JPH06172340A - New compound of xanthone and active oxygen eliminating agent or aldose reductase inhibitor comprising the same as active ingredient - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an active oxygen eliminating agent and an aldose reductase inhibitor without any fear of tachyphylaxis or side effects. CONSTITUTION:This compound of the formula (R is H or methyl), e.g. 3,6-di(3- methyl-2-butenyl)-1,4,5-trihydroxyxanthone. The compound is obtained by pulverizing a dried wood of Garcinia subelliptica belonging to the family Guttiferae and extracting the resultant pulverized substance with an organic solvent (e.g. methanol). An active oxygen eliminating agent is capable of manifesting excellent effects on peroxylipid suppressing, free radical and superoxide eliminating actions and useful for preventing and treating various diseases caused by in vivo reaction with excess active oxygen. An aldose reductase inhibitor is useful for preventing and treating diabetic complications such as diabetic cataract, retinopathy, renal failure, peripheral neuropathy and arteriosclerosis. This compound is used in the form of a medicine or a food.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to novel xanthone compounds, active oxygen scavenging agents and aldose reductase inhibitors containing them as active ingredients.

[0002]

2. Description of the Related Art In a normal living body, when bacteria or viruses, which are foreign substances to the body, enter, the phagocytes dissolve and remove the foreign substances taken in,
It has a function of producing active oxygen in cells to dissolve foreign substances. However, during abnormal times, more than necessary active oxygen is produced, which flows out to the outside of phagocytes and exerts the action of lysing in various tissues in the body to lyse normal cells or to stimulate various cells. It will cause obstacles.

In particular, the polyunsaturated fatty acid has a property that, due to its structure, it is very susceptible to a reaction by active oxygen generated in the living body and easily becomes a chemically active alkyl radical. Further, it reacts with oxygen to form a peroxide called hydroperoxide, that is, a lipid peroxide, via a peroxy radical. It further decomposes and polymerizes to give various aldehydes, ketones, polymers and the like.

The reaction in the living body due to the active oxygen as described above is also a cause of the occurrence of diseases such as cancer, arteriosclerosis, hypertension, and senile dementia. Further, in relation to aging, the relationship with lipid peroxidation has attracted particular attention. This is because it is considered that free radicals derived from active oxygen induce peroxidation of unsaturated fatty acids, which are constituents of biological membranes, and the resulting cell and tissue damage leads to aging.

The increase in lipid peroxide with aging is
It has already been proved by animal experiments. That is, it can be said that the ability of the living body to remove active oxygen, free radicals, lipid peroxides and the like decreases with aging. These cause the functional deterioration of cells, metabolic disorders, etc., and cause various diseases as described above.

[0006] The function of aldose reductase in the living body is still unknown, but at present, it is considered to work for regulating intracellular osmotic pressure. This aldose reductase is an enzyme involved in producing sorbitol from glucose in the polyol metabolism system.

[0007] The importance of the metabolism of polyol was revealed by its finding as a fructose production pathway which is an energy source of sperm. Before and after that, it was revealed that aldose reductase, which is the rate-limiting enzyme of this metabolic pathway, is present in capillaries, peripheral nerves, lenses, retinas, etc. where diabetic complications frequently occur. The importance in relation to is beginning to be recognized.

[0008] Normally, most of glucose taken up into cells is metabolized to glycolysis by hexokinase, which has a stronger affinity for glucose than aldose reductase, but in hyperglycemic conditions such as diabetes. In insulin-independent tissues, the increased aldose reductase activity facilitates the metabolism of polyols, causing various diabetic complications.

[0009]

To date, a large number of compounds exhibiting an active oxygen removing action and an aldose reductase inhibiting action have been reported, but most of them have been synthesized by a chemical method, and their properties have been reported. Currently, it is inevitable that the tachyphylaxis and various side effects caused by continuous use are unavoidable.

An object of the present invention is to provide an active oxygen scavenging agent and an aldose reductase inhibitory agent containing an extract from a plant, which is scarcely concerned in terms of such tachyphylaxis and side effects, as an active ingredient. is there.

[0011]

According to the present invention, a novel xanthone compound represented by the following general formula:
Isolated from organic solvent extract of Fukugi: R, R ', R "': hydrogen atom or methyl group

The xanthone compounds represented by the following general formula, including these novel xanthone compounds, act as an active oxygen scavenging agent or an active ingredient of an aldose reductase inhibitor. R ₁ : hydroxyl group, methoxy group R ₂ , R ₅ : hydrogen atom, hydroxyl group, methoxy group R ₃ : hydrogen atom, 3-methyl-2-butenyl group R ₄ : hydrogen atom, 1,1-dimethyl-2-butenyl group R ₆ : hydrogen atom, hydroxyl group, methoxy group, 3-methyl-2-butenyl group R ₇ : hydrogen atom, methoxy group R ₈ : hydrogen atom, hydroxyl group

[0013] Fukugi (Garcinia subelliptica) is a tall tree that belongs to the Hypericumaceae family and is widely distributed in the subtropical region south of Amami Oshima and reaches a height of about 15 to 20 m. It is planted as a windbreak forest in Okinawa and the Yaeyama Islands. . Since the core material of Fukugi has a deep yellow color, it has been used as a raw material for yellow dye in the old days, and it was also prescribed as a folk medicine for the treatment of asthma.

For such plants of the Hypericumaceae, many component studies have been conducted before, and it is known that xanthone compounds, bisflavone compounds and the like are contained. However, it has not been known at all that an organic solvent extract of Fukugi has an active oxygen scavenging action and an aldose reductase inhibitory action.

The xanthones (9-xanthenone) compound represented by the above general formula [I], [II] or [III] can be obtained by crushing a dried material of Fukugi and extracting it with an organic solvent. Examples of the organic solvent include n-hexane, chloroform, acetone, n-butanol, ethanol, methanol, ethyl acetate, methylene chloride and the like, and extraction with these organic solvents is performed in multiple stages. At this time, the extract is distributed between water and a water-immiscible organic solvent such as n-hexane, benzene, or ethyl acetate, and is suitable for column chromatography using a carrier such as silica gel, Celite, alumina, polystyrene, or dextran. Attached.

In addition to the above-mentioned xanthone compounds, the extract contains a novel 4 ', 6-dihydroxy-precursor which is a precursor thereof.
2,3 ', 4-trimethoxybenzophenone Which is converted into 2,3 ', 4,4', 6-pentamethoxybenzophenone by methyl etherification. These act as active ingredients of aldose reductase inhibitors.

In addition to the xanthone compounds represented by the above general formula [I], [II] or [III], known 1,6-dihydroxy-5-methoxyxanthone, 1,8-dihydroxy-6-methoxyxanthone , 4- (1,1-dimethyl-2-butenyl) -1,2,5-
The general formula [IV] including trihydroxyxanthone
The xanthone compound represented by the above acts as an active ingredient of an active oxygen scavenger or an aldose reductase inhibitor.

These xanthone compounds are provided in the form of medicines or foods. When it is used as a medicine, it is provided in the form of powder, granules, tablets, dragees, capsules, liquids, etc., and when it is used as a food, it is provided in the form of gum, candy, jelly, tablet confectionery, beverages, etc. It When used as a medicine, it is administered by oral administration, parenteral administration, inhalation, rectal administration, topical administration and the like. Parenteral administration includes subcutaneous injection, intravenous administration, intramuscular administration, intranasal administration, infusion and the like. The amount used is generally in the range of about 0.1 to 200 mg / kg body weight each time, and is usually administered 1 to 5 times a day. However, the exact dose is determined within the above range in consideration of the patient's age, body weight, symptoms, administration route, and the like.

[0019]

INDUSTRIAL APPLICABILITY The present invention provides an active oxygen scavenging agent and an aldose reductase inhibitor containing, as an active ingredient, a xanthone compound extracted and isolated from Fukurogi.

This active oxygen scavenging agent shows excellent effects on lipid peroxide inhibitory action, free radical scavenging action, superoxide scavenging action and the like, and is triggered by the reaction in vivo with excess active oxygen. It is effective in the prevention and treatment of various diseases caused.

Further, this aldose reductase inhibitor has an extremely excellent effect on the aldose reductase inhibitory action, and is effective for diabetic cataract, retinopathy,
It is effective in preventing and treating diabetic complications such as renal failure, peripheral neuropathy and arteriosclerosis.

[0022]

EXAMPLES The present invention will now be described with reference to examples.

Example 1 30 kg of dried material of Fukugi (collected on Ishigaki Island) was crushed and then at room temperature.
It was immersed in 90 L of methanol for 3 weeks and extracted. The filtrate was concentrated under reduced pressure, and the concentrate was added with 10 L of ethyl acetate and 10 L of water.
Distributed in. The ethyl acetate layer was concentrated under reduced pressure and the extract 50
I got 0g. After dissolving this extract in 1.5 L of methanol, 500 g of Celite was added and stirred, and the methanol was completely distilled off under reduced pressure.

The Celite adsorbent thus obtained is pulverized into fine powder and packed in a glass column (6 cm diameter). Charge the mixture with n-hexane.
(5 L), methylene chloride (12 L), ethyl acetate (15 L) and methanol (15 L) were sequentially extracted, and fraction 1 (1.5 g), fraction 2 (25 g) and fraction 3 (100
g) and fraction 4 (250 g) were obtained.

The whole amount of the fraction 2 was subjected to silica gel chromatography (Merck Kieselgel 60, 70 to 230 mesh, 750 g), and n-hexane-ethyl acetate (volume ratio 1: 1).
It was eluted with 3.2 L of the mixed solvent and fractionated into fractions 5 to 11 of 400 ml each. Fraction 6 (3.9 g) was subjected to column chromatography (Pharmacia Sephadex LH-
20, 400 ml) and eluted with methanol to fractionate into fractions 12 to 17 of about 25 ml each. Fraction 16 ~
17 was again subjected to silica gel chromatography (Merck Kiesel
gel 60, 230-400 mesh, 62g), n-hexane-
Elution with a mixed solvent of ethyl acetate (volume ratio 2: 1) and fractionation into fractions 13 to 38 of about 30 ml each yielded fraction 18
From 19 to 27 mg of orange needle crystals (test compound I) were obtained.

Since this crystal exhibits the following physicochemical properties, 3,6-di (3
-Methyl-2-butenyl) -1,4,5-trihydroxyxanthone was confirmed. Melting point: 206-209 ℃ Infrared absorption spectrum (CHCl ₃ ) ν cm ^-1 : 3725,1660,162
0,1510 UV absorption spectrum (EtOH) λ nm: 206 (ε24600), 250
(ε30300), 264 (ε26900), 320 (ε9020) High resolution EI mass spectrum: 380.1617 [M], calcd. 380.
_{1624 for C 23 H 24 O 5} EI mass spectrum: (. Rel.int) m / z 380 [M], 324 1 H NMR (400MHz, DMSO-d 6): δ1.72 (6H, s), 1.73 ( 6H, s),
3.40 (2H, d, J = 6.8Hz), 3.45 (2H, d, J = 6.8Hz), 5.32 (2H, t,
J = 6.8Hz), 6.56 (1H, s), 7.20 (1H, d, J = 7.8Hz), 7.54 (1H,
d, J = 7.8Hz), 9.21 (1H, s), 9.87 (1H, s), 11.8 (1H, s) ¹³ C NMR (100MHz, DMSO-d ₆ ): δ17.6 (× 2), 25.4 ( × 2), 2
8.3, 28.6, 106.2, 109.5, 114.5, 118.4, 121.1, 121.
2, 124.9, 132.6, 132.8, 134.5, 134.6, 137.1, 142.
0, 142.9, 143.9, 152.0, 181.4

Example 2 To a solution of 7 mg of the novel xanthone compound obtained in Example 1 in 0.5 ml of anhydrous dimethylformamide was added 3 mg of sodium hydride at 0 ° C., and the mixture was stirred for 10 minutes and then methyl iodide 0.5 was added. ml was added. Return the temperature of the reaction solution to room temperature,
After stirring for 1 day, water was added and the mixture was extracted with ether. The ether layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. 8.9 mg of the obtained concentrate was subjected to silica gel chromatography (Merck Ki
eselgel 60, 70-230 mesh, 0.5 g) and eluted with a mixed solvent of n-hexane-ethyl acetate (volume ratio 2: 1) to give a new xanthone compound, 2,6-di (3-methyl- 3.8 mg of 2-butenyl) -1,4,5-trimethoxyxanthone was obtained as an amorphous powder. Infrared absorption spectrum (CHCl ₃ ) ν cm ^-1 : 1660,1602,156
6,1489 High resolution EI mass spectrum: 422.2068 [M], calcd. 422.
_{2093 for C 26 H 30 O 5} EI mass spectrum: (. Rel.int) m / z 422 [M] (100), 407 1 H NMR (400MHz, CDCl 3): δ1.75 (6H, d, J = 1.0Hz), 1.76 (6
H, d, J = 1.0Hz), 3.49 (4H, d, J = 7.3Hz), 3.97 (3H, s), 4.01
(3H, s), 4.09 (3H, s), 5.29 (2H, m), 6.58 (1H, s), 7.14 (1
H, d, J = 8.3Hz), 7.95 (1H, d, J = 8.3Hz)

Example 3 Fraction 8 (3.15 g) obtained in Example 1 was subjected to column chromatography (Sephadex LH-20, 400 ml) and eluted with methanol to obtain 25 ml fractions.
Fractionated to 39-43. Fractions 41 to 42 (1.06 g) were again subjected to silica gel chromatography (Wakogel C-300, 20
0 g) and eluted with a mixed solvent of chloroform-methanol (volume ratio 9: 1) to give orange needle crystals (test compound I
49 mg of I) was obtained.

Since this crystal has the following physicochemical properties, it was confirmed that it was a novel xanthone compound, 1,2,5-trihydroxyxanthone. Melting point: 248-251 ℃ Infrared absorption spectrum (CHCl ₃ ) ν cm ^-1 : 3400,1649,159
0,1494 Ultraviolet absorption spectrum (EtOH) λ nm: 204 (ε9200), 243
(ε15600), 262 (ε17200) High resolution EI mass spectrum: 244.0374 [M], calcd. 244.
0372 for C ₁₃ H ₈ O ₅ EI Mass spectrum: m / z (rel.int.) 244 [M] (100) ¹ H NMR (400MHz, DMSO-d ₆ ): δ6.99 (1H, d, J = 9.2Hz), 7.26
(1H, t, J = 7.8Hz), 7.33 (1H, dd, J = 7.8,2.0Hz), 7.34 (1H,
d, J = 9.2Hz), 7.60 (1H, dd, J = 7.8,2.0Hz), 9.34 (1H, s), 1
0.47 (1H, s), 12.5 (1H, s) ¹³ C NMR (100MHz, DMSO-d ₆ ): δ106.2, 108.5, 114.6, 12
0.6, 120.7, 123.8, 124.5, 139.3, 145.5, 146.4, 14
7.4, 148.1, 182.5

Example 4 5.5 mg of the novel xanthone compound obtained in Example 3 was subjected to the same reaction as in Example 2 to obtain 15.2 mg of a concentrate. This concentrate was similarly subjected to silica gel chromatography and eluted with methylene chloride-ethyl acetate (volume ratio 5: 1) mixed solvent to give a new xanthone compound 1,
7 mg of 2,5-trimethoxyxanthone was obtained as an amorphous powder. Infrared absorption spectrum (CHCl ₃ ) ν cm ^-1 : 1650,1590,147
0,1440 High resolution EI mass spectrum: 286.0820 [M], calcd. 286.
0841 for C ₁₆ H ₁₄ O ₅ EI Mass spectrum: m / z (rel.int.) 286 [M] (98), 271 (10
0) ¹ H NMR (400 MHz, CDCl ₃ ): δ3.94 (3H, s), 4.02 (3H, s), 4.0
3 (3H, s), 7.20 (1H, dd, J = 7.8,1.5Hz), 7.26 (1H, t, J = 7.8H
z), 7.37 (2H, s), 7.87 (1H, dd, J = 7.8,1.5Hz)

Example 5 Fraction 10 (1.2 g) obtained in Example 1 was subjected to silica gel chromatography (Wakogel C-300, 60 g) and mixed with ethyl acetate-methylene chloride (volume ratio 1: 5). Upon elution, orange prismatic crystals (test compound III) became 3
5 mg was obtained.

Since this crystal has the following physicochemical properties, it was confirmed to be a novel xanthone compound, 2,6-dihydroxy-1,5-dimethoxyxanthone. Melting point: 224-226 ° C Infrared absorption spectrum (CHCl ₃ ) ν cm ^-1 : 3217,1685,150
8 Ultraviolet absorption spectrum (EtOH) λ nm: 204 (ε16100), 238
(ε45600), 310 (ε10000) High resolution EI mass spectrum: 288.0619 [M], calcd. 288.
0634 for C ₁₅ H ₁₂ O ₆ EI Mass spectrum: m / z (rel.int.) 288 [M] (85), 270 (10
0) ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 3.78 (3H, s), 3.88 (3H, s),
6.92 (1H, d, J = 9.3Hz), 7.28 (1H, d, J = 9.3Hz), 7.72 (1H, d,
J = 9.3Hz), 9.42 (1H, s), 10.56 (1H, s) ¹³ C NMR (100MHz, DMSO-d ₆ ): δ60.7, 60.9, 113.4, 113.
5, 115.3, 115.9, 121.3, 123.2, 134.0, 145.3, 146.
7, 149.5, 149.8, 155.4, 174.3

Example 6 5.0 mg of the novel xanthone compound obtained in Example 5 was subjected to the same reaction as in Example 2 to obtain 15.2 mg of a concentrate. This concentrate was similarly subjected to silica gel chromatography and eluted with a mixed solvent of methylene chloride-ethyl acetate (volume ratio 4: 1) to give 1,2,5,6-new xanthones.
Tetramethoxyxanthone 7 mg was obtained as an amorphous powder. Infrared absorption spectrum (CHCl ₃ ) ν cm ^-1 : 1655,1601 High resolution EI mass spectrum: 316.0925 [M], calcd. 316.
0947 for C ₁₇ H ₁₆ O ₆ EI Mass spectrum: m / z (rel.int.) 316 [M] (95), 301 (10
0) ¹ H NMR (400 MHz, CDCl ₃ ): δ3.94 (3H, s), 4.00 (3H, s), 4.0
1 (6H, s), 6.98 (1H, d, J = 9.3Hz), 7.32 (1H, d, J = 9.3Hz),
7.34 (1H, d, J = 9.3Hz), 8.05 (1H, d, J = 9.3Hz)

Example 7 Fraction 9 (1.78 g) obtained in Example 1 was subjected to silica gel chromatography (Wakogel C-300, 170 g), and methylene chloride-ethyl acetate (volume ratio 12: 1) mixed solvent was used. It was eluted and fractionated into fractions 44 to 50 of about 100 ml each.

Fraction 44 (161 mg) was subjected to column chromatography packed with Cosmocil 75C ₁₈ -OPN (manufactured by Nacalai Tesque, 10 g), which is a carrier for reversed phase chromatography, and methanol-water (volume ratio 8: 2) Elution with the mixed solvent gave 7 mg of a powder (test compound IV).

Since this powder has the following physicochemical properties, it is a precursor of a novel xanthone compound.
It was confirmed to be ′, 6-dihydroxy-2,3 ′, 4-trimethoxybenzophenone. Infrared absorption spectrum (CHCl ₃ ) ν cm ^-1 : 3400,1618,157
9,1514 Ultraviolet absorption spectrum (EtOH) λ nm: 206 (ε56700), 226
(ε26300), 305 (ε16700) High resolution EI mass spectrum: 304.0957 [M], calcd. 304.
0967 for C ₁₆ H ₁₆ O ₆ EI Mass spectrum: m / z (rel.int.) 304 [M] (78), 303 [M-
1] ¹ H NMR (400 MHz, CDCl ₃ ): δ3.53 (3H, s), 3.77 (3H, s), 3.8
1 (3H, s), 5.96 (1H, d, J = 2.0Hz), 6.17 (1H, d, J = 2.0Hz),
6.89 (1H, d, J = 7.8Hz), 7.15 (1H, dd, J = 7.8,2.0Hz), 7.24
(1H, d, J = 2.0Hz) ¹³ C NMR (100MHz, CDCl ₃ ): δ55.2, 56.0, 56.3, 91.4, 9
3.7, 105.9, 110.8, 113.2, 124.1, 133.9, 145.9, 14
9.1, 161.4, 164.9, 165.8, 197.2

Example 8 3.5 m of the novel xanthone precursor compound obtained in Example 7
With respect to g, the same reaction as in Example 2 was carried out to obtain a concentrate of 37.5 mg. This concentrate was similarly subjected to silica gel chromatography, and n-hexane-ethyl acetate (volume ratio 1:
1) Elution with a mixed solvent gave 2.3 mg of 2,3 ', 4,4', 6-pentamethoxybenzophenone as an amorphous powder. Infrared absorption spectrum (CHCl ₃ ) ν cm ^-1 : 1653,1583,151
0,1456 High resolution EI mass spectrum: 332.1265 [M], calcd. 332.
1260 for C ₁₈ H ₂₀ O ₆ EI Mass spectrum: m / z (rel.int.) 332 [M] (72), 315 (5
6), 301 (9), 195 (100) ¹ H NMR (400MHz, CDCl ₃ ): δ3.70 (6H, s), 3.87 (3H, s), 3.9
2 (3H, s), 3.93 (3H, s), 6.18 (2H, s), 6.81 (1H, d, J = 8.4H
z), 7.30 (1H, dd, J = 8.4,2.0Hz), 7.60 (1H, d, J = 2.0Hz)

Example 9 Fraction 43 (59 mg) obtained in Example 3 was subjected to silica gel chromatography (Merck Kieselgel 60, 230-400 mesh, 10 g), and methylene chloride-ethyl acetate (volume ratio) was used.
Elution with a 15: 1 mixed solvent gave 17 mg of orange prismatic crystals (test compound V).

Since this crystal has the following physicochemical properties, it was confirmed to be 1,2-dihydroxy-5,6-dimethoxyxanthone which is a novel xanthone compound. Melting point: 166-168 ℃ Infrared absorption spectrum (film) ν cm ^-1 : 3429,1726,158
9,1452 Ultraviolet absorption spectrum (EtOH) λ nm: 207 (ε14500), 235
(ε19000), 263 (ε13500) High-resolution EI mass spectrum: 288.0621 [M], calcd. 288.
0634 for C ₁₅ H ₁₂ O ₆ EI Mass spectrum: m / z (rel.int.) 288 [M] (100), 245 (3
0), 228 (32) ¹ H NMR (400MHz, DMSO-d ₆ ): δ3.94 (3H, s), 3.98 (3H, s),
6.98 (1H, d, J = 8.8Hz), 7.25 (1H, d, J = 8.8Hz), 7.28 (1H, d,
J = 8.8Hz), 7.90 (1H, d, J = 8.8Hz), 9.34 (1H, s), 12.58 (1
H, s) ¹³ C NMR (100 MHz, DMSO-d ₆ ): δ56.5, 60.9, 106.1, 108.
1, 109.6, 113.9, 121.1, 123.9, 135.6, 140.2, 147.
7, 148.2, 150.2, 158.0, 181.5

Example 10 Fraction 40 (280 mg) obtained in Example 3 was subjected to silica gel chromatography (Wakogel C-300, 50 g),
Elution with a mixed solvent of ethyl acetate-methylene chloride (volume ratio 15: 1) gave 7.8 mg of a yellow powder (test compound VI).

The physicochemical properties of this powder are described in J. Chem. So
c. Perkin Trans. It was identified as 1,6-dihydroxy-5-methoxyxanthone because it was identical to that of the compound described in I, page 1831 (1981).

Example 11 Ocher crystals from the fraction 50 obtained in Example 7
22 mg of (test compound VII) was obtained. The physicochemical properties of this crystal are described in J. Chem. Soc. It was identified as 4- (1,1-dimethyl-2-butenyl) -1,2,5-trihydroxyxanthone since it was identical to that of the compound described in (C), page 2186 (1966).

Example 12 Fraction 7 (1.78 g) obtained in Example 1
Silica gel chromatography (Merck Kieselgel 60, 2
30-400 mesh, 170 g) Methylene chloride-ethyl acetate (volume ratio 12: 1) mixed solvent elution and column chromatography (Sephadex LH-20, 30 ml) methanol-methylene chloride (volume ratio 8: 2) mixture Repeated elution with the solvent gave 13 mg of yellow needle crystals (test compound VIII).

The physicochemical properties of this crystal are described in Helv. Chim.
It was identified as 1,8-dihydroxy-6-methoxyxanthone, since it was identical to that of the compound described in Acta., 68: 2359 (1985).

[Pharmacological Action] Regarding the test compounds I to VIII,
In order to confirm that these compounds have an active oxygen scavenging action and an aldose reductase inhibitory action, the following four types of tests were conducted. Lipid peroxide inhibition test (LPO): 7 (W / V)% rat brain homogenate in 40 mM phosphate buffer (pH 7.4, 14.2 mM Na concentration)
50 μl of the test compound or water (blank) is added to 5 ml (containing Cl), and the mixture is shaken at 37 ° C. for 1 hour. Next, after adding 2 ml of 28% trichloroacetic acid aqueous solution, centrifugation at 3,000 rpm for 10 minutes was performed. It was heated for a minute and reacted. Spectrophotometer to measure the concentration of the resulting red solution
(Wavelength 532 nm) was quantified to determine the inhibition rate. At that time, control
As a (reference), a 28% trichloroacetic acid aqueous solution was added before shaking at 37 ° C., and the same reaction and treatment was used. Free radical scavenging test (DPPH): 0.1M concentration of 1,
Ethanol solution of 1-diphenyl-2-picrylhydrazyl
0.3 ml of the test compound was added to 2.7 ml, and the amount of decrease in absorbance after 20 minutes was measured with a spectrophotometer (wavelength 517 nm). In addition,
The inhibition rate was calculated assuming that 15 μg / ml (final concentration) of ascorbic acid was 100%. Superoxide elimination test (SO): 0.3M potassium phosphate buffer (pH 7.8, ethylenediaminetetraacetic acid)
Disodium salt 0.6 mM contained) 250 μl, Cytochrome C (0.06 mM)
250 μl, 0.3 mM xanthine aqueous solution 250 μl and water 500 μl
To the mixed solution containing 150 μl of the test compound or water, 100 μl of xanthine oxidase (7.5 to 15 × 10 ⁻⁵ mM) was added.
After the addition of, the increase in absorbance at a wavelength of 550 nm at 25 ° C was continuously recorded for 2 minutes, and a 1-minute change value was obtained from the linear part,
This was defined as the inhibition rate. Aldose reductase inhibitory activity test (AR): (Preparation of enzyme solution)
After homogenization in M phosphate buffer (pH 7.4) and centrifugation, the supernatant was salted out with 40-75% ammonium sulfate aqueous solution. The resulting enzyme solution was adjusted to a concentration of 0.015 to 0.020 U / ml. 1 U at this time indicates the activity of oxidizing 1 μM NADPH in 1 minute. (Activity test) 0.2M phosphate buffer (pH 6.2), 2M ammonium sulfate aqueous solution 200μl, 16mM NADPH 10μl, enzyme solution 20μ
l, 250 μl water and 10 μl test compound or water (blank)
Was added, 10 μl of 1.0 M DL-glyceraldehyde was added thereto, and the enzyme reaction was carried out at 30 ° C. The amount of decrease in NADPH after 10 minutes was determined from the decrease in absorbance at a wavelength of 340 nm, and the inhibition rate was calculated.

The results obtained are shown in the following table. The concentration of each test compound is 10 μg / ml. Inhibition rate (%) Test compound LPO DPPH SO AR I 18.6 24.0 0.0 18.9 II 40.5 94.2 67.3 39.9 III 4.4 2.6 5.0 46.9 IV 5.6 0.0 0.0 21.7 V 76.0 57.6 29.1 31.4 VI 12.2 5.2 33.5 57.8 VII 56.1 29.6 60.0 40.9 VIII 96.0 91.8 29.1 24.4

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Harumi Tako Insei, Kawabe-cho, Iwaki, Fukushima 63 (72) Inventor Mitsuaki Kodama 286 Nishiyama, Kamihama-cho, Tokushima, Tokushima

Claims (8)

[Claims] 1. A general formula (Wherein R is a hydrogen atom or a methyl group) and xanthone compounds. 2. The general formula (Here, R ′ is a hydrogen atom or a methyl group) A xanthone compound. 3. The general formula (Here, R ″ is a hydrogen atom or a methyl group) A xanthone compound. 4. An active oxygen scavenging agent comprising an organic solvent extract of Fukugi containing the xanthone compound according to claim 1. 5. An aldose reductase inhibitor comprising an organic solvent extract of Fukugi containing the xanthone compound of claim 1. 6. The general formula (Here, R ₁ is a hydroxyl group or a methoxy group, and R ₂ , R ₅
Is a hydrogen atom, a hydroxyl group or a methoxy group, R ₃ is a hydrogen atom or a 3-methyl-2-butenyl group, R ₄ is a hydrogen atom or a 1,1-dimethyl-2-butenyl group, R ₆ is A hydrogen atom, a hydroxyl group, a methoxy group or a 3-methyl-2-butenyl group, R ₇ is a hydrogen atom or a methoxy group, and R ₈ is a hydrogen atom or a hydroxyl group) effective xanthone compounds Active oxygen scavenging agent as a component. 7. The general formula (Here, R ₁ is a hydroxyl group or a methoxy group, and R ₂ , R ₅
Is a hydrogen atom, a hydroxyl group or a methoxy group, R ₃ is a hydrogen atom or a 3-methyl-2-butenyl group, R ₄ is a hydrogen atom or a 1,1-dimethyl-2-butenyl group, R ₆ is A hydrogen atom, a hydroxyl group, a methoxy group or a 3-methyl-2-butenyl group, R ₇ is a hydrogen atom or a methoxy group, and R ₈ is a hydrogen atom or a hydroxyl group) effective xanthone compounds An aldose reductase inhibitor as a component. 8. The general formula An aldose reductase inhibitor comprising a benzophenone derivative represented by (wherein R ″ is a hydrogen atom or a methyl group) as an active ingredient.