KR19980021543A - Chromone derivatives and preparation method thereof - Google Patents

Abstract

The present invention relates to a novel chromone compound derived from aloesin, which is one of the active ingredients of aloe. More specifically, the present invention relates to a novel chromone derivative represented by the following formula (1), a preparation method thereof, and a pharmaceutical composition containing the compound of formula (1) as an active ingredient.

[Formula 1]

In the above formula,

R ₁ represents a group of R ₄ -CO-, wherein R ₄ represents phenyl mono- or di-substituted or unsubstituted by hydroxy, acyloxy, halogen, alkyl, alkoxy, amino, nitro or acylamino , Alkenyl, alkyl, or phenylalkenyl unsubstituted or substituted by hydroxy, acyloxy, halogen, alkyl, alkoxy, amino or nitro at the phenyl moiety,

R ₂ and R ₃ each represent hydrogen;

R ₂ represents a benzoyl group,

R ₁ and R ₃ each represent hydrogen;

R ₃ represents an alkyl or benzyl group unsubstituted or substituted by hydroxy, alkyl, alkoxy, amino or nitro at the phenyl moiety,

R ₁ and R ₂ each represent hydrogen.

Description

Chromone derivatives and preparation method thereof

The present invention relates to a novel chromone compound derived from aloesin, which is one of the active ingredients of aloe. More specifically, the present invention is a novel chromone derivative of Formula 1 below, which has excellent cell growth promotion and cell damage suppression as a derivative of aloesin, a preparation method thereof, and a pharmaceutical composition containing the chromone derivative as an active ingredient. It is about.

[Formula 1]

In the above formula,

R ₁ represents a group of R ₄ -CO-, wherein R ₄ represents phenyl mono- or di-substituted or unsubstituted by hydroxy, acyloxy, halogen, alkyl, alkoxy, amino, nitro or acylamino , Alkenyl, alkyl, or phenylalkenyl unsubstituted or substituted by hydroxy, acyloxy, halogen, alkyl, alkoxy, amino or nitro at the phenyl moiety,

R ₂ and R ₃ each represent hydrogen;

R ₂ represents a benzoyl group,

R ₁ and R ₃ each represent hydrogen;

R ₃ represents an alkyl or benzyl group unsubstituted or substituted by hydroxy, alkyl, alkoxy, amino or nitro at the phenyl moiety,

R ₁ and R ₂ each represent hydrogen.

Aloe is a medicinal plant belonging to the family Liliaceae and has been widely used in folklore since ancient times because of its various effects. The main ingredients contained in aloe are anthrone-based substances such as aloin and homonataloin, aloe-emodin, chrysopanol and aloe saponarin. anthraquinone-based substances such as aloesaponarin I and II, and aloesin, aloeresin-A, isoaloeresin-A, aloeresin-C , Aloeresin-D, rabai-chromone and the like are known.

According to the prior art, aloesine has been reported to have a strong cell growth promoting effect by the present inventors among the chromone compounds of aloe, and it has also been found to have a sunscreen effect and a skin lightening activity on the skin. Based on these findings, the present inventors introduced various substituents into the side chain sites while maintaining the basic structure of aloesin to prepare various derivatives, and confirmed their pharmacological activity. As a result, it was confirmed that the chromone compounds of the formula (1) defined above exhibited more potent cell growth-promoting action than aloesin and inhibited cell damage such as inhibitory effect on kidney toxicity by chemicals such as cisplatin. The invention was completed.

1 is a graph showing the inhibitory effect of the compound of Formula 1 of the present invention on the renal toxicity induced by cisplatin administration by the NBT reduction rate by O ₂ radicals.

Accordingly, an object of the present invention is to provide a novel chromone compound represented by the following formula (1).

[Formula 1]

In the above formula,

R ₁ represents a group of R ₄ -CO-, wherein R ₄ represents phenyl mono- or di-substituted or unsubstituted by hydroxy, acyloxy, halogen, alkyl, alkoxy, amino, nitro or acylamino , Alkenyl, alkyl, or phenylalkenyl unsubstituted or substituted by hydroxy, acyloxy, halogen, alkyl, alkoxy, amino or nitro at the phenyl moiety,

R ₂ and R ₃ each represent hydrogen;

R ₂ represents a benzoyl group,

R ₁ and R ₃ each represent hydrogen;

R ₃ represents an alkyl or benzyl group unsubstituted or substituted by hydroxy, alkyl, alkoxy, amino or nitro at the phenyl moiety,

R ₁ and R ₂ each represent hydrogen.

Preferred among the chromone compounds of formula (I) according to the invention are those in which R ₁ represents a group of R ₄ -CO-, wherein R ₄ is mono- or di-substituted by hydroxy, acyloxy, halogen, alkyl or acylamino Or phenylalkenyl unsubstituted or substituted by hydroxy or alkoxy at the alkenyl, alkyl, or phenyl moiety, R ₂ and R ₃ each represent hydrogen; R ₂ represents a benzoyl group and R ₁ and R ₃ each represent hydrogen; R ₃ represents an alkyl or benzyl group, and R ₁ and R ₂ are each compounds representing hydrogen.

Among these preferred compounds, particularly preferred chromone compounds of the formula (1) in which R ₁ represents a group of R ₄ -CO-, wherein R ₄ is represented by hydroxy, acetyloxy, fluoro, methyl or acetylamino Mono- or di-substituted or unsubstituted phenyl, 2-propenyl, methyl, or phenyl-1-propenyl unsubstituted or substituted by hydroxy or methoxy at the phenyl moiety, R ₂ and R ₃ Each represents hydrogen; R ₂ represents a benzoyl group, and R ₁ and R ₃ each represent hydrogen; R ₃ represents a methyl or benzyl group, and R ₁ and R ₂ are each compounds representing hydrogen.

Representative examples of the compound of formula 1 according to the present invention include the following compounds:

8-C-β-D- [2'-O-para-acetylaminobenzoyl] glucopyranosyl-7-hydroxy-5-methyl-2- (2-oxopropyl) -4H-1-benzopyran-4 -On,

8-C-β-D-glucopyranosyl-7-O-benzoyl-5-methyl-2- (2-oxopropyl) -4H-1-benzopyran-4-one,

And

8-C-β-D- [2'-O- (E) -para-methoxycinnamoyl] glucopyranosyl-7-hydroxy-5-methyl-2- (2-oxopropyl) -4H-1 -Benzopyran-4-one.

The present invention also provides a method for preparing the chromone compound of Chemical Formula 1.

According to the present invention, the chromone compound of Chemical Formula 1 is

a) acylating aloesin of formula (5) with an organic acid of formula (6) or a reactive derivative thereof to produce a compound of formula (7), and obtaining a compound of formula (2) by transfer reaction of the resulting compound of formula (7),

b) reacting aloesin of formula 5 with benzoic acid to give a compound of formula 3,

c) can be prepared by a method of reacting aloesin of formula 5 with a compound of formula 8 to yield a compound of formula 4:

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

R ₄ -COOH

[Formula 7]

[Formula 8]

R ₃ -X

In the above formula,

R ₂ represents a benzoyl group,

R ₃ represents an alkyl or benzyl group unsubstituted or substituted by hydroxy, alkyl, alkoxy, amino or nitro at the phenyl moiety,

R ₄ represents phenyl mono- or di-substituted or unsubstituted by hydroxy, acyloxy, halogen, alkyl, alkoxy, amino, nitro or acylamino, or hydroxy, acyloxy at the alkenyl, alkyl or phenyl moiety. Phenylalkenyl unsubstituted or substituted by halogen, alkyl, alkoxy, amino or nitro,

X represents a halogen.

Hereinafter, the method of the present invention will be described in more detail.

Method (a):

According to the method (a) of the present invention, aloesin of formula 5 is acylated with an organic acid of formula 6 or a reactive derivative thereof to produce a compound of formula 7, wherein R ₁ is R ₄ by a transfer reaction of the compound of formula 7 It is possible to obtain compounds of formula (1), ie compounds of formula (2), which represent a group of -CO-, and R ₂ and R ₃ each represent hydrogen.

As the acylating agent in the acylation reaction of the method (a), an organic acid represented by the formula (6) or a reactive derivative thereof is used. Halides or anhydrides of organic acids may be used as the reactive derivative of the organic acid of formula (6). In the present reaction, the organic acid or the reactive derivative thereof can be used in a molar ratio of 1: 1-3, preferably 1: 1.2-1.5 with respect to aloesin.

This acylation reaction generally does not adversely affect the reaction with conventional solvents such as acetone, dioxane, acetonitrile, chloroform, dichloromethane, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl In sulfoxide, N, N-dimethylformamide, pyridine and the like or mixtures thereof.

When the organic acid of formula 6 is used in the free acid form in the acylation reaction, the reaction is preferably carried out in the presence of conventional condensing agents and bases. For this purpose, the condensing agents preferably used in the present invention are N, N'-dicyclohexylcarbodiimide, N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide and the like. Carbodiimide compounds, in particular N, N'-dicyclohexylcarbodiimide. Suitable bases used in the reaction also include inorganic bases such as alkali metal bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal or alkaline earth metal carbonates (e.g. sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, etc.) and Organic bases such as trialkylamines (eg trimethylamine, triethylamine, etc.) or pyridine compounds (eg pyridine, picoline, 4-dimethylaminopyridine, etc.).

The reaction temperature is not critical and the acylation reaction is generally carried out under cooling or warming, preferably at room temperature.

The compound of formula (7) produced by the acylation reaction as described above is transferred to the phenolic hydroxy group at position 7 without further treatment in situ and acyl group R ₄ -CO- is positioned at position 7 Transitioning to the hydroxyl group position of position 2 of the nearest sugar from to yields the desired compound of formula (2).

The resulting target compound can be separated and purified by post-treatment by conventional methods such as recrystallization, column chromatography, and the like.

Method (b):

In addition, among the compounds of the formula 1, compounds in which R ₁ and R ₃ are hydrogen and R ₂ represents a benzoyl group, that is, the compound of formula 3 are easily prepared by reacting aloesin of formula 5 with benzoic acid according to the method (b). can do.

In this reaction, benzoic acid is preferably used in the form of anhydride. In this reaction, benzoic acid is used in a molar ratio of 1: 1 to 3, preferably 1: 1.2 to 1.5, relative to aloesin.

The reaction of process (b) generally does not adversely affect the reaction, for example acetone, dioxane, acetonitrile, chloroform, dichloromethane, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl In sulfoxide, N, N-dimethylformamide, pyridine and the like or mixtures thereof.

The reaction of process (b) is also preferably carried out in the presence of a base, and bases which are preferably used for this purpose include alkali metal bicarbonates (eg sodium bicarbonate, potassium bicarbonate, etc.), alkali metal or alkaline earth metal carbonates (eg Inorganic bases such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like and trialkylamines (e.g. trimethylamine, triethylamine, etc.) or pyridine compounds (e.g. pyridine, picoline, 4-dimethylaminopyridine, etc.); The same organic base is included, in particular pyridine compounds.

After the reaction is completed, the compound of formula 3 produced can be separated and purified by conventional methods such as recrystallization, column chromatography and the like.

Method (c):

Among the compounds of formula (I) according to the invention, compounds wherein R ₁ and R ₂ are hydrogen and R ₃ represents alkyl or benzyl groups unsubstituted or substituted by hydroxy, alkyl, alkoxy, amino or nitro at the phenyl moiety, ie Compounds of formula (4) can be prepared by protecting all of the hydroxy groups of aloesin of formula (5) according to method (c) and then reacting with halogen compounds of formula (8) and removing the protecting groups from the resulting compounds.

The hydroxyl groups present in aloesine can be protected by acylating in a conventional manner, preferably using organic acids or reactive derivatives of organic acids such as organic acid halides, organic acid anhydrides and the like. The protection reaction is carried out in a solvent in the presence of a base and, if necessary, in the presence of a condensing agent. Bases, condensing agents and solvents which may be used for this purpose may include those mentioned in connection with the acylation reaction of process (a) above. Especially preferably, this protection reaction is carried out using acetic anhydride in the presence of pyridine to obtain a compound in which all five hydroxy groups present in aloesin are protected with an acetyl group and can be used in the next reaction.

The reaction temperature of this protective reaction is not particularly limited, but generally the reaction is carried out under cooling or warming, preferably at room temperature.

The protected compound thus obtained is subsequently reacted with a halogen compound of formula (8). The reaction is carried out in the presence of a strong base such as lithium bistrimethylsilylamide, such as acetone, dioxane, acetonitrile, chloroform, dichloromethane, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, ethyl acetate , Dimethyl sulfoxide, N, N-dimethylformamide, pyridine and the like or mixtures thereof, particularly preferably in tetrahydrofuran.

The reaction is generally carried out under cooling, preferably at a temperature of -78 ° C.

The resulting compound is subsequently subjected to a base such as alkali or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate, magnesium carbonate, sodium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, alkali metal or alkaline earth metal hydroxides, sodium methoxide, The desired compound of formula 4 is prepared by removing hydroxy protecting group by hydrolysis using inorganic base such as alkali metal alkoxide such as sodium ethoxide, potassium t-butoxide and the like. For this purpose, alkali metal carbonates such as potassium carbonate are preferably used as the base.

The reaction temperature is not particularly limited and is generally carried out under cooling to heating, preferably at room temperature.

The desired compound produced by method (c) can be separated and purified by conventional post-treatment methods such as recrystallization, column chromatography and the like.

The chromone compound of Formula 1 according to the present invention has a cell growth promoting action and cell damage inhibitory action, in particular, growth promotion and damage inhibition action for hepatocytes can be used as a preventive and therapeutic agent for liver disease.

Accordingly, the present invention also relates to a pharmaceutical composition for promoting cell growth and inhibiting cell damage, which contains a chromone compound of formula 1 as an active ingredient. Upon clinical use of a composition containing a compound of formula 1 according to the invention, the composition of the invention may be combined with a carrier which is customary in the pharmaceutical art, for example, in formulations customary in the pharmaceutical art, such as tablets, capsules, tro Injectable preparations, ointments in the form of oral preparations such as dentifrices, solutions and suspensions, injectable solutions or suspensions, or ready-to-use injectable dry powders which can be prepared by injection into a distillation shoe for injection. It may be formulated into various preparations such as topical preparations such as creams and liquids.

Carriers that can be used in the compositions of the present invention are conventional in the pharmaceutical field, for example in the case of oral preparations, binders, suspending agents, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments And fragrances. In the case of injectables, there are preservatives, analgesics, solubilizers, stabilizers, and the like, and in the case of topical administration, there are bases, excipients, lubricants, and preservatives. The pharmaceutical preparations thus prepared can be administered orally or parenterally, eg, intravenously, subcutaneously, intraperitoneally, or topically. In addition, in order to prevent the decomposition of the drug by gastric acid during oral administration, an antacid may be used in combination, or a solid oral dosage form such as a tablet may be formulated into a formulation coated with enteric skin.

The dosage of the novel chromone compound of formula 1 according to the present invention to the human body is appropriately selected depending on the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, the severity of the disease to be treated, etc. Generally, however, the adult is allowed to be administered in an amount of 5 to 500 mg, preferably 10 to 200 mg per day. Accordingly, when preparing the composition of the present invention in unit dosage form, each unit dosage form is formulated to contain 5 to 500 mg, preferably 10 to 200 mg of the compound of formula 1 in consideration of the above-mentioned effective dosage range. Can be mad. The unit dosage form thus formulated may be divided into several times, preferably 1 to 6 times, using specialized dosage methods or at regular time intervals according to the judgment of an expert who monitors or observes the administration of the drug as needed and the needs of the individual. can do.

The present invention is explained in more detail by the following examples and experimental examples, but the present invention is not limited in any way by these.

Example 1

₂₈ H ₂₈ O ₁₀ : Synthesis of Compound (1))

Take 100 mg (0.254 mM) of aloesin, 45.1 mg (0.305 mM) of cinnamic acid, 62.8 mg (0.305 mM) of dicyclohexylcarbodiimide, and 3.1 mg (0.0254 mM) of 4-dimethylaminopyridine, and place in a round flask. After addition, 5 ml of tetrahydrofuran was added thereto, and the mixture was stirred at room temperature for 12 hours under a nitrogen stream. After completion of the reaction by adding 1 ml of methanol, the mixture was dried under reduced pressure and chromatographed on a silica gel column using a mixed solvent of chloroform / methanol (12/1 → 8/1) as the eluent to yield 33.2 mg (1) of the titled compound (1). 25%) was obtained.

Melting Point: 150-154 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3402, 1716, 1652, 1600, 1385

Mass spectrum (FAB +, m / z): 525 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

2.24 (3H, s), 2.54 (3H, s), 5.05 (1H, d, J = 10.0 Hz), 5.53 (1H, t, J = 10.0 Hz), 6.10 (1H, s), 6.18 (1H, d , J = 16.0 Hz), 6.47 (1H, s), 7.36 (1H, d, J = 16.0 Hz), 7.22-7.49 (5H, m)

Example 2

₂₆ H ₂₆ O ₁₁ : Synthesis of Compound (2))

100 mg (0.254 mM) of aloesin, 37.1 mg (0.305 mM) of salicylic acid, 62.8 mg (0.305 mM) of dicyclohexylcarbodiimide, and 3.1 mg (0.0254 mM) of 4-dimethylaminopyridine were placed in a round flask and nitrogen-substituted. Thereafter, 5 ml of tetrahydrofuran was added thereto, followed by stirring at room temperature for 12 hours under a nitrogen stream. After completion of the reaction by adding 1 ml of methanol, the mixture was dried under reduced pressure and chromatographed on a silica gel column using a mixed solvent of chloroform / methanol (12/1 → 8/1) as the eluent to give 22.2 mg of the titled compound (2) (yield). 17%).

Melting Point: 144-147 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3436, 1699, 1684, 1653

Mass spectrum (FAB +, m / z): 515 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

2.25 (3H, s), 2.50 (3H, s), 5.15 (1H, d, J = 10.0 Hz), 5.71 (1H, t, J = 10.0 Hz), 6.10 (1H, s), 6.40 (1H, s ), 6.71 (2H, m), 7.30 (1H, t, J = 8.0 Hz), 7.70 (1H, d, J = 8.0 Hz)

Example 3

₂₆ H ₂₆ O ₁₀ : Synthesis of Compound (3))

100 mg (0.254 mM) of benzoic acid, 37.1 mg (0.305 mM) of benzoic acid, 62.8 mg (0.305 mM) of dicyclohexylcarbodiimide, and 3.1 mg (0.0254 mM) of 4-dimethylaminopyridine were added to a round flask and nitrogen-substituted. Thereafter, 5 ml of tetrahydrofuran was added thereto, and the mixture was stirred at room temperature under nitrogen stream for 60 hours. After completion of the reaction by adding 1 ml of methanol, the mixture was dried under reduced pressure and chromatographed on a silica gel column using a mixed solvent of chloroform / methanol (12/1 → 8/1) as the eluent to obtain 79.4 mg of the titled compound (3). 63%) was obtained.

Melting Point: 141-143 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3420, 1718, 1653, 1601, 1386, 1272

Mass spectrum (FAB +, m / z): 499 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

2.25 (3H, s), 2.50 (3H, s), 5.15 (1H, d, J = 9.0 Hz), 5.65 (1H, t, J = 9.0 Hz), 6.10 (1H, s), 6.39 (1H, s ), 7.26 (2H, t, J = 7.5 Hz), 7.40 (1H, t, J = 7.5 Hz), 7.89 (2H, brd)

Example 4

₂₃ H ₂₆ O ₁₀ : Synthesis of Compound (4))

Take 100 mg (0.254 mM) of aloesin, 26.3 mg (0.305 mM) of crotoninic acid, 62.8 mg (0.305 mM) of dicyclohexylcarbodiimide, and 3.1 mg (0.0254 mM) of 4-dimethylaminopyridine. After substitution, 5 ml of tetrahydrofuran was added thereto, and the mixture was stirred at room temperature for 60 hours under a nitrogen stream. After completion of the reaction by adding 1 ml of methanol, the mixture was dried under reduced pressure and chromatographed on a silica gel column using a mixed solvent of chloroform / methanol (12/1 → 8/1) as the eluent to obtain 46.9 mg of the titled compound (4) (yield). 40%) was obtained.

Melting Point: 116-120 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3421, 1653, 1600, 1559

Mass spectrum (FAB +, m / z): 463 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

1.75 (3H, d, J = 6.4 Hz), 2.31 (3H, s), 2.66 (3H, s), 5.07 (1H, d, J = 9.8 Hz), 5.57 (1H, t, J = 9.8 Hz), 5.62 (1H, d, J = 15.0 Hz), 6.17 (1H, s), 6.59 (1H, s), 6.74 (1H, m)

Example 5

₂₈ H ₂₈ O ₁₂ : Synthesis of Compound (5))

100 mg (0.254 mM) of acetylsalicylic acid, 54.9 mg (0.305 mM) of acetylsalicylic acid, 62.8 mg (0.305 mM) of dicyclohexylcarbodiimide, and 3.1 mg (0.0254 mM) of 4-dimethylaminopyridine were added to a round flask and nitrogen-substituted. After the addition, 5 ml of tetrahydrofuran was added thereto, and the mixture was stirred at room temperature for 60 hours under a nitrogen stream. After completion of the reaction by adding 1 ml of methanol, the mixture was dried under reduced pressure and chromatographed on a silica gel column using a mixed solvent of chloroform / methanol (12/1 → 8/1) as an eluent to obtain 49.3 mg of the titled compound (5) (yield). 35%) was obtained.

Melting Point: 155-158 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3421, 1685, 1654, 1559, 1386

Mass spectrum (FAB +, m / z): 557 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

1.80 (3H, s), 2.30 (3H, s), 2.68 (3H, s), 5.04 (1H, d, J = 9.6 Hz), 5.51 (1H, t, J = 9.6 Hz), 6.18 (1H, s ), 6.64 (1H, s), 6.79 (1H, d, J = 8.0 Hz), 6.77 (1H, t, J = 8.0 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.85 (1H, d , J = 8.0Hz)

Example 6

₂₆ H ₂₆ O ₁₂ : Synthesis of Compound (6))

Take 100 mg (0.254 mM) of aloe sine, 47.0 mg (0.305 mM) of gentisyl acid, 62.8 mg (0.305 mM) of dicyclohexylcarbodiimide, and 3.1 mg (0.0254 mM) of 4-dimethylaminopyridine. After the addition, 5 ml of tetrahydrofuran was added thereto, and the mixture was stirred at room temperature for 60 hours under a nitrogen stream. After completion of the reaction by adding 1 ml of methanol, the mixture was dried under reduced pressure and chromatographed on a silica gel column using a mixed solvent of chloroform / methanol (12/1 → 8/1) as the eluent to yield 13.3 mg (Yield) of the titled compound (6). 9.9%).

Melting Point: 126-129 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3436, 1718, 1652, 1541

Mass spectrum (FAB +, m / z): 531 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

2.29 (3H, s), 2.63 (3H, s), 5.23 (1H, d, J = 10.0 Hz), 5.75 (1H, t, J = 10.0 Hz), 6.20 (1H, s), 6.52 (1H, s ), 6.64 (1H, d, J = 8.8 Hz), 6.88 (1H, dd, J = 2.8, 8.8 Hz), 7.21 (1H, brd)

Example 7

₂₆ H ₂₅ O ₁₀ F: Synthesis of Compound (7))

100 mg (0.254 mM) of aloecin, 58.1 mg (0.305 mM) of 4-fluorobenzoic acid, 62.8 mg (0.305 mM) of dicyclohexylcarbodiimide, and 3.1 mg (0.0254 mM) of 4-dimethylaminopyridine were added to a round flask. After adding and nitrogen-substituted, tetrahydrofuran 5ml was added thereto, and it stirred for 60 hours at room temperature under nitrogen stream. After completion of the reaction by adding 1 ml of methanol, the mixture was dried under reduced pressure and chromatographed on a silica gel column using a mixed solvent of chloroform / methanol (12/1 → 8/1) as an eluent to give 62.9 mg (Yield) of the titled compound (7). 48.0%).

Melting Point: 135-138 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3446, 1717, 1654, 1603, 1508

Mass spectrum (FAB +, m / z): 517 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

2.34 (3H, s), 2.60 (3H, s), 5.21 (1H, d, J = 9.3 Hz), 5.73 (1H, d, J = 9.3 Hz), 6.19 (1H, s), 6.48 (1H, s ), 7.08 (2H, t, J = 8.7 Hz), 7.87 (2H, brdH)

Example 8

8-C-β-D- [2'-O-acetyl] glucopyranosyl-7-hydroxy-5-methyl-2- (2-oxopropyl) -4H-1-benzopyran-4-one ( C ₂₁ H ₂₄ O ₁₀ : Synthesis of Compound (8))

100 mg (0.254 mM) of aloesin, 17.4 µl (0.305 mM) of glacial acetic acid, 62.8 mg (0.305 mM) of dicyclohexylcarbodiimide, and 3.1 mg (0.0254 mM) of 4-dimethylaminopyridine were added to a round flask and nitrogen-substituted. Thereafter, 5 ml of tetrahydrofuran was added thereto, and the mixture was stirred for 48 hours at room temperature under a nitrogen stream. After completion of the reaction by adding 1 ml of methanol, the mixture was dried under reduced pressure and chromatographed on a silica gel column using a mixed solvent of chloroform / methanol (12/1 → 8/1) as the eluent to give 81.8 mg of the title compound (8) (yield). 73.9%) was obtained.

Melting Point: 156-162 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3412, 1726, 1661, 1602, 1386, 1227

Mass spectrum (FAB +, m / z): 437 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

1.77 (3H, s), 2.29 (3H, s), 2.69 (3H, s), 5.07 (1H, d, J = 10.0 Hz), 5.51 (1H, t, J = 10.0 Hz), 6.15 (1H, s ), 6.65 (1 H, s)

Example 9

₂₇ H ₂₈ O ₁₀ : Synthesis of Compound (9))

100 mg (0.254 mM) of aloecin, 41.5 mg (0.305 mM) of 4-methylbenzoic acid, 62.8 mg (0.305 mM) of dicyclohexylcarbodiimide, and 3.1 mg (0.0254 mM) of 4-dimethylaminopyridine were added to a round flask. After nitrogen replacement, 5 ml of tetrahydrofuran was added thereto, followed by stirring at room temperature for 60 hours under a nitrogen stream. After completion of the reaction by adding 1 ml of methanol, the mixture was dried under reduced pressure and chromatographed on a silica gel column using a mixed solvent of chloroform / methanol (12/1 → 8/1) as the eluent to give 58.7 mg of the titled compound (9) (yield). 45.2%).

Melting Point: 138-141 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3425, 1651, 1605, 1379

Mass spectrum (FAB +, m / z): 513 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

2.33 (3H, s), 2.33 (3H, s), 2.59 (3H, s), 5.21 (1H, d, J = 9.9 Hz), 5.73 (1H, t, J = 9.9 Hz), 6.20 (1H, s ), 6.62 (1H, s), 7.16 (2H, d, J = 7.9 Hz), 7.70 (2H, d, J = 7.9 Hz)

Example 10

₂₈ H ₂₉ O ₁₁ N: Synthesis of Compound (10))

100 mg (0.254 mM) of aloecin, 54.6 mg (0.305 mM) of para-acetylaminobenzoic acid, 62.8 mg (0.305 mM) of dicyclohexylcarbodiimide, and 3.1 mg (0.0254 mM) of 4-dimethylaminopyridine were added to a round flask. After adding and replacing with nitrogen, 5 ml of tetrahydrofuran was added thereto, and the mixture was stirred for 48 hours at room temperature under a nitrogen stream. After completion of the reaction by adding 1 ml of methanol, the mixture was dried under reduced pressure and chromatographed on a silica gel column using a mixed solvent of chloroform / methanol (12/1 → 8/1) as the eluent to give 61.3 mg of the title compound (10) (yield). 43.5%).

Melting Point: 180-182 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3392, 2925, 1653, 1604, 1263, 1083

Mass spectrum (FAB +, m / z): 556 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

2.11 (3H, s), 2.28 (3H, s), 2.59 (3H, s), 5.19 (1H, d, J = 10.0 Hz), 5.75 (1H, t, J = 10.0 Hz), 6.21 (1H, s ), 6.55 (1H, s), 7.54 (2H, d, J = 8.5 Hz), 7.75 (2H, brd)

Example 11

8-C-β-D-glucopyranosyl-7-O-benzoyl-5-methyl-2- (2-oxopropyl) -4H-1-benzopyran-4-one (C ₂₆ H ₂₆ O ₁₀ Synthesis of Compound (11))

Take 100 mg (0.254 mM) of aloe sine and 68.95 mg (0.305 mM) of benzoic anhydride, place in a round flask, replace with nitrogen, add 5 ml of tetrahydrofuran and 49.30 µl (0.610 mM) of anhydrous pyridine, and add room temperature under nitrogen stream. Stirred for 60 h. After completion of the reaction by adding 1 ml of methanol, the mixture was dried under reduced pressure and chromatographed on a silica gel column using a mixed solvent of chloroform / methanol (12/1 → 8/1) as the eluent to give 53.0 mg (yield) of the titled compound (11). 41.9%) was obtained.

Melting Point: 171-174 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3437, 1743, 1654, 1603, 1246, 1090

Mass spectrum (FAB +, m / z): 499 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

2.22 (3H, s), 2.73 (3H, s), 5.01 (1H, d, J = 9.7 Hz), 4.05 (1H, t, J = 9.7 Hz), 6.12 (1H, s), 6.69 (1H, s ), 7.45 (2H, t, J = 7.3 Hz), 7.58 (1H, t, J = 7.3 Hz), 8.02 (2H, d, J = 7.3 Hz)

Example 12

₂₆ H ₂₈ O ₉ : Synthesis of Compound (12))

100 mg (0.254 mM) of aloesin was added to a round flask, and nitrogen-substituted. Then, 0.3 ml of pyridine was added to dissolve it, and 0.6 ml of acetic anhydride was added thereto, followed by stirring at room temperature under nitrogen stream for 12 hours. The reaction product was chromatographed on a silica gel column using diethyl ether as eluent to afford 105.8 mg (yield 69.0%) of aloesin-pentaacetate. 100 mg (0.16 mM) of Aloecin-Pentaacetate was added to a round flask and nitrogen-substituted. Then, 3 ml of tetrahydrofuran was added thereto, stirred at -78 ° C for 30 minutes, and 0.2 ml of 1.0 M lithium bistrimethylsilylamide was added thereto. Slowly added. After further stirring the reaction mixture for 30 minutes, 24.3 μl (0.305 mM) of benzyl bromide was added thereto, and the reaction mixture was maintained at −78 ° C. for 6 hours, and then gradually heated up to further react at room temperature for 3 hours. One drop of saturated ammonium chloride solution was added to terminate the reaction, followed by extraction three times with ethyl acetate, and the ethyl acetate layer was washed once with saturated sodium chloride solution. The solution was dehydrated with anhydrous forget-me-not, concentrated under reduced pressure, chromatographed on a silica gel column using diethyl ether as eluent, concentrated under reduced pressure, dissolved in potassium carbonate / methanol solution and stirred for 12 hours. ) 37.9 mg was obtained.

Melting Point: 157-159 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3435, 1651, 1380, 1276

Mass spectrum (FAB +, m / z): 485 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

2.29 (3H, s), 2.58 (3H, s), 3.91 (1H, d, J = 12.3 Hz), 3.74 (1H, m), 4.99 (1H, d, J = 10.0 Hz), 5.92 (1H, s ), 6.63 (1H, s), 7.1-7.2 (5H, m)

Example 13

₂₀ H ₂₄ O ₉ : Synthesis of Compound (13))

100 mg (0.254 mM) of aloesin was added to a round flask, and nitrogen-substituted. Then, 0.3 ml of pyridine was added to dissolve it, and 0.6 ml of acetic anhydride was added thereto, followed by stirring at room temperature under nitrogen stream for 12 hours. The reaction product was chromatographed on a silica gel column using diethyl ether as eluent to afford 105.8 mg (yield 69.0%) of aloesin-pentaacetate. 100 mg (0.16 mM) of Aloecin-Pentaacetate was added to a round flask and nitrogen-substituted. Then, 3 ml of tetrahydrofuran was added thereto, stirred at -78 ° C for 30 minutes, and 0.2 ml of 1.0 M lithium bistrimethylsilylamide was added thereto. Slowly added. After further stirring the reaction mixture for 30 minutes, 12.5 μl (0.305 mM) of methyl iodide was added thereto, and the reaction mixture was maintained at −78 ° C. for 6 hours, and then gradually raised to a temperature at room temperature for 3 hours. One drop of saturated ammonium chloride solution was added to terminate the reaction, followed by extraction three times with ethyl acetate, and the ethyl acetate layer was washed once with saturated sodium chloride solution. The solution was dehydrated with anhydrous forget-me-not, concentrated under reduced pressure, chromatographed on silica gel column using diethyl ether as eluent, concentrated under reduced pressure, dissolved in potassium carbonate / methanol solution and stirred for 12 hours to obtain the title compound (13). ) 16.0 mg was obtained.

Melting Point: 158-161 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3436, 1651, 1386

Mass spectrum (FAB +, m / z): 409 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

1.41 (3H, d, J = 6.4 Hz), 2.21 (3H, s), 2.64 (3H, s), 4.89 (1H, d, J = 10.3 Hz), 6.12 (1H, s), 6.57 (1H, s )

Example 14

₂₈ H ₂₈ O ₁₁ : Synthesis of Compound (14))

Take 100 mg (0.254 mM) of aloesin, 50.0 mg (0.305 mM) of para-coumarilic acid, 62.8 mg (0.305 mM) of dicyclohexylcarbodiimide, and 3.1 mg (0.0254 mM) of 4-dimethylaminopyridine, and place it in a round flask. After nitrogen substitution, 5 ml of tetrahydrofuran was added thereto, followed by stirring at room temperature for 30 hours under a nitrogen stream. After completion of the reaction by adding 1 ml of methanol, the mixture was dried under reduced pressure and chromatographed on a silica gel column using a mixed solvent of chloroform / methanol (12/1 → 8/1) as an eluent to give 66.7 mg of the title compound (14) (yield). 48.7%) was obtained.

Melting Point: 146-150 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3436, 1651, 1605, 1107

Mass spectrum (FAB +, m / z): 541 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

2.32 (3H, s), 2.64 (3H, s), 5.13 (1H, d, J = 9.6 Hz), 5.63 (1H, t, J = 9.6 Hz), 6.08 (1H, d, J = 15.6 Hz), 6.19 (1H, s), 6.57 (1H, s), 6.74 (2H, d, J = 8.4 Hz), 7.35 (2H, d, J = 8.4 Hz), 7.39 (1H, d, J = 15.6 Hz)

Example 15

₂₉ H ₃₀ O ₁₁ : Synthesis of Compound (15))

A round flask was prepared by taking 100 mg (0.254 mM) of aloecin, 54.3 mg (0.305 mM) of 4-methoxycinnamic acid, 62.8 mg (0.305 mM) of dicyclohexylcarbodiimide, and 3.1 mg (0.0254 mM) of 4-dimethylaminopyridine. It was added to the nitrogen substituted, tetrahydrofuran 5ml was added thereto and stirred for 72 hours at room temperature under a nitrogen stream. After completion of the reaction by adding 1 ml of methanol, the mixture was dried under reduced pressure and chromatographed on a silica gel column using a mixed solvent of chloroform / methanol (12/1 → 8/1) as eluent to give 65.9 mg of the title compound (15) (yield). 46.9%).

Melting Point: 135-140 ℃

Infrared Absorption Spectrum (KBr) cm ^-1 : 3430, 1761, 1653, 1604, 1171

Mass spectrum (FAB +, m / z): 555 [M + H] ⁺

Hydrogen Magnetic Resonance Spectrum (δ ppm, CD ₃ OD):

2.33 (3H, s), 2.64 (3H, s), 3.79 (3H, s), 5.13 (1H, d, J = 9.4 Hz), 5.63 (1H, t, J = 9.4 Hz), 6.13 (1H, d , J = 16.0 Hz), 6.19 (1H, s), 6.57 (1H, s), 6.88 (2H, d, J = 8.7 Hz), 7.41 (1H, d, J = 16.0 Hz), 7.43 (2H, d , J = 8.7 Hz)

Experimental Example 1 Cell Growth Promotion Effect

The cell growth promoting effect of the compound of formula 1 according to the present invention was evaluated by the following thymidine introduction amount measurement method.

After dissolving 13.8 g of DMEM (Dulbecco's Modified Eagle's Medium, manufactured by Gibco) in 1 L of deionized water, the pH was adjusted to 7.4 using sodium carbonate and hydrochloric acid solution, and 10 ml calf serum, 1 × 10 ⁷ M insulin and gentamicin 50 ml. The culture was prepared by sterilization with a Millipore filter. The culture medium was inoculated with SK-HEP-1, a human liver cancer cell line distributed by Seoul National Cancer Institute, at a rate of 1 × 10 ⁶ cells per 25 cm 2 of T flask for 48 hours in a 37 ° C. incubator maintaining 5% carbon dioxide gas. Incubated. The culture was transferred to a 24-well culture vessel and passaged for 1 day, after which the test compound was dissolved in 70% ethanol and added at a concentration of 0.001 to 10 µg per ml of culture. The control group was treated with the same amount of 70% ethanol as a solvent instead of the compound. After 12 hours of treatment with the test compound, ³ H-labeled thymidine was treated to a concentration of 1 μCi / ml, and after 12 hours, the medium was removed from each well, the cells were fixed with methanol, and PBS (phosphate buffered saline). )). Wash twice with 10% trichloroacetic acid to remove unreacted thymidine. Cells were lysed with 1N sodium hydroxide and neutralized with 1N hydrochloric acid, and then radioactivity introduced into DNA was measured by scintillation counter (Pharmacia 1024).

The measured results are shown in Table 1 below.

Concentration (μM) Percentage of control Compound (3) Compound (5) Compound (12) Compound (13) Control 100 100 100 100 0.001 110 110 0.01 190 160 250 220 0.1 450 210 320 220 0.5 400 260 One 310 130 200 230 5 160 420 10 210 120 160 270

From the results described in Table 1, it was found that the compound of Formula 1 of the present invention has an effect of promoting the growth of SK-HEP-1 liver cancer cells.

Experimental Example 2: Kidney toxicity inhibitory effect

Fifteen hours after intraperitoneal casein administration of SD rats, the anesthetized rats were rinsed with saline containing 0.2% heparin, and the solution was centrifuged at 1200 rpm to add Tris-NH ₄ Cl and left on ice for 30 minutes. After centrifugation at 1200rpm, the isolated neutrophils were identified under a microscope, washed three times with Hank's BSS solution and counted.

Cisplatin was added at 0.02 mg / ml to the isolated neutrophil 4 × 10 ⁷ cells / ml to induce the production and secretion of superoxide anions. That is, NBT (Nitro Blue Tetrazolium) (0.8 ml) and neutrophils (0.1 ml) were preincubated for 1 minute, followed by cisplatin, incubated for 15 minutes, and centrifuged at 2500 rpm. 0.5N HCl (1 mL) and DMSO were added to the precipitate, mixed well with a vortex mixer, and the absorbance was measured at 560 nm.

In the case of the test group, each test compound (a few μg / ml) and the neutrophils (0.1 ml) were incubated for 10 minutes, followed by centrifugation to separate the neutrophils. Was carried out in the same manner as the cisplatin administration. The measured result is shown in FIG.

In FIG. 1, the renal toxicity inhibitory effect of the compound of the present invention was confirmed by expressing the absorbance (%) of formazan produced by NBT reduction induced by O ₂ radicals secreted from neutrophils by cisplatin stimulation. .

As shown in FIG. 1, the amount of O ₂ produced when the neutrophils were pretreated with the compounds of the formula (I) according to the present invention, in particular, with the compounds (6), (12) and (13), was 30% as compared with the addition of only cisplatin. , 30% and 15%, respectively, and these compounds were found to have a renal toxicity-reducing effect by cisplatin.

Experimental Example 3: Acute Toxicity Test

In order to determine the toxicity of the compounds of the present invention, acute toxicity was measured by oral administration and subcutaneous injection of compounds (3), (5), (12) and (13), which are representative compounds of the present invention, in the following manner.

(1) Acute Toxicity by Oral Administration

As the test animals, ICR mice weighing about 19 ± 1 g were given the maximum dose of 6.8 g / kg for each test compound and the azeotropic ratio of 1.5, respectively, 4.53 g / kg, 3.02 g / kg, 2.01 g / kg, and 1.34. A total of five dose groups of g / kg were divided. In each group, 10 males and females were used to observe the number, clinical symptoms, weight change and gross anatomical findings of animals that died for 14 days after oral administration of the above-mentioned dose of the test compound. Five test animals administered with physiological saline only were compared and evaluated as controls.

As a result, no animals died in any of the test groups during the 14 days of the entire test period, and therefore, the LD ₅₀ obtained by oral administration of the compound of the present invention was judged to be 6.8 g / kg or more. In addition, no significant weight change was observed in each test group compared to the control group, and no gross anatomical findings were observed.

(2) Acute Toxicity by Subcutaneous Injection

As the test animals, the SD rats of about-weight body weight were dosed at the maximum dose of 6.8 g / kg for each test compound and the azeotropic ratio was 1.5 at 4.53 g / kg, 3.02 g / kg, 2.01 g / kg and 1.34 g /, respectively. A total of five dose groups of kg were divided. In each group, 10 males and females were used to observe the number, clinical symptoms, weight change and gross anatomical findings of animals that died for 14 days after oral administration of the above-mentioned dose of the test compound. Five test animals administered with physiological saline only were compared and evaluated as controls.

As a result, no animals died in any of the test groups during the 14 days of the entire test period, and therefore, the LD ₅₀ obtained by oral administration of the compound of the present invention was judged to be 6.8 g / kg or more. In addition, no significant weight change was observed in each test group compared to the control group, and no gross anatomical findings were observed.

Claims (9)

Chromone derivatives represented by the following formula (1): [Formula 1] In the above formula, R ₁ represents a group of R ₄ -CO-, wherein R ₄ represents phenyl mono- or di-substituted or unsubstituted by hydroxy, acyloxy, halogen, alkyl, alkoxy, amino, nitro or acylamino , Alkenyl, alkyl, or phenylalkenyl unsubstituted or substituted by hydroxy, acyloxy, halogen, alkyl, alkoxy, amino or nitro at the phenyl moiety, R ₂ and R ₃ each represent hydrogen; R ₂ represents a benzoyl group, R ₁ and R ₃ each represent hydrogen; R ₃ represents an alkyl or benzyl group unsubstituted or substituted by hydroxy, alkyl, alkoxy, amino or nitro at the phenyl moiety, R ₁ and R ₂ each represent hydrogen. The compound according to claim 1, represented by the following general formula (2): Formula 2 In the above formula, R ₄ represents phenyl mono- or di-substituted or unsubstituted by hydroxy, acyloxy, halogen, alkyl or acylamino, or substituted or unsubstituted by hydroxy or alkoxy at an alkenyl, alkyl or phenyl moiety. Phenylalkenyl. 3. A compound according to claim 2, wherein R ₄ represents phenyl mono- or di-substituted or unsubstituted by hydroxy, acetyloxy, fluoro, methyl or acetylamino, or hydroxy at 2-propenyl, methyl or phenyl; Or phenyl-2-propenyl unsubstituted or substituted by methoxy. The compound according to claim 1, represented by the following general formula (3): [Formula 3] In the above formula, R ₂ represents a benzoyl group. The compound according to claim 1, represented by the following general formula (4): [Formula 4] In the above formula, R ₃ represents an alkyl or benzyl group. A compound according to claim 5, wherein R ₃ represents a methyl or benzyl group. The compound according to claim 1, wherein 8-C-β-D- [2'-O- (E) -crotonoyl] glucopyranosyl-7-hydroxy-5-methyl-2- (2-oxopropyl)- 4H-1-benzopyran-4-one, 8-C-β-D- 8-C-β-D-glucopyranosyl-7-O-benzoyl-5-methyl-2- (2-oxopropyl) -4H-1-benzopyran-4-one, and a compound selected from the group consisting. a) acylating aloesin of formula (5) with an organic acid of formula (6) or a reactive derivative thereof to produce a compound of formula (7), and obtaining a compound of formula (2) by transfer reaction of the resulting compound of formula (7), b) reacting aloesin of formula 5 with benzoic acid to give a compound of formula 3, c) a process for preparing a chromone derivative of formula (I) characterized by reacting aloesin of formula (5) with a compound of formula (8) to obtain a compound of formula (4): [Formula 1] [Formula 2] [Formula 3] [Formula 4] [Formula 5] [Formula 6] R ₄ -COOH [Formula 7] [Formula 8] R ₃ -X In the above formula, R ₁ represents a group of R ₄ -CO-, wherein R ₄ represents phenyl mono- or di-substituted or unsubstituted by hydroxy, acyloxy, halogen, alkyl, alkoxy, amino, nitro or acylamino , Alkenyl, alkyl, or phenylalkenyl unsubstituted or substituted by hydroxy, acyloxy, halogen, alkyl, alkoxy, amino or nitro at the phenyl moiety, R ₂ and R ₃ each represent hydrogen; R ₂ represents a benzoyl group, R ₁ and R ₃ each represent hydrogen; R ₃ represents an alkyl or benzyl group unsubstituted or substituted by hydroxy, alkyl, alkoxy, amino or nitro at the phenyl moiety, R ₁ and R ₂ each represent hydrogen; X represents a halogen. A composition for promoting cell growth and inhibiting cell damage, which contains a chromone derivative according to any one of claims 1 to 7 as an active ingredient together with a pharmaceutically acceptable carrier.