JPH07224087A - Steroid derivative - Google Patents

Abstract

PURPOSE:To obtain a new steroid derivative efficiently and stereoselectively synthesizable by synthetic organic chemical technique without the need for using natural substance-derived materials with problems such as concerning resource security, having proliferation inhibitory activity against oncocytes, thus useful as an antineoplastic agent etc. CONSTITUTION:This new steroid derivative having antineoplastic activity is expressed by formula I (R is a 1-13C alkyl; A is hydroxyl group or a group becoming hydroxyl group through ready hydrolysis; X and Y are combined into oxo or a 2-3C alkylenedioxy; X is hydroxyl, a 1-5C alkoxyl or a group becoming hydroxyl group through ready hydrolysis; Y is H or 1-5C alkoxyl; when X is hydroxyl or a group becoming hydroxyl through ready hydrolysis, Y is H; when X is a 1-5C alkoxyl, Y is also a 1-5C alkoxyl). This new compound can be obtained by protecting the hydroxyl group of 3beta,12beta-dihydroxy-5alpha- pregnan-20-one followed by alkylation with a Grignard reagent and dehydration and then Oppenauer oxidation of the product which is, in turn, treated with a peroxide.

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art As a substance having a structure similar to that of the compound of the present invention, Xestospong described in JP-A-5-4998.
A compound isolated from sponge of the ia genus (hereinafter referred to as compound A) is known. Compound A 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 A
Since there are 5 asymmetric carbons in the side chain, efficient stereoselective synthesis thereof 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 activity which can be synthesized by an organic synthetic chemistry method.

[0004]

Means for Solving the Problems As a result of intensive studies on the simplification of the 17-position side chain of compound A, the present inventors have reduced the asymmetric carbon of the 17-position side chain to 2 Were found to exhibit the same antitumor effect as Compound A, and the present invention was completed.

The present invention will be described below. The present invention has the formula (I)

[0006]

[Chemical 2]

(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 form a hydroxyl group. X and Y together form an oxo group or a carbon group. It represents an alkylenedioxy group having 2 or 3 atoms, X represents a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or a group which is easily hydrolyzed to form a hydroxyl group, and Y represents a hydrogen atom or 1 carbon atom. 5 represents an alkoxy group of 5 to 5, provided that Y is a hydrogen atom when X is a hydroxyl group or a group that is easily hydrolyzed to a hydroxyl group, and Y is a carbon atom when X is an alkoxy group having 1 to 5 carbon atoms. A steroid derivative represented by the formula 1 to 5) or a salt thereof.

In the present invention, the alkyl group means a linear or branched alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, isopentyl group. , Hexyl group,
Examples thereof include isohexyl group, heptyl group, isoheptyl group, octyl group, isooctyl group, nonyl group, isononyl group, decyl group, isodecyl group, dodecyl group, isododecyl group, tridecyl group and isotridecyl group. Of these, an isobutyl group, an isopentyl group, an isohexyl group, an isoheptyl group, and an isooctyl group are preferable. The alkoxy group means a linear or branched alkoxy group, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a pentoxy group, and an isopentoxy group. . Of these, a methoxy group and an ethoxy group are preferable.

The group easily hydrolyzed to a hydroxyl group means a group which is easily hydrolyzed to a hydroxyl group by a common hydrolysis reaction with an acid or an alkali, and examples thereof include a substituted alkanoyloxy group, a sulfooxy group and a phosphonooxy group. , A phosphinooxy group and the like. Among these, the substituted alkanoyloxy group includes, for example, N, N-dimethylglycyloxy group, N, N-diethylglycyloxy group, 3- (N, N-dimethylamino) propionyloxy group, 3- (N, N -Diethylamino) propionyloxy group, 4- (N, N-dimethylamino) butyryloxy group, succinyloxy group, glutaryloxy group, 3
-Sulfopropionyloxy group and the like. Of these groups which are easily hydrolyzed to form a hydroxyl group, N, N-dimethylglycyloxy group, N, N-diethylglycyloxy group, succinyloxy group and 3-sulfopropionyloxy group are preferable.

The salt in the present invention means a pharmaceutically acceptable salt, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid and acetic acid. , Propionic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, succinic acid, ascorbic acid, malic acid, salicylic acid, trifluoroacetic acid, methanesulfonic acid, salts with organic acids such as paratoluenesulfonic acid, or sodium, potassium, etc. Examples thereof include salts with alkali metals, salts with alkaline earth metals such as magnesium and calcium, salts with alkylamines such as triethylamine, and ammonium salts.

The compound represented by the formula (I) of the present invention can be prepared according to the literature (Chem. Ber., 100 , 464, 1967).
Described steroid derivative 3β, 12β-dihydroxy-
Using 5α-pregnan-20-one (1) as a starting material, it can be synthesized according to the production methods shown in the following scheme 1, scheme 2 and scheme 3. The production method of the compound of the present invention will be outlined below in order.

First, the production method of the compound of the present invention obtained by the synthetic method shown in Scheme 1 and Scheme 2 will be outlined.

[0013]

[Chemical 3]

[0014]

[Chemical 4]

The compound (1) is reacted with methoxymethyl chloride in the presence of a base such as diisopropylethylamine to give a derivative (2) in which hydroxyl groups at the 3- and 12-positions are protected, and then a Grignard reagent is applied to the compound (2). Let the 20-position alcohol (3): low polar isomer and (4):
The highly polar isomer is 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 20,22- (E).
-Olefin form (5) is obtained as the main product. Further, the compound (5) is led to the 3-position ketone body (6) by Oppenauer oxidation, and then reacted with an alcohol having 1 to 5 carbon atoms, ethylene glycol or propylene glycol in the presence of an acid catalyst such as paratoluenesulfonic acid. Three
The protected ketone of position ketone (7) is obtained. Continuing, compound (7)
In the presence of a vanadium catalyst, and in the presence or absence of a base such as sodium hydrogencarbonate, with tert-butyl hydroperoxide to give a 20,22-β-epoxy compound (8): a highly polar isomer and The 20,22-α-epoxy form (9): low polarity isomer is obtained with a production ratio of about 16: 1 to 5: 1. Then, aluminum te is added to the compound (8).
A base such as rt-butoxide, lithium diisopropylamide or bromomagnesium diisopropylamide is reacted to give an allyl alcohol derivative (10), and metachloroperbenzoic acid is further reacted in the presence of a base such as sodium hydrogencarbonate to give the compound of the present invention. An epoxy alcohol compound (11) which is a compound can be obtained.

Further, the compound (11) is treated with an acid such as acetic acid to obtain the 3-ketoepoxy alcohol compound (12) which is the compound of the present invention.

The allyl alcohol compound (10) is prepared 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,
After being led to a 22-β-epoxy compound (13) and further treated with an acid such as hydrogen chloride in an organic solvent to give a mixture of 12β-acetoxyallyl alcohol compound (14) and 22α-acetoxy compound (15), carbonic acid It can also be obtained by a method of hydrolyzing acetate using a base such as potassium.

Next, a method for producing the compound of the present invention obtained by the synthetic method shown in Scheme 3 will be outlined.

[0019]

[Chemical 5]

First, the 3β, 12β-dihydroxy-20,22- (E) -olefin compound (5) obtained by the production method shown in Scheme 1 was added in the presence of a vanadium catalyst and in the presence of a base such as sodium hydrogen carbonate. Or in the absence of te
rt-Butyl hydroperoxide is allowed to act, and 2
0,22-β-epoxy compound (16): main product and 2
0,22-α-epoxy compound (17): about 1 by-product
Obtained at a production ratio of 0: 1. Then, the compound (16) is reacted with a base such as aluminum tert-butoxide, lithium diisopropylamide or bromomagnesium diisopropylamide to give an allyl alcohol compound (18), and further in the presence or absence of a base such as sodium hydrogencarbonate. Then, 3β, 12β-dihydroxyepoxy alcohol compound (19), which is the compound of the present invention, can be obtained by reacting with metachloroperbenzoic acid.

The allyl alcohol compound (18) can be obtained by a method which passes through the 3β, 12β-diacetoxy compound (20 and 21) and the 3β, 22α-diacetoxy compound (22) according to the alternative method shown in Scheme 2. be able to.

Next, a method for producing a compound having a group which is easily hydrolyzed to form a hydroxyl group among the compounds of the present invention will be outlined. These compounds are the compounds (1
It can be produced using 1), (12) or (19) as a raw material.

First, for a compound in which the group which is easily hydrolyzed to a hydroxyl group is a substituted alkanoyloxy group, a corresponding substituted alkanoic acid, an acid halide of a substituted alkanoic acid or an acid anhydride of a substituted alkanoic acid is used as a compound (11 ), (1
It can be obtained by reacting the esterification conditions generally used for 2) or (19). Compounds in which the substituted alkanoyloxy group is a 3-sulfopropionyloxy group are compounds (11) and (12)
Alternatively, it can be obtained by reacting (19) with acrylic acid or acryloyl chloride under a commonly used esterification condition to obtain an acrylic ester, and subsequently reacting this with sodium pyrosulfite.

The compound (sulfuric acid monoester) in which the group easily hydrolyzed to a hydroxyl group is a sulfooxy group is reacted with the compound (11), (12) or (19) by a sulfur trioxide / pyridine complex. Can be obtained.

A compound in which the group which is easily hydrolyzed to a hydroxyl group is a phosphonooxy group (phosphoric acid monoester)
Reacts with compound (11), (12) or (19) under generally used conditions for phosphoric acid esterification to obtain a protected phosphoric acid triester, followed by deprotection. Can be obtained. Alternatively, the reaction is carried out under generally used conditions for phosphite conversion to give a protected phosphite triester, which is subsequently oxidized by a conventional method to be converted into a protected phosphite triester. After that, it can also be obtained by deprotection.

The compound in which the group easily hydrolyzed to a hydroxyl group is a phosphinooxy group (phosphorous acid monoester) is generally used for the compound (11), (12) or (19). It can be obtained by conducting the reaction under the conditions of phosphorous acid monoesterification.

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

When the steroid compound of the present invention or a salt thereof is used as a drug, it is used as a carrier usually used in pharmaceutical compositions (eg talc, gum arabic, lactose,
Magnesium stearate, corn starch, etc.)
Oral or parenteral administration formulation Examples of the dosage form include tablets, granules, powders, capsules, syrups, suspensions and injections. The dose is 1 to 500 mg when treating an adult, and this 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.

[0029]

INDUSTRIAL APPLICABILITY According to the present invention, a novel steroid derivative in which the 17-position side chain structure is simplified (asymmetric carbon is reduced) is stereoselectively substituted for the compound A derived from a marine natural product, which has a problem in securing resources. And provided by an efficient organic synthetic method. The novel steroid derivative of the present invention is compound A
It has a growth inhibitory effect on tumor cells and is easily provided by an organic synthetic method, and thus is useful as a drug having an antitumor effect.

[0030]

EXAMPLES The present invention will be described in more detail with reference to examples. In addition, a after the compound number described in the examples
Shows the case where R of the compound in scheme 1, scheme 2 and scheme 3 is isobutyl, and b shows the case where R of the compound in scheme 1 and scheme 2 is isopentyl. Further, c shows the case where R of the compound in scheme 1 and scheme 2 is methyl, and d shows the case where R of the compound in scheme 1 and scheme 2 is tridecyl.

Example 1 (When R of the Compounds in Scheme 1 and Scheme 2 is Isobutyl and X and Y are Linked to Ethylenedioxy) 1) Synthesis of Compound (2) 7.0 g of Compound (1) is converted into methylene chloride. It was dissolved in 70 ml, 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 (2) fraction. The solvent was distilled off and recrystallized from hexane to give 6.7 g of colorless prism crystals (2) (yield: 76).
%)Obtained.

Mp: 94-95 ° C. Anal. Calcd for C ₂₅ H ₄₂ O ₅ : C, 7
1.05; H, 10.02 Found: C, 71.2
5; H, 10.10 IR (KBr) cm ⁻¹ : 1701, 1150, 1042 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.74 (3
H, s), 0.82 (3H, s), 2.19 (3H,
s), 2.68 (1H, t, J = 8Hz), 3.34
(3H, s), 3.36 (3H, s), 3.34-3.
43 (1H, m), 3.43 to 3.58 (1H, m),
4.63-4.74 (4H, m) FABMS (+ KI) m / z: 461 (MK ^<+> ).

2) Synthesis of Compound (3a) and Compound (4a) 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 stirred for 30 minutes. Continue to 3
After cooling to ℃, 10.0 g of compound (2) 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,
It was 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 (3a) from the fraction eluted earlier. ), And 1.57 g of a colorless oily product (4a) (yield 13
%)Obtained.

Compound (3a) IR (neat) cm ⁻¹ : 3430, 1152, 105
0 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.83 (3
H, s), 0.85 (3H, s), 0.87 (3H,
d, J = 5 Hz), 0.88 (3H, d, J = 5H
z), 1.18 (3H, s), 3.31 to 3.59 (2
H, m), 3.35 (3H, s), 3.41 (3H,
s), 4.67 (2H, s), 4.70 (1H, d, J
= 6 Hz), 4.84 (1H, d, J = 6 Hz), 5.
15 (1H, brs) FABMS (+ KI) m / z: 533 (MK ⁺ ).

Compound (4a) IR (neat) cm ^-1 : 3431, 1152, 105
0 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.82 (3
H, s), 0.85 (3H, s), 0.87 (3H,
d, J = 6 Hz), 0.89 (3H, d, J = 6H
z), 1.03 (3H, s), 3.33 to 3.43 (1
H, m), 3.36 (3H, s), 3.40 (3H,
s), 3.42 to 3.58 (1H, m), 4.67 (2
H, s), 4.70 (1H, d, J = 6 Hz), 4.8
3 (1 H, d, J = 6 Hz) FABMS (+ KI) m / z: 533 (MK ⁺ ).

3) Synthesis of compound (5a) 9.45 g of compound (3a) and 1.57 g of compound (4a)
Was dissolved in 330 ml of isopropanol, 1.98 ml of concentrated hydrochloric acid 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 [eluted with chloroform: ethyl acetate = 10: 1 (v / v)] to obtain a compound (5a) fraction. This was distilled off of the solvent and recrystallized from ethyl acetate to give colorless fine needle crystals (5a) of 5.8.
7 g (yield 68%) was obtained.

Mp: 195-198 ° C. Anal. Calcd for C ₂₆ H ₄₄ O ₂ : C, 8
0.35; H, 11.41 Found: C, 80.6
4; H, 11.59 IR (KBr) cm ^-1 : 3460, 2949, 292
_{^{5,2867,1466 1 H-NMR (CDCl 3}} ) δ
(Ppm): 0.73 (3H, s), 0.81 (3H,
s), 0.89 (6H, d, J = 5Hz), 1.67
(3H, s), 1.90 (2H, t, J = 6Hz),
2.29 (1H, t, J = 8Hz), 3.50 to 3.6
8 (2H, m), 5.51 (1H, t, J = 6Hz) FABMS (+ KI) m / z: 427 (MK ⁺ ).

4) Synthesis of compound (6a) 2.0 g of compound (5a) was dissolved in 62 ml of toluene,
16 ml of cyclohexanone was added, and a Dean Stark trap was attached and refluxed for 10 minutes. 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].
Elution with (v / v)] and purification with colorless fine needle crystals (6
1.45 g (yield 73%) of a) was obtained.

Mp: 103-105 ° C. Anal. Calcd for C ₂₆ H ₄₂ O ₂ : C, 8
0.77; H, 10.95 Found: C, 80.6
5; H, 11.02 IR (KBr) cm ⁻¹ : 3555, 3420, 1719 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.76 (3
H, s), 0.86 (3H, d, J = 5Hz), 0.8
7 (3H, d, J = 5Hz), 1.02 (3H, s),
1.67 (3H, s), 3.61 (1H, dd, J = 1
0 and 5Hz), 5.52 (1H, dt, J = 6)
and 1 Hz) FABMS (+ KI) m / z: 425 (MK ⁺ ).

5) Synthesis of compound (7a) 1.8 g of compound (6a) was dissolved in 90 ml of benzene,
2.6 ml of ethylene glycol and 0.08 g of paratoluenesulfonic acid were added, and a Dean Stark trap was attached, and the mixture was refluxed for 10 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 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 (7a) ( Yield 78%) was obtained.

Mp: 146-147 ° C. Anal. Calcd for C ₂₈ H ₄₆ O ₃ : C, 7
8.09; H, 10.77 Found: C, 78.2
7; H, 10.77 IR (KBr) cm ⁻¹ : 3459, 2952, 1467 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.73 (3
H, s), 0.82 (3H, s), 0.89 (6H,
d, J = 6 Hz), 1.67 (3H, s), 1.90
(1H, t, J = 6Hz), 2.30 (1H, t, J =
10 Hz), 3.59 (1H, dd, J = 10 and
5Hz), 3.93 (4H, s), 5.52 (1H,
t, J = 6 Hz) FABMS (+ KI) m / z: 469 (MK ⁺ ).

6) Synthesis of compound (8a) and compound (9a) 1.2 g of compound (7a) was dissolved in 30 ml of methylene chloride under a nitrogen atmosphere, 15 mg of vanadium oxide acetylacetonate was added, and the mixture was stirred at room temperature for 10 minutes. did. The solution was ice-cooled and then tert-butyl hydroperoxide (3.
1.7 ml of 3N methylene chloride solution) was added dropwise, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. The reaction solution was diluted with diethyl ether, passed through a short column of Florisil, and then concentrated. The obtained crude product was subjected to silica gel flash column chromatography [eluting with hexane: ethyl acetate = 3: 1 (v / v)], and 54 mg (yield) of colorless powder (9a) from the fraction eluted earlier. 4%) and 860 mg of colorless powder (8a) from the fraction eluted later.
(Yield 68%) was obtained.

Compound (8a) mp: 130-132 ° C. Anal. Calcd for C ₂₈ H ₄₆ O ₄ : C, 7
5.29; H, 10.38 Found: C, 75.2
5; H, 10.50 IR (KBr) cm ^-1 : 3455, 3338, 293
7,1105,1073,1021 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.70 (3
H, s), 0.79 (3H, s), 0.94 (3H,
d, J = 7Hz), 0.97 (3H, d, J = 7H
z), 1.27 (3H, s), 3.23 (1H, dd,
J = 11 and 5 Hz), 3.34 (1H, t, J
= 7 Hz), 3.92 (4H, s) FABMS m / z: 447 (MH ^<+> ).

Compound (9a) mp: 105 to 108 ° C. Anal. Calcd for C ₂₈ H ₄₆ O ₄ : C, 7
5.29; H, 10.38 Found: C, 75.4.
8; H, 10.48 IR (KBr) cm ^-1 : 3468, 2948,287
2,1469,1073 ¹ H-NMR (CDCl ₃ ) δ
(Ppm): 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 4 Hz), 3.92 (4H,
s), 4.42 (1H, s) FABMS (+ KI) m / z: 485 (MK ⁺ ).

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

Mp: 222-223 ° C. Anal. Calcd for C ₂₈ H ₄₆ O ₄ : C, 7
5.29; H, 10.38. Found: C, 75.5
0; H, 10.52 IR (KBr) cm ⁻¹ : 3310, 2950, 286
_{^{8,1358 1 H-NMR (CDCl 3}} ) δ (ppm): 0.73 (3
H, s), 0.82 (3H, s), 0.91 (3H,
d, J = 5Hz), 0.92 (3H, d, J = 5H)
z), 3.47 (1H, dd, J = 10 and 4H
z), 3.94 (4H, s), 4.25 (1H, t, J
= 7 Hz), 4.93 (1H, s), 5.09 (1H,
s) FABMS (+ KI) m / z: 485 (MK ^<+> ).

8) Synthesis of compound (11a) 0.28 g of compound (10a) was added to 6.9 ml of methylene chloride.
Dissolved in water, cooled in an ice-water bath and cooled to 0.
065 g and 0.188 g of metachloroperbenzoic acid were added, and the mixture was stirred for 4 hours and 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 was subjected to silica gel column chromatography [eluting with hexane: ethyl acetate = 3: 2 (v / v)] to give the compound (11
a) Fractions were obtained. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-hexane to give colorless fine needle crystals (11a) of 0.1.
7 g (yield 58%) was obtained.

Mp: 174-176 ° C. Anal. Calcd for C ₂₈ H ₄₆ O ₅ : C, 7
2.69; H, 10.02. Found: C, 72.8
3; H, 10.12 IR (KBr) cm ^-1 : 3368, 2948,287
_{^{0,1096 1 H-NMR (CDCl 3}} ) δ (ppm): 0.68 (3
H, s), 0.80 (3H, s), 0.91 (3H,
d, J = 6Hz), 0.94 (3H, d, J = 6H
z), 2.14 (1H, t, J = 8Hz), 2.88.
(1H, d, J = 4Hz), 3.06 (1H, d, J =
4 Hz), 3.36 (1H, dd, J = 10 and
5 Hz), 3.44 (1H, dd, J = 10 and
4Hz), 3.93 (4H, s), 4.14 (1H, b
rs) LSIMS (+ KI) m / z: 501 (MK ⁺ ).

9) Synthesis of compound (12a) 0.23 g of compound (11a) 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 the solvent away was purified by silica gel column chromatography [eluting with hexane: ethyl acetate = 1: 1 (v / v)], and 0.13 g (colorless powder (12a)) was obtained. Yield 63%)
Obtained.

Mp: 188-190 ° C. Anal. Calcd for C ₂₆ H ₄₂ O ₄ : C, 7
4.60; H, 10.11. Found: C, 74.7
3; H, 10.26 IR (KBr) cm ^-1 : 3426,2943,286
9,1708,1030 ¹ H-NMR (CDCl ₃ ) δ
(Ppm): 0.72 (3H, s), 0.90 (3H,
d, J = 6Hz), 0.95 (3H, d, J = 6H
z), 1.00 (3H, s), 2.89 (1H, d, J
= 4 Hz), 3.07 (1H, d, J = 4 Hz), 3.
39 (1H, dd, J = 10 and 4 Hz), 3.
45 (1H, dd, J = 10 and 4Hz), 4.
21 (1H, brs) LSIMS (+ KI) m / z: 457 (MK ⁺ ).

Hereinafter, another method for synthesizing the compound (10a) will be described. 10) Synthesis of compound (13a) 3.51 g of compound (8a) was dissolved in 40 ml of pyridine, 3.7 ml of acetic anhydride and 0.48 g of 4-dimethylaminopyridine were 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 (13a) ( Yield 94%).

Mp: 169-171 ° C. Anal. Calcd for C ₃₀ H ₄₈ O ₅ : C, 7
3.73; H, 9.90 Found: C, 73.8.
3; H, 9.96 IR (KBr) cm ^-1 : 2957, 2930, 173
^{1,1245 1 H-NMR (DMSO-} d 6) δ (ppm): 0.75
(3H, s), 0.79 (3H, s), 0.90 (6
H, d, J = 6 Hz), 1.15 (3H, s), 2.0
0 (3H, s), 2.44 (1H, dd, J = 9 an
d 3Hz), 3.82 (4H, s), 4.53 (1
H, dd, J = 11 and 5 Hz) LSIMS m / z: 489 (MH ⁺ ).

11) Compound (14a) and compound (15)
Synthesis of a) To 0.41 g of compound (13a), 16 ml of 0.01N hydrogen chloride-ethyl acetate solution was added, 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 (14a) and compound (15a). 0.40 g (yield 97%) of the mixture was obtained. A part of this mixture was separated by silica gel column chromatography [eluting with hexane: ethyl acetate = 5: 1 (v / v)], and a colorless powder (15a) was obtained from the fraction eluting first and eluted later. A colorless powder (14a) was obtained from the fraction.

Compound (14a) mp: 68 to 70 ° C. IR (KBr) cm ⁻¹ : 3502, 1714, 137
1,1268 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.82 (3
H, s), 0.89 (3H, d, J = 6Hz), 0.9
1 (3H, d, J = 6Hz), 0.93 (3H, s),
1.92 (3H, s), 2.33 (1H, dd, J = 1
0 and 8 Hz), 3.92 (4H, s), 3.9
8 to 4.08 (1H, m), 4.67 (1H, dd, J
= 10 and 5 Hz), 4.97 (1H, s),
5.02 (1H, s) LSIMS (+ KI) m / z: 527 (MK ⁺ ).

Compound (15a) mp: 143-149 ° C. IR (KBr) cm ⁻¹ : 3508,1737,136
8,1240 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.78 (3
H, s), 0.83 (3H, s), 0.91 (3H,
d, J = 6Hz), 0.93 (3H, d, J = 6H
z), 2.06 (3H, s), 2.22 (1H, t, J
= 10 Hz), 3.47 (1H, dd, J = 10 an
d 5Hz), 3.93 (4H, s), 5.17 (1
H, s), 5.27 (1H, s), 5.40 (1H,
t, J = 6 Hz) LSIMS (+ KI) m / z: 527 (MK ⁺ ).

12) Synthesis of compound (10a) Mixture of compound (14a) and compound (15a) 3.08
g was dissolved in 90 ml of methanol, 1.75 g of anhydrous potassium carbonate 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 (10a) ( 97%).

Example 2 (When R of the compound in Scheme 1 and Scheme 2 is isopentyl and X and Y are linked to each other to be ethylenedioxy) 1) Synthesis of compound (3b) and compound (4b) ), A colorless oily substance (3b) and a colorless oily substance (4b) were obtained from the compound (2).

Compound (3b) IR (neat) cm ⁻¹ : 3429, 2948, 115
_{^{2,1101,1050,1024,756 1 H-NMR (CDCl 3}} ) δ (ppm): 0.83 (3
H, s), 0.85 (3H, s), 0.87 (6H,
d, J = 7 Hz), 1.19 (3H, s), 3.36
(3H, s), 3.42 (3H, s), 4.68 (2
H, s), 4.71 (1H, d, J = 7 Hz), 4.8
4 (1H, d, J = 7Hz), 5.19 (1H, br
s) FABMS (+ KI) m / z: 547 (MK ^<+> ).

Compound (4b) IR (neat) cm ⁻¹ : 3430, 2932, 115
1,1102,1049,1025,756 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.82 (3
H, s), 0.83 (3H, s), 0.87 (6H,
d, J = 7 Hz), 1.05 (3H, s), 3.36
(3H, s), 3.42 (3H, s), 4.68 (2
H, s), 4.71 (1H, d, J = 7 Hz), 4.7
8 (1H, br s), 4.84 (1H, d, J = 7H
z) FABMS (+ KI) m / z: 547 (MK ⁺ ).

2) Synthesis of compound (5b) Compound (3b) was prepared according to the production method described in 3) of Example 1.
A colorless powder (5b) was obtained from the mixture of and (4b).

Mp: 162-164 ° C. Anal. Calcd for C ₂₇ H ₄₆ O ₂ : C, 8
0.54; H, 11.52 Found: C, 80.5
1; H, 11.44 IR (KBr) cm ^-1 : 3469, 2950, 292
6,2868,1470 ¹ H-NMR (CDCl ₃ ) δ
(Ppm): 0.74 (3H, s), 0.82 (3H,
s), 0.88 (6H, d, J = 6Hz), 1.68
(3H, s), 2.01 (1H, dt, J = 7Hz),
2.28 (1H, t, J = 9Hz), 3.48 to 3.6
8 (2H, m), 5.48 (1H, t, J = 7 Hz) LSIMS (+ KI) m / z: 441 (MK ⁺ ).

3) Synthesis of compound (6b) Compound (5b) was prepared according to the production method described in 4) of Example 1.
A colorless powder (6b) was obtained from IR (KBr) cm ^-1 : 3554, 3436, 295
0,1720,1384,1020 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.77 (3
H, s), 0.87 (6H, d, J = 7Hz), 1.0
2 (3H, s), 1.69 (3H, br s), 3.6
1 (1H, dd, J = 11 and 4Hz), 5.4
9 (1H, brd, J = 6 Hz) LSIMS (+ KI) m / z: 439 (MK ⁺ ).

4) Synthesis of compound (7b) Compound (6b) was prepared according to the production method described in 5) of Example 1.
A colorless powder (7b) was obtained from mp: 116-118 ° C IR (KBr) cm ^-1 : 3459,2952,293
4,1383,1099,1071,1014 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.72 (3
H, s), 0.83 (6H, d, J = 7Hz), 0.8
8 (3H, s), 1.68 (3H, br s), 2.2
7 (1H, br t, J = 9Hz), 3.58 (1H,
dd, J = 11 and 5 Hz, 3.92 (4H,
s), 5.49 (1H, br d, J = 6 Hz) LSIMS m / z: 445 (MH ⁺ ).

5) Synthesis of compound (8b) and compound (9b) According to the production method described in Example 1 6), compound (7b)
Colorless powder (8b) and colorless powder (9b) from about 5: 1
Obtained in the ratio of. Compound (8b) mp: 115-118 ° C IR (KBr) cm ^-1 : 3436,2947,287
1,1385, 1137, 1098, 1072, 102
_{^{2 1 H-NMR (CDCl 3}} ) δ (ppm): 0.69 (3
H, s), 0.80 (3H, s), 0.89 (6H,
d, J = 7 Hz), 1.29 (3H, s), 3.19-
3.32 (2H, m), 3.92 (4H, s) LSIMS m / z: 461 (MH ⁺ ).

Compound (9b) mp: 79 to 82 ° C. IR (KBr) cm ⁻¹ : 3436, 2952, 287
2,1386,1136,1102,1072,102
6 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.82 (3
H, s), 0.85 (3H, s), 0.91 (6H,
d, J = 7 Hz), 1.30 (3H, s), 2.71
(1H, t, J = 6Hz), 3.18 (1H, dd, J
= 11 and 4 Hz), 3.92 (4H, s) LSIMS m / z: 461 (MH ⁺ ).

6) Synthesis of compound (10b) Compound (8b) was prepared according to the production method described in Example 1 7).
A colorless powder (10b) was obtained from mp: 144-145 ° C IR (KBr) cm ^-1 : 3269, 2945, 287
0,1359,1112,1096,1073,102
4,901 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.74 (3
H, s), 0.81 (3H, s), 0.87 (6H,
d, J = 7 Hz), 2.34 (1H, br t, J = 1)
0 Hz), 3.42 to 3.54 (1 H, m), 3.92
(4H, s), 4.10 (1H, t, J = 6Hz),
4.93 (1H, s), 5.07 (1H, s) LSIMS (+ KI) m / z: 499 (MK ⁺ ).

7) Synthesis of compound (11b) Compound (10) was prepared according to the production method described in Example 1, 8).
Colorless needle crystals (11b) were obtained from b). mp: 148-150 ° C Anal. Calcd for C ₂₉ H ₄₈ O ₅ : C, 7
3.08; H, 10.14 Found: C, 72.8.
5; H, 10.28 IR (KBr) cm ⁻¹ : 3392, 2946, 286
9,1096,1073,1030 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.69 (3
H, s), 0.80 (3H, s), 0.88 (3H,
d, J = 6 Hz), 0.89 (3H, d, J = 6H
z), 2.15 (1H, br t, J = 8 Hz), 2.
85 (1H, d, J = 4Hz), 3.06 (1H, d,
J = 4 Hz), 3.27 to 3.35 (1H, m), 3.
37 (1H, dd, J = 11 and 4 Hz), 3.
92 (4H, s) LSIMS m / z: 477 (MH ^<+> ).

8) Synthesis of compound (12b) Compound (11) was prepared according to the production method described in Example 1 9).
A colorless powder (12b) was obtained from b). IR (KBr) cm ^-1 : 3401,2951,286
9,1703,1028 ¹ H-NMR (CDCl ₃ ) δ
(Ppm): 0.71 (3H, s), 0.88 (3H,
d, J = 7Hz), 0.90 (3H, d, J = 7H
z), 1.00 (3H, s), 2.86 (1H, d, J
= 4 Hz), 3.07 (1H, d, J = 4 Hz), 3.
30 (1H, dd, J = 10 and 4 Hz), 3.
41 (1H, dd, J = 10 and 4 Hz) EIMS m / z: 432 (M ⁺ , 0.89%), 27
2 (base) High resolution EIMS m / z: Calcd for C _{27
H 44 O 4: 432.3240 Found:} 432.3
235.

9) Separate Synthesis of Compound (10b) According to the production method described in 10), 11) and 12) of Example 1, compound (10b) was obtained from compound (8b).

Example 3 (When R is Methyl and X is Ethylenedioxy in Schemes 1 and 2) 1) Synthesis of Compound (3c) and Compound (4c) According to the production method described in Example 1-2). Then, a colorless oily substance (3c) and a colorless oily substance (4c) were obtained from the compound (2).

Compound (3c) IR (neat) cm ⁻¹ : 3429, 2932, 144
_{^{7,1383,1214,1152 1 H-NMR (CDCl 3}} ) δ (ppm): 0.82 (3
H, s), 0.87 (3H, s), 0.89 (3H,
t, J = 6 Hz), 1.19 (3H, s), 3.37
(3H, s), 3.41 (3H, s), 3.30-3.
60 (2H, m), 4.68 (2H, s), 4.70
(1H, d, J = 6Hz), 4.85 (1H, d, J =
6 Hz), 5.19 (1 H, br s) LSIMS (+ KI) m / z: 491 (MK ⁺ ).

Compound (4c) IR (neat) cm ^-1 : 3435, 2930, 146
_{^{5,1447,1384,1152 1 H-NMR (CDCl 3}} ) δ (ppm): 0.87 (3
H, s), 0.88 (3H, s), 0.89 (3H,
t, J = 6 Hz), 1.02 (3H, s), 3.36
(3H, s), 3.41 (3H, s), 3.30-3.
60 (2H, m), 4.68 (2H, s), 4.70
(1H, d, J = 6Hz), 4.83 (1H, d, J =
6 Hz) LSIMS (+ KI) m / z: 491 (MK ⁺ ).

2) Synthesis of compound (5c) Compound (3c) was prepared according to the production method described in 3) of Example 1.
A colorless powder (5c) was obtained from the mixture of and (4c).

Mp: 150 to 151 ° C. IR (KBr) cm ⁻¹ : 3306, 2927, 285
_{^{6,1449,1382,1043 1 H-NMR (CDCl 3}} ) δ (ppm): 0.73 (3
H, s), 0.82 (3H, s), 1.57 (3H,
s), 2.20 to 2.40 (1H, m), 3.48 to
3.70 (2H, m), 5.57 (1H, q, J = 6H
z) EIMS m / z: 346 (M ⁺ , 18.0%), 32
8 (base).

3) Synthesis of compound (6c) Compound (5c) was prepared according to the production method described in 4) of Example 1.
A colorless powder (6c) was obtained from. mp: 155-161 ° C IR (KBr) cm ^-1 : 3540,3436,294
1,216,2860,1716 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.75 (3
H, s), 1.01 (3H, s), 1.59 (3H,
s), 1.60 (3H, d, J = 6Hz), 3.60
(1H, dd, J = 12 and 5 Hz) 5.57
(1H, q, J = 6Hz) LSIMS m / z: 345 (MH ⁺ ).

4) Synthesis of compound (7c) Compound (6c) was prepared according to the production method described in 5) of Example 1.
A colorless powder (7c) was obtained from mp: 173-177 ° C IR (KBr) cm ^-1 : 3477,2946,138
3,1096,1072 ¹ H-NMR (CDCl ₃ ) δ
(Ppm): 0.73 (3H, s), 0.82 (3H,
s), 1.60 (3H, t, J = 6Hz), 1.64
(3H, s), 2.20 to 2.40 (1H, m), 3.
57 (1H, dd, J = 8 and 3 Hz), 3.9
3 (4H, s), 5.58 (1H, q, J = 5Hz) LSIMS m / z: 381 (MH ⁺ ).

5) Synthesis of compound (8c) and compound (9c) Compound (7c) was prepared according to the production method described in 6) of Example 1.
Colorless powder (8c) and colorless powder (9c) from about 5: 1
Obtained in the ratio of. Compound (8c) mp: 152-157 degreeC IR (KBr) cm < ^-1 >: 3468,2941,145.
5,1386,1103,1069 LSIMS m / z: 405 (MH ^<+> ).

Compound (9c) mp: 154-156 ° C. IR (KBr) cm ⁻¹ : 3468, 2944, 144
5,1072 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.81 (3
H, s), 0.84 (3H, s), 1.28 (3H,
d, J = 5 Hz), 1.30 (3H, s), 2.88
(1H, q, J = 5Hz), 3.17 (1H, dd, J
= 8 and 5 Hz), 3.92 (4H, s) LSIMS m / z: 405 (MH ⁺ ).

6) Synthesis of compound (10c) Compound (8c) was prepared according to the production method described in 7) of Example 1.
A colorless powder (10c) was obtained from. mp: 208-211 ° C IR (KBr) cm ^-1 : 3272,2927,135
9,1097,1071 ¹ H-NMR (CDCl ₃ ) δ
(Ppm): 0.75 (3H, s), 0.84 (3H,
s), 1.28 (3H, d, J = 5Hz), 2.42
(1H, t, J = 8Hz), 3.54 (1H, dd, J
= 8 and 4 Hz), 3.95 (4H, s), 4.
47 (1H, q, J = 5Hz), 4.90 (1H,
s), 5.14 (1H, s) FABMS m / z: 405 (MH ^<+> ).

7) Synthesis of compound (11c) Compound (10) was prepared according to the production method described in Example 1, 8).
A colorless powder (11c) was obtained from c). mp: 188-196 ° C IR (KBr) cm ^-1 : 3436,2942,137
_{^{4,1103,1071,1028 1 H-NMR (CDCl 3}} ) δ (ppm): 0.70 (3
H, s), 0.81 (3H, s), 1.28 (3H,
d, J = 5Hz), 2.10 (1H, t, J = 8H
z), 2.95 (1H, d, J = 3Hz), 3.08
(1H, d, J = 3Hz), 3.35 (1H, dd, J
= 8 and 4 Hz), 3.64 (1H, q, J = 5)
Hz), 3.94 (4H, s) FABMS m / z: 421 (MH ^<+> ).

8) Synthesis of compound (12c) Compound (11) was prepared according to the production method described in Example 1 9).
A colorless powder (12c) was obtained from c). mp: 155-160 ° C IR (KBr) cm ^-1 : 2949,1698,107
6,1028 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.73 (3
H, s), 1.00 (3H, s), 1.26 (3H,
d, J = 5 Hz), 2.96 (1H, d, J = 3H)
z), 3.09 (1H, d, J = 3Hz), 3.38.
(1H, dd, J = 8 and 4Hz), 3.64 (1
H, q, J = 5 Hz) LSIMS m / z: 377 (MH ⁺ ).

The separate synthesis of compound (10c) is described below. 9) Synthesis of compound (13c) Compound (8) was prepared according to the production method described in 10) of Example 1.
A colorless powder (13c) was obtained from c). mp: 177-182 ° C IR (KBr) cm ^-1 : 2952,1730,137
6,1249,1094,1021 ¹ H-NMR (acetone-d ₆ ) δ (ppm): 0.84
(3H, s), 0.90 (3H, s), 1.18 (3
H, d, J = 4 Hz), 1.21 (3H, s), 2.0
4 (3H, s), 2.59 (1H, q, J = 4Hz),
3.88 (4H, s), 4.57 (1H, dd, J = 8)
and 4 Hz) LSIMS m / z: 447 (MH ⁺ ).

10) Compound (14c) and compound (15)
Synthesis of c) Based on the production method described in 11) of Example 1, the compound (13
A colorless powder (14c) and a colorless powder (15c) were obtained from c). Compound (14c) mp: 163 to 167 ° C. IR (KBr) cm ⁻¹ : 1717, 1373, 126
0,1101 ¹ H-NMR (acetone-d ₆ ) δ (ppm): 0.86
(3H, s), 1.22 (3H, d, J = 4Hz),
1.86 (3H, s), 2.46 (1H, t, J = 8H
z), 3.87 (4H, s), 3.98 (1H, q, J
= 4 Hz), 4.55 (1H, dd, J = 8 and
4Hz), 4.90 (1H, s), 5.11 (1H,
s) FABMS m / z: 447 (MH ^<+> ).

Compound (15c) mp: 116-118 ° C. IR (KBr) cm ⁻¹ : 3460, 2933, 173
0,1372,1243,1073 ¹ H-NMR (acetone-d ₆ ) δ (ppm): 0.68
(3H, s), 0.84 (3H, s), 1.28 (3
H, d, J = 5 Hz), 1.96 (3H, s), 2.2
5 (1H, t, J = 8Hz), 3.35 to 3.48 (1
H, m), 3.88 (4H, s), 5.08 (1H,
s), 5.25 (1H, s), 5.60 (1H, q, J
= 5 Hz) FABMS m / z: 447 (MH ⁺ ).

11) Synthesis of Compound (10c) Compound (14) was prepared according to the production method described in 12) of Example 1.
colorless powder (10) from the mixture of c) and compound (15c).
c) was obtained.

Example 4 (when R in Scheme 1 and Scheme 2 is tridecyl and X and Y are linked to ethylenedioxy) 1) Synthesis of Compound (3d) and Compound (4d) In Example 1, 2) A colorless oil (3d) and a colorless oil (4d) were obtained from the compound (2) according to the production method described.

Compound (3d) IR (neat) cm ⁻¹ : 3430, 2921, 285
1,1464,1152,1050 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.81 (3
H, s), 0.85 (3H, s), 0.88 (3H,
t, J = 5 Hz), 1.20 (3H, s), 3.30-
3.60 (2H, m), 3.37 (3H, s), 3.4
0 (3H, s), 4.67 (2H, s), 4.71 (1
H, d, J = 5Hz), 4.85 (1H, d, J = 5H)
z) FABMS (+ KI) m / z: 659 (MK ⁺ ).

Compound (4d) IR (neat) cm ^-1 : 2926,1151,110
_{^{2,1050,1025 1 H-NMR (CDCl 3}} ) δ (ppm): 0.83 (3
H, s), 0.84 (3H, s), 0.88 (3H,
t, J = 5 Hz), 1.04 (3H, s), 3.30-
3.60 (2H, m), 3.37 (2H, s), 3.4
2 (2H, s), 4.68 (2H, s), 4.71 (1
H, d, J = 5Hz), 4.84 (1H, d, J = 5H)
z) LSIMS (+ KI) m / z: 659 (MK ⁺ ).

2) Synthesis of compound (5d) Compound (3d) was prepared according to the production method described in 3) of Example 1.
A colorless powder (5d) was obtained from the mixture of and (4d).

Mp: 82 to 84 ° C. IR (KBr) cm ⁻¹ : 3441, 2917, 285
0.1469 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.74 (3
H, s), 0.82 (3H, s), 0.87 (3H,
t, J = 5 Hz), 1.68 (3H, s), 2.28
(1H, t, J = 8Hz), 3.50 to 3.70 (2
H, m), 5.50 (1 H, t, J = 5 Hz) LSIMS (+ KI) m / z: 553 (MK ⁺ ).

3) Synthesis of compound (6d) Compound (5d) was prepared according to the production method described in 4) of Example 1.
A colorless powder (6d) was obtained from mp: 88-91 ° C IR (KBr) cm ^-1 : 2922,1720,1469 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.76 (3
H, s), 0.88 (3H, t, J = 5Hz), 1.0
2 (3H, s), 1.68 (3H, s), 3.61 (1
H, dd, J = 8 and 4 Hz), 5.50 (1
H, t, J = 5 Hz) LSIMS m / z: 513 (MH ⁺ ).

4) Synthesis of Compound (7d) Compound (6d) was prepared according to the production method described in 5) of Example 1.
A colorless powder (7d) was obtained from mp: 89 to 91 ° C. IR (KBr) cm ⁻¹ : 3459, 2918, 1472 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.74 (3
H, s), 0.82 (3H, s), 0.88 (3H,
t, J = 5 Hz), 1.67 (3H, s), 2.28
(1H, t, J = 8Hz), 3.58 (1H, dd, J
= 8 and 4 Hz), 3.93 (4H, s), 5.
50 (1 H, t, J = 5 Hz) LSIMS m / z: 557 (MH ⁺ ).

5) Synthesis of compound (8d) and compound (9d) According to the production method described in Example 1 6), compound (7d)
Colorless powder (8d) and colorless powder (9d) from about 8: 1
Obtained in the ratio of. Compound (8d) IR (KBr) cm ^-1 : 3435,2922,285
2,1469,1072 ¹ H-NMR (CDCl ₃ ) δ
(Ppm): 0.70 (3H, s), 0.80 (3H,
s), 0.88 (3H, t, J = 5Hz), 3.18-
3.34 (2H, m), 3.93 (4H, s), 4.4
2 (1H, s) FABMS m / z: 573 (MH ^<+> ).

Compound (9d) mp: 88 to 91 ° C. IR (KBr) cm ⁻¹ : 3486, 2921, 1471 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.82 (3
H, s), 0.84 (3H, s), 0.89 (3H,
t, J = 5 Hz), 2.71 (1H, t, J = 6H
z), 3.18 (1H, dd, J = 8 and 4H
z), 3.92 (4H, s) FABMS m / z: 573 (MH ^<+> ).

6) Synthesis of compound (10d) Compound (8d) was prepared according to the production method described in Example 1 7).
A colorless powder (10d) was obtained from mp: 130-131 ° C IR (KBr) cm ^-1 : 3294, 2926,135
_{^{8,1073 1 H-NMR (CDCl 3}} ) δ (ppm): 0.74 (3
H, s), 0.83 (3H, s), 0.88 (3H,
t, J = 5 Hz), 2.32 (1H, t, J = 8H
z), 3.48 (1H, dd, J = 8 and 4H
z), 3.93 (4H, s), 4.13 (1H, t, J
= 5 Hz), 4.93 (1H, s), 5.08 (1H,
s) LSIMS m / z: 573 (MH ^<+> ).

7) Synthesis of compound (11d) Compound (10d) was prepared according to the production method described in Example 1-8).
A colorless powder (11d) was obtained from d). mp: 80-82 ° C IR (KBr) cm ^-1 : 3401,9222,147
1,1072 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.70 (3
H, s), 0.81 (3H, s), 0.88 (3H,
t, J = 5 Hz), 2.87 (1H, d, J = 3H
z), 3.06 (1H, d, J = 3Hz), 3.30-
3.42 (2H, m), 3.93 (4H, s) FABMS m / z: 589 (MH ⁺ ).

8) Synthesis of compound (12d) Compound (11) was prepared according to the production method described in Example 1 9).
A colorless powder (12d) was obtained from d). mp: 125-129 ° C IR (KBr) cm ^-1 : 3411,924,170
9,1262,1029 ¹ H-NMR (CDCl ₃ ) δ
(Ppm): 0.82 (3H, s), 0.88 (3H,
t, J = 5 Hz), 1.00 (3H, s), 2.89
(1H, d, J = 3Hz), 3.07 (1H, d, J =
3Hz), 3.31 to 3.45 (2H, m) LSIMS
(+ KI) m / z: 583 (MK ⁺ ).

The separate synthesis of compound (10d) is described below.

9) Synthesis of compound (13d) Compound (8) was prepared according to the production method described in 10) of Example 1.
A colorless powder (13d) was obtained from d). mp: 104 to 107 ° C. IR (KBr) cm ⁻¹ : 2922, 1728, 1255 ¹ H-NMR (acetone-d ₆ ) δ (ppm): 0.83
(3H, s), 0.88 (3H, t, J = 5Hz),
0.89 (3H, s), 1.21 (3H, s), 2.0
3 (3H, s), 3.85 (4H, s), 4.60 (1
H, dd, J = 8 and 4 Hz) FABMS m / z: 615 (MH ⁺ ).

10) Compound (14d) and compound (15)
Synthesis of d) Based on the production method described in 11) of Example 1, the compound (13
Compound (14d) and compound (15) which are colorless powders from d)
A mixture of d) was obtained. Compound (14d) ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.78 (3
H, s), 0.81 (3H, s), 0.88 (3H,
t, J = 5 Hz), 1.91 (3H, s), 3.82 ~
3.95 (1H, m), 3.95 (4H, s), 4.6
8 (1H, dd, J = 8 and 4Hz), 4.98
(1H, s), 5.02 (1H, s).

Compound (15d) ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.82 (3
H, s), 0.88 (3H, t, J = 5Hz), 0.9
1 (3H, s), 2.06 (3H, s), 3.48 (1
H, dd, J = 8 and 4 Hz), 3.94 (4
H, s), 5.19 (1H, s), 5.24 (1H,
s), 5.27 (1H, t, J = 6Hz).

11) Synthesis of Compound (10d) Compound (14) was prepared according to the production method described in 12) of Example 1.
a colorless powder (10) from the mixture of d) and the compound (15d).
d) was obtained. Example 5 (When R of the compound in Scheme 3 is isobutyl) 1) Synthesis of compound (16a) and compound (17a) 0.2 g of compound (5a) was dissolved in 6.5 ml of methylene chloride under a nitrogen atmosphere, and then oxidized. 0.001 g of vanadium acetylacetonate was added and cooled in an ice water bath. To this solution, 0.25 ml of tert-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 colorless powder of compound (16a) and compound (1).
0.19 g of the mixture of 7a) was obtained [containing about 10% by-product (17a) from the ¹ H-NMR spectrum]. In addition,
By recrystallizing this mixture with ethyl acetate-hexane, 0.15 g (yield 72%) of a single product of compound (16a) was obtained.
%)Obtained.

Compound (16a) mp: 204-207 ° C. Anal. _{Calcd for C 26 H 44 O 3} : C, 7
7.18; H, 10.96 Found: C, 77.1.
4; H, 11.11 IR (KBr) cm ^-1 : 3386, 3284, 294
8,2871,1045 ¹ H-NMR (CDCl ₃ ) δ
(Ppm): 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 to 3.6
7 (1H, m), 4.50 (1H, s) LSIMS (+ KI) m / z: 443 (MK ⁺ ).

Compound (17a) ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.82 (3
H, s), 0.84 (3H, s), 0.93 (3H,
d, J = 5Hz), 0.97 (3H, d, J = 5H
z), 2.75 (1H, t, J = 6Hz), 3.17.
(1H, dd, J = 12 and 5Hz), 3.49-
3.67 (1H, m), 4.42 (1H, s).

2) Synthesis of compound (18a) Compound (16) was prepared according to the production method described in 7) of Example 1.
A colorless powder (18a) was obtained from a). mp: 224-226 ° C. Anal. _{Calcd for C 26 H 44 O 3} : C, 7
7.18; H, 10.96 Found: C, 77.2.
8; H, 11.16 IR (KBr) cm ^-1 : 3368, 2953, 293
1,2868,1468 ¹ H-NMR (CDCl ₃ ) δ
(Ppm): 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 =
10 Hz), 3.07 (1 H, br s), 3.48
(1H, dd, J = 11Hz and 5Hz), 3.
50-3.70 (1H, m), 3.68 (1H, br
s), 4.27 (1H, t, J = 7Hz), 4.95.
(1H, s), 5.11 (1H, s) FABMS (+ KI) m / z: 443 (MK ⁺ ).

3) Synthesis of compound (19a) Compound (18) was prepared according to the production method described in 8) of Example 1.
A colorless powder (19a) was obtained from a). mp: 169-171 ° C. Anal. Calcd for C ₂₆ H ₄₄ O ₄ : C, 7
4.24; H, 10.54 Found: C, 74.1.
9; H, 10.76 IR (KBr) cm ^-1 : 3478,3288,293
4,2858,1030 ¹ H-NMR (CDCl ₃ ) δ
(Ppm): 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 =
8Hz), 2.87 (1H, d, J = 4Hz), 3.0
6 (1H, d, J = 4Hz), 3.36 (1H, dd,
J = 12 and 5 Hz), 3.42 (1H, dd,
J = 10 and 4 Hz), 3.49 to 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 Foun
d: 459.2870.

The separate synthesis of compound (18a) is described below. 4) Synthesis of Compound (20a) Compound (16) was prepared according to the production method described in 10) of Example 1.
A colorless amorphous substance (20a) was obtained from a). Anal. Calcd for C ₃₀ H ₄₈ O ₅ : C, 7
3.73; H, 9.90 Found: C, 73.7.
3; H, 9.98 IR (KBr) cm ^-1 : 2955, 1737, 146
8,1370,1245,1024 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.83 (3
H, s), 0.86 (3H, s), 0.95 (3H,
d, J = 7 Hz), 0.96 (3H, d, J = 7H
z), 1.24 (3H, s), 2.01 (3H, s),
2.04 (3H, s), 2.61 (1H, dd, J = 9)
and 2 Hz), 4.56 to 4.77 (2H, m) LSIMS m / z: 489 (MH ⁺ ).

5) Compound (21a) and compound (22)
Synthesis of a) Based on the production method described in 11) of Example 1, the compound (20
a) to colorless amorphous (21a) and colorless powder (22a)
Got Compound (21a) Anal. Calcd for C ₃₀ H ₄₈ O ₅ : C, 7
3.73; H, 9.90 Found: C, 73.7.
2; H, 10.06 IR (KBr) cm ^-1 : 3510, 2956, 173
_{^{8,1718,1248,1028 1 H-NMR (CDCl 3}} ) δ (ppm): 0.83 (3
H, s), 0.90 (3H, d, J = 6Hz), 0.9
2 (3H, d, J = 6Hz), 0.93 (3H, s),
1.93 (3H, s), 2.01 (3H, s), 2.3
2 (1H, t, J = 10 Hz), 3.97 to 4.08
(1H, m), 4.58 to 4.76 (2H, m), 4.
97 (1H, s), 5.03 (1H, s) LSIMS (+ KI) m / z: 527 (MK ⁺ ).

Compound (22a) mp: 128 to 130 ° C. Anal. Calcd for C ₃₀ H ₄₈ O ₅ : C, 7
3.73; H, 9.90 Found: C, 73.8.
6; H, 10.02 IR (KBr) cm ^-1 : 3470, 2954, 173
4,1714,1264,1024 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.80 (3
H, s), 0.85 (3H, s), 0.93 (3H,
d, J = 6Hz), 0.95 (3H, d, J = 6H
z), 2.04 (3H, s), 2.08 (3H, s),
2.23 (1H, t, J = 10Hz), 3.50 (1
H, dd, J = 11 and 6 Hz), 4.57-
4.78 (1H, m), 5.18 (1H, s), 5.2
8 (1H, s), 5.42 (1H, t, J = 6Hz) LSIMS (+ KI) m / z: 527 (MK ⁺ ).

6) Synthesis of compound (18a) Compound (21a) was prepared according to the production method described in 12) of Example 1.
colorless powder (18) from the mixture of a) and compound (22a).
a) was obtained.

Example 6 (Synthesis of a compound represented by the formula (I) of the present invention in which a group which is easily hydrolyzed to form a hydroxyl group is an N, N-dimethylglycyloxy group) Compound (23a ) (R is isobutyl, A is a hydroxyl group, X is N, N-dimethylglycyloxy and Y is a hydrogen atom), compound (24a) (R is isobutyl, A is N, N-dimethylglycyloxy, and X is a hydroxyl group). And Y is a hydrogen atom) and compound (25a) (R is isobutyl, A and X are both N, N-dimethylglycyloxy and Y is a hydrogen atom). 0.04 g of compound (19a) is added to 1.5 ml of methylene chloride.
Dissolved in N, N-dimethylglycine 0.012 g, 4
-Dimethylaminopyridine 0.006 g and 1- (3-
Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.027 g) was added, and the mixture was stirred at room temperature for 30 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 and the obtained residue was subjected to silica gel flash column chromatography [ethyl acetate: methanol = 30:
1 (v / v) elution], and a colorless powder (1
9a) 0.008 g (20% recovery), colorless caramel-like substance (23a) 0.011 g (yield 23%), colorless caramel-like substance (24a) 0.006 g (yield 13%).
And 0.016 g (yield 29%) of a colorless caramel-like substance (25a) were obtained.

Compound (23a) IR (KBr) cm ^-1 : 3396,2952,287
_{^{0,1744,1468,1204 1 H-NMR (CDCl 3}} ) δ (ppm): 0.70 (3
H, s), 0.83 (3H, s), 0.91 (3H,
d, J = 6Hz), 0.96 (3H, d, J = 6H
z), 2.35 (6H, s), 2.96 (1H, d, J
= 5 Hz), 3.07 (1H, d, J = 5 Hz), 3.
13 (2H, s), 3.32 to 3.49 (2H, m),
4.19 (1H, br s), 4.69 to 4.88 (1
H, m) FABMS (+ KI) m / z: 544 (MK ⁺ ).

Compound (24a) IR (KBr) cm ^-1 : 3442,2928,287
2,1748,1468,1198,1166,103
0 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.67 (3
H, s), 0.80 (3H, s), 0.91 (3H,
d, J = 5Hz), 0.94 (3H, d, J = 5H
z), 2.36 (6H, s), 2.72 (1H, d, J
= 5 Hz), 3.08 (1H, d, J = 5 Hz), 3.
20 (2H, s), 3.33 (1H, dd, J = 11)
and 5 Hz), 3.50 to 3.68 (1 H, m),
4.17 (1H, br s), 4.98 (1H, dd,
J = 10 and 4 Hz) FABMS (+ KI) m / z: 544 (MK ⁺ ).

Compound (25a) IR (KBr) cm ^-1 : 3438,2952,287
2,1746,1468,1198,1150 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.67 (3
H, s), 0.82 (3H, s), 0.91 (3H,
d, J = 5Hz), 0.94 (3H, d, J = 5H
z), 2.34 (6H, s), 2.36 (6H, s),
2.72 (1H, d, J = 4Hz), 3.08 (1H,
d, J = 4 Hz), 3.14 (2H, s), 3.20
(2H, s), 3.33 (1H, dd, J = 11 an
d 5 Hz), 4.17 (1H, br s), 4.69
~ 4.88 (1H, m), 4.97 (1H, dd, J =
10 and 4 Hz) FABMS (+ KI) m / z: 629 (MK ⁺ ).

Example 7 (Synthesis of a compound of the formula (I) of the present invention in which a group which is easily hydrolyzed to form a hydroxyl group is a succinyloxy group) Compound (26a) (R is isobutyl, A and X are both succinyloxy and Y is a hydrogen atom) A compound (19a) 0.062g is melt | dissolved in pyridine 1.0 ml, succinic anhydride 0.074g and 4-dimethylamino pyridine 0.038g are added, and it is room temperature. It was stirred for 16 hours. Ethyl acetate was added to the reaction solution, which was washed successively with 5% hydrochloric acid and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by silica gel column chromatography [chloroform: methanol: acetic acid = 25: 1: eluting with a catalytic amount (v / v)].
0.062 g (yield 68%) of colorless amorphous (26a) was obtained.

IR (KBr) cm ^-1 : 2956,173
6,1715,1166 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.67 (3
H, s), 0.83 (3H, s), 0.89 (3H,
d, J = 6Hz), 0.94 (3H, d, J = 6H
z), 2.50 to 2.75 (8H, m), 2.78 (1
H, d, J = 4Hz), 3.09 (1H, d, J = 4H)
z), 3.38 (1H, dd, J = 11 and 5H
z), 4.63 to 4.83 (1H, m), 4.91 (1
H, dd, J = 10 and 3 Hz) FABMS (+ KI) m / z: 659 (MK ⁺ ). 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 cell suspension (MEM containing 10% fetal bovine serum)
(Suspended in the medium) was added and cultured for 24 hours. To this, 100 μl of a test compound solution dissolved in dimethyl sulfoxide and diluted with a medium (final concentration of dimethyl sulfoxide was 0.5
%) Was added and the cells were further cultured for 72 hours. After culturing 4,
5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide reagent (coloring reagent) was added, and the mixture was further cultured for 4 hours.

As a control, 100 μl of a medium (final concentration of dimethyl sulfoxide 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 that 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 (12a) and compound A] against KB cells.

[0119]

[Table 1]

Front page continued (72) Inventor Tatsuhiko Sano 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. Company (72) Inventor Taiji Yamada 2-18-12 Nanyodai, Hachioji, Tokyo

Claims (2)

[Claims] 1. The formula: (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 form a hydroxyl group. X and Y together form an oxo group or 2 carbon atoms
Alternatively, 3 represents an alkylenedioxy group, X represents a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms, or a group which is easily hydrolyzed to form a hydroxyl group, and Y represents a hydrogen atom or 1 to 5 carbon atoms. Indicates an alkoxy group. However, when X is a hydroxyl group or a group which is easily hydrolyzed to a hydroxyl group, Y is a hydrogen atom, and when X is an alkoxy group having 1 to 5 carbon atoms, Y is an alkoxy group having 1 to 5 carbon atoms. is there. ) A steroid derivative represented by or a salt thereof. 2. The steroid derivative or a salt thereof according to claim 1, wherein the alkyl group is an isobutyl group, an isopentyl group, an isohexyl group, an isoheptyl group or an isooctyl group.