JPH08245505A - Diterpene derivative, its production and antitumor agent containing the same as active ingredient - Google Patents

Abstract

PURPOSE: To obtain a new compound useful as physiologically active substances including technical products of medicines and agrochemicals, their intermediates and antitumor agents. CONSTITUTION: This compound of formula I [R<1> is H or a 1-20C acyloxy; R<2> and R<5> are each H or pivalyl and R<3> and R<4> are each H when R<1> is H, on the other hand, R<2> and R<5> are each H, a 1-20C acyl, a (substituted)benzoyl, a (substituted)benzyl, trityl, etc., when A<1> is the 1-20C acyloxy], e.g. 1,3- oxyingenol 20-trityl ether. The compound of formula I is obtained by reacting a compound of formula II [R<11> is H or a 1-20C acyloxy; R<12> is pivalyl when R<11> is H, on the other hand, R<12> is a 1-20C acyl, a (substituted)benzoyl, a (substituted)benzyl, trityl, etc., when R<11> is a 1-20C acyloxy] with a halide of the formula R<13> X [R<13> is a 1-20C acyl, a (substituted)benzoyl, a (substituted) benzyl, trityl, etc.; X is a halogen].

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel diterpene derivative, a method for producing the same, and an antitumor agent containing the same as an active ingredient. The diterpene derivative according to the present invention is useful as a physiologically active substance such as a drug substance or agrochemical drug substance, and is particularly useful as an antitumor agent. Further, it is also useful as an intermediate for the production of physiologically active substances such as drug substance and agricultural chemicals.

[0002]

BACKGROUND OF THE INVENTION The diterpenes ingenol and 13-
Oxyingenol is contained in many plants. As a plant containing these, Euphorbiaceae (Eupor
Biaceae) plants and the like. The Euphorbiaceae plant, Euphorbia, brine (Euphorbia kansui Liou), Horutosou (Euphorbia lathyris
L. ), Hanakirin ( Euphorbia Milli )
i )) and the like. Of these plants,
The root of Euphorbia cansui is the herbal medicine Amisei ( E
It is used in Chinese medicine as uphorbiakansui radix).

Some of the present inventors have reported that diterpenes such as 13-oxyingenol-13-dodecanoate-20-hexanoate were isolated from Amami and the structure was determined. In addition, 13-oxyingenol-13-
1 derived from dodecanoate-20-hexanoate
The structures of compounds such as 3-oxyingenol are also reported. (Pure and Applied Chemistry (Pure and Applied Chem
Istry), 41 (1-2), 175-99 (197)
5); Tetrahedron Letters (Tetrahedr)
on Letters), 2527 (1974)).

On the other hand, diterpene derivatives such as taxol are known as antitumor agents.

[0005]

INDUSTRIAL APPLICABILITY The present invention is useful as a physiologically active substance including drug substance and agricultural chemicals, particularly useful as an antitumor agent, and further physiologically active substance including drug substance and agricultural chemicals. It is intended to provide a novel diterpene derivative which is useful as an intermediate for producing a substance.

[0006]

The present inventors have completed the present invention as a result of intensive studies on the above problems.

That is, the feature of the present invention is that the general formula [I]

[0008]

Embedded image

[In the formula, R ¹ is a hydrogen atom or has 1 to 1 carbon atoms.
20 represents an acyloxy group, and when R ¹ is a hydrogen atom, R ² and R ⁵ are the same or different and represent a hydrogen atom or a pivalyl group, and R ³ and R ⁴ represent a hydrogen atom, while R 1 Is an acyloxy group having 1 to 20 carbon atoms, R ²
R ^{5 s} are the same or different and each is a hydrogen atom, an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, COOR.
^Six, CONR ⁷ R ⁸ group, or, -CR ⁹ by any two of the bond to each other R ¹⁰ - a group or a -CO- group. C
In the OOR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. In the —CR ⁹ R ¹⁰ — group, R ⁹ and R ¹⁰ are the same or different and each represent a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted phenyl group, or they are linked to each other and n is 4 , it is 5 - a group - (CH _{2) n.} However, R ¹ , R ² , and R ⁵ are not hydrogen atoms at the same time, and when R ¹ is an n-dodecanoyl group and R ³ is a hydrogen atom, (R ² , R ⁴ , and R ⁵ are hydrogen atoms, or Only one of them is 2,3-dimethylbutanoyl group), (R ² , R ⁴ and R ⁵ are acetyl groups), (R ² is 2, 3
-Dimethylbutanoyl group, R ⁴ is hydrogen atom or acetyl group, R 5 is n-hexadecanoyl group), (R ² is 2,3
-A dimethylbutanoyl group in which R ⁴ and R ⁵ are bonded to each other-
C (CH ₃ ) ₂ -group), (R ² , R ⁴ are hydrogen atoms, R ⁵ is n)
-Hexanoyl group), (R ² , R ⁵ are benzoyl groups, R ⁴
Is a hydrogen atom), or (R ² , R ³ are linked to each other to -C
O- group and R ^4, and R ⁵ are linked together -CO- group), but when R ¹ is an n- decanoyl group R ² is 2,3-dimethyl-butanoyl group, R ^3, R ⁴ and R ⁵ are not hydrogen atoms. ] It is a diterpene derivative characterized by being represented by these.

The present invention also provides a manufacturing method (1).

[0011]

[Chemical 9]

In the general formula [II] [in the formula, R ¹¹ represents a hydrogen atom or an acyloxy group having 1 to 20 carbon atoms, and when R ¹¹ is a hydrogen atom, R ¹² represents a pivalyl group;
When R ¹¹ is an acyloxy group having 1 to 20 carbon atoms,
R ¹² represents an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group, or a CONR ⁷ R ⁸ group. CO
In the OR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. ] The diterpene derivative represented by these and general formula [III] [In formula, R < ¹³ > is a C1-C20 acyl group,
Substituted or unsubstituted benzoyl group, substituted or unsubstituted benzyl group, trityl group, COOR ⁶ group, CONR ⁷
R ⁸ group is shown, and X is a halogen atom. ⁶ COOR groups,
In the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. Formula [IV] [wherein, characterized by reacting a halide represented by], R ¹¹ represents an acyloxy group hydrogen atom or a C 1-20, when R ¹¹ is a hydrogen atom , R ¹² and R ¹⁴ represent a pivalyl group,
R ¹⁵ represents a hydrogen atom or a pivalyl group, while when R ¹¹ is an acyloxy group having 1 to 20 carbon atoms, R ¹² is an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzoyl group, or a substituted Or an unsubstituted benzyl group, trityl group,
COOR ⁶ group and CONR ⁷ R ⁸ group are shown, and R ¹⁴ has 1 carbon atom.
To 20 acyl groups, substituted or unsubstituted benzoyl groups, substituted or unsubstituted benzyl groups, trityl groups, C
OOR ⁶ group, CONR ⁷ R ⁸ group, R ¹⁵ is a hydrogen atom,
An acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group, and a CONR ⁷ R ⁸ group are shown. COOR ⁶ radical, in CONR ⁷ R ⁸ group R ^6,
R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or a carbon number of 1 to 1.
5 represents a lower alkyl group. However, R ¹² , R ¹⁴ , and R ¹⁵
Are not acetyl groups at the same time. ] It exists in the manufacturing method of the diterpene derivative represented by this.

Furthermore, the present invention provides a manufacturing method (2).

[0014]

[Chemical 10]

General formula [V] [wherein R ¹⁶ has 1 to 2 carbon atoms]
0 represents an acyloxy group, R ¹⁷ and R ¹⁸ are the same or different and each represent a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted phenyl group, or they are linked to each other and n is 4, 5 is a - a group - (CH _{2) n.} ] And a diterpene derivative represented by the general formula [III] [in the formula, R ¹³
Represents an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group, a CONR ⁷ R ⁸ group, and X represents a halogen atom. In the COOR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ^{7 and} R ⁸ are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. ] The compound represented by the general formula [V
I] [In the formula, R ¹⁶ represents an acyloxy group having 1 to 20 carbon atoms, and R ¹⁷ and R ¹⁸ are the same or different and each is a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group. Represents a group or is linked to each other and n is 4, 5;
It shows a (CH ₂ ) _n -group. R ¹⁹ is an acyl group having 1 to 20 carbon atoms excluding a 2,3-dimethylbutanoyl group, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group, a CONR ⁷ R ⁸ Indicates a group. In the COOR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ ,
R ⁸ is the same or different and represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. ] It exists in the manufacturing method of the diterpene derivative represented by this.

The present invention also provides a manufacturing method (3).

[0017]

[Chemical 11]

General formula [VII] [wherein R ²⁰ has 1 carbon atom]
Indicates 20 acyloxy group, R ^21, R ²² are the same or different hydrogen atom, an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group , COOR ⁶ groups, CONR ⁷ R
⁸ groups are shown. In the COOR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. ] A diterpene derivative represented by the formula [VIII] [wherein R ²⁰ represents an acyloxy group having 1 to ²⁰ carbon atoms, and R ²¹ and R ²² are the same or in phase. Differently, a hydrogen atom, an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group and a CONR ⁷ R ⁸ group are shown. CO
In the OR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. ] It exists in the manufacturing method of the diterpene derivative represented by this.

Furthermore, the present invention provides a manufacturing method (4).

[0020]

[Chemical 12]

General formula [VI] [In the formula, R ¹⁶ is a carbon number of 1 to
20 represents an acyloxy group, R ¹⁷ and R ¹⁸ are the same or different and are a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms,
Or a substituted or unsubstituted phenyl radical, n is a 4,5 linked together - a group - (CH _{2) n.} R
¹⁹ is 1 to 1 carbon atoms excluding 2,3-dimethylbutanoyl group
20 acyl groups, substituted or unsubstituted benzoyl groups,
Substituted or unsubstituted benzyl group, trityl group, COO
R ⁶ group and CONR ⁷ R ⁸ group are shown. COOR ⁶ groups, CONR
R ^6, R ^7, R ⁸ in ⁷ R ⁸ radicals are identical or different and a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms. ] De-CR ¹⁷ R ¹⁸ -group from the diterpene derivative represented by the general formula [IX] [wherein R ¹⁶ represents an acyloxy group having 1 to 20 carbon atoms, and R ¹⁹ represents 2,3-
Acyl group having 1 to 20 carbon atoms excluding dimethylbutanoyl group, substituted or unsubstituted benzoyl group, substituted or unsubstituted benzyl group, trityl group, COOR ⁶ group, CO
The NR ⁷ R ⁸ group is shown. In the COOR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ and R ⁸ are the same or different and each is a hydrogen atom,
A lower alkyl group having 1 to 5 carbon atoms is shown. ] It exists in the manufacturing method of the diterpene derivative represented by this.

The present invention also provides a manufacturing method (5).

[0023]

[Chemical 13]

General formula [X] [In the formula, R ²³ represents a hydrogen atom or an acyloxy group having 1 to 20 carbon atoms. A diterpene derivative represented by the general formula [III] [wherein R ¹³ is an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group,
COOR ⁶ group and CONR ⁷ R ⁸ group are shown, and X is a halogen atom. COOR ⁶ radical, in CONR ⁷ R ⁸ group R ^6,
R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or a carbon number of 1 to 1.
5 represents a lower alkyl group. ] The general formula [XI] characterized by reacting with a halide represented by
[In the formula, R ²³ represents a hydrogen atom or an acyloxy group having 1 to 20 carbon atoms, and when R ²³ is a hydrogen atom, R ²⁴ represents a hydrogen atom or a pivalyl group, R ²⁵ represents a hydrogen atom,
R ²⁶ represents a pivalyl group, while R ²³ has 1 to 20 carbon atoms.
When R ²⁴ and R ²⁵ are the same or different, a hydrogen atom, an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, COOR ⁶ groups, CONR ⁷ R ⁸
R ²⁶ represents a C 1-20 acyl group, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group,
A CONR ⁷ R ⁸ group is shown. In the COOR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. ] It exists in the manufacturing method of the diterpene derivative represented by this.

Furthermore, the present invention provides a manufacturing method (6).

[0026]

Embedded image

General formula [XII] [In the formula, R ²³ has 1 carbon atom.
~ 20 represents an acyloxy group. And a diterpene derivative represented by the formula [XIII] [wherein R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group] or, n is 4, 5 connected to each other - a group - (CH _{2) n.} A general formula [XIV], wherein R ²³ represents an acyloxy group having 1 to 20 carbon atoms, R ²⁶ and R ²⁷ are hydrogen atoms or are bonded to each other. Represents a —CR ³⁰ R ³¹ — group, and R
²⁸ and R ²⁹ are bonded to each other to represent a —CR ³⁰ R ³¹ — group. −
^{CR 30 R 31 - R 30,} R 31 are the same or different and a hydrogen atom in the group, a lower alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl radical, n and connected to each other
There is a 4,5 - a group - (CH _{2) n.} ] It exists in the manufacturing method of the diterpene derivative represented by this.

The present invention also resides in an antitumor agent containing a diterpene derivative represented by the general formula [I] as an active ingredient.

The present invention will be specifically described below.

Examples of the acyloxy group having 1 to 20 carbon atoms which is mentioned as the substituent in the general formulas [I] to [XIV] include, for example, formyloxy group, acetoxy group, propanoyloxy group, butanoyloxy group and penta. Noyloxy group, hexanoyloxy group, pivaloyloxy group,
2,3-dimethylbutanoyloxy group, 2,4-octadienoyloxy group, n-decanoyloxy group, 2,4
-Decadienoyloxy group, 2,4-undecadienoyloxy group, dodecanoyloxy group, 2,4,6,8,
Examples thereof include a 10-tetradecapentaenoyloxy group, a hexadecanoyloxy group and an octadecanoyloxy group.

Examples of the acyl group having 1 to 20 carbon atoms include formyl group, acetyl group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group, pivaloyl group, 2,3-dimethylbutanoyl group and 2,4-octadienoyl group. Group, n-decanoyl group, 2,4-decadienoyl group, 2,4-undecadienoyl group, dodecanoyl group, 2,4,6,8,10-tetradecapentaenoyl group, hexadecanoyl group, octa Examples thereof include decanoyl group.

Examples of the substituted or unsubstituted benzoyl group include benzoyl group, p-chlorobenzoyl group, p
Examples of the substituted or unsubstituted benzyl group include a benzyl group, a p-chlorobenzyl group, a p-methylbenzyl group, and a p-methylbenzyl group.
-Methoxybenzyl group and the like, and examples of the lower alkyl group having 1 to 5 carbon atoms include methyl group, ethyl group, propyl group, isopropyl group, and the like, and substituted or unsubstituted phenyl group Can include, for example, a phenyl group, a p-chlorophenyl group, a p-methylphenyl group, and the like, and the halogen atom can include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The compound represented by the general formula [I] has a plurality of asymmetric carbon atoms, and therefore many stereoisomers exist. The diterpene derivative of the present invention includes all of these stereoisomers. As a specific example of the configuration of the compound of the present invention represented by the general formula [I], an ingenol derivative represented by the following formula [XV] can be mentioned.

[0034]

[Chemical 15]

[In the formula, R ^{1 to} R ⁵ have the same meanings as described above. Among the compounds of the present invention, the compounds shown in Table 1 can be given as specific examples of the ingenols represented by the general formula [XV].

[0036]

[Table 1]

The diterpene derivative of the present invention can be derived from ingenol and 13-oxyingenol. Ingenol can be obtained by hydrolyzing an ingenol derivative widely contained in plants and the like, and 13-oxyingenol can be obtained by hydrolyzing a 13-oxyingenol derivative widely contained in plants and the like. be able to. For example, ingenol and 13-oxyingenol can be obtained by fractionating the sweetened ethanol extract, followed by hydrolysis and isolation and purification.

The diterpene derivative represented by the general formula [I] of the present invention is, for example, the above-mentioned six production methods (1) to (6).
Can be obtained by

The reaction represented by the production method (1) is carried out in the presence of a base in a solvent or without a solvent. The reaction time is 1 hour to several days, preferably 2 hours to 2 days. The reaction temperature is 0 ° C to 200 ° C, preferably 10 ° C to 120 ° C.
° C.

Examples of the base include organic bases such as pyridine, triethylamine, N, N-dimethylaniline and 4-dimethylaminopyridine, alkali metal hydroxides such as potassium hydroxide and alkali metal such as sodium carbonate and potassium carbonate. Carbonates, alkali metal hydrides such as sodium hydride, and metal oxides such as silver oxide are used.

As the solvent, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran,
Ethers such as diethylene glycol dimethyl ether, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, acetonitrile, isobutyronitrile, etc. Nitriles, dimethylformamide, dimethylsulfoxide and the like are used.

The amount of the reagent used in the reaction is usually [I] of the diterpene derivative of the general formula [II].
II] of the halide is 1 equivalent to a large excess, and the amount of the base is 1 equivalent to a large excess.

The reaction represented by the production method (2) is carried out in the presence of a base in a solvent or without a solvent. The reaction time is 1 hour to several days, preferably 2 hours to 2 days. The reaction temperature is 0 ° C to 200 ° C, preferably 10 ° C to 1
It is 20 ° C.

Examples of the base include organic bases such as pyridine, triethylamine, N, N-dimethylaniline and 4-dimethylaminopyridine, alkali metal hydroxides such as potassium hydroxide, and alkali metal hydroxides such as sodium carbonate and potassium carbonate. Carbonates, alkali metal hydrides such as sodium hydride, and metal oxides such as silver oxide are used.

As the solvent, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran,
Ethers such as diethylene glycol dimethyl ether, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, acetonitrile, isobutyronitrile, etc. Nitriles, dimethylformamide, dimethylsulfoxide and the like are used.

The amount of the reagent used in the reaction is usually [II] with respect to 1 equivalent of the diterpene derivative of the general formula [V].
The halide of [I] is in a large excess from 1 equivalent, and the amount of the base is in a large excess from 1 equivalent.

In the detritylation shown in the production method (3), the reaction of detritylation by hydrolysis is carried out in a solvent in the presence of an acid catalyst. The reaction time is 1 hour to several days, preferably 2 hours to 24 hours. Reaction temperature is 0 ℃
To 200 ° C, preferably 10 ° C to 50 ° C. As the acid catalyst, organic acids such as p-toluenesulfonic acid and acetic acid, and mineral acids such as hydrochloric acid, sulfuric acid and perchloric acid are used. Examples of the solvent include alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran and diethylene glycol dimethyl ether, halogenated carbonization such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene. Hydrogen, acetonitrile, nitriles such as isobutyronitrile, water, etc. are used.

The amount of the reagent to be used in the reaction is usually 1 × acid per 1 equivalent of the diterpene derivative of the general formula [VII].
It is 10 ⁻⁷ equivalent to 0.5 equivalent.

The reaction represented by the production method (4) is carried out in a solvent in the presence of an acid catalyst. The reaction time is 1 hour to several days, preferably 2 hours to 5 days. The reaction temperature is 0 ° C to 2
The temperature is 00 ° C, preferably 10 ° C to 50 ° C. As the acid catalyst, organic acids such as p-toluenesulfonic acid and acetic acid, and mineral acids such as hydrochloric acid, sulfuric acid and perchloric acid are used. As the solvent, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran and diethylene glycol dimethyl ether,
Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene, nitriles such as acetonitrile and isobutyronitrile, and water are used.

The amount of the reagent to be used in the reaction is usually 1 × 1 for the acid with respect to 1 equivalent of the diterpene derivative of the general formula [VI].
It is from 0 ^-7 equivalent to 0.5 equivalent.

The reaction represented by the production method (5) is carried out in the presence of a base in a solvent or without a solvent. The reaction time is 1 hour to several days, preferably 2 hours to 2 days. The reaction temperature is 0 ° C to 200 ° C, preferably 10 ° C to 1
It is 20 ° C. Examples of the base include organic bases such as pyridine, triethylamine, N, N-dimethylaniline and 4-dimethylaminopyridine, hydroxides of alkali metals such as potassium hydroxide, carbonates of alkali metals such as sodium carbonate and potassium carbonate, Alkali metal hydrides such as sodium hydride and metal oxides such as silver oxide are used. As the solvent, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethers such as diethylene glycol dimethyl ether, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, etc. The halogenated hydrocarbons, acetonitrile, nitriles such as isobutyronitrile, dimethylformamide, dimethylsulfoxide and the like are used.

The amount of the reagent used in the reaction is usually [II] based on 1 equivalent of the diterpene derivative of the general formula [X].
The halide of [I] is in a large excess from 1 equivalent, and the amount of the base is in a large excess from 1 equivalent.

The reaction represented by the production method (6) is carried out in the presence or absence of an acid catalyst in a solvent. The reaction time is 1 hour to several days, preferably 1 hour to 10 hours. The reaction temperature is 0 ° C to 200 ° C, preferably 10 ° C to
50 ° C. As the acid catalyst, organic acids such as p-toluenesulfonic acid and acetic acid, and mineral acids such as hydrochloric acid, sulfuric acid and perchloric acid are used. Examples of the solvent include alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran and diethylene glycol dimethyl ether, halogenated carbonization such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene. Hydrogen, acetonitrile, nitriles such as isobutyronitrile, water, etc. are used.

The amount of the reagent to be used in the reaction is usually 1 equivalent to a large excess of the carbonyl compound of the general formula [XIII] with respect to 1 equivalent of the diterpene derivative of the general formula [XII], and the acid is from 1 × 10 ^-7 equivalents. It is 5 equivalents.

The diterpene derivatives according to the invention have valuable pharmacological properties, especially antitumor activity. That is, it has high growth inhibitory activity against tumor cells and is useful as an antitumor agent.

When the compound according to the present invention is used as an antitumor agent, oral administration and parenteral administration (subcutaneous, intravenous, muscular,
For example, sternum injection) or rectal administration. The dose is usually 0.01 to 500 mg / kg / day as the amount of the active ingredient, although it varies depending on the type of tumor, symptoms of human being as a target, age and administration method. The active ingredient is administered in the form of a preparation prepared by mixing with an appropriate pharmaceutical carrier. The dosage forms include tablets, granules, fine granules,
Powders, capsules, injections, eye drops, eye ointments or suppositories are used. The amount of active ingredient contained in the preparation is about 0.01 to 99.99%. In addition, the antitumor agent according to the present invention can be administered by mixing with other agents.

[0057]

INDUSTRIAL APPLICABILITY According to the present invention, it is useful as a physiologically active substance such as a drug substance or agrochemical active ingredient, and further useful as an intermediate for producing a physiologically active substance including a drug substance or agrochemical active ingredient. A diterpene derivative can be provided. Since these diterpene derivatives have antitumor activity, they are expected to be used as antitumor agents.

[0058]

EXAMPLES Next, the present invention will be specifically described by way of examples, but the present invention is not limited to these examples.

Reference Example 1 Isolation and Purification of Ingenol and 13-Oxyingenol from Sweetening 50 kg of sweetening commercially available in the People's Republic of China was subjected to the following extraction procedure using about 60 L of ethanol. That is, the agitator was put in a container of a blender, ethanol was added to such an extent that the agitator was soaked, crushed, and transferred to a plastic tank.
The remaining ethanol was added to a plastic tank and left at room temperature for 1 week. While still standing, it was shaken several times to improve the extraction efficiency. The mixture after standing was suction filtered to obtain an ethanol extract. The ethanol extract was concentrated under reduced pressure to obtain 810 g of an ethanol extract.

Fractionation was performed using 74.4 g of this ethanol extract. First, the ethanol extract was fractionated by liquid-liquid partition. That is, the mixture was partitioned in two layers of methanol-hexane, the hexane layer was taken out, water and ethyl acetate were added to the remaining methanol, and the mixture was partitioned.
The methanol layer was taken out. The ethyl acetate layer was concentrated under reduced pressure to obtain 17.78 g of a brown viscous oily substance. This is silica gel column chromatography (WAKOGEL
C-300 Wako Pure Chemical Industries, developing solvent: methanol-
Chloroform, methanol concentration 0%, 1%, 2%, 5
%, 10%, 50% in sequence) to obtain 6 fractions.

Of these, the fourth fraction (2.518 g) of NM
When R was measured, a peak of olefin proton near δ6 ppm, which is characteristic of ingenol derivatives and 13-oxyingenol derivatives, could be observed. Therefore, after hydrolyzing the fourth fraction, it was decided to isolate and purify 13-oxyingenol. That is, the fourth fraction was added with 50 m of methanol.
It was dissolved in L, 5 mL of 10% NaOH aqueous solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with chloroform. The chloroform layer is a 1N NaOH aqueous solution,
It was washed successively with saturated brine and dried over MgSO ₄ . Mg
After removing SO _{4, it} was concentrated under reduced pressure to obtain 1.690 g of a residue.

This was subjected to silica gel column chromatography (WAKOGEL C-300 manufactured by Wako Pure Chemical Industries,
Developing solvent: Methanol-chloroform system, methanol concentration 0%, 1%, 2%, 3%, 5%, 8%, 16%). From the fraction eluted at a methanol concentration of around 5%, 298 mg of 13-oxyingenol was obtained.

Immediately after the above fractions, the methanol concentration was 8%.
292 mg of the fraction eluted up to the vicinity was subjected to reverse phase column chromatography (YMC GEL ODS-AQ120.
-S50, developing solvent: water-methanol system, water concentration 50
%, 25%, 12.5%, 5%, 2.5%, 0%, and then developed with chloroform). Water concentration 50%
. Ingenol 149.
4 mg was obtained, which was also 1 from the fraction eluted at around 5%.
48.4 mg of 3-oxyingenol was obtained.

Example 1 Synthesis of 13-oxyingenol 20-trityl ether (Compound No. 1) 13-oxyingenol 48.6 mg, trityl chloride 265.5 mg, 4-dimethylaminopyridine 1
18.6 mg was melt | dissolved in DMF5 ml, and it stirred at 100 degreeC for 1 hour. The reaction mixture was poured into saturated aqueous NH ₄ Cl solution and extracted with ethyl acetate. The acetic acid layer was washed with saturated saline and then dried over MgSO ₄ . The MgSO ₄ was filtered off and the filtrate was concentrated under reduced pressure to give a residue of 441.1 mg. This is silica gel column chromatography (WAKOGEL
C-300 Wako Pure Chemical Industries, developing solvent: methanol-
Chloroform, methanol concentration 0%, 1%, 2%, 4
%, 8%, 16%). Fractions eluted at a methanol concentration of around 1% were collected and concentrated under reduced pressure to give 13-oxyingenol 20-trityl ether (Compound No. 1) (57.5 mg, yield 81%).

Viscous oil to solid.

¹ H-NMR (CDCl ₃ , δppm) 7.44-7.23 (15H, m), 6.06 (1H,
d, J = 4.4 Hz), 5.85 (1H, d, J = 1.
5Hz), 4.30 (1H, s), 4.15 (1H, d
d, J = 12.1, 4.4 Hz), 4.00 (1H,
s), 3.70 (2H, s), 3.10 (1H, m),
2.75 (1H, dd, J = 16.4, 3.3 Hz),
2.53 (1H, m), 2.20 (3H, m), 1.8
3 (3H, d, J = 1.5Hz), 1.25 (22H,
s), 1.09 (3H, s), 0.96 (3H, d, J
= 7.1 Hz), 0.88 (3H, t, J = 6.5H
z).

IR (microscopic reflection method / aluminum plate deposition, c
m ⁻¹ ) 3419, 2954, 2925, 2854, 1737,
1724, 1593, 1490.

Example 2 Synthesis of 13-oxyingenol-3-pivalate 20-trityl ether (Compound No. 2) 13-oxyingenol 20-trityl ether 4
A mixture of 8.0 mg, N, N-dimethylaniline 0.5 ml and pivalyl chloride 0.5 ml was stirred at 50 ° C. for 24 hours. The reaction mixture was poured into water and extracted with diethyl ether. Ether layer is 1N HCl aqueous solution, 1NNa
It was washed successively with an aqueous OH solution and saturated brine, and dried over MgSO ₄ . After removing MgSO ₄ by filtration and concentrating under reduced pressure, the residue 2
90.3 mg was obtained.

This was subjected to silica gel column chromatography (WAKOGEL C-300 manufactured by Wako Pure Chemical Industries, Ltd.,
Developing solvent: ethyl acetate-hexane system, ethyl acetate concentration 5
%, 10%, 20%). Of these, the second fraction was fractionated by silica gel thin layer chromatography (developing solvent: 1% methanol-chloroform). 22.7 mg of a fraction having an Rf value of about 0.8
It was 13-oxyingenol-3-pivalate 20-trityl ether (Compound No. 2) (yield 43.
%).

Viscous oil.

¹ H-NMR (CDCl ₃ , δppm) 7.43-7.22 (15H, m), 6.00 (1H,
d, J = 1.4 Hz), 5.92 (1H, d, J = 4.
5Hz), 5.47 (1H, s), 4.27 (1H,
d, J = 2.8 Hz), 4.18 (1H, m), 3.8
5 (1H, m), 3.70 (1H, m), 3.61 (1
H, m), 2.80-2.55 (2H, m), 2.60
-2.15 (3H, m), 1.75 (3H, d, 1.4
Hz), 1.25 (19H, s), 1.22 (12H,
s), 1.08 (3H, s), 0.98 (3H, d, J
= 7.1 Hz), 0.88 (3H, t, J = 7.0H
z).

IR (microscopic reflection method / aluminum plate deposition, c
m ^-1 ) 3461, 2958, 2927, 2856, 1726,
1157.

Example 3 Synthesis of 13-oxyingenol-3-pivalate (Compound No. 3) 22.7 mg of 13-oxyingenol-3-pivalate 20-trityl ether (Compound No. 2) was dissolved in methanol. , P-toluenesulfonic acid (2 mg) were added, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water and extracted with diethyl ether. The ether layer was washed successively with 1N NaOH aqueous solution and saturated brine, and dried over MgSO ₄ . After the MgSO ₄ was filtered off, it was concentrated under reduced pressure to give a residue 24.
3 mg was obtained. This was fractionated by silica gel column chromatography (WAKOGELC-300, manufactured by Wako Pure Chemical Industries, developing solvent: ethyl acetate-hexane system, ethyl acetate concentration 10%, successively developing at 50%), 13-
Oxyingenol-3-pivalate (Compound No. 3)
8.7 mg was obtained (yield 53%).

Viscous oil.

¹ H-NMR (CDCl ₃ , δppm) 6.02 (2H, m), 5.40 (1H, s), 4.1
6 (2H, breads), 4.12 (1H, m),
4.06 (2H, m), 3.46 (1H, s), 2.8
0-2.55 (2H, m), 2.21 (2H, t, J =
7.3 Hz), 2.16 (1 H, m), 1.78 (3
H, d, J = 1.3 Hz), 1.25 (19 H, s),
1.24 (9H, s), 1.20 (3H, s), 1.0
7 (3H, s), 0.98 (3H, d, J = 7.0H
z), 0.88 (3H, t, J = 6.5Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ^-1 ) 3423, 2958, 2925, 2856, 1724,
1713, 1160.

[Example 4] Synthesis of 13-oxyingenol-3,20-dipivalate (Compound No. 4) A mixture of 43.1 mg of 13-oxyingenol, 1 ml of pivalyl chloride and 2 ml of pyridine was stirred at room temperature for 20 hours. did. The reaction mixture was poured into water and extracted with ethyl acetate. The acetic acid layer was washed successively with a 1N HCl aqueous solution, a 1N NaOH aqueous solution and a saturated saline solution, and dried over MgSO ₄ . M
After removing gSO ₄ by filtration and concentrating under reduced pressure, the residue was 548.2 m.
g was obtained. This was fractionated by silica gel column chromatography (WAKOGEL C-300, manufactured by Wako Pure Chemical Industries, developing solvent: ethyl acetate-hexane system, ethyl acetate concentrations of 5%, 10%, and 20% in sequence, and fractionated).
19.1 mg of 3-oxyingenol-3,20- dipivalate (Compound No. 4) was obtained (yield 33.6%).

Viscous oil.

¹ H-NMR (CDCl ₃ , δ ppm) 6.08 (1 H, d, J = 4.8 Hz), 6.03 (1
H, d, J = 1.4 Hz), 5.41 (1H, s),
4.76 (1H, d, J = 12.8Hz), 4.48
(1H, d, J = 12.8 Hz), 4.07 (1H, d
d, J = 12.1, 4.8 Hz), 3.84 (1H, b
roads), 3.48 (1H, s), 2.72 (1
H, dd, J = 16.7, 2.8 Hz), 2.60 (1
H, m), 2.21 (3H, m), 1.76 (3H,
d, J = 1.4 Hz), 1.25 (19H, s), 1.
23 (12H, s), 1.18 (9H, s), 1.06
(3H, s), 0.98 (3H, d, J = 7.2H
z), 0.88 (3H, t, J = 6.5Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ^-1 ) 3504, 2960, 2929, 2856, 1727,
1710, 1159.

Example 5 Synthesis of 13-oxyingenol-3,20-bis (dimethylcarbamate) (Compound No. 5) 13-oxyingenol 14.6 mg, dimethylcarbamoyl chloride 0.1 mL, potassium carbonate 102. 8 mg
Was made into a suspension with 10 mL of acetonitrile, and refluxed with heating for 20 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with saturated saline,
Dry with O ₄ . After removing MgSO ₄ by filtration, the residue was concentrated under reduced pressure to obtain a residue (19.0 mg).

This was fractionated by silica gel thin layer chromatography (developing solvent: 1% methanol-chloroform). A fraction of 2.8 mg having an Rf value of about 0.4 was again fractionated by silica gel thin layer chromatography (developing solvent: 50% ethyl acetate-hexane twice developed). A target 1.3-oxyingenol-3,20-bis (dimethylcarbamate) (Compound No. 5) was 1.3 mg of a fraction having an Rf value of about 0.4 (yield 7%).

Viscous oil.

¹ H-NMR (CDCl ₃ , δppm) 6.22 (1H, m), 5.95 (1H, d, J = 1.
2Hz), 5.48 (1H, breads), 4.90
(1H, s), 4.66 (1H, d, J = 12,3H
z), 4.45 (1H, d, 12.3 Hz), 3.90.
(1H, m), 3.0-2.8 (7H, m), 2.7-
2.3 (2H, m), 2.22 (2H, t, J = 7.5
Hz), 1.91 (3H, d, J = 1.2Hz), 1.
30 (3H, s), 1.26 (19H, s), 1.11
(3H, s), 0.96 (3H, d, J = 6.9H
z), 0.88 (3H, t, J = 6.3Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ^-1 ) 2958, 2926, 2854, 1817, 1722,
1711.

Example 6 Synthesis of 13-oxyingenol-20-benzyl ether (Compound No. 9) 19.2 mg of 13-oxyingenol, 23.7 mg of benzyl bromide, 17.0 mg of silver oxide were added to 1 m of DMF.
It was dissolved in L and stirred at room temperature for 2 days. The reaction mixture was diluted with diethyl ether, washed successively with water and saturated brine, and dried over MgSO ₄ . After removing MgSO ₄ by filtration, the residue was concentrated under reduced pressure to obtain a residue (30.0 mg). Silica gel column chromatography (developing solvent: 50
% Ethyl acetate-hexane) to obtain 3.8 mg of 13-oxyingenol-20-benzyl ether (Compound No. 9) (yield 17%).

Compound No. 9 Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 7.37 (5H, m), 6.01 (1H, d, J = 3.
5Hz), 5.90 (1H, d, J = 1.4Hz),
4.79 (1H, d, J = 11.6Hz), 4.65
(1H, d, J = 11.6Hz), 4.32 (1H,
s), 4.15 (2H, m), 4.04 (1H, s),
3.96 (1H, dd, J = 12.3, 5.5Hz),
3.78 (1H, d, J = 9.0 Hz), 2.96 (1
H, d, J = 9.0 Hz), 2.67 (1 H, m),
2.40 (1H, m), 2.20 (2H, t, J = 7.
5Hz), 2.10 (1H, m), 1.75 (3H,
d, J = 1.4 Hz), 1.25 (19H, s), 1.
20 (3H, s), 1.06 (3H, s), 0.95
(3H, d, J = 7.2 Hz), 0.88 (3H, t,
J = 6.2 Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ⁻¹ ) 3456, 2954, 2926, 1726, 1456,
1381, 1146, 1117.

[Example 7] Synthesis of 13-oxyingenol-20-pivalate (Compound No. 11) 13.1 mg of 13-oxyingenol, 142.4 mg of pivalyl chloride and 196.0 mg of pyridine were dissolved in 3 mL of dichloromethane. The mixture was stirred at room temperature for 14 hours.
The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over MgSO ₄ . After removing MgSO ₄ by filtration, the residue was concentrated under reduced pressure to obtain a residue (30.0 mg).
This is subjected to silica gel column chromatography (developing solvent: methanol-chloroform system, methanol concentration 0
%, 1% sequentially) and 13-oxyingenol-20-pivalate (Compound No. 11) 11.
8 mg was obtained (yield 67%).

Compound No. 11 Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 6.06 (1H, d, J = 4.1Hz), 5.91 (1
H, d, J = 0.8 Hz), 4.69 (1H, d, J =
13.0Hz), 4.54 (1H, d, J = 13.0H
z), 4.43 (1H, d, J = 6.3 Hz), 4.0
8 (1H, s), 4.04 (1H, dd, J = 15.
4,4.1 Hz), 3.67 (1H, d, J = 10.7)
Hz), 3.00 (1H, d, J = 10.7Hz),
2.73 (1H, dd, J = 16.6, 2.6Hz),
2.58 (1H, m), 2.43 (1H, m), 2.2
0 (2H, t, J = 7.6Hz), 2.19 (1H,
m), 1.85 (3H, d, J = 0.8Hz), 1.
25 (19H, s), 1.21 (3H, s), 1.19
(9H, s), 1.08 (3H, s), 0.97 (3
H, d, J = 7.2 Hz), 0.89 (3H, t, J =
5.8 Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ^-1 ) 3440, 2958, 2927, 2854, 1728,
1462, 1381, 1282, 1147, 1117.

Example 8 13-oxyingenol-20- (methyl carbonate) (Compound No. 13) and 13-oxyingenol-3,4-carbonyldioxide-20- (methyl carbonate) (Compound No. 22) 1) Oxygengenol (16.4 mg), methyl chloroformate (96.0 mg) and pyridine (159.8 mg) were dissolved in dichloromethane (2 mL), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and this was diluted with water, 1
The mixture was washed successively with aqueous NH Cl solution, aqueous 1 N NaOH solution and saturated saline solution, and dried over MgSO ₄ . After removing MgSO ₄ by filtration, the residue was concentrated under reduced pressure to obtain 16.8 mg of a residue. High-performance liquid chromatography (column: TSKgel O
H-120, developing solvent: 50% ethyl acetate-hexane,
Fractionation by detection conditions: UV 300 nm), 13-oxyingenol-20- (methyl carbonate) (Compound No. 13) 3.0 mg (yield 17%) and 13-oxyingenol-3,4-carbonyl dioxide -2
0- (methyl carbonate) (Compound No. 22) 7.1
mg (yield 41%) was obtained.

Compound No. 13 Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 6.13 (1H, br.d, J = 4.2Hz), 5.9
2 (1H, d, J = 1.5Hz), 4.78 (1H,
d, J = 12.3 Hz), 4.59 (1H, d, J = 1
2.3 Hz), 4.45 (1H, d, J = 6.7H)
z), 4.10 (1H, br.s), 4.03 (1H,
m), 3.78 (3H, s), 3.73 (1H, br.
d, J = 11.4 Hz), 2.79 (1H, d, J = 1
1.4 Hz), 2.72 (1H, dd, J = 16.4,
2.8 Hz), 2.40 (2H, m), 2.20 (2
H, t, J = 7.5 Hz), 2.19 (1H, m),
1.86 (3H, d, J = 1.5Hz), 1.25 (1
9H, s), 1.21 (3H, s), 1.07 (3H,
s), 0.97 (3H, d, J = 7.0Hz), 0.8
8 (3H, t, J = 6.5Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ⁻¹ ) 3431, 2956, 2926, 2854, 1743,
1730, 1444, 1383, 1275, 1147,
1117.

Compound No. 22 Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 6.25 (1H, m), 6.00 (1H, d, J = 1.
6 Hz), 5.21 (1H, 2), 4.78 (1H,
d, J = 12.2 Hz), 4.59 (1H, d, J = 1
2.2Hz, 4.03 (1H, d, J = 9.9H)
z), 3.80 (3H, s), 3.75 (1H, m),
2.99 (1H, d-like), 2.76 (2H, d
d, J = 16.4, 2.6 Hz), 2.51 (1H,
m), 2.21 (2H, t, J = 7.4Hz), 2.0
2 (2H, dd, J = 16.4, 8.8Hz), 1.9
3 (3H, br.s), 1.25 (22H, s), 1.
09 (3H, s), 0.94 (3H, d, J = 7.0H
z), 0.88 (3H, t, J = 6.7Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ⁻¹ ) 3462, 2956, 2926, 2854, 1813,
1751, 1444, 1377, 1279, 1119,
1032.

Example 9 Synthesis of 13-oxyingenol-5,20-acetonide (Compound No. 17) 154.2 mg of 13-oxyingenol was added to p-toluenesulfonic acid monohydrate-acetone solution ( 0.47m
g / mL) 10 mL, and stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate, which was diluted with 1NN
The solution was washed successively with an aqueous solution of aOH and saturated saline and dried over MgSO ₄ . After removing MgSO ₄ by filtration and concentrating under reduced pressure, the residue 1
62.3 mg was obtained. This is a silica gel column
Fractionation was performed by chromatography (developing solvent: ethyl acetate-hexane system, ethyl acetate concentration 30%, 80% sequentially) to obtain 91.5 mg of 13-oxyingenol-5,20-acetonide (Compound No. 17). (Yield 55
%).

Compound No. 17 Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 5.89 (1H, d, J = 1.4Hz), 5.77 (1
H, m), 4.28 (1H, d, J = 4.5Hz),
4.18 (2H, br.s), 4.04 (1H, m),
3.93 (1H, br.s), 3.57 (1H, s),
2.74 (1H, dd, J = 16.6, 3.1Hz),
2.58 (1H, d, J = 4.5Hz), 2.57 (1
H, m), 2.20 (2H, t, J = 7.4Hz),
2.14 (1H, dd, J = 16.6, 6.3 Hz),
1.86 (3H, d, J = 1.4Hz), 1.41 (3
H, s), 1.35 (3H, s), 1.25 (19H,
s), 1.23 (3H, s), 1.07 (3H, s),
0.95 (3H, d, J = 7.0Hz), 0.88 (3
H, t, J = 6.3 Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ^-1 ) 3444, 2954, 2926, 2854, 1738,
1728, 1462, 1454, 1379, 1223
1157, 1119, 1072.

Example 10 Synthesis of 13-oxyingenol-3,4: 5,20-diacetonide (Compound No. 16) 13-oxyingenol 48.9 mg, p-toluenesulfonic acid monohydrate 108 0.3 mg of acetone 10 m
It was dissolved in L and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with 1N NaOH aqueous solution and saturated brine, and dried over MgSO ₄ . The MgSO ₄ was filtered off and the residue was concentrated under reduced pressure to give a residue of 48.7 mg.
This was subjected to silica gel column chromatography (developing solvent: ethyl acetate-hexane system, ethyl acetate concentration 2%,
Fractionation was performed at 5% and 10%, respectively, to obtain 27.3 mg of 13-oxyingenol-3,4: 5,20-diactonide (Compound No. 16) (yield 49%).

Compound No. 16 Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 5.94 (1H, d, J = 1.5Hz), 5.68 (1
H, dd, J = 3.6, 2.0 Hz), 4.87 (1
H, s), 4.26 (1H, dd, J = 14.1, 1.
8Hz), 4.10 (1H, d, J = 14.1Hz),
3.94 (1H, br.s), 3.54 (1H, m),
2.72 (1H, dd, J = 16.3, 2.8Hz),
2.61 (1H, m), 2.21 (2H, t, J = 7.
5 Hz), 2.14 (1H, dd, J = 16.3, 1)
0.2Hz), 1.86 (3H, d, J = 1.5H
z), 1.55 (3H, s), 1.51 (3H, s),
1.41 (3H, s), 1.33 (3H, s), 1.2
5 (19H, s), 1.22 (3H, s), 1.06
(3H, s), 0.98 (3H, d, J = 7.0H
z), 0.88 (3H, t, J = 6.4Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ^-1 ) 2980, 2927, 2854, 1738, 1732,
1462, 1452, 1381, 1223, 1211
1163, 1146.

[Example 11] 13-oxyingenol-5,20-acetonide-3
-Synthesis of octadecanoate (Compound No. 18) 13-oxyingenol-5,20-acetonide 1
2.5 mg, octadecanoyl chloride 0.3 mL,
1 mL of pyridine was dissolved in 3 mL of dichloromethane, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate, which was washed successively with water, 1N HCl aqueous solution, 1N NaOH aqueous solution and saturated brine, and dried over MgSO ₄ . M
After removing gSO ₄ by filtration and concentrating under reduced pressure, the residue was 192.2 m.
g was obtained. This was fractionated by repeating silica gel column chromatography (developing solvent: 10% ethyl acetate-hexane) twice, and 13-oxyingenol-5,20-acetonide-3-octadecanoate (compound No. 18) 15.2 mg was obtained (yield 83
%).

Compound No. 18 Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 6.03 (1H, d, J = 1.5Hz), 5.76 (1
H, m), 5.55 (1H, s), 4.28 to 3.98.
(4H, m), 3.17 (1H, s), 2.77-2.
60 (2H, m), 2.36 (2H, t, J = 7.3H
z), 2.22 (1H, m), 2.20 (2H, t, J
= 7.4 Hz), 1.77 (3H, d, J = 1.5H
z), 1.46 (3H, s), 1.42 (3H, s),
1.25 (49H, s), 1.20 (3H, s), 1.
06 (3H, s), 0.99 (3H, d, J = 7.0H
z), 0.88 (6H, t, J = 6.4Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ^-1 ) 3398, 2953, 2926, 2850, 1732,
1713, 1468, 1383, 1375, 1369,
1230, 1200, 1159, 1120, 1066
1016.

Example 12 Synthesis of 13-oxyingenol-3-octadecanoate (Compound No. 6) 13-oxyingenol-5,20-acetonide-3
Octadecanoate 10.0 mg was added to perchloric acid methanol solution (70% perchloric acid 0.34 mL / methanol 10
(0 mL) 2 mL, and stirred at room temperature for 20 hours. The reaction mixture was diluted with diethyl ether and this was diluted with water, 1
Wash with NNaOH aqueous solution and saturated saline solution in that order and MgSO ₄
Dried in. After removing MgSO ₄ , the residue was concentrated under reduced pressure to obtain 16.1 mg of a residue. This was subjected to high performance liquid chromatography (column: TSKgelOH-120, developing solvent: 50% ethyl acetate-hexane, detection condition: UV30.
0-nm), 13-oxyingenol-3
-6.3 mg of octadecanoate (Compound No. 6) was obtained (yield 66%).

Compound No. 6 Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 6.02 (2H, m), 5.44 (1H, s), 4.2
1-4.02 (5H, m), 3.50 (1H, s),
2.79 to 2.52 (2H, m), 2.41 (2H, m
t, J = 7.3 Hz), 2.22 (1 H, m), 2.2
1 (2H, t, J = 7.3Hz), 1.79 (3H,
d, J = 1.4 Hz), 1.25 (48 H, s), 1.
20 (3H, s), 1.07 (3H, s), 0.97
(3H, d, J = 7.0Hz), 0.88 (6H, t,
J = 6.4 Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ^-1 ) 2926, 2854, 1740, 1466, 1381
1169, 1119.

The physical properties of the compounds synthesized by the same method are shown below.

[Example 13] 13-Oxyingenol-3-dodecanoate (Compound No. 7) Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 6.07 to 6.00 (2H, m), 5.45 (1H,
s), 4.26 to 4.02 (5H, m), 3.51 (1
H, s), 2.78 to 2.54 (2H, m), 2.41
(2H, t, J = 7.4Hz), 2.23 (1H,
m), 2.21 (2H, t, J = 7.4Hz), 1.7
9 (3H, d, J = 1.3Hz), 1.26 (19H,
s), 1.25 (18H, s), 1.20 (3H,
s), 1.07 (3H, s), 0.97 (3H, d, J
= 7.0 Hz), 0.88 (6H, t, J = 6.5H
z).

IR (microscopic reflection method / aluminum plate deposition, c
m ⁻¹ ) 3462, 2954, 2931, 2854, 1740,
1730, 1466, 1381, 1171, 1119.

[Example 14] 13-oxyingenol-20-benzoate (Compound No. 8) Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 8.04 (2H, d-like), 7.58 (1H, t
-Like), 7.45 (2H, t-like), 6.
17 (1H, dd, J = 4.4, 1.1 Hz), 5.9
3 (1H, d, J = 1.4Hz), 4.96 (1H,
d, J = 12.8 Hz), 4.81 (1H, d, J = 1)
2.8 Hz, 4.48 (1H, d, J = 4.2H
z), 4.11 (1H, s), 4.08 (1H, dd,
J = 10.3, 4.4 Hz), 3.77 (1 H, m),
3.00 (1H, d, J = 10.5Hz), 2.75
(1H, dd, J = 16.6, 3.2Hz), 2.47
(2H, m), 2.21 (2H, t, J = 7.5H
z), 2.19 (1H, m), 1.86 (3H, d, J
= 1.4 Hz), 1.25 (19H, s), 1.23
(3H, s), 1.08 (3H, s), 0.98 (3
H, d, J = 7.2 Hz), 0.88 (3H, t, J =
6.5 Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ⁻¹ ) 3419, 2954, 2926, 2854, 1722,
1452, 1377, 1271, 1146, 1115.

Example 15 13-Oxyingenol-3-hexanoate (Compound No. 10) Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 6.03 (2H, m), 5.45 (1H, s), 4.2
3 to 4.10 (4H, m), 4.05 (1H, d, J =
2.9 Hz), 3.51 (1 H, s), 2.79-2.
34 (2H, m), 2.41 (2H, t, J = 7.5H
z), 2.22 (1H, m), 2.21 (2H, t, J
= 7.5 Hz), 1.79 (3H, br.s), 1.7
9 (7H, m), 1.25 (18H, s), 1.20
(3H, s), 1.07 (3H, s), 0.97 (3
H, d, J = 7.2 Hz), 0.89 (6H, m).

IR (microscopic reflection method / aluminum plate deposition, c
m ⁻¹ ) 3466, 2956, 2933, 2854, 1736,
1466, 1381, 1173, 1120.

Example 16 13-Oxyingenol-3-benzoate (Compound No. 12) Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 8.03 (2H, d, J = 7.3Hz), 7.62 (1
H, t, J = 7.3 Hz), 7.48 (2H, t, J =
7.3 Hz, 6.10 (1H, d, J = 1.2H
z), 6.06 (1H, m), 5.74 (1H, s),
4.40 (1H, m), 4.22 to 4.06 (4H,
m), 3.61 (1H, s), 2.73 (2H, m),
2.22 (1H, m), 2.21 (2H, t, J = 7.
5Hz), 1.85 (3H, d, J = 1.2Hz),
1.25 (19H, s), 1.16 (3H, s), 1.
06 (3H, s), 1.04 (3H, m), 0.88
(3H, t, J = 6.8Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ^-1 ) 3469, 2953, 2926, 2854, 1738,
1722, 1601, 1452, 1383, 1275,
1176, 1117.

Example 17 Ingenol-3,20-dipivalate (Compound No. 1
4) Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 6.11 (1H, d, J = 4.4Hz), 6.03 (1
H, br. s), 5.42 (1H, s), 4.76 (1
H, d, J = 12.8 Hz), 4.46 (1H, d, J
= 12.8 Hz), 4.42 (1H, d, J = 6.7H)
z), 4.10 (1H, dd, J = 11.4, 4.4H
z), 3.81 (1H, d, J = 6.4 Hz), 3.6
3 (1H, d, J = 6.4 Hz), 3.39 (1H,
s), 2.49 (1H, m), 2.26 (1H, dd)
d, J = 15.1, 8.7, 2.5 Hz), 1.75
(1H, dt, J = 15.1, 5.7 Hz), 1.75
(3H, br.s), 1.24 (9H, s), 1.17
(9H, s), 1.07 (3H, s), 1.05 (3
H, s), 0.97 (3H, d, J = 7.2 Hz),
0.95 (1H, m), 0.69 (1H, q, J = 8.
0 Hz).

IR (microscopic reflection method / aluminum plate deposition, c
m ⁻¹ ) 3444, 2974, 2935, 2872, 1732,
1711, 1481, 1460, 1398, 1381
1367, 1284, 1188, 1163.

Example 18 Ingenol-20-pivalate (Compound No. 15) Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 6.10 (1H, br.d, J = 4.5Hz), 5.9
6 (1H, m), 4.71 (1H, d, J = 12.8H
z), 4.52 (1H, d, J = 12.8 Hz), 4.
42 (1H, d, J = 6.7 Hz), 4.10 (1H,
dd, J = 11.7, 3.7 Hz), 4.03 (1H,
s), 3.64 (1H, d, J = 10.1 Hz), 2.
97 (1H, d, J = 10.1Hz), 2.32 (2
H, m), 2.23 (1H, d, J = 6.7 Hz),
1.85 (3H, s), 1.76 (1H, m), 1.1
8 (9H, s), 1.11 (3H, s), 1.07 (3
H, s), 0.98 (3H, d, J = 7.2 Hz),
0.95 (1H, m), 0.72 (1H, m).

IR (microscopic reflection method / aluminum plate deposition, c
m ^-1 ) 3440, 2958, 2935, 2871, 1726,
1713, 1481, 1462, 1396, 1381
1367, 1282, 1157.

Example 19 13-Oxyingenol-5,20-acetonide-3
-Dodecanoate (Compound No. 19) Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 6.03 (1H, d, J = 1.4Hz), 5.76 (1
H, m), 5.54 (1H, s), 4.29 to 3.99.
(4H, m), 3.18 (1H, s), 2.78-2.
60 (2H, m), 2.36 (2H, t, J = 7.2H
z), 2.22 (1H, m), 2.21 (2H, t, J
= 7.4 Hz), 1.77 (3H, d, J = 1.4H
z), 1.44 (3H, s), 1.41 (3H, s),
1.25 (37H, s), 1.20 (3H, s), 1.
06 (3H, s), 0.99 (3H, d, J = 7.2H
z), 0.88 (6H, m).

IR (microscopic reflection method / aluminum plate deposition, c
m ^-1 ) 3406, 2956, 2931, 2854, 1738,
1711, 1466, 1381, 1221, 1200,
1163, 1120, 1068.

Example 20 3-Oxyingenol-5,20-acetonide-3-
Hexanoate (Compound No. 20) Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 6.04 (1H, br.s), 5.75 (1H, m),
5.55 (1H, s), 4.34 to 3.98 (4H,
m), 3.18 (1H, s), 2.80 to 2.60 (2
H, m), 2.37 (2H, t, J = 7.5 Hz),
2.22 (1H, m), 2.21 (2H, t, J = 7.
5 Hz), 1.77 (3H, br.s), 1.47 (3
H, s), 1.41 (3H, s), 1.33 (7H,
m), 1.25 (18H, s), 1.20 (3H,
s), 1.08 (3H, s), 0.99 (3H, d, J
= 7.2 Hz), 0.89 (6H, m).

IR (microscopic reflection method / aluminum plate deposition, c
m ^-1 ) 3406, 2956, 2927, 2854, 1738,
1711, 1462, 1381, 1242, 1221
1200, 1169, 1122, 1095, 1066.

[Example 21] 13-oxyingenol-5,20-acetonide-3
-Benzoate (Compound No. 21) Viscous oil.

¹ H-NMR (200 MHz / CDCl ₃ ,
δppm) 8.02 (2H, d-like), 7.60 (1H, t
-Like), 7.47 (2H, t-like), 6.
11 (1H, d, J = 1.6Hz), 5.80 (1H,
s), 5.79 (1H, m), 4.31 to 4.06 (4
H, m), 3.27 (1H, s), 2.78 (1H,
m), 2.73 (1H, dd, J = 16.8, 2.8H
z), 2.26 (1H, m), 2.22 (2H, t, J
= 7.5 Hz), 1.83 (3H, d, J = 1.6H)
z), 1.50 (3H, s), 1.47 (3H, s),
1.25 (19H, s), 1.18 (3H, s), 1.
07 (3H, d, J = 4.7Hz), 1.06 (3H,
s), 0.89 (3H, t, J = 6.4).

IR (microscopic reflection method / aluminum plate deposition, c
m ⁻¹ ) 3454, 2954, 2927, 2854, 1726,
1452, 1381, 1373, 1273, 1223
1188, 1161, 1109, 1097, 1068.

[Example 22] Mouse lymphocytic leukemia cells (P388) were treated with 2-hydroxyethyl disulfide (5 µm).
M, 100 μg / ml of kanamycin sulfate was added 10
% Fetal bovine serum-containing RPMI-1640 medium, cultured cells were prepared at 1 × 10 ⁴ cells / ml, and the compound of the present invention and doxorubicin hydrochloride (ADM) as a control example were added to a predetermined concentration, CO ₂ incubator (CO ₂ 5%,
The culture was performed at 100% humidity and 37 ° C for 4 days. The number of surviving cells was measured by the MTT colorimetric method, and the 50% cell growth inhibitory concentration (IC ₅₀ ) was determined from the growth inhibition rate relative to the control group.
Table 2 shows the results.

[0146]

[Table 2]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroyuki Watanabe Tosui Water Source Pond No. 4 Company No. 208, Doi 2-chome, Shinnanyo, Yamaguchi Prefecture

Claims (8)

[Claims] 1. A compound represented by the general formula [I]: [In the formula, R ¹ represents a hydrogen atom or an acyloxy group having 1 to 20 carbon atoms, and when R ¹ is a hydrogen atom, R ² , R ^2
5 are the same or different and represent a hydrogen atom or a pivalyl group,
R ³ and R ⁴ represent hydrogen atoms, while R ¹ has ¹ to 2 carbon atoms.
When it is an acyloxy group of 0, R ^{2 to} R ⁵ are the same or different and are a hydrogen atom, an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group. , COOR ⁶ groups, CONR ⁷ R ⁸
A group or any two of them are bonded to each other to -CR ⁹ R ¹⁰
-Group or -CO- group is shown. COOR ⁶ groups, CON
In the R ⁷ R ⁸ group, R ⁶ , R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. −
In the CR ⁹ R ¹⁰ -group, R ⁹ and R ¹⁰ are the same or different and each independently represent a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted phenyl group, or they are linked to each other and n is 4, 5 is a - a group - (CH _{2) n.} However, R ¹ ,
R ² and R ⁵ are not hydrogen atoms at the same time, and when R ¹ is an n-dodecanoyl group and R ³ is a hydrogen atom, (R ² ,
R ^4, R ⁵ is a hydrogen atom or, of which only one or 2,3-dimethyl-butanoyl ^{group), (R 2, R 4} ,
(R ⁵ is acetyl group), (R ² is 2,3-dimethylbutanoyl group, R ⁴ is hydrogen atom or acetyl group, R ⁵ is n-hexadecanoyl group), (R ² is 2,3-dimethylbutanoyl group) R ⁴ and R ⁵ are bonded to each other by a noyl group to form a —C (CH ₃ ) ₂ — group),
(R ² and R ⁴ are hydrogen atoms, R ⁵ is n-hexanoyl group),
(R ² and R ⁵ are benzoyl groups, R ⁴ is a hydrogen atom), or (R ² and R ³ are linked to each other to form a —CO— group, and R ⁴ and R ⁵ are linked to each other to form a —CO— group) When R ¹ is an n-decanoyl group and R ² is a 2,3-dimethylbutanoyl group, R ³ , R ⁴ and R ⁵ are not hydrogen atoms. ] The diterpene derivative represented by these. 2. [Chemical formula 2] Formula [II] [In the formula, R ¹¹ is a hydrogen atom or a carbon number 1
When R ¹¹ is a hydrogen atom, R ¹² is a pivalyl group, while when R ¹¹ is an acyloxy group having 1 to 20 carbon atoms, R ¹² is 1 carbon atom. To 20 acyl groups, substituted or unsubstituted benzoyl groups, substituted or unsubstituted benzyl groups, trityl groups, C
An OOR ⁶ group and a CONR ⁷ R ⁸ group are shown. COOR ⁶ groups, CO
In the NR ⁷ R ⁸ group, R ⁶ , R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. ] And a diterpene derivative represented by the general formula [III]
[In the formula, R ¹³ represents an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group, or a CONR ⁷ R ⁸ group, and X represents a halogen. Indicates an atom. COOR ⁶ groups, CONR ⁷
In the R ⁸ group, R ⁶ , R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. [IV] [wherein R ¹¹ represents a hydrogen atom or an acyloxy group having 1 to 20 carbon atoms, and when R ¹¹ is a hydrogen atom, , R ¹² and R ¹⁴ represent a pivalyl group, R ¹⁵ represents a hydrogen atom or a pivalyl group, while R ¹¹ represents a carbon number of 1 to 20.
When it is an acyloxy group of, R ¹² has 1 to 20 carbon atoms.
Acyl group, substituted or unsubstituted benzoyl group, substituted or unsubstituted benzyl group, trityl group, COOR ⁶
Group, CONR ⁷ R ⁸ group, R ¹⁴ is an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group,
CONR ⁷ R ⁸ group is shown, R ¹⁵ is a hydrogen atom, and has 1 to 2 carbon atoms.
0 represents an acyl group, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group, and a CONR ⁷ R ⁸ group. COO
In the R ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. However, R ¹² , R ¹⁴ , and R ¹⁵ are not acetyl groups at the same time. ] The manufacturing method of the diterpene derivative represented by these. Claim 3: In the general formula [V] [in the formula, R ¹⁶ represents an acyloxy group having 1 to 20 carbon atoms, R ¹⁷ and R ¹⁸ are the same or different and each is a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, substituted or unsubstituted. A substituted phenyl group or linked to each other and n is 4, 5
It is - a group - (CH _{2) n.} ] The diterpene derivative represented by these and general formula [III] [In formula, R < ¹³ > has a carbon number of 1-
20 acyl groups, substituted or unsubstituted benzoyl groups,
Substituted or unsubstituted benzyl group, trityl group, COO
R ⁶ group and CONR ⁷ R ⁸ group are shown, and X is a halogen atom. In the COOR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ ,
R ⁸ is the same or different and represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. ] The compound represented by the general formula [VI] [wherein R ¹⁶ represents an acyloxy group having 1 to 20 carbon atoms, R
¹⁷ and R ¹⁸ are the same or different and each is a hydrogen atom or a carbon number of 1 to 1.
5 is a lower alkyl group, a substituted or unsubstituted phenyl group, or they are linked to each other and n is 4, 5-(C
A group - H _{2) n.} R ¹⁹ is an acyl group having 1 to 20 carbon atoms excluding a 2,3-dimethylbutanoyl group, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group, a CONR ⁷ R ⁸ Indicates a group. In the COOR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ ,
R ⁸ is the same or different and represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. ] The manufacturing method of the diterpene derivative represented by these. 4. A compound represented by the formula: General formula [VII] [In the formula, R ²⁰ represents an acyloxy group having 1 to ²⁰ carbon atoms, and R ²¹ and R ²² are the same or different and each is a hydrogen atom, an acyl group having 1 to 20 carbon atoms, substituted or unsubstituted. A substituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group, and a CONR ⁷ R ⁸ group are shown. In the COOR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ ,
R ⁸ is the same or different and represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. ] The general formula [VII] characterized by detritylating the diterpene derivative represented by
I] [In the formula, R ²⁰ represents an acyloxy group having 1 to ²⁰ carbon atoms, and R ²¹ and R ²² are the same or different and each is a hydrogen atom, an acyl group having 1 to 20 carbon atoms, or a substituted or unsubstituted benzoyl group. Group, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group, and a CONR ⁷ R ⁸ group. COOR
^In group ⁶ and CONR ⁷ R ⁸ , R ⁶ , R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. ] The manufacturing method of the diterpene derivative represented by these. 5. A method according to claim 5, wherein General formula [VI] [In the formula, R ¹⁶ represents an acyloxy group having 1 to 20 carbon atoms, and R ¹⁷ and R ¹⁸ are the same or different and each is a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, substituted or unsubstituted. A substituted phenyl group or linked to each other and n is 4,
5 is a - a group - (CH _{2) n.} R ¹⁹ is an acyl group having 1 to 20 carbon atoms excluding 2,3-dimethylbutanoyl group,
Substituted or unsubstituted benzoyl group, substituted or unsubstituted benzyl group, trityl group, COOR ⁶ group, CONR ⁷
An R ⁸ group is shown. R in the COOR ⁶ group and the CONR ⁷ R ⁸ group
⁶ , R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. ] De-CR ¹⁷ R ¹⁸ -group from the diterpene derivative represented by the general formula [IX] [wherein R ¹⁶ represents an acyloxy group having 1 to 20 carbon atoms, and R ¹⁹ represents It represents an acyl group having 1 to 20 carbon atoms excluding a 2,3-dimethylbutanoyl group, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group, and a CONR ⁷ R ⁸ group. In the COOR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ ,
R ⁸ is the same or different and represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. ] The manufacturing method of the diterpene derivative represented by these. 6. embedded image General formula [X] [In formula, R < ²³ > is a hydrogen atom, carbon number 1-20.
Represents an acyloxy group. And a diterpene derivative represented by the general formula [III] [wherein R ¹³ is an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, COOR]
⁶ groups and CONR ⁷ R ⁸ groups are shown, and X is a halogen atom. In the COOR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ ,
R ⁸ is the same or different and represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms. A compound represented by general formula [XI] [wherein R ²³ represents a hydrogen atom or an acyloxy group having 1 to 20 carbon atoms, and when R ²³ is a hydrogen atom, , R ²⁴ represents a hydrogen atom or a pivalyl group, R ²⁵ represents a hydrogen atom, R ²⁶
Represents a pivalyl group. On the other hand, when R ²³ is an acyloxy group having 1 to 20 carbon atoms, R ²⁴ and R ²⁵ are the same or different and each is a hydrogen atom, an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted group. A substituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a COOR ⁶ group, a CONR ⁷ R ⁸ group, R ²⁶ represents an acyl group having 1 to 20 carbon atoms, a substituted or unsubstituted benzyl group, a trityl group , COOR ⁶ groups, CO
The NR ⁷ R ⁸ group is shown. In the COOR ⁶ group and the CONR ⁷ R ⁸ group, R ⁶ , R ⁷ and R ⁸ are the same or different and each is a hydrogen atom,
A lower alkyl group having 1 to 5 carbon atoms is shown. ] The manufacturing method of the diterpene derivative represented by these. 7. embedded image General formula [XII] [In formula, R < ²³ > shows a C1-C20 acyloxy group. And a diterpene derivative represented by the formula [XIII] [wherein R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group] or, n is 4, 5 connected to each other - a group - (CH _{2) n.} A general formula [XIV], wherein R ²³ represents an acyloxy group having 1 to 20 carbon atoms, R ²⁶ and R ²⁷ are hydrogen atoms or are bonded to each other. Represents a —CR ³⁰ R ³¹ — group, and R ²⁸ and R ²⁹ are bonded to each other to represent a —CR ³⁰ R ³¹ — group. In a —CR ³⁰ R ³¹ — group, R ³⁰ and R ³¹ are the same or different and are a hydrogen atom,
A lower alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted phenyl group, or a — (CH ₂ ) _n — group in which n is 4 or 5 are linked to each other. ] The manufacturing method of the diterpene derivative represented by these. 8. An antitumor agent comprising the diterpene derivative according to claim 1 as an active ingredient.