JPH0959295A - Steroid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new steroid derivative stereoselectively synthesizable in high efficiency by an organic synthetic chemical means, having simplified structure of the side chain at 17 position, exhibiting excellent antitumor action and useful as an antitumor agent, etc. SOLUTION: The objective compound is a new steroid derivative (salt) expressed by formula I (R is a 1-13C alkyl; A is hydroxyl group or a group easily hydrolyzable to form hydroxyl group; X and Y together form oxo or a 2-3C alkylenedioxy or X and Y are each H, hydroxy, a 1-5C alkoxy or a group easily hydrolyzable to form hydroxyl group; Y is H when X is hydroxyl group, etc.; X is H when Y is hydroxyl group, etc.; Y is a 1-5C alkoxy when X is a 1-5C alkoxy). The compound is useful as an antitumor agent, etc. The compound can be synthesized in high efficiency and stereoselectivity by using a steroid expressed by formula II as a starting substance and subjecting the substance to various reactions using organic synthetic chemical means.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel steroid derivative having an antitumor effect.

[0002]

As a substance having a structure similar to that of the compound of the present invention, Xestospo described in JP-A-7-70171.
A compound isolated from sponge of the genus ngia (hereinafter referred to as compound C) is known. Compound C has an excellent antitumor effect and is expected as a novel anticancer agent. However, since it is derived from marine natural products, there was a problem in securing resources and it was difficult to provide a large-scale stable supply. In addition, 17 of compound C
Since five asymmetric carbons are present in the side chain, efficient stereoselective synthesis was extremely difficult.

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel steroid compound having an antitumor effect, which can be efficiently and stereoselectively synthesized by a synthetic organic chemical method.

[0004]

Means for Solving the Problems As a result of intensive studies on the simplification of the 17-position side chain of compound C, the present inventors have found that the novel steroid derivative of the present invention in which the 17-position side chain has asymmetric carbon atoms reduced to two. Were found to exhibit an antitumor effect equivalent to that of Compound C, and the present invention was completed.

Hereinafter, the present invention will be described.

The present invention has the formula (I)

[0007]

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(Wherein R represents an alkyl group having 1 to 13 carbon atoms, A represents a hydroxyl group or a group which is easily hydrolyzed to form a hydroxyl group, and X and Y together form an oxo group or a carbon group. It represents an alkylenedioxy group having 2 or 3 atoms, or X and Y each represent a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms, or a group which is easily hydrolyzed to form a hydroxyl group. Is a hydroxyl group or a group easily hydrolyzed to a hydroxyl group, Y is a hydrogen atom, and Y is
X is a hydrogen atom when is a hydroxyl group or a group which is easily hydrolyzed to a hydroxyl group. When X is an alkoxy group having 1 to 5 carbon atoms, Y is an alkoxy group having 1 to 5 carbon atoms. ) And a pharmaceutically acceptable salt thereof.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the alkyl group means a linear or branched alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and the like. Can be mentioned. Of these, an isobutyl group is preferred.

The group easily hydrolyzed to a hydroxyl group means a group which is easily hydrolyzed to a hydroxyl group by a conventional hydrolysis reaction with an acid or an alkali, and examples thereof include an alkanoyloxy group and a substituted alkanoyloxy group. Examples thereof include a sulfooxy group and a phosphonooxy group. Examples of the alkanoyloxy group include an acetoxy group, a propionyloxy group, a butyryloxy group and an isobutyryloxy group. Of these, acetoxy group is preferred. Examples of the substituted alkanoyloxy group include N, N-dimethylglycyloxy group, N, N-diethylglycyloxy group, 3- (N, N-dimethylamino) propionyloxy group, 3- (N, N-diethylamino group. )
Examples include propionyloxy group, 4- (N, N-dimethylamino) butyryloxy group, succinyloxy group, glutaryloxy group, 3-sulfopropionyloxy group and the like. Among these, N, N-dimethylglycyloxy group, N, N-diethylglycyloxy group and succinyloxy group are preferable.

The pharmaceutically acceptable salt in the present invention means
For example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,
Salts with inorganic acids such as phosphoric acid, formic acid, acetic acid, propionic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid,
Lactobionic acid, camphorsulfonic acid, isethionic acid, succinic acid, ascorbic acid, malic acid, salicylic acid, trifluoroacetic acid, methanesulfonic acid, salts with organic acids such as paratoluenesulfonic acid, or salts with alkali metals such as sodium , Salts with alkaline earth metals such as magnesium and calcium, ammonium salts, salts with alkylamines such as triethylamine, and the like.

The compound represented by the formula (I) of the present invention can be prepared according to the method described in the literature (Chem. Ber., 100, 464, 1967).
The steroid derivative 3β, 12β-dihydroxy-5α-pregnan-20-one (1) described in (1) is used as a starting material and can be synthesized according to the production methods shown in FIGS. 1 to 9 below. The production method of the compound of the present invention will be outlined below in order.

First, in the compound represented by the formula (I) of the present invention, is A a hydroxyl group, and X and Y together are an oxo group or an alkylenedioxy group having 2 or 3 carbon atoms. , X and Y respectively represent a hydrogen atom, a hydroxyl group, and an alkoxy group having 1 to 5 carbon atoms, which will be outlined below (FIGS. 1 to 6).

[0014]

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[0015]

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[0016]

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[0017]

[Chemical 6]

[0018]

[Chemical 7]

[0019]

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The compound is a compound (12) or compound (11) (X and Y together represent an alkylenedioxy group having 2 or 3 carbon atoms) obtained by the synthetic method shown in FIGS. Or both X and Y represent an alkoxy group having 1 to 5 carbon atoms), compound (20) and compound (3
It can be obtained by reacting 0) with a reagent such as Li ₂ CuCl ₄ or LiCl. FIG. 6 shows the synthesis of the compound (34) of the present invention in which A is a hydroxyl group and X and Y together are an oxo group.

The followings are compound (12) and compound (11).
(X and Y together represent an alkylenedioxy group having 2 or 3 carbon atoms, or both X and Y represent an alkoxy group having 1 to 5 carbon atoms), compound (20) and compound ( The synthetic method of 30) will be sequentially described.

1) Compound (12) and Compound (11)
(X and Y together represent an alkylenedioxy group having 2 or 3 carbon atoms, or both X and Y represent an alkoxy group having 1 to 5 carbon atoms.) (FIGS. 1 and 2) ) The compound (1) is reacted with methoxymethyl chloride in the presence of a base such as diisopropylethylamine to give a derivative (2) in which the hydroxyl groups at the 3- and 12-positions are protected, and then the compound (2) is reacted with a Grignard reagent. The low-polar isomer 20-position alcohol (3) and the high-polar isomer (4) are obtained. Subsequently, the mixture of the compound (3) and the compound (4) is treated with an acid such as concentrated hydrochloric acid in a lower alcohol such as isopropanol to obtain a 20,22- (E) -olefin compound (5) as a main product. Further compound (5)
To the 3-position ketone body (6) by Oppenauer oxidation, and then reacted with alcohol such as methanol or ethylene glycol in the presence of an acid catalyst such as paratoluenesulfonic acid to obtain a 3-position ketone protected body (7). Subsequently, the compound (7) in the presence of a vanadium catalyst, and in the presence or absence of a base such as sodium hydrogencarbonate,
By reacting tert-butyl hydroperoxide, 2
0,22-β-epoxy compound (8): highly polar isomer and 2
0,22-α-epoxy compound (9): low polar isomer of about 1
Obtained at a production ratio of 6: 1 to 5: 1. Then, compound (8)
The reaction with a base such as aluminum tert-butoxide, lithium diisopropylamide or bromomagnesium diisopropylamide to give an allyl alcohol derivative (1
0) and further reacted with metachloroperbenzoic acid in the presence of a base such as sodium hydrogen carbonate to obtain an epoxy alcohol compound (11). Furthermore, the compound (1
The 3-ketoepoxy alcohol compound (12) can be obtained by treating 1) with an acid such as acetic acid. Also,
In the compound (10), when X and Y are taken together to form a compound having an alkylenedioxy group having 2 or 3 carbon atoms, the compound is treated with an acid such as acetic acid to obtain a 3-ketone body (13), followed by (13 ) To an alcohol such as methanol in the presence of an acid catalyst such as p-toluenesulfonic acid, whereby both X and Y have 1 to 1 carbon atoms.
A compound (10) having an alkoxy group of 5 can be obtained. The allyl alcohol compound (10) is obtained by another method, that is, by reacting the compound (8) with acetic anhydride in the presence of an organic base such as pyridine, 12β-acetoxy-20,22-β.
-Leading to the epoxy compound (14) and further acting an acid such as hydrogen chloride in an organic solvent to give a mixture of 12β-acetoxyallyl alcohol compound (15) and 22α-acetoxy compound (16), and then adding potassium carbonate or the like. It can also be obtained by a method of hydrolyzing acetate using a base.

2) Synthesis of compound (20) (FIG. 3) 3β, 12β-dihydroxy-20,22- (E) -olefin (5) obtained by the production method shown in FIG. 1 was prepared in the presence of a vanadium catalyst. At the same time, in the presence or absence of a base such as sodium hydrogen carbonate, tert-butyl hydroperoxide is allowed to act to give 20,22-β of the main product.
-Epoxy compound (17) and by-product 20,22-α-
The epoxy body (18) is obtained with a production ratio of about 10: 1. Then, to the compound (17), aluminum tert-butoxide,
React with a base such as lithium diisopropylamide or bromomagnesium diisopropylamide to lead to an allyl alcohol derivative (19), and further react with metachloroperbenzoic acid in the presence or absence of a base such as sodium hydrogencarbonate to give 3β, 12β. A dihydroxyepoxy alcohol body (20) can be obtained.

The allyl alcohol compound (19) is shown in FIG.
It can also be obtained by a method involving the 3β, 12β-diacetoxy form (21 and 22) and the 3β, 22α-diacetoxy form (23), which is based on the alternative method shown in (3).

3) Synthesis of compound (30) (FIGS. 4 and 5) The compound (5) was subjected to Mitsunobu reaction with an aromatic carboxylic acid such as 4-nitrobenzoic acid to form a 3-position α-ester (2).
This is led to 4) and then hydrolyzed with a base such as potassium carbonate to obtain the 3-position α-hydroxy compound (25). Subsequently, the compound (25) was allowed to act with tert-butyl hydroperoxide in the presence of a vanadium catalyst and simultaneously with the presence or absence of a base such as sodium hydrogencarbonate to give a 20,22-β-epoxy compound (26 ), 20, 22-
The α-epoxy compound (27) and the ring-closed compound (28) at the 12- and 22-positions are obtained at a production ratio of about 14: 1: 3 to 20: 1: 1. Then, the compound (26) is reacted with acetic anhydride in the presence of an organic base such as pyridine to obtain a 3α, 12β-diacetoxy-20,22-β-epoxy compound (31),
Furthermore, by reacting an acid such as hydrogen chloride in an organic solvent, 3α,
After forming a mixture of the 12β-diacetoxyallyl alcohol compound (32) and the 3α, 22α-diacetoxy compound (33), the acetate is hydrolyzed with a base such as potassium carbonate to obtain an allyl alcohol compound (29). Further, the allyl alcohol compound (29) is reacted with metachloroperbenzoic acid under the presence or absence of a base such as sodium hydrogen carbonate to give a 3α-hydroxyepoxy alcohol compound (3
0) can be obtained. In addition, the allyl alcohol compound (29) is prepared by another method, that is, the compound (26) is replaced by aluminum te.
It can also be obtained by a method of reacting a base such as rt-butoxide, lithium diisopropylamide or bromomagnesium diisopropylamide.

Next, of the compounds represented by the formula (I) of the present invention, a method for producing a compound having a group in which A is easily hydrolyzed to form a hydroxyl group will be outlined. These compounds are shown in Figure 1
Compounds (11), (12), and (2) whose synthetic methods are shown in FIG.
It can be manufactured using 0) and (30) as raw materials.

First, for a compound in which the group easily hydrolyzed to a hydroxyl group is an alkanoyloxy group, the corresponding alkanoic acid, alkanoic acid halide, or alkanoic acid anhydride is converted into compound (11), ( 12), (20) and (30) by reacting the compound obtained by the reaction under the commonly used esterification conditions with hydrogen chloride in an organic solvent such as ethyl acetate. Obtainable. A compound in which the group that is easily hydrolyzed to a hydroxyl group is a substituted alkanoyloxy group is
The corresponding substituted alkanoic acid, acid halide of the substituted alkanoic acid, or acid anhydride of the substituted alkanoic acid is converted to the compound (1
1), (12), (20) and (30) in an organic solvent such as ethyl acetate, the compound obtained by reacting under the conditions of esterification generally used,
It can be obtained by reacting with hydrogen chloride.
The compound whose substituted alkanoyloxy group is a 3-sulfopropionyloxy group is compound (11), (12),
A compound obtained by reacting (20) and (30) with acrylic acid or acryloyl chloride under commonly used esterification conditions to obtain an acrylic ester, and subsequently reacting this with sodium pyrosulfite. Can be obtained by reacting with hydrogen chloride in an organic solvent such as ethyl acetate.

The compound (sulfuric acid monoester) in which the group which is easily hydrolyzed to form a hydroxyl group is a sulfoxy group is a compound of sulfur trioxide / pyridine with respect to compounds (11), (12), (20) and (30). It can be obtained by reacting the compound obtained by reacting the complex with hydrogen chloride in an organic solvent such as ethyl acetate.

A compound in which the group easily hydrolyzed to form a hydroxyl group is a phosphonooxy group (phosphoric acid monoester)
Are compounds (11), (12), (20) and (30)
The reaction is carried out under the conditions of phosphoric acid esterification generally used for obtaining a protected phosphoric acid triester, followed by deprotection of the compound obtained in an organic solvent such as ethyl acetate, It can be obtained by reacting with hydrogen chloride. Alternatively, the reaction may be carried out under the generally used phosphite esterification conditions to obtain a protected phosphite triester, which is then oxidized by a conventional method to be converted to the protected phosphite triester. After that, the compound obtained by deprotection can also be obtained by reacting with hydrogen chloride in an organic solvent such as ethyl acetate.

Among the compounds of the present invention, the compound capable of forming a salt can be obtained by the treatment generally used to obtain the corresponding salt.

Among the compounds represented by the formula (I) of the present invention, A is an N, N-diethylglycyloxy group, and X
FIG. 7 shows a method for synthesizing a hydrochloride (36) in which Y and Y are together an oxo group. Dihydrochloride (39) and (40) wherein Y is a hydrogen atom and A and X are both N, N-dimethylglycyloxy group and N, N-diethylglycyloxy group.
FIG. 8 shows the synthetic method of A is a N, N-dimethylglycyloxy group, Y is a hydroxyl group and X is a hydrogen atom (43) and both A and Y are N, N-dimethylglycyloxy groups and X is hydrogen. Atomic dihydrochloride (4
The synthetic method of 4) is shown in FIG.

[0032]

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[0033]

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[0034]

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When the steroid compound of the present invention or a pharmaceutically acceptable salt thereof is used as a drug, it is a carrier usually used in pharmaceutical compositions (eg, talc, gum arabic, lactose, magnesium stearate, corn starch, etc.). It is mixed with to prepare a preparation for oral or parenteral administration. The dosage forms include tablets, granules, powders,
Capsules, syrups, suspensions, injections can be mentioned. The dose is 1 to 500 m when treating an adult
g, which is administered in 2 to 3 divided doses per day. This dose can be appropriately increased or decreased depending on the age, weight and condition of the patient.

[0036]

INDUSTRIAL APPLICABILITY According to the present invention, stereoselection of a novel steroid derivative in which the side chain structure at the 17-position is further simplified (the number of asymmetric carbons is reduced) is replaced with the known seafood-derived compound C, which has a problem in securing resources. It was provided by a synthetic organic method which is efficient and efficient. INDUSTRIAL APPLICABILITY The novel steroid derivative of the present invention has a growth inhibitory effect on tumor cells comparable to that of Compound C and can be easily provided by an organic synthetic method.
It is useful as a drug having an antitumor effect.

[0037]

EXAMPLES The present invention will be described in more detail with reference to examples. In addition, the compound numbers described in Examples are shown in FIG.
It corresponds to the compound number shown in 9. The compounds described in the examples are compounds of the present invention represented by formula (I) in which R is isobutyl. In addition, compounds in which X and Y of the compounds shown in FIGS. 1 and 2 are together an ethylenedioxy group will be described in Examples. Compounds (10a) and (11) shown in FIG. 2 in which X and Y are both methoxy groups are referred to as compounds (10a) and (11a), and are described in the examples.

Example 1) Synthesis of compound (2) 7.0 g of compound (1) was dissolved in 70 ml of methylene chloride, 5.05 g of methoxymethyl chloride and 8.10 g of diisopropylethylamine were added, and the mixture was refluxed for 7 hours.
After allowing to cool, ice water was added to the reaction solution and extracted with ethyl acetate,
The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was subjected to silica gel column chromatography [hexane:
Elution with ethyl acetate = 2: 1 (v / v)] was performed to obtain the compound fraction. This was recrystallized from hexane to obtain 6.7 g (yield 76%) of colorless prism crystals (2).

Mp: 94-95 ° C. Anal.Calcd for C ₂₅ H ₄₂ O ₅ : C, 71.05;
H, 10.02 Found: C, 71.25; H, 10.10 IR (KBr) cm ^-1 : 1701,1150,1042 ¹ H-NMR (CDCl ₃ ) δ: 0.74 (3H, s), 0.82 (3H, s),
2.19 (3H, s), 2.68 (1H, t, J = 8Hz), 3.34 (3H, s), 3.36 (3H, s),
3.34 to 3.43 (1H, m), 3.43 to 3.58 (1H, m), 4.63 to 4.74 (4H, m) FABMS (+ KI) m / z: 461 (MK ⁺ ).

2) Synthesis of Compound (3) and Compound (4) Under argon atmosphere, a solution of 10.72 g of isoamyl bromide in 100 ml of diethyl ether was added dropwise to 2.01 g of magnesium at room temperature, and the mixture was stirred for 30 minutes. Continue to 3
After cooling to ℃, compound (2) 10.0 g benzene 1
The 00 ml solution was added dropwise at 5 ° C or lower, and the mixture was further stirred at 3 ° C for 3 hours. Pour the reaction solution into an aqueous solution of ammonium chloride,
Extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a colorless oil. This was purified by silica gel column chromatography [eluting with hexane: ethyl acetate = 3: 1 (v / v)], and 9.45 g (yield 81%) of colorless oil (3) from the fraction eluted earlier. ) And 1.57 g (13% yield) of colorless oily substance (4) from the fractions eluted later.
Obtained.

Compound (3) IR (neat) cm ^-1 : 3430,1152,1050 ¹ H-NMR (CDCl ₃ ) δ: 0.83 (3H, s), 0.85 (3H, s),
0.87 (3H, d, J = 5Hz), 0.88 (3H, d, J = 5Hz), 1.18 (3H, s), 3.31
~ 3.59 (2H, m), 3.35 (3H, s), 3.41 (3H, s), 4.67 (2H, s), 4.70
(1H, d, J = 6Hz), 4.84 (1H, d, J = 6Hz), 5.15 (1H, brs) FABMS (+ KI) m / z: 533 (MK ⁺ ).

Compound (4) IR (neat) cm ^-1 : 3431,1152,1050 ¹ H-NMR (CDCl ₃ ) δ: 0.82 (3H, s), 0.85 (3H, s),
0.87 (3H, d, J = 6Hz), 0.89 (3H, d, J = 6Hz), 1.03 (3H, s), 3.33
~ 3.43 (1H, m), 3.36 (3H, s), 3.40 (3H, s), 3.42 ~ 3.58 (1H,
m), 4.67 (2H, s), 4.70 (1H, d, J = 6Hz), 4.83 (1H, d, J = 6Hz) FABMS (+ KI) m / z: 533 (MK ⁺ ).

3) Synthesis of compound (5) A mixture of 9.45 g of compound (3) and 1.57 g of compound (4) was dissolved in 330 ml of isopropanol, and concentrated hydrochloric acid (1.
98 ml was added and the mixture was refluxed for 9 hours. After cooling the reaction solution, the solvent was evaporated, the obtained residue was dissolved in chloroform and washed with saturated saline. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a crude product. This was subjected to silica gel column chromatography [eluting with chloroform: ethyl acetate = 10: 1 (v / v)], and the compound fraction was recrystallized with ethyl acetate to give colorless fine needle crystals (5). 5.87 g (yield 68%) was obtained.

Mp: 195-198 ° C. Anal.Calcd for C ₂₆ H ₄₄ O ₂ : C, 80.35;
H, 11.41 Found: C, 80.64; H, 11.59 IR (KBr) cm ^-1 : 3460,2949,2925,2867,1466 ¹
1 H-NMR (CDCl ₃ ) δ: 0.73 (3H, s), 0.8
1 (3H, s), 0.89 (6H, d, J = 5Hz), 1.67 (3H, s), 1.90 (2H, t, J = 6H
z), 2.29 (1H, t, J = 8Hz), 3.50-3.68 (2H, m), 5.51 (1H, t, J = 6
Hz) FABMS (+ KI) m / z: 427 (MK ⁺ ).

4) Synthesis of compound (6) 2.0 g of compound (5) was dissolved in 62 ml of toluene, 16 ml of cyclohexanone was added, and the mixture was refluxed for 10 minutes with a Dean Stark trap. Subsequently, 1.58 g of aluminum isopropoxide was added and the mixture was refluxed for 1 hour.
Dilute hydrochloric acid was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline, and then dried over anhydrous magnesium sulfate.
The crude product obtained by distilling off the solvent was subjected to silica gel column chromatography [hexane: ethyl acetate = 6: 1 (v
/ V)]] to obtain 1.45 g (yield 73%) of colorless fine needle crystals (6).

Mp: 103-105 ° C. Anal.Calcd for C ₂₆ H ₄₂ O ₂ : C, 80.77;
H, 10.95 Found: C, 80.65; H, 11.02 IR (KBr) cm ^-1 : 3555,3420,1719 ¹ H-NMR (CDCl ₃ ) δ: 0.76 (3H, s), 0.86 (3H, d, J
= 5Hz), 0.87 (3H, d, J = 5Hz), 1.02 (3H, s), 1.67 (3H, s), 3.61
(1H, dd, J = 10 and 5Hz), 5.52 (1H, dt, J = 6 and 1Hz) FABMS (+ KI) m / z: 425 (MK ⁺ ).

5) Synthesis of compound (7) 1.8 g of compound (6) was dissolved in 90 ml of benzene, 2.6 ml of ethylene glycol and 0.08 g of paratoluenesulfonic acid were added, and the mixture was refluxed for 10 minutes with a Dean Stark trap. . Ethyl acetate was added to the reaction solution, which was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by silica gel column chromatography [eluting with hexane: ethyl acetate = 5: 1 (v / v)] to obtain 1.56 g of colorless powder (7) ( Yield 7
8%) was obtained.

Mp: 146-147 ° C. Anal.Calcd for C ₂₈ H ₄₆ O ₃ : C, 78.09;
H, 10.77 Found: C, 78.27; H, 10.77 IR (KBr) cm ⁻¹ : 3459,2952,1467 ¹ H-NMR (CDCl ₃ ) δ: 0.73 (3H, s), 0.82 (3H, s),
0.89 (6H, d, J = 6Hz), 1.67 (3H, s), 1.90 (1H, t, J = 6Hz), 2.30
(1H, t, J = 10Hz), 3.59 (1H, dd, J = 10 and 5Hz), 3.93 (4H, s),
5.52 (1H, t, J = 6Hz) FABMS (+ KI) m / z: 469 (MK ⁺ ).

6) Synthesis of Compound (8) and Compound (9) 1.2 g of Compound (7) was added to methylene chloride 3 in a nitrogen atmosphere.
After dissolving in 0 ml, 15 mg of vanadium oxide acetylacetonate was added, and the mixture was stirred at room temperature for 10 minutes. After ice-cooling the solution, 1.7 ml of tert-butyl hydroperoxide (3.3N methylene chloride solution) was added dropwise, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. After diluting the reaction solution with diethyl ether and passing it through a short column of Florisil,
Concentrated. The obtained crude product was subjected to silica gel flash column chromatography [hexane: ethyl acetate = 3:
1 (v / v)], and 54 mg (yield 4%) of colorless powder (9) from the fraction eluted first and 860 mg (yield of colorless powder (8) from the fraction eluted later). 68
%)Obtained.

Compound (8) mp: 130-132 ° C. Anal.Calcd for C ₂₈ H ₄₆ O ₄ : C, 75.29;
H, 10.38 Found: C, 75.25; H, 10.50 IR (KBr) cm ^-1 : 3455,3338,2937,1105,1073,102
_{^{1 1 H-NMR (CDCl 3}} ) δ: 0.70 (3H, s), 0.79 (3H, s),
0.94 (3H, d, J = 7Hz), 0.97 (3H, d, J = 7Hz), 1.27 (3H, s), 3.23
(1H, dd, J = 11 and 5Hz), 3.34 (1H, t, J = 7Hz), 3.92 (4H, s) FABMS m / z: 447 (MH ⁺ ).

Compound (9) mp: 105 to 108 ° C. Anal.Calcd for C ₂₈ H ₄₆ O ₄ : C, 75.29;
H, 10.38 Found: C, 75.48; H, 10.48 IR (KBr) cm ⁻¹ : 3468,2948,2872,1469,1073 ¹ H-NMR (CDCl ₃ ) δ: 0.82 (3H, s), 0.84 (3H, s),
0.94 (3H, d, J = 5Hz), 0.97 (3H, d, J = 5Hz), 1.27 (3H, s), 2.76
(1H, t, J = 6Hz), 3.17 (1H, dd, J = 10 and 4Hz), 3.92 (4H, s),
4.42 (1H, s) FABMS (+ KI) m / z: 485 (MK ⁺ ).

7) Synthesis of compound (10) After dissolving 100 mg of compound (8) in 2 ml of toluene, 60 mg of aluminum tert-butoxide was added and the mixture was heated under reflux for 2 hours. Dilute the reaction with diethyl ether,
After adding 300 μl of a saturated aqueous solution of magnesium sulfate and vigorously stirring at room temperature, excess anhydrous magnesium sulfate was added,
Stir for a further 10 minutes. The crude product obtained by concentration after filtration is purified by silica gel column chromatography [eluting with hexane: ethyl acetate = 5: 1 (v / v)] to give 59 mg of colorless powder (10) (yield 59%).

Mp: 222-223 ° C. Anal.Calcd for C ₂₈ H ₄₆ O ₄ : C, 75.29;
H, 10.38 Found: C, 75.50; H, 10.52 IR (KBr) cm ^-1 : 3310,2950,2868,1358 ¹ H-NMR (CDCl ₃ ) δ: 0.73 (3H, s), 0.82 (3H, s) ,
0.91 (3H, d, J = 5Hz), 0.92 (3H, d, J = 5Hz), 3.47 (1H, dd, J = 10
and 4Hz), 3.94 (4H, s), 4.25 (1H, t, J = 7Hz), 4.93 (1H, s), 5.
09 (1H, s) FABMS (+ KI) m / z: 485 (MK ⁺ ).

8) Synthesis of compound (11) 0.28 g of compound (10) was dissolved in 6.9 ml of methylene chloride and cooled in an ice-water bath to obtain sodium hydrogencarbonate 0.06.
Add 5 g and 0.188 g of metachloroperbenzoic acid and add 4
After stirring for an hour, the mixture was further stirred at room temperature for 6 hours. Aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a crude product. This is subjected to silica gel column chromatography [hexane: ethyl acetate =
3: 2 (v / v)] and the compound fraction (0.27 g) was recrystallized from ethyl acetate-hexane,
0.17 g (yield 58%) of colorless fine needle crystals (11) were obtained.

Mp: 174-176 ° C. Anal.Calcd for C ₂₈ H ₄₆ O ₅ : C, 72.69;
H, 10.02 Found: C, 72.83; H, 10.12 IR (KBr) cm ^-1 : 3368,2948,2870,1096 ¹ H-NMR (CDCl ₃ ) δ: 0.68 (3H, s), 0.80 (3H, s) ,
0.91 (3H, d, J = 6Hz), 0.94 (3H, d, J = 6Hz), 2.14 (1H, t, J = 8H
z), 2.88 (1H, d, J = 4Hz), 3.06 (1H, d, J = 4Hz), 3.36 (1H, dd, J =
10 and 5Hz), 3.44 (1H, dd, J = 10 and 4Hz), 3.93 (4H, s), 4.
14 (1H, brs) LSIMS (+ KI) m / z: 501 (MK ⁺ ).

9) Synthesis of compound (12) 0.23 g of compound (11) was dissolved in 10 ml of 80% (w / w) acetic acid aqueous solution and stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by silica gel column chromatography [eluting with hexane: ethyl acetate = 1: 1 (v / v)] to obtain 0.13 g of colorless powder (12) ( Yield 63%).

Mp: 188-190 ° C. Anal.Calcd for C ₂₆ H ₄₂ O ₄ : C, 74.60;
H, 10.11 Found: C, 74.73; H, 10.26 IR (KBr) cm ⁻¹ : 3426,2943,2869,1708,1030 ¹ H-NMR (CDCl ₃ ) δ: 0.72 (3H, s), 0.90 (3H, d, J
= 6Hz), 0.95 (3H, d, J = 6Hz), 1.00 (3H, s), 2.89 (1H, d, J = 4H
z), 3.07 (1H, d, J = 4Hz), 3.39 (1H, dd, J = 10 and 4Hz), 3.45
(1H, dd, J = 10 and 4Hz), 4.21 (1H, brs) LSIMS (+ KI) m / z: 457 (MK ⁺ ).

A separate method for synthesizing the compound (12) will be described below.

10) Synthesis of compound (13) 0.466 g of compound (10) was suspended in 23 ml of 80% (w / w) aqueous acetic acid solution and heated at 50 to 70 ° C. for 15 minutes to dissolve. The reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed successively with water, 5% aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and colorless powder (13) (0.413 g)
(Yield 98.3%) was obtained.

Mp: 205-209 ° C. Anal.Calcd for C ₂₆ H ₄₂ O ₃ : C, 77.56;
H, 10.52 Found: C, 77.64; H, 10.56 IR (KBr) cm ⁻¹ : 3294,2953,2935,1714,1024 ¹ H-NMR (CDCl ₃ ) δ: 0.77 (3H, s), 0.91 (3H, d, J
= 6Hz), 0.92 (3H, d, J = 6Hz), 1.03 (3H, s), 3.02 (2H, s), 3.52
(1H, dd, J = 11 and 5Hz), 4.27 (1H, t, J = 6Hz), 4.94 (1H, s),
5.12 (1H, s) LSIMS (+ KI) m / z: 441 (MK ⁺ ).

11) Synthesis of compound (10a) 0.413 g of compound (13) was dissolved in 30 ml of methanol, 0.019 g of paratoluenesulfonic acid was added, and the mixture was stirred at room temperature for 15.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and then dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to give colorless powder (10a) 0.460.
g (yield 100%) was obtained.

Mp: 162 to 166 ° C. IR (KBr) cm ⁻¹ : 3334,2952,1470,1444,1072,105
4,1020 ¹ H-NMR (CDCl ₃ ) δ: 0.75 (3H, s), 0.83 (3H, s),
0.93 (3H, d, J = 7Hz), 0.94 (3H, d, J = 7Hz), 2.35 (1H, t, J = 10H
z), 3.16 (3H, s), 3.20 (3H, s), 3.49 (1H, dd, J = 11 and 5Hz),
4.27 (1H, t, J = 7Hz), 4.94 (1H, s), 5.12 (1H, s) LSIMS (+ KI) m / z: 487 (MK ⁺ ).

12) Synthesis of compound (11a) 0.442 g of compound (10a) was added to 20 ml of methylene chloride.
The resulting mixture was dissolved in water, 0.279 g of sodium hydrogen carbonate and 0.325 g of metachloroperbenzoic acid were added, and the mixture was stirred at room temperature for 6 hours. A saturated aqueous solution of sodium thiosulfate was added to the reaction solution, extracted with ethyl acetate, washed successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography [hexane:
Elution with ethyl acetate = 2: 1 (V / V)], and 0.360 g of colorless powder (11a) from the fraction eluted first.
(Yield 78.6%), and 0.021 g (Yield 5.1%) of colorless powder (12) was obtained from the fraction eluted later.

Mp: 149-152 ° C. IR (KBr) cm ⁻¹ : 3372,2956,1470,1444,1072,105
2,1024 ¹ H-NMR (CDCl ₃ ) δ: 0.68 (3H, s), 0.78 (3H, s),
0.91 (3H, d, J = 7Hz), 0.95 (3H, d, J = 7Hz), 2.88 (1H, d, J = 4H
z), 3.06 (1H, d, J = 4Hz), 3.13 (3H, s), 3.18 (3H, s), 3.31 ~ 3.
50 (2H, m), 4.16 (1H, brs) LSIMS (+ KI) m / z: 503 (MK ⁺ ).

13) Synthesis of compound (12) 0.347 g of compound (11a) was dissolved in 9.3 ml of 80% (w / w) aqueous acetic acid solution, and the mixture was stirred at room temperature for 5 minutes. Ethyl acetate was added to the reaction solution, which was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained crude product was subjected to silica gel column chromatography [eluting with hexane: ethyl acetate = 1: 1 (V / V)] to obtain 0.270 g of colorless powder (12) ( Yield 86.5%) was obtained.

Hereinafter, another method for synthesizing the compound (10) will be described. 14) Synthesis of compound (14) 3.51 g of compound (8) is dissolved in 40 ml of pyridine,
3.7 ml of acetic anhydride and 0.4 of 4-dimethylaminopyridine.
48 g was added and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction solution, which was washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by silica gel column chromatography [eluting with hexane: ethyl acetate = 5: 1 (v / v)] to give 3.61 g of colorless powder (14) ( Yield 94%).

Mp: 169-171 ° C. Anal.Calcd for C ₃₀ H ₄₈ O ₅ : C, 73.73;
H, 9.90 Found: C, 73.83; H, 9.96 IR (KBr) cm ^-1 : 2957,2930,1731,1245 ¹ H-NMR (DMSO-d ₆ ) δ: 0.75 (3H, s), 0.79 (3
H, s), 0.90 (6H, d, J = 6Hz), 1.15 (3H, s), 2.00 (3H, s), 2.44 (1
H, dd, J = 9 and 3Hz), 3.82 (4H, s), 4.53 (1H, dd, J = 11 and 5
Hz) LSIMS m / z: 489 (MH ⁺ ).

15) Compound (15) and Compound (16)
Synthesis of Compound (14) To 0.41 g of compound (14) was added 16 ml of 0.01N hydrogen chloride-ethyl acetate solution, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by silica gel column chromatography [eluting with hexane: ethyl acetate = 4: 1 (v / v)] to give compound (15) and compound (16). 0.40g of mixture
(Yield 97%) was obtained. A part of this mixture was subjected to silica gel column chromatography [hexane: ethyl acetate = 5:
Elution at 1 (v / v)], and colorless powder (16) was obtained from the fraction eluting first, and colorless powder (15) was obtained from the fraction eluting later.

Compound (15) mp: 68 to 70 ° C. IR (KBr) cm ⁻¹ : 3502,1714,1371,1268 ¹ H-NMR (CDCl ₃ ) δ: 0.82 (3H, s), 0.89 (3H, d) , J
= 6Hz), 0.91 (3H, d, J = 6Hz), 0.93 (3H, s), 1.92 (3H, s), 2.33
(1H, dd, J = 10 and 8Hz), 3.92 (4H, s), 3.98 ~ 4.08 (1H, m),
4.67 (1H, dd, J = 10 and 5Hz), 4.97 (1H, s), 5.02 (1H, s) LSIMS (+ KI) m / z: 527 (MK ⁺ ).

Compound (16) mp: 143-149 ° C IR (KBr) cm ^-1 : 3508,1737,1368,1240 ¹ H-NMR (CDCl ₃ ) δ: 0.78 (3H, s), 0.83 (3H, s) ),
0.91 (3H, d, J = 6Hz), 0.93 (3H, d, J = 6Hz), 2.06 (3H, s), 2.22
(1H, t, J = 10Hz), 3.47 (1H, dd, J = 10 and 5Hz), 3.93 (4H, s),
5.17 (1H, s), 5.27 (1H, s), 5.40 (1H, t, J = 6Hz) LSIMS (+ KI) m / z: 527 (MK ⁺ ).

16) Synthesis of compound (10) 3.08 g of a mixture of compound (15) and compound (16) was dissolved in 90 ml of methanol and anhydrous potassium carbonate 1.7 was added.
5 g was added, and the mixture was stirred at room temperature for 10 hours. Water was added to the residue obtained by distilling off the reaction solution, extracted with methylene chloride, washed with saturated brine and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by silica gel column chromatography [eluting with methylene chloride: ethyl acetate = 4: 1 (v / v)] to obtain 2.72 g of compound (10) ( 97%).

17) Compound (17) and Compound (18)
Synthesis of Compound (5) 0.2 g of methylene chloride under nitrogen atmosphere 6.
After dissolving in 5 ml, vanadium oxide acetylacetonate (0.001 g) was added and the mixture was cooled in an ice-water bath. Ter this solution
0.25 ml of t-butyl hydroperoxide (3.3N methylene chloride solution) was added, and the mixture was stirred for 1 hour and then at room temperature for 5 hours. The reaction solution was diluted with methylene chloride, florisil was added, and the mixture was passed through a silica gel short column [eluted with ethyl acetate] to obtain a crude product. This was purified by silica gel column chromatography [eluting with chloroform: ethyl acetate = 5: 1 (v / v)] to obtain 0.19 g of a colorless powdery mixture of compound (17) and compound (18). Approximately 10% of by-product (18) is contained from ¹ H-NMR spectrum]. By recrystallizing this mixture with ethyl acetate-hexane, the compound (1
0.15 g (yield 72%) of a single product of 7) was obtained.

Compound (17) mp: 204 to 207 ° C. Anal.Calcd for C ₂₆ H ₄₄ O ₃ : C, 77.18;
H, 10.96 Found: C, 77.14; H, 11.11 IR (KBr) cm ^-1 : 3386,3284,2948,2871,1045 ¹ H-NMR (CDCl ₃ ) δ: 0.70 (3H, s), 0.78 (3H, s),
0.95 (3H, d, J = 4Hz), 0.98 (3H, d, J = 4Hz), 1.27 (3H, s), 3.23
(1H, dd, J = 12 and 5Hz), 3.35 (1H, t, J = 6Hz), 3.48-3.67 (1
H, m), 4.50 (1H, s) LSIMS (+ KI) m / z: 443 (MK ⁺ ).

Compound (18) ¹ H-NMR (CDCl ₃ ) δ: 0.82 (3H, s), 0.84 (3H, s),
0.93 (3H, d, J = 5Hz), 0.97 (3H, d, J = 5Hz), 2.75 (1H, t, J = 6H
z), 3.17 (1H, dd, J = 12 and 5Hz), 3.49-3.67 (1H, m), 4.42
(1H, s).

18) Synthesis of Compound (19) According to the production method described in Example 7), a colorless powder (19) was obtained from the compound (17). _{mp: 224~226 ℃ Anal.Calcd for C 26} H 44 O 3: C, 77.18;
H, 10.96 Found: C, 77.28; H, 11.16 IR (KBr) cm ^-1 : 3368,2953,2931,2868,1468 ¹ H-NMR (CDCl ₃ ) δ: 0.75 (3H, s), 0.84 (3H, s),
0.91 (3H, d, J = 6Hz), 0.93 (3H, d, J = 6Hz), 2.35 (1H, t, J = 10H
z), 3.07 (1H, brs), 3.48 (1H, dd, J = 11Hz and 5Hz), 3.50 ~
3.70 (1H, m), 3.68 (1H, brs), 4.27 (1H, t, J = 7Hz), 4.95 (1H,
s), 5.11 (1H, s) FABMS (+ KI) m / z: 443 (MK ⁺ ).

19) Synthesis of Compound (20) A colorless powder (20) was obtained from the compound (19) according to the production method described in Example 8). _{mp: 169~171 ℃ Anal.Calcd for C 26} H 44 O 4: C, 74.24;
H, 10.54 Found: C, 74.19; H, 10.76 IR (KBr) cm ⁻¹ : 3478,3288,2934,2858,1030 ¹ H-NMR (CDCl ₃ ) δ: 0.67 (3H, s), 0.79 (3H, s),
0.92 (3H, d, J = 6Hz), 0.94 (3H, d, J = 6Hz), 2.13 (1H, t, J = 8H
z), 2.87 (1H, d, J = 4Hz), 3.06 (1H, d, J = 4Hz), 3.36 (1H, dd, J =
12 and 5Hz), 3.42 (1H, dd, J = 10 and 4Hz), 3.49 ~ 3.67 (1
H, m) FABMS (+ KI) m / z: 459 (MK ⁺ ) High resolution FABMS (+ KI) m / z: Calcd
_{for C 26 H 44 O 4 K} : 459.2877 Found: 459.2870.

The separate synthesis of compound (19) is described below. 20) Synthesis of compound (21) According to the production method described in Example 14), compound (17)
From this, colorless amorphous (21) was obtained. Anal. Calcd for C ₃₀ H ₄₈ O ₅ : C, 73.73;
H, 9.90 Found: C, 73.73; H, 9.98 IR (KBr) cm ^-1 : 2955,1737,1468,1370,1245,102
4 ¹ H-NMR (CDCl ₃ ) δ: 0.83 (3H, s), 0.86 (3H, s),
0.95 (3H, d, J = 7Hz), 0.96 (3H, d, J = 7Hz), 1.24 (3H, s), 2.01
(3H, s), 2.04 (3H, s), 2.61 (1H, dd, J = 9 and 2Hz), 4.56〜4.
77 (2H, m) LSIMS m / z: 489 (MH ⁺ ).

21) Compound (22) and Compound (23)
According to the production method described in Example 15), compound (21)
From this, colorless amorphous (22) and colorless powder (23) were obtained. Compound (22) Anal.Calcd for C ₃₀ H ₄₈ O ₅ : C, 73.73;
H, 9.90 Found: C, 73.72; H, 10.06 IR (KBr) cm ^-1 : 3510,2956,1738,1718,1248,102
8 ¹ H-NMR (CDCl ₃ ) δ: 0.83 (3H, s), 0.90 (3H, d, J
= 6Hz), 0.92 (3H, d, J = 6Hz), 0.93 (3H, s), 1.93 (3H, s), 2.01
(3H, s), 2.32 (1H, t, J = 10Hz), 3.97 ~ 4.08 (1H, m), 4.58 ~ 4.
76 (2H, m), 4.97 (1H, s), 5.03 (1H, s) LSIMS (+ KI) m / z: 527 (MK ⁺ ).

Compound (23) mp: 128 to 130 ° C. Anal.Calcd for C ₃₀ H ₄₈ O ₅ : C, 73.73;
H, 9.90 Found: C, 73.86; H, 10.02 IR (KBr) cm ^-1 : 3470,2954,1734,1714,1264,102
4 ¹ H-NMR (CDCl ₃ ) δ: 0.80 (3H, s), 0.85 (3H, s),
0.93 (3H, d, J = 6Hz), 0.95 (3H, d, J = 6Hz), 2.04 (3H, s), 2.08
(3H, s), 2.23 (1H, t, J = 10Hz), 3.50 (1H, dd, J = 11 and 6Hz),
4.57 to 4.78 (1H, m), 5.18 (1H, s), 5.28 (1H, s), 5.42 (1H, t, J
= 6 Hz) LSIMS (+ KI) m / z: 527 (MK ⁺ ).

22) Synthesis of Compound (19) Compound (22) was prepared according to the production method described in Example 16).
A colorless powder (19) was obtained from the mixture of and (23).

23) Synthesis of Compound (24) [When Ar of (24) in FIG. 4 is 4-nitrophenyl] 2.50 g of Compound (5), 1.29 g of 4-nitrobenzoic acid
And 2.02 g of triphenylphosphine are dissolved in 25 ml of tetrahydrofuran, 1.32 ml of diethyl azodicarboxylate is added dropwise under ice cooling, and under nitrogen atmosphere,
The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography [hexane: ethyl acetate = elute with 8: 1 (V / V)] to give a pale yellow amorphous substance (24). Was obtained (3.08 g, yield 88.2%).

IR (KBr) cm ^-1 : 3558,2952,2869,1
723,1530,1347,1277 ¹ H-NMR (CDCl ₃ ) δ: 0.75 (3H, s), 0.87 (3H, s),
0.88 (3H, d, J = 6Hz), 0.89 (3H, d, J = 6Hz), 1.68 (3H, s), 2.30
(1H, t, J = 9Hz), 3.63 (1H, dd, J = 11 and 5Hz), 5.32 (1H, br
s), 5.51 (1H, t, J = 7Hz), 8.16 to 8.36 (4H, m) FABMS (+ KI) m / z: 576 (MK ⁺ ).

24) Synthesis of compound (25) 0.109 g of compound (24) was dissolved in a mixed solvent of 1.0 ml of methanol and 0.5 ml of tetrahydrofuran, 0.06 g of anhydrous potassium carbonate was added, and the mixture was stirred at room temperature for 3 hours. did. After completion of the reaction, water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline solution, and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography [eluting with hexane: ethyl acetate = 4: 1 (V / V)] to give a colorless powder (2
5) was obtained (0.062 g, yield 78.8%).

Mp: 158-162 ° C. Anal.Calcd for C ₂₆ H ₄₄ O ₂ : C, 80.35;
H, 11.41 Found: C, 80.31; H, 11.40 IR (KBr) cm ^-1 : 3556,3325,2953,2926,1466,144
7,1383 ¹ H-NMR (CDCl ₃ ) δ: 0.74 (3H, s), 0.78 (3H, s),
0.89 (6H, d, J = 6Hz), 1.68 (3H, s), 1.91 (2H, t, J = 6Hz), 2.30
(1H, t, J = 10Hz), 2.39 (1H, brs), 3.60 (1H, dd, J = 11and 5H
z), 4.00 to 4.08 (1H, m), 5.52 (1H, t, J = 6Hz) LSIMS (+ KI) m / z: 427 (MK ⁺ ).

25) Synthesis of compound (26), compound (27) and compound (28) a) In the absence of sodium hydrogencarbonate 0.1176 g of compound (25) in 2.5 ml of methylene chloride
Dissolved in vanadium oxide acetylacetonate 0.0
08 g was added, and the mixture was cooled in an ice water bath under a nitrogen atmosphere. Tert-Butyl hydroperoxide (3.86
Methylene chloride solution) (0.24 ml) was added dropwise, and the mixture was stirred under ice cooling for 1 hour and further at room temperature for 1.5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel flash column chromatography [hexane: ethyl acetate = 3: 1 (V /
V), and 0.0168 g (yield 13.7%) of colorless powder (28) from the fraction to be eluted first, and 0.0062 g of colorless powder (27) from the fraction to be eluted next. Yield 5.1%), colorless amorphous (2%
6) was obtained in an amount of 0.0877 g (yield: 71.7%).

B) In the presence of sodium hydrogen carbonate 0.221 g of compound (25) was dissolved in 5.7 ml of methylene chloride, and vanadium oxide acetylacetonate 0.01
5 g and 0.144 g of sodium hydrogen carbonate were added, and the mixture was cooled in an ice-water bath under a nitrogen atmosphere. To this solution, 0.445 ml of tert-butyl hydroperoxide (3.86 M methylene chloride solution) was added dropwise, and the mixture was stirred for 4 hours under ice cooling. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel flash column chromatography [eluted with hexane: ethyl acetate = 3: 1 (V / V)] to give compound (28) and compound (28) from the fraction eluted first. 0.018 g of a mixture of compound (27) (yield 8.6
%), 0.1% of compound (26) from the fraction eluted later.
76 g (yield 84.2%) was obtained.

Compound (26) Anal.Calcd for C ₂₆ H ₄₄ O ₃ : C, 77.18;
H, 10.96 Found: C, 77.36; H, 10.99 IR (KBr) cm ^-1 : 3571,3339,2924,1468,1385,102
5,1007 ¹ H-NMR (CDCl ₃ ) δ: 0.71 (3H, s), 0.76 (3H, s),
0.96 (3H, d, J = 6Hz), 0.97 (3H, d, J = 6Hz), 1.27 (3H, s), 3.24
(1H, dd, J = 11 and 5Hz), 3.35 (1H, t, J = 6Hz), 4.04 (1H, br
s), 4.50 (1H, s, exchangeable) FABMS (+ KI) m / z: 443 (MK ⁺ ).

Compound (27) mp: 158-162 ° C. Anal.Calcd for C ₂₆ H ₄₄ O ₃ : C, 77.18;
H, 10.96 Found: C, 76.95; H, 10.97 IR (KBr) cm ^-1 : 3436,2927,2872,1468,1386,102
9,1006 ¹ H-NMR (CDCl ₃ ) δ: 0.79 (3H, s), 0.84 (3H, s),
0.94 (3H, d, J = 6Hz), 0.97 (3H, d, J = 6Hz), 1.28 (3H, s), 2.76
(1H, t, J = 5Hz), 3.18 (1H, dd, J = 11 and 5Hz), 4.00 ~ 4.08 (1
H, m), 4.44 (1H, s, exchangeable) FABMS (+ KI) m / z: 443 (MK ⁺ ).

Compound (28) mp: 225-227 ° C. Anal.Calcd for C ₂₆ H ₄₄ O ₃ : C, 77.18;
H, 10.96 Found: C, 77.15; H, 10.99 IR (KBr) cm ^-1 : 3401,2950,2917,2869,1070,100
_{^{1 1 H-NMR (CDCl 3}} ) δ: 0.61 (3H, s), 0.81 (3H, s),
0.90 (3H, d, J = 6Hz), 0.96 (3H, d, J = 6Hz), 1.13 (3H, s), 2.94
(1H, dd, J = 11 and 5Hz), 3.09 (1H, dd, J = 10 and 3Hz), 4.03
(1H, brs) FABMS (+ KI) m / z: 443 (MK ⁺ ).

26) Synthesis of Compound (29) According to the production method described in Example 7), colorless powder (29) was obtained from compound (26). _{mp: 110~113 ℃ Anal.Calcd for C 26} H 44 O 3: C, 77.18;
H, 10.96 Found: C, 77.05; H, 11.24 IR (KBr) cm ^-1 : 3339,2926,1639,1469,1023,100
3,906 ¹ H-NMR (CDCl ₃ ) δ: 0.74 (3H, s), 0.79 (3H, s),
0.89 (3H, d, J = 6Hz), 0.91 (3H, d, J = 6Hz), 2.33 (1H, t, J = 9H
z), 3.53 (1H, dd, J = 11 and 4Hz), 4.05 (1H, brs), 4.24 (1H,
t, J = 6Hz), 4.93 (1H, s), 5.08 (1H, s) FABMS (+ KI) m / z: 443 (MK ⁺ ).

27) Synthesis of Compound (30) According to the production method described in Example 8), colorless fine needle crystals (30) were obtained from compound (29). _{mp: 201~203 ℃ Anal.Calcd for C 26} H 44 O 4: C, 74.24;
H, 10.54 Found: C, 74.48; H, 10.72 IR (KBr) cm ⁻¹ : 3435,2922,2869,1005 ¹ H-NMR (CDCl ₃ ) δ: 0.68 (3H, s), 0.76 (3H, s) ,
0.90 (3H, d, J = 7Hz), 0.95 (3H, d, J = 7Hz), 2.18 (1H, t, J = 10H
z), 2.44 (1H, d, J = 5Hz, exchangeable), 2.85 (1H, d, J = 4Hz),
3.05 (1H, d, J = 4Hz), 3.32 ~ 3.48 (2H, m), 4.04 (1H, brs), 4.2
5 (1H, s, exchangeable) FABMS (+ KI) m / z: 459 (MK ⁺ ).

The separate synthesis of compound (29) is described below. 28) Synthesis of compound (31) Compound (26) was prepared according to the production method described in Example 14).
A colorless powder (31) was obtained from _{mp: 131~134 ℃ Anal.Calcd for C 30} H 48 O 5: C, 73.73;
H, 9.90 Found: C, 73.93; H, 10.06 IR (KBr) cm ^-1 : 2960,2933,2875,1736,1245 ¹ H-NMR (DMSO-d ₆ ) δ: 0.76 (3H, s), 0.81 ( 3
H, s), 0.90 (6H, d, J = 6Hz), 1.98 (3H, s), 2.00 (3H, s), 2.44 (1
H, dd, J = 8 and 3Hz), 4.52 (1H, dd, J = 11 and 5Hz), 4.87 (1
H, brs) FABMS (+ KI) m / z: 527 (MK ⁺ ).

29) Compound (32) and Compound (33)
Synthesis of compound (31) according to the production method described in Example 15).
From this, colorless powder (32) and colorless powder (33) were obtained. Compound (32) mp: 171-172 ° C Anal.Calcd for C ₃₀ H ₄₈ O ₅ : C, 73.73;
H, 9.90 Found: C, 73.54; H, 9.98 IR (KBr) cm ^-1 : 3548,2958,1733,1715,1261,123
6 ¹ H-NMR (CDCl ₃ ) δ: 0.80 (3H, s), 0.91 (3H, d, J
= 7Hz), 0.92 (3H, d, J = 7Hz), 0.94 (3H, s), 1.93 (3H, s), 2.05
(3H, s), 2.32 (1H, t, J = 9Hz), 4.02 (1H, dd, J = 9 and 5Hz), 4.6
6 (1H, dd, J = 11 and 5Hz), 4.98 (1H, s), 5.00 (1H, brs), 5.02
(1H, s) FABMS (+ KI) m / z: 527 (MK ⁺ ).

Compound (33) mp: 114-116 ° C. IR (KBr) cm ⁻¹ : 3535,2952,2871,1736,1371,124
5,1021 ¹ H-NMR (CDCl ₃ ) δ: 0.78 (3H, s), 0.81 (3H, s),
0.91 (3H, d, J = 6Hz), 0.93 (3H, d, J = 6Hz), 2.04 (3H, s), 2.06
(3H, s), 2.22 (1H, t, J = 9Hz), 3.42-3.55 (1H, m), 5.02 (1H, b
rs), 5.18 (1H, s), 5.27 (1H, s), 5.41 (1H, t, J = 6Hz) FABMS (+ KI) m / z: 527 (MK ⁺ ).

30) Synthesis of compound (29) Compound (32) was prepared according to the production method described in Example 16).
A colorless powder (29) was obtained from the mixture of and (33). 31) Synthesis of compound (34) 0.060 g of compound (12) was added to tetrahydrofuran 1.5
Dissolve in ml and under argon atmosphere in the literature (Tetrah
edron Letters, Volume 27, 3697
Page, 1986) prepared by the method described in Li ₂ CuC.
Tetrahydrofuran solution of l ₄ (1 mol / l) 0.29
ml was added, and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction solution, which was washed successively with water and saturated saline and then dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography [eluting with methylene chloride: acetone = 6: 1 (V / V)] to give colorless amorphous (34) as 0. 0.063 g (yield 97.0%) was obtained.

IR (KBr) cm ^-1 : 3403,2952,2868,1
713,1446,1065 ¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, d, J = 5Hz), 0.95
(3H, s), 0.98 (3H, d, J = 5Hz), 1.02 (3H, s), 3.43 (1H, dd, J = 11
and 5Hz), 3.88 (2H, s), 3.90-4.10 (1H, m) FABMS m / z: 455 (MH ^<+> ).

32) Synthesis of Compound (35) 0.050 g of Compound (12) was dissolved in 3.0 ml of methylene chloride, and N, N-diethylglycine sodium salt 0.02 was dissolved.
7 g, 4-dimethylaminopyridine 0.007 g and 1
-(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.046 g) was added, and the mixture was stirred at room temperature for 18 hours. Ethyl acetate was added to the reaction solution, which was washed successively with water and saturated saline and then dried over anhydrous sodium sulfate.
The crude product obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography [ethyl acetate: methanol = 1.
Elution with 0: 1 (V / V)] to obtain 0.050 g (yield 78.7%) of a colorless caramel-like substance (35).

IR (KBr) cm ^-1 : 3435, 2955, 1742, ¹
714,1159 ¹ H-NMR (CDCl ₃ ) δ: 0.70 (3H, s), 0.90 (3H, d, J
= 7Hz), 0.96 (3H, d, J = 7Hz), 1.00 (3H, s), 1.05 (6H, t, J = 7H
z), 2.66 (4H, q, J = 7Hz), 2.73 (1H, d, J = 4Hz), 3.08 (1H, d, J = 4
Hz), 3.40-3.30 (1H, m), 3.34 (2H, s), 4.22 (1H, s), 4.95 (1
H, dd, J = 10 and 3 Hz) LSIMS m / z: 532 (MH ⁺ ).

33) Synthesis of compound (36) To a solution of 0.050 g of compound (35) in 5.0 ml of ethyl acetate was added 0.5 ml of 4N hydrogen chloride ethyl acetate solution with stirring at room temperature. The solvent was distilled off under reduced pressure to obtain colorless amorphous (36) (0.051 g, yield 90.0%).

IR (KBr) cm ^-1 : 3236,2952,1750,1
712,1220 ¹ H-NMR (DMSO-d ₆ ) δ: 0.85 (3H, s), 0.86 (3
H, d, J = 7Hz), 0.95 (3H, d, J = 7Hz), 0.96 (3H, s), 1.22 (6H, t, J
= 7Hz), 3.10 ~ 3.40 (5H, m), 4.20 ~ 4.40 (2H, m), 5.37 (1H, d,
J = 10Hz), 6.31 (1H, d, J = 3Hz), 6.85 (1H, s), 10.10 (1H, brs) LSIMS m / z: 568 [(M-HCl) H ⁺ ].

34) Synthesis of compound (37) 0.063 g of compound (20) was dissolved in 3.0 ml of methylene chloride, and 0.036 g of N, N-dimethylglycine, 0.018 g of 4-dimethylaminopyridine and 1- ( 3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.080 g) was added, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction solution, which was washed successively with water and saturated saline and then dried over anhydrous sodium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography [ethyl acetate: methanol = 10: 1 (V /
Elution with V)] to obtain 0.063 g (yield 71.2%) of a colorless caramel-like substance (37).

IR (KBr) cm ^-1 : 3438,2952,2872,1
746,1468,1198,1150 ¹ H-NMR (CDCl ₃ ) δ: 0.67 (3H, s), 0.82 (3H, s),
0.91 (3H, d, J = 5Hz), 0.94 (3H, d, J = 5Hz), 2.34 (6H, s), 2.36
(6H, s), 2.72 (1H, d, J = 4Hz), 3.08 (1H, d, J = 4Hz), 3.14 (2H,
s), 3.20 (2H, s), 3.33 (1H, dd, J = 11 and 5Hz), 4.17 (1H, b
rs), 4.69-4.88 (1H, m), 4.97 (1H, dd, J = 10 and 4Hz) FABMS (+ KI) m / z: 629 (MK ⁺ ).

35) Synthesis of compound (38) 0.360 g of compound (20) was dissolved in 15 ml of methylene chloride, and N, N-diethylglycine sodium salt 0.38 was dissolved.
0 g, 4-dimethylaminopyridine 0.100 g and 1
0.640 g of-(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added, and the mixture was stirred at room temperature for 8.5 hours. Ethyl acetate was added to the reaction solution, which was washed successively with water and saturated saline and then dried over anhydrous sodium sulfate.
The crude product obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography [ethyl acetate: methanol = 9:
1 (V / V) for elution] to obtain 0.461 g (yield 85.7%) of a colorless caramel-like substance (38).

IR (KBr) cm ^-1 : 3436, 2965, 1739, ¹
470,1453,1386,1185 ¹ H-NMR (CDCl ₃ ) δ: 0.66 (3H, s), 0.81 (3H, s),
0.90 (3H, d, J = 5Hz), 0.94 (3H, d, J = 5Hz), 1.05 (12H, t, J = 7H
z), 2.50 to 2.77 (9H, m), 3.06 (1H, d, J = 4Hz), 3.21 to 3.40 (1
H, m), 3.26 (2H, s), 3.34 (2H, s), 4.65〜4.85 (1H, m), 4.85〜
5.00 (1H, m) LSIMS m / z: 647 (MH ⁺ ).

36) Synthesis of Compound (39) To a solution prepared by dissolving 0.206 g of Compound (37) in 10 ml of ethyl acetate, 1.74 ml of 1N hydrogen chloride-ethyl acetate solution was added with stirring at room temperature. The resulting precipitate is collected by filtration,
The colorless powder (39) was washed with diethyl ether to 0.
217 g (yield 88.9%) was obtained.

Mp: 176-179 ° C IR (KBr) cm ^-1 : 3420,2956,1746,1470,1368,123
2,1006 ¹ H-NMR (DMSO-d ₆ ) δ: 0.79 (3H, s), 0.82 (3
H, s), 0.89 (3H, d, J = 5Hz), 0.92 (3H, d, J = 5Hz), 2.81 (6H, s),
2.86 (6H, s), 3.28 (1H, dd, J = 11 and 4Hz), 3.69 (1H, d, J = 11
Hz), 3.87 (1H, d, J = 11Hz), 4.15 (2H, s), 4.30 (1H, d, J = 17H
z), 4.45 (1H, d, J = 17Hz), 4.65-4.85 (1H, m), 5.37 (1H, d, J =
10Hz), 6.46 (1H, brs, exchangeable), 6.94 (1H, brs, exchan
geable), 10.52 (2H, brs, exchangeable) FABMS m / z: 627 [(M-2HCl) H ^<+ >].

37) Synthesis of compound (40) To a solution of 0.155 g of compound (38) dissolved in 3.0 ml of ethyl acetate, 0.5 ml of 4N hydrogen chloride ethyl acetate solution was added with stirring at room temperature. The solvent was distilled off under reduced pressure to obtain 0.170 g (yield 97.1%) of colorless powder (40).

Mp: 150-156 ° C IR (KBr) cm ^-1 : 3216,2952,2584,1748,1470,122
4 ¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, s), 0.90 (3H, s),
0.94 (3H, d, J = 7Hz), 0.96 (3H, d, J = 7Hz), 1.45 (12H, t, J = 8H
z), 3.20 ~ 3.55 (9H, m), 3.85 (4H, s), 3.92 (1H, d, J = 17Hz),
4.21 (1H, d, J = 17Hz), 4.70 ~ 4.93 (1H, m), 5.54 (1H, d, J = 7H
z) LSIMS m / z: 683 [(M-HCl) H ⁺ ].

38) Compound (41) and Compound (42)
Synthesis of compound (30) (0.120 g) was dissolved in methylene chloride (4.2 ml), N, N-dimethylglycine (0.050 g), 4-dimethylaminopyridine (0.028 g) and 1- (3-dimethylaminopropyl) -3- Ethylcarbodiimide hydrochloride (0.125 g) was added, and the mixture was stirred at room temperature for 18.5 hours.
Ethyl acetate was added to the reaction solution, which was washed successively with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel flash column chromatography [ethyl acetate: methanol = 30:
1 (v / v)], and 0.066 g (yield 45.8%) of colorless powder (41) from the fraction eluted earlier, and colorless amorphous (42) from the fraction eluted later. ) To 0.067
g (yield 39.6%) was obtained.

Compound (41) mp: 71 to 75 ° C. IR (KBr) cm ⁻¹ : 3432,2928,1748,1470,1198,116
4 ¹ H-NMR (CDCl ₃ ) δ: 0.68 (3H, s), 0.78 (3H, s),
0.93 (3H, d, J = 7Hz), 0.95 (3H, d, J = 7Hz), 2.38 (6H, s), 2.73
(1H, d, J = 4Hz), 3.10 (1H, d, J = 4Hz), 3.21 (2H, s), 3.34 (1H, d
d, J = 11 and 5Hz), 4.06 (1H, brs), 4.98 (1H, dd, J = 9 and 4H
z) FABMS (+ KI) m / z: 544 (MK ⁺ ).

Compound (42) IR (KBr) cm ⁻¹ : 3446,2952,2872,2772,1746,146
8,1202,1150,1066 ¹ H-NMR (CDCl ₃ ) δ: 0.67 (3H, s), 0.78 (3H, s),
0.89 (3H, d, J = 6Hz), 0.94 (3H, d, J = 6Hz), 2.36 (6H, s), 2.37
(6H, s), 2.72 (1H, d, J = 4Hz), 3.07 (1H, d, J = 4Hz), 3.17 (2H,
s), 3.19 (2H, s), 3.33 (1H, dd, J = 11 and 5Hz), 4.16 (1H, br
s), 4.96 (1H, dd, J = 10 and 4Hz), 5.10 (1H, brs) FABMS (+ KI) m / z: 629 (MK ⁺ ).

39) Synthesis of compound (43) To a solution of 0.028 g of compound (41) in 2.0 ml of ethyl acetate was added 0.11 ml of 1N hydrogen chloride ethyl acetate solution with stirring at room temperature. The solvent was evaporated under reduced pressure to obtain 0.029 g (yield 90.6%) of colorless powder (43).

Mp: 168 to 172 ° C. IR (KBr) cm ⁻¹ : 3420,2926,1752,1232,1004 ¹ H-NMR (CDCl ₃ ) δ: 0.78 (3H, s), 0.89 (3H, s),
0.96 (3H, d, J = 6Hz), 0.98 (3H, d, J = 6Hz), 3.07 (6H, s), 3.35
~ 3.52 (1H, m), 3.82 (2H, s), 4.04 (1H, brs), 4.00 ~ 4.18 (1
H, m), 4.50-4.68 (1H, m), 5.59 (1H, d, J = 10Hz) FABMS (+ KI) m / z: 580 [(M-HC
l) K ⁺ ].

40) Synthesis of compound (44) To a solution of 0.026 g of compound (42) in 2.0 ml of ethyl acetate was added 0.132 ml of 1N hydrogen chloride ethyl acetate solution with stirring at room temperature. The solvent was distilled off under reduced pressure to obtain 0.031 g (yield 100%) of colorless powder (44).

Mp: 199-203 ° C IR (KBr) cm ^-1 : 3418,2934,1746,1470,1368,123
4 ¹ H-NMR (DMSO-d ₆ ) δ: 0.78 (3H, s), 0.82 (3
H, s), 0.90 (3H, d, J = 6Hz), 0.93 (3H, d, J = 6Hz), 2.82 (6H, s),
2.85 (6H, s), 3.21〜3.32 (1H, m), 3.68 (1H, d, J = 11Hz), 3.87
(1H, d, J = 11Hz), 4.18 (2H, s), 4.29 (1H, d, J = 16Hz), 4.43 (1
H, d, J = 16Hz), 5.09 (1H, brs), 5.37 (1H, d, J = 10Hz), 6.44 (1
H, brs, exchangeable), 6.94 (1H, s, exchangeable), 10.48
(2H, brs, exchangeable) FABMS (+ KI) m / z: 665 [(M-2HC
l) K ⁺ ].

The usefulness of the present invention will be shown below with reference to test examples. Test Example Proliferation Inhibitory Effect on KB Cells (In Vitro) 1) Test Method 1 × 10 ³ KB cells / well in each flat-bottom 96-well plate
0.1 ml of cell suspension (MEM containing 10% fetal bovine serum)
(Floating in the medium) and cultured for 24 hours. To this, 100 μl of a test compound solution dissolved in dimethylsulfoxide and diluted with a medium (dimethylsulfoxide final concentration: 0.5)
%) Was added and the cells were further cultured for 72 hours. After culture,
A 5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide reagent (coloring reagent) was added, and the cells were further cultured for 4 hours.

As a control, 100 μl of medium (final concentration of dimethyl sulfoxide was 0.5%) was added, and the cells were cultured in the same manner. After culturing, remove the medium and add 150 μl of cells.
Was dissolved in dimethylsulfoxide and the absorbance was measured, the ratio of the absorbance of the test compound group to the absorbance of the control group was determined, and the 50% growth inhibitory concentration (IC ₅₀ ) was calculated.

2) Test Results Table 1 shows the IC ₅₀ of the test compounds [compound (34) and compound C described in Example 31] to KB cells.

[0119]

[Table 1]

Continued Front Page (72) Inventor Taiji Yamada 2-18-12 Nanyodai, Hachioji, Tokyo

Claims (1)

[Claims] (1) Formula (1) (In the formula, R represents an alkyl group having 1 to 13 carbon atoms,
A represents a hydroxyl group or a group which is easily hydrolyzed to a hydroxyl group, X and Y together represent an oxo group or an alkylenedioxy group having 2 or 3 carbon atoms, or X and Y are each a hydrogen atom. , A hydroxyl group, an alkoxy group having 1 to 5 carbon atoms, or a group which is easily hydrolyzed to form a hydroxyl group. However, Y is a hydrogen atom when X is a hydroxyl group or a group which is easily hydrolyzed to a hydroxyl group, and X is a hydrogen atom when Y is a hydroxyl group or a group which is easily hydrolyzed to a hydroxyl group. When X is an alkoxy group having 1 to 5 carbon atoms, Y is an alkoxy group having 1 to 5 carbon atoms. )
And a pharmaceutically acceptable salt thereof.