JPH093037A - Phenylsulfone derivative and method for producing the same - Google Patents

Abstract

PURPOSE: To obtain a new phenyl sulfone derivative having excellent carcinogenesis-suppressing action and useful as an antitumor agent. CONSTITUTION: This compound is expressed by formula I (R1 is OH or a lower alkoxy, etc.; A is an ethylene chain or an ethenylene chain; W<1> and Z<1> are each independently H, OH or a lower alkoxy, etc.), e.g. 2',5'-dibenzyloxyphenyl(2,3-dibenzyloxyphenyl)vinyl sulfone. The exemplified substance of formula I expressed by formula IV is obtained by reacting a compound of formula II (R<2> is a lower alkoxy, etc.) with a compound of formula III (W<2> and Z<2> are each independently H or a lower alkoxy, etc.). Tetrabutylammonium bromide can be added to accelerate the reaction.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel phenyl sulfone derivative or a pharmaceutically acceptable salt thereof. The compound of the present invention has an excellent inhibitory effect on carcinogenesis and is useful as an antitumor agent.

[0002]

2. Description of the Related Art Conventional phenyl sulfone derivatives include, for example, Synthesis (1975) 453-4.
Phenyl (methoxy-substituted phenyl) vinyl sulfones described in 55 are known. However, in these documents, there is no description that the compound has an antitumor effect.

On the other hand, the mechanism of carcinogenesis consists of two steps, initiation and promotion, and a carcinogen acting on this promotion step is called a carcinogenic promoter. There are still many unclear points about the mechanism of the carcinogenic promotion process, and development of antitumor agents based on various carcinogenic promotion action mechanisms has been carried out, but no sufficiently satisfactory antitumor agent has been found yet. Is the current situation.

[0004]

Therefore, the object of the present invention is to suppress carcinogenesis, particularly to suppress the carcinogenic promotion process,
It is to provide a compound useful as an antitumor agent.

[0005]

The inventors of the present invention have conducted extensive studies to solve these problems, and as a result, the novel phenylsulfone derivative represented by the following general formula (1) has an excellent carcinogenic inhibitory action. The present invention has been completed and the present invention was found to be useful as a medicine, particularly as an antitumor agent.

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

[0007]

Embedded image

[In the formula, R ¹ represents a hydroxyl group, a lower alkoxy group or an aralkyloxy group, A represents an ethylene chain or an ethenylene chain, and W ¹ and Z ¹ are the same or different and are a hydrogen atom, a hydroxyl group or a lower alkoxy group. Group or aralkyloxy group. ] The present invention provides a phenyl sulfone derivative or a pharmaceutically acceptable salt thereof and a method for producing the same.

The present invention also provides an antitumor agent comprising a phenylsulfone derivative represented by the above general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

In the above general formula (1), each group defined by R ¹ , A, W ¹ and Z ¹ and the other groups described in the present specification are more specifically as follows. .

Examples of the lower alkoxy group are methoxy, ethoxy, n-propoxy, isopropoxy and n-.
Butoxy, isobutoxy, sec-butoxy, tert
Examples thereof include linear or branched alkoxy groups having 1 to 6 carbon atoms such as -butoxy, n-pentyloxy, isopentyloxy, and n-hexyloxy groups. Examples of the aralkyloxy group include benzyloxy, phenethyloxy, phenylpropyloxy, and other alkoxy groups having 1 to 6 carbon atoms substituted with a phenyl group.

Examples of the salt of the phenyl sulfone 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 salts of a compound of the general formula (1) with an acidic group, particularly a phenolic hydroxyl group, for example, a salt with an alkali metal or alkaline earth metal such as sodium, potassium, magnesium, calcium; ammonia, methyl. Amine,
Dimethylamine, piperidine, cyclohexylamine,
Examples thereof include organic salts with amines such as triethylamine.

In the compound represented by the general formula (1), R ¹ is a hydroxyl group, A is an ethenylene chain,
It is preferred that W ¹ and Z ¹ are hydroxyl groups. More preferred compounds are those in which R ¹ is a hydroxyl group, A is an ethenylene chain, Z ¹ is a hydroxyl group at the 4-position of the benzene ring, and W ¹
Is a compound that substitutes at the 3-position of the benzene ring with a hydroxyl group.

The compound of the general formula (1) includes isomers based on a double bond, isomers based on an asymmetric carbon atom, etc., but the present invention includes each of these isomers and mixtures thereof. Be done. This compound (1) may also exist as a solvate such as a hydrate, and the present invention also includes these solvates.

The phenyl sulfone derivative represented by the general formula (1) of the present invention can be produced, for example, according to the following reaction process formula.

[0016]

[Chemical 6]

[Wherein R ² represents a lower alkoxy group or an aralkyloxy group, R ³ represents a hydroxyl group or a lower alkoxy group, W ² and Z ² are the same or different and are a hydrogen atom, a lower alkoxy group or an aralkyl group. Represents an oxy group,
W ³ and Z ³ are the same or different and each represents a hydrogen atom, a hydroxyl group or a lower alkoxy group. ]

That is, the compound (1-a) is obtained by reacting the compound represented by the general formula (2) with the benzaldehyde derivative represented by the general formula (3).
Further, the compound (1-a) can be converted to the compound (1-b) by subjecting it to a hydrogenation reaction. On the other hand, when the compound (1-a) or the compound (1-b) has an aralkyloxy group (at least one of R ² , W ² and Z ² )
When each is an aralkyloxy group), the compound (1-c) or compound (1-d) [compound in which the aralkyloxy group is converted to a hydroxyl group] can be obtained by dearalkyloxylation. it can. In addition, the compound (1
-C) is also subjected to a hydrogenation reaction to give compound (1-
d).

The compound (2) used as a raw material for the above reaction is described in, for example, J. Chem. Soc. , 630-
633 (1945) and J. Org. Chem. , 3
1, 3671 to 3682 (1966) and the following Reference Examples 1 to 3 for synthesis.

The reaction for obtaining the compound (1-a) from the compound (2) and the compound (3) is described in, for example, J. Chem. So
c. Perkin I. , 1646-1651 (197
According to the method described in 8), it is carried out in a suitable solvent under basic conditions or acidic conditions.

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 and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; acetone, methyl ethyl ketone, Alkyl ketones such as methyl isobutyl ketone;
Aprotic polar solvents such as N, N-dimethylformamide, acetonitrile and dimethylsulfoxide can be exemplified.

Examples of the basic compound include organic basic compounds such as triethylamine, diisopropylamine, piperazine, piperidine, pyridine, 4-dimethylaminopyridine and tertiary amines such as DBU; and sodium carbonate, potassium carbonate and the like. Alkali metal carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal hydrides such as sodium hydride and potassium hydride An inorganic basic compound can be illustrated. Examples of the acidic compound include organic acids such as oxalic acid, formic acid, acetic acid and p-toluenesulfonic acid, and inorganic acids such as hydrochloric acid, sulfuric acid, 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, cetyldimethylbenzylammonium chloride or the like can be added as a catalyst.

The raw material is preferably the benzaldehyde derivative (3) per 1 mol of the compound of the general formula (2), preferably 1 to 5
The molar equivalent is used, more preferably 1.1 to 2 molar equivalents, and the catalyst can be appropriately selected depending on the combination of reaction reagents, preferably 0.01 to 0.7 molar equivalents, more preferably 0.1 to 0.7 molar equivalents. Used at 0.5 molar equivalents. Also, a catalyst may not be needed. The reaction temperature is usually 0 ° C to the boiling point of the solvent, preferably 5 to 80 ° C. The reaction time is usually 1 to 120 hours, preferably 12 to
36 hours.

The reaction for obtaining the compound (1-c) from the compound (1-a) or the compound (1-d) from the compound (1-b) is carried out according to a usual debenzylation reaction. An example of debenzylation is a method of reacting N, N-dimethylaniline and aluminum chloride in a suitable solvent.

The solvent 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; methyl acetate and ethyl acetate. , Acetic acid esters such as butyl acetate; aromatic hydrocarbons such as benzene, toluene, xylene; N, N-dimethylformamide,
Aprotic polar solvents such as acetonitrile and dimethyl sulfoxide can be exemplified.

The reaction ratio is 0.1 to 2 molar equivalents of N, N-dimethylaniline, preferably 0.2 to 1 molar equivalents, relative to 1 mole of compound (1-a) or compound (1-b). , Aluminum chloride is used in an amount of 1 to 12 molar equivalents, preferably 3 to 10 molar equivalents.

The reaction temperature is usually about -30 to 50 ° C, preferably -10 to 30 ° C. The reaction time is usually 0.5 to 12 hours, preferably 1 to 5 hours.

Further, the compound (1-a) or the compound (1-
c) has antitumor activity by itself, but can be used as an intermediate raw material, or can be used in a reaction to obtain compound (1-b) or compound (1-d) without isolation.

The hydrogenation reaction of compound (1-a) or compound (1-c) is carried out, for example, by reacting hydrogen in the presence of a catalyst in an inert solvent.

The solvent is not particularly limited as long as it does not participate in the reaction, and for example, methanol, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, dioxane, acetic acid and the like can be used alone or in combination. As the catalyst, for example, palladium carbon, platinum or the like can be used. The reaction rate is the compound (1-a) or the compound (1-
c) 0.01 to 2 g of catalyst, preferably 0.
It is good to use 1 to 0.5 g. The reaction temperature is usually 0 to 1
The temperature is about 00 ° C, preferably 10 to 50 ° C. The reaction time is usually 0.5 to 12 hours, preferably 1 to
4 hours.

Compounds (1-a), (1-b), (1-c) and (1-d) of the present invention obtained by the above method
Can be isolated and purified by an ordinary separation and purification means such as column chromatography, recrystallization, vacuum distillation and the like.
Further, the means for converting these compounds into pharmaceutically acceptable salts is carried out by a conventional method.

The compound (1) of the present invention has a carcinogenic promoter-inhibiting action, that is, an excellent carcinogenic-inhibiting action as shown in the test examples below, and is useful as an antitumor agent.

In using the compound of the present invention as a medicine, various dosage forms can be adopted depending on the purpose of prevention or treatment, and examples of the dosage form include pills, tablets, powders, capsules, granules and the like. Oral preparations; any of parenteral preparations such as injections, suppositories, ointments, patches, aerosols, eye drops, nasal drops, etc., and their administration forms are known methods commonly used by those skilled in the art. Can be manufactured by

In the case of preparing an oral solid preparation, after adding an excipient and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring / flavoring agent, etc. to the compound of the present invention, Tablets, coated tablets, granules, powders, capsules and the like can be produced by a conventional method. 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 and the like; lubricants such as purified talc, stearate, borax, polyethylene glycol and the like; coloring agents such as titanium oxide,
Iron oxide and the like; examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid, and the like.

In the case of preparing an oral liquid preparation, an oral solution, a syrup, an elixir and the like are prepared by adding a flavoring / flavoring agent, a buffer, a stabilizer and the like to the compound of the present invention by a conventional method. You can In this case, the flavoring / flavoring agents may be those listed above, the buffering agents include sodium citrate and the like; and the stabilizing agents include tragacanth, gum arabic, gelatin and the like.

In the case of preparing an injection, a pH adjusting agent, a buffering agent, a stabilizer, an isotonicity agent, a local anesthetic, etc. are added to the compound of the present invention, and subcutaneous, intramuscular, or intravenous injection is carried out by a conventional method. 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; Sodium chloride, glucose, etc .; local anesthetics include procaine hydrochloride, lidocaine hydrochloride, etc.

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, cacao butter, fatty acid triglyceride and the like, 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, a base, a stabilizer, a wetting agent, a preservative and the like usually used in the compound of the present invention are blended as necessary, and they are 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 or the like 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 it is generally 1 in 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.

[0042]

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

Reference Example 1 Synthesis of 2,5-dihydroxyphenylmethyl sulfone:
Suspend 20 g (0.3 mol) of zinc powder in 50 ml of water and
After cooling to 1, 25.4 ml of methanesulfonyl chloride was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Furthermore, concentrated hydrochloric acid 50 ml
Was added and stirred at 0 ° C. for 5 minutes, and then the reaction solution was filtered to obtain a filtrate. 15 g of 1,4-benzoquinone was added to the obtained filtrate.
(0.14 mol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered, the obtained residue was washed with hot chloroform, and then recrystallized with a mixed solution of methanol-chloroform to obtain 20 g (yield 76%) of 2,5-dihydroxyphenylmethylsulfone.

Melting point: 121 to 124 ° C. ¹ H-NMR (DMSO-d ₆ ): δ 10.1 (bs, 1H), 9.3 (bs, 1H), 6.
89 to 7.12 (m, 3H), 3.20 (s, 3H) IR (KBr): 3300, 1520, 1445, 12
70, 1140 cm ^-1

Reference Example 2 Synthesis of 2,5-dibenzyloxyphenylmethyl sulfone: 1.88 g of 2,5-dihydroxyphenylmethyl sulfone obtained in Reference Example 1, 4.15 g of potassium carbonate and 2.8 ml of benzyl bromide were used. The mixture was heated under reflux in 50 ml of acetone for 4 hours. After cooling, water was added to crystallize, the residue was collected by filtration, washed with water, and the obtained residue was recrystallized from methanol to obtain 2.95 g of 2,5-dibenzyloxyphenylmethylsulfone (yield 80 %)Obtained.

Melting point: 119 to 121 ° C. ¹ H-NMR (DMSO-d ₆ ): δ 7.4 to 7.3 (m, 13H), 5.26 (s, 2)
H), 5.12 (s, 2H), 3.24 (s, 3H)

Reference Example 3 Synthesis of 2,5-dimethoxyphenylmethylsulfone: 1.88 g of 2,5-dihydroxyphenylmethylsulfone obtained in Reference Example 1 and 1.5 ml of methyl iodide in the presence of 4.15 g of potassium carbonate. , Heated to reflux in 50 ml of acetone for 4 hours. After cooling, the insoluble matter was filtered off, the filtrate was concentrated, the obtained residue was distributed between diethyl ether and water, the organic layer was separated, dried over anhydrous magnesium sulfate and the solvent was distilled off. Was recrystallized from a water-ethanol mixture,
2,5-dimethoxyphenylmethyl sulfone 1.08
g (yield 50%) was obtained.

Melting point: 72 to 74 ° C. ¹ H-NMR (CDCl ₃ ): δ 7.51 (d, 1H, J = 2.8 Hz), 7.00
7.12 (m, 2H), 3.96 (s, 3H), 3.8
2 (s, 3H), 3.22 (s, 3H)

Example 1 Synthesis of 2 ', 5'-dibenzyloxyphenyl (2,3-dibenzyloxyphenyl) vinyl sulfone (Compound 1): 2,5-dibenzyloxyphenyl obtained in Reference Example 2 0.37 g of methyl sulfone, 0.36 g of 2,3-dibenzyloxybenzaldehyde and 0.06 g of tetrabutylammonium bromide were dissolved in a mixed solution of 20 ml of 40% sodium hydroxide aqueous solution and 15 ml of dichloromethane and stirred at room temperature for 2 days. 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 toluene-methanol mixture to give the title compound (Compound 1).
Was obtained (0.43 g, yield 64%).

Melting point: 126 to 128 ° C. ¹ H-NMR (CDCl ₃ ): δ 7.84 (d, 1H, J = 15.7 Hz), 7.68
(D, 1H, J = 3.1 Hz), 6.75 to 7.50
(M, 26H), 5.12 (s, 2H), 5.10
(S, 2H), 5.07 (s, 2H), 4.98 (s,
2H)

Example 2 Compound 2 was prepared in the same manner as in Example 1 using appropriate starting materials.
~ 12 were synthesized. 2 ', 5'-dibenzyloxyphenyl (3,4-dibenzyloxyphenyl) vinyl sulfone (Compound 2)

Yield: 45% Melting point: 132-133 ° C. ¹ H-NMR (CDCl ₃ ): δ 7.63 (d, 1H, J = 3 Hz), 6.65-7.4
5 (m, 26H), 5.11 (s, 2H), 5.06
(S, 2H), 5.01 (s, 2H), 4.96 (s,
2H)

2 ', 5'-dibenzyloxyphenyl (2,4-dibenzyloxyphenyl) vinyl sulfone (Compound 3) Yield: 23% Melting point: 133-135 ° C ¹ H-NMR (CDCl ₃ ): δ 7.67 (d, 1H, J = 15.6 Hz), 7.62
(D, 1H, J = 3.1 Hz), 6.40 to 7.40
(M, 26H), 4.99 (s, 4H), 4.95
(S, 2H), 4.91 (s, 2H)

2 ', 5'-dibenzyloxyphenyl (2
-Benzyloxy-3-methoxyphenyl) vinyl sulfone (Compound 4) Yield: 40% Melting point: 91-93 ° C ¹ H-NMR (CDCl ₃ ): δ 7.83 (d, 1H, J = 15.7 Hz), 7.67
(D, 1H, J = 3.1 Hz), 6.74 to 7.50
(M, 20H), 7.20 (d, 1H, J = 15.7H
z), 5.10 (s, 2H), 5.07 (s, 2H),
4.95 (s, 2H), 3.88 (s, 3H)

2 ', 5'-dibenzyloxyphenyl (4
-Benzyloxy-3-methoxyphenyl) vinyl sulfone (Compound 5) Yield: 32% Melting point: 142-143 ° C ¹ H-NMR (CDCl ₃ ): δ 7.63 (d, 1H, J = 3 Hz), 6. 60-7.4
7 (m, 21H), 6.82 (d, 1H, J = 15.4)
Hz), 5.11 (s, 2H), 5.07 (s, 2)
H), 5.01 (s, 2H), 3.70 (s, 3H)

2 ', 5'-Dibenzyloxyphenyl (2,3-dimethoxyphenyl) vinyl sulfone (Compound 6) Yield: 77% Melting point: 151-153 ° C ¹ H-NMR (CDCl ₃ ): δ 7. 76 (d, 1H, J = 15.7Hz), 7.64
(D, 1H, J = 3.1 Hz), 6.68 to 7.45
(M, 15H), 7.21 (d, 1H, J = 15.7H
z), 5.11 (s, 2H), 5.01 (s, 2H),
3.79 (s, 3H), 3.66 (s, 3H)

2 ', 5'-Dibenzyloxyphenyl (2,4-dimethoxyphenyl) vinyl sulfone (Compound 7) Yield: 22% Melting point: 165-167 ° C ¹ H-NMR (CDCl ₃ ): δ 7. 65 (d, 1H, J = 3.1 Hz), 7.58
(D, 1H, J = 15.4 Hz), 6.28 to 7.48
(M, 15H), 7.18 (d, 1H, J = 15.4H
z), 5.09 (s, 2H), 5.00 (s, 2H),
3.76 (s, 3H), 3.60 (s, 3H)

2 ', 5'-Dibenzyloxyphenyl (3,4-dimethoxyphenyl) vinyl sulfone (Compound 8) Yield: 51% Melting point: 179-180 ° C ¹ H-NMR (CDCl ₃ ): δ 7. 64 (d, 1H, J = 3.0Hz), 6.65
7.50 (m, 16H), 6.84 (d, 1H, J = 1
5.4 Hz), 5.08 (s, 2H), 5.02 (s,
2H), 3.83 (s, 3H), 3.69 (s, 3H)

2 ', 5'-dibenzyloxyphenyl (4
-Benzyloxyphenyl) vinyl sulfone (Compound 9) Yield: 30% Melting point: 178-179 ° C ¹ H-NMR (CDCl ₃ ): δ 7.63 (d, 1H, J = 3.0 Hz), 6.77 ~
7.44 (m, 8H), 5.07 (s, 2H), 5.0
2 (s, 4H)

2 ', 5'-dimethoxyphenyl (2,3
-Dimethoxyphenyl) vinyl sulfone (Compound 10) Yield: 49% Melting point: 138-139 ° C ¹ H-NMR (CDCl ₃ ): δ 7.94 (d, 1H, J = 15.6 Hz), 7.56
(D, 1H, J = 3 Hz), 7.25 (d, 1H, J =
15.6 Hz), 6.90 to 7.14 (m, 5H),
3.91 (s, 3H), 3.88 (s, 3H), 3.8
7 (s, 3H), 3.83 (s, 3H)

2 ', 5'-dimethoxyphenyl (3,4
-Dimethoxyphenyl) vinyl sulfone (Compound 11) Yield: 15% Melting point: 169-170 ° C ¹ H-NMR (CDCl ₃ ): δ 7.56 (d, 1H, J = 15.4 Hz), 7.49
(D, 1H, J = 3.0 Hz), 6.76 to 7.3
(M, 6H), 3.86 (s, 6H), 3.84 (s,
3H), 3.77 (s, 3H)

2 ', 5'-dimethoxyphenyl (3,4
-Dibenzyloxyphenyl) vinyl sulfone (Compound 1
2) Yield: 18% Melting point: 189-191 ° C ¹ H-NMR (CDCl ₃ ): δ 7.47 (d, 1H, J = 15.4 Hz), 7.47
(D, 1H, J = 3.1 Hz), 6.80 to 7.42
(M, 16H), 5.14 (s, 2H), 5.11
(S, 2H), 3.81 (s, 3H), 3.76 (s,
3H)

2 ', 5'-dimethoxyphenyl (2,3
-Dibenzyloxyphenyl) vinyl sulfone (Compound 1
3) Yield; 22% Melting point; 103 to 105 ° C ¹ H-NMR (CDCl ₃ ): δ 7.85 (d, 1H, J = 15.6 Hz), 7.47.
(D, 1H, J = 3.0 Hz), 6.80 to 7.43
(M, 16H), 7.19 (d, 1H, J = 15.6H
z), 5.08 (s, 2H), 4.97 (s, 2H),
3.76 (s, 3H), 3.71 (s, 3H)

Example 3 Synthesis of 2 ', 5'-dihydroxyphenyl (2,3-dihydroxyphenyl) vinyl sulfone (Compound 14):
1.05 g of 2 ', 5'-dibenzyloxyphenyl (2,3-dibenzyloxyphenyl) vinyl sulfone (Compound 1) obtained in Example 1 and 1.1 ml of N, N-dimethylaniline were added to 40 ml of anhydrous dichloromethane. Was dissolved in water, 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 purified by silica gel column chromatography. 0.24 g (yield 51%) of the compound (Compound 14) was obtained.

Melting point: 173-176 ° C. ¹ H-NMR (DMSO-d ₆ ): δ 7.70 (d, 1H, J = 15.6 Hz), 7.39
(D, 1H, J = 15.5 Hz), 7.16 (d, 1
H, J = 2.9 Hz, 7.00 (dd, 1H, J =
7.7 Hz), 6.89 (dd, 1H, J ₁ = 8.8H
z, J ₂ = 2.9 Hz), 6.84 (d, 1H, J =
6.6 Hz), 6.80 (d, 1H, J = 8.8H
z), 6.64 (t, 1H, J = 7.8 Hz), 3.4
(Bs, 1H)

Example 4 Synthesis of 2 ', 5'-dihydroxyphenyl (3,4-dihydroxyphenyl) vinyl sulfone (Compound 15):
In the same manner as in Example 3, instead of 2 ', 5'-dibenzyloxyphenyl (2,3-dibenzyloxyphenyl) vinyl sulfone, 2', 5 'obtained in Example 2 was used.
The reaction was performed using -dibenzyloxyphenyl (3,4-dibenzyloxyphenyl) vinyl sulfone (Compound 2) to obtain 0.19 g (yield 41%) of the title compound (Compound 15).

Melting point: 189-193 ° C. ¹ H-NMR (DMSO-d ₆ ): δ 9.4 (bs, 2H), 7.36 (d, 1H, J = 1)
5.5 Hz), 7.15 (d, 1H, J = 3 Hz),
7.05 (d, 1H, J = 15.5 Hz), 6.7-
7.05 (m, 5H), 3.4 (bs, 1H)

Example 5 Synthesis of 2 ', 5'-dihydroxyphenyl (2,3-dihydroxyphenyl) ethyl sulfone (Compound 16):
0.67 g of 2 ', 5'-dibenzyloxyphenyl (2,3-dibenzyloxyphenyl) vinyl sulfone (Compound 1) obtained in Example 1 was dissolved in 40 ml of ethyl acetate to obtain 100 mg of 5% palladium carbon. In addition, the mixture was stirred under a hydrogen stream at room temperature for 2 hours. After completion of the reaction, the insoluble material was filtered off, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain 0.15 g (yield 48%) of the title compound (Compound 16).

Melting point: 177 to 180 ° C. ¹ H-NMR (DMSO-d ₆ ): δ 9.3 (bs, 1H), 6.4 to 7.2 (m, 6H),
3.51 (m, 2H), 2.79 (m, 2H)

Example 6 Compounds 17 to 21 were synthesized in the same manner as in Example 5 using appropriate starting materials. 2 ', 5'-Dihydroxyphenyl (3,4-dihydroxyphenyl) ethyl sulfone (Compound 17) Yield; 94% Melting point; 197-198 ° C ¹ H-NMR (DMSO-d ₆ ): δ 10.21 (bs , 1H), 9.35 (bs, 1H),
8.75 (bs, 2H), 6.3 to 7.2 (m, 6)
H), 3.60 (m, 2H), 3.53 (m, 2H),

2 ', 5'-dihydroxyphenyl (2,
4-dihydroxyphenyl) ethyl sulfone (Compound 1
8) Yield; 83% Melting point: 213-217 ° C ¹ H-NMR (DMSO-d ₆ ): δ 10.12 (bs, 1H), 9.33 (bs, 2H),
9.05 (bs, 1H), 6.0-7.1 (m, 6
H), 3.52 (m, 2H), 2.73 (m, 2H)

2 ', 5'-dihydroxyphenyl (2-
Hydroxy-3-methoxyphenyl) ethyl sulfone (Compound 19) Yield: 63% Melting point: 138-139 ° C. ¹ H-NMR (DMSO-d ₆ ): δ 10.14 (bs, 1H), 9.32 (bs , 1H),
8.62 (bs, 1H), 6.6 to 7.2 (m, 6)
H), 3.76 (s, 3H), 3.59 (m, 2H),
2.76 (m, 2H)

2 ', 5'-dihydroxyphenyl (2,
3-dimethoxyphenyl) ethyl sulfone (Compound 2
0) Yield; 77% Melting point; 102-105 ° C ¹ H-NMR (DMSO-d ₆ ): δ 10.20 (bs, 1H), 9.31 (bs, 1H),
6.7 to 7.2 (m, 6H), 3.77 (s, 3H),
3.62 (s, 3H), 3.49 (m, 2H), 2.7
5 (m, 2H)

2 ', 5'-dihydroxyphenyl (3,
4-dimethoxyphenyl) ethyl sulfone (Compound 2
1) Yield; 90% Melting point; 159 to 160 ° C ¹ H-NMR (CDCl ₃ ): δ 8.35 (bs, 1H), 6.54 to 7.1 (m, 6)
H), 3.76 (s, 6H), 3.35 (m, 2H),
2.76 (m, 2H)

Test Example 1 With respect to the compound of the present invention, its carcinogenic promoter inhibitory action 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. And many of the compounds that suppress the promotion of phospholipid metabolism by 12-O-tetradecanoylphorbol-13-acetate (TPA), which is known as a typical carcinogenic promoter, suppress the carcinogenic promotion in vivo and suppress the tumor. It has become clear that the incidence of Therefore, it is possible to use a method of measuring the efficacy of suppressing the phospholipid metabolism enhancement of cells by TPA as an index of the anti-promoter action.

The culture cells used were HeLa cells of human cervical cancer cells, Eagle MEM containing 10% fetal calf serum.
The culture was carried out in 2 ml of the liquid, 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 solution. The same amount of dimethyl sulfoxide alone was added to the control. Carcinogenic promoter TPA (50 nM) and radioactive inorganic phosphate 1 hour later
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 the radioactivity of ³² Pi incorporated therein was measured. The inhibition rate was calculated by the following formula. The results are shown in Table 1.

[0077]

[Equation 1]

[0078]

[Table 1]

As shown in Table 1, the compounds of the present invention are TPA.
Since it suppresses the increase of radioactive phosphorus uptake into the phospholipids of cultured cells by S. cerevisiae, it has an oncogenic promoter-suppressing action. In these experiments, no deaths were observed in each compound-administered group, and no change in appearance was observed.

[0080]

[Table 2] Formulation Example 1 Tablets Tablets were prepared in the following blending ratio according to a conventional method. Compound 14 100 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

[0081]

[Table 3] Formulation Example 2 Granules Granules were prepared in the following mixing ratio according to a conventional method. Compound 14 200 mg Mannitol 540 mg Corn starch 100 mg Crystalline cellulose 100 mg Hydroxypropyl cellulose 50 mg Talc 10 mg 1000 mg per packet

[0082]

[Table 4] Formulation Example 3 Fine granules Fine granules were prepared in the following blending ratio according to a conventional method. Compound 15 200 mg Mannitol 520 mg Corn starch 100 mg Crystalline cellulose 100 mg Hydroxypropyl cellulose 70 mg Talc 10 mg 1000 mg per packet

[0083]

[Table 5] Formulation Example 4 Capsule A capsule was prepared in the following mixing ratio according to a conventional method. Compound 15 100 mg Lactose 50 mg Corn starch 47 mg Crystalline cellulose 50 mg Talc 2 mg Magnesium stearate 1 mg 300 mg per capsule

[0084]

[Table 6] Formulation Example 5 Syrup A syrup was prepared in the following blending ratio according to a conventional method. Compound 15 1 g Purified sucrose 60 g Ethyl parahydroxybenzoate 5 mg Butyl parahydroxybenzoate 5 mg Perfume Suitable amount Coloring agent Suitable amount Purified water Suitable amount Total 100 ml

[0085]

[Table 7] Formulation Example 6 Injections Injections were prepared in the following proportions according to a conventional method. Compound 16 100mg Distilled water for injection qs 2ml in 1 ampoule

[0086]

[Table 8] Formulation Example 7 Suppository A suppository was prepared according to a conventional method in the following mixing ratio. Compound 17 100 mg Huy step tetrazole S-55 1400 mg (saturated fatty acids from lauric acid to stearic acid mono -, di -, tri - glyceride mixtures, made Dainama site Nobel) 1 per 1500mg

[0087]

EFFECT OF THE INVENTION Phenylsulfone derivative (1) of the present invention
Has an activity of suppressing carcinogenesis and is extremely useful as an antitumor agent.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Knikowski Antony Jedi Pyrek Ego 3 / 1,80-225 Gdansk, Poland (72) Inventor Tetsuji Asao Yamaguchi 5063-1, Tokorozawa, Saitama Prefecture 5072-1, 48-2-504 (72) Inventor, Saisuke Tsubasa 1-2-5, Makinohonmachi, Hirakata-shi, Osaka (72) Inventor Yuji Yamada 2-2953-21 Higashisayamagaoka, Tokorozawa, Saitama

Claims (7)

[Claims] 1. A compound of the general formula (1) [In the formula, R ¹ represents a hydroxyl group, a lower alkoxy group or an aralkyloxy group, A represents an ethylene chain or an ethenylene chain, W ¹ and Z ¹ are the same or different and are a hydrogen atom, a hydroxyl group, a lower alkoxy group or an aralkyl group. Indicates an oxy group. ] The phenyl sulfone derivative represented by these, or its pharmaceutically acceptable salt. 2. The compound according to claim ¹ , wherein the aralkyloxy groups of R ¹ , W ¹ and Z ¹ are benzyloxy groups. 3. The compound according to claim 1, wherein A is an ethenylene chain. 4. The compound according to claim 3, wherein R ¹ , W ¹ and Z ¹ are hydroxyl groups. 5. The compound according to claim 1, wherein A is an ethylene chain. 6. A compound represented by the general formula (2): [In the formula, R ² represents a lower alkoxy group or an aralkyloxy group. A compound represented by the general formula (3): [In the formula, W ² and Z ² are the same or different and each is a hydrogen atom,
A lower alkoxy group or an aralkyloxy group is shown. ] The benzaldehyde derivative represented by the formula [1] Wherein, R ^2, W ² and Z ² are as defined above. ] The manufacturing method of the phenyl sulfone derivative represented by these. 7. An antitumor agent comprising the phenylsulfone derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.