JP5408660B2 - Paraterphenyl compound, pharmacologically acceptable salt thereof, production method and use thereof - Google Patents

Description

  The present invention relates to a novel paraterphenyl compound, a pharmacologically acceptable salt thereof, a production method and use thereof, and in particular, a compound useful as a pharmaceutical such as an autoimmune disease therapeutic agent and an allergic disease therapeutic agent, The present invention relates to a pharmacologically acceptable salt, a production method and use thereof.

  The present inventors have found that dibenzofuran compounds contained in Thelephora vialis, a mushroom belonging to the family Basidiomycetes belonging to the family Ibustake, have radical scavenging activity, β-hexosaminidase release inhibitory activity and tumor necrosis factor (TNF). -It discovered that it had alpha production inhibitory activity (patent document 1).

  As an antiallergic substance that can be produced by chemical synthesis, for example, there is a paraterphenyl compound represented by the following formula (I) (Patent Document 2).

(Wherein R ^{1 to} R ¹³ are hydrogen, halogen, lower alkyl, lower alkoxy, etc., X is —O—, —CH ₂ —, —NR ¹⁴ — or —S (O) _p —, Y Is lower alkyl or lower alkenyl.)

The paraterphenyl compound suppresses IgE production in the process until mature B cells differentiate into antibody-producing cells and produce antibodies, and does not suppress the production of IgG, IgM and / or IgA produced simultaneously. It is an IgE selective production inhibitor containing a very weakly suppressing substance.
JP 2007-70251 A International Publication No. 98/04508 Pamphlet

  The present inventors have heretofore demonstrated that viarinin A (vialinin A) derived from Thelephora vialis belonging to the family Basidiomycete Ibottake is equivalent to or stronger than FK-506, which is a commercially available immunosuppressant. It has been confirmed that it has oxidation activity. Thelephora vialis has been eaten as an edible candy for a long time as “Tsuboi Bamboo”, and it can be said that the safety of Baylinin A has been confirmed.

  However, since the dibenzofuran compound is a natural product derived from Thelephora vialis, in order to obtain the dibenzofuran compound, it was necessary to extract it from a large amount of thelephora vials. The burden of production cost was great.

  Therefore, the present invention provides a compound that can be produced by chemical synthesis, has excellent tumor necrosis factor (TNF) -α production inhibitory activity, and has very little harmful action, and further a medicament containing the compound. The purpose is to provide.

  While the present inventors are examining the manufacturing method by the chemical synthesis of vialinin A (vialinin A), the tumor necrosis factor is made into the novel paraterphenyl compound or its pharmacologically acceptable salt obtained by the synthesis | combination. It has been found that it has (TNF) -α production inhibitory activity and antiallergic activity, and has very few harmful effects.

The present invention is based on such knowledge and relates to the following [1] to [15].
[1] A paraterphenyl compound represented by the formula (1) or a pharmacologically acceptable salt thereof.

(Wherein R ₁ and R ₂ each independently represents an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, an alkoxyalkyl group, a siloxyalkyl group, a phenyl group, or an alkylene group having 3 or 4 carbon atoms, R ₃ and R ₄ each independently represent hydrogen or a hydroxyl-protecting group.)

[2] The paraterphenyl compound or pharmacologically acceptable salt thereof according to [1] above, wherein R ₃ and R ₄ are both hydrogen.
[3] R ₃ and R ₄ are each independently an alkyl group having 1 to 4 carbon atoms, R ₅ OCH ₂ — (wherein R ₅ represents an alkyl group having 1 to 4 carbon atoms). The paraterphenyl compound or pharmacologically acceptable salt thereof according to [1] above, characterized in that
[4] The paraterphenyl compound of any one of [1] to [3] above, wherein the alkoxyalkyl group is an alkoxymethyl group, and the siloxyalkyl group is a siloxymethyl group, or a compound thereof Pharmacologically acceptable salt.
[5] 2 ′, 3 ′, 4,4 ″ -tetrahydroxy-5 ′, 6′-dimethylparaterphenyl or 4,4 ″ -dihydroxy-2 ′, 3′-bis (methoxymethoxy) -5 The paraterphenyl compound or a pharmaceutically acceptable salt thereof according to the above [1], which is', 6'-dimethylparaterphenyl.
[6] A compound represented by the formula (2) and an organoboron compound represented by the formula (3) are reacted to form a paraterphenyl compound represented by the formula (4), and R ₃ ′ and The method for producing a paraterphenyl compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [5] above, wherein R ₄ ′ is eliminated.

(Wherein R ₁ and R ₂ each independently represents an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, an alkoxyalkyl group, a siloxyalkyl group, a phenyl group, or an alkylene group having 3 or 4 carbon atoms). , R ₃ ′ and R ₄ ′ each independently represent a hydroxyl protecting group, and R ₆ and R ₇ each independently represent a leaving group.)

(Wherein R ₈ represents a hydroxyl-protecting group)

(Wherein R ₁ and R ₂ each independently represents an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, an alkoxyalkyl group, a siloxyalkyl group, a phenyl group, or an alkylene group having 3 or 4 carbon atoms, R ₃ ′ and R ₄ ′ each independently represent a hydroxyl protecting group.)

[7] The paraterphenyl compound as described in [6] above, wherein the compound represented by the formula (2) is obtained by introducing a hydroxyl-protecting group into the compound represented by the formula (5) Or a method for producing a pharmacologically acceptable salt thereof.

(Wherein R ₁ and R ₂ each independently represents an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, an alkoxyalkyl group, a siloxyalkyl group, a phenyl group, or an alkylene group having 3 or 4 carbon atoms, R ₆ and R ₇ each independently represent a leaving group.)

[8] The above [6] or [7], wherein R ₃ ′ and R ₄ ′ are each independently a silyl group, an alkyl group, an alkoxyalkyl group, a siloxyalkyl group or an acyl group. A method for producing a paraterphenyl compound or a pharmacologically acceptable salt thereof.
[9] R ₃ ′ and R ₄ ′ are each independently an alkyl group having 1 to 4 carbon atoms, R ₅ OCH ₂ — (where R ₅ represents an alkyl group having 1 to 4 carbon atoms). The method for producing a paraterphenyl compound or a pharmacologically acceptable salt thereof according to the above [6] or [7].
[10] R ₆ and R ₇ are each independently a halogen, an alkylsulfonyloxy group (the alkyl group may be substituted) or an arylsulfonyloxy group (the aryl group may be substituted). The process for producing a paraterphenyl compound or a pharmacologically acceptable salt thereof according to any one of [6] to [9] above,
[11] The paraterphenyl compound of any one of the above-mentioned [6] to [10] or pharmacologically acceptable thereof, wherein R ₈ is a tert-butyldimethylsilyl group Method for producing salt.
[12] The paraterphenyl compound of any one of [6] to [11] above, wherein the alkoxyalkyl group is an alkoxymethyl group, and the siloxyalkyl group is a siloxymethyl group, or a compound thereof A method for producing a pharmacologically acceptable salt.
[13] A pharmaceutical comprising the paraterphenyl compound or a pharmacologically acceptable salt thereof according to the above [1] to [5].
[14] The medicament according to [13] above, which is a tumor necrosis factor (TNF) -α production inhibitor.
[15] The medicament according to [13] above, which is a therapeutic agent for autoimmune disease or allergic disease.

  ADVANTAGE OF THE INVENTION According to this invention, the novel paraterphenyl compound useful as a pharmaceutical or its pharmacologically acceptable salt, Furthermore, the pharmaceutical which uses this compound as an active ingredient can be provided at low cost.

  The novel paraterphenyl compound or pharmaceutically acceptable salt thereof according to the present invention has excellent tumor necrosis factor (TNF) -α production inhibitory activity, and as a tumor necrosis factor (TNF) -α production inhibitor, It is also useful as a therapeutic agent for autoimmune diseases and allergic diseases involving tumor necrosis factor (TNF) -α. Furthermore, the compound according to the present invention is excellent in that it is not mutagenic and does not cause side effects due to calcium channel inhibition.

It is a figure which shows the test result of the tumor necrosis factor (TNF)-(alpha) production inhibition test with respect to RBL-2H3 cell. It is a figure which shows the effect with respect to the mouse | mouth type II collagen arthritis of Example 1. FIG. In the figure, (A) is a figure which shows the fluctuation | variation of the average value of a body weight, (B) is a figure which shows the fluctuation | variation of an arthritis score.

  The paraterphenyl compound or pharmacologically acceptable salt thereof according to the present invention is represented by the formula (1).

(Wherein R ₁ and R ₂ each independently represents an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, an alkoxyalkyl group, a siloxyalkyl group, a phenyl group, or an alkylene group having 3 or 4 carbon atoms, R ₃ and R ₄ each independently represent hydrogen or a hydroxyl-protecting group.)

  In the above, examples of the alkyl group having 1 to 6 carbon atoms include a linear or branched alkyl group having 1 to 6 carbon atoms. Specifically, for example, a methyl group, an ethyl group, an n-propyl group, Isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl Group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl Group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2, 2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl It can be mentioned 2-methylpropyl group. Of these, an alkyl group having 1 to 4 carbon atoms is preferable, and a methyl group is particularly preferable.

  In the above, examples of the cyclic alkyl group include a cyclic alkyl group having 3 to 6 carbon atoms, and specific examples include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.

  In the above, examples of the alkoxyalkyl group include those obtained by substituting one or more alkoxy groups having 1 to 6 carbon atoms with the above linear or branched alkyl group having 1 to 6 carbon atoms. The alkoxy moiety may be further substituted with a similar alkoxy group. As the alkoxyalkyl group, an alkoxymethyl group is preferable, and examples thereof include a methoxymethyl (MOM) group and a methoxyethoxymethyl group.

  In the above, examples of the siloxyalkyl group include a siloxy group having a linear or branched alkyl group having 1 to 6 carbon atoms, such as a siloxymethyl group.

In the above, an alkylene group having 3 or 4 carbon atoms means that R ₁ and R ₂ are combined to form a cyclic structure, and R ₁ and R ₂ are combined to form a trimethylene group or a tetramethylene group. To form a group. As a result, examples of the cyclic structure formed include 5-membered rings and 6-membered rings. R ₁ and R ₂ may further form an alkenyl group, for example, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group. Examples thereof include those having 2 to 4 carbon atoms such as a group.

In the above, when R ₃ and R ₄ are hydrogen, the hydroxyl group adjacent to the benzene ring tends to form quinone and tends to be colored, so that R ₃ and R ₄ each have a hydroxyl group. It may be a protecting group. Examples of such protecting groups include groups generally used for protecting hydroxyl groups in chemical reactions without limitation, but alkyl groups having 1 to 4 carbon atoms or R ₅ OCH ₂ — are preferred from the viewpoint of the pharmacological activity of the compound. . R ₅ represents an alkyl group having 1 to 4 carbon atoms and is linear or branched such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, or a tert-butyl group. Chain alkyl groups. In addition, when both R ₃ and R ₄ are hydrogen, they are preferable compounds because they have good pharmacological activity.

  Moreover, as a salt accept | permitted pharmacologically, if it is a salt formed with an acid or a base, it will not specifically limit, For example, an alkali metal salt can be mentioned.

Next, the manufacturing method of the paraterphenyl compound or its pharmacologically acceptable salt shown by Formula (1) is demonstrated. The paraterphenyl compound represented by the formula (1) or a pharmacologically acceptable salt thereof is obtained by reacting a compound represented by the following formula (2) with an organoboron compound represented by the formula (3). In the case of obtaining a paraterphenyl compound represented by the formula (4) and obtaining a compound in which R ₃ and / or R ₄ is hydrogen in the compound of the formula (1), R ₃ ′ and / or R ₄ ′ is hydrolyzed. It can be obtained by desorption by subjecting to decomposition or the like.

(Wherein R ₁ and R ₂ each independently represents an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, an alkoxyalkyl group, a siloxyalkyl group, a phenyl group, or an alkylene group having 3 or 4 carbon atoms, R ₃ ′ and R ₄ ′ each independently represent a hydroxyl-protecting group, and R ₆ and R ₇ each independently represent a leaving group.)

(Wherein R ₈ represents a hydroxyl-protecting group)

(Wherein R ₁ and R ₂ each independently represents an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, an alkoxyalkyl group, a siloxyalkyl group, a phenyl group, or an alkylene group having 3 or 4 carbon atoms, R ₃ ′ and R ₄ ′ each independently represent a hydroxyl protecting group.)

The compound represented by the above formula (4) is a paraterphenyl compound according to the present invention, in which R ₃ and R ₄ are both hydroxyl protecting groups in the above formula (1). The compound obtained by removing both R ₃ ′ and R ₄ ′ from the compound represented by the above formula (4) is a compound obtained by removing both R ₃ ′ and R ₄ ′ in the above formula (1), wherein R ₃ and R ₄ are both hydrogen. It is a paraterphenyl compound.

In the above formula, R ₃ ′ and R ₄ ′ represent a hydroxyl-protecting group. As such a protecting group, a group generally used for protecting a hydroxyl group in a chemical reaction can be mentioned without limitation, but a silyl group, an alkyl group, an alkoxyalkyl group, a siloxyalkyl group or an acyl group is preferred.

  Examples of the silyl group include trisubstituted silyl groups such as a trimethylsilyl group, a triethylsilyl group, and a tert-butyldimethylsilyl group.

  As said alkyl group, a C1-C6 linear or branched alkyl group is mentioned, for example, Specifically, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, n-hexyl, isohexyl Group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl Group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1- Examples include ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, etc. It is possible.

  In the above, examples of the alkoxyalkyl group include those obtained by substituting one or more alkoxy groups having 1 to 6 carbon atoms with the above linear or branched alkyl group having 1 to 6 carbon atoms. The alkoxy moiety may be further substituted with an alkoxy group. As the alkoxyalkyl group, an alkoxymethyl group is preferable, and examples thereof include a methoxymethyl (MOM) group and a methoxyethoxymethyl group.

  In the above, examples of the siloxyalkyl group include a siloxy group having a linear or branched alkyl group having 1 to 6 carbon atoms, and a siloxymethyl group, a trimethylsiloxy group, and the like are preferable.

  Examples of the acyl group include an acetyl group and a phenylacetyl group.

As the _{R 3} 'and _{R 4',} alkyl group, or _R 5 OCH ₂ 1 to 4 carbon atoms - it is preferred. The alkyl group having 1 to 4 carbon atoms and R ₅ are the same as described above. When such a protecting group is used as R ₃ ′ and R ₄ ′, a paraterphenyl compound having excellent pharmacological activity can be obtained.

The leaving group in R ₆ and R ₇ is a reactive group that is removed when the compound (2) and the compound (3) are reacted. As such a group, a leaving group generally used in a chemical reaction can be mentioned without limitation, and a halogen, an alkylsulfonyloxy group or an arylsulfonyloxy group is particularly preferable.

  Examples of the halogen include fluorine, chlorine, bromine and iodine, and bromine and iodine are particularly preferable.

  Examples of the alkylsulfonyloxy group and arylsulfonyloxy group include a sulfonyloxy group having an alkyl group having 1 to 7 carbon atoms or an aryl group, and the alkyl group or aryl group may be substituted with a halogen or the like. Examples include a methanesulfonyloxy group, a paratoluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like, and a trifluoromethanesulfonyloxy group is particularly preferable.

As R ₈ , a group generally used as a protecting group in a chemical reaction can be mentioned without limitation, and a tert-butyldimethylsilyl group (TBS) is preferable.

  The compound represented by the above formula (2) can be produced by introducing a protecting group into the hydroxyl group of the compound represented by the formula (5).

(Wherein R ₁ and R ₂ each independently represents an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group, an alkoxyalkyl group, a siloxyalkyl group, a phenyl group, or an alkylene group having 3 or 4 carbon atoms, R ₆ and R ₇ each independently represent a leaving group.)

  The compound represented by the above formula (2) can be synthesized based on, for example, the method described in Homer. L .: Stum, K. Liebig. Ann. Chem, 1995, 597. 1. That is, the compound of the above formula (5) was added to a solvent and stirred, and a metal hydride or alkyl lithium was added to the solution in an inert gas atmosphere at 0 to 5 ° C. in an amount of 2.0 to 2.5 molar equivalents are added dropwise.

  Examples of the solvent include N, N-dimethylformamide. Examples of the inert gas include nitrogen gas and argon gas. Examples of the metal hydride include sodium hydride, and examples of the alkyl lithium include methyl lithium and n-butyl lithium.

  30-60 minutes after adding metal hydride or alkyllithium, 2.0-2.5 molar equivalents of alkyl halide are added dropwise, stirred at 0-5 ° C for 2.5-3 hours, and then at room temperature. Stir for 1-2 hours.

  Examples of the alkyl halide include halides such as chloromethyl methyl ether, bromomethyl methyl ether, and chloromethyl phenyl sulfide.

  Next, a saturated aqueous solution of ammonium chloride is added and stirred for 1 to 2 hours, followed by extraction with ether or the like.

  The obtained extract is washed with water and brine, dried and concentrated. As a drying method, for example, anhydrous sodium sulfate, anhydrous magnesium sulfate or the like can be used. As a concentration method, for example, it can be performed by vacuum concentration or the like.

  When the obtained residue is purified, the compound represented by the above formula (2) can be obtained as a crystalline solid. The purification treatment can be performed using, for example, silica gel chromatography.

  The compound of the above formula (5) can be easily produced according to a known compound or a known compound, and described in, for example, Homer. L .: Stum, K. Liebig. Ann. Chem. 1995, 597. 1. Can be synthesized by a method similar to that described above.

  In the present invention, in order to obtain the compound represented by the above formula (4) from the compound represented by the above formula (2), the organoboron compound represented by the above formula (3) is used and the Suzuki-Miyaura coupling reaction is utilized. Thus, it is preferable to use a method in which a carbon-carbon bond is formed to form a paraterphenyl skeleton of the compound represented by the above formula (4). Here, the hydroxyl-protecting group in the organoboron compound represented by the above formula (3) is preferably a tert-butyldimethylsilyl group. The reaction conditions for the reaction are exemplified below, but the present invention is not limited thereto.

  A mixture obtained by adding 15 mole equivalents of alcohol to 1 mole of the compound represented by the above formula (2) and 2.0 to 2.5 mole equivalents of the compound represented by the above formula (3) at room temperature under an inert gas atmosphere is 30. Stir for minutes to dissolve solids. Examples of the alcohol include propanol.

  To the resulting solution was added 5 mol% equivalent of palladium catalyst, 15 mol% equivalent of trialkylphosphine, 300 mol% equivalent of 2M aqueous sodium carbonate solution, and 100 to 200 wt% of water, and the mixture was heated to 100 to 105 ° C. Stir for 12 hours and then cool at room temperature. Examples of the palladium catalyst and trialkylphosphine include palladium acetate and triphenylphosphine.

  After adding water, the resulting solution is extracted. Extraction can be performed using ethyl acetate, ether, dichloromethane or the like.

  The obtained extract is washed with water and brine, dried and concentrated. As a drying method, for example, anhydrous sodium sulfate, anhydrous magnesium sulfate or the like can be used. As a concentration method, for example, it can be performed by vacuum concentration or the like.

When the obtained residue is purified, the compound represented by the above formula (4) is obtained as a crystalline solid. The purification treatment can be performed using, for example, silica gel chromatography. This compound is a compound in which R ₃ and R ₄ are both protecting groups in the above (1).

  The compound is subjected to a hydrolysis reaction. For example, 1 mol equivalent of the compound represented by the above formula (4) is added to 400% by weight of degassed methanol and stirred, and a 10% by weight hydrogen chloride methanol solution is added thereto under an inert gas atmosphere at room temperature. Stir for 7-12 hours.

Finally, the reaction solution is concentrated under reduced pressure, and the residue is treated with a solvent to obtain a compound in which R ₃ and R ₄ are both hydrogen in the above formula (1) as white crystals. Examples of the processing solvent include an n-hexane-ether-methanol mixed solvent.

  Moreover, the pharmacologically acceptable salt of the paraterphenyl compound concerning this invention can be manufactured by a known method.

  The paraterphenyl compound represented by the above formula (1) or a pharmacologically acceptable salt thereof has a tumor necrosis factor (TNF) -α production inhibitory effect. Tumor necrosis factor (TNF) -α is an autoimmune disease such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, hay fever (allergic rhinitis), allergic conjunctivitis, insect bites, atopic dermatitis It is a chemical substance involved in allergic diseases such as penicillin shock, bronchial asthma and urticaria. Tumor necrosis factor (TNF) -α is also called an inflammatory cytokine and is a substance produced in the late stage (3 to 6 hours) of the allergic onset process. Therefore, the paraterphenyl compound or pharmacologically acceptable salt thereof according to the present invention is useful as an active ingredient for producing a therapeutic agent for autoimmune diseases and allergic diseases.

  In order to use the paraterphenyl compound represented by the above formula (1) or a pharmacologically acceptable salt thereof for therapeutic purposes, the compound and the pharmacologically acceptable salt thereof are formulated as active ingredients. Orally or parenterally. The dosage varies depending on symptoms, age, sex, body weight, dosage form, etc., for example, when administered orally to adults, the daily dose is usually 0.1 to 1000 mg, about 2 to 6 times a day It can also be administered separately.

  When formulating the paraterphenyl compound represented by the above formula (1) or a pharmacologically acceptable salt thereof, the dosage form is not limited, and tablets, pills, capsules, drops, lozenges, Solid preparations such as chewable agents, powders and granules, and liquid preparations such as aqueous agents, suspensions and emulsions can be prepared, and these preparations can be administered orally. In addition, it can be used parenterally as an injection, such as intravenous, intramuscular, or subcutaneous, or as a suppository or patch.

  In the case of a solid preparation, cellulose and derivatives thereof such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, starch such as wheat starch, corn starch, sodium carboxymethyl starch, dextrin and derivatives thereof, gum arabic, sodium alginate, etc. An excipient such as a natural polymer compound, sugars such as glucose, lactose, maltose, sorbitol, maltitol, mannitol and derivatives thereof, and inorganic salts such as sodium chloride, calcium phosphate, calcium carbonate, and magnesium silicate can be used. In addition, if necessary, binders such as guar gum, synthetic aluminum silicate, stearic acid, polymeric polyvinylpyrrolidone, lubricants such as talc, magnesium stearate, polyethylene glycol 6000, adipic acid, calcium stearate, sucrose, etc. Disintegrating agent, ethyl acrylate / methyl methacrylate copolymer dispersion, caramel, carnauba wax, shellac, sucrose, pullulan and other coating agents, bengara, yellow iron oxide, black iron oxide, carmine, edible blue No. 1, edible yellow No. 4, Coloring agents such as edible yellow No. 4 aluminum lake, edible red No. 2 and copper chlorophyllin sodium can also be used. In the case of liquid preparations such as injections, ascorbic acid, tocopherol acetate, natural vitamin E, antioxidants such as propyl gallate, solubilizing agents such as ethanol, propylene glycol, glycerin, polyethylene glycol, sucrose fatty acid ester, soybean Suspending or emulsifying agents such as lecithin, polyoxyethylene hydrogenated castor oil, polyoxyethylene monostearate, buffers such as citric acid, sodium citrate, acetic acid, sodium acetate, sodium hydroxide, aspartame, liquorice extract, A flavoring agent such as saccharin, a preservative such as sodium benzoate, sodium edetate, sorbic acid, sodium sorbate, methyl paraoxybenzoate, butyl paraoxybenzoate and the like can be contained.

  Hereinafter, the present invention will be described in detail with reference to examples.

[Example 1 and Example 2]
According to the following procedure, 2 ′, 3 ′, 4,4 ″ -tetrahydroxy-5 ′, 6′-dimethylparaterphenyl (Example 1) and 4,4 ′, which are one of new paraterphenyl compounds '-Dihydroxy-2', 3'-bis (methoxymethoxy) -5 ', 6'-dimethylparaterphenyl (Example 2) was prepared.

(In the formula, Me represents a methyl group, MOM represents a methoxymethyl group, DMF represents dimethylformamide, Ac represents an acetyl group, and Ph represents a phenyl group.)

  Using compound (6), compound (7) was synthesized based on the method described in Homer. L .: Stum, K. Liebig. Ann. Chem. 1995, 597. 1.

  Compound (7) (4.28 g, 14.5 mmol) was added to N, N-dimethylformamide (35 mL) and stirred. To this mixed solution was added sodium hydride (60% oil) at 0 ° C. in an argon atmosphere. Medium dispersion, 1.48 g, 37.1 mmol) was added. After 5 minutes, bromomethyl methyl ether (2.95 mL, 36.2 mmol) was added dropwise, stirred at 0 ° C. for 2.5 hours, and then stirred at room temperature for 1 hour. After adding saturated aqueous ammonium chloride solution, the mixture was stirred for 1 hour and then extracted with ether. The obtained extract was washed with water and brine, dried and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 40: 1) to give compound (8) (1,4-dibromo-2,3-bis (methoxymethoxy) -5,6-dimethyl. Benzene) (4.79 g, 86%) was obtained as a crystalline solid. Table 1 shows the physical properties of this compound (8).

  A mixture obtained by adding 1-propanol (2.5 mL) to compound (8) (154 mg, 0.40 mmol) and compound (9) (232 mg, 0.92 mmol) was stirred at room temperature for 30 minutes under an argon atmosphere. Was dissolved. To the resulting solution was added palladium acetate (4.5 mg, 20 μmol), triphenylphosphine (15.7 mg, 60 μmol), 2M aqueous sodium carbonate (0.60 mL, 1.20 mmol), water (0.2 mL), and 100 The mixture was heated to ˜105 ° C. and stirred for 11 hours, and then allowed to cool to room temperature. After adding water, the resulting solution was extracted with ethyl acetate. The obtained extract was washed with water and brine, dried and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 4: 1), and the compound (10) (4,4 ″ -dihydroxy-2 ′, 3 ′) which was Example 2 of the present invention was obtained. -Bis (methoxymethoxy) -5 ′, 6′-dimethylparaterphenyl) (146 mg, 89%) was obtained as white crystals. Table 1 shows the physical properties of this compound (10).

  Compound (10) (382 mg, 0.93 mmol) is dissolved in degassed methanol (2.0 mL), a 10% hydrogen chloride methanol (2.0 mL) solution is added under an argon atmosphere, and the mixture is stirred at room temperature for 7 hours. And then concentrated under reduced pressure. The obtained solid was treated with n-hexane-ether-methanol to obtain the compound (11) (2 ′, 3 ′, 4,4 ″ -tetrahydroxy-5 ′, 6 ′) which is Example 1 of the present invention. -Dimethylparaterphenyl) (273 mg, 91%) was obtained as white crystals. Table 1 shows the physical properties of this compound (11).

[Test Example 1] Tumor necrosis factor (TNF) -α production inhibition test Using the compounds of Example 1 and Example 2 as samples, tumor necrosis factor (TNF) -α production inhibition activity was measured as follows. Rat basophilic leukemia (RBL-2H3) cells are sensitized with anti-DNP-IgE antibody, seeded on a 24-well plate at 2.0 × 10 ⁵ cells / mL, and cultured at 37 ° C. for 24 hours. did. After washing each well, 10 ⁻³ to 10 ⁴ nM of the sample was added and kept at 37 ° C. for 15 minutes. Then, DNP-BSA (manufactured by Cosmo Bio) was added and reacted at 37 ° C. for 3 hours. The culture supernatant of each well is collected, and tumor necrosis factor (TNF) -α released from the cells at the time of degranulation is subjected to ELISA method (enzyme immunoassay) using Rat TNF-α Immunoassay kit (Biosource). The tumor necrosis factor (TNF) -α inhibitory activity was determined from the measured value. At that time, FK-506 generally used as an immunosuppressant was used as a comparative example. The results are shown in Table 2 and FIG. 1 as tumor necrosis factor (TNF) -α production inhibition rate (%).

  From the results in Table 2 and FIG. 1, it was found that the compounds of Example 1 and Example 2 have excellent tumor necrosis factor (TNF) -α production inhibitory activity.

  From the above results, the compound containing the novel paraterphenyl compound of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is an autoimmune disease or allergic disease involving tumor necrosis factor (TNF) -α. It became clear that it is effective as a therapeutic agent. In addition, the tumor necrosis factor (TNF) -α production inhibitory activity of the compound comprising the novel paraterphenyl compound of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is included in Thelephora vialis. It has a stronger activity than baalynin A.

[Test Example 2] Biological Utility Test The biological utility (bioavailability) of the compounds of Examples 1 and 2 was measured. Rats were orally administered 100 mg / kg (n = 2) for the compound of Example 1 and 50 mg / kg (n = 3) for the compound of Example 2, respectively, and the compounds of Example 1 and Example 2 were administered. Each was intravenously administered at 1 mg / kg (each n = 3), and then an experiment was conducted according to the scheme shown in Table 3.

The measurement conditions of high performance liquid chromatography (HPLC) are as follows.
Equipment: Agilent 1100 (Agilent Technologies)
Analytical column: Capcellpak C18 MGII (4.6mm ID x 100mm, 5μm, Shiseido)
Column set temperature: 40 ° C
Autosampler set temperature: 4 ° C
Injection volume: 20 μL
Mobile phase: Mobile phase A; 0.1% by volume formic acid solution
Mobile phase B; acetonitrile gradient: Mobile phase A and mobile phase B were mixed and controlled according to Table 3.
Valve position: 0 to 1.5 minutes; disposal
1.5-6.5 minutes; introduced into MS / MS
6.5 to 8.0 minutes; disposal

The measurement conditions of mass spectrometry (MS / MS) are as follows.
Equipment: API4000 (Applied Biosystems / MDS SCIEX)
Ion source: Turbo VTM (electrospray ionization)
Scan type: MRM (Multiple Reaction Monitoring)
Polarity: negative
ResolutionQ1: Unit
ResolutionQ3: Unit
Curtain Gas: 10
Ion source gas 1:60
Ion source gas 2:60
Temperature: 600 ° C
Collision Gas: 8
Ion spray voltage: -4500V
Detected ions: Example 1; (Q1) m / z321, (Q3) m / z306
Example 2; (Q1) m / z 409, (Q3) m / z 364
p-Hydroxybenzoate (internal standard); (Q1) m / z193, (Q3) m / z92

  About the compound of Example 1 and Example 2, the pharmacokinetic (PK) parameter in each case was calculated from the figure which plotted the plasma concentration after oral administration or intravenous administration versus time, and administration Biological utility (bioavailability) was calculated from the area under the plasma concentration-time curve per unit volume (AUC) value. The results are shown in Tables 5 and 6.

  From Tables 5 and 6, the biological usefulness (bioavailability) is 16.9% for the compound of Example 1 and 54.1% for the compound of Example 2, both of which are orally absorbable. It was shown to be excellent.

Test Example 3 Pharmacological Test Next, the pharmacological effect of Example 1 according to the present invention was examined using a collagen arthritis (CIA) model in mice. The dose of the compound of Example 1 is set to 2 doses of 20 mg / kg body weight and 100 mg / kg body weight, and for each dose, once a day from 21 to 49 days after the first sensitization with type II collagen. Each was administered orally for 28 days. In addition, the compound of Example 1 was melt | dissolved in 0.5% methylcellulose aqueous solution, and it used for the description test. In addition, 0.5% methylcellulose aqueous solution as a control was used as a control, and 1 mg / kg body weight prednisolone per dose was used as a positive control. The n numbers of the compound of Example 1 (20 mg / kg body weight) administration group, the same (100 mg / kg body weight) administration group, the control group, and the positive control group were 6, respectively.

  On the 21st, 24th, 28th, 31st, 35th, 38th, 42th, 45th and 49th day after the first sensitization with type II collagen, the state of arthritis of the mouse limbs was visually observed and scored according to the following criteria. Observation during the administration period of Examples and the like was performed before the administration. In addition, mice were weighed on the 20th day after the first sensitization and before the observation of the limb arthritis on the 21st, 28th, 35th, 42th and 49th days.

[Criteria]
0 points: No inflammatory symptoms, normal 1 point: One finger is swollen red (one joint has edema)
2 points: 2 or more fingers are swollen red (more than 2 joints or edema in the instep)
3 points: Fingers and heels are swollen in red (ankle edema is observed)
4 points: joint movement of the entire limb is poor (severe edema or joint deformation is observed)

  The arthritis score was obtained by adding the scores of the limbs to each individual value and displaying the average value and standard error of each group. The measured body weight was also expressed as the average value and standard error of each group. Regarding the arthritis score, a Mann-whitney U test was performed between the control group, the administration group of each dose of the compound of Example 1, and the control group and the positive control group. For the measured body weight, the equidispersity was tested by F test between the control group and the administration group of each dose of the compound of Example 1, and between the control group and the positive control group. In the case of unequal variance, Aspin-Welch t-test was performed. In both cases, the significance level was expressed as p <0.05, and was divided into p <0.05 and p <0.01. The test results are shown in FIG. 2A for the measured body weight and in FIG. 2B for the arthritis score.

  As is clear from FIG. 2, in the control group, arthritis having an average score of 0.1 was observed on the 24th day after the first sensitization, and the average score was 1.1 from the 28th day to the 49th day after the first sensitization. It increased linearly to ˜7.7, and the onset of arthritis that was apparent as a CIA model was confirmed. Moreover, with the onset of arthritis, weight loss and continuous increase suppression were observed from the 28th day to the 49th day after the first sensitization.

  In contrast, as is clear from FIG. 2, in the compound administration group of Example 1 of the present invention, no difference was observed in the 20 mg / kg body weight administration group from the control group, but 100 mg / kg body weight. In the administration group, arthritis did not develop until the 24th day after the first sensitization, and the average score showed a low transition of 0.4 to 5.3, indicating that the symptoms of arthritis were suppressed. . Regarding the body weight transition, no significant difference was observed between the 100 mg / kg body weight administration group of the compound of Example 1 and the control administration group. It was judged that there was no significant impact.

[Test Example 4] Mutagenicity test (Ames test)
The mutagenicity of the compound of Example 1 was examined by a reverse mutagenicity test using bacteria (Ames test). The test was carried out as follows using Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2uvrA as bacteria, in the absence and presence of S9mix.

(1) A dimethyl sulfoxide (DMSO) solution of each dose of the compound of Example 1 and 0.1 mL each of DMSO as a negative control are placed in a sterilized test tube, and 0.1 M sodium phosphate buffer in the absence of S9mix 0.5 mL of the liquid (pH 7.4), and in the presence of S9mix, 0.5 mL of S9mix was added and mixed, and further 0.1 mL of the bacterial suspension was added.
(2) The above mixture was shaken at 37 ° C. for 20 minutes (90 times / min) and incubated (pre-incubation).
(3) After completion of the pre-incubation, 2 mL of the melted agar solution was added to the mixed solution and overlaid on a minimal glucose agar medium.
(4) After the overlaid agar solidified, it was cultured at 37 ° C. for 48 hours.
(5) After culturing, the presence or absence of precipitates was visually observed, and the growth of bacteria was observed under a stereoscopic microscope.
(6) The number of revertant colonies on the plate was measured using an automatic colony counter (CA-11, manufactured by System Science Co., Ltd.). At that time, area correction and count-off correction were performed.
(7) The number of plates was 2 plates / dose in the dose setting test and the main test.

  The results are shown in Table 6 as the average value of the number of colonies measured for each of the compound of Example 1 and the negative control. Regarding the test results, regardless of the presence or absence of S9mix for any of the test strains, the number of revertant colonies increased more than twice the number of revertant colonies of the negative control as the test substance dose increased, and the increase When reproducibility was observed, the test substance was determined to be mutagenic (positive), and in other cases, negative.

  As is clear from Table 7, the compound of Example 1 of the present invention showed growth inhibition of the test bacteria from 78.1 μg / plate in the S9mix non-added system and 39.1 μg / plate in the S9mix added system. Up to 39.1 μg / plate and 19.5 μg / plate, respectively, there was no difference in the number of revertant colonies from the negative control, and it was judged to have no mutagenicity (negative).

[Test Example 5] hERG inhibition test Experimental Method As shown below, the whole cell clamp method was used.
(1) The cells were perfused with an extracellular fluid having the following composition at a perfusion rate of about 4 mL / min.
Extracellular fluid composition:
Sodium chloride 137 (mM)
Potassium chloride 4
HEPES 10
Calcium chloride 1.8
Magnesium chloride 1
Glucose 10
Adjust pH to 7.31 to 7.39 with sodium hydroxide aqueous solution. (2) Use a glass electrode having a resistance value of 2.8 to 6.0 MΩ. Filled.
Electrode composition:
Potassium chloride 130 (mM)
Magnesium chloride 1
EGTA 5
HEPES 10
Adjust pH to 7.20 with aqueous potassium hydroxide solution (3) After breaking the patch membrane under the electrode, patch clamp amplifier (pCLAMP9; Axon Instruments Inc., Molecular Devices) The membrane potential of the cells was fixed at −80 mV by EPC8 (HEKA Elektronik).
(4) A test pulse of +20 mV, duration 1.5 seconds, and −40 mV, duration 1.5 seconds was applied continuously every 15 seconds.
(5) A carrier (0.1% by volume dimethyl sulfoxide solution), Example 1 as a test substance, or positive after a lapse of 1 minute or more after a stable current having a tail current peak value of 500 pA or more was obtained A control, E-4031, was applied. Cells and the cell-seeded cover glass were replaced with each application.
(6) The temperature of the perfusate in the perfusion tank was 22.6 ° C to 25.8 ° C.
(7) The obtained current was recorded on a computer with patch clamp software via a patch clamp amplifier.

2. Data processing Analysis of the obtained tail peak current was performed using analysis software (Clampfit 9; Axon Instruments Inc., Molecular Devices). Two waveforms were analyzed immediately before application of the test substance or the like and 10 minutes after switching from the extracellular fluid to the carrier, test substance or positive control application solution, and the peak value of the tail current was determined. For any data, a relative value (% before) with respect to the value before application was obtained. Moreover, the inhibition rate by a test substance was calculated | required according to the following formula | equation.
Inhibition rate (%) = 100−A / B × 100
A: Average relative value to pre-application value of test substance group B: Average relative value to pre-application value of vehicle control group

3. Statistical treatment The relative value (% before) of each group with respect to the pre-application value was expressed as mean ± standard deviation. Statistical processing was performed on the relative value (% before) with respect to the pre-application value in any group. As a test of the difference between the average values in the carrier application group and the positive control application group, the uniformity of the variance between the two groups was tested by F test. As a result, because of equal variance, Student's t-test was performed. Since a significant difference was observed by Student's t-test, statistical processing was performed between the carrier application group and the test substance application group at each concentration as follows.

  Statistical processing between the above-mentioned multigroups (carrier application group and test substance and positive control concentration application groups) was carried out by equivalence test using the Bartlett method. As a result, because of unequal variance, Shirley-Williams test was performed. The significance level was 5% for the Barlett test for equal variance test and F test, 5% for Student's t-test, and 5% for one-sided Shirley-Williams test. The above statistical processing was performed using a SAS system, Release 8.2; SAS Institute Inc.).

  The results are shown in Table 8.

  As is apparent from Table 8, when dimethyl sulfoxide as a carrier was applied at 0.1% by volume, the hERG current was 92.2% compared to before application. In contrast, when the compound of Example 1 was applied at a concentration of 1 μM and 3 μM, the hERG current was 100.4% and 90.5% compared to before application, and the residual current ratio after 10 minutes (% before) ) Was not significantly different from the carrier application group. In addition, when E-4031 which is a positive control was applied at a concentration of 0.1 μM, the hERG current was 7.2% compared to that before application, and a statistically significant decrease was observed compared to the carrier application group. It was.

  From the above results, it was shown that hERG inhibition was not observed for the compound of Example 1 of the present invention at the concentrations of 1 μM and 3 μM, and side effects due to the inhibition of the potassium ion channel could be avoided.

Industrial availability

  According to the present invention, a novel paraterphenyl compound having a tumor necrosis factor (TNF) -α production inhibitory activity can be provided by chemical synthesis.

  The novel paraterphenyl compound or pharmaceutically acceptable salt thereof according to the present invention has excellent tumor necrosis factor (TNF) -α production inhibitory activity and is useful as a therapeutic agent for autoimmune diseases and allergic diseases. is there. In addition, the compound according to the present invention is excellent in that it has no mutagenicity and does not cause side effects due to calcium channel inhibition.

  Although several specific embodiments of the present invention have been described in detail, those skilled in the art will recognize that various modifications may be made to the specific embodiments shown without departing from the teachings and advantages of the invention. It is possible to make changes. Accordingly, all such modifications and changes are intended to be included within the spirit and scope of the invention as claimed in the following claims.

  This application is based on Japanese Patent Application No. 2007-229029 filed in Japan (filing date: September 4, 2007), the contents of which are incorporated in full herein.

Claims (14)

A paraterphenyl compound represented by formula (1) or a pharmacologically acceptable salt thereof.

(In Formula (1) , R ₁ and R ₂ are each independently an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. 6 represents an alkoxyalkyl group formed by substituting one or more alkoxy groups, a siloxyalkyl group having 1 to 6 carbon atoms or a phenyl group , and R ₁ and R ₂ are bonded to form 3 or 3 carbon atoms. And may form an alkylene group of 4. R ₃ and R ₄ each independently represents hydrogen , a silyl group, an alkyl group, an alkoxyalkyl group, a siloxyalkyl group, or an acyl group. R ₁ And R ₂ Are each independently an alkyl group having 1 to 6 carbon atoms, and R ₃ And R ₄ Each independently represents hydrogen, an alkyl group having 1 to 4 carbon atoms, or R ₅ OCH ₂ -(Where R ₅ The paraterphenyl compound or a pharmacologically acceptable salt thereof according to claim 1, wherein is a group represented by (C 1 represents an alkyl group having 1 to 4 carbon atoms). The paraterphenyl compound or a pharmaceutically acceptable salt thereof according to claim 2 , wherein R ₃ and R ₄ are both hydrogen. R ₃ and _{R 4} are both R ₅ OCH ₂ - (wherein, _{R 5} represents an alkyl group having 1 to 4 carbon atoms), characterized in that a group represented by para of claim 2 A terphenyl compound or a pharmacologically acceptable salt thereof.   2 ′, 3 ′, 4,4 ″ -tetrahydroxy-5 ′, 6′-dimethylparaterphenyl, or 4,4 ″ -dihydroxy-2 ′, 3′-bis (methoxymethoxy) -5 ′, The paraterphenyl compound or pharmacologically acceptable salt thereof according to claim 1, which is 6'-dimethylparaterphenyl. A compound represented by the formula (2) and an organoboron compound represented by the formula (3) are reacted to form a paraterphenyl compound represented by the formula (4), and R ₃ ′ and / or R _{4 as} necessary. The method for producing a paraterphenyl compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein 'is eliminated.

(In Formula (2) , R ₁ and R ₂ are each independently an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. 6 alkoxy group alkoxy key Shiarukiru group formed by replacing one or more, represents an acyloxyalkyl group or a phenyl group having a carbon number of 1 to 6 alkyl groups, R ₁ and R ₂ bonded to the 3 carbon atoms or 4 may form an alkylene group. in R 3 _'and R _4' are each independently, silyl group, an alkyl group, an alkoxyalkyl group, an acyloxyalkyl group or an acyl group, R ₆ and R ₇ And each independently represents a leaving group.)

(In formula (3) , R ₈ represents a silyl group, an alkyl group, an alkoxyalkyl group, a siloxyalkyl group or an acyl group.)

(In Formula (4) , R ₁ and R ₂ are each independently an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. 6 represents an alkoxyalkyl group formed by substituting one or more alkoxy groups, a siloxyalkyl group having 1 to 6 carbon atoms or a phenyl group , and R ₁ and R ₂ are bonded to form 3 or 3 carbon atoms. 4 may form an alkylene group of 4. R ₃ ′ and R ₄ ′ each independently represents a silyl group, an alkyl group, an alkoxyalkyl group, a siloxyalkyl group or an acyl group. The compound represented by the formula (2) is obtained by introducing a silyl group, an alkyl group, an alkoxyalkyl group, a siloxyalkyl group or an acyl group into the compound of the formula (5). The manufacturing method of the paraterphenyl compound or its pharmacologically acceptable salt as described in 1 above.

(In Formula (5) , R ₁ and R ₂ are each independently an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. 6 represents an alkoxyalkyl group formed by substituting one or more alkoxy groups, a siloxyalkyl group having 1 to 6 carbon atoms or a phenyl group , and R ₁ and R ₂ are bonded to form 3 or 3 carbon atoms. And may form an alkylene group of 4. R ₆ and R ₇ each independently represent a leaving group.) The silyl group is a tri-substituted silyl group, the alkyl group is an alkyl group having 1 to 6 carbon atoms, the alkoxyalkyl group is one or more alkoxy groups having 1 to 6 carbon atoms in the alkyl group having 1 to 6 carbon atoms A substituted alkoxyalkyl group, wherein the siloxyalkyl group is a siloxy group having an alkyl group having 1 to 6 carbon atoms, and the acyl group is an acetyl group or a phenylacetyl group, The manufacturing method of the paraterphenyl compound of Claim 7, or its pharmacologically acceptable salt. Group (wherein, _{R 5} is represents an alkyl group having 1 to 4 carbon atoms) represented by - R ₃ 'and _{R 4'} are each independently an alkyl group having 1 to 4 carbon atoms, or R ₅ OCH ₂ The method for producing a paraterphenyl compound or a pharmacologically acceptable salt thereof according to claim 6, wherein: R ₆ and R ₇ are each independently a halogen, an alkylsulfonyloxy group (alkyl may be substituted) or an arylsulfonyloxy group (aryl may be substituted), The manufacturing method of the paraterphenyl compound of any one of Claims 6-9, or its pharmacologically acceptable salt. The method for producing a paraterphenyl compound or a pharmacologically acceptable salt thereof according to any one of claims 6 to 10, wherein R ₈ is a tert-butyldimethylsilyl group. . A pharmaceutical comprising the paraterphenyl compound or a pharmacologically acceptable salt thereof according to any one of claims 2 to 5. The medicament according to claim 12, which is a tumor necrosis factor (TNF) -α production inhibitor. The medicament according to claim 12, which is a therapeutic agent for autoimmune disease or allergic disease.