JPH0925278A - 2-thioflavone derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new 2-thioflavone derivative having excellent antitumor activity and cancer inhibition activity and useful as a drug for the treatment of cancer. SOLUTION: This 2-thioflavone derivative is expressed by formula I (R<1> , R<2> , W<1> and Z<1> are each H, a lower alkyl or an aralkyl; the bond annexed with a dotted line may be double bond), e.g. 2-(3,4-dibenzyloxyphenyl)-5,8- dibenzyloxythioflavone. The thioflavone derivative of formula I can be produced e.g. by reacting acetoquinone with a compound of formula II ((n) is an integer of 1-6; Y is H, a lower alkoxy or a halogen) to obtain a compound of formula III wherein R<1> and R<2> are each H, optionally substituting R<1> and R<2> with aralkyl or alkyl, adding a benzaldehyde derivative to the product to obtain a compound of formula IV, subjecting the compound to cyclization reaction accompanying deprotection reaction and dehydrogenating the obtained 2-thioflavanone derivative. The compounds of formula III and formula IV are also new compounds.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 2-thioflavone derivative or a salt thereof, and a medicament containing the same, which has excellent antitumor activity and carcinogenesis suppressing activity and is useful for cancer treatment.

[0002]

As an antitumor agent having a 2-phenylthioflavone skeleton, for example, JP-A-2-6473,
Anti-Cancer Drug Des., Vol. 4 (2), 161-169 (198
9), J. Med. Chem., Vol. 24 (7), 853 to 858 (1981), J. Med.
Heterocycl. Chem., Vol. 22 (6), 1593-1596 and J. He
The compounds described in terocycl. Chem., Vol. 22 (3), 821 to 824 are known.

However, these compounds have not been fully satisfactory as antitumor agents.

On the other hand, examples of 2-phenyl-5,8-substituted thioflavone derivatives include, for example, West German Patent Publication 8038.
No. 03 describes 2-phenyl-5,8-dimethoxythioflavone and 2- (4-methoxyphenyl) -5,8-dimethoxythioflavone.

However, this publication does not describe that these compounds have antitumor activity.

[0006]

Therefore, an object of the present invention is to provide a novel compound having excellent antitumor activity and useful as a medicine.

[0007]

In view of such circumstances, the inventors of the present invention have conducted extensive studies, and as a result, the novel 2-thioflavone derivative represented by the following general formula (1) has excellent antitumor activity and The present invention has been completed by discovering that it has a carcinogenic inhibitory action and is useful as a drug for treating cancer.

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

[0009]

Embedded image

[Wherein R ¹ , R ² , W ¹ and Z ¹ are the same or different and each represents a hydrogen atom, a lower alkyl group or an aralkyl group, and the broken line indicates that it may be a double bond. Show. ] The 2-thioflavone derivative represented by these or its salt, its manufacturing method, and its manufacturing intermediate are provided.

The present invention also provides a medicament containing the above-mentioned 2-thioflavone derivative or a salt thereof as an active ingredient.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The 2-thioflavone derivative of the present invention is represented by the above general formula (1), in which R is
Each group represented by ¹ , R ² , W ¹ and Z ¹ , and each group described in the present specification are specifically as follows.

As the lower alkyl group, for example, methyl,
1 to 10 carbon atoms such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl groups
6 straight chain or branched chain alkyl groups can be mentioned.

Examples of the aralkyl group include benzyl,
Examples thereof include those in which an alkyl group having 1 to 6 carbon atoms such as phenethyl or phenylpropyl group is substituted with a phenyl group.

Examples of the lower alkoxy group are methoxy, ethoxy, n-propoxy, isopropoxy and n-.
Butoxy, isobutoxy, sec-butoxy, tert
Examples include straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms such as -butoxy, n-pentyloxy, isopentyloxy, and n-hexyloxy groups.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the salt of the 2-thioflavone derivative represented by the general formula (1) of the present invention include basic salts prepared by reacting a pharmaceutically acceptable basic compound. Examples of the base salt include a base with an acidic group of the compound of the general formula (1), particularly a phenolic hydroxyl group, such as sodium, potassium,
Examples thereof include salts with alkali metals such as magnesium and calcium and alkaline earth metals. The 2-thioflavone derivative (1) of the present invention may have a plurality of isomers, and each of these isomers and a mixture thereof are also included in the present invention. Furthermore, the 2-thioflavone derivative (1) is
It may exist as a solvate such as a hydrate.

The 2-thioflavone derivative (1) of the present invention
Then, in the general formula (1), R¹, R ^Two, W¹And Z¹of
Those in which all are hydrogen atoms are preferred. Also, this article
In addition to the matter, OW¹Is also substituted at the 4-position of the benzene ring
Is more preferred, especially OW ¹And OZ¹Is a benzene ring
Those substituted at the 3- and 4-positions are preferred.

The 2-thioflavone derivative (1) of the present invention
Can be produced, for example, according to the following reaction formula.

[0020]

Embedded image

[In the formula, R ¹ , R ² , W ¹ and Z ¹ are the same as defined above, Y is a hydrogen atom, a lower alkoxy group or a halogen atom, and n is an integer of 1 to 6. That is, acetoquinone (5) is reacted with compound (6) to obtain compound (3) in which R ¹ and R ² are hydrogen atoms,
If necessary, R ¹ and R ² may be substituted with an aralkyl or an alkyl group, and then compound (7) may be added to give compound (2), which is subjected to a ring-closing reaction involving a deprotection reaction. -A thioflavanone derivative (1-a) can be obtained. Moreover, the obtained 2-thioflavanone derivative (1-a) can be converted into a 2-thioflavone derivative (1-b) by subjecting it to a dehydrogenation reaction.

A detailed description of each step is as follows.
The compounds (2) and (3) are novel compounds,
The present invention also provides these compounds.

(Step 1) In the above general formula (3), a compound in which R ¹ and R ² in the formula are hydrogen atoms is represented by the general formula (6) together with a known acetoquinone represented by the chemical formula (5). It can be produced by reacting the represented compound in a suitable solvent.

The solvent is not particularly limited as long as it does not participate in the reaction, for example, methanol, ethanol, 1
-Propanol, 2-propanol, 1-butanol,
Alcohols such as 2-butanol; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; acetic acid esters such as methyl acetate, ethyl acetate, butyl acetate; benzene, toluene Aromatic hydrocarbons such as; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; N, N-
Aprotic polar solvents such as dimethylformamide, acetonitrile, dimethylsulfoxide and the like can be mentioned.

As the reaction raw material, it is preferable to use the compound of the general formula (6) in an amount of 1 to 5 molar equivalents, particularly 1.5 to 3 molar equivalents, relative to 1 mole of acetoquinone (5). The reaction temperature is from 0 ° C to the boiling point of the solvent, preferably from 5 to 40 ° C. The reaction time is 15 to 90 minutes, preferably 20.
~ 60 minutes.

Further, in the general formula (3), R in the formula¹And R
^TwoIs a benzyl group, R is ¹And R^TwoIs a hydrogen source
The child compound (3) is benzylated by a known and conventional method.
It can be manufactured by doing.

The solvent used for the benzylation is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; acetic acid. Acetates such as methyl, ethyl acetate and butyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; alkyl ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide Aprotic polar solvents and the like. Examples of the benzyl halide used for benzylation include benzyl bromide, benzyl chloride, benzyl iodide and the like.

Examples of the basic compound used for benzylation include triethylamine, diisopropylamine,
Organic basic compounds such as tertiary amines such as pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate;
Alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; inorganic basic compounds such as alkali metal hydrides such as sodium hydride and potassium hydride. Can be mentioned.

The reaction raw material was prepared by adding 1 mol of benzyl halide to 1 mol of the compound (3) in which R ¹ and R ² are hydrogen atoms.
It is preferable to use 10 to 10 molar equivalents, particularly 1.5 to 6 molar equivalents, and the basic compound 1 to 12 molar equivalents, particularly 1.5 to 7 molar equivalents. The reaction temperature is about 0 to 100 ° C,
Preferably it is 10-80 degreeC. Reaction time is 0.5-1
It is 2 hours, preferably 1 to 5 hours.

Further, in the general formula (3), R ¹ and R ² in the formula
Is a lower alkyl group, the compound (3) in which R ¹ and R ² are hydrogen atoms is alkylated by a known and conventional method, for example, a method using an alkylating agent in the presence of a basic compound. It can be manufactured.

The solvent used here is not particularly limited as long as it does not participate in the reaction, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-
Alcohols such as butanol and 2-butanol; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; acetic acid esters such as methyl acetate, ethyl acetate and butyl acetate; benzene ,
Aromatic hydrocarbons such as toluene; Alkyl ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; N, N-dimethylformamide, acetonitrile,
An aprotic polar solvent such as dimethyl sulfoxide and the like can be mentioned.

Examples of the alkylating agent used here include alkyl halides such as alkyl bromide, alkyl chloride and alkyl iodide, and dialkyl sulfates.

Examples of the basic compound used here include trialkylamines such as triethylamine and diisopropylamine; carbonates such as sodium carbonate, potassium carbonate and silver carbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Compounds: inorganic basic compounds such as alkali metal hydrides such as sodium hydride and potassium hydride.

As the reaction raw material, the alkylating agent is 1 to 5 molar equivalents, particularly 1 to 2 molar equivalents, and the basic compound is 1 to 5 relative to 1 mole of the compound (3) in which R ¹ and R ² are hydrogen atoms. It is preferred to use molar equivalents, especially 1-2 molar equivalents. The reaction temperature is about 0 ° C to the boiling point of the solvent, preferably room temperature to 100 ° C. The reaction time is 1 to 48 hours, preferably 1 to 24 hours.

The compound (3) thus obtained is
It can be isolated as an intermediate or used in Step 2 without isolation.

(Step 2) The compound represented by the general formula (2) is the compound represented by the general formula (3) and the general formula (7).
The known compound represented by, for example, J. Chem. Soc. Perk
According to the method described in in I 1646 to 1651 (1978), it can be produced by reacting in a suitable solvent under basic conditions or acidic conditions.

The solvent used here is not particularly limited as long as it does not participate in the reaction, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-
Alcohols such as butanol and 2-butanol; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; acetone, Examples thereof include alkyl ketones such as methyl ethyl ketone and methyl isobutyl ketone; aprotic polar solvents such as N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide.

Examples of the basic compound include organic basic compounds such as tertiary amines such as triethylamine, diisopropylamine, piperazine, piperidine, pyridine, 4-dimethylaminopyridine and DBU; alkali such as sodium carbonate and potassium carbonate. Metal carbonates; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; inorganic metals such as alkali metal hydrides such as sodium hydride and potassium hydride Basic compounds are mentioned.
Examples of the acidic compound include oxalic acid, formic acid, acetic acid, p-toluenesulfonic acid, and other organic acids; hydrochloric acid, sulfuric acid,
Examples thereof include inorganic acids such as phosphoric acid and hydrobromic acid.

For the purpose of accelerating the reaction, for example, a quaternary ammonium salt such as tetrabutylammonium bromide, tetrabutylammonium chloride, trimethylbenzylammonium chloride or cetyldimethylbenzylammonium chloride may be added as a catalyst. The reaction raw material is 1 to 5 mol equivalent of the benzaldehyde derivative (7) per 1 mol of the compound of the general formula (3),
It is particularly preferable to use 1.1 to 2 molar equivalents, and the catalyst can be appropriately selected depending on the combination of reaction reagents,
It is preferred to use from 0.01 to 0.7 molar equivalents, especially from 0.1 to 0.5 molar equivalents. In addition, the addition of a catalyst is not necessary in some cases. The reaction temperature is from 0 ° C to the boiling point of the solvent, preferably from 5 to 80 ° C. Reaction time is 1
It is 120 hours, preferably 12 to 36 hours.
In addition, the compound of the general formula (2) can be used as the intermediate raw material in the step 3 with or without isolation.

(Step 3) The compound represented by the general formula (1-a) (thioflavanone derivative) is the same as the compound represented by the general formula (2), for example, Chem. Soc. Rev. 345 to 371.
According to the method described in (1977), it can be produced by sequentially reacting silver nitrate, cetyltrimethylammonium bromide and p-toluenesulfonic acid in a suitable solvent.

The solvent used here is not particularly limited as long as it does not participate in the reaction, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-
Alcohols such as butanol and 2-butanol; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; acetic acid esters such as methyl acetate, ethyl acetate and butyl acetate; benzene ,
Aromatic hydrocarbons such as toluene; Alkyl ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; N, N-dimethylformamide, acetonitrile,
An aprotic polar solvent such as dimethyl sulfoxide can be used, and these can be used alone or in combination.

The starting materials for the reaction are 1 to 10 molar equivalents of silver nitrate, particularly 2 to 5 molar equivalents of cetyltrimethylammonium bromide, and 0.1 mole of silver nitrate per mole of the compound of the general formula (2).
It is preferred to use ˜5 molar equivalents, especially 0.5 to 3 molar equivalents, and p-toluenesulfonic acid 1 to 10 molar equivalents, especially 1.5 to 5 molar equivalents. The reaction temperature is 0 ° C to the boiling point of the solvent, preferably 5 to 100 ° C. The reaction time is 1 to 12 hours, preferably 2 to 5 hours.
Further, in the step 3, in addition to the above method, the compound (1-a) of the present invention can be produced by performing a reaction in trifluoroacetic acid. The reaction raw material in this case is 5 to 50 ml of trifluoroacetic acid per 1 g of the compound of the general formula (2), especially 1
It is preferable to use 0 to 30 ml. The reaction temperature is 0 ° C to the boiling point of the solvent, preferably 5 to 50 ° C. The reaction time is 0.1 to 12 hours, preferably 0.5 to
5 hours.

Further, the benzyl compound (R
A compound of the general formula (1-a) in which at least one of ¹ , R ² , W ¹ or Z ¹ is a benzyl group can be converted into the corresponding alcohol by a conventional debenzylation reaction. An example of debenzylation is N, N in a suitable solvent.
-A method of reacting with dimethylaniline and aluminum chloride.

The solvent used here is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, diisopropyl ether, tetrahitorofuran and dioxane; Acetic acid esters such as methyl acetate, ethyl acetate and butyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; aprotic polar solvents such as N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide.

The starting materials for the reaction are the benzyl compound (1-
N, N-dimethylaniline is used in an amount of 0.1 to 2 molar equivalents, particularly 0.2 to 1 molar equivalent, and aluminum chloride is used in an amount of 1 to 12 molar equivalents, particularly 3 to 10 molar equivalents, relative to 1 mole of the compound of a). Is preferred. The reaction temperature is about -30 to 50 ° C, preferably -10 to 30 ° C. The reaction time is 0.5 to 12 hours, preferably 1 to 5 hours.

The compound of the general formula (1-a) has antitumor activity and carcinogenesis suppressing activity by itself, but it can be isolated as an intermediate material or can be used in Step 4 without isolation. .

(Step 4) The compound represented by the general formula (1-b) is obtained by reacting the compound represented by the general formula (1-a) in a suitable solvent in the presence of a dehydrogenating agent. It can be manufactured. The solvent used here is not particularly limited as long as it does not participate in the reaction, and for example, methanol, ethanol, 1-propanol, 2-propanol, 1-
Alcohols such as butanol and 2-butanol; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; acetic acid esters such as methyl acetate, ethyl acetate and butyl acetate; benzene ,
Aromatic hydrocarbons such as toluene; Alkyl ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; N, N-dimethylformamide, acetonitrile,
An aprotic polar solvent such as dimethyl sulfoxide and the like can be mentioned.

Examples of the dehydrogenating agent include 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DD
Q), palladium carbon, etc. can be illustrated.

The reaction raw material is the compound 1 of the general formula (1-a).
1 to 5 molar equivalents of dehydrogenating agent, especially 1 to 3
It is preferred to use molar equivalents. The reaction temperature is 0 ° C to the boiling point of the solvent, preferably 10 to 130 ° C.
The reaction time is 1 to 48 hours, preferably 1 to 24 hours.

Further, the benzyl compound (the compound of the present invention) obtained by the above reaction can be subjected to a debenzylation reaction in the same manner as described above to produce an alcohol compound (the compound of the present invention).

The compound of the present invention (1
-A) and (1-b) can be isolated and purified by a usual separation and purification means such as column chromatography, recrystallization, vacuum distillation and the like.

When the compound of the present invention is used as a medicine, various administration forms can be adopted depending on the purpose of prevention or treatment, and examples of the form include pills, tablets, powders, capsules and granules. Oral preparations, oral preparations, injections, suppositories, ointments, patches, parenteral preparations such as aerosols, eye drops, nasal drops, and the like, and these administration forms are the conventional production methods known to those skilled in the art. Can be manufactured by

In the case of preparing an oral solid preparation, after adding an excipient, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring / flavoring agent, etc. to the compound of the present invention, By the method, tablets, coated tablets, granules, powders, capsules and the like can be produced. Such additives may be those commonly used in the art, and examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch,
Calcium carbonate, kaolin, microcrystalline cellulose, silicic acid, etc., as the binder, water, ethanol, propanol,
Simple syrup, glucose solution, starch solution, gelatin solution,
Carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc., as disintegrants, dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearin. Acid monoglyceride, lactose, etc., lubricants such as purified talc, stearate, borax, polyethylene glycol, etc., coloring agents such as titanium oxide,
Examples of the flavoring / flavoring agent include iron oxide and the like, such as sucrose, orange peel, citric acid, and tartaric acid.

When preparing a liquid preparation for oral administration, a flavoring agent, a buffering agent, a stabilizer and the like are added to the compound of the present invention to prepare an internal solution, a syrup, an elixir and the like by a conventional method. be able to. In this case, the above-mentioned examples of the corrigent / flavoring agent are exemplified, the buffer includes sodium citrate and the like, and the stabilizer includes tragacanth, gum arabic, gelatin and the like.

When preparing an injection, a pH adjusting agent, a buffer, a stabilizer, an isotonicity agent, a local anesthetic, etc. are added to the compound of the present invention, and subcutaneous, intramuscular, intravenous Injectables can be manufactured. In this case, sodium citrate, sodium acetate, sodium phosphate, etc. are used as the pH adjuster and buffer, sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid, etc. are used as the stabilizer, and isotonic agents are used as the isotonicity agent. Examples of the local anesthetic include sodium chloride and glucose, and examples of the local anesthetic include procaine hydrochloride and lidocaine hydrochloride.

When a suppository is prepared, the compound of the present invention may be added to the compound of the present invention by a carrier known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., if necessary, and Tween (registered trademark). It can be produced by a conventional method after adding a surfactant or the like.

In the case of preparing an ointment, the base, stabilizer, wetting agent, preservative and the like usually used in the compound of the present invention are blended, if necessary, and mixed and formulated by a conventional method. . Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like.

In the case of producing a patch, the above-mentioned ointment, cream, gel, paste, etc. may be applied to an ordinary support by a conventional method. As the support, a woven or non-woven fabric made of cotton, staple fiber or chemical fiber, or a film or foam sheet of soft vinyl chloride, polyethylene, polyurethane or the like is suitable.

The amount of the compound of the present invention to be blended in each of the above-mentioned dosage unit forms is not constant depending on the symptoms of the patient to which it is applied or the dosage form thereof, but generally it is 1 for an oral preparation per dosage unit form. It is preferable that the dose is ˜1000 mg, the injection is 0.1-500 mg, and the suppository is 5-1000 mg. The daily dose of the drug having the above-mentioned administration form cannot be unconditionally determined depending on the patient's symptoms, body weight, sex, etc., but is usually 0.1 to 500 per adult per day.
The dose may be 0 mg, preferably 1 to 1000 mg, and it is preferable to administer this once or in 2 to 4 divided doses.

[0060]

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

Example 1 Synthesis of 2,5-dihydroxy-6- (p-methoxybenzylmercapto) acetophenone: p-methoxy-α-
Dissolve 0.7 ml of toluenethiol in 4 ml of ethanol,
After adding 300 mg of acetoquinone at room temperature, 30 at the same temperature
Stirred for minutes. After completion of the reaction, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography,
550 mg (yield 90%) of 2,5-dihydroxy-6- (p-methoxybenzylmercapto) acetophenone was obtained.

¹ H-NMR (CDCl ₃ ): δ 10.9 (bs, 1H), 7.12 (d, 1H, J = 9.1Hz), 6.97 (d, 1H, J = 9.1
Hz), 6.87 (d, 2H, J = 8.8Hz), 6.75 (d, 2H, J = 8.8Hz), 3.78
(s, 3H), 3.75 (s, 2H), 2.71 (s, 3H)

Example 2 Synthesis of 2,5-dimethoxy-6- (p-methoxybenzylmercapto) acetophenone: 550 mg of 2,5-dihydroxy-6- (p-methoxybenzylmercapto) acetophenone obtained in Example 1 And 0.45 ml of dimethylsulfate were heated to reflux for 30 minutes in 10 ml of acetone in the presence of 830 mg of anhydrous potassium carbonate. After cooling, the insoluble matter was filtered off, the filtrate was concentrated, the obtained residue was distributed between chloroform and water, the organic layer was separated, dried over anhydrous magnesium sulfate and the solvent was distilled off. Purification by silica gel column chromatography gave 540 mg (yield 90%) of 2,5-dimethoxy-6- (p-methoxybenzylmercapto) acetophenone.

¹ H-NMR (CDCl ₃ ): δ 6.7 to 7.1 (m, 6H), 3.96 (s, 3H), 3.85 (s, 3H), 3.75 (s, 3
H), 3.74 (s, 2H), 2.17 (s, 3H)

Example 3 Synthesis of 2,5-dibenzyloxy-6- (p-methoxybenzylmercapto) acetophenone: 550 mg of 2,5-dihydroxy-6- (p-methoxybenzylmercapto) acetophenone obtained in Example 1 650 mg of potassium carbonate and 0.52 ml of benzyl bromide were heated to reflux in 15 ml of acetone for 1.5 hours. After completion of the reaction, the solvent was distilled off, and the obtained residue was distributed between chloroform and water,
The organic layer was separated, dried over anhydrous magnesium sulfate and the solvent was distilled off, and the obtained residue was recrystallized from methanol,
576 mg of 2,5-dibenzyloxy-6- (p-methoxybenzylmercapto) acetophenone (yield 66
%)Obtained.

Melting point: 115 to 117 ° C. ¹ H-NMR (CDCl ₃ ): δ 7.2 to 7.5 (m, 10H), 6.94 (d, 2H, J = 8.8 Hz), 6.78 (s, 2H),
6.65 (d, 2H, J = 8.8Hz), 6.96 (s, 2H), 6.92 (s, 2H), 3.94 (s,
2H), 3.68 (s, 3H), 2.14 (s, 3H)

Example 4 2 ', 3,4,5'-Tetrabenzyloxy-6'-(p
-Methoxybenzylmercapto) chalcone (Compound 1)
Synthesis of 2,5-dibenzyloxy-, obtained in Example 3
6- (p-methoxybenzylmercapto) acetophenone 436 mg, 3,4-dibenzyloxybenzaldehyde 429 mg and tetrabutylammonium bromide 64
mg was dissolved in a mixed solution of 4 ml of 50% potassium hydroxide aqueous solution and 4 ml of dichloromethane, and the mixture was stirred at room temperature for 60 hours. After completion of the reaction, dichloromethane was added, the organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off, and the obtained residue was recrystallized with a chloroform-methanol mixture,
635 mg (yield 90%) of the title compound (Compound 1) was obtained.

Melting point: 159 to 161 ° C. ¹ H-NMR (CDCl ₃ ): δ 6.45 to 7.54 (m, 30H), 6.66 (d, 1H, J = 15.5Hz), 5.17 (s, 2)
H), 5.13 (s, 2H), 5.07 (s, 2H), 4.97 (s, 2H), 3.94 (s, 2H),
3.57 (s, 3H)

Example 5 Compound 2 was prepared in the same manner as in Example 4 using appropriate starting materials.
~ 6 were synthesized. 2,2 ', 4,5'-Tetrabenzyloxy-6'-(p-methoxybenzylmercapto) chalcone (Compound 2)

Yield: 51% Melting point: 119 to 120 ° C. ¹ H-NMR (CDCl ₃ ): δ 6.45 to 7.55 (m, 31H), 5.08 (s, 2H), 5.07 (s, 2H), 4.97 (s ,
2H), 4.89 (s, 2H), 3.93 (s, 2H), 3.57 (s, 3H)

2,2 ', 3,5'-Tetrabenzyloxy-6'-(p-methoxybenzylmercapto) chalcone (Compound 3)

Yield: 86% ¹ H-NMR (CDCl ₃ ): δ 6.75 to 7.60 (m, 31H), 6.57 (d, 1H, J = 8.7Hz), 5.12 (s, 2H),
5.07 (s, 2H), 4.87 (s, 2H), 4.81 (s, 2H), 3.94 (s, 2H), 3.
62 (s, 3H)

2 ', 5'-dibenzyloxy-3,4-dimethoxy-6'-(p-methoxybenzylmercapto)
Chalcone (Compound 4)

Yield: 73% Melting point: 117-118 ° C. ¹ H-NMR (CDCl ₃ ): δ 6.55-7.55 (m, 31H), 5.10 (s, 2H), 5.01 (s, 2H), 3.99 (s ,
2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.64 (s, 3H)

3,4-dibenzyloxy-2 ', 5'-dimethoxy-6'-(p-methoxybenzylmercapto)
Chalcone (Compound 5)

Yield: 45% Melting point: 92-94 ° C. ¹ H-NMR (CDCl ₃ ): δ 6.55-7.55 (m, 31H), 5.19 (s, 2H), 5.16 (s, 2H), 3.95 (s ,
2H), 3.86 (s, 3H), 3.70 (s, 3H), 3.62 (s, 3H)

2 ', 3,4,5'-tetramethoxy-
6 '-(p-methoxybenzylmercapto) chalcone (Compound 6)

Yield: 66% Melting point: 158-160 ° C. ¹ H-NMR (CDCl ₃ ): δ 6.55-7.05 (m, 10H), 6.67 (d, 1H, J = 16.1Hz), 3.91 (s, 2
H), 3.85 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.66 (s, 3H),
3.61 (s, 3H)

Example 6 Synthesis of 2- (3,4-dimethoxyphenyl) -5,8-dimethoxythioflavanone (Compound 7): 2 ', 3,4,5'-tetramethoxy obtained in Example 5 -6'-
0.96 g of (p-methoxybenzylmercapto) chalcone (Compound 6) was dissolved in 50 ml of 90% ethanol, 1.36 g of silver nitrate was added, and the mixture was heated under reflux for 2 hours. After cooling, the solvent was removed by filtration, and the obtained residue was washed with ethanol and water to obtain 0.66 g (yield 52%) of a silver derivative. Next, 0.66 g of the obtained silver derivative and 2.07 g of cetyltrimethylammonium bromide were added to 220 ml of ethyl acetate.
A mixture of 88 ml of water and 88 ml of water was added, and the mixture was stirred at room temperature for 30 minutes.
After completion of the reaction, ethyl acetate was added, the organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was washed with methanol to give a thiol compound of 0.2
2 g (yield 43%) was obtained.

Next, 0.22 g of the obtained thiol compound and 0.35 g of p-toluenesulfonic acid were added to dichloromethane 2
2 ml was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, dichloromethane and water were added, the organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give the title compound (compound 7 ) 0.18 g (yield 50
%)Obtained.

Melting point: 134-135 ° C. ¹ H-NMR (CDCl ₃ ): δ 7.00 (dd, 1H, J ₁ = 8.3Hz, J ₂ = 2.4Hz), 6.97 (d, 1H, J = 8.7Hz),
6.97 (d, 1H, J = 2.4Hz), 6.87 (d, 1H, J = 8.3Hz), 6.73 (d, 1H,
J = 8.7Hz), 4.60 (dd, 1H, J ₁ = 13.7Hz, J ₂ = 2.9Hz), 3.92 (s, 3
H), 3.911 (s, 3H), 3.908 (s, 3H), 3.89 (s, 3H), 3.35 (dd, 1
H, J ₁ = 13.7Hz, J ₂ = 15.1Hz), 3.14 (dd, 1H, J ₁ = 15.1Hz, J ₂ = 3.0
Hz)

Example 7 Synthesis of 2- (3,4-dimethoxyphenyl) -5,8-dimethoxythioflavanone (Compound 7): 2 ', 3,4,5'-tetramethoxy obtained in Example 5 -6'-
80 mg of (p-methoxybenzyl mercapto) chalcone (Compound 6) was dissolved in 1.5 ml of trifluoroacetic acid and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into an aqueous sodium hydrogen carbonate solution, extracted with chloroform, washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain the title compound ( 30 mg (yield 50%) of compound 7) was obtained.

¹ H-NMR (CDCl ₃ ): δ 7.00 (dd, 1H, J ₁ = 8.3Hz, J ₂ = 2.4Hz), 6.97 (d, 1H, J = 8.7Hz),
6.97 (d, 1H, J = 2.4Hz), 6.87 (d, 1H, J = 8.3Hz), 6.73 (d, 1H,
J = 8.7Hz), 4.60 (dd, 1H, J ₁ = 13.7Hz, J ₂ = 2.9Hz), 3.92 (s, 3
H), 3.911 (s, 3H), 3.908 (s, 3H), 3.89 (s, 3H), 3.35 (dd, 1
H, J ₁ = 13.7Hz, J ₂ = 15.1Hz), 3.14 (dd, 1H, J ₁ = 15.1Hz, J ₂ = 3.0
Hz)

Example 8 Compound 8 was prepared in the same manner as in Example 6 using appropriate starting materials.
~ 12 were synthesized. 2- (3,4-dibenzyloxyphenyl) -5,8-dibenzyloxythioflavanone (Compound 8)

Yield: 61% Melting point: 168-169 ° C ¹ H-NMR (CDCl ₃ ): δ 7.15-7.60 (m, 20H), 7.06 (d, 1H, J = 2Hz), 6.97 (dd, 1H, J ₁
= 8.3Hz, J ₂ = 2Hz), 6.96 (d, 1H, J = 8.8Hz), 6.94 (d, 1H, J = 8.3
Hz), 6.72 (d, 1H, J = 8.8Hz), 5.19 (s, 4H), 5.16 (two d, 2H,
J = 11.7Hz), 5.11 (s, 2H), 4.55 (dd, 1H, J ₁ = 13.7Hz, J ₂ = 2.5H
z), 3.27 (dd, 1H, J ₁ = 15.1Hz, J ₂ = 13.7Hz), 3.08 (dd, 1H, J ₁ =
15.1Hz, J ₂ = 2.9Hz)

2- (2,4-dibenzyloxyphenyl)
-5,8-Dibenzyloxythioflavanone (Compound 9)

Yield: 41% Melting point: 186-188 ° C. ¹ H-NMR (CDCl ₃ ): δ 7.2-7.6 (m, 21H), 6.92 (d, 1H, J = 9Hz), 6.67 (d, 1H, J = 9H
z), 6.57 (m, 2H)

2- (2,3-dibenzyloxyphenyl)
-5,8-Dibenzyloxythioflavanone (Compound 1
0)

Yield: 26% Melting point: 106-107 ° C. ¹ H-NMR (CDCl ₃ ): δ 6.96-7.60 (m, 23H), 6.92 (d, 1H, J = 9Hz), 6.69 (d, 1H, J = 9
Hz), 5.15 (s, 2H), 5.13 (s, 2H), 5.10 (m, 3H), 5.06 (s, 2
H), 3.25 (dd, 1H, J ₁ = 15.4Hz, J ₂ = 13.3Hz), 2.87 (dd, 1H, J ₁ =
15.3Hz, J ₂ = 3.1Hz)

2- (3,4-dimethoxyphenyl)-
5,8-Dibenzyloxythioflavanone (Compound 11)

Yield: 30% Melting point: 149-151 ° C ¹ H-NMR (CDCl ₃ ): δ 6.9-7.6 (m, 13H), 6.83 (d, 1H, J = 8.1Hz), 6.67 (d, 1H) , J = 9
Hz), 5.05 (two d, 2H), 5.03 (s, 2H), 4.56 (dd, 1H, J ₁ = 13.3
Hz, J ₂ = 3Hz), 3.87 (s, 3H), 3.86 (s, 3H), 3.31 (dd, 1H, J ₁ = 1
5Hz, J ₂ = 13.5Hz), 3.08 (dd, 1H, J ₁ = 15.1Hz, J ₂ = 3.1Hz)

2- (3,4-dibenzyloxyphenyl)
-5,8-Dimethoxythioflavanone (Compound 12)

Yield: 33% Melting point: 118-120 ° C. ¹ H-NMR (CDCl ₃ ): δ 6.8-7.5 (m, 14H), 6.69 (d, 1H, J = 9.1Hz), 5.15 (s, 4H ),Four.
51 (dd, 1H, J ₁ = 13.2Hz, J ₂ = 3.3Hz), 3.87 (s, 3H), 3.85 (s, 3
H), 3.23 (dd, 1H, J ₁ = 15.0Hz, J ₂ = 13.3Hz), 3.04 (dd, 1H, J ₁ =
(15.0Hz, J ₂ = 3.3Hz)

Example 9 Synthesis of 2- (3,4-dihydroxyphenyl) -5,8-dihydroxythioflavanone (Compound 13): 2- (3,4-dibenzyloxyphenyl) obtained in Example 8
-5,8-Dibenzyloxythioflavanone (Compound 8)
1.0 g and 1.1 ml of N, N-dimethylaniline were dissolved in 40 ml of anhydrous dichloromethane, 1.6 g of aluminum chloride was added under ice cooling, and the mixture was stirred at 0 ° C. for 3 hours under an argon stream. After completion of the reaction, the reaction solution was poured into cold 5% hydrochloric acid aqueous solution, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off, and the obtained residue was recrystallized with an acetone-chloroform mixed solution, 0.14 g (yield 30%) of the title compound (Compound 13) was obtained.

Melting point: 214 to 222 ° C. ¹ H-NMR (acetone): δ 12.3 (s, 1H), 8.1 (bs, 3H), 7.08 (d, 1H, J = 8.8Hz), 7.01
(d, 1H, J = 1.8Hz), 6.86 (m, 2H), 6.55 (d, 1H, J = 8.8Hz), 4.6
4 (dd, 1H, J ₁ = 13.2Hz, J ₂ = 2.8Hz), 3.40 (dd, 1H, J ₁ = 13.3Hz, J
₂ = 16.5Hz), 3.06 (dd, 1H, J ₁ = 16.5Hz, J ₂ = 2.9Hz)

Example 10 Compound 1 was prepared in the same manner as in Example 9 using appropriate starting materials.
4-16 were synthesized. 2- (2,4-dihydroxyphenyl) -5,8-dihydroxythioflavanone (Compound 14)

Yield: 28% Melting point: 267 ° C. (decomposition) ¹ H-NMR (acetone): δ 12.3 (s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H ), 7.
28 (d, 1H, J = 8.3Hz), 7.07 (d, 1H, J = 8.8Hz), 6.54 (d, 1H, J =
8.8Hz), 6.47 (d, 1H, J = 2.4Hz), 6.40 (dd, 1H, J ₁ = 8.3Hz, J ₂ =
2.4Hz), 5.00 (dd, 1H, J ₁ = 13.3Hz, J ₂ = 3.0Hz), 3.48 (dd, 1H,
J ₁ = 16.5Hz, J ₂ = 12.9Hz), 3.01 (dd, 1H, J ₁ = 16.5Hz, J ₂ = 2.9H
z)

2- (2,3-dihydroxyphenyl)-
5,8-Dihydroxythioflavanone (Compound 15)

Yield: 23% Melting point: 232-233 ° C. ¹ H-NMR (acetone): δ 12.3 (s, 1H), 8.69 (s, 1H), 8.48 (s, 1H), 7.77 (s, 1H) , 7.
08 (d, 1H, J = 8.8Hz), 6.99 (dd, 1H, J ₁ = 9.4Hz, J ₂ = 1.7Hz), 6.
85 (dd, 1H, J ₁ = 7.9Hz, J ₂ = 1.6Hz), 6.73 (t, 1H, J = 7.7Hz), 6.
56 (d, 1H, J = 8.8Hz), 5.13 (dd, 1H, J ₁ = 12.5Hz, J ₂ = 2.9Hz),
3.49 (dd, 1H, J ₁ = 16.5Hz, J ₂ = 12.5Hz), 3.09 (dd, 1H, J ₁ = 16.6
Hz, J ₂ = 3.1Hz)

2- (3,4-dihydroxyphenyl)-
5-Hydroxy-8-methoxythioflavanone (Compound 16)

Yield: 11% Melting point: 178-180 ° C. ¹ H-NMR (acetone): δ 12.3 (s, 1H), 8.10 (s, 1H), 8.07 (s, 1H), 7.23 (d, 1H, J = 9.
0Hz), 7.00 (s, 1H), 6.85 (s, 1H), 6.65 (d, 1H, J = 8.9Hz),
4.65 (dd, 1H, J ₁ = 13.5Hz, J ₂ = 2.9Hz), 3.83 (s, 3H), 3.41 (d
d, 1H, J ₁ = 16.5Hz, J ₂ = 13.3Hz), 3.05 (dd, 1H, J ₁ = 12.5Hz, J ₂ =
(2.9Hz)

Example 11 Synthesis of 2- (3,4-dibenzyloxyphenyl) -5,8-dibenzyloxythioflavone (Compound 17): 2- (3,4-di obtained in Example 8) Benzyloxyphenyl) -5,8-dibenzyloxythioflavanone (Compound 8) 266 mg and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone 109 mg were dissolved in anhydrous toluene 5 ml and heated for 2 hours. Refluxed. After cooling, chloroform was added and the insoluble material was filtered off, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain 146 mg (yield 55%) of the title compound (Compound 17).

Melting point; 98-99 ° C. ¹ H-NMR (CDCl ₃ ): δ 7.3-7.7 (m, 22H), 7.14 (bs, 1H), 7.09 (d, 1H, J = 9.0Hz),
7.03 (d, 1H, J = 8.3Hz), 6.96 (d, 1H, J = 8.8Hz), 5.26 (s, 2
H), 5.25 (s, 4H), 5.23 (s, 2H)

Example 12 Compounds 18 to 19 were synthesized in the same manner as in Example 11 using appropriate starting materials. 2- (2,4-dibenzyloxyphenyl) -5,8-dibenzyloxythioflavone (Compound 18)

Yield: 62% Melting point: 158-160 ° C. ¹ H-NMR (CDCl ₃ ): δ 7.2-7.8 (m, 22H), 7.15 (d, 1H, J = 8.9Hz), 6.93 (s, 1H ),
6.91 (d, 1H, J = 2.3Hz), 6.78 (dd, 1H, J ₁ = 8.6Hz, J ₂ = 2.4Hz),
5.31 (s, 2H), 5.26 (s, 2H), 5.20 (s, 4H)

2- (2,3-dibenzyloxyphenyl)
-5,8-Dibenzyloxythioflavone (Compound 19)

Yield: 64% Melting point: 130-131 ° C. ¹ H-NMR (CDCl ₃ ): δ 6.96-7.7 (m, 25H), 6.92 (d, 1H, J = 8.9Hz), 5.21 (s, 2H ),
5.17 (s, 2H), 5.16 (s, 2H), 5.03 (s, 2H)

Example 13 Synthesis of 2- (3,4-dihydroxyphenyl) -5,8-dihydroxythioflavone (Compound 20): Example 1
2- (3,4-dibenzyloxyphenyl) obtained in 1
-5,8-Dibenzyloxythioflavone (Compound 17)
0.66 g and 1.5 ml of N, N-dimethylaniline were dissolved in 60 ml of anhydrous dichloromethane, 2.4 g of aluminum chloride was added under ice cooling, and the mixture was stirred at room temperature under an argon stream for 3 hours. After the reaction was completed, the reaction solution was poured into cold 5% hydrochloric acid aqueous solution
The mixture was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was recrystallized from a mixed solution of acetone-chloroform to obtain 0.09 g of the title compound (Compound 20) (yield 30%). )Obtained.

Melting point: 293 ° C. (decomposition) ¹ H-NMR (acetone): δ 13.53 (s, 1H), 9.3 (bs, 1H), 8.7 (bs, 1H), 8.5 (bs, 1H),
7.34 (d, 1H, J = 2.3Hz), 7.27 (dd, 1H, J ₁ = 8.3Hz, J ₂ = 2.3Hz),
7.22 (d, 1H, J = 8.8Hz), 7.02 (d, 1H, J = 8.2Hz), 7.02 (s, 1H),
6.79 (d, 1H, J = 8.8Hz)

Example 14 Compounds 21 to 22 were synthesized in the same manner as in Example 13 using appropriate starting materials.

2- (2,4-dihydroxyphenyl)-
5,8-Dihydroxythioflavone (Compound 21)

Yield: 16% Melting point:> 300 ° C. (decomposition) ¹ H-NMR (acetone): δ 13.6 (s, 1H), 9.2 (bs, 2H), 9.0 (bs, 1H), 7.43 (d, 1H, J = 8.
4Hz), 7.18 (d, 1H, J = 8.8Hz), 7.17 (s, 1H), 6.77 (d, 1H, J =
8.8Hz), 6.60 (d, 1H, J = 2.3Hz), 6.55 (dd, 1H, J ₁ = 8.5Hz, J ₂ =
2.3Hz)

2- (2,3-dihydroxyphenyl)-
5,8-Dihydroxythioflavone (Compound 22)

Yield: 19% Melting point:> 260 ° C. (decomposition) ¹ H-NMR (acetone): δ 13.52 (s, 1H), 9.24 (bs, 1H), 8.96 (bs, 1H), 8.16 (bs, 1
H), 7.25 (d, 1H, J = 8.8Hz), 7.18 (s, 1H), 7.07 (d, 2H, J = 8.3
Hz), 6.90 (t, 1H, J = 7.8Hz), 6.83 (d, 1H, J = 8.8Hz)

Formulation Examples Formulation examples using the compound of the present invention are shown below.

[0116]

[Table 1] Formulation Example 1 Tablets Tablets were prepared in the following blending ratio according to a conventional method. Compound 20 100 mg Lactose 47 mg Corn starch 50 mg Crystalline cellulose 50 mg Hydroxypropyl cellulose 15 mg Talc 2 mg Magnesium stearate 2 mg Ethyl cellulose 30 mg Unsaturated fatty acid glyceride 2 mg Titanium dioxide 2 mg 300 mg per tablet

[0117]

[Table 2] Formulation Example 2 Granules Granules were prepared in the following mixing ratio according to a conventional method. Compound 20 200 mg Mannitol 540 mg Corn starch 100 mg Crystalline cellulose 100 mg Hydroxypropyl cellulose 50 mg Talc 10 mg 1000 mg per packet

[0118]

[Table 3] Formulation Example 3 Fine Granules Fine granules were prepared in the following mixing ratio according to a conventional method. Compound 21 200 mg Mannitol 520 mg Corn starch 100 mg Crystalline cellulose 100 mg Hydroxypropyl cellulose 70 mg Talc 10 mg 1000 mg per packet

[0119]

[Table 4] Formulation Example 4 Capsule A capsule was prepared in the following mixing ratio according to a conventional method. Compound 21 100 mg Lactose 50 mg Corn starch 47 mg Crystalline cellulose 50 mg Talc 2 mg Magnesium stearate 1 mg 300 mg per capsule

[0120]

[Table 5] Formulation example 5 Syrup preparation A syrup preparation was prepared according to a conventional method in the following mixing ratio. Compound 21 1 g Purified sucrose 60 g Ethyl parahydroxybenzoate 5 mg Butyl parahydroxybenzoate 5 mg Perfume Adequate colorant Appropriate purified water Appropriate amount Total 100 ml

[0121]

[Table 6] Formulation Example 6 Injections Injections were prepared in the following mixing ratios according to a conventional method. Compound 22 100mg Distilled water for injection qs 2ml in 1 ampoule

[0122]

[Table 7] Formulation Example 7 Suppository A suppository was prepared according to a conventional method in the following mixing ratio. Compound 22 100 mg Witepsol S-55 1400 mg (mono-, di-, tri-glyceride mixture of saturated fatty acids from lauric acid to stearic acid , manufactured by Dynamite Nobel) 1500 mg per one

Test Example 1 Hereinafter, the content of the present invention will be described in more detail with reference to the results of pharmacological tests. In these experiments, no deaths were observed in each compound-administered group, and no change in appearance was observed.

With respect to the compound of the present invention, its inhibitory effect on carcinogenic promoter was measured. Although the mechanism of the carcinogenic promotion process is still unclear at present, enhancement of phospholipid metabolism of cells is recognized in this process, and this enhancement is considered to be one of the factors of the action mechanism. 12-O, which is known as a typical oncogenic promoter
-Tetradecanoylphorbol-13-acetate (T
It has been clarified that many of the compounds that suppress the promotion of phospholipid metabolism by PA) suppress the carcinogenic promotion in vivo and reduce the tumor incidence. Therefore, a method of measuring the efficacy of suppressing the phospholipid metabolism enhancement of cells by TPA was used as an index of the antipromoter action. The cultured cells used were HeL of human cervical cancer cells.
2 ml of Eagle's MEM solution containing 10% fetal calf serum
The cells were cultivated in a medium, and a single layer was grown on the entire surface of a culture vessel having a diameter of 35 mm and used for the experiment.

The test compound was dissolved in dimethyl sulfoxide and added to the culture medium. The same amount of dimethyl sulfoxide alone was added to the control. Carcinogenic promoter T after 1 hour
PA (50 nM) and radioactive inorganic phosphate ³² Pi (4 μCi
/ Dish) was added and the culture was continued for another 4 hours. Then, the phospholipids of the cells were extracted, and ³² P incorporated into them was taken up.
The radioactivity of i was measured. The inhibition rate was calculated by the following formula. Table 8 shows the results.

[0126]

[Equation 1]

[0127]

[Table 8]

As shown in Table 8, the compound (1) of the present invention suppressed the enhancement of radioactive phosphorus uptake into phospholipids in cultured cells by TPA.

[0129]

INDUSTRIAL APPLICABILITY The 2-thioflavone derivative of the present invention has an antitumor activity and a carcinogenesis suppressing activity, and is extremely useful as a drug represented by a cancer therapeutic agent.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Knikowski Antony Jedi Poland, Gdansk 80-225, Pilequegogo 3/1 (72) Inventor Tetsuji Asao Yamaguchi 5063-1, 48-2, 504, Tokorozawa, Saitama Prefecture (72) ) Inventor, Susato Nishino 1-2-5, Makinohonmachi, Hirakata-shi, Osaka Prefecture (72) Yuji Yamada 2-2953-21 Higashisayamagaoka, Tokorozawa, Saitama

Claims (10)

[Claims] 1. The following general formula (1): [Wherein R ¹ , R ² , W ¹ and Z ¹ are the same or different and each represents a hydrogen atom, a lower alkyl group or an aralkyl group,
The dashed line indicates that it may be a double bond. ] The 2-thioflavone derivative represented by these, or its salt. 2. The 2-thioflavone derivative or a salt thereof according to claim ¹ , wherein R ¹ , R ² , W ¹ and Z ¹ are hydrogen atoms in the general formula (1). 3. The 2-thioflavone according to claim ¹ , wherein in the general formula (1), R ¹ , R ² , W ¹ and Z ¹ are hydrogen atoms and OW ¹ is substituted at the 4-position of the benzene ring. Derivative or salt thereof. 4. In the general formula (1), R ¹ , R ² , W ¹ and Z ¹ are hydrogen atoms, and OW ¹ and OZ ¹ are substituted at the 3rd and 4th positions of the benzene ring. The 2-thioflavone derivative or the salt thereof according to 1. 5. The following general formula (2): [Wherein R ¹ , R ² , W ¹ and Z ¹ are the same or different and each represents a hydrogen atom, a lower alkyl group or an aralkyl group,
Y represents a hydrogen atom, a lower alkoxy group or a halogen atom, and n represents an integer of 1 to 6. ] The compound represented by these. 6. The following general formula (3): [In the formula, R ¹ and R ² are the same or different and each is a hydrogen atom,
Represents a lower alkyl group or an aralkyl group, Y represents a hydrogen atom, a lower alkoxy group or a halogen atom, and n represents 1
Represents an integer of from 6 to 6. ] The compound represented by these. 7. The following general formula (2): [Wherein R ¹ , R ² , W ¹ and Z ¹ are the same or different and each represents a hydrogen atom, a lower alkyl group or an aralkyl group,
Y represents a hydrogen atom, a lower alkoxy group or a halogen atom, and n represents an integer of 1 to 6. ] The compound represented by the following general formula (1-a) characterized by carrying out a ring closure reaction accompanied by a deprotection reaction: ^{Wherein, R 1, R 2, W} 1 and Z ¹ have the same meanings as defined above. ] The manufacturing method of the 2-thioflavanone derivative represented by these. 8. The following general formula (1-a): [In the formula, R ¹ , R ² , W ¹ and Z ¹ are the same or different and each represents a hydrogen atom, a lower alkyl group or an aralkyl group. ] The 2-thioflavanone derivative represented by the following general formula (1-b) characterized by subjecting to dehydrogenation ^{Wherein, R 1, R 2, W} 1 and Z ¹ have the same meanings as defined above. ] The manufacturing method of the 2-thioflavone derivative represented by these. 9. The method according to any one of claims 1 to 4,
A medicine comprising a thioflavone derivative or a salt thereof as an active ingredient. 10. The method according to claim 1, wherein
-A cancer therapeutic agent containing a thioflavone derivative or a salt thereof as an active ingredient.