JP2003321491A - Triterpene compounds - Google Patents

Abstract

(57) [Summary] [Solution] General formula (1) (In the formula, R ¹ represents a hydrogen atom, a monosaccharide residue or a disaccharide residue, and R ² represents the following formulas (a) to (e); A triterpene compound represented by the formula: [Effect] The compound of the present invention has high antitumor activity and is effective for treating various tumors such as pharyngeal cancer, lung cancer, and colon cancer. Further, the compound of the present invention has an angiogenesis inhibitory effect, and can control not only tumors but also various in vivo diseases related to angiogenesis such as diabetic retinopathy.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel triterpene compound and a medicine such as an antitumor agent and an angiogenesis inhibitor.

[0002]

2. Description of the Related Art Up to now, many searches have been conducted for medicines such as antitumor agents, which are made from natural products. Vinca alkaloids, camptothecin, podophyllotoxin and the like are typical examples, and these natural products are used as pharmaceuticals by further chemical modification. However, currently used therapeutic agents have tumor cells acquired resistance to many anti-cancer agents, and thus have limited effective treatment in long-term treatment. As one of the methods to solve this problem, it is necessary to develop a large number of anticancer agents based on extensive research.

Up to now, research on the antitumor component of Cucurbitaceae has been conducted mainly on pumpkin genus ( Cucurbita ) plants, and in the case of Trichosanthes plants, it is a plant belonging to the same genus, T. kirilowii . Ng et al., Gen Pharm
acol., (1992) Vol. 23 (4), 579-590], etc., but the effect has not been sufficiently obtained.

In recent years, the report by Folkkmam et al. (See Non-patent Document 1) that angiogenesis is strongly involved in the growth of solid tumors and metastasis of tumors (see Non-Patent Document 1) has triggered an angiogenesis inhibitor to become a new anticancer agent. It is attracting attention as a target. Recently, VEGF (Vascular Endothelial Growth Fac
to: vascular endothelial growth factor) and angiopoietin ligands and their receptor systems have been clarified one after another, and it has become clear that angiogenesis is also involved in diabetic retinopathy. It is considered to be effective for treating and ameliorating not only cancer but also various diseases in the body.

[0005] The angiogenesis inhibitor makes solid cancer a so-called "military attack" by inhibiting the formation of blood vessels, which are the nutrient supply pathways necessary for the growth of solid cancer, and as a result, the cancer reducing action. Is a drug expected. Furthermore, while conventional anticancer agents have a cytocidal effect that acts not only on cancer cells but also on somatic cells, serious side effects are a problem, whereas angiogenesis inhibitors are vascular endothelial cells. Since it acts specifically on cells and is expected to have very few side effects, an angiogenesis inhibitor that is clinically applicable has not been found yet.

[0006]

[Non-Patent Document 1] Folkman et al., Nature, (1980) Vol. 28.
8, 551-556

[0007]

Therefore, an object of the present invention is to provide a compound useful as an antitumor agent and an angiogenesis inhibitor.

[0008]

[Means for Solving the Problems] As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that Trichosanthes trixpidata
The present invention has been completed by the discovery that a novel triterpene compound having a wide range of antitumor effect and angiogenesis suppressing effect exists in an extract of icuspidata ).

That is, the present invention has the following general formula (1):

[0010]

[Chemical 4]

(Wherein R ¹ represents a hydrogen atom, a monosaccharide residue or a disaccharide residue, and R ² represents the following formulas (a) to (e),

[0012]

[Chemical 5]

A triterpene compound represented by the formula (2), and a general formula (2)

[0014]

[Chemical 6]

(In the formula, R ³ represents a hydrogen atom or a monosaccharide residue, and R ⁴ and R ^{5 each} represent a hydrogen atom and the other represents a hydroxy group, or R ⁴ and R ⁵ together represent an oxo group, and R ⁶ Represents a hydrogen atom or a disaccharide residue).

The present invention also provides the above general formula (1) or (2).
The present invention provides a drug such as an antitumor agent and an angiogenesis inhibitor containing the triterpene compound represented by.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formulas (1) and (2), R ¹
Examples of the monosaccharide residue represented by R ³ and R ³ include a glucosyl group, a xylosyl group, an arabinosyl group, a ribosyl group, a galactosyl group, a talosyl group, a quinovosyl group, a fucosyl group, a rhamnosyl group, and an apiosyl group. A group (including an α-glucosyl group and a β-glucosyl group; the same applies hereinafter) is particularly preferable. The disaccharide residue represented by R ¹ and R ⁶ may be a rhamnosyl-glucosyl group, a glucosyl-rhamnosyl group, a rhamnosyl-glucosyl group, even if it is a combination of residues of the same kind such as a glucosyl-glucosyl group. Etc., glucosyl group, xylosyl group,
Examples include arabinosyl group, ribosyl group, galactosyl group, tarosyl group, quinovosyl group, fucosyl group, rhamnosyl group, disaccharide residue in the form in which monosaccharides of the same type or different types selected from apiosyl groups are bonded, and among these, glucosyl -Glucosyl group and rhamnosyl-glucosyl group are particularly preferable.

Since the triterpene compounds represented by the general formulas (1) and (2) have a plurality of asymmetric carbon atoms, there are a large number of isomers in the form of a chimpanzee, and any of these isomers are included in the present invention. Among these, preferable three-dimensional structures are as follows.

[0019]

[Chemical 7]

[0020]

[Chemical 8]

[0021]

[Chemical 9]

The carbon atom to which the hydroxy group in the structures of the formulas (a) to (c) is bonded may be an asymmetric carbon atom, but these can have the following stereostructures.

[0023]

[Chemical 10]

The triterpene compound of the present invention may be obtained by chemical synthesis, for example, Trichosanthes tricuspidata (Thai name: Khe-
Ka-Daeng). This plant is a cucurbitaceae plant native to Thailand, and is a vine plant widely distributed from southern China to southern Asia and the southwestern part. The plant is used as an antipyretic agent, an analgesic agent during dislocation, an anthelmintic agent, and a therapeutic agent for migraine in Thailand, but there is no report that it has an antitumor effect or an angiogenesis suppressing effect.

To extract the above-mentioned triterpene compound from Trichosanthes tricuspidata, for example, a single water-soluble substance such as water, a lower alcohol such as ethanol, acetone or acetic acid can be extracted from the fruit, seed, root or whole plant of the plant. Examples thereof include a method of extracting with an organic solvent, a method of extracting with a mixture of water and a lower alcohol or acetone, or a solvent in which a lower alcohol or acetone is mixed with a hydrophobic organic solvent such as chloroform or acetate. further,
The extract obtained is concentrated, an appropriate amount of water is added, and then n-
A soluble fraction is obtained in the order of hexane, diethyl ether, ethyl acetate and n-butanol, and the residue is used as a water fraction. The water-soluble fraction thus obtained may be further defatted. Further, the compound of the present invention can be isolated by concentrating the obtained water-soluble fraction or fractionating it as it is using a column or the like.

When the compound of the present invention is used as a medicine, Trichosanthes trixpidata ( Tric
hosanthes tricuspidata ), or may be used as an extract before purification. As the extract, a crude extract containing at least one of these compounds may be used, but it is preferable to use a highly purified product.

The thus-obtained triterpene compound of the present invention or a plant extract containing the same has excellent antitumor activity and angiogenesis inhibitory activity as described below, and is useful as an antitumor agent for mammals including humans. .

The compound of the present invention can be administered as it is, but within a range that does not reduce the effect, it is mixed with a carrier such as a dispersion aid, an excipient and the like which is usually used in the formulation, and a powder formulation, It can be used in the form of liquid preparations, capsule preparations, suspension preparations, emulsion preparations, syrup preparations, elixir preparations, granule preparations, pill preparations, tablets, troche preparations, limonade preparations or other oral preparations or injection preparations.

Examples of such carriers include water-soluble monosaccharides or oligosaccharides or polysaccharides such as mannitol, lactose and dextran; for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
Gel-forming or water-soluble celluloses such as methylcellulose; water-absorbing and poorly water-soluble celluloses such as crystalline cellulose, α-cellulose, crosslinked sodium carboxymethylcellulose, and derivatives thereof;
Water-absorbing and poorly water-soluble polysaccharides such as hydroxypropyl starch, carboxymethyl starch, cross-linked starch, amylose, amylopectin, pectin and their derivatives; water absorption such as gum arabic, tragacanth gum, glycomannan and their derivatives And sparingly water-soluble gums; for example, polyvinylpyrrolidone, crosslinked polyacrylic acid and salts thereof, crosslinked vinyl polymers such as crosslinked polyvinyl alcohol, polyhydroxyethyl methacrylate and derivatives thereof; molecules such as liposomes such as phospholipids and cholesterol Mention may be made of lipid sugars which form aggregates.

The dose of the drug of the present invention may be adjusted appropriately according to the symptoms of the patient. For example, in the case of an extract of Trichosanthes tricuspidata, the solid amount is 0.1 to 10 g / day, preferably. Is preferably 0.5 to 5 g / day, particularly preferably 1 to 2 g / day. In the case of a triterpene compound, it is preferable to administer 1 to 1000 mg / day, preferably 10 to 500 mg / day, and particularly 50 to 200 mg / day.

[0031]

The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Production Example 1 Trichosanthes tr
icuspidata ) Preparation of Extract 1.2 kg of the fruit of the plant was extracted with hot methanol for 3 hours. After cooling, it was filtered with a filter paper and the solvent was distilled off under reduced pressure to obtain 224 g of an extracted solid.

Production Example 2 The extracted solid matter of Production Example 1 was dispersed in water, and diethyl ether was added.
Degreased in. Take the aqueous phase and add styrene and divinylbenze.
Was used as a copolymerized porous polymer. Elution is
Water, methanol, and acetone were added in this order for three fractions. Me
Take the tanol fraction (47.0g) and chromatograph on silica gel.
Offered to Elution was performed with ethyl acetate / methanol (9:
1), ethyl acetate / methanol / water (4: 1: 0.1,
7: 3: 0.3, 6: 4: 1) in order, and 8 fractions (images
Minutes M1 to M8) were obtained. Fraction M6 (2.2g)
50 by column chromatography using silylated silica gel
Fractionation with 80% water / methanol gave 7 fractions (M6-
1 to M6-7) were obtained. This fraction M6-4 is used as a packing material.
Liamine II (silica gel chemically bonded to polyamine)
High performance liquid chromatography used (mobile phase: 90% acetonitrile
), Followed by octadecyl silylated silica gel
High performance liquid chromatography (mobile phase: 85% acetonitril
Compound (A) (in the formula (1a), R
¹= Β-glucosyl group (β-Glc), R²= (A-1)) 24 mg
It was This glucoside was enzymatically decomposed by the method of Kohda et al.
It was That is, 15 mg of compound (A) was added to 0.5 mL of methano.
The crude hesperidinase aqueous solution (100 mg /
20 mL) was added. The mixture was stirred at a temperature of 37 ° C for 2 days. Anti
After that, the reaction solution was extracted with ethyl acetate, concentrated to dryness, and combined.
Object (B) (in formula (1a), R¹= H, R ²= (A-1))
8 mg was obtained.

Compound (A) colorless amorphous [α] _D ²³ −71.1 ° (CH ₃ OH, C = 0.6) Negative HR-FAB-MS ( m / z ): 677.3542 (C ₃₆ H ₅₃ O ₁₂ req)
uires 677.3536) ¹ H-NMR (C ₅ D ₅ N): (skeleton part) 6.52 (1H, dd , J = 16, 5H
z), 6.44 (1H, d , J = 2Hz), 6.38 (1H, d , J = 16Hz), 5.6
3 (1H, br.s. ), 5.25 (1H, bt , J = 8Hz ), 4.61 (1H, d ,
J = 5Hz), 3.66 (1H, br.s. ), 3.17 (1H, d , J = 14Hz), 2.
85 (1H, d , J = 14Hz), 2.83 (1H, d , J = 6Hz), 2.14 (1H,
m ), 1.96 (3H, m ), 1.84 (1H, d , J = 13Hz), 1.56 (3H,
s ), 1.54 (3H, s ), 1.52 (3H, s ), 1.50 (3H, s ), 1.4
0 (3H, s ), 1.27 (3H, s ), 1.25 (3H, s ), 1.00 (3H, s )
(Sugar part) 5.51 (1H, d , J = 8Hz), 4.70 (1H, dd , J = 1)
2, 2Hz), 4.56 (1H, dd , J = 12, 4Hz), 4.47 (1H, dd , J
= 9,9Hz), 4.30 (1H, dd , J = 9, 9Hz), 4.22 (1H, dd , J =
9, 8Hz), 4.06 (1H, m ) ¹³ C-NMR (C ₅ D ₅ N): 214.4, 197.1, 146.8, 141.7, 137.
0, 126.0, 121.1, 120.6, 100.7, 81.6, 78.7, 78.4, 7
6.3, 74.4, 71.4, 70.7, 69.9, 62.0, 56.9, 51.1, 50.
0, 49.5, 49.1, 48.4, 45.6, 41.8, 35.5, 30.8, 30.7,
27.6, 24.7, 23.9, 20.8, 20.3, 20.1, 18.1

Compound (B) colorless amorphous [α] _D ²³ -14.6 ° (CH ₃ OH, C = 0.8) Negative HR-FAB-MS ( m / z ): 515.3024 (C ₃₀ H ₄₃ O ₇ requ)
ires 515.3008) ¹ H-NMR (C ₅ D ₅ N): 6.53 (1H, dd , J = 16, 6Hz), 6.39 (1
H, d , J = 16Hz), 6.32 (1H, d , J = 3Hz), 5.68 (1H, br.
s. ), 5.26 (1H, t , J = 7Hz), 4.61 (1H, d , J = 5Hz), 3.74
(1H, br.s. ), 3.19 (1H, d , J = 14Hz), 2.85 (1H, d , J
= 13Hz), 2.84 (1H, d , J = 7Hz), 2.23 (1H, m ), 1.96 (3
H, m ), 1.87 (1H, d , J = 13Hz), 1.59 (3H, s ), 1.55 (3
H, s ), 1.52 (3H, s ), 1.51 (3H, s ), 1.45 (3H, s ),
1.30 (6H, s ), 1.13 (3H, s ) ¹³ C-NMR (C ₅ D ₅ N): 214.1, 198.9, 147.3, 141.8, 137.
7, 126.0, 120.6, 116.0,81.7, 76.4, 71.4, 69.9, 56.
6, 51.7, 49.9, 49.1, 48.6, 45.6, 42.0, 35.1, 30.8,
28.1, 24.7, 24.0, 20.8, 20.4, 20.2, 18.2

Production Example 3 Fraction M6 (2.2 g) of Production Example 2 was treated in the same manner as above, and simultaneously with the above compound, compound (C) (in the formula (1a), R ¹ = β-Glc, R 111 mg of ² = (a-2)) was obtained. 20 mg of this compound (C) was enzymatically decomposed by the method of Production Example 2 to give compound (D) (in the formula (1a), R ¹ = H, R ²
= (A-2)) was obtained.

Compound (C) colorless amorphous [α] _D ²³ −43.8 ° (CH ₃ OH, C = 3.7) Negative HR-FAB-MS ( m / z ): 677.3530 (C ₃₆ H ₅₃ O ₁₂ req)
uires 677.3536) ¹ H-NMR (C ₅ D ₅ N): (skeleton part) 6.57 (1
H, d , J = 16Hz), 6.50 (1H, dd , J = 16, 6Hz), 6.45 (1H,
d , J = 2Hz), 5.64 (1H, br.s. ), 5.31 (1H, t , J = 7Hz),
5.15 (1H, d , J = 6Hz), 3.69 (1H, br.s. ), 3.23 (1H,
d , J = 15Hz), 2.89 (1H, d , J = 15Hz), 2.85 (1H, d , J = 7
Hz), 2.14 (1H, m ), 1.98 (3H, m ), 1.82 (1H, d , J = 13
Hz), 1.60 (3H, s ), 1.55 (3H, s ), 1.52 (3H, s ), 1.5
0 (3H, s ), 1.39 (3H, s ), 1.24 (6H, s ), 1.00 (3H, s )
(Sugar part) 5.50 (1H, d , J = 8Hz), 4.69 (1H, dd , J = 1)
2, 2Hz), 4.55 (1H, dd , J = 12, 3Hz), 4.46 (1H, dd , J
= 9, 9Hz), 4.30 (1H, dd , J = 9, 9Hz), 4.21 (1H, dd , J
= 9, 8Hz), 4.05 (1H, m ) ¹³ C-NMR (C ₅ D ₅ N): 214.5, 197.1, 146.8, 142.1, 137,
126.8, 121.2, 120.9, 100.7, 78.7, 78.4, 76.8, 76.
5, 74.4, 71.4, 70.7, 69.8, 57.2, 51.0, 49.8, 49.4,
49.2, 48.5, 46.8, 41.9, 35.6, 30.7, 30.7, 27.5, 2
3.9, 21.8, 20.8, 20.4, 20.2, 20.0, 18.0

Compound (D) colorless amorphous [α] _D ²³ -12.2 ° (CH ₃ OH, C = 0.9) Negative HR-FAB-MS ( m / z ): 515.3025 (C ₃₀ H ₄₃ O ₇ requ
ires 515.3008) ¹ H-NMR (C ₅ D ₅ N): 6.58 (1H, d , J = 16Hz), 6.51 (1H, d
d , J = 16, 6Hz), 6.33 (1H, d , J = 3Hz), 5.68 (1H, br.
s. ), 5.34 (1H, t , J = 7Hz), 5.17 (1H, d , J = 5Hz), 3.77
(1H, br.s. ), 3.25 (1H, d , J = 15Hz), 2.88 (1H, d , J
= 14Hz), 2.86 (1H, d , J = 6Hz), 2.23 (1H, m ), 2.02 (2
H, m ), 2.00 (1H, m ), 1.85 (1H, d , J = 13Hz), 1.65 (3
H, s ), 1.53 (6H, s ), 1.51 (3H, s ), 1.45 (3H, s ),
1.30 (3H, s ), 1.27 (3H, s ), 1.13 (3H, s ) ¹³ C-NMR (C ₅ D ₅ N): 214.3, 198.9, 147.3, 142.1, 137.
7, 126.8, 120.6, 116.1,76.8, 76.5, 71.5, 69.9, 57.
3, 51.2, 49.7, 49.2, 48.6, 46.9, 42.1, 35.2, 30.8,
28.1, 24.0, 21.9, 20.8, 20.4, 20.2, 18.1

Production Example 4 30 mg of the compound (C) was dissolved in ethanol, 8 mg of palladium carbon was added, and catalytic hydrogenation was carried out at room temperature for 2 hours. The reaction solution was concentrated to dryness to obtain 28 mg of compound (E) (in formula (1b), R ¹ = β-Glc, R ² = (b-1)).

Compound (E) colorless amorphous [α] _D ²³ −123.3 ° (CH ₃ OH, C = 1.9) Negative HR-FAB-MS ( m / z ): 679.3680 (C ₃₆ H ₅₅ O ₁₂ req)
uires 679.3693) ¹ H-NMR (C ₅ D ₅ N): (skeleton part) 6.46 (1H, d , J = 2Hz),
5.63 (1H, br.s. ), 5.19 (1H, t , J = 7Hz), 4.42 (1H, d ,
J = 10Hz), 3.72 (1H, br.s. ), 3.30 (1H, d , J = 14Hz),
2.93 (1H, d , J = 14Hz), 2.77 (1H, d , J = 7Hz), 2.34 (3
H, m ), 2.11 (1H, m ), 1.98 (4H, m ), 1.88 (1H, m ), 1.
80 (1H, d , J = 13Hz), 1.58 (3H, s ), 1.55 (3H, s ), 1.
42 (6H, s ), 1.39 (3H, s ), 1.27 (3H, s ), 1.23 (3H,
s ), 1.01 (3H, s ) (sugar portion) 5.47 (1H, d , J = 8Hz), 4.
69 (1H, dd , J = 12, 3Hz), 4.56 (1H, dd , J = 12, 3Hz),
4.46 (1H, dd , J = 9, 9Hz), 4.29 (1H, dd , J = 9, 9Hz),
4.21 (1H, dd , J = 9, 8Hz), 4.04 (1H, m ) ¹³ C-NMR (C ₅ D ₅ N): 214.5, 197.1, 146.8, 137.0, 121.
0, 120.9, 100.6, 78.6, 78.4, 77.5, 76.8, 74.4, 71.
3, 70.7, 69.8, 62.0, 57.3, 51.1, 49.9, 49.4, 49.2,
48.5, 46.8, 42.0, 41.9, 35.6, 30.2, 30.0, 27.6, 2
7.3, 23.9, 21.5, 20.8, 20.4, 20.2, 18.1

Production Example 5 Fraction M5 (4.2 g) was fractionated by column chromatography using octadecyl silica gel with 50% -80% water / methanol to give 7 fractions (M5-1 to M5-7). Obtained. This fraction M5-3 was purified by high performance liquid chromatography (mobile phase: 90% acetonitrile) using polyamine II as a packing material, and compound (F) (in formula (1a), R ¹ = β-Glc, R ² = (C
-1)) 62 mg and compound (G) (in formula (1a),
R ¹ = β-Glc, R ² = (c-2)) 137 mg was obtained. These glucosides were enzymatically decomposed by the method of Production Example 2 to obtain 20 mg of compound (F) from compound (H) (in formula (1a),
R ¹ = H, R ² = (c-1)) 11 mg, compound (G) 20 mg to compound (I) (in formula (1a), R ¹ = H, R ² = (c-
2)) was obtained.

Compound (F) colorless amorphous [α] _D ²² −55.8 ° (CH ₃ OH, C = 2.3) Negative HR-FAB-MS ( m / z ): 693.3447 (C ₃₆ H ₅₅ O ₁₂ req)
uires 693.3486) ¹ H-NMR (C ₅ D ₅ N): (skeleton part) 6.45 (1H, d , J = 2Hz),
5.63 (1H, br.s. ), 5.04 (1H, t , J = 8Hz ), 4.55 (1H, d
d , J = 10, 2Hz), 3.68 (1H, br.s. ), 3.64 (1H, dd , J = 1
6, 10Hz), 3.36 (1H, dd , J = 16, 2Hz), 3.29 (1H, d , J
= 15Hz), 3.02 (1H, d , J = 7Hz), 2.87 (1H, d , J = 14Hz),
2.13 (1H, m ), 1.92 (2H, m ), 1.88 (1H, m ), 1.69 (1H,
d , J = 13Hz), 1.63 (3H, s ), 1.52 (3H, s ), 1.50 (3H,
s ), 1.48 (3H, s ), 1.40 (3H, s ), 1.27 (3H, s ), 1.19
(3H, s ), 1.00 (3H, s ) (sugar moiety) 5.47 (1H, d , J = 8
Hz), 4.69 (1H, dd , J = 12, 2Hz), 4.56 (1H, dd , J = 12,
3Hz), 4.46 (1H, dd , J = 9, 9Hz), 4.28 (1H, dd , J = 9,
9Hz), 4.21 (1H, dd , J = 9, 8Hz), 4.04 (1H, m ) ¹³ C-NMR (C ₅ D ₅ N): 216.0, 213.9, 197.1, 146.8, 137.
0, 120.8, 120.8, 100.6, 80.3, 78.6, 78.4, 75.8, 74.
4, 72.0, 70.7, 70.6, 61.9, 57.7, 51.0, 49.5, 49.4,
49.2, 48.7, 46.2, 41.8, 41.0, 35.5, 27.5, 27.4, 2
4.8, 24.7, 23.8, 20.8, 20.3, 20.1, 18.3

Compound (G) colorless amorphous form [α] _D ²² −64.4 ° (CH ₃ OH, C = 0.8) Negative HR-FAB-MS ( m / z ): 693.3477 (C ₃₆ H ₅₅ O ₁₂ req)
uires 693.3486) ¹ H-NMR (C ₅ D ₅ N): (skeleton part) 6.44 (1H, d , J = 2Hz),
5.63 (1H, br.s. ), 4.96 (1H, t , J = 8Hz ), 4.63 (1H, d
d , J = 9, 3Hz), 3.68 (1H, br.s. ), 3.65 (1H, dd , J = 15,
3Hz), 3.62 (1H, dd , J = 15, 9Hz), 3.29 (1H, d , J = 15
Hz), 2.94 (1H, d , J = 7Hz), 2.88 (1H, d , J = 15Hz), 2.
13 (1H, m ), 1.92 (2H, m ), 1.88 (1H, m ), 1.69 (1H,
d , J = 13Hz), 1.70 (3H, s ), 1.50 (9H, s ), 1.39 (3H,
s ), 1.29 (3H, s ), 1.20 (3H, s ), 0.99 (3H, s ) (sugar moiety) 5.45 (1H, d , J = 8Hz), 4.69 (1H, dd , J = 12, 2H
z), 4.55 (1H, dd , J = 12, 4Hz), 4.45 (1H, dd , J = 9, 9
Hz), 4.28 (1H, dd , J = 9, 9Hz), 4.20 (1H, dd , J = 9, 8H
z), 4.03 (1H, m ) ¹³ C-NMR (C ₅ D ₅ N): 215.5, 214.0, 197.1, 146.8, 136.
9, 120.8, 120.8, 100.6,80.2, 78.6, 78.3, 74.7, 74.
4, 72.2, 70.7, 70.4, 61.9, 58.8, 51.0, 49.4, 49.2,
49.2, 48.5, 46.4, 41.7, 40.8, 35.5, 27.5, 27.0, 2
5.4, 25.1, 23.8, 20.7, 20.4, 20.1, 18.2

Compound (H) colorless amorphous [α] _D ²¹ −34.0 ° (CHCl ₃ , C = 0.8) Negative HR-FAB-MS ( m / z ): 531.2986 (C ₃₀ H ₄₃ O ₈ requ
ires 531.2957) ¹ H-NMR (CDCl ₃ ): 5.94 (1H, d , J = 3Hz),
5.76 (1H, br.s. ), 4.47 (1H, t , J = 8Hz ), 3.97 (1H,
dd , J = 10, 1Hz), 3.51 (1H, br.s. ), 3.23 (1H, d , J = 1
4Hz), 2.99 (1H, dd , J = 17, 10Hz), 2.72 (1H, d , J = 14
Hz), 2.62 (1H, d , J = 7Hz), 2.57 (1H, dd , J = 17, 1Hz),
2.38 (1H, m ), 2.02 (2H, m ), 1.90 (2H, m ), 1.44 (3
H, s ), 1.39 (3H, s ), 1.35 (3H, s ), 1.24 (6H, s ),
1.20 (3H, s ), 1.02 (3H, s ), 1.00 (3H, s ) ¹³ C-NMR (CDCl ₃ ): 214.0, 212.7, 198.7, 144.6, 136.
9, 120.6, 114.8, 79.3,74.4, 72.2, 71.6, 55.9, 50.
8, 48.8, 48.4, 47.6, 45.5, 41.6, 39.3, 34.7,27.9,
25.7, 24.8, 23.6, 20.2, 20.1, 19.8, 18.4

Compound (I) colorless amorphous form [α] _D ²¹ −61.2 ° (CHCl ₃ , C = 1.0) Negative HR-FAB-MS ( m / z ): 531.2909 (C ₃₀ H ₄₃ O ₈ requ)
ires 531.2957) ¹ H-NMR (CDCl ₃ ): 5.94 (1H, d , J = 3Hz), 5.76 (1H, br.
s. ), 4.39 (1H, t , J = 8Hz), 3.91 (1H, dd , J = 10, 2H
z), 3.50 (1H, br.s. ), 3.21 (1H, d , J = 14Hz), 2.98
(1H, dd , J = 16, 1Hz), 2.70 (1H, d , J = 14Hz), 2.68 (1
H, dd , J = 16, 10Hz), 2.55 (1H, d , J = 7Hz), 2.38 (1H,
m ), 2.02 (2H, m ), 1.87 (2H, m ), 1.42 (3H, s ), 1.39
(3H, s ), 1.35 (3H, s ), 1.25 (3H, s ), 1.22 (3H,
s ), 1.19 (3H, s ), 1.02 (3H, s ), 0.99 (3H, s ) ¹³ C-NMR (CDCl ₃ ): 215.5, 212.9, 198.7, 144.6, 136.
9, 120.7, 114.9, 79.4, 74.3, 72.3, 71.1, 57.5, 50.
7, 48.8, 48.4, 47.6, 45.7, 41.6, 38.3, 34.7,27.9,
25.7, 24.7, 24.3, 23.6, 20.2, 20.1, 19.8, 18.3

Production Example 6 Fraction M2 (4.2 g) of Production Example 2 was fractionated by column chromatography using octadecyl silica gel with 50% -80% water / methanol to give compound (J) (formula (1a)). In, R ¹ = β-Glc, R ² = (d-1)) 100 mg was obtained. This glucoside was enzymatically decomposed by the method of Production Example 2 to give compound (K)
Got

Compound (J) colorless amorphous [α] _D ²³ −42.3 ° (CH ₃ OH, C = 4.9) Negative HR-FAB-MS ( m / z ): 659.3451 (C ₃₆ H ₅₁ O ₁₁ req)
uires 659.3431) ¹ H-NMR (C ₅ D ₅ N): (skeleton part) 6.45 (1H, d , J = 2Hz),
5.64 (1H, br.s. ), 4.93 (1H, t , J = 8Hz ), 4.82 (1H,
s ), 4.76 (1H, s ), 3.71 (1H, br.s. ), 3.39 (1H, d , J =
14Hz), 3.32 (1H, m ), 3.09 (1H, m ), 2.93 (1H, d , J =
14Hz), 2.91 (1H, d , J = 7Hz), 2.55 (1H, t , J = 8Hz), 2.
14 (1H, m ), 1.92 (1H, m ), 1.88 (2H, m ), 1.68 (3H,
s ), 1.67 (3H, d , J = 7Hz), 1.62 (3H, s ), 1.54 (3H,
s ), 1.41 (3H, s ), 1.27 (3H, s ), 1.20 (3H, s ), 1.0
2 (3H, s ) (sugar moiety) 5.56 (1H, d , J = 7Hz), 4.70 (1H,
dd , J = 12, 1Hz), 4.70 (1H, dd , J = 12, 1Hz), 4.58 (1
H, dd , J = 11, 3Hz), 4.47 (1H, dd , J = 9, 9Hz), 4.29
(1H, dd , J = 9, 9Hz), 4.22 (1H, dd , J = 9, 8Hz), 4.05
(1H, m ) ¹³ C-NMR (C ₅ D ₅ N): 214.8, 213.9, 197.0, 146.8, 145.
5, 137.0, 120.9, 120.7, 110.3, 100.6, 80.0, 78.6, 7
8.4, 74.4, 70.7, 70.4, 62.0, 59.1, 50.9, 49.6, 49.
4, 49.1, 48.7, 46.5, 41.8, 35.8, 35.6, 32.2, 27.5,
25.5, 23.9, 22.7, 20.8, 20.4, 20.2, 18.3

Compound (K) colorless amorphous [α] _D ¹⁹ −10.7 ° (CH ₃ OH, C = 0.8) Negative HR-FAB-MS ( m / z ): 497.3024 (C ₃₀ H ₄₃ O ₇ requ)
ires 497.3008) ¹ H-NMR (C ₅ D ₅ N): 6.32 (1H, d , J = 3Hz), 5.69 (1H, br.
s. ), 4.93 (1H, t , J = 8Hz ), 4.83 (1H, br.s. ), 4.77
(1H, br.s. ), 3.77 (1H, br.s. ), 3.38 (1H, d , J = 13H
z), 3.32 (1H, m ), 3.09 (1H, m ), 2.91 (1H, d , J = 8H
z), 2.90 (1H, d , J = 13Hz), 2.55 (1H, t , J = 8Hz), 2.2
3 (1H, m ), 1.90 (3H, m ), 1.71 (1H, d , J = 13Hz), 1.6
8 (3H, s ), 1.60 (3H, s ), 1.57 (3H, s ), 1.45 (3H,
s ), 1.33 (3H, s ), 1.22 (3H, s ), 1.13 (3H, s ) ¹³ C-NMR (C ₅ D ₅ N): 214.8, 213.7, 198.9, 147.4, 145.
5, 137.7, 120.5, 115.8, 110.3, 80.1, 70.3, 59.0, 51.
0, 49.5, 49.3, 48.6, 48.7, 46.7, 42.0, 35.8, 35.2,
32.2, 28.0, 25.4, 23.9, 22.7, 20.8, 20.4, 20.2, 1
8.4

Production Example 7 Fraction M7 (5.2 g) of Production Example 2 was fractionated by column chromatography using octadecyl silica gel with 50% -80% water / methanol to obtain 11 fractions (M7-1 to M7). -11) was obtained. The fractions M7-9 and M7-10 were purified by high performance liquid chromatography (mobile phase: 30% acetonitrile) using octadecylsilylated silica gel as a packing material, and compound (L) (in formula (2a), R ³ = β-Glc, R ⁴ R ⁵ = O
52 mg of H, R ⁶ = β-Glc-α-rhamnosyl group (Rhan) was obtained. 15 mg of this compound (L) was enzymatically decomposed by the method of Production Example 2 to give compound (M) (in the formula (2a), R ³ =
H, R ⁴ R ⁵ = OH, R ⁶ = H) was obtained.

Compound (L) colorless amorphous [α] _D ²³ + 6.4 ° (CH ₃ OH, C = 1.7) Negative HR-FAB-MS ( m / z ): 945.5419 (C ₄₈ H ₈₁ O ₁₈ req)
uires 945.5422) ¹ H-NMR (C ₅ D ₅ N): (skeleton part) 5.47 (1H, br.d. , J = 5H
z), 3.65 (1H, br.s. ), 1.57 (3H, s ), 1.56 (3H, s ),
1.53 (3H, s ), 1.29 (3H, s ), 1.22 (3H, s ), 1.00 (3
H, d , J = 7Hz), 0.89 (3H, s ), 0.87 (3H, s ). (Sugar part) 6.43 (1H, d , J = 1Hz), 5.10 (1H, d , J = 7Hz), 4.85
(1H, d , J = 8 Hz), 4.82 (1H, m ), 4.76 (1H, d , J = 1.7
Hz), 4.61 (1H, dd , J = 9, 3Hz), 4.48 (1H, dd , J = 12,
3Hz), 4.43 (1H, dd , J = 12, 2Hz), 4.33 (1H, dd , J = 1
2, 5Hz), 4.28 (1H, overlapped), 4.20 (5H, overlappe
d), 4.08 (1H, dd , J = 9, 9Hz), 3.92 (1H, overlappe
d), 3.83 (2H overlapped), 1.71 (1H, d , J = 6Hz), ¹³ CN
MR (C ₅ D ₅ N): 144.2, 118.4, 107.2, 101.7, 97.1, 87.
8, 81.6, 79.8, 78.6, 78.0, 77.8, 77.5, 77.3, 75.4,
74.2, 72.6, 72.3, 72.1, 71.7, 69.5, 63.0, 51.2, 4
9.7, 47.4, 43.5, 42.3, 41.6, 40.1, 36.8, 36.1, 34.
5, 33.9, 32.7, 29.5, 28.9, 28.3, 27.6, 26.7, 26.3,
26.2, 24.5, 23.8, 21.8, 19.2, 18.9, 18.6, 17.0

Compound (M) colorless amorphous [α] _D ²³ + 37.5 ° (CH ₃ OH, C = 0.6) Negative HR-FAB-MS ( m / z ): 475.3732 (C ₃₀ H ₅₁ O ₄ requ)
ires 475.3787) ¹ H-NMR (C ₅ D ₅ N): 5.65 (1H, br.s. ), 3.73 (1H, br.
s. ), 1.53 (3H, s ), 1.48 (3H, s ), 1.42 (3H, s ), 1.3
4 (3H, s ), 1.19 (3H, s ), 1.00 (3H, d , J = 6Hz), 0.94
(3H, s ), 0.90 (3H, s ) ¹³ C-NMR (C ₅ D ₅ N): 144.2, 119.2, 79.1, 77.9, 76.2, 7
2.7, 51.0, 49.8, 47.4, 43.6, 43.2, 41.2, 40.2, 36.
9, 36.3, 34.5, 34.2, 30.8, 29.0, 28.2, 27.2, 26.7,
26.1, 25.9, 25.8, 24.6, 19.3, 18.9, 17.0

Production Example 8 The fraction M7 (5.2 g) of Production Example 2 was purified in the same manner as for compound (L), and compound (N) (in formula (2a), R ³ = β-Glc, R ⁴ R ⁵ = O, R ⁶ = β-Glc-α-Rha
m) 10 mg were obtained.

Compound (N) colorless amorphous [α] _D ²³ + 26.1 ° (CH ₃ OH, C = 2.8) Negative HR-FAB-MS ( m / z ): 943.5252 (C ₄₈ H ₇₉ O ₁₈ req)
uires 943.5266) ¹ H-NMR (C ₅ D ₅ N): (skeleton part) 4.49 (1H, br.d. , 4.6),
3.65 (1H, br.s. ), 1.58 (3H, s ), 1.57 (3H, s ), 1.5
1 (6H, s ), 1.12 (3H, s ), 0.94 (3H, s ), 0.91 (3H, d ,
J = 6Hz), 0.72 (3H, s ) (sugar portion) 6.43 (1H, br.s. ),
5.10 (1H, d , J = 7Hz), 4.85 (1H, m ), 4.83 (1H, d , J
= 8Hz), 4.76 (1H, d , J = 1 Hz), 4.61 (1H, dd , J = 9, 3H
z), 4.50 (1H, dd , J = 12, 3Hz), 4.44 (1H, dd , J = 12,
2Hz), 4.34 (1H, overlapped), 4.29 (1H, overlappe
d), 4.20 (5H, overlapped), 4.09 (1H, dd , J = 10, 9H
z), 3.92 (1H, overlapped), 3.83 (2H overlapped),
1.71 (1H, d , J = 6Hz) ¹³ C-NMR (C ₅ D ₅ N): 213.8, 141.2, 118.5, 107.2, 101.
7, 97.2, 84.1, 81.6, 79.8, 78.7, 78.2, 78.0, 77.5,
77.3, 75.5, 74.2, 72.6, 72.3, 72.1, 71.7, 69.5, 6
2.9, 62.7, 50.1, 49.6, 49.0, 48.9, 48.7, 43.9, 41.
9, 35.9, 35.9, 34.5, 33.7, 28.6, 28.4, 28.3, 28.1,
25.8, 24.1, 23.8, 22.1, 21.9, 20.3, 18.7, 18.6, 1
8.2

Example 9 As the fraction M3 obtained in Production Example 2, the compound (O) (formula M3
In (1a), R ¹= Β-Glc, R²= (C-3)) 6.
2 g was obtained. 30 mg of this compound (O) was used in the method of Production Example 2.
Enzymatically decomposes with compound (P) (smell of formula (1a)
And R¹= H, R²= (C-3)) was obtained.

Compound (O) colorless amorphous [α] _D ²⁰ −61.5 ° (CH ₃ OH, C = 2.2) ¹ H-NMR (C ₅ D ₅ N): (skeleton part) 6.45 (1H, br.s ) . ), 5.64
(1H, br.s. ), 4.92 (1H, t , J = 8Hz ), 3.70 (1H, br.
s. ), 3.47 (1H, ddd , J = 16, 11, 5Hz), 3.32 (1H, d , J =
15Hz), 3.27 (1H, ddd , J = 16, 11, 5Hz), 2.95 (1H, d ,
J = 7Hz), 2.89 (1H, d , J = 14Hz), 2.18 (2H, m ), 2.12 (1
H, m ), 1.92 (1H, m ), 1.86 (1H, m ), 1.85 (1H, m ), 1.6
9 (1H, d , J = 13Hz), 1.62 (3H, s ), 1.51 (3H, s ), 1.40
(3H, s ), 1.36 (3H, s ), 1.36 (3H, s ), 1.27 (3H, s ), 1.
18 (3H, s ), 1.00 (3H, s ) (sugar moiety) 5.46 (1H, d , J = 8H
z), 4.69 (1H, br.d. , J = 12Hz ), 4.62 (1H, dd , J = 9, 9
Hz), 4.56 (1H, dd , J = 12, 3Hz), 4.28 (1H, dd , J = 9, 9
Hz), 4.21 (1H, dd , J = 8, 8Hz), 4.04 (1H, m ) ¹³ C-NMR (C ₅ D ₅ N): 216.1, 214.0, 197.1, 146.8, 137.
0, 120.9, 120.5, 100.6, 80.1, 78.6, 78.4, 74.4, 70.
7, 70.3, 69.1, 61.9, 58.9, 50.9, 49.6, 49.4,49.3,
48.6, 46.5, 41.8, 38.4, 35.5, 32.7, 30.0, 29.8, 2
7.5, 25.5, 23.8, 20.8, 20.3, 20.1, 18.3

Compound (P) colorless amorphous [α] _D ²⁰ −42.9 ° (CHCl ₃ , C = 1.16) ¹ H-NMR (C ₅ D ₅ N): 6.32 (1H, d , J = 3H), 5.69 (1H, br.
s. ), 4.92 (1H, t , J = 8Hz ), 3.77 (1H, br.s. ), 3.47
(1H, ddd , J = 16, 11, 5Hz), 3.32 (1H, d , J = 15Hz), 3.
27 (1H, ddd , J = 16, 11, 5Hz), 2.95 (1H, d , J = 7Hz),
2.89 (1H, d , J = 14Hz), 2.18 (2H, m ), 2.12 (1H, m ),
1.92 (1H, m ), 1.86 (1H, m ), 1.85 (1H, m ), 1.69 (1H,
d , J = 13Hz), 1.62 (3H, s ), 1.51 (3H, s ), 1.40 (3H,
s ), 1.36 (3H, s ), 1.36 (3H, s ), 1.27 (3H, s ), 1.18 (3
H, s ), 1.00 (3H, s ) ¹³ C-NMR (C ₅ D ₅ N): 216.1, 214.0, 198.9, 147.4, 137.
7, 120.5, 115.8, 80.1, 70.3, 69.1, 58.9, 50.9, 49.
6, 49.3, 48.7, 48.6, 46.5, 41.8, 38.4, 35.5, 32.7,
30.0, 29.8, 27.5, 25.5, 23.8, 20.8, 20.3, 20.1, 1
8.3

Test Example 1 As a test sample for cytotoxic activity against tumor cells, the compounds (B), (D), (H), (I), (I) obtained in Production Examples 2, 3, 5, 7 and 9 were used. M) and (P) were used. The tumor cells include pharyngeal cancer cells (KB cells; American Type Culture Collection (AT
CC)), lung cancer cells (A549 cells; purchased from ATCC), and colon cancer cells (HT29 cells; purchased from ATCC). In the case of A549 cells and HT29 cells, 10 days
% Heat-inactivated fetal calf serum (FCS), 10 g / mL gentamicin-containing F-12 medium (manufactured by Sigma-Aldrich) was added to each well of a 96-well plate by 240 μl / well, and The cells were seeded so that the number of cells per well was 4 × 10 ³ cells. In the case of KB cells, the cell suspension prepared in Dulbecco's modified Eagle medium (manufactured by Nissui Pharmaceutical Co., Ltd.) containing 10% FCS on day 0 of the experiment was dispensed at 50 μl per well of a 96-well plate, 2 x 1 cells per well
The cells were seeded so as to give 0 ³ cells. These cells are 5
The cells were cultured under the conditions of% CO ₂ and 37 ° C.

On the first day of the experiment, a medium containing a fixed concentration of the test sample was added to the cell culture system by serial dilution. On the third day of the experiment, the cytotoxic activity of the test sample was measured using TetraColor One cell proliferation (Seikagaku Corporation) for A549 cells and HT29 cells, and CellTiter 96 ^TM A for KB cells.
It measured using Queous One Solution Cell Proliferation (made by Promega). The methods used to measure the cytotoxic activity used in this study are spectroscopically detecting and quantifying the activity of dehydrogenase in intracellular mitochondria using synthetic chromogenic substrates (WST-8 and MTS). Was used to measure the absorbance at a wavelength of 490 nm.
The concentration of the test sample when the number of cells was reduced to 50% was calculated by setting the cell number when culturing various cells in a medium not containing the test sample as 100%, and using this as the IC ₅₀ (μg / mL) did. The strength of activity of the test sample was evaluated by IC ₅₀ . The results obtained are listed in Table 1.

[0059]

[Table 1]

As shown in Table 1, compounds (B) to
(I) has cytotoxic activity against any of KB cells, A549 cells and HT29 cells, and particularly compound (I)
High activity was observed. On the other hand, the compound (M) showed cytotoxic activity on A549 cells and was found to have high selectivity.

Test Example 2 Angiogenesis Inhibitory Effect (Vascular Endothelial Cell Growth Inhibitory Activity) As test samples, the compounds (B), (D), (H) and (I) obtained in Production Examples 2, 3 and 5 were used. It was used. Human umbilical cord endothelial cells (HUVE cells; purchased from Dainippon Pharmaceutical Co., Ltd.) were used as cells.

1) Cells and Culture HUVE cells were cultured in CS-C medium (Cell Systems Corporation) and cultured in 100 mm collagen type I coated dish (manufactured by Iwaki Glass) under the conditions of 5% CO ₂ and 37 ° C. did. When used in the experiment, the cells were washed with PBS (-), trypsinized, and 1000 before reaching confluence.
What was centrifuged at xg for 8 minutes was diluted to a cell suspension having an appropriate concentration.

2) Proliferation Inhibition Assay HUVE cells were plated on 96-well collagen type I coated plate at 5 × 10 ³ cells / 50 μL / well and cultured under the conditions of 5% CO ₂ and 37 ° C. After 4 hours, 50 μL of Dulbecco's modified Eagle's medium containing the test substance was added to each well and cultured for 4 days (5% CO ₂ , 37%).
℃). After culturing, 10 μL of WST-8 solution (Tetra Col
or One Cell proliferation assay system, manufactured by Seikagaku Corporation) was added to each hole. Incubate for 2 hours (5% C
O ₂ at 37 ° C) and microplate reader (SPECTRA M
The absorbance at 490 nm was measured with AX 250, Molecular Devices Ca, USA). Assuming that the absorbance of the control group (DMSO only added) is 100%, 50% of the test substance dissolved in DMSO is used.
The% growth inhibitory concentration (IC ₅₀ ) was determined. The results obtained are listed in Table 2.

[0064]

[Table 2]

As shown in Table 2, all the compounds were HU
Inhibition of VEC growth, and particularly high effects were observed for compounds (H) and (I).

Test Example 3 Compound (H) or (I) obtained in Production Example 5 was used as a test sample for angiogenesis inhibitory effect (capillary network formation inhibitory activity of vascular cells). Bovine aortic endothelial cells (BAE cells; purchased from Dainippon Pharmaceutical Co., Ltd.) were used as cells, and Dulbecco's modified Eagle medium containing 10% FCS (DMEM: Nissui Pharmaceutical Co., Ltd.) was used as the culture medium. I was there.

1) Cells and Culture BAE cells were cultured in Dulbecco's modified Eagle medium (Nissui Pharmaceutical) containing 10% fetal bovine serum and antibiotics. BA
E cells were cultured in a 100 mm collagen type I coated dish under the conditions of 5% CO ₂ and 37 ° C., and when used in the experiment, they were washed with PBS (−) before reaching confluency, treated with trypsin, and What was centrifuged at xg for 8 minutes was diluted to a cell suspension having an appropriate concentration.

2) Capillary network (lumen) formation in collagen type I gel Montesano et al. (Montesano, R.et.al, J. Cell Biol. 97:
1648-1652, 1983.) was partially modified. Collagen type I solution was prepared from adult rat tail,
Diluted with 0.1% (v / v) acetic acid solution. 10x concentrated DMEM
1 volume, 4 volumes of collagen type I solution and 11.76
Five volumes of a mg / mL sodium hydrogen carbonate solution were mixed on ice to give a collagen mixture. 96 ice-cold collagen mixture
50 μL was dispensed into each well of the well culture plate and gelled at 37 ° C. Approximately 2 × 10 ⁴ BAE cells are plated in each hole so that the surface of the gel becomes confluent.
Cultured for 2 days. Remove the medium on the gel and add 50
μL of ice-cold collagen mixture was added and left at 37 ° C. for 20 minutes to solidify the gel. 50 μL of Dulbecco's modified Eagle medium containing the test substance dissolved in DMSO was added to each well and cultured. 72 hours later, the formation of the capillary network (lumen) was observed under a microscope. The criteria for the effect of the test substance are negative (ineffective) when the network is formed, positive (effective) when the network is not formed at all or is fragmented even if formed, and apparently no network due to cytotoxicity. When it was not formed, it was regarded as toxic. If the test result is positive, the effective minimum concentration of the test substance in the test concentration range is described. The results obtained are listed in Table 3.

[0069]

[Table 3]

As shown in Table 3, Compounds (H) and (I) were found to have a capillary network formation inhibitory activity, and Compound (I) had a particularly high inhibitory activity.

[0071]

The compound of the present invention has high antitumor activity,
It is effective in treating various tumors such as pharyngeal cancer, lung cancer, and colon cancer. In addition, the compound of the present invention has an anti-angiogenic effect, and is capable of controlling not only tumors but also various diseases in vivo related to angiogenesis such as diabetic retinopathy.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Tripetch Kanchanaphum             2-5, Hikarigaoka, Higashi-ku, Hiroshima-shi, Hiroshima Asian text             Kaika Kaikan (72) Inventor Shusuke Hashimoto             1-1-19 Higashishimbashi, Minato-ku, Tokyo Stock market             Company Yakult Head Office (72) Inventor Ritsuo Aiyama             1-1-19 Higashishimbashi, Minato-ku, Tokyo Stock market             Company Yakult Head Office (72) Inventor Ken Matsuzaki             1-1-19 Higashishimbashi, Minato-ku, Tokyo Stock market             Company Yakult Head Office F-term (reference) 4C086 AA01 AA02 AA03 DA11 GA17                       MA01 MA52 MA66 NA14 ZB26                 4C088 AB19 AC04 AC05 AC11 CA06                       ZB26                 4C091 AA02 BB03 BB06 CC03 DD03                       EE07 FF02 FF06 GG01 HH02                       HH04 JJ01 KK12 LL03 LL06                       MM01 NN02 NN12 PA03 PA05                       PA09 PB03 QQ01

Claims (7)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ represents a hydrogen atom, a monosaccharide residue or a disaccharide residue, and R ² represents the following formulas (a) to (e): Represents a group selected from). 2. A compound represented by the general formula (2): (In the formula, R ³ represents a hydrogen atom or a monosaccharide residue, and R ⁴ and R
⁵ is a hydrogen atom and the other is a hydroxy group or the other is an oxo group together, and R ⁶ is a hydrogen atom or a disaccharide residue). 3. A medicine comprising the triterpene compound according to claim 1 or 2 as an active ingredient. 4. The medicine according to claim 3, which is an antitumor agent. 5. The medicine according to claim 3, wherein the triterpene compound according to claim 1 or 2 is contained as a Trichosanthes trixpidata extract containing the compound. 6. An angiogenesis inhibitor comprising the triterpene compound according to claim 1 or 2 as an active ingredient. 7. The angiogenesis inhibitor according to claim 6, wherein the triterpene compound according to claim 1 or 2 is contained as a Trichosanthes tricuspidata extract containing the compound.