as those defined above.)

The compound (XIVa) can be obtained by reacting the compound (VIIa) with an equivalent to an excess amount of the compound (XV) represented by the formula:

® R3'H wherein R*! has the same meaning as that defined above, for 1 minute to 24 hours in the presence of a base and a condensing agent in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used.

Examples of the inert solvent include chloroform, methylene chloride, methyl : acetate, ethyl acetate, propyl acetate, isopropyl acetate, methanol, and ethanol.

Examples of the condensing agent include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCI) hydrochloride, and 1,3-dicyclohexylcarbodiimide. Examples of the base include triethylamine, diisopropylethylamine, dimethylaminopyridine, and pyridine.

The compound (XIVa) can also be obtained by treating the compound (VIIa) with a chlorinating agent in an inert solvent or in the absence of a solvent at a : temperature ranging from an ice-cooling temperature to a boiling point of a solvent used (at a boiling temperature of the chlorinating agent when no solvent is used) to convert the compound into a corresponding acid chloride, and reacting the resulting acid chloride with the compound (XV) represented by the formula: R3!H wherein R8! has the same meaning as that defined above in an inert solvent in the presence of a base at a temperature ranging from an ice-cooling temperature to a boiling point of a oo solvent used. Examples of the chlorinating agent include phosphorus oxychloride, "phosphorus pentachloride, phosphorus trichloride, thionyl chloride, and thionyl : ~ bromide. Examples of the inert solvent for the chlorination include chloroform, : methylene chloride, 1,2-dichloroethane, toluene, and benzene. Examples of the inert : solvent for the condensation reaction include chloroform, methylene chloride, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, tetrahydrofuran, methanol, and ethanol. Examples of the base include triethylamine, diisopropylethylamine, dimethylaminopyridine, and pyridine.

Preparation 10

Among the compounds (I), the compound wherein -X----Y- is -CH=CH- or -CH2-C(=0)-, and R? is a hydroxy! group (the compounds (XV1a) and (XV1Ib)) can be : obtained by carrying out deprotection at the 5-position of the compounds obtained in

Preparations 1 to 9 and other methods. ~~ CORRECTED SHEET 28 09/10/2002

OCH;

R1 4 OCH,

H,C~ 07 TO. 4 1 CH . CH, X15 Pd 3

Hoe 07 To. Il 0 |2

TY No CH 13 0 °

HyC™ | CH,CH,4 0 0)

Lor

O—

CH

R22

OCH

R

4 OCH,

H,C~ “07 TO. 4 CH, CH

H,C™ ~O7 TO... A 0 |? 13 0 - _CHg

HC | CH,CHj 0) 0] ow 0

CH

(XV1a)o (XVI1b)

OH

(In the scheme, R1, R22 and -X1----Y!- have the same meanings as those defined above.)

The compound (XVIa) or (XVIb) can be obtained by treating the compound obtained in Preparations 1 to 9 for 1 minute to 24 hours with a catalytic amount to an

® amount serving as a solvent of a desilylating agent in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used.

As the inert solvent, tetrahydrofuran, ether, benzene, toluene, pyridine, isopropyl acetate, and the like may be used alone or as a mixture thereof. Examples of the desilylating agent include hydrogen fluoride, hydrochloric acid, hydrogen 3 bromide, sulfuric acid, and hydrogen fluoride/pyridine complex.

The tri(lower alkyl)silyloxy group at the 5-position is sometimes converted into a hydroxyl group depending on reaction conditions for conversion of a functional group at the other position.

Preparation 11

Among the compounds (I), the compound wherein R2 represents a carbonyl group together with the carbon atom at the 5-position (the compound (Ic)) can be obtained by oxidizing the compound (XVIaa) wherein -X----Y- is -CH=CH- among the compound (XVIa) obtained in Preparation 10.

OCH3j rR! 4 OCH;

H,C~ “O07 TO. 4" 23

CHs 22 ~_.-CHa

H,c~ S07 TO. 0 @]

HC | CH,CHj

O 0) ow (XV1aa) 0)

CH;

OH

OCH,

R' 4 OCH;

H,c~ “07 TO. 4' 23 CH

CHa 22 CMs

HC 0] O.._ J 0 13 CH, 0

HyC™ | CH,CH,4 0) O oH 0 (1) CHy 0 (In the scheme, R! has the same meaning as that defined above.)

The compound (Ic) can be prepared by treating the compound (XVIaa) with an equivalent to an excess amount of an oxidizing agent in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used. The reaction is

® generally finished in 1 minute to 2 days.

Examples of the inert solvent include chloroform, methylene chloride, and 1,2-dichloroethane. Examples of the oxidizing agent include manganese dioxide, pyridinium chlorochromate, chromium trioxide, and pyridinium dichromate.

The compound wherein R2 forms a hydroxime group together with the carbon atom at the 5-position can be obtained by further reacting the resulting compound (Ic) with hydroxylamine or a salt thereof (examples of the salt include acid addition salts having the same meaning as that defined above).

The reaction of the compound (Ic) with hydroxylamine or a salt thereof can be carried out in the presence or absence of a base in an inert solvent at a temperature ranging from -78°C to a boiling point of a solvent used. The hydroxylamine or a salt thereof and the base can be used in an equivalent to an excess amount. The reaction is generally finished in 1 minute to 2 days.

Examples of the inert solvent include lower alcohols such as methanol, ethanol and propanol, ethers such as ether and tetrahydrofuran, and halogenated hydrocarbons such as chloroform, methylene chloride and 1,2-dichloroethane.

Examples of the base include pyridine, 2,6-dimethylpyridine, dimethylaminopyridine, triethylamine, and diisopropylamine.

Preparationl2

The compound, wherein the double bond between the 22- and 23-positions are reduced (ivermectin derivatives, the compounds (B1)), can be prepared by the method set out below.

OCH,

HO. fF) OCH;

He No” To. 4' 23

I CHs 22 CH

H,C” 07 0... AN. _~_ 0 13 CHa oY - HiC™” | CH,CH, . 0) 0 ’ (AT) | | oH _ : 0 } CH,

Ra - 11b1

R OCH; Y

H,C~ “O07 To. } 4' 23

CH, 22 .-CHj © CHyCT C07 ol. UA 0 13 CH, ) oo 0 . H,C™ | CH,CH;

Oo Oo oH (81) 0

R22 }

By using as a starting material an ivermectin derivative (Al), which is a known compound or can be prepared by a method similar to known methods, the corresponding carbonyl compound can be obtained through oxidation at the 4”-position according to a conventional method. The compound (B1) can be obtained y CORRECTED SHEET 09/10/2002 Co

® by using the resulting compound for a reaction with the compound represented by the - formula: (RO):P(O)CHzR 8! wherein R has the same meaning as that defined above, and R!%! represents a cyano group or a lower alkenyloxycarbonyl group in 2 manner similar to that described in Preparation 1.

For the preparation of the compound wherein R'"*" is a carboxyl group among the compounds (B1), the compound wherein R'™® is a cyano group or a lower : alkenyloxycarbonyl group among the compounds (B1) is used as a starting material and subjected to a’ reaction in a manner similar to Preparation 4.

The compound wherein R! is a cyanomethyl group or a carboxymethyl group and -X:---Y- is -CH-CH2- can be prepared by catalytically reducing the compound : obtained in Preparation 1 wherein RI is a cyano group or the compound obtained in : Preparation 4 wherein RU is a carboxyl group for 1 minute to 100 hours in the : presence of a catalyst such as triphenylphosphinerhodium chloride and a hydrogen source such as hydrogen and ammonium formate in a solvent such as benzene at a temperature ranging from 0°C to a boiling point of a solvent used. oo

Deprotection of the hydroxyl group at the 5-position in the above compounds can be carried out according to the method described in Preparation 10.

Preparation 13 : Co :

The compound wherein only the hydroxyl group at the 47-position of the avermectin B2a derivative (the compound (C)) is oxidized into the corresponding carbonyl group (the compound<(D)) or that wherein the hydroxyl groups at the 4”- and 23-positions of the compounds (C) are oxidized into the corresponding carbonyl groups, respectively (the compound (E)), can be prepared by treating the compound (C) with an appropriate oxidizing reagent. 34 CORRECTED SHEET : 05/10/2002

OCH; : .

HO. “ OCH3

H,C™ "O” O. OH “ CH3 2 A, -CHs

HC” O° O._X Oo 3 13 (0) CH3

HaC” CH,CH3 0.0 oe ll OH SE Lo (Cc) © CHa

R24 \ 0) “ ¢ OCH,

HaC™ "0" O._ Oo a DI 3 ) 13 N 9) CH3

H.C” CH,CH;

O40

OCH3 |OH

Hs ‘

HyC 0” 0. OH da Ca ’ CHa 2.93 -CHs ’

HC” 0” 0._~ 0) 3 . 0 CHs (E)

H,C’ CH,CH4 04.0

OH

R a (D) (In the scheme, R22 has the same meaning as that defined above.)

The compound wherein R is a cyano group or a carboxyl group can be prepared by treating the compound (D) wherein only the hydroxyl group at the 4”-position is oxidized into the corresponding carbonyl group in a manner similar to that in Preparation 1 or 4.

. @

Preparation 14

Among the compounds (I), the compound (F), wherein -X----Y- is -CH2-CH(OH)-, and R!¢ is a cyano group, a lower alkoxycarbonyl group or a lower alkenyloxycarbonyl group, can be prepared using the compound (D) obtained in

Preparation 13 as a starting material in a manner similar to that in Preparation 1.

Preparation 15

Among the compounds (I), the compound (G), wherein -X----Y- is -CH:-CH(R!32)- wherein R132 represents a lower alkylcarbonyloxy group which has the same meaning as that defined above, and R1!¢ is a cyano group, a lower alkoxycarbonyl group or a lower alkenyloxycarbonyl group, can be prepared using the compound (F) obtained in Preparation 14 as a starting material in a manner similar to that in Preparation 5 (i.e., lower-alkanoylation of the hydroxyl group).

Preparation 16

Among the compounds (I), the compound (H) wherein -X----Y- is —CH2-CH(R13)- wherein R13 has the same meaning as that defined above, and R1lcis a carboxyl group can be prepared by hydrolyzing the compound (F) or (G) wherein -X----Y- is -CH2-CH(R13)- wherein R3 has the same meaning as that defined above, and Rlic is a cyano group, a lower alkoxycarbonyl group or a lower alkenyloxycarbonyl group in a conventional manner.

The aforementioned methods are typical examples of the preparations of the compounds (I), and the preparations of the compounds (I) are not limited to those explained above. It can be easily understood by a person skilled in the art that the compounds of the present invention can be prepared by other methods and the compounds (I) can also be obtained by carrying out the above methods in an appropriate combination or with an appropriate modification or alteration, if necessary.

In addition, the compounds (I) can also be obtained by an appropriate combination of the methods for converting a functional group which are usually used

® in the field of synthetic organic chemistry. For example, the compound wherein R?2 is a methoxy group can be prepared by a conventional methylation of the hydroxyl group of the corresponding compound wherein R2 is a hydroxyl group. Similarly, the compound wherein R? is a lower alkoxyl group can be prepared by alkylation. For converting functional groups, desired conversions of functional groups can efficiently be made by protecting appropriate functional groups by methods for protection and deprotection conventionally used in the field of synthetic organic chemistry [e.g., see

Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons Inc. (1981)], if necessary. :

Specific examples of the aforementioned preparation and other preparations are described in Examples, and accordingly, a person skilled in the art can prepare any compounds falling within the compound (I) by referring to the above general explanations and specific explanations in Examples, and by appropriately choosing starting materials, reagents and reaction conditions and adding an appropriate alteration or modification, if necessary.

Purification of the desired compounds in the aforementioned preparations can be made by an appropriate combination of methods ordinarily used in the filed of synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, crystallization, and various chromatography and the like. Synthetic intermediates may be subjected to a next reaction without purification.

Isomers such as regio isomers, geometrical isomers, tautomers and optical isomers may exist as the compounds (I). Any possible isomers and mixtures thereof in any proportion fall within the scope of the present invention. When a bond of a functional group that substitutes on a carbon atom forming a double bond is represented by a waved line in the specification, it means that the compound is an E- or Z-compound, or a mixture thereof.

For the preparation of a salt of the compound (I), a resulting salt, per se, may be purified when the compound (I) is obtained in the form of a salt. When a product is obtained in a free form, a salt may be isolated and purified after dissolving or suspending the product in a suitable solvent, and adding an acid or a base thereto to form a salt. The compounds (I) and salts thereof may exist in the forms of adducts with water or various solvents (i.e., hydrates or solvates), and these adducts also fall

. @ into the scope of the present invention. Moreover, any forms of crystal also fall into the scope of the present invention.

Specific examples of the compounds (I) obtained according to the present invention are shown in Tables 1 to 8. However, the compounds of the present invention are not limited to these examples. In the tables, OTBDMS represents tert-butyldimethylsilyloxy (OSi(CHj3)2C(CHs)s), and (a) and (b) represent two isomers based on the hydroxyl group of the oxime moiety (Compounds 9 and 10, and

Compounds 12 and 13) or two isomers based on the exomethylene at the 4”-position (Compounds 18 and 19). The isomers appended by (a) represent those having a larger Rf value (lower polarity) and the isomers appended by (b) represent those having a smaller Rf value (higher polarity) in thin-layer chromatography. Asa developing solvent, one of the following solvents was used.

Toluene/acetone = 4/1

Toluene/ethyl acetate = 6/1

BN

Table 1 R' OCH;

NS

& OCH,

H,c~ “07 TO. 4 CH 22 3 CHa

IO HC” 07 TOL A 0 13 o CH,

HaC™~ CH,CH, 0x0 ow 0 oh (I a)

Se

Compound No. R11 RZ 1 CO5,CH5CH34 OTBDMS 2 CO5CH5CH3 OH 3 CH,OH OTBDMS 4 CH,OH OH

CHO OTBDMS

6 CO,CHj3 OTBDMS 7 CO,CHj4 OH 8 CHO OH 9 CH=N-OH(a) OH

CH=N-OH(b) OH

. @

Table 1 (continued) ~ Compound No. rR! R? 11 CHoNHCH34 OH 12 CH=N-OCH3(a) OH 13 CH=N-OCH3(b) OH 14 CHoNH» OTBDMS

CN(a) OTBDMS

A

16 CH,0 _N OTBDMS

S

0) 17 CH,0 ZZ OTBDMS 0) 18 CO5CHoCH=CHy(a) OTBDMS 19 CO,CH5CH=CHy(b) OTBDMS

CO5,CHoCH=CH> OH

. @

Table 1 (continued)

Compound No. 0 R?

NN

21 CHO AN OH s 22 CH=N-NHCONH>, OH 23 CN OH 24 COOH OTBDMS 25 COOH OH

SN

26 ovo, 12 OH 0

CHO J \ 27 —_ OH

H wo A 28 N OTBDMS 0 och, 29 CN(b) OTBDMS roy LJ)

N OH

0 oP ocoHys

Table 1 (continued)

Compound No. r11 RZ

I: ¥ 0 OH

CH,0” 0 32 CH,OCOCH3 OTBDMS ~C! 33 ovo, JT OTBDMS 0

Ge! 34 CH,0 | _N OH o)

CON © OTBDMS 7 36 CON © OH 37 cosor— OH oN

Table 2

R'" OCH, :

N

4" OCHs

H,c~ “07 TO. ee eee eam | 4 CH, - _ 23 CH, R

HC 07 TO... AS 0

CH

13 0) 3

HaC™ | CH,CH3j

Os _O

OH

0 (Ic)

CHa 5° nnn

Compound No. R11 38 CHO 39 CH>0OH y a

Table 3

R'? OCH, x 4 OCH;

H,c~ S07 To. 0) 4 CH, ,, HZ CH;

Hic” 07 oo AR ot - 13 0 CHa

HsC | CH,CHs

Os__0O oH 0 (Ib)

R2

Compound No. Rr11a R2 40 CO,CH3 OTBDMS 41 CO-CH3 OH a

Table 4 OCH, 0 4 OCH;

H,c~ “O07 TO. rR? 4 CH, 22 IS .-CHj

Hy,C™ ~07 TO... 0) oo i 13 0 CHs

HsC™ | CH,CH, - 0s__0O oH 7 © CH; (1d)

R?

Compound No. RZ R23 42 OTBDMS OH 43 OTBDMS =0 a

Table 5 R™ OCH, 4 OCH;

HsC Oo T0.. R23 4 CH, ” | 23 CH, eo ON oo ON or CH:

HC” | CH,CHj 0s _O ow 0 (1d)

CH,

RZ

Compound No. R'1¢ R? R23 44 CO,CH; OTBDMS =O 45 CO,CHs OH -0 46 CO,CH,CH=CH, OTBDMS -0 47 COOH OH OH 48 CN OH OH 49 CN OH OCOCHS; 50 CO,CH,CH=CH, OTBDMS OH 51 COOH OTBDMS OH 52 COOH OH OCOCHS3 78 CO,CHjs OH OH wr ®

Tables R' OCH } NN 4 OCH;

H,c~ “O07 To. 4 CH; 2 23 CH,

HiC™ 07 TO... A 0) 13 No CH;

H,C™” | CH,CH, 0 oO ow 0) (I a)

CH,

EE » cA

Compound No. R11 R? 53 CH0c0—< ON =0 54 CN =0 55 CH0c0—< ON =N~OH 56 CN =N ~QH 57 COOH =0 58 COOH =N ~OH 61 COO'Bu OTBDMS 63 COO'Bu OH a

Table 6 (continued)

Compound No. R11 R2 65 CH=CHCO,CH>CH=CH> OTBDMS 66 CH=CHCOOH OH 0 67 C—S \_NHCOCHj3 OTBDMS 9 68 C—S \_NHCOCHj; OH 69 CH>NHOCH3, OH 70 CH-CI OTBDMS 71 CH»CI ~~ OH 72 CHoNH» OTBDMS 73 CH>NH» OH /\ 74 CHo>—N NH OH

NE

@

Table 7

OCH

OCH,

H,C~ O07 To. ¢ CH; 22 AZ .--CHs oo

He” Yo” To. SN 0 3 chy

H.C” | CH,CHj ®] (eo ow fo) (I a)

CHa

RZ

Compound No. =R?’ R2

CN

59 =c OTBDMS

CHa

CN

60 =c OTBDMS er

CH

CN

62 =c OH

CH

CN

64 =c7_ OH

CH a

Table 8 OCH;

Rix

H,c~ ~0~ TO. 4 CH; 0g 20 CHa

H,C™ ~07 TO... A 0)

I LI CC Tory

HsC™ | CH,CH,4

O~_ _O

OH Ivermectin derivatives o- CH;

R2

Compound No. R! RZ 79 OH OTBDMS 80 =0 ~ OTBDMS 81 =CHCO,CH>CH=CH> OTBDMS 82 =CHCO,CH5CH=CH> OTBDMS 83 =CHCN OTBDMS 84 =CHCN OTBDMS 85 =CHCOOH OH 86 =CHCN OH 87 CH,COOH OH 88 CH>CN OH

®

As the active ingredient of the medicament of the present invention, one or more substances selected from the group consisting of the compounds in the free form and physiologically acceptable salts thereof, and hydrates thereof and solvates thereof can be used. Any mixture of isomers or an isomer in a pure form may be used. The medicament of the present invention is generally provided in the form of a pharmaceutical composition which comprises one or more pharmaceutical additives and the aforementioned substance as an active ingredient. The route of administration is not particularly limited, and the medicament can be orally administered using preparations such as tablets, granules, capsules, syrups and powders, or parenterally administered by means of injection, intrarectal administration, transdermal administration or the like. Pharmaceutical formulations suitable for oral or parenteral administration are well-known to persons skilled in the art, and they can appropriately choose pharmaceutical additives suitable for the manufacture of the pharmaceutical formulations.

The medicament of the present invention may be applied to various parasitic diseases, and the kinds of the parasitic disease are not particularly limited. The medicament of the present invention may be applied to a human or a mammal other than a human. When the medicament is applied to a mammal other than a human, the medicament may be administered as a pharmaceutical composition, or alternatively, a pharmaceutical composition or the aforementioned active ingredient per se may be added to a feed. The compound of the present invention may be applied as pesticides such as an agent for controlling injurious insects such as blowflies, cockroaches, fleas and the like.

Examples

The present invention will be explained more specifically with reference to : examples. However, the present invention is not limited to these examples.

Analytical data of the compounds described in the examples were measured by using the following apparatus. The number and structure of the compounds are the same as those described in Table 1 to 8 set out above.

IR: Horiba FT-210

NMR: JEOL (Nippon Denshi) JMN-EX270 hg MS: JEOL (Nippon Denshi) JMS-AX505

Solution A used in the following examples is a solution which is obtained by mixing 10 ml of hydrogen fluoride/pyridine complex, 6 ml of pyridine and 12 ml of tetrahydrofuran and stored in a polypropylene container below -10°C.

Among starting materials used in the following examples, 5-tert-butyldimethylsilyloxyavermectin B2a (5-O-tert-butyldimethylsilylavermectin

B2a) is described in Tetrahedron Letters, Vol. 31, pp. 3525-3528 (1990) and J. Med.

Chem. Vol. 25, pp. 658-663 (1982), and 5-tert-butyldimethylsilyloxy-7-trimethyl- silyloxyavermectin Bla is described in U.S. Patent No. 4,895,837.

Reference Example 1: Preparation of 5-O-tert-butyldimethylsilyl-4” 23-dioxo- avermectin B2a (compound {a])

In 3.5 ml of isopropyl acetate, 1.12 g of 5-O-tert-butyldimethylsilylavermectin

B2a was dissolved, and 0.65 ml of dimethylsulfoxide (DMSO) and 1.5 ml of . triethylamine were added to the solution under nitrogen gas atmosphere at -30°C. A solution of 0.6 ml of phenyl dichlorophosphate in 1.5 ml of isopropyl acetate was : added slowly and dropwise thereto, and the mixture was stirred under nitrogen gas atmosphere below -20°C for 1 hour and 30 minutes.

Then, a 1% aqueous phosphoric acid solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and dried over anhydrous : sodium sulfate, and then the solvent was evaporated under reduced pressure to give a crude product. The resulting crude product was purified by column chromatography on silica gel using eluting solvents of hexane/ethyl acetate = 4/1 to 2/1 to give 610 mg of the compound [a] in a 55% yield.

HR-FAB-MS: Calculated; Cs54Hs+015Si (M+Nal* 1023.5477, Found; 1023.5507

IR(KBr) A maxcm-l: 3469, 2962, 2933, 1739, 1724, 1452, 1124, 1054, 1006, 989 : 'H NMR (270MHz, CDCls, partial data) § (ppm): 5.76 (1H, m), 5.70 (2H, m), 5.48 (1H, : s), 5.30 (1H, s), 5.26 (1H, m), 4.90 (1H, t, J = T.3Hz), 4.73 (1H, d, J = 3.3Hz), 4.64 (1H, d, J =15.8Hz), 4.53 (1H, d, J = 16.1Hz), 4.38 (2H, m), 4.15 (1H, m), 3.98 (1H, s), 3.89 (1H, brs), 3.77 (1H, d, J = 5.6Hz), 3.46 (3H, s), 3.39 (3H, s), 3.28 (1H, t, J = 8.9Hz), © 1.76 (3H, s), 1.11 (3H, d, J = 6.9Hz), 0.09 (6H, 5) 52 CORRECTED SHEET : 09/10/2002

. @ 13C-NMR (67.8MHz, CDCls) 4 (ppm): 206.9, 205.8, 173.7, 140.1, 137.5, 137.3, 135.4, 124.8, 119.2, 117.6, 117.1, 100.5, 97.9, 94.7, 81.7, 81.0, 80.2, 80.0, 79.0, 77.9, 76.4, 70.6, 69.3, 68.1, 67.7, 67.6, 66.8, 60.3, 58.2, 56.3, 51.3, 46.3, 45.6, 40.3, 39.4, 39.3, 35.9, 35.8, 34.4, 33.7, 27.2, 25.7, 25.7, 25.7, 20.2, 19.9, 18.3, 15.0, 13.8, 12.3, 11.5, 8.6, -4.7, -5.0

Example 1: Preparation of Compound 1

To 0.5 ml of a 1.0 mol/L tetrahydrofuran solution of lithium hexamethyldisilazane, 0.1 ml of ethyl diethylphosphonoacetate was added, and the resulting mixture was stirred under ice-cooling (0°C) for 30 minutes. Then, a solution of 235 mg of 5-O-tert-butyldimethylsilyl-4”-oxoavarmectin Bla represented by the following formula dissolved in 0.8 ml of tetrahydrofuran was added to the mixture, and the mixture was stirred at room temperature for 4 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product. The resulting crude product was purified by column chromatography on silica gel using stepwise elution with eluting solvents of hexane/ethyl acetate = 8/1~4/1~2/1~1/1 to give 72 mg of Compound 1 in a 29% yield.

. @

OCH3 0) 4 OCH;

H,C~ ~O0~ TO. 4 CH, ny 23 CH,

He” S07 To. - Xe 0 3 -

HsC™” | CH,CH, oO 0 oH

Oo

CH

OTBDMS

HR-FAB-MS: Calculated; CssHg0015Si[M+Na]* 1077.5946, Found; 1077.5947

H NMR(270MHz, CDCls, partial data) 6 (ppm): 5.82 (1H, s), 5.73 (3H, m), 5.53 (1H, dd, J = 2.3,9.9Hz), 5.43 (1H, m), 5.33 (1H, m), 5.31 (1H, d, J = 7.7Hz), 5.13 (1H, s), 4.98 (1H,m), 4.75 (1H, d, J=2.9Hz), 4.67 (1H, d, J = 14.8Hz), 4.56 (1H, d, J = 14.8Hz), 4.48 (1H, m), 4.40 (1H, m), 4.17 (2H, q, J = 7.2Hz), 3.91 (1H, s), 3.44 (3H, s), 3.36 (3H, s), 1.77 (3H, s), 0.91 (9H, 8), 0.11 (6H, s)

Example 2: Preparation of Compound 2

In 1.5 ml of tetrahydrofuran, 50 mg of Compound 1 obtained in Example 1 was dissolved, 0.2 ml of the solution A was added thereto, and the mixture was stirred at room temperature for a night. Pyridine was added on an ice bath, and an aqueous sodium hydrogencarbonate solution was added for neutralization, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product. The resulting crude product was purified by column chromatography on silica gel using stepwise elution with eluting solvents of hexane/2-propanol = 85/15~4/1~3/1 to give 27 mg of Compound 2 in a 62% yield.

HR-FAB-MS: Calculated; Cs2H76015[M+Na]* 963.5081, Found; 963.5082

. @®

IR(KBr) A maxcm-1: 3482, 2969, 2933, 1720, 1654, 1457, 1382, 1159, 1120, 991 'H NMR (270MHz, CDCls, partial data) § (ppm): 5.82 (1H, s), 5.73 (3H, m), 5.53 (1H, dd, J = 2.3, 9.9Hz), 5.40 (3H, m), 5.13 (1H, s), 4.98 (1H, m), 4.75 (1H, 4, J = 2.9Hz), 4.46 (2H, m), 4.17 (2H, q, J = 7.2Hz), 4.01 (1H, s), 3.44 (3H, s), 3.35 (3H, s), 1.85 (3H, 5) 1BC-NMR (67.8MHz, CDCls) 6 (ppm): 173.7, 165.8, 156.4, 139.5, 138.1, 137.9, 136.3,

EE 135.1, 127.7, 124.6, 120.4, 118.2, 118.0, 117.1, 96.2, 95.7, 95.0, 81.9, 80.3, 80.2, 79.0, 78.9,74.8, 70.1, 68.4, 68.3, 68.3, 68.1, 67.7, 67.4, 60.3, 57.1, 56.4, 45.6, 40.4, 39.7, 36.6, 35.1, 34.7, 34.2, 33.4, 30.5, 27.5, 20.1, 19.9, 19.3, 17.9, 16.3, 15.0, 14.2, 12.9, 12.0

Example 3: Preparation of Compound 3

In 1.5 ml of methylene chloride, 164 mg of Compound 6 obtained in Example 6 was dissolved, 0.55 ml of a 1.0 mol/L tetrahydrofuran solution of diisobutylaluminium hydride was dropwise added thereto at -78°C and then the mixture was stirred at the same temperature for 2 hours. Methanol was added thereto for inactivation of the excess reagent, and further celite and sodium sulfate decahydrate were added thereto. The mixture was stirred at room temperature for minutes and filtered. The residue was washed with ethyl acetate. The organic layers were combined and concentrated under reduced pressure to give a crude product. The resulting crude product was purified by column chromatography on silica gel using stepwise elution with eluting solvents of methylene chloride/tetrahydrofuran = 20/1~10/1~6/1 to give 132 mg of Compound 3 in a 83% yield.

HR-FAB-MS: Calculated; CssHss014Si[M+Na]* 1035.5840, Found; 1035.5841

IR(KBr) A maxem-1: 3477, 2962, 2931, 1735, 1718, 1459, 1380, 1160, 1124, 989 'H NMR (270MHz, CDCls, partial data) § (ppm): 5.70 (5H, m), 5.51 (1H, dd, J = 2.3, 9.9Hz), 5.36 (3H, m), 4.97 (1H, m), 4.73 (1H, d, J = 3.3Hz), 4.58 (2H, q, J = 4.8Hz), 4.39 (2H, m), 4.27 (3H, m), 3.93 (1H, s), 3.45 (3H, s), 3.38 (3H, s), 1.78 (3H, 5s), 1.31 (3H, d, J = 6.3Hz), 1.22 (3H, d, J = 6.3Hz), 1.12 (3H, d, J = 7.0Hz), 0.89 (9H, s), 0.10 (6H, s)

Example 4: Preparation of Compound 4 a

In 1 ml of tetrahydrofuran, 87 mg of Compound 3 obtained in Example 3 was dissolved, 1 ml of the solution A was added thereto, and the mixture was stirred at room temperature for a night. Then, the reaction mixture was treated and purified in the manners similar to those in Example 2 to give 49 mg of Compound 4 in a 64% yield.

HR-FAB-MS: Calculated; CsoH7401s[M+Nal* 921.4976, Found; 921.4922

TR(KBr) 2 maxem-L: 3465, 2967, 2933, 1735, 1718, 1457, 1378, 1180, 1118, 989 1H NMR (270MHz, CDCls, partial data) é (ppm): 5.88 (1H, m), 5.73 (4H, m), 5.54 (1H, dd, J = 2.6, 9.9Hz), 5.37 (3H, m), 4.98 (1H, m), 4.76 (1H, d, J = 3.0Hz), 4.67 (2H, s), 3.45 (3H, s), 3.36 (3H, s), 1.86 (3H, s), 1.33 (3H, d, J = 6.6Hz), 1.25 (3H, d, J = 5.9Hz), 1.14 (3H, d, J = 6.9Hz) 13C-NMR (67.8MHz, CDCls) 6 (ppm): 173.7, 141.6, 139.5, 138.1, 137.9, 136.3, 135.1, 127.7, 125.9, 124.7, 120.4, 118.3, 118.0, 96.7, 95.7, 95.0, 81.9, 80.4, 79.9, 79.0, 74.9, 73.2, 68.4, 68.3, 68.3, 67.7, 67.5, 67.1, 58.4, 56.9, 55.8, 45.7, 40.4, 39.8, 36.6, 35.1, 34.7, 34.2, 33.2, 30.6, 27.5, 20.2, 19.9, 18.2, 18.0, 16.4, 15.1, 12.9, 12.0 (one peak was not observed because of overlapping with another peak.)

Example 5: Preparation of Compound 5

In 3 ml of methylene chloride, 791 mg of Compound 3 obtained in Example 3 was dissolved, 0.8 g of manganese dioxide was added thereto, and the mixture was stirred for 1 day. The reaction mixture was diluted with diethyl ether and passed through a dry silica gel column, and the silica gel column was washed with diethyl ether. The resulting diethyl ether solution was concentrated under reduced pressure to give a crude product. The resulting crude product was purified by column chromatography on silica gel using stepwise elution with eluting solvents of hexane/ethyl acetate = 4/1~2/1~1/1 to give 628 mg of Compound 5 in a 80% yield.

HR-FAB-MS: Calculated; CseHssO14Si[M+Nal* 1033.5684, Found; 1033.5740

IR(KBr) 1 maxcm-1: 3444, 2962, 2933, 1727, 1660, 1461, 1384, 1160, 1124, 1008, 989 1H NMR (270MHz, CDCls, partial data) 6 (ppm): 10.3 (1H, d, J = 7.3Hz), 5.90 (1H, d,

J = 7.3Hz2), 5.74 (4H, m), 5.54 (1H, dd, J = 2.3, 9.9Hz), 5.48 (1H, m), 5.33 (2H, m), 4.99 (1H, m), 4.78 (1H, s), 4.43 (1H, br.s), 4.13 (1H, s), 3.45 (3H, s), 3.44 (3H, s), 3.31 (1H, t,

J =9.2Hz), 2.03 (1H, m), 1.79 (3H, s), 1.35 (3H, d, J = 6.3Hz), 1.15 (3H, d, J = 6.9Hz),

. @ 0.13 (6H, s) 13C-NMR (67.8MHz, CDCls) 6 (ppm): 193.7, 174.1, 158.7, 140.2, 137.5, 137.4, 136.2, 135.1, 127.7, 125.1, 124.8, 119.2, 118.3, 117.1, 97.3, 95.7, 95.0, 82.0, 80.5, 80.2, 80.0, 79.1, 75.2, 74.8, 69.4, 68.4, 68.3, 67.9, 67.2, 67.0, 56.7, 56.4, 45.7, 40.4, 39.6, 36.5, 36.4, 35.1, 34.6, 34.2, 30.5, 27.5, 25.8, 25.8, 25.8, 20.3, 20.0, 18.4, 18.1, 17.6, 16.3, 15.1, 12.9, 12.0, -4.6, -4.9

Example 6: Preparation of Compound 6

To 0.55 ml of a 1.0 mol/L tetrahydrofuran solution of lithium hexamethyldisilazane, 0.11 ml of methyl diethylphosphonoacetate was added, and the resulting mixture was stirred under ice-cooling (0°C) for 30 minutes. Then, 464 mg of 5-O-tert-butyldimethylsilyl-4”-oxoavermectin Bla dissolved in 1.4 ml of tetrahydrofuran was added to the mixture, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then treated and purified in the manners similar to those in Example 1 to give 402 mg of Compound 6 in a 82% yield.

HR-FAB-MS: Calculated; Cs7Hsgs015Si[M+Nal]* 1063.5790, Found; 1063.5840

IR(KBr) A maxcm-t: 3444, 2962, 2933, 1727, 1660, 1461, 1384, 1160, 1124, 1008, 989 1H NMR (270MHz, CDCls, partial data) 6 (ppm): 5.84 (1H, s), 5.72 (3H, m), 5.54 (1H, dd, J = 2.3, 9.9Hz), 5.44 (1H, t, J = 7.2Hz), 5.35 (1H, m), 5.32 (1H, s), 5.13 (1H, s), 4.98 (1H, m), 4.76 (1H, s), 4.52 (2H, q, J = 4.9Hz), 4.45 (2H, m), 3.72 (3H, s), 3.45 (3H, s), 3.37 (3H, s), 1.78 (3H, s), 1.49 (3H, s), 1.41 (3H, d, J = 6.6Hz), 1.24 (3H, d, J = 6.3Hz), 1.13 (3H, d, J = 6.9Hz), 0.92 (9H, s), 0.13 (6H, s)

Example 7: Preparation of Compound 7

In 2 ml] of tetrahydrofuran, 67 mg of Compound 6 obtained in Example 6 was dissolved, 0.3 ml of the solution A was added thereto, and the mixture was stirred at room temperature for a night. Then, the reaction mixture was treated and purified in the manners similar to those in Example 2 to give 41 mg of Compound 7 in a 67% yield.

HR-FAB-MS: Calculated; Cs1H7401s[M+Na]* 949.4925, Found; 949.4955

IR(KBr) A maxcm-1: 3446, 2967, 2933, 1724, 1456, 1382, 1159, 1120, 987 1H NMR (270MHz, CDCls, partial data) § (ppm): 5.77 (5H, m), 5.53 (1H, dd, J = 2.6,

. © 9.9Hz), 5.40 (3H, m), 5.12 (1H, s), 4.98 (1H, m), 4.75 (1H, d, J = 3.9Hz), 4.66 (2H, s), 4.48 (1H, m), 4.28 (1H, br.s), 3.71 (3H, s), 3.45 (3H, s), 3.36 (3H, s), 1.85 (3H, s), 1.47 (3H, s), 1.40 (3H, d, J = 7.6Hz), 1.23 (3H, d, J =5.9Hz), 1.12 (3H, d, J = 6.9Hz) 13C-NMR (67.8MHz, CDCls) 5 (ppm): 173.7, 166.2, 156.8, 139.5, 138.0, 137.9, 136.2, 135.1, 127.7, 124.6, 120.4, 118.2, 118.0, 116.6, 96.1, 95.7, 95.0, 81.9, 80.3, 80.2, 79.0, 78.9, 74.8, 70.2, 68.4, 68.3, 68.3, 68.1, 67.7, 67.4, 57.1, 56.5, 51.3, 45.6, 40.4, 39.7, 36.6, 35.1, 34.7, 34.2, 33.4, 30.5, 27.4, 20.1, 19.9, 19.3, 17.9, 16.3, 15.0, 13.0, 12.0

Example 8: Preparation of Compound 8

In 1 ml of tetrahydrofuran, 93 mg of Compound 5 obtained in Example 5 was dissolved, 1 ml of the solution A was added thereto, and the mixture was stirred at room temperature for a night. Then, the reaction mixture was treated and purified in the manners similar to those in Example 2 to give 62 mg of Compound 8 in a 75% yield.

HR-FAB-MS: Calculated; C50H72014[M+Nal]* 919.4819, Found; 919.4821

IR(KBr) A maxem-1: 3453, 2967, 2933, 1723, 1673, 1456, 1378, 1160, 1118, 991 1H NMR (270MHz, CDCls, partial data) 6 (ppm): 10.36 (1H, d, J = 7.6Hz), 5.90 (1H, d,

J = 7.6Hz), 5.86 (1H, m), 5.74 (3H, m), 5.53 (1H, dd, J = 2.3, 9.9Hz), 5.48 (1H, m), 5.41 (2H, m), 4.98 (1H, m), 4.78 (1H, br.s), 4.68 (1H, s), 4.53 (2H, m), 4.29 (1H, br.s), 3.45 (3H, s), 3.43 (3H, s), 2.02 (1H, m), 1.87 (3H, s), 1.36 (3H, d, J = 6.6Hz), 1.25 (3H, d, J = 6.9Hz), 1.16 (3H, d, J = 6.3Hz) 13C-NMR (67.8MHz, CDCls) 6 (ppm): 193.6, 173.7, 158.7, 139.6, 138.0, 138.0, 136.2, 135.1, 127.7,125.1, 124.7, 120.4, 118.3, 118.0, 97.3, 95.7, 95.0, 82.0, 80.5, 80.4, 79.1, 75.2, 74.9, 68.4, 68.3, 68.3, 67.7, 67.3, 67.2, 67.1, 56.7, 56.4, 45.7, 40.4, 39.7, 36.6, 36.4, 35.1, 34.6, 34.2, 30.5, 27.5, 20.2, 19.9, 18.1, 17.7, 16.3, 15.1, 12.9, 12.0

Example 9: Preparation of Compounds 9 and 10

To a solution of 103 mg of Compound 5 obtained in Example 5 dissolved in 0.3 ml of ethanol, 21 mg of hydroxylamine hydrochloride and 0.5 ml of pyridine were added, and the resulting mixture was stirred at room temperature for 1 hour. To the reaction solution was added an aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over

. @ anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product.

The resulting crude product was dissolved in 1 ml of tetrahydrofuran, 0.5 ml of the solution A was added thereto, and the mixture was stirred at room temperature for a night. To the reaction solution was added pyridine and an aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a crude product. The resulting crude product was purified by column chromatography on silica gel using stepwise elution with eluting solvents of toluene/acetone = 10/1 to 5/1 to give 81 mg of a mixture of Compounds 9 and 10 in a 69% yield.

Compounds 9 and 10 are isomers based on the hydroxyl group of the oxime.

The mixture was separated by thin-layer chromatography with a developing solvent of toluene/acetone = 4/1 to give 45 mg of Compound 9 having the Rf value of 0.33, and mg of Compound 10 having the Rf value of 0.23, respectively.

Compound 9:

HR-FAB-MS: Calculated; C50H7sNO1M+Na]+ 934.4928, Found; 934.4918

IR(KXBr) A maxcm-1: 3417, 2967, 2933, 1714, 1456, 1378, 1160, 1118, 993 'H NMR (270MHz, CDCls, partial data) § (ppm): 8.31 (1H, d, J = 10.2Hz), 6.08 (1H, d,

Jd = 10.2Hz), 5.84 (1H, m), 5.74 (3H, m), 5.54 (1H, dd, J = 2.3, 9.9Hz), 5.41 (3H, m), 4.77 (1H, s), 4.67 (2H, s), 4.45 (1H, m), 4.29 (2H, m), 4.14 (1H, br.s), 3.46 (3H, s), 3.36 (3H, s), 1.86 (3H, s), 1.37 (3H, d, J = 6.6Hz), 1.25 (3H, d, J = 6.3Hz), 1.15 (3H, d, J = 6.9Hz)

Compound 10:

HR-FAB-MS: Calculated; Cso0H7sN O14 M+Na]+ 934.4928, Found; 934.4929 }

IR(KBr) A maxcm-1: 3417, 2967, 2933, 1714, 1456, 1378, 1160, 1118, 993 1H NMR (270MHz, CDCls, partial data) § (ppm): 7.72 (1H, d, J = 9.6Hz), 6.71 (1H, d,

Jd = 9.6Hz), 5.85 (1H, m), 5.74 (3H, m), 5.55 (1H, dd, J = 2.6, 9.9Hz), 5.43 (4H, m), 4.77 (1H, d, J = 3.0Hz), 4.67 (2H, s), 4.48 (1H, m), 4.37 (1H, m), 4.28 (1H, d, J = 7.2H2z), 3.45 (3H, s), 3.37 (3H, s), 1.86 (3H, s), 1.40 (3H, d, J = 6.6Hz), 1.25 (3H, d, J = 6.3Hz), 1.15 (3H, d, J = 6.9Hz) 13C-NMR (67.8MHz, CDCls) 6 (ppm): 173.7, 148.0, 144.9, 139.5, 138.1, 137.9, 136.3,

. © 135.8, 135.1, 127.7, 124.7, 120.4, 118.3, 118.1, 112.0, 97.0, 95.8, 95.1, 81.9, 80.4, 79.2, 79.2, 79.1, 74.9, 74.0, 68.4, 68.4, 67.9, 67.7, 67.4, 56.9, 56.3, 45.7, 40.5, 39.8, 36.6, 35.5, 35.2, 34.7, 34.2, 30.6, 27.5, 20.2, 19.9, 18.3, 18.1, 16.4, 15.1, 13.0, 12.0

Example 10: Preparation of Compound 11

To a solution of 30 mg of Compound 5 obtained in Example 5 dissolved in 0.4 ml of isopropyl acetate, 6 mg of zinc(II) chloride and 20 ul of heptamethyldisilazane were added, and the resulting mixture was heated to 45°C and stirred. The reaction was continued at the same temperature for 4 hours. After the mixture was cooled to 0°C, 0.4 ml of ethanol and 5 mg of sodium borohydride was added thereto, and then the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added a saturated brine and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product.

The resulting crude product was purified by thin-layer chromatography on silica gel of 0.5 mm thickness using a developing solvent of methylene chloride/methanol = 9/1 to give 5-O-tert-butyldimethylsilyl-4”-N-methylamino- ethylideneavermectin Bla.

The resulting 5-O-tert-butyldimethylsilyl-4”-N-methylaminoethylidene- avermectin Bla was dissolved in 0.4 ml of tetrahydrofuran, 0.2 ml of the solution A was added thereto, and the mixture was stirred at room temperature for a night.

The mixture was then treated in a manner similar to that in Example 2, and purified by column chromatography on silica gel using stepwise elution with eluting solvents of methylene chloride/methanol = 6/1 to 2/1 and methanol to give 6 mg of Compound 11 in a 68% yield. ’

HR-FAB-MS: Calculated; C51H77NO13(M+Na]l* 912.5475, Found; 912.5460

IR(KBr) A maxem-1: 3477, 2931, 1737, 1716, 1454, 1118, 989 1H NMR (270MHz, CDCls, partial data) 6 (ppm): 5.79 (4H, m), 5.61 (1H, m), 5.55 (1H, dd, J = 2.3, 9.9Hz), 5.38 (3H, m), 4.99 (1H, m), 4.76 (1H, d, J = 3.0Hz), 4.68 (2H, s), 4.40 (1H, m), 4.27 (2H, m), 3.46 (3H, s), 3.35 (3H, s), 2.49 (3H, s), 1.87 (3H, s), 1.34 (3H, d, J = 6.3Hz), 1.15 (3H, d, J = 6.9Hz)

® Example 11: Preparation of Compounds 12 and 13

In 0.3 ml of ethanol, 87 mg of Compound 5 obtained in Example 5 was dissolved, 22 mg of methyloxyamine hydrochloride and 0.5 ml of pyridine were added thereto, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added an aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product.

The resulting crude product was dissolved in 1 ml of tetrahydrofuran, 0.5 ml of the solution A was added thereto, and the mixture was stirred at room temperature for a night. To the reaction solution was added pyridine and an aqueous sodium : hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product. The resulting crude product was purified by column chromatography on silica gel using an eluting solvent of toluene/acetone = 8/1 to give 86 mg of a mixture of Compounds 12 and 13 in a 100% yield.

Compounds 12 and 13 are isomers based on the methoxy group of the oxime.

The mixture was separated by thin-layer chromatography with an eluting solvent of toluene/acetone = 4/1 to give 40 mg of Compound 12 having the Rf value of 0.54, and mg of Compound 13 having the Rf value of 0.49.

Compound 12: -

HR-FAB-MS: Calculated; Cs1H7sNO1w[M+Naj* 948.5084, Found; 948.5142

IR(KBr) A maxcm-L: 3467, 2967, 2933, 1735, 1716, 1457, 1157, 1118, 1041, 989 'H NMR (270MHz, CDCls, partial data) 6 (ppm): 8.28 (1H, d, J = 10.3Hz), 6.09 (1H, d,

J =10.3Hz), 5.73 (5H, m), 5.54 (1H, dd, J = 2.3, 9.9Hz), 5.40 (3H, m), 4.99 (1H, m), 4.76 (1H, d, J = 3.0Hz), 4.67 (2H, s), 4.45 (1H, m), 4.29 (2H, m), 3.89 (3H, s), 3.45 (3H, s), 3.35 (3H, s), 1.87 (3H, s), 1.36 (3H, 4, J = 6.6Hz), 1.25 (3H, d, J = 6.3Hz), 1.15 (3H, d, J = 6.9Hz)

Compound 13:

HR-FAB-MS: Calculated; C5:H7sN O14 M+Nal+ 948.5084, Found; 948.5093

IR(KBr) A maxcm-l: 3455, 2968, 2933, 1731, 1716, 1456, 1378, 1159, 1118, 1052, 995 61 CORRECTED SHEET + 09/10/2002 oe ¢

. @ 'H NMR (270MHz, CDCls, partial data) § (ppm): 7.63 (1H, d, J = 9.6Hz), 6.61 (1H, d,

J =9.6Hz), 5.85 (1H, m), 5.74 (3H, m), 5.55 (1H, dd, J = 2.6, 9.9Hz), 5.43 (4H, m), 4.99 (1H, m), 4.77 (1H, d, J = 3.0Hz), 4.67 (2H, s), 3.92 (3H, s), 3.45 (3H, s), 3.37 (3H, s), 1.87 (3H, 5), 1.39 (3H, d, J = 6.6Hz), 1.15 (3H, d, J = 6.9Hz)

Example 12: Preparation of Compound 14

To a solution of 200 mg of Compound 5 obtained in Example 5 dissolved in 5 ml] of isopropyl acetate, 30 mg of zinc(II) chloride and 175 1 of hexamethyldisilazane were added, and the mixture was heated to 50°C and stirred. The reaction was continued at the same temperature for 3 hours. After the reaction mixture was cooled to 0°C, 25 mg of sodium borohydride was added thereto, and the mixture was stirred at room temperature for 1 hour. Saturated brine was added thereto, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product. The resulting crude product was purified by column chromatography on silica gel using stepwise elution with eluting solvents of hexane/acetone = 3/1~2/1~1/1, and acetone and then methanol to give 16 mg of

Compound 14 in a 10% yield.

HR-FAB-MS: Calculated; C56HssNO13Si[M+Nal* 1034.5983, Found; 1034.5956

IR(KBr) A maxcm-1: 3482, 2962, 2931, 1735, 1716, 1457, 1380, 1160, 1124, 1083, 991 1H NMR (270MHz, CDCls, partial data) § (ppm): 5.73 (5H, m), 5.54 (1H, dd, J = 2.3, 9.9Hz), 5.32 (3H, m), 4.98 (1H, m), 4.77 (1H, br.s), 4.68 (1H, d, J = 15.8Hz), 4.57 (1H, d, J = 14.2Hz), 4.39 (2H, m), 4.27 (1H, br.s), 3.44 (3H, s), 3.38 (3H, s), 1.78 (3H, s), 1.33 (3H, d, J = 6.3Hz), 1.14 (3H, 4, J = 6.9Hz), 0.13 (6H, s)

Example 13: Preparation of Compounds 15 and 29

To 150 x1 of a 1.0 mol/L tetrahydrofuran solution of lithium hexamethyldisilazane, 30 ul of diethylphosphonocyanomethyl was added, and the resulting mixture was stirred under ice-cooling (0°C) for 30 minutes. Then, a solution of 109 mg of 5-O-tert-butyldimethylsilyl-4”-oxoavermectin Bla dissolved in 0.5 ml of tetrahydrofuran was added to the mixture, and the mixture was stirred at room temperature for 2 hours. The mixture was then treated and purified in the

. ® manners similar to those in Example 1 to give 90 mg of a mixture of Compounds 15 and 29 in a 80% yield.

Compounds 15 and 29 are isomers based on the 4”-exomethylene moiety.

The mixture was separated by thin-layer chromatography using a developing solvent of toluene/ethyl acetate = 4/1 to give 16 mg of Compound 15 having the Rf value of 0.59, and 57 mg of Compound 29 having the Rf value of 0.54.

Compound 29:

HR-FAB-MS: Calculated; Cs6HssNO13Si[M+Na]* 1030.5670, Found; 1030.5688

IR(KBr) 1 maxem-1: 3482, 2962, 2935, 2221, 1735, 1712, 1463, 1378, 1160, 1124, 1010, 991 1H NMR (270MHz, CDCls, partial data) § (ppm): 5.73 (4H, m), 5.54 (1H, dd, J = 2.6, 9.9Hz), 5.45 (1H, t, J = 4.3Hz), 5.35 (3H, m), 4.98 (1H, m), 4.77 (1H, d, J = 3.3Hz), 4.68 (1H, d, J = 14.9Hz), 4.57 (1H, d, J = 14.5Hz), 4.45 (2H, m), 4.30 (1H, m), 3.48 (3H, s), 3.44 (3H, s), 1.78 (3H, s), 1.35 (3H, d, J = 6.3Hz), 1.14 (3H, d, J = 6.9Hz), 0.13 (6H, s)

Example 14: Preparation of Compound 16

In 0.5 ml of methylene chloride, 102 mg of Compound 3 obtained in Example 3 was dissolved, 0.2 ml of pyridine, 55 mg of nicotinoyl chloride hydrochloride and 13 mg of 4-dimethylaminopyridine were added thereto, and the mixture was stirred for 5 days. To the reaction solution was added an aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product. The resulting crude product was purified by column chromatography on silica gel using stepwise elution with eluting solvents of hexane/ethyl acetate = 10/1~6/1~2/1 to give 70 mg of Compound 16 in a 62% yield.

HR-FAB-MS: Calculated; Ce2Ho1NO15Si[M+Na]* 1140.6055, Found; 1140.6058

IR(KBr) A maxem-l: 3438, 2962, 2929, 1727, 1280, 1124, 987 'H NMR (270MHz, CDCls, partial data) § (ppm): 9.21 (1H, d, J = 1.6Hz), 8.76 (1H, dd,

J = 1.6, 4.6Hz), 8.28 (1H, dt, J = 2.0, 8.2Hz), 7.37 (1H, m), 5.72 (5H, m), 5.52 (1H, dd,

J = 2.5, 9.9Hz), 5.39 (3H, m), 5.15 (1H, dd, J = 7.6, 13.2Hz), 5.01 (2H, m), 4.75 (1H, d,

J = 3.0Hz), 4.66 (1H, d, J = 16.2Hz), 4.55 (1H, d, J = 16.8Hz), 4.32 (1H, br.s), 3.44 (3H,

. @ s), 3.36 (3H, s), 1.76 (3H, s), 1.35 (3H, d, J = 6.6Hz), 1.12 (3H, d, J = 6.6Hz), 0.11 (6H, s)

Example 15: Preparation of Compound 17

In 0.5 ml of methylene chloride, 102 mg of Compound 3 obtained in Example 3 was dissolved, 0.2 ml of pyridine, 52 mg of isonicotinoyl chloride hydrochloride and 12 mg of 4-dimethylaminopyridine were added thereto, and the mixture was stirred a oo for 5 days. The reaction mixture was subjected to post-treatment and purified in the manners similar to those in Example 14 to give 51 mg of Compound 17 in a 46% yield. " HR-FAB-MS: Calculated; Ce2H91NO15Si[M+Na]l* 1140.6055, Found; 1140.6049 ] IR(KBr) 1 maxcm-1: 3450, 2962, 2933, 1731, 1461, 1378, 1276, 1160, 1124, 993 1H NMR (270MHz, CDCls, partial data) 6 (ppm): 8.78 (2H, dd, J = 1.7, 4.4Hz), 7.85 (2H, dd, J = 1.7, 4.4Hz), 5.73 (6H, m), 5.55 (1H, dd, J = 2.3, 9.9Hz), 5.41 (2H, s), 5.14 (1H, dd, J = 7.6, 13.2Hz), 5.02 (2H, m), 4.77 (1H, d, J = 3.0Hz), 4.67 (1H, d, J = 16.2Hz), 4.57 (1H, d, J = 16.2Hz), 4.33 (1H, br.s), 4.12 (1H, s), 3.46 (3H, s), 3.38 (3H, s), 1.78 (3H, s), 1.37 (3H, d, J = 6.6Hz), 1.26 (3H, d, J = 6.6Hz), 1.14 (3H, d, J = 6.9Hz), 0.92 (9H, s), 0.13 (6H, s) 13C-NMR (67.8MHz, CDCls) § (ppm): 173.9, 164.9, 150.5, 150.5, 142.9, 140.1, 137 4, 137.3, 136.2, 135.1, 127.7, 124.7, 122.8, 122.8, 120.1, 119.3, 118.3, 117.3, 96.8, 95.7, 95.0, 82.0, 80.2, 80.1, 80.0, 79.0, 74.8, 73.4, 69.4, 68.4, 68.3, 67.9, 67.4, 67.3, 62.0, 56.9, 56.0,45.7,40.4, 39.6, 36.5, 35.1, 34.7, 34.2, 30.5, 27.4, 25.8, 25.8, 25.8, 20.2, 20.0, 18.4, 18.3, 18.0, 16.3, 15.1, 12.9, 12.0, -4.6, -4.9 (two peaks were not observed because of overlappings with other peaks.)

Example 16: Preparation of Compounds 18 and 19

To 150 41 of a 1.0 mol/L tetrahydrofuran solution of lithium hexamethyldisilazane, 40 41 of allyl diethylphosphonoacetate was added, and the resulting mixture was stirred under ice-cooling (0°C) for 30 minutes. Then, a solution of 109 mg of 5-O-tert-butyldimethylsilyl-4”-oxoavermectin Bla dissolved in 0.5 ml of tetrahydrofuran was added to the mixture, and the mixture was stirred at room temperature for 3 hours. The mixture was then treated and purified in the manners similar to those in Example 1 to give 100 mg of a mixture of Compounds 18

. @ and 19 in a 86% yield.

Compounds 18 and 19 are isomers based on the 4”-exomethylene moiety.

The mixture was separated by thin-layer chromatography using an eluting solvent of toluene/ethyl acetate = 6/1 to give 14 mg of Compound 18 having the Rf value of 0.49, and 69 mg of Compound 19 having the Rf value of 0.40.

Compound 18:

HR-FAB-MS: Calculated; CssHsoNO15Si[M+Na]* 1089.5946, Found; 1089.5914

IR(KBr) 1 maxcm-1: 3482, 2962, 2933, 1720, 1654, 1457, 1388, 1159, 1124, 1085, 989

H NMR (270MHz, CDCls, partial data) 0 (ppm): 5.93 (2H, m), 5.74 (4H, m), 5.51 (2H, m), 5.32 (3H, m), 4.98 (1H, m), 4.76 (1H, d, J = 3.0Hz), 4.62 (2H, m), 4.43 (1H, br.s), 4.08 (1H, s), 3.92 (1H, br.s), 3.45 (3H, s), 3.24 (3H, 5), 1.78 (3H, s), 1.24 (3H, d, J = 5.9Hz), 1.12 (3H, d, J = 6.9Hz), 0.92 (9H, s), 0.12 (6H, s)

Compound 19:

HR-FAB-MS: Calculated; CsoHsoNO15SifM+Nal+* 1089.5946, Found; 1089.5908

IR(KBr) A maxcm-1: 3453, 2962, 2933, 1724, 1652, 1457, 1386, 1159, 1124, 1006, 991

IH NMR (270MHz, CDCls, partial data) é (ppm): 5.93 (1H, m), 5.87 (1H, s), 5.73 (4H, m), 5.54 (1H, d, J = 2.3, 9.9Hz), 5.46 (1H, m), 5.26 (4H, m), 5.15 (1H, s), 5.01 (1H, m), 4.77 (1H, br.s), 4.62 (3H, m), 4.52 (1H, m), 4.43(1H, br.s), 3.46 (3H, s), 3.37 (3H, s), 1.79 (3H, s), 1.42 (3H, d, J = 6.6Hz), 1.25 (83H, d, J = 6.0Hz), 1.14 (3H, d, J = 6.9Hz), 0.13 (6H, s)

Example 17: Preparation of Compound 20

In 2.0 ml of tetrahydrofuran, 213 mg of Compound 19 obtained in Example 16 was dissolved, 0.3 ml of the solution A was added thereto, and the mixture was stirred at room temperature for a night. Then, the reaction mixture was treated and purified in the manners similar to those in Example 2 to give 178 mg of Compound 20 in a 93% yield.

HR-FAB-MS: Calculated; CssH76015[M+Na]* 975.5081, Found; 975.5082

IR(KBr) A maxcm-1: 3475, 2967, 2933, 1722, 1652, 1456, 1382, 1159, 1120, 1010, 989 1H NMR (270MHz, CDCls, partial data) d (ppm): 5.95 (1H, m), 5.86 (2H, m), 5.73 (3H, m), 5.54 (1H, dd, J = 2.3, 9.9Hz), 5.41 (3H, m), 5.29 (2H, m), 5.13 (1H, s), 4.97 (1H, m), 4.76 (1H, d, J = 3.0Hz), 4.67 (1H, s), 4.62 (1H, d, J = 6.0Hz), 4.50 (1H, q, J = 6.6Hz),

. @® 4.28 (1H, d, J = 5.0Hz), 3.45 (3H, s), 3.36 (3H, s), 1.86 (3H, s), 1.41 (3H, d, J = 6.6Hz), 1.24 (3H, d, J = 6.0Hz), 1.13 (3H, d, J = 6.9Hz2) 13C-NMR (67.8MHz, CDCls) § (ppm): 173.5, 165.2, 157.0, 139.5, 137.9, 137.8, 136.1, 135.0, 132.0, 127.7, 124.6, 120.3, 118.3, 118.2, 117.9, 116.6, 96.1, 95.7, 94.9, 81.8, 80.3, 80.2, 79.1, 78.8, 74.8, 70.0, 68.2, 68.1, 67.6, 67.3, 64.9, 60.3, 57.0, 56.4, 45.5, 39.7, 36.5, 35.0, 34.1, 33.3, 30.5, 27.4, 25.2, 20.9, 20.0, 19.8, 19.3, 17.8, 16.3, 15.0, 14.1, 12.9, 11.9

Example 18: Preparation of Compound 21

In 1.5 ml of tetrahydrofuran, 58 mg of Compound 16 obtained in Example 14 was dissolved, 0.3 ml of the solution A was added thereto, and the mixture was stirred at room temperature for a night. Then, the reaction mixture was treated and purified in the manners similar to those in Example 2 to give 52 mg of Compound 21 in an approximately 100% yield.

HR-FAB-MS: Calculated; Cs6H77015[M+Nal* 1026.5190, Found; 1026.5197

IR(KBr) A maxcm-1: 3475, 2967, 2933, 1727, 1591, 1456, 1280, 1118, 989 1H NMR (270MHz, CDCls, partial data) 6 (ppm): 9.23 (1H, d, J = 1.6Hz), 8.78 (1H, dd,

J = 1.6, 4.9Hz), 8.30 (1H, dt, J = 2.0, 7.9Hz), 7.40 (1H, dd, J = 4.9, 7.9Hz), 5.74 (5H, m), 5.55 (1H, dd, J = 2.3, 9.9Hz), 5.41 (3H, m), 5.15 (1H, dd, J = 7.6, 12.5Hz), 5.02 (2H, m), 4.77 (1H, d, J = 3.3Hz), 4.68 (2H, s), 3.46 (3H, s), 3.38 (3H, s), 1.87 (3H, s), 1.37 (8H, d, J = 6.6Hz), 1.26 (3H, d, J = 5.9Hz), 1.20 (3H, d, J = 6.9Hz), 1.15 (3H, d, J = 6.9Hz) 13C-NMR (67.8MHz, CDCls) § (ppm): 173.6, 165.1, 156.4, 150.8, 142.7, 139.6, 138.0, 137.9, 137.1, 136.2, 135.1, 127.7, 126.0, 124.7, 123.3, 120.4, 120.3, 118.2, 118.0, 96.7, 95.7, 95.0, 81.9, 80.3, 80.1, 79.1, 79.0, 74.8, 73.3, 68.3, 68.3, 67.7, 67.4, 67.3, 61.6, 56.9, 56.0, 53.4, 45.6, 40.4, 39.7, 36.6, 35.1, 34.7, 34.2, 34.1, 30.5, 27.4, 20.1, 19.9, 18.3, 18.0, 16.3, 15.0, 12.9, 12.0

Example 19: Preparation of Compound 22

To a solution of 38 mg of Compound 5 obtained in Example 5 dissolved in 0.1 ml of ethanol, 12 mg of semicarbazide hydrochloride and 0.2 ml of pyridine were added, and the resulting mixture was stirred at room temperature for a night. To the reaction solution was added an aqueous sodium hydrogencarbonate solution and

Claims

What is claimed is:

1. A compound represented by the general formula (I) or a salt thereof: OCHj3 RANA ~ B | . HC” 07 TO. 4 CH, 2 _.-CH3 H,C™ 07 TO. A 0) (2 HsC™ | ~ CH.CH, oO 0) oH @) (1) CH, R2 wherein -X----Y- represents -CH=CH-, -CH2-C(=0)-, -CH2-CHz-, or -CH2-CH(R13)-; a line ---- between R! and a carbon atom at the 4”-position represents a single or double bond; a line ---- between R? and a carbon atom at the 5-position represents a single or double bond; 1) when -X----Y- represents -CH=CH-, the line ---- between R! and a carbon atom at the 4”-position represents a double bond; R1 represents (R11}(R12)C [wherein Rl! represents a substituted or unsubstituted lower alkyl group; a formyl group; a lower alkoxylcarbonyl group, the alkyl moiety of the said lower alkoxycarbonyl group may be substituted with a heterocyclic group; -CH=N-OR3 wherein R3 represents a hydrogen atom or a lower alkyl group; a lower alkenyloxycarbonyl group; -CH=N-NH-CONHz; a cyano group; -COR* wherein R¢ represents a hydroxyl group or N(R5)(R6) wherein which R% and R® form a nitrogen containing heterocyclic group together with the adjacent nitrogen atom; a vinyl group substituted with a lower alkenyloxycarbonyl group; -CO-S-CH2-CHz-NH-CO-Rx wherein Rx represents a lower alkyl group; or -CH=CH-COOH; and R12 represents a hydrogen atom, or when R!! represents a cyano group, R12 represents a hydrogen atom or a lower alkyl group]; when the line ---- between R2 and a carbon atom at the 5-position represents a single bond, R2? represents a hydroxyl group, a lower alkoxyl _ group, or a tri(lower alkyl)silyloxy group; or when the line ---- between R? and a ) carbon atom at the 5-position represents a double bond, R2 forms a carbonyl group or a hydroxime group (-C(=NOH)) together with the carbon atom at the 5-position; 2) when -X----Y- represents -CHz-C(=0)-, the line ---- between R! and a carbon atom at the 4”-position represents a double bond; R1 represents (R11a)(R123a)C [wherein R112 represents a lower alkoxycarbonyl group, the alkyl moiety of the said lower alkoxycarbonyl group may be substituted with a heterocyclic group, or -COOCH2CH=CHz2; and R122 represents a hydrogen atom}; the line ---- between R2 and a carbon atom at the 5-position represents a single bond; and R2 represents a hydroxyl group, a lower alkoxyl group, or a tri(lower alkyl)silyloxy group; 3) when -X----Y- represents -CH2-CHa-, R1 represents (R115)(R12b)C [wherein R11P represents a cyano group, a carboxyl group, or a lower alkenyloxycarbonyl group; and R12b represents a hydrogen atom]; or when the line ---- between R! and a carbon atom at the 4”-position represents a single bond, Rl! may represent a carboxymethyl group or a cyanomethyl group; the line ---- between R2 and a carbon atom at the 5-position represents a single bond; and R? represents a hydroxyl group, a lower alkoxyl group, or a tri(lower alkyl)silyloxy group; 4) when -X----Y- represents -CHz-CH(R13)-, the line ---- between R! and a carbon atom at the 4”-position represents a double bond; R! represents (R11c)(R12¢)C [wherein Rlic represents a cyano group, a carboxyl group, a lower alkoxycarbonyl group or a lower alkenyloxycarbonyl group; and R12c represents a hydrogen atom]; R13 represents a hydroxyl group or a lower alkylcabonyloxy group; the line ---- between R2 and a carbon atom at the 5-position represents a single bond;

- } \ and R2? represents a hydroxyl group, a lower alkoxyl group or a tri(lower alkyl)silyloxy group.

2. The compound or the salt thereof according to claim 1 wherein -X---Y- is -CH=CH-.

3. The compound or the salt thereof according to claim 2 wherein Ri! represents a substituted or unsubstituted lower alkyl group, a cyano group, or -COR4 wherein R* has the same meaning as that defined in claim 1.

4. The compound or the salt thereof accoraing to any one of claims 1 to 3 - wherein R2 is hydroxyl group or a tri(lower alkyl)silyloxy group. oo

5. The compound or the salt thereof according to claim 1 wherein -X----Y- is -CH2-CHa-. :

6. The compound or the salt thereof according to claim 5 wherein Rb is a cyano group or a carboxyl group.

7. Amedicament which comprises as an active ingredient the compound or : the physiologically acceptable salt thereof according to any one of claims 1 to 6.

8. A use of the compound or the physiologically acceptable salt thereof according to any one of claims 1 to 6 for the therapeutic treatment of parasitosis. :

9. An agent for therapeutic treatment of parasitosis which comprises as an active ingredient the compound or the physiologically acceptable salt thereof according to any one of claims 1 to 6.

10. A use of the compound or the physiologically acceptable salt thereof Co according to any one of claims 1 to 6 for the manufacture of an antiparasitic agent. 122 : Amended Sheet 31/07/2002