JPH10310598A - Sterol compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound comprising a specific sterol compound capable of efficiently and stereoselectively synthesizing by organic synthetic chemical method, having excellent in vivo antitumor action and useful as a medicine such as anticancer agent. SOLUTION: This new sterol compound is represented by formula I (R is nonyl or decyl) and has excellent in vivo antiulcer action and is capable of stereoselectively synthesizing by organic synthetic chemical method and is useful as a medicine, etc., e.g. anticancer agent. The compound is obtained by using 3β,12β-dihydroxy-5 α-pregnan20 one as a starting material, protecting the hydroxyl group, reacting the compound with a Grignard feagent to afford a substance having alcohol at 20 position, dehydrating the substance to provide 20,22(E)-olefin substance of formula of formula III, oxidizing the substance to afford 20,22-epoxy substance, protecting hydroxyl group, subjecting the epoxy substance to hydrochloric acid treatment, oxidizing the resultant 3β,12β-diacetoxyallyl alcohol substance of formula IV to provide 20, 21-epoxy substance and deprotecting the resultant substance.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a sterol compound having an antitumor effect and useful as a medicine.

[0002]

BACKGROUND OF THE INVENTION As a compound having a structure similar to that of the present compound, Xestospong described in JP-A-5-4998 is disclosed.
A compound isolated from genus ia sponge (hereinafter, referred to as compound A) is known. Compound A has excellent antitumor activity and is expected as a novel anticancer agent. However, since compound A is derived from marine natural products, there is a problem in securing resources, and it has been difficult to provide a stable supply in large quantities. In addition, since five asymmetric carbons are present in the side chain at the 17-position of compound A, efficient stereoselective synthesis thereof was extremely difficult.

In order to solve this problem, the present inventors have invented a compound group in which the side chain at the 17-position of compound A is simplified and can be supplied by an organic synthetic chemical method (Japanese Patent Laid-Open No. 7-224087). No.).

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a sterol compound which can be synthesized by an organic synthetic chemical method and has a better antitumor effect.

[0005]

Means for Solving the Problems The present inventors disclosed in Japanese Patent Laid-Open No.
The antitumor effects of the compounds described in JP-A-224087 were compared and studied in more detail. As a result, JP-A-7-2
Compounds which are included in the claims of Japanese Patent No. 24087 but which are not specifically described are known compounds A and
A compound exhibiting an excellent antitumor effect, which is significantly greater than the compounds specifically described in JP-A-224087,
The present invention has been completed.

Hereinafter, the present invention will be described.

The present invention provides a compound of the formula [I]

[0008]

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(Wherein R represents a nonyl group or a decyl group).

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention is described in the literature (Che).
m. Ber., Vol. 100, p. 464, 1967).
Using α-pregnan-20-one (1) as a starting material, it can be synthesized according to the production methods shown in the following schemes 1 and 2. The synthesis method of the compound of the present invention will be outlined below.

[0011]

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[0012]

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The compound (1) is reacted with chloromethyl methyl ether in the presence of a base such as N, N-diisopropylethylamine to obtain a derivative (2) in which the hydroxyl groups at the 3- and 12-positions are protected. The compound (2) is reacted with a Grignard reagent prepared from 1-bromodecane or 1-bromoundecane to obtain the 20-position alcohol (3): a low-polar isomer and (4): a high-polar isomer. Subsequently, the mixture of compound (3) and compound (4) is reacted with an acid such as concentrated hydrochloric acid, concentrated sulfuric acid or paratoluenesulfonic acid in a lower alcohol such as isopropanol to give 20,22- (E)-.
The olefin (5) is obtained as the main product. Compound (5) is reacted with tert-butyl hydroperoxide or cumene hydroperoxide in the presence of a catalytic amount of vanadium oxide acetylacetonate and in the presence or absence of a base such as sodium bicarbonate to give 20,22.
-Β-epoxy compound (6): highly polar isomer and 20,22
-Α-epoxy compound (7): about 10: 1 to less polar isomer
Obtained at a production ratio of 5: 1. The mixture of compound (6) and compound (7) is reacted with acetic anhydride in a solvent such as pyridine in the presence of a base such as 4-dimethylaminopyridine to give 3β,
The 12β-diacetoxy compounds (8) and (9) are obtained. Both compounds were separated by column chromatography, and the resulting β-epoxy compound (8) contained an acid such as hydrogen chloride.
Reaction in an organic solvent such as ethyl acetate
β-diacetoxyallyl alcohols (10) and 3
A mixture of β, 22α-diacetoxy compound (11) is obtained.
Both compounds were separated by column chromatography, and the resulting compound (10) was reacted in an organic solvent containing an acid such as hydrogen chloride, such as ethyl acetate, to give the compound (1).
0) and a mixture of compound (11). Both compounds are separated by column chromatography, and the same operation as described above is repeated on the obtained compound (10) to obtain a compound (11). Compound (11) is reacted with tert-butyl hydroperoxide or cumene hydroperoxide in the presence of a catalytic amount of vanadium oxide acetylacetonate to obtain a 20,21-epoxy compound (12). Compound (12) is reacted with a base such as potassium carbonate in a lower alcohol such as methanol to give compound (1) of the present invention.
Obtain 3).

The compound (13) of the present invention can also be synthesized by the following method. That is, a mixture of the compound (10) and the compound (11) is reacted with a base such as potassium carbonate in a lower alcohol such as methanol to obtain a triol compound (14). Subsequently, compound (1)
Epoxidation of 4) with metachloroperbenzoic acid in the presence or absence of a base such as sodium bicarbonate gives compound (13) of the present invention.

When the sterol compound of the present invention is used as a pharmaceutical, it is mixed with a carrier usually used in a pharmaceutical composition (eg, talc, gum arabic, lactose, magnesium stearate, corn starch) and is orally or parenterally administered. Formulation for administration. Examples of the dosage form include tablets, granules, powders, capsules, syrups, suspensions and injections, which can be appropriately selected depending on the condition, age and purpose of treatment of the patient. The dose is 1 to 500 mg when treating an adult,
This is administered once or twice or three times a day. This dosage can be appropriately increased or decreased depending on the age, weight and condition of the patient.

[0016]

Industrial Applicability According to the present invention, a sterol compound having an excellent antitumor effect, which is far superior to the known compound A and the compounds specifically described in JP-A-7-224087, can be synthesized by an organic synthetic chemical method. sponsored. The sterol compound of the present invention has a remarkably excellent in vivo antitumor effect among the compound group encompassed in the claims of JP-A-7-224087, and is easily prepared by an organic synthetic chemical method. Since it can be supplied, it is useful as a drug having an antitumor effect.

[0017]

The present invention will be described in more detail with reference to the following examples. The compound numbers described in the examples correspond to the compound numbers shown in Scheme 1 and Scheme 2. In addition, a attached to the compound number described in the examples indicates a case where R of the compound shown in Scheme 1 and Scheme 2 is a nonyl group (n-C ₉ H ₁₉ ), and b is shown in Scheme 1 and Scheme 2. R of the compound obtained is a decyl group (nC ₁₀ H
₂₁ ).

Example 1 (when R in the compounds shown in Schemes 1 and 2 is a nonyl group) 1) Synthesis of compound (2) 7.0 g of compound (1) was dissolved in 70 ml of dichloromethane, and chloromethyl methyl ether was dissolved. 5.05 g and N, N-
8.10 g of diisopropylethylamine was added, and the mixture was refluxed for 7 hours. After cooling, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent is purified by silica gel column chromatography [hexane: ethyl acetate = 2: 1 (v / v)].
And the compound fraction was obtained. This was recrystallized from hexane to obtain 6.7 g 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) νcm ^-1 : 1701,1150,1042 ¹ H-NMR (200 MHz, CDCl ₃ ) δ ppm: 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), 3.34-3.43 (1H, m), 3.43-3.58 (1H,
m), 4.63-4.74 (4H, m) FABMS (+ KI) m / z: 461 (MK ⁺ ).

2) Synthesis of compound (3a) and compound (4a) To 603 mg of magnesium were added 20 ml of diethyl ether and a catalytic amount of iodine, and under nitrogen atmosphere, a solution of 4.71 g of 1-bromodecane in 40 ml of diethyl ether was added dropwise at room temperature. And stirred for 1 hour. After cooling the Grignard reagent solution to 0 ° C., a solution of 3.00 g of compound (2) in 15 ml of benzene was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour.
The reaction solution was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. This is eluted with silica gel column chromatography [hexane: ethyl acetate = 3: 1 (V / V)].
Then, 4.05 g of a mixture of the compound (3a) and the compound (4a) was obtained. This mixture was used for the next reaction without separation. A part of this mixture was separated by the same silica gel column chromatography as above, and a colorless viscous substance (3a) was obtained from the fraction eluted earlier, and a colorless viscous substance (4a) was obtained from the fraction eluted later. .

Compound (3a) IR (neat) νcm ^-1 : 3431,2927,1467,1152,110
1,1050,1024 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
83 (3H, s), 0.86 (3H, s), 0.88 (3H, t, J = 6.5Hz), 1.19 (3H, s),
1.97-2.07 (1H, m), 3.32-3.40 (1H, m), 3.37 (3H, s), 3.41 (3
H, s), 3.42-3.56 (1H, m), 4.68 (2H, s), 4.70 (1H, d, J = 6.9H
z), 4.84 (1H, d, J = 6.9 Hz), 5.18 (1H, s) FABMS (+ KI) m / z: 603 (MK ⁺ ).

Compound (4a) IR (neat) νcm ^-1 : 3434,2927,1467,1151,110
2,1050,1024 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
83 (3H, s), 0.84 (3H, s), 0.88 (3H, t, J = 6.7Hz), 1.05 (3H, s),
1.97-2.07 (1H, m), 3.33-3.43 (1H, m), 3.37 (3H, s), 3.42 (3
H, s), 3.43-3.57 (1H, m), 4.68 (2H, s), 4.70 (1H, d, J = 6.7H
z), 4.79 (1H, s), 4.83 (1H, d, J = 6.6 Hz) FABMS (+ KI) m / z: 603 (MK ⁺ ).

3) Synthesis of compound (5a) 4.05 g of a mixture of compound (3a) and compound (4a) was dissolved in 100 ml of isopropanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was refluxed for 6.5 hours. After cooling the reaction solution, the residue obtained by evaporating the solvent was purified by silica gel column chromatography [eluted with hexane: ethyl acetate = 2: 1 (V / V)] to give a colorless amorphous (5a). 2.40
g was obtained.

IR (KBr) vcm ^-1 : 3459,2925,285
3,1467,1042 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
74 (3H, s), 0.82 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.28 (1H, t, J
= 9.6Hz), 3.52-3.66 (2H, m), 5.49 (1H, t, J = 7.2Hz) FABMS (+ KI) m / z: 497 (MK ⁺ ).

4) Synthesis of Compound (6a) 2.40 g of Compound (5a) was dissolved in 90 ml of dichloromethane, 1.32 g of sodium hydrogen carbonate and 138 mg of vanadium oxide acetylacetonate were added, and the mixture was cooled to 0 ° C. under a nitrogen atmosphere. . To this solution was added tert-butyl hydroperoxide (3.86 M dichloromethane solution) 1
3.5 ml was added, and the mixture was stirred at 0 ° C. for 3.5 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography [eluted with hexane: ethyl acetate = 2: 1 to 3: 2 (V / V)] to obtain compound (6a). And a mixture of compound (7a) [(6
a) was the main product]. This mixture was used for the next reaction without separation. A mixture of compound (7a) and compound (6a) was obtained from the fraction eluted first by the above chromatography, and colorless amorphous (6a) was obtained from the fraction eluted later.

Compound (6a) IR (KBr) νcm ^-1 : 3400,2925,1467,1047 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
69 (3H, s), 0.80 (3H, s), 0.88 (3H, t, J = 6.7Hz), 1.29 (3H, s),
3.23 (1H, dd, J = 11.3 and 4.6Hz), 3.29 (1H, t, J = 6.1Hz), 4.
44 (1H, s) FABMS (+ KI) m / z: 513 (MK ⁺ ).

5) Synthesis of compound (8a) 1.90 g of a mixture of compound (6a) and compound (7a) was dissolved in 20 ml of pyridine, and 2.04 g of acetic anhydride and 2.04 g of acetic anhydride were added.
-Dimethylaminopyridine (244 mg) was added, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate was added to the reaction solution, which was washed sequentially with dilute hydrochloric acid and saturated saline, and then dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography [eluted with hexane: ethyl acetate = 8: 1 (V / V)]. 1.26 g of substance (8a)
Subsequently, a fraction containing the compound (9a) was obtained.

Compound (8a) IR (neat) νcm ^-1 : 2926,2855,1739,1468,136
9,1245,1024 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
82 (3H, s), 0.86 (3H, s), 0.88 (3H, t, J = 6.5Hz), 1.25 (3H, s),
2.01 (3H, s), 2.05 (3H, s), 2.57 (1H, dd, J = 8.5 and2.4Hz),
4.61 (1H, dd, J = 11.1 and 4.8 Hz), 4.62-4.75 (1H, m) LSIMS m / z: 559 (MH ^<+> ).

6) Compound (10a) and compound (11)
Synthesis of a) To 6.92 g of compound (8a) was added 500 ml of a 0.01 N hydrogen chloride acetate solution, and the mixture was stirred at room temperature for 5 hours.
A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution, and the mixture was washed with saturated saline and dried over anhydrous magnesium sulfate.
The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel flash column chromatography [eluted sequentially with hexane: ethyl acetate = 10: 1 to 4: 1 (V / V)]. Colorless viscous substance (11a) from the eluted fraction
3.37 g, and 3.14 g of a colorless viscous substance (10a) were obtained from the fraction eluted later.

Compound (10a) 3.14 obtained here
200 g of a 0.01 N hydrogen chloride acetate solution was added to the resulting mixture, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution, and the mixture was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was subjected to silica gel flash column chromatography [hexane: ethyl acetate = 8: 1 to 5: 1].
(Eluted sequentially with (V / V)] to obtain 1.28 g of compound (11a) from the fraction eluted first, and 1.40 g of compound (10a) from the fraction eluted later. 1.40 g of this compound (10a) was reacted in the same manner as described above, to give compound (11a) (5.55 g in total yield) and compound (10a).
a) (yield 644 mg) was obtained.

Compound (10a) IR (neat) νcm ^-1 : 3469,2927,2845,1737,137
0.1247,1026 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
84 (3H, s), 0.88 (3H, t, J = 6.8Hz), 0.91 (3H, s), 1.92 (3H, s),
2.01 (3H, s), 2.33 (1H, t, J = 9.9Hz), 3.84-3.91 (1H, m), 4.61
-4.74 (2H, m), 4.97 (1H, s), 5.02 (1H, s) LSIMS m / z: 597 (MH ⁺ ).

Compound (11a) IR (neat) νcm ^-1 : 2928,1736,1243,1024 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
78 (3H, s), 0.84 (3Hs), 0.88 (3H, t, J = 6.7Hz), 2.02 (3H, s),
2.08 (3H, s), 2.21 (1H, t, J = 9.9Hz), 3.49 (1H, dd, J = 11.0 an
d 4.9Hz), 4.61-4.75 (1H, m), 5.18 (1H, s), 5.25 (1H, s), 5.2
7 (1H, t, J = 7.2Hz) LSIMS m / z: 597 (MH ⁺ ).

7) Synthesis of Compound (12a) 5.55 g of Compound (11a) was added to 200 m of dichloromethane.
After cooling to 0 ° C. under a nitrogen atmosphere, 3.75 g of 80% cumene hydroperoxide and 3 m of dichloromethane were added.
Then, the mixture was stirred at 0 ° C. for 4.5 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure is flash column chromatography on silica gel [hexane: ethyl acetate = eluted with 5: 1 to 4: 1 (V / V)].
Then, 4.81 g of a colorless viscous substance (12a) was obtained.

IR (neat) vcm ^-1 : 3436,2927,28
54,1736,1241,1028 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
67 (3H, s), 0.82 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.02 (3H, s),
2.08 (3H, s), 2.73 (1H, d, J = 3.9Hz), 3.07 (1H, d, J = 3.9Hz),
3.34 (1H, dd, J = 11.0 and 4.6Hz), 4.18 (1H, s), 4.62-4.75
(1H, m), 4.77 (1H, t, J = 6.7Hz) FABMS m / z: 575 (MH ⁺ ).

8) Synthesis of compound (13a) 4.81 g of compound (12a) was dissolved in 150 ml of methanol, and 3.47 g of anhydrous potassium carbonate was added, followed by stirring at room temperature for 1 hour. Ethyl acetate was added to the reaction solution, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure is flash column chromatography on silica gel [hexane: ethyl acetate = 1: 1 to 2: 3 (V / V)].
And 3.0 g of the compound fraction was obtained. This was recrystallized from hexane-ethyl acetate to give a colorless powder (13a).
2.54 g was obtained.

Mp: 74-77 ° C. Anal. Calcd for C ₃₁ H ₅₄ O ₄ : C, 75.87;
H, 11.09 Found: C, 75.57; H, 11.29 IR (KBr) νcm ^-1 : 3401, 2926, 2853 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
69 (3H, s), 0.81 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.86 (1H, d, J
= 4.0Hz), 3.05 (1H, d, J = 4.0Hz), 3.30-3.41 (1H, m), 3.37 (1H
H, dd, J = 10.9 and 4.6Hz), 3.52-3.66 (1H, m), 4.15 (1H, br
s) LSIMS (+ KI) m / z: 529 (MK ⁺ ).

The method for separately synthesizing the compound (13a) is shown below. 9) Synthesis of compound (14a) 1.02 mixture of compound (10a) and compound (11a)
g was dissolved in 70 ml of methanol, and 1.26 g of anhydrous potassium carbonate was added, followed by stirring at room temperature for 5 hours. The reaction solution was evaporated under reduced pressure, chloroform was added to the obtained residue, and the mixture was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography [eluted with chloroform: ethyl acetate = 1: 1 (V / V)] to obtain 758 mg of a colorless powder (14a). Was.

[0038] mp: 166~168 ℃ IR (KBr) νcm -1: 3306,2927,2854,1467,1022 1 H-NMR (300MHz, CDCl 3) δppm: 0.
74 (3H, s), 0.83 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.32 (1H, t, J
= 9.9Hz), 3.47 (1H, dd, J = 11.2 and 4.8Hz), 3.51-3.67 (1H,
m), 4.13 (1H, t, J = 7.0 Hz), 4.93 (1H, s), 5.07 (1H, s) LSIMS (+ KI) m / z: 513 (MK ⁺ ).

10) Synthesis of compound (13a) 750 mg of compound (14a) was added to 100 m of dichloromethane.
and 599 mg of 70% metachloroperbenzoic acid was added, followed by stirring at room temperature for 19 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with an aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [hexane: ethyl acetate = 1: 2 (V / V)].
And 750 mg of the compound fraction was obtained. This was recrystallized from hexane-ethyl acetate to give a colorless powder (13
658 mg of a) were obtained.

Example 2 (when R in the compounds shown in Schemes 1 and 2 is a decyl group) 11) Compound (3
b) and Synthesis of Compound (4b) According to the method described in 2) of Example 1, the reaction was carried out using 1-bromoundecane instead of 1-bromodecane to give compound (3b) and compound (4b). Obtained.

Compound (3b) Anal. Calcd for C ₃₆ H ₆₆ O ₅ : C, 74.69;
H, 11.49 Found: C, 74.68; H, 11.54 IR (KBr) νcm ^-1 : 3431,2927,2853,1467,1382,1
152,1101,1050,1024 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
83 (3H, s), 0.86 (3H, s), 0.88 (3H, t, J = 6.6Hz), 1.19 (3H, s),
1.98-2.08 (1H, m), 3.33-3.39 (1H, m), 3.36 (3H, s), 3.41 (3
H, s), 3.43-3.58 (1H, m), 4.66 (2H, s), 4.70 (1H, d, J = 6.8H
z), 4.84 (1H, d, J = 6.8 Hz), 5.17 (1H, s, exchangeable) FABMS (+ KI) m / z: 617 (MK ⁺ ).

Compound (4b) Anal. Calcd for C ₃₆ H ₆₆ O ₅ : C, 74.69;
H, 11.49 Found: C, 74.52; H, 11.53 IR (neat) vcm ^-1 : 3435,2927,2853,1467,136
7,1151,1101,1050,1024 ¹ H-NMR (300 MHz, C
DCl ₃ ) δ ppm: 0.83 (3H, s), 0.84 (3H, s), 0.88 (3H,
tJ = 6.7Hz), 1.05 (3H, s), 3.32-3.42 (1H, m), 3.36 (3H, s),
3.41 (3H, s), 4.68 (2H, s), 4.70 (1H, d, J = 6.8Hz), 4.78 (1H,
s, exchangeable), 4.83 (1H, d, J = 6.8 Hz) FABMS (+ KI) m / z: 617 (MK ⁺ ).

12) Synthesis of Compound (5b) Compound (3b) was prepared according to the method described in 3) of Example 1.
Compound (5b) was obtained from a mixture of b) and compound (4b).

Mp: 80-83 ° C. IR (KBr) νcm ⁻¹ : 3446,2921,2851,1470,1449,1
381,1081,1045 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
74 (3H, s), 0.82 (3H, s), 0.88 (3H, t, J = 6.7Hz), 1.67 (3H, s),
2.27 (1H, t, J = 9.6Hz), 3.52-3.66 (2H, m), 5.49 (1H, t, J = 6.9
Hz) FABMS m / z: 471 (MH ^<+> ).

13) Synthesis of Compound (6b) Compound (5b) was prepared according to the method described in 4) of Example 1.
Compound (6b) was obtained from b).

Compound (6b) IR (KBr) νcm ^-1 : 3401,2924,2854 ¹ H-NMR (300 MHz, CDCl ₃ ) δppm: 0.
69 (3H, s), 0.80 (3H, s), 1.29 (3H, s), 3.23 (1H, dd, J = 11.1 a
nd 4.5Hz), 3.29 (1H, t, J = 6.0Hz), 3.52-3.66 (1H, m), 4.43
(1H, s) LSIMS (+ KI) m / z: 527 (MK ⁺ ).

14) Synthesis of Compound (8b) Compound (6b) was prepared according to the method described in 5) of Example 1.
Compound (8b) was obtained from a mixture of b) and compound (7b).

Compound (8b) IR (neat) νcm ^-1 : 2926,2854,1737,1245 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
82 (3H, s), 0.86 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.01 (3H, s),
2.05 (3H, s), 2.57 (1H, dd, J = 8.7 and 2.4Hz), 4.60 (1H, dd,
J = 11.0 and 4.9 Hz), 4.61-4.74 (1H, m) FABMS (+ KI) m / z: 611 (MK ⁺ ).

15) Compound (10b) and compound (11)
Synthesis of b) According to the method described in 6) of Example 1, compound (8)
Compound (10b) and compound (11b) were obtained from b).

Compound (10b) IR (neat) νcm ^-1 : 3479,2926,2854,1737,124
5,1027 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
84 (3H, s), 0.88 (3H, t, J = 6.7Hz), 0.92 (3H, s), 1.92 (3H, s),
2.01 (3H, s), 2.33 (1H, dd, J = 10.8 and 9.1Hz), 3.85-3.93
(1H, m), 4.62-4.75 (2H, m), 4.98 (1H, s), 5.02 (1H, s) FABMS (+ KI) m / z: 611 (MK ⁺ ).

Compound (11b) IR (neat) νcm ^-1 : 3543,2926,2854,1736,124
3,1024 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
78 (3H, s), 0.84 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.02 (3H, s),
2.08 (3H, s), 2.21 (1H, t, J = 9.9Hz), 2.32 (1H, d, J = 2.8Hz),
3.44-3.53 (1H, m), 4.62-4.75 (1H, m), 5.18 (1H, s), 5.25 (1H, m)
H, s), 5.27 (1H, t, J = 7.2 Hz) FABMS (+ KI) m / z: 611 (MK ⁺ ).

16) Synthesis of compound (12b) Compound (11b) was prepared according to the method described in 7) of Example 1.
Compound (12b) was obtained from b). IR (neat) νcm ^-1 : 3452,2926,2854,1735,124
1,1029 ¹ H-NMR (200 MHz, CDCl ₃ ) δ ppm: 0.
67 (3H, s), 0.82 (3H, s), 0.88 (3H, t, J = 6.5Hz), 2.02 (3H, s),
2.08 (3H, s), 2.73 (1H, d, J = 3.8Hz), 3.07 (1H, d, J = 3.8Hz),
3.34 (1H, dd, J = 10.8 and 4.6Hz), 4.18 (1H, s), 4.59-4.78
(1H, m), 4.78 (1H, t, J = 6.6Hz) FABMS m / z: 589 (MH ⁺ ).

17) Synthesis of Compound (13b) According to the method described in 8) of Example 1, compound (12b)
Compound (13b) was obtained from b). mp: 70-73 ° C Anal. Calcd for C ₃₂ H ₅₆ O ₄ : C, 74.14;
H, 11.18 Found: C, 75.88 ; H, 11.21 IR (KBr) νcm -1: 3401,2926,2852 1 H-NMR (200MHz, CDCl 3) δppm: 0.
69 (3H, s), 0.80 (3H, s), 0.88 (3H, t, J = 6.5Hz), 2.14 (1H, t, J
= 9.6Hz), 2.25 (1H, brs, exchangeable), 2.86 (1H, d, J = 3.9
Hz), 3.05 (1H, d, J = 3.9Hz), 3.26-3.42 (1H, m), 3.37 (1H, dd,
J = 11.1 and 4.7Hz), 3.49-3.72 (1H, m), 4.18 (1H, br s, exc
hageable) FABMS (+ KI) m / z: 543 (MK ⁺ ) High-resolution FABMS (+ KI) m / z: Calcd fo
_{r C 32 H 56 O 4 K} : 543.3816 Found: 5
43.3813.

Hereinafter, a separate synthesis method of compound (13b) will be described. 18) Synthesis of Compound (14b) Compound (10b) was prepared according to the method described in 9) of Example 1.
Compound (14b) from a mixture of Compound (11b) and Compound (11b)
I got IR (KBr) νcm ⁻¹ : 3401,2926,2854 ¹ H-NMR (300 MHz, CDCl ₃ ) δppm: 0.
74 (3H, s), 0.83 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.32 (1H, t, J
= 10.1Hz), 3.47 (1H, dd, J = 11.4 and 4.7Hz), 3.52-3.66 (1
H, m), 4.13 (1H, t, J = 6.9 Hz), 4.93 (1H, s), 5.07 (1H, s) FABMS (+ KI) m / z: 527 (MK ⁺ ).

19) Synthesis of Compound (13b) Compound (1b) was prepared according to the method described in 10) of Example 1.
Compound (13b) was obtained from 4b).

The usefulness of the compound of the present invention will be described below with reference to Test Examples.

Test Example In Vivo Life Prolonging Effect on L1210 Leukemia 1) Test Method 1 × 10 ⁵ L1210 leukemia cells were implanted intraperitoneally into DBA / 2 female mice, and tumor cells were collected from the ascites on the 7th day. Prepare a cell suspension of 5 × 10 ⁵ viable cells / ml (suspended in Hank's balanced salt solution), and prepare 0.2 ml of the suspension.
(1 × 10 ⁵ / animal) was used for CDF ₁ female mice (7 weeks old)
Was implanted intraperitoneally. The test compound suspended in 0.5% gum arabic-physiological saline was intraperitoneally administered for 5 days from the day following the cell transplantation, with the cell transplant day being day 0. The effect was determined by determining the median survival time (MST) of the mice and T / C = (MST of the test compound administration group) / (MST of the control group) × 100 (%).

2) Test Results Compounds (13a) and (13b) of the present invention, known compounds A and compounds specifically described in JP-A-7-224087 (R is an isobutyl group; hereinafter, compound B) ) And peripheral compounds of the compound of the present invention which are included in the claims of JP-A-7-224087 but not specifically described [R represents a heptyl group (n-C ₇ H ₁₅ ), an octyl group (n-C ₈ H ₁₇ ), a compound of an undecyl group (nC ₁₁ H ₂₃ ) and a tridecyl group (nC ₁₃ H ₂₇ ), hereinafter referred to as compound C, compound D, compound E and compound F, respectively.
Effect of in vivo on L1210 leukemia in vivo (T /
Table 1 shows the number of surviving mice at C (observed up to day 30) and day 30 (6 mice per group).

[0059]

[Table 1]

Compound (13a) and compound (1) of the present invention
3b) has a remarkable life-prolonging effect (T /
C and the number of surviving mice) are useful as a drug having an antitumor effect.

Reference Example [Synthesis of Compound C, Compound D, Compound E and Compound F] The method described in Example 1-2) was carried out in accordance with the method of Example 1.
The same reaction was carried out using 1-bromooctane, 1-bromononane, 1-bromododecane and 1-bromotetradecane instead of -bromodecane, to synthesize Compound C, Compound D, Compound E and Compound F.

Compound Cmp: 140-145 ° C. IR (KBr) νcm ⁻¹ : 3401, 2927, 2854 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
69 (3H, s), 0.81 (3H, s), 0.88 (3H, t, J = 6.8Hz), 2.16 (1H, dd,
J = 10.9 and 9.2Hz), 2.85 (1H, d, J = 3.9Hz), 3.06 (1H, d, J =
3.9 Hz), 3.28-3.42 (2H, m), 3.52-3.70 (1H, m) FABMS (+ KI) m / z: 501 (MK ⁺ ).

Compound Dmp: 128-131 ° C. Anal. Calcd for C ₃₀ H ₅₂ O ₄ : C, 75.58;
H, 10.99 Found: C, 75.40; H, 11.05 IR (KBr) νcm ^-1 : 3401, 2927, 2853 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
69 (3H, s), 0.80 (3H, s), 0.88 (3H, t, J = 6.8Hz), 2.14 (1H, dd,
J = 10.6 and 8.9Hz), 2.86 (1H, d, J = 4.0Hz), 3.05 (1H, d, J =
4.0 Hz), 3.30-3.40 (2H, m), 3.52-3.65 (1H, m) FABMS (+ KI) m / z: 515 (MK ⁺ ).

Compound Emp: 97-101 ° C. Anal. Calcd for C ₃₃ H ₅₈ O ₄ : C, 76.40;
H, 11.27 Found: C, 76.13; H, 11.39 IR (KBr) νcm ^-1 : 3420, 2925, 2853 ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.
68 (3H, s), 0.80 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.16 (1H, t, J
= 9.9Hz), 2.84 (1H, d, J = 4.0Hz), 3.05 (1H, d, J = 4.0Hz), 3.27
-3.34 (1H, m), 3.37 (1H, dd, J = 11.0 and 4.6Hz), 3.51-3.66
(1H, m) FABMS (+ KI) m / z: 557 (MK ⁺ ).

Compound Fmp: 84-89 ° C. Anal. Calcd for C ₃₅ H ₆₂ O ₄ : C, 76.87;
H, 11.43 Found: C, 76.79 ; H, 11.71 IR (KBr) νcm -1: 3401,2924,2852 1 H-NMR (300MHz, CDCl 3) δppm: 0.
69 (3H, s), 0.80 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.15 (1H, dd,
J = 10.8 and 9.0Hz), 2.85 (1H, d, J = 4.0Hz), 3.05 (1H, d, J =
4.0Hz), 3.28-3.35 (1H, m), 3.37 (1H, dd, J = 11.0 and 4.6H
z), 3.51-3.67 (1H, m) FABMS (+ KI) m / z: 585 (MK ⁺ ).

Claims (1)

[Claims] (1) Formula (1) (Wherein, R represents a nonyl group or a decyl group).