WO1986004058A1 - Quinone derivatives, process for their preparation, and medicinal composition containing same - Google Patents

Abstract

Quinone derivatives represented by general formula (I), wherein R1 and R2 may be the same or different and each represents hydrogen, methyl or methoxy or, when taken together, R1 and R2 represent -CH=CH-CH=CH-, R3 represents hydrogen or methyl, R4 represents an optionally substituted aliphatic, aromatic or heterocyclic group, R5 represents methyl, methoxy, optionally substituted hydroxymethyl, an optionally amidated or esterified carboxyl group, Z represents formula (II) or formula (III), n represents an integer of 0 to 10, m represents an integer of 0 to 3, and k represents an integer of 0 to 5, provided that Z and k of the repeating units within the brackets may optionally vary when m represents 2 or 3 are novel, and show an effect of improving metabolism of polyvalent unsaturated fatty acids, particularly an effect of inhibiting production of fatty acid peroxides (i.e., antioxidant effect) or production of 5-lipoxygenase metabolites on mammals, thus being useful as antiasthmatic agent, antiallergic agent, brain circulation improving agent, etc.

Description

 Specification

 Quinone derivatives, their production and

 Pharmaceutical composition comprising

 The present invention relates to a novel quinone derivative having a therapeutic and preventive action against bronchial asthma, immediate allergic disease, various inflammations, arteriosclerosis, endotoxin shock caused by infection, a process for producing the same, and a process for producing the same. The present invention relates to a pharmaceutical composition which can be used in the field of medicine.

 Background technology

 Traditionally, it has been difficult to effectively treat or prevent bronchial asthma. In recent years, SRS-A (slow reacting substance of anaphylaxis), which has long been known as one of the important chemical mediators of immediate hypersensitivity and asthma, is a 5-lipoxygenase metabolite of arachidonic acid, In other words, it has been revealed and noted that it is composed of leukotrienes. Leukotrienes are potent chemical mediators of allergic or inflammatory reactions and are thought to primarily cause contraction of the end lung airways and are associated with dyspnea associated with bronchial asthma. In addition, leukotrienes have increased capillary permeability and potent leukocyte migration, and are closely related to edema and cell infiltration, which are the main symptoms of inflammation, T '. Strong vasoconstriction is also thought to lead to coronary artery failure and angina. As the relationship between leukotrienes and pathophysiology has been elucidated, the importance of inhibitors of 5-lipoxygenase, the first enzyme in the biosynthesis of leukotrienes, has been recognized. ing.

Flavone as a compound already having 5-lipoxygenase inhibitory action Compound, quinone compound [US Patent No. 4271083, EPC Publication No. NO.21841, US Patent No. 4358461], catechol compound [Ciin. Exp. Pharmacol. Physiol, 8, 654-655 (1981)], phenol , Flavone compounds

[Biochem. Biophys. Res. Comraun. 116, 612-618 (1983)], acetylene compounds [E'nr. J. Biochem. 139, 577-583 (1984)] and the like are known. However, none of these are fully satisfactory in drug metabolism and respiratory dynamics.

 The present invention provides a novel quinone compound which is less likely to be inactivated by a metabolic system and has excellent drug-potency as compared with a known compound known to have a 5-lipoxygenase inhibitory action. To provide.

 Disclosure of the invention

 The present invention

 1. General formula-

(I)

(Wherein, RL.R ² is the same or different and represents a hydrogen atom, a methyl group or a methoxy group, or! ^ And! ^ Are mutually bonded, so that —CH = CH— CH R ³ represents a hydrogen atom or a methyl group, R * represents an optionally substituted aliphatic group, aromatic group or heterocyclic group, R ⁵ represents a methyl group, a methoxy group, Z represents —C≡C—, an optionally substituted hydroxymethyl group, a carboxyl group that may be esterified or amidated, -CH _£

Represents a group represented by n represents an integer of O to 10, m represents an integer of 0 to 3, and k represents an integer of 0 to 5. However, when m is 2 or 3, Z and 1 ^ can be changed arbitrarily in the repeating unit in []. ), A quinone derivative represented by

 2General formula

( ^Π )

(Wherein, RR ² , R ³ .R, R ⁵ , Z, k, m and n are as defined above, and R ⁶ is a hydrogen atom, methyl group, methoxymethyl group, benzyl group, 2-tetrahydropyranyl And R ⁷ represents a hydrogen atom, a hydroxyl group, a methoxy group, a methoxymethyloxy group, a benzyloxy group, or a 2-tetrahydrovinyloxy group.) And an oxidizing agent. A method for producing a quinone derivative represented by the general formula (I)

 and

 3. a pharmaceutical composition comprising a compound represented by the general formula (I) as an active ingredient;

I can do it. In the general formula (I), examples of the aliphatic group represented by R ⁴ include an alkyl group having 14 carbon atoms such as methyl, ethyl, η-propyl, i-propyl, η-butyl, i-butyl and t-butyl. Examples of aromatic groups include alkenyl groups having 24 carbon atoms such as vinyl and aryl, and cycloalkyls having 37 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples thereof include aryl groups such as phenyl and naphthyl. Examples of the heterocyclic groups include phenyl (2-phenyl, 3-phenyl) and furyl (2-furyl, 3-phenyl). — Ruffles). These aromatic groups and heterocyclic groups may have 15 substituents, preferably 13 substituents, at any position on the ring. Examples of such substituents include a hydroxyl group and a fluorine group. Halogen atoms such as nitrogen, chlorine and bromine, alkyl groups having 13 carbon atoms such as methyl and ethyl, alkoxy groups having 13 carbon atoms such as methoxy and ethoxy, acetyl group, phenyl group, ρ-tolyl group, and m-tolyl group , Pyridyl group (2-pyridyl, 3-pyridyl), 3-pyridylmethyl group, benzoyl group; hydroxyl group, methylenedioxy group, trimethylene group, 1 imidazolyl group, 1 imidazolylmethyl group (1 CH ₂ — ). When the aliphatic group is a cycloalkyl group, it may have 15 substituents, preferably 13 substituents, at any position on the ring. And alkyl groups having 13 carbon atoms, such as ethyl and ethyl;

The hydroxymethyl group represented by R ⁵ may be substituted and may be an unsubstituted hydroxymethyl group, for example, methoxymethyl, acetomethyl, ditoxoxy, aminocarbonyloxymethyl, substituted aminocarboxyloxymethyl (eg, , Methylaminocarbonyloxymethyl, ethylaminocarbonyloxymethyl, dimethylaminocarbonyloxymethyl, phenylaminocarbonyloxymethyl), on-ring aminocarbonyloxy Examples of esterified carboxyl groups include methyl (eg, morpholinocarbonyloxymethyl, piperidinocarbonyloxymethyl) and the like. Examples of the esterified carboxyl group include those having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, and butoxycarbonyl. And alkoxycarbonyl having 7 to 8 carbon atoms, such as phenoxycarbonyl. Ami de of carboxyl group represented by R ⁵ may be a well also ring on § Mi Bruno carbonyl in substitution § amino carbonyl which the amino group is substituted. Examples of the substituent of the amino group of the substituted aminocarbon include alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, and butyl, and aryl having 6 to 10 carbon atoms such as phenyl and naphthyl. May have a substituent such as hydroxyl, amino.nitro, halogen, methyl, methoxy, etc. at any position on the ring), and a hydroxyl group. Specific examples of the modified galboxyl group include, for example, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, phenylaminocarbonyl, p-hydroxyphenylaminocarbonyl, P-methoxy. Phenylaminocarbonyl, m-chlorophenylaminocarbonyl, diphenyl Such as amino carbonyl, and the like. Examples of the ring-forming amino group luponyl include perforinocarbonyl, piperidinocarbonyl, hydroxyaminogalbonyl, N-hydroxy-1-N-methylaminokarponyl, —hydroxy-N-phenylaminocarbonyl, and the like. can give.

 The compound represented by the general formula (I) according to the present invention can be produced by reacting the compound represented by the general formula (II) with an oxidizing agent.

Oxidation of the compound represented by the general formula (Π) is represented by R ^s and R ^s in the formula (Π). Type and reaction conditions of the oxidizing agent to be used by R ⁷ are different.

Compounds in which R ⁶ and R ⁷ are hydrogen atoms in the general formula (E), ie, phenol compounds, can be easily converted to quinone compounds (I) by using Fremy's salt as an oxidizing agent. I can guide you. In this case, the amount of Fremi monosalt used is about 2 to 4 mol per 1 mol of the compound (Π), and the solvents used are methanol, acetonitrile, ethanol, dioxane, 1,2-dimethoxyethane and these solvents. An aqueous solvent or the like is preferably used. The reaction temperature is 10-80 ° C, and the reaction time is usually about 2-10 hours. In the general formula (II), a compound in which R ⁶ is a hydrogen atom and R ⁷ is a hydroxyl group, that is, a hydroquinone compound is a mild oxidizing agent, for example, air, oxygen, fremi-salt, ferric chloride, sulfate (2) The compound can be easily led to the quinone compound (I) using iron, hydrogen peroxide, peracid, or the like. These reactions are usually performed in the presence of a solvent, and examples of the solvent include methanol, acetonitrile, dioxan, 1,2-dimethoxetane, and a water-containing solvent system composed of these organic solvents and water. When using air or oxygen as the oxidizing agent, the pH of the reaction solution is maintained from neutral to weakly alkaline (pH 7.0 to pH 9.0). An appropriate buffer solution (eg, phosphate buffer) is used to maintain the pH. The reaction temperature is -5 to 30 ° C, and the reaction time is usually up to 1 hour. When ferric chloride, ferric sulfate, flemish monosalt, hydrogen peroxide, and peracid (eg, peracetic acid, m-chloro-saturated benzoic acid) are used as the oxidizing agent, the amount of the oxidizing agent used is the compound ( Π) It is preferably about 1 to 4 mol per 1 mol. The reaction temperature is usually -10 to 30 ° C, and the reaction time is usually up to 1 hour.

In the general formula (II), a compound in which R ⁸ is a methyl group, a methoxymethyl group, a benzyl group, a 2-tetrahydrobilanyl group and R ^{7 is a} methoxy group, a benzyloxy group, or a 2-tetrahydropyranyloxy group, ie, a hydroquino group. The diether compound can be silver oxide (Ag 2 O 3) or sulfuric acid By using a compound (hereinafter referred to as CAN) as an oxidizing agent, the compound can be easily led to the quinone compound (I). When silver oxide (AgO) is used, the reaction is performed in water or a water-containing organic solvent (eg, dioxane, acetonitrile) in the presence of sulfuric acid at a temperature range of -10 ° C to 30 ° C. When CAN is used as an oxidizing agent, it is preferable to use CAN alone or CAN and pyridine-2,6-dicarboxylic acid N-oxide, pyridine-2 in a water-containing organic solvent (clear, acetonitrile, methanol), especially in water-acetonitrile. , 4, 6-Tricarboxylic acid or pyridin-1,2,6-dicarboxylic acid. The appropriate mixing ratio of CAN to the above-mentioned pyridincarboxylic acids is usually about 1: 1 (molar equivalent). The reaction temperature is about 15 ° C to 30 ° C.

 The compound in which Z in the general formula (I) is -CH = CH- can also be produced by returning a compound in which the general formula (I) is one C≡C-. This reaction is usually carried out by partial reduction using quinoline and a Lindlar catalyst in a solvent such as methanol, ethanol or ethyl acetate. The amount of the catalyst used is about 1Ζ50 to 1/5 (weight) with respect to 1 mole of the starting compound, and quinoline is used at about 1/10 to 2 (weight) per catalyst weight. The reaction temperature is 1 Q ° C to 30 ° C, and the reaction time is about 4 hours.

In the general formula (I), R ⁵ is a molyoxymethyl group, a Ν-substituted carboxy oxymethyl group, a hydroxyaminocarbonyl group, a —substituted hydroxyaminocarbonyl group, a hydroxymethyl group, a carboxyl group. , alkoxy carbonyl group, § Mi Roh carbonyl group, the compound is substituted § Mi Bruno carbonyl group, R ⁵ Gahi Dorokishimechiru group, forces carboxyl group, the compound is alkoxycarbonyl two group or § sill O carboxymethyl group It can be derived by the following reactions known per se ^Ten

[Where A is (where R ¹ , R ² , R ³

¹⁺ , 11, 111, and 2 are as defined above), R ⁸ and R ⁹ are an alkyl group of 〇 ₃ , R ^1Q is a lower alkyl or aryl group of ₇ , R ¹¹ and R ¹² represents a hydrogen atom or a C ^ ₇ lower alkyl group or aryl group.]

 The quinone compound (I) thus produced can be isolated and collected by means of separation and purification known per se (eg, chromatography-crystallization method).

 The quinone compound (I) of the present invention has the general formula

(Wherein each symbol is as defined above), the interconversion is easily carried out by chemical or biochemical oxidation and reduction reaction between the quinone nucleus and the hydroquinone nucleus. It is possible. Generally, the quinone derivative (Ha) is easily oxidized by oxygen, air, etc., and therefore, the hydroquinone compound (Ha) is usually treated as a stable compound as the quinone compound (I). The chemical and biochemical interconversion between the hydroquinone compound (Ha) and the quinone compound (I) is easy, so that the quinone compound (I) and the hydroquinone compound (Ha) Can be regarded as having equivalent properties if they exhibit pharmacological effects under physiological conditions.

 The quinone compound (I) can be easily converted to a hydroquinone compound by reducing it using a mild reducing agent such as sodium hydroxide sulfite, sodium acid sulfite, or sodium borohydride by a method known per se. Compound (Π a).

 The quinone compound (I) is structurally an optically active compound having a chiral nucleus side chain alpha (having an asymmetric center at carbon. Therefore, the compound (II) of the present invention can be either an optically active compound or a racemic compound. Also means.

The compound (I) of the present invention can improve the metabolism of polyunsaturated fatty acids (linoleic acid, arlinolenic acid. —Especially—the effect of inhibiting the production of peroxide fatty acids (antioxidant effect) or the metabolites of 5-riboxigenases (eg, leukotrienes, 5-hydroxyeicosatetraenoic acid, 5 —poxyeicosate traenoic acid) , Lipoxins, etc.), and has extremely low toxicity and side effects. Therefore, the compound (I) of the present invention is useful for mammals (mouse, rat, egret, monkey, horse, human, etc.) for bronchial asthma, psoriasis, inflammation, immediate-temporal arergy, arteriosclerosis, atherosclerosis. Degenerative arteriosclerosis, immunodeficiency, low resistance to bacterial infection It is expected to have therapeutic and prophylactic effects on various diseases such as the following. It is useful as a medicament such as an anti-infection enhancer or prostaglandin-thromboxane metabolism improver. When R * in the general formula (I) is a group containing a pyridyl group or an imidazole group, the compound has a thromboxane synthase inhibitory effect in addition to the above-mentioned effects. It can be used as an antithrombotic agent for the prevention and treatment of arrhythmias.

 The compound of the present invention has low toxicity and is a pharmaceutical composition as it is or mixed with a pharmaceutically acceptable carrier or excipient known per se [eg, tablets, capsules (including soft capsules and microcapsules) ), Liquid, injection, suppository] can be safely administered orally or parenterally. Dosage varies depending on the subject of administration, administration route, symptoms, etc. ^ For example, when orally administered to an adult asthmatic patient, it is usually about 0.1 mg / kg to 20 ing / kg as a single dose. It is convenient to administer about body weight, preferably about 0.2 mg / kg to about 10 mgZkg body weight, about once or twice a day.

The compound (I) of the present invention has a bulky group at the carbon at the alpha (α) -position of the side chain of the quinone nucleus, and has a unique structure that makes it less susceptible to inactivation by metabolism in vivo. shows the superior efficacy in drug effective concentration can be maintained time ^_ low dose in the blood as compared to the quinone compound. When R ⁴ is a functional group containing an imidazole group or a pyridyl group, it has a double inhibitory effect on 5-lipoxygenase and tolboxane synthase simultaneously and specifically. It is convenient for application as a system drug. The compound (Π) can be produced by any of the following methods.

(Wherein RL. RS. RS. R +. R SZ, k, m and n have the same meanings as above, R ¹³ is a methoxymethyl group, a benzyl group, a 2-tetrahydrobiranyl group, and R ¹⁴ is a hydrogen atom. Atom, a methoxymethyloxy group or a 2-tetrahydropyranyloxy group.) Can be obtained by deprotection by a known acidic hydrolysis or catalytic reduction.

 In the compound (Π), the general formula

(CH _; ) R ⁵ (Ec)

(Wherein 11 1 ^2, 1 ^3, 1, 1 ^5, [11 Oyopi 11 Ari the same meanings as defined above, R 15

--Me

Represents a hydrogen atom or a hydroxyl group, or 乂 A, A, _e

Indicates 0. The compound represented by the general formula

Wherein each symbol is as defined above, and a compound represented by the general formula:

X ^X -CH- (CH-CCH ₂ ) _k ¾-R ⁵ )

(Where k, m, n, R ⁵ and Z t have the same meanings as above, X ¹ is a hydroxyl group, an acetyl group, a lower alkoxy or a halogen atom, and R ¹⁶ is a group represented by R ⁺ Or a methoxy group)) in the presence of an acid catalyst. In the compound (He), a compound in which R ⁵ is a carboxyl group is represented by the general formula

ζθ one

R ⁴ -CC = 0 (V)

CH ₂ ) _n-

(Wherein, R ⁺ has the same meaning as described above, and n ² represents 2 or 3.) in the presence of an acid catalyst. This condensation reaction is carried out in a nonpolar solvent (eg, methylene chloride, chloroform, benzene, toluene, isopropyl ether, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane) in an acid catalyst. (Examples: boron trifluoride ethyl ether, aluminum chloride, tin chloride, P-toluenesulfonic acid, D- 10-100 in the presence of camphorsulfonic acid. It is performed in the temperature range of C.

 Since this condensation reaction depends on the solubility of compound (II) in the solvent and the reactivity of the acid catalyst and compound (iy) or (V), the reaction catalyst depends on the combination of compound (no, and (V)). The amount of the acid catalyst to be used is in the range of about 20 to 3.0 moles per 1 mole of the compound (ΠΙ) This reaction is preferably performed under anoxic conditions. In the reaction at, a phenolic or hydroquinone compound (He) is obtained.

 Compound (lib) has the general formula

(Id)

(Wherein, RR ² , R ³ , R ⁺ and n are as defined above, R ¹⁷ is a methyl group, a benzyl group, a 2-tetrahydroviranyl group and a methoxymethyl group, and R ¹⁸ is a hydrogen atom, a A methoxy group, a benzyloxy group, a 2-tetrahydroxylanyloxy group, and a methoxymethyloquine group.

(Where

And n are as defined above, and X ² is Indicates a halogen atom. ), Which is then converted to a compound of the general formula

(CH ₂ ^-Y ^! (W)

 km

(In the formula, k and m are as defined above, Y ¹ represents a hydrogen atom, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group or a 2-tetrahydropyranyloxy group, and Z ₂ represents —CC 1 and 1 This condensation reaction which can be produced by a condensation reaction with a compound represented by) differs in the basic reaction conditions used depending on Z in the compound (VE). For example, when Z is a single C≡C group, n-butyllithium, sodium hydride, lithium hydride, sodium amide, etc. are used as basic reagents. On the other hand, potassium carbonate if a Z Gar ⁰ "0" group, hydroxide Na Toriumu, hydroxide force Riumu, and hydrogenated Natoriumu is used.

CH ₃

In the general formula (Π), a compound in which Z is —C—, k is 0, and R ⁵ is a carboxy group or an alkoxycarbonyl group is obtained by condensing both compound (YI) and isobutyrate in the presence of a base. Can also be manufactured. In this case, lithium isopropylamide is preferably used as the base. This reaction is carried out in an inert solvent (eg, diethyl ether, tetrahydrofuran) in an atmosphere of an inert gas (eg, argon, helium, nitrogen) in a temperature range of −40 ° C. to 30 ° C.

Compound (Hd) was obtained by subjecting the phenolic property of compound (lie) or the hydroxyl group of hydroquinone to any of methylation, benzylation, 2-tetrahydropyranylation, or methoxymethylation. Later lithium hydride aluminum Can be produced by a reductive alcoholation reaction known per se in a conventional manner.

 Compound (E d) has the general formula

(In the formula, !!!!!!!!!!! ^^ ぉ ^^ is the same meaning as above.)

(IX)

(Wherein the X ² and η are as defined above, Upsilon ² is a hydrogen atom, a hydroxyl group, 2-te Torahi Dorobiraniru group, a carboxyl group or a _{- C (C Η 3) 2} C 0 0 Η group represented by The compound can be produced by reacting a compound represented by).

The reaction between compound (W) and compound .ox) is performed by converting a methylene group of a benzyl group into an anion in the presence of a strong base (eg, η-butyllithium, methyllithium, lithium diisopropylamide, etc.). The compound (lid) is obtained by reacting the ω-halogenoalkyl derivative (IX). The reaction is carried out in the presence of anhydrous' tetrahydrofuran, getyl ether, 1,2-dimethoxetane in the presence of tetramethylethylenediamine at a temperature range of 0 ° to 70 ° C. Preferred reaction temperature conditions are in the range of room temperature to 65 ° C. In the compound (H), the compound (lb-1) in which R ⁺ is a methyl group and m is 0 can be produced according to a reaction known per se.

Y

 (H b-1)

(Where R

Y ² and R ⁵ are as defined above, and r represents an integer of 1 to 5. )

 BEST MODE FOR CARRYING OUT THE INVENTION

Example 1 (Compound No. i)

2,3.5—Trimethylhydroquinone (3.1 g, 0.02 mol) and 6-acetoxie 6— (2-Chenyl) hexylate (5.6 g, 0.02 mol) in toluene solution (50 ml) in D-camphor Add 10-sulfonic acid (O.lg) and add 6.5 at & 0 The mixture was heated and stirred for hours. After cooling, ethanol (100 ml) and a 10% aqueous ferric chloride solution (20 ml) were added to the reaction solution, and the mixture was stirred for 10 minutes. The reaction product was extracted with isopropyl ether, the organic layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with isopropyl ether hexane (1: 1). — (3,5,6-trimethyl-1,4-benzoquinone-2-yl) —ethyl (6-g) -hexanate (5.6 g, 76%) was obtained. Table 1 shows the physical properties and nuclear magnetic resonance spectrum data. Compound numbers 2 to 8 were produced according to this example. Example 2 (Compound No. 9)

 2,3,5-Trimethylhydroquinone (3.ig, 0.02 mol) and 8-acetoxy 8-phenyloctanic acid (6.0 g, 0.021 mol) are added to toluene (80 ml), and the mixture is triflated with stirring. The reaction mixture was stirred at room temperature for 4 days, the solvent was distilled off under reduced pressure, the residue was dissolved in tetrahydrofuran (50 ml), and a 10% aqueous ferric chloride solution was added. The product was extracted twice with ethyl acetate while washing the organic layer, washed with water, dried and concentrated under reduced pressure, and the resulting crude product was applied to a silica gel column. The product was eluted with a mouth pill, and the quinone compound was recrystallized from isopropyl ether to give 8-phenyl-8- (3,5,6-trimethyl-1,4,1-benzoquinone-12- ) Octanoic acid (5.8 g, 78%) was obtained Physical and nuclear magnetic resonance spectrum data. The results are shown in Table 1. Compound numbers 10 to 19 and 50, 51 were produced according to this example.

Example 3 (Compound No. 20)

A solution of 2-methyl-1,4-naphthohydroquinone (3.6 g, 0.02 ml) and 6-ethoxy 6- (4-methoxyphenyl) hexanoic acid (5.6 g, Q.021 mol) in toluene (50nd Add D-camphor-10-sulfonic acid (O.lg) to The mixture was heated and stirred with C for 18 hours. After cooling, the solvent is distilled off under reduced pressure and then tetrahydrogen Mouth furan (20 ml) was added. A 10% aqueous ferric chloride solution was added thereto, and the mixture was stirred for 10 minutes, and then the reaction product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with isopropyl ether. 6- (3-Methylnaphth-1,4-quinone-12-yl) -6- (4-methoxyphenyl) hexanoic acid (3.5 g, 45%). This product was recrystallized with isopropyl ether. Physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. Compound No. 21 was produced according to this example.

Example 4 (Compound No. 22)

 To a toluene solution (60 ml) of 2,3,5-trimethylhydroquinone (3.1 g, 0.02 mol) and 6-hydroxy-6- (4-methoxyphenyl) hexanoic acid (5. Og, 0.021 mol) D-Enzyme-1 10-sulfonic acid (O.lg) was added, and the mixture was heated and stirred at 70 ° C for 20 hours. The solvent was distilled off from the reaction solution under reduced pressure, and tetrahydrofuran (50 ml) was added to dissolve the reaction solution. A 10% aqueous ferric chloride solution was further added, followed by stirring at room temperature for 10 minutes. The reaction product was extracted with ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with isopropyl ether to give 6- (3,5,6-trimethyl-11,4-benzoquinone-2-yl) -16- (4-methoxyphenyl). Xanic acid (5. lg, 76%) was obtained. Physical properties and nuclear magnetic resonance spectrum data are shown in Table i. Compound Nos. 23 to 34 and 68 were produced according to this example.

Example 5

Aluminum chloride (0.7 g, 5.2 mmol) was added to 1,2-dichloroethane solution (20 ml) of hydroquinone (0.5 g, 4.5 mmol) and 4-phenylbutyrolactone (0.8 g, 4.9 mmol). The mixture was ripened and stirred at 60 ° C for 3 hours. After cooling, 2 N hydrochloric acid (40 ml) was added to the reaction solution, and the mixture was stirred for 10 minutes. Etch the reaction solution The organic layer was washed with water and dried, and the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with isopropyl ether ethyl acetate (1: 1). 4-Dihydroxy-1-phenyl) butyric acid (0.6 g, 49%) was obtained. Oily material Nuclear magnetic resonance spectrum: <5 2.43 (4H) ₍ 4.24 (1H), δ.60 (3Η), 7.3Ό (5Η)

Example 6 (Compound No. 35)

 A solution of 2,3,5-trimethylhydroquinone (1.5 g, 0. (U mol) in 1,2-dichloroethane (20 mO) was added to aluminum chloride (1.4 g, 0.01 mol), and the mixture was ripened to 80 ° C. To this mixed solution was added dropwise a solution of 4-phenylbutyrolactone (1.6 g, 0. (U mol) in 1,2-dichloroethane (10 ml)) over 2 hours, and the reaction was continued under the same conditions for 18 hours. After cooling, the reaction mixture was added with 2N-hydrochloric acid (40 mi), stirred for 10 minutes, extracted with isopropyl ether, washed with water, dried, and the solvent was distilled off. (SO ml), a 10% aqueous ferric chloride solution (5 ml) was added, and the mixture was stirred for 10 minutes at room temperature.The reaction product was extracted twice with ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with isopropyl ether.Then, 4- (3,5,6-trimethyl-1-, 4 Benzoquinone-12-yl) -4-phenylbutyric acid (1.2 g, 38%) was obtained The physical properties and nuclear magnetic resonance spectra are shown in Table 1. According to the present example. Compound Nos. 36 to 38 are manufactured † '' '

Example 7 (Compound No. 40)

2,3-Dimethoxy 6-methyl-1,4-hydroquinone (5.5 g, 0.03 mol) and 5-phenyl-5-valerolactone (5.3 g, 0.03 mol) in toluene solution (80 ml) at room temperature Boron trifluoride getyl ether (0.25 ml) was added dropwise. After the reaction solution was stirred at 50 ° C for 20 hours, it was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 ml), 10% aqueous ferric chloride (iOmi) was added, and the mixture was stirred for 10 minutes. Stirred. The reaction product was extracted with ethyl acetate, and the organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with isopropyl ether. 5- (5,6-Dimethoxy-3-methyl-1,4-benzoquinone-2-yl) -5-phenylvaleric acid (6.5 g) , 57%). This product was recrystallized with isopropyl ether monoethyl acetate. Physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. Compound No. 39 was produced according to this example.

Example 8 (Compound No. 41)

 4-Phenyl-4- (3,5,6-trimethyl-1,4-benzoquinon-2-yl) butanoic acid (1.2 g) is dissolved in ethanol (50 ml), and thionyl chloride (0.4 ml) is added. For 4 hours. After concentrating the reaction mixture under reduced pressure, the residue is dissolved in isopropyl ether, the organic layer is washed with water, dried, concentrated under reduced pressure, applied to a silica gel column and chromatographed, and the desired product is eluted with isopropyl ether. Ethyl phenyl-4- (3,5,6-trimethyl-4-benzoquinone-2-yl) butanoate (l.lg, 84%) was obtained. Physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. Compound No. 42 was produced according to this example.

Example 9 (Compound No. 43)

Boron trifluoride getyl ether (100 ml) was added to a toluene solution (100 ml) of 2,4-methyl-1,4-hydronaphthoquinone (3.5 g, 20 mmol) and 1,6-diacetoxyhexylvesicene (6.0 g, 21mniol). 0.5 ml) and stirred at 60 ° C for 20 hours. After the solvent was distilled off, the residue was dissolved in tetrahydrofuran (50 ml), and an aqueous solution of ferric chloride was added, and the reaction was carried out at room temperature for 10 minutes. The reaction product was deoiled with ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with isop-σ-pyrether-ethyl acetate (1: 1) to give 6-acetoxy-1-1 (3-methyl-1,4-naphthoquinone-1— Yl) -1 monophenylhexane (3.0 g, 38%) was obtained. The physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. Compound No. 44 was produced according to this example.

Example 10 (Compound No. 45)

 7- (2,5-Dimethoxy-3,4,6-trimethylphenyl) -1 7-phenylheptanol (1.85 g, 5.0 mmole) is dissolved in a mixed solution of acetonitrile (12 ml) and water (6 ml). Then, a cooled solution of ceric ammonium nitrate (8.22 g, 5 × 3 niniole) in 50% aqueous acetonitrile (16 ml) was added dropwise over 20 minutes under ice-cooling. After continuing ice-cold stirring for another 20 minutes, acetonitrile was distilled off under reduced pressure. Isopropyl ether was added to the residue for extraction. Take out the isopropyl ether layer, wash with brine, dry (magnesium sulfate), and evaporate the solvent. The residue was purified by silica gel column chromatography (elution with isopropyl ether), and 7- (3,5,6-trimethyl-1,4-benzoquinone-2-yl) -1- Thus, phenylheptanol (1.53 g, g0%) was obtained. Table 1 shows the physical properties and nuclear magnetic resonance spectrum. Compound numbers 9, 10, 4, 35, 36, 46 to 55, and 64 to 67 were produced according to this example.

Example 11 (Compound No. 56)

7- (2,3.4,5-tetramethoxy-1-6-methylphenyl) -1-7-phenylheptanol 2Jlg (a.Ommole), 2.51 g of 2,6-pyridinedicarboxylic acid (5 X 3 maraudal ole) 'A mixed solvent of acetonitrile (12 ml) and water (6 ml) was added, and a cooled solution of 8.22 g (5 x 3 mmole) of 50% aqueous acetonitrile (16 ml) was added dropwise over 20 minutes under ice-cooling. After further stirring under ice-cooling for 20 minutes, insolubles were filtered off, and acetonitrile was distilled off under reduced pressure. Isopropyl ether was added to the residue for extraction. Remove the isopropyl ether layer, wash with brine, dry (magnesium sulfate), and evaporate the solvent. The residue was subjected to silica gel column chromatography, purified and purified (isopropionate). The mixture was eluted with toluene / ethyl acetate) and 1.56 g (84%) of 7- (5,6-dimethoxy-3-methyl-1,4,4-benzoquinone-2-yl) -17-phenylheptanol. The physical properties and nuclear magnetic resonance spectrum are shown in Table 1. Compound No. 57 was produced according to this example.

Example 12 (Compound No. 58)

 6- (3,5,6-trimethyl-1,4-benzoquinone-2-yl) -1-6-hexylhexanol 1.20g (3.68 ole), cyanic acid rim 0.90g (3.68X 3mmole) Toluene (10ml) was added and stirred at room temperature. 1.38 g (3.68x3.3mmole) of trifluoroacetic acid was dropped in 5 minutes. After 5 minutes, raise the reaction temperature to 40 and stir at 35-40 ° C for 3 hours. Water was added, insolubles were filtered off, and isopropyl ether was added to the filtrate, followed by extraction. Take out the organic layer, wash with brine ^, dry (magnesium sulfate), and evaporate the solvent. The residue was subjected to silica gel column chromatography, purified and eluted with isopropyl ether, 6- (3,5,

There was obtained 0.79 g (58%, isopropyl ether recombination) of 6-trimethyl-1,4-benzoquinone-12-yl) -6-phenylhexyl force-bamate. Table 1 shows the physical properties and nuclear magnetic resonance spectrum data. Compound No. 59 was produced according to this example.

Example 13 (Compound No. 60)

6- (3,5.6-Trimethyl-1,4,1-benzoquinone-12-yl) -1-6-phenylhexanol (0.98 g, 3.0 mmole) and methyl isocyanate (0.17 g, 3.0 mmol) dissolved in dichloromethane (10 ml) Add stannic chloride 35, αJ2 (3 X 1 ZlQmmole) to the dragon ole at room temperature and stir for 30 minutes. Add ice water to stop the reaction and extract. Take out the dichloromethane layer, wash with brine, dry (magnesium sulfate), and evaporate the solvent. The residue was subjected to silica gel column chromatography and purified (elution with isopropyl ether), and N-methyl 6- (3,5,6-trimethyl-1,4,1-benzoquinone-12-yl) -1-6- Hueni, I.09 g (95%, reconstituted with isopropyl ether) was obtained. Table 1 shows the physical properties and nuclear magnetic resonance spectrum data. Compound number ^ was produced according to this example.

Example U (Compound No. 62)

 7- (3,5,6-trimethyl-1,4,1-benzoquinone-2-yl) -1 7-phenyl-2-heptin-1-ol (1.01g, 3.0mmole) Ethyl acetate (20ml) solution A Lindlar catalyst (90 mg) and quinoline (152) were added, and catalytic reduction was performed at room temperature. The reaction was stopped when the absorption of hydrogen (73 ml) almost stopped in 3 hours, and the catalyst was filtered off. The ethyl ether was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with isopropyl ether) to give (Z) -7- (3,5,6-trimethyl-11,41). Benzoquinone-1-yl) -7-phenyl-2-heptene-1-ol (0.95 g, 94%) was obtained. Table 1 shows the physical properties and the nuclear magnetic resonance spectrum data.

Example 15 (Compound No. 52)

 7— (3,5,6—trimethyl-1,4—benzoquinone—2—, yl) -1 7—phenyl—2—heptin—1—ol (1. Olg, S. Ommole), acetate (15 ml) solution was added dropwise at room temperature with Diones reagent (2.25 ml) in 15 minutes. After stirring at room temperature for another 30 minutes, acetate was distilled off under reduced pressure. The residue was extracted with isopropyl ether: water. The isopropyl ether layer is taken out, washed with brine, and dried (magnesium sulfate—the solvent is distilled off. The residue is reconstituted with isopropyl ether to give 7— (3,5,6—trimethyl-1,4-benzoquinone-2). 1- 7-Phenyl-2-heptic acid (0.7 ig, 68%) was obtained.

 Table 1 shows the physical properties and nuclear magnetic resonance spectrum data.

Example 16 (Compound No. ^)

4- [7— (3,5,6-trimethyl-1,4-benzoquinone-2-yl) —7-phenylheptoxy] benzoic acid 0.92g (2.0mmole) dichloromethane To the solution (10 ml) was added thionyl chloride (0.44 ml) 2 x 3 mmole) and dimethylformamide (8 J2), and the mixture was stirred at 40 ° C for 1 hour. The solvent was distilled off, and the residue was dissolved in tetrahydrofuran (Oml) and cooled with ice. After adding 0.21 g (2 Xl. Sinmole) of hydroxylamine hydrochloride, a solution of 0.34 g (2 X 2 mmole) of sodium hydrogen carbonate in water (5 ml) was added. After continuing ice-cold stirring for 15 minutes, tetrahydrofuran was distilled off under reduced pressure. The residue was extracted with ethyl acetate. Take out the ethyl ethyl shaking layer, wash with brine, dry (magnesium sulfate), and evaporate the solvent. The residue was subjected to silica gel column chromatography, purified (eluted with ethyl acetate), and purified with 4- [7- (3,5,6-trimethyl-1,4-benzoquinone-12-yl) -17-phenyl] [Phenylheptoxy] benzohydroxamic acid (0.86 g, 91%) was obtained. Table 1 shows the physical properties and nuclear magnetic resonance spectrum data.

Example No. 7 (Compound No. 68)

 6- (3,5,6-Trimethyl-1; 4-benzoquinone-2-yl) -1 6- (2-Chenyl) hexylate (l.'7g, 4.5nimole) in tetrahydrofuran (10ml ) Was added with 6 N hydrochloric acid (10 ml), and the mixture was ripened and stirred at 70 ° C for 17 hours. After cooling, isopropyl ether was added, and the organic layer was washed twice with water. The organic layer was dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with isopropyl ether-ethyl ester (1: 1), and recrystallized from isopropyl ether to give 6- (3,5,6-trimethyl-1,4-benzoquino) 2- (yl) -2-Y- (2-phenyl) hexanoic acid (lg, 70%) was obtained.

 Table 1 shows the physical properties and nuclear magnetic resonance spectrum data.

Example 18 (Compound No. 73)

Lithium aluminum hydride was added to a tetrahydrofuran solution (50 ml) containing 10- (3,5,6-trimethyl-1,4-benzoquinone-12-yl) -1-methyl 10-phenyldecanoate (2.4 g, 6 mmole). (1.0 g, 27 iole) followed by 60 The mixture was ripened and stirred for 3 hours. After cooling the reaction solution, water was added to stop the reaction, and 2N hydrochloric acid was added to adjust the pH to 4.0. A 10% aqueous solution of diiron chloride (5 ml) was added thereto, and the mixture was reacted at room temperature for 10 minutes. Ethyl acetate was added to the reaction solution for extraction. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with isopropyl ether-ethyl acetate (1: 1) to give 10- (3,5,6-trimethyl-1,4). —Benzoquinone-1-yl) -10-phenyldecane-1-ol (2. Og) was obtained. The physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. Compound numbers 74 to 84 were produced according to this example.

Example 19 (Compound No. 69)

 6- (3,5,6-trimethyl-1,4,1-benzoquinone-12-yl) -1-6-phenylhexanoic acid (0.7g, 2minole) Thionyl chloride (2 ml) was added to the solution (10 ml), and the mixture was stirred at 6Q ° C for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in 1,2-dichloroethane (20 ml). To this was added hydroxylamine hydrochloride (0.5 g), followed by saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with ethyl acetate to extract the product, and the organic layer was washed with water and dried, and the solvent was distilled off. The obtained residue was subjected to silica gel gel chromatography, eluted with isopropyl ether-ethyl acetate (1: 1), and the desired product was recrystallized from isopropyl ether-ethyl acetate to give 6- (3,5) , 6-trimethyl-1,4-benzoquinone-2-yl) -6-phenylhexanehydroxamic acid (0.7 g. 96%) was obtained. Physical properties and nuclear magnetic resonance spectra are shown in Table 1. Compound numbers 70 to 72 were produced according to this example.

Example 20 (Compound No. 77)

1-acetoxy 6- (3-methyl-1,4-naphthoquinone-2-yl) tetrahydrofuran solution containing 1-6-phenylhexane (2.8 g, 7.2 mmoLe) 6 N hydrochloric acid (20 ml) was added to the liquid (20 ml), and the mixture was heated with stirring at 70 ° C. for 5 hours. After cooling, ethyl acetate was added to separate the organic layer, and the organic layer was washed with water and dried. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with isopropyl ether-ethyl acetate (1: 1), and the desired product was recrystallized from isopropyl ether to give 1-hydroxyl. — 6— (3—Methyl-1,4-naphthoquinone—2-yl) —6—N-Hexane (2. lg) was obtained. Table 1 shows physical properties and nuclear magnetic resonance spectrum data. Compound Nos. 75, 79 and 81 were produced according to this example.

Table 1 below shows the physical properties and nuclear magnetic resonance spectra of the compounds produced according to the above Examples. The melting point is uncorrected.

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Table 1 (continued)

Table 1 (continued)

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Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

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Table 1 (continued)

 Compound Nuclear magnetic resonance spectrum

 No. TMS internal standard <5 values (ppm)

5 7 1 1-1 β (6Η) 1 17 6H 2 0-2 4 (2ID 2 OliSID 3 94C6H ^> ) 4.25 (1H), 7.23 (5H), 8.00 (1H)

1 1 -1 · υ υϋ 1 · Q7ί ('fυ5ϋH' ώ · 0υ-? Ά. (9 ώΏ 9

4.28C1H), 4.60C2H), 7.24 (5Η)

all

4.29 (1H), 4.63 (2H), 7.23 (5H)

6 0 0 UU · ι / ΐ υΐ ώ υ ώ ¾ν> _ 11) 11. 1 1 | 311

 4.02 (2Η), 4.29 (1Η), 4.δ6 (1Η), 7.24 (5Η)

6 1 1 1 -1

1 97ί6 Uiίl) 0-ώ? 4f? I iTi)? 0υ4¾3ιϋ1ίΠ9 * 7f βU ¾ OiΗl ") j

4.02 (2H), 4.29 (1H), 4.60 (1H), 7.23 (5H)

6 2 i.2-i. (W, t -2A (W, 1.97C6H), 2.03 (3Η), 4.1δ (2Η), 4.30 (1Η), δ.53 (2Η), 7.23 (5Η)

6 3 1.1-1J (8H), 1.94 (6H), 2.0-2.4 (2H), 2.02 (3H), 3.85 (2H),! 4.28 (1H), 6.6-6.9 (2H) ₍ 7.0-7.4C7H), 7.4-7.7 (2H)

! ί t 3

t 5

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Table 1 (continued)

 Compound Nuclear magnetic resonance spectrum number TMS internal standard (value (ppm)

 7 · 丄 · · 0 丄 υΐΐ ώ ώ 丄 ώ 丄 ύίΐ,, ， ϊ ϊ ϊ 3 ϊ 1 ώΓ ϊ ¾ΐ 丄 丄 ノ ノ

 7.25 (5H) J.67 (2H), 8.05 (2H)

7 Q I. V 丄 • O V i,. 上 011, 11, 0 乙, 11, ύ, 0 0, ί)

4.45 (1Η), δ.78 (2Η), 7.24 (2Η), 7.63 (2Η) ₍ 8.01 (2Η)

丄 丄 /, / 3, 011 No, Otsu No. 0 11 No, ^ .1 Otsu No. ύ, No. 33 ώΐ! No, 0.3 /, 011 No,

4.46 (1Η), 6.85 (2Η), 7.13 (1Η)

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! 8 3 j 1.1-1.8 (10Η) Γ2 ^ί .03 (3Η), 2.00-2.3 (4Η), 2.85 (4Η), 3.60 (2Η),

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1 Example 21 (Compound No. go)

Toluene (15 ml) was added to 1.28 g (5.0 mmole) of 2,5,6-trimethylhydroquinone 0.7 ^ (5.Ommole), 7- (4-chlorophenyl) -1-7-hydroxyheptanoic acid, Heated to 60 ° C and stirred. 0.19 ml (5.0 × 0.3 ole) of boron trifluoride ether was added, and stirring was continued at 60 ° C. for 15 hours. After the reaction, most of the toluene was distilled off, the residue was dissolved in tetrahydrofuran (20 ml), ferric chloride (2.7 g (10.0 mmol) aqueous solution Oml) was added, and the mixture was stirred at room temperature for 20 minutes. Tetrahydrofuran was distilled off, and ethyl acetate was added to the residue to extract a product. Take out the organic layer, wash with brine, and dry (magnesium sulfate). The ethyl sulphate solution was applied to a short sily gel (10 g), and was eluted with ethyl sulphate. The fractions containing the target compound are collected, concentrated under reduced pressure, and the residue is reconstituted with ethyl acetate / isopropyl ether to give 7- (4-chlorophenyl) -17- (3,5,6-trimethyl-1, 4-Benzoquinone-2-yl) heptanoic acid i.52 g (78%) was obtained.

Table 1 (continued)

Table 1 (continued)

χ V (Ό ((HΗΗ6Ηΐ, —- And

Example 22 (Compound No. 98)

 Trimethylhydroquinone (1.5 g, 10 O IMOI) and 4- (1-hydroxyxethyl) chenyl-2--2-acid (2.5 g, 8.5 bandol) were added to 5 Oml of toluene. D-Camphorsulfonic acid (0.2 g) was added, and the mixture was heated and stirred at 50 ° C for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure. The residue was dissolved in THF, a 2nd aqueous solution of chloride was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was extracted with isopropyl ether. After the organic layer was washed with water and dried, the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography — (eluent; I £: hexane = 1: 1) and purified with 5— Yl) ethyl] Chenil 2-ethyl acid was obtained. (2.4 g, 72%) This was hydrolyzed with 6N hydrochloric acid in THF to give 5-[(1-3,5,6-trimethyl-1, 2: benzoquinone-1-yl) ethyl] Chenyl-2-acetic acid was obtained. (2.1 g, 90%)

δ 6.69 (2 H, m) 4.61 (1 H, m) 3.73 (2 H'.s) 1.98 (9 H, s) 1.6 1 (3 Hd, 7 hz)

Example 23 (Compound No. 9 9)

2.2 g (2 IMOI) of trimethylhydroquinone and 3 g (i.5 (nmol)) of 4-ethyl-1-ethylphenylacetate were added to 10 mL of toluene. 0.2 g of D-force sulfonic acid was added. After the addition, the reaction solution was heated and stirred for 18 hours at 60 ° C. After the reaction solution was cooled, the solvent was distilled off under reduced pressure, the residue was dissolved in THF, and an aqueous ferric chloride solution was added. Isopropyl ether (IPE) was added to the reaction solution, washed with water, dried, and the solvent was distilled off under reduced pressure The crude product was purified by silica gel column chromatography (eluent: IPE). — {1 — (3,5,6-trimethyl-1,4-benzoquinon-2-yl) ethyl} phenylacetate was hydrolyzed with 6N hydrochloric acid in THF. 4— {1 — (3, 5, 6— trimethyl— 1, 4 1-benzoquinone-2-yl) ethyl (Lg, yield 31%) This compound was recrystallized from IPE. mp 142—143 ° (: δ 8.70 (1 H, CO OH) 7.1 9 (4 H, s) 4.5 2 (1 H, m) 3.5 8 (2 H, s) 1.9 8 (9 Hs) 1. 5 7 (2 H, d, 7 hz)

Example 24 (Compound No. 100)

 Trimethyl sigma quinone (1.5 g, 10 mmol) and 4,4-dimethoxybenzohydrol (2.4 g, 10 mmol) were added to 80 ml of toluene. D-force sulfonic acid (0.1 g) was added, and the mixture was ripened and stirred at 60 ° C for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure. The residue was dissolved in THF, an aqueous ferric chloride solution was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was extracted with isopropyl ether. The organic layer was washed with water and dried, and then the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (eluent; IFE: hexane = 1: 2), and bis (4-methonethiphenyl) -1,3,5,6-trimethyl-11,4 Nzoquinonylmethane was obtained. (2.9 g, 8 1%) δ 7.04 (4 H, d, 8 hz) 6.7 7 (4 H, d, 8 hz) 5.8 3 (1 H, s) 3.7 6 (6 H, s) l .98 ( 6 H, s) to 8 2 (3 H, s)

Example 2a (Compound No. 101)

Me Trimethylhydroquinone (4.4 g, 4 mmol) and benzal chloride (2.3 g, 1.4 mmol) were added to 100 ml of toluene. After adding 3 ′ / boron oxyethyl ether (0.5 ml), the reaction solution was ripened and stirred at 50 ° C. for 18 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure. The residue was dissolved in THF, an aqueous ferric chloride solution was added, and the mixture was stirred at room temperature for 10 minutes. After adding isopropyl ether (IPE) to the reaction solution, washing with water and drying, the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography— (eluent: IPE) to give phenylbis-1,3,5,6-trimethyl ether and 4-benzoquinonylmethane. (4 g, 74% yield)

δ 7.1 7 (δ Η, m) 3.7 1 (1 H, s) 2.0 0 (1 2 H.s) 1.7 8 (6 H, s)

Example 26 (Compound No. 102)

 7- (ί, 4: -dimethoxy 3-, 5,6-trimethyl) phenyloctanoic acid (2 g, 6.2 mmol) was added to a 30% aqueous solution of acetonitrile (20 ml) and cooled under ice-cooling. A 50% aqueous solution of acetone ammonium nitrate (1.37 g, 25i0i) in 50% acetonitrile (20 ml) was added dropwise. The reaction solution was stirred for 20 minutes as it was, and extracted with IPE. The organic layer was washed with water, dried and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent;

1 PE) purified. (1.6 g, 72%)

2.9 2 (1 H ₍ m) 2.3 '(3 H, t, 6 hz) 2.0 2 (3 H, s) 1.99 9 (6 H, s) 1.59 (6 H, m) 1.2 1 ( 3 H, d, 7 hz)

Example 27 (Compound No. 119)

Trimethylhydroquinone 0.76 g (5.0 mmole), m- (3-Trifluoromethyltylphenyl) -one 1.45 g (5 Jmmole) of 7-hydroxyheptanoic acid, 2-dichloroethane (15 inl) were added, and the mixture was heated to 80 ° C and heated. Add 9 ml (5.0 x G. 3 mmole) of boron trifluoride ether ether Q, and stir at 80 ° C for 2 hours. I continued to cook. After air cooling, the solvent was evaporated, the residue was dissolved in tetrahydrofuran (15 ml), a solution of ferric chloride (2.7 g, 10.0 mmole) and water (10 ml) was added, and the mixture was stirred at room temperature for 20 minutes. The tetrahydrofuran was distilled off, and ethyl acetate was added to the residue for extraction. The organic layer was taken out, washed with brine, dried (magnesium sulfate), and distilled off with ethyl ester. The residue was subjected to silica gel column chromatography, and eluted with isopropyl ether. The fractions containing the target compound are collected, concentrated under reduced pressure, and the residue is reconstituted with isopropyl ether / hexane to give 7- (3-trifluoromethylphenyl) -17- (3,5,6-trimethyl-1, 0.50 g (24%) of 4-benzoquinone-12-yl) heptanoic acid was obtained.

Example 28 (Compound No. 126)

 Trimethylhydroquinone 0.76g (5.0mmole), 7-Hydroxy 7- [4- (1-Imidazolyl) phenyl] heptanoic acid 1.51g (5.0mmole), 1, 2-Dichloroethane (15nil), add 80 ° Heat to C and stir. 1.42 ml (5.0 x 2.3 mmole) of boron triethyl ether was added dropwise. Stir at C for 2 hours. Then add methanol (15 ml) and stir at 80 ° C for another 2 hours. After air cooling, the solvent was distilled off, the residue was dissolved in tetrahydrofuran (20 ml), a solution of ferric chloride (2.7 g, 10.0 mtnole) and water (10 ml) was added, and the mixture was stirred at room temperature for 20 minutes. The tetrahydrofuran was distilled off, and the residue was extracted with chloroform. The organic layer is taken out, and an aqueous solution of sodium hydrogen carbonate is added, and the mixture is washed, washed with a salt solution, and dried (magnesium sulfate). The residue was subjected to silica gel gel chromatography and eluted with ethyl acetate. The fractions containing the target compound were collected and the solvent was distilled off under reduced pressure to give 7- [4- (1-imidazolyl) phenyl] -7- (3,5,6-1trimethyl-1, 1-4 benzoquinone-1 2 —Yl) 1.70 g (78%) of methyl heptanoate were obtained.

Example 29 (Compound No. 127)-

7— [4— (1—imidazolyl) phenyl] —7— (3,5,6—trimethyl 1.70 g (3.92 mmole) of methyl 1,4-benzoquinone-2-yl) heptanoate was dissolved in acetic acid (17 ml), concentrated hydrochloric acid (7.8 ml) was added, and the mixture was stirred at 100 ° C for 1 hour. Hmm. Solvent evaporation. Acetone was added to the residue and concentrated under reduced pressure. The precipitated crystals are collected by filtration. Recombined with ethanol / ethyl ether 7- [4- (1-imidazolyl) phenyl] -1 7- (3.5,6-trimethyl-1,4-benzoquinone-12-yl) heptanoic acid 1.30 g (73%) of the salt were obtained.

Example 30 (Compound No. 133)

6— [4-((1-imidazolyl) benzyl] —— 6— (3,5,6-trimethyl-1,4,4-benzoquinone-12-yl) methyl hexanoate 3.50 g (8.06 mmole) ) Was dissolved in acetic acid (35 ml), concentrated hydrochloric acid (16. iml) was added, and the mixture was stirred at 100 ° C for 1 hour. Solvent evaporation. Add acetate to the residue and concentrate under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with chloroform / methanol (6: 1). The fractions containing the target compound are collected, concentrated under reduced pressure, and the residue is crystallized from ethanol / ethyl ether to give 6- [4- (1-imidazolyl) benzyl] -1-6— (3,5,6- 2.94 g (87%) of trimethyl-1,4-benzoquinone-2-yl) hexanoic acid were obtained.

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() ,， 2Hyo 4 3ί¾ ί (ρ0 唞 TMS 5 Experimental Example 15 Inhibition of 5-lipoxygenase

10 ⁷ RBL-1 cells (rat basophilic leukemia cells) are suspended in 0.5 ml of MCM (mast cell medium), and a test solution (MCM 0.5 ml, arachidonic acid 50 g, A—23187 10〃) prepared in advance is prepared. g, the final concentration of the quinone compound is 1 zM, 0.1 M, 0.01 M and M), and the reaction is carried out at 37 ° C for 20 minutes. After the reaction, add ethanol 4nd and 4-dimethoxy-12-methyl-3- (3-methoxypropyl) naphthalene as an internal standard drug, shake well, and leave at room temperature for 10 minutes. Then, centrifuge for 10 minutes at 2000 rpm to separate the supernatant. The supernatant is dried under reduced pressure. Add 0.5 ml of a 60% aqueous methanol solution to the concentrate. Take 100 J2 of this solution and perform high performance liquid chromatography to quantify 5-HETE (δ-hydroxyeicosatetraenoic acid). 5- HETE measured absorbance at 237nm with an ultraviolet absorption monitor.

51 The production inhibition rate (IE) of HETE is represented by (1 ^^) x100.

 • a

a is the peak height or area value of the internal standard peak when no quinone compound is contained, and b is the peak height or peak value of the internal standard peak when the quinone compound is contained. Indicates the area.

 [Experimental result]

桔果as shown in Table 2, it showed a strong production inhibitory activity of 5-HETE _c

Table 25-Effect of suppressing HETE production

χ δ-HETE production inhibitory effect (IC ₅ ) is the concentration of a drug (10 ” ⁸ Μ) that controls peak height or area by 50% in high-performance liquid sigma chromatography of 5-HETE in the control group. Indicated by

Action against the airway narrowing reaction of Example 2 Morumotsu bets Imunoguropuri down 0 ₁ involved

 Male and female Hartley-type guinea pigs weighing about 350 g were weighed in orange and muar (Orange, R.P. and Moore, E.G., J.Immunol., 116, 392-). (P. 397, 1976), intraperitoneal injection of a milk (1 ml) consisting of ovalbumin (1 mg) and Freund's complete adjuvant (Wako Pure Chemical Industries, Ltd.). Made a work. 3 weeks after sensitization Sensitization The serum antibody titers of guinea pigs and guinea pigs were measured by a 3-hour guinea pig passive cutaneous anaphylaxis reaction (PCA). Guinea pigs showing CA positivity were used as sensitized animals. Airway constriction reactions based on antigen-antibody reactions are described by Kontzett-Slur.

Rossler) method (Konzett, H. and Rossler, R., Naunyn-Schmiedeberg's Arch. Exp. Path. Pharmak, 185, 71-74, 1940). The guinea pig was fixed in a dorsal position under urethane (i.5 g lkg, intravenous administration) anesthesia, tracheotomy, and connected to a respirator (manufactured by Harvard) via a tracheal force neura. The side of the tracheal force regulator was connected to an airway constriction transducer (7020, Ugobasil). 1 forward air amount 5 to 7 ml, air number 70 times / min, a load pressure to the lung (10cm, H ₂ 0), the amount of air overflowing through the transducer Rekuchigurafu - 8 S

(Rectigrapy-8 S · ΗEi Sokki). Garamine on animals

After intravenous administration of (gallamine triethiodide) 1 mgZkg, 1 mgZkg of the antigen ovalbumin antigen dissolved in physiological saline was intravenously administered to induce an airway gonasal reaction. Airway constriction response was recorded for 15 minutes. The drug was suspended in a 5% gum arabic solution, and administered 1 hour before the antigen administration. Table 3 below shows the results of the inhibition rate (%) of airway constriction reaction involving guinea pigs related to imnoglobulin GL.

Experimental Example 3 Acute toxicity test in mice (acute toxicity) Five-week-old ICR male mice were grouped into 5 mice, each sample was orally administered at 1000 mg / kg, and the number of deaths for 7 days was measured.

Table 3 shows typical examples of the above test results.

Table 3 Morumotsu bets Imunoguropuri down 0 ₁ (1 ₁₎ Acute in inhibition and mice body airway constriction reaction involving toxic

Oral dose is ZOmg / kg, non-fasting.

For the control group, ³⁵ indicates P <0.05, ' ^χ ·' ^χ Reference example 1

 Thionyl chloride (40 ml) was added to monoethyl ester of suberic acid (40 g, 0.2 mole), and the mixture was ripened at 40 ° C for 2 hours. After cooling, excess thionyl chloride was removed under reduced pressure, and the resulting oil was dissolved in benzene (300 ml) and cooled with ice. Aluminum chloride (80 g, 0.6 mole) was gradually added to the mixture. After the reaction solution was stirred at room temperature for 2 hours, it was poured into ice-water (500IR1). Concentrated hydrochloric acid (100 ml) was added to this solution, followed by stirring. The organic layer was separated, washed with water, dried and concentrated. The obtained ketocarboxylic acid ethyl ester was dissolved in ethanol (200 ml) and cooled with ice. To this solution was added sodium borohydride (5 g) little by little, and the reaction solution was stirred at room temperature for 1 hour. After the excess reagent was decomposed with acetone, water (400 ml) was added, and the product was extracted with isopropyl ether. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was dissolved in a mixed solvent of methanol (200 ml) and water (100 ml), and sodium hydroxide / 15 g) was added thereto, followed by stirring at room temperature. Two hours later, the reaction solution was concentrated under reduced pressure, and 2N hydrochloric acid was added to adjust the pH to 4.G. The product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure to give 8-hydroxy-8-funinylocanoic acid (25 g). Physical properties and nuclear magnetic resonance spectra are shown in Table 4.

Reference example 2

 8-Hydroxy acid 8-Diphenyloctanic acid (25 g) is dissolved in dichloromethane (100 ml), glacial acetic acid (12 ml), pyridine (25 ml), dimethylaminopyridine (O.lg) are added, and the mixture is stirred at room temperature for 3 hours. did. After the reaction solution was washed with water, it was washed twice with 2 N hydrochloric acid. The organic layer was washed with water, dried, and concentrated under reduced pressure to obtain 8-acetox-8-phenyloxytanoic acid (21 g). Table 4 shows the physical properties and nuclear magnetic resonance spectrum data.

Reference example 3

Ethyl 5- (4-methoxybenzoyl) pentanoate (50 g, 0.19 mole) The ethanol solution (500 ml) was cooled on ice, and sodium borohydride (10 g) was gradually added thereto. One hour after the reaction, water (200 ml) and 2 N hydrochloric acid (50 ml) were added, and the mixture was concentrated under reduced pressure. The product was dissolved in ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. Methanol (300 ml), water (100 ml) and sodium hydroxide (40 g) were added to the product, and the mixture was stirred for 2 hours, and methanol was removed under reduced pressure. After washing the aqueous layer with isopropyl ether, the aqueous layer was adjusted to pH 4 J with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with isopropyl ether-ethyl acetate (1: 1). First, 6-ethoxy-6- (4-methoxyphenyl) hexanoic acid was eluted. (21 g) followed by 6-hydroxy-6- (4-methoxyphenyl) hexanoic acid (20 g).

Reference example 4

 3-Ethanol solution (200 ml) of benzoylpropionic acid (35 g, 0.5 ml) was ice-cooled, and sodium borohydride (lgG, 0.26 moie) was added little by little. After stirring for 2 hours, water (200 ml) and 2N hydrochloric acid (100 ml) were added. After the reaction solution was concentrated under reduced pressure, the product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was dissolved in toluene (300 ml), D-camphor-10-sulfonic acid (O.lg) was added, and the mixture was ripened and refluxed for 1 hour. After cooling, the reaction solution was washed with aqueous sodium bicarbonate solution and water, and the organic layer was dried and squeezed under reduced pressure to obtain 4-phenyl 4-butenolide (30 g). Oily substance. Nuclear magnetic resonance spectrum: <5 2.00-2.80 (4 mm), 5.42 (1 mm), 7.32 (5 mm).

 In a similar manner, 5-phenyl-5-pentanolide was produced from 4-benzylbutanoic acid. Oily substance. Nuclear magnetic resonance spectrum: δ 1.30-2.20 (4Η), 2.40-2.70 (2Η), 5.40 (1Η), 7.30 (5Η) ο

Reference Example 5

Magnesium (2 g, 0.05 mole) was added to tetrahydrofuran (50 ml), A solution of bromobenzene (8 g, 0.05 mole) in tetrahydrofuran (20 ml) was added dropwise with stirring. After refluxing for 1 hour, the mixture was cooled to −70 ° C., and a solution of <5-valerolactone (6 g, 0.05 mole) in tetrahydrofuran (20 ml) was added dropwise. After stirring at one 60 ° C for 30 minutes, the temperature was raised to the nitriding temperature over 1 hour. 2N Hydrochloric acid was added to the reaction solution, and ethyl acetate was added to extract the product. The organic layer was washed with water, dried and concentrated under reduced pressure. The product was subjected to silica gel column chromatography and eluted with isopropyl ether monoethyl acetate (1: 1) to give 5-benzoylpentan-1-ol (5.5 g). This was dissolved in ethanol (50 ml), and after cooling with ice, sodium borohydride (l.Og) was added and the mixture was stirred for 1 hour. Water (50 ml) was added to the reaction solution, and ethanol was removed under reduced pressure. The product was extracted with ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 ml), to which pyridin (20 ml) and acetic anhydride (8 ml) were added, and the mixture was allowed to stand at room temperature for 18 hours. Ether (100 ml) was added to the reaction solution, washed with water, 2N hydrochloric acid and water in that order. The ether layer was dried and concentrated under reduced pressure to give 1-phenyl-1,6-diacetoxyhexane (6 g). . The physical properties and nuclear magnetic resonance spectrum data are shown in Table 4.

Reference example 6

1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene dissolved in anhydrous tetrahydrofuran (lOOmi) in 10.0 g (38.6 mole) in an argon atmosphere at 140 ° C under an argon atmosphere. 24.1 ml (38.Snioie) of the solution was added dropwise in 10 minutes, and the mixture was further stirred for 20 minutes. Next, add 3.32g (38.6xQ.6mole) of the first screen bromide and stir at 140-1-2Q ° C for 1 hour. Then, after adding 6.60 g (38.6 mole) of benzyl bromide dissolved in tetrahydrofuran (15 ml), the cooling bath was removed, and the mixture was stirred at 70 ° C for 1 hour. Cool on ice, add 1 N hydrochloric acid (50 ml) and stir. The tetrahydrofuran is distilled off under reduced pressure, isopropyl ether is added to the residue, and the insoluble matter is filtered through Hyfloss-Parcel. Another. The isopropyl ether layer is taken out, washed with water, brine, dried (magnesium sulfate), and the solvent is distilled off. The residual liquid was distilled under reduced pressure to obtain 8.62 g (83%) of 1-benzyl-2,5-dimethoxy-1,3,4,6-trimethylbenzene. bp 0.3 14 (! ~ 142.C, mp 70 ~ 71.C

Similarly, 1- (4-methoxybenzyl-1-2.5-dimethoxy-3,4,6-trimethylbenzene, mp 53 steps 54 ° C and 1-benzyl-2-methyl—3,4,5, 6-Tetramethoxybenzene, bp 0.3 148-150 ° C was produced.

Reference Example 7

Dissolved in anhydrous tetrahydrofuran (70 ml) and dissolved in 1-benzyl-1,2,5-dimethoxy 3,4,6-trimethylbenzene 7 J2g (26.0minole), 1,1,2,2-tetramethylethylene 50 in 4.32 ml (26xl.lmmole) of argon under an argon atmosphere. In C, add 16.3 ml (26 mtnole) of n-butyllithium.hexane solution in 10 minutes, and stir at 50-56 ° C for 20 minutes. Next, 5.80 g (26 mmole) of tetrahydrofuran (3-bromopropanol / tetrahydropyranyl ether dissolved in 30 mD) was added dropwise over 10 minutes, and the mixture was further stirred at 50 ° C for 10 minutes. Aqueous solution of phosphoric acid was added to make it acidic, and extracted with isopropyl ether.The organic layer was taken out, washed with saturated saline, dried (magnesium sulfate), and the solvent was distilled off. 7 (kl), add p-toluenesulfonic acid 0.25g (26 ii / 20mmole), stir for 15 minutes at 70 ° C, air-cool, neutralize by adding sodium hydrogencarbonate aqueous solution, solvent Distillation The residue was extracted by adding isopropyl ether and water Isopropyl ether layer Washed with brine, dried (magnesium sulfate), and evaporated The residue was subjected to silica gel column chromatography and purified. T (isopropyl ether solution Source) 4- (2,5 dimethyl-1,3,4,6-trimethylphenyl) -4-phenylbutanol 7.00 g (82%) Physical properties and nuclear magnetic resonance spectrum are shown in Table 5. Show Then T ^ -o

Reference Example 8

 1.35 g (5.0 iMole) of 1-benzyl-1,2,5-dimethoxy-1,3,4,6-trimethylbenzene dissolved in anhydrous tetrahydrofuran (15 ml) and 1,1,2,2-tetramethyl 3.1 ml (5.Qnunole) of n-butyllithiumhexane solution was dropped into 0.83 ml (5 x 1.lmmole) of methylethylenediamine at 50 ° C in 5 minutes under argon atmosphere in 5 minutes, and then 50 to 55 Stir for 25 minutes. Then, 11-hexyl bromide 0.832 (5.0111111016) dissolved in tetrahydrofuran (5 |) 11) was added dropwise in 5 minutes, and the mixture was further stirred at 50 ° C for 10 minutes. The reaction solution was cooled on ice, acidified by adding a 10% aqueous solution of phosphoric acid, and the product was extracted with isopropyl ether. The organic layer is removed, washed with brine, dried (magnesium sulfate), and evaporated. The residual solution was subjected to silica gel column chromatography, purified (elution with hexane / isopropyl ether), and 7- (2,5-dimethylethoxy-3,4,6-trimethylphenyl) -17-phenylheptane 1.37 g (77%) was obtained. Physical properties and nuclear magnetic resonance spectrum data are shown in Table 5.

Reference Example 9

1-benzyl-2,5-dimethoxy-1,3,4,6-trimethylbenzene 4.05 g (15 mmole) and 1,1,2,2-tetramethylfuran dissolved in anhydrous tetrahydrofuran (40 ml) 9.4 ml (15 mmole) of n-butyllithium hexane solution was dropped into 2.49 ml (15 x l. Lmmole) of tylenediamine at 50 ° C in an argon atmosphere over a period of δ minutes. Stir at C for 25 minutes. Next, 0.98 g (5.0 mmole) of 6-bromohexanoic acid and 1,1,2,2-tetramethylethylenediamine (0.76 mK, 5.0 mniole) dissolved in tetrahydrofuran (10 ml) were mixed for 5 minutes. And stir at 50 ° C for another 10 minutes. The reaction solution was cooled on ice, acidified by adding a 10% aqueous solution of phosphoric acid, and the product was extracted with isopropyl ether. Remove the organic layer and wash with saturated saline. Sodium hydroxide (aqueous solution) for organic layer (50ml) Add and extract. The aqueous layer was taken out, acidified with a 10% aqueous solution of phosphoric acid, and extracted with isopropyl ether. The isopropyl ether layer is taken out, washed with brine, dried (magnesium sulfate), and evaporated to obtain a crude condensate.-On the other hand, methanol (10 ml) is cooled to 110 ° C and chlorided. Thionyl 1.08nil (15 mmole) was added dropwise in 10 minutes. After 10 minutes, the above crude condensate dissolved in methanol (10 ml) was added dropwise in 10 minutes. After 20 minutes, remove the ice bath and stir at room temperature for 30 minutes. The solvent was distilled off, and isopropyl ether and water were added to the residue to remove the oil from the product. The isoprene pill ether layer was washed with saline, dried (magnesium sulfate), and the solvent was distilled off. The residual solution was subjected to silica gel column chromatography, purified (eluted with isopropyl ether and hexane), and 7- (2,5-dimethyl-3-, 4,6-trimethylphenyl) -methyl 7-phenylheptanoate l. OOg was obtained. Physical properties and nuclear magnetic resonance spectrum data are shown in Table 5.

Reference example 10 '

1-Benzyl-2,3,4.5-tetramethoxy-6-methylbenzene dissolved in anhydrous tetrahydrofuran (15 ml) and 51 g (5.0 dandelions) and 1,1,2,2-tetramethylethylenediamine Under argon atmosphere, 3.1 ml (5.0 mmole) of n-butyllithium'hexane solution was added dropwise to 0.83 ml (5 x 1.1 mmole) of the amide at 5 ° C over 5 minutes, and further-5 to 0 ° C Stir at C for 25 minutes. Next, 4-chlorobutanol.tetrahydroviranyl ether Q.96 g (5.0 mmole) dissolved in tetrahydrofuran (5 ml) was added dropwise in 5 minutes, and the mixture was stirred on ice for 15 minutes. Then remove the ice bath and stir at room temperature for 20 minutes. The reaction solution was cooled on ice, acidified with a 10% aqueous solution of phosphoric acid, and the product was extracted with isopropyl ether. The organic layer was taken out, washed with brine, dried (magnesium sulfate), the residue was dissolved in methanol (15πι1), and 48 mg (5 X 1/20 mmole) of ρ-toluenesulfonic acid was added. Stir for 15 minutes. After air cooling, aqueous sodium hydrogen carbonate solution The solution was added for neutralization, and the solvent was distilled off. Isopropyl ether and water were added to the residue for extraction. The isopropyl ether layer was washed with brine, dried (magnesium sulfate), and evaporated. The residue was purified by silica gel column chromatography (eluted with isopropyl ether). 5- (2,3,4,5-tetramethoxy-1-6-methylphenyl) -1-5-phenylpentan-1-ol 1.29 g (69%) were obtained. Physical properties and nuclear magnetic resonance spectrum data are shown in Table 5.

Reference Example 11

 To 4-28- (2,5-dimethoxy-3,4,6-trimethylphenyl) -1-phenylbutane-1-ol 3.28 g (10.0 mmole) and triethylamine 2.10 ml (10 x L 5 mmole) dissolved in dichloromethane (30 ml) In one step, a solution of 1.37 g (10 X i.2 mmole) of methanesulfonyl chloride in dichlormethane (10 ml) was added dropwise over 30 minutes, and the reaction was further continued for 20 minutes under ice-cooling. The reaction was quenched by adding cold water to the reaction mixture, the dichloromethane layer was removed, washed sequentially with cold dilute hydrochloric acid and brine, dried (magnesium sulfate), and evaporated. The residue was dissolved in acetone (50 ml), and 4.5 g of sodium iodide (10x3 oleole) was added, and the mixture was stirred at 50 ° C for 2 hours. Acetone was distilled off, and isopropyl ether and water were added to the residue to remove the oil from the product. Take out the isopropyl ether layer, wash with brine, dry (magnesium sulfate), and evaporate the solvent. The shallow distillate is purified by silica gel column chromatography (hexane / isopropyl ether elution). 1- 4- (2,5-dimethoxy-1,3,4,6-trimethylphenyl) ) 4.07 g (93%) of 4-phenylbutane were obtained. Table 5 shows the physical properties and nuclear magnetic resonance spectrum data.

Reference Example 12 'Z

1—Iodo 4— (2,5-Dimethoxy-1,3,4,6—trimethylphenyl) -1-phenylbutane 4.19 g (5.0 «ole) of cimethylsulfoxide (30 ml) To the solution was added 0.74 g (5 X 3 mmole) of sodium cyanide, and the mixture was stirred at 50 ° C for 2 hours. The reaction solution is cooled on ice, isopropyl ether and water are added, and the mixture is stirred. Take out the isopropyl ether layer, wash with brine, dry (magnesium sulfate), and evaporate the solvent. The residual solution was subjected to silica gel column chromatography and purified (eluted with isopropyl ether / hexane) to give 5- (2,5-dimethoxy-3,4,6-trimethylphenyl) -1-5-phenylvaleronitrile 1.65 g (98%) %). Table 5 shows physical properties and nuclear magnetic resonance spectrum data.

Reference Example 13

 Dissolve 5- (2,5-dimethoxy-3,4,6-trimethylphenyl) -1-5-phenylvaleronitrile l. (Ug (3.0mmole) in ethanol (10ml) and add 3N sodium hydroxide (10 ml) and stirred overnight (15 hours) at 90 ° C. After air cooling, ethanol was distilled off under reduced pressure, isopropyl ether was added to the residue, and a 10% aqueous solution of phosphoric acid was added to make the mixture acidic. Extraction Wash with brine, dry (magnesium sulfate), evaporate the solvent, and crystallize the desired product with isopropyl ether to give 5- (2,5-dimethoxy-1,3,4,6-trimethylphenyl). 1) 5-phenylvaleric acid 1.06 g (gg%) mpi 42 to 3 ° C. Physical properties and nuclear magnetic resonance spectrum data are shown in Table 5.

Reference example U

Anhydrous pyridine (20 ml) was stirred carefully while slowly adding 2.40 g (4.0X6nnnole) of chromium trioxide, which had been dried well at 15 to 20 ° C, to prepare an orange-yellow porphyry solution. , 5-Dimethoxy-3,4,6-trimethylphenyl) -6-phenylhexane-one-ol and a solution of 42 g (4.0 mmole) of pyridine (Ιπι 加 え) are added and stirred at room temperature. The reaction solution was poured into ice water, and the product was extracted with dichloromethane.The dichloromethane layer was removed, the solvent was distilled off, and isopropyl ether and 1N hydrochloric acid were added to the residue to extract the product. Take out the isopropyl ether layer and wash with brine. Next, 0.5N NaOH (50 ml) was added to the isopropyl ether layer to transfer the product to the aqueous layer. The aqueous layer was taken out, a 10% aqueous solution of phosphoric acid was added to make the solution acidic, and carboxylic acid was extracted with isopropyl ether. The isopropyl ether layer is removed, washed with brine, dried (magnesium sulfate), and evaporated. The residue was purified by silica gel column chromatography (isopropyl ether elution), and 6- (2,5-dimethylethoxy 3,4,6-trimethylphenyl) -16-phenylhexanoic acid was purified. 1.07 g (72%) was obtained. Physical properties and nuclear magnetic resonance spectrum data are shown in Table 5.

Reference Example 15

 7- (2,5-Dimethoxy-1,3,4,6-trimethylphenyl) -17-phenylheptanoic acid lJ9g (5.0iMole) is dissolved in methanol (20ml), and 1N sodium hydroxide (lOnU) is added. In addition, stir at 50 ° C for 2 hours. After air cooling, methanol was distilled off under reduced pressure. The residue was acidified by adding 10% aqueous phosphoric acid, and the product was extracted with isopropyl ether. Take out the isopropyl ether layer, wash with brine, dry (magnesium sulfate), evaporate the solvent and remove 7- (2,5-dimethoxy-1,3,4,6-trimethylphenyl) -17-phenylheptane Acid i.92ga00%). Physical properties and nuclear magnetic resonance spectrum data are shown in Table 5.

Reference example-' ^: '

To a suspension of sodium amide 0.873 (12.8 1.25 1.¼111016) in anhydrous tetrahydrofuran (10 ml) at room temperature under argon atmosphere and propargyl alcohol • tetrahydrobiranyl ether 2.24 g (12.8 x 1.25 oleole) A furan (15 ml) solution was added dropwise over 5 minutes. After the addition, raise the reaction temperature to 50 ° C and stir for 1 hour. Then, at-5 ° C, add hexamethylphosphoramide (6 ml), and add 1-iodide 4- (2,5-dimethoxy-3,4,6- A solution of 5.60 g (12.8 mmole) of tetramethylhydrofuran (23 ml) in 4-methylbutane) was dropped in 10 minutes. After continuing ice-cold stirring for an additional 30 minutes, remove the ice bath and stir at room temperature for 30 minutes. The reaction was cooled on ice, saturated aqueous ammonium chloride was added to stop the reaction, and isopropyl ether was added to extract the product. The organic layer is removed, washed with saturated saline, dried (magnesium sulfate), and the solvent is distilled off. The residue was dissolved in methanol (50 ml), and 0.12 g (12.8 x 20 mmole) of p-toluenesulfonic acid was added, and the mixture was stirred at 70 ° C for 15 minutes. After air cooling, the mixture was neutralized by adding an aqueous sodium hydrogen carbonate solution, and the solvent was distilled off. The product was extracted by adding isopropyl ether and water to the residue. The isopropyl ether layer was removed, washed with brine, dried (magnesium sulfate), and evaporated. The residual solution was subjected to silica gel column chromatography, purified (eluted with isopropyl ether / hexane), and subjected to 7- (2,5-dimethyloxy 3,4,6-trimethylphenyl) -7-phenyl 4.31 g (92%) of 2-ru-2-heptin-1-ol were obtained. Physical properties and nuclear magnetic resonance spectrum data are shown in Table 5.

Reference Example 17

 9- (2,5-dimethoxy-1,3,4,6-trimethylphenyl) -1-9-phenyl 3-nonin-1-ol 1J70g (5.0mmole) 5% in ethanol (20ml) solution Palladium-carbon (0.2 g) was added, and catalytic reduction was performed at room temperature for 2 hours. The catalyst was filtered off, and ethanol was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and purified (eluted with isopropyl ether) to give 9- (2,5-dimethoxy-1,3,4,6-trimethylphenyl) -19-phenylnonanol 1.97 g (99%). Table 5 shows the physical properties and nuclear magnetic resonance spectrum data.

Reference example 18 '

P-methyl hydroxybenzoate 1.52g (10.0mmole) in dimethylformamide (15mi) solution under ice-cooling, sodium hydride (60%, oily) 0.42g (10x Then add 05 ole) and stir for 5 minutes. Remove the ice bath and add a solution of 4.80 g (10.0 mmoles) of dimethylformamide (15 ml) of 1-iodide 7- (2,5-dimethoxy-3,4,6-trimethylphenyl) -17-phenylheptane. Addition. Then raise the temperature to 50 ° C and stir for 1 hour. After cooling on ice, dilute hydrochloric acid was added to stop the reaction, and the product was extracted with isopropyl ether. Remove the isopropyl ether layer, wash with brine, dry (magnesium sulfate), and evaporate the solvent. The residual liquid was subjected to silica gel column chromatography, purified (eluted with hexane / isopropyl ether), and purified with 4- [7- (2,5-dimethoxy-3,4,6-trimethylphenyl) -17-phenylheptyl. 4.95 g (98%) of methyl [benzo] benzoate was obtained. Physical properties and nuclear magnetic resonance spectrum data are shown in Table 5.

Reference Example 19

'In a solution of diisopropylamine (0.50mK3.0xl.2mniole) in anhydrous tetrahydrofuran (5ml) under an argon atmosphere —20. In C, 2.1 ml (3.Qxl.lmmole) of n-butyllithium.hexane solution was added dropwise in 5 minutes, and the mixture was further stirred at −205 for 10 minutes. The mixed solution was kept at 120 ° C, and a solution of 0.38 g (3.0 X l.lmmole) of ethyl isobutyrate in tetrahydrofuran (4 ml) was added dropwise over 5 minutes. One 20 ~-δ after stirring for 20 minutes, — 20. In C, a solution of 1.36 g (3.0 mmole) of 1-iodide 5- (2,5-dimethoxy-1,3,4,6-trimethylphenyl) -5-phenylpentane in tetrahydrofuran (14 ml) was added. Drop in 5 minutes. Then, stir at 20-1Q ° C for 1.5 hours. The reaction solution was cooled on ice, 1 N hydrochloric acid was added to stop the reaction, and isopropyl ether and sodium chloride were added to extract the product. The organic layer was taken out, washed with saturated saline, dried (magnesium sulfate), and evaporated. The residue was subjected to silica gel column chromatography and purified (eluted with hexane / isopropyl ether) to give 7- (2,5-dimethoxy3,4,6-trimethylphenyl) -1,1-dimethyl-1-ethyl. 7-phenylheptanoic acid 1.20 g (91%) of chill were obtained. Physical properties and nuclear magnetic resonance spectrum data are shown in Table 5.

Reference Example 20

 7- (2,5-Dimethoxy 3,4,6-trimethylphenyl) -1,2,2-dimethyl-7-phenylheptanoate 1.20 g (2.73 mmole) of ethanol (12 ml) was added to a 3N solution. Add sodium hydroxide (9 mi) and stir at 90 ° C for 15 hours. After air-cooling, ethanol was distilled off under reduced pressure. A 10% aqueous solution of phosphoric acid was added to the residue to make it acidic, and the product was extracted with isopropyl ether. The isopropyl ether layer was washed with brine, dried (magnesium sulfate), and evaporated to remove 7- (2,5-dimethoxy3,4,6-trimethylphenyl) -1,2-dimethyl-7-phenylheptanoic acid. l.llg (99%) was obtained. Table 5 shows the physical properties and the nuclear magnetic resonance spectrum data.

Reference Example 2 1 * "

6-Methyl 4- [1- (imidazolyl) benzoyl] hexanoate 9.00 g (30 mmole) was dissolved in methanol (90 ml), and the mixture was stirred on ice and stirred. 0.86 g (30 X 0.75 mmole) of sodium borohydride was added, and the ice-cold stirring was continued for 30 minutes. After adding acetone, the solvent was distilled off. The residue was extracted by adding black form and water. Remove the form layer from the mouth, wash with brine, dry (magnesium sulfate), evaporate the solvent and remove methyl 9.10 g of 7-hydroxy-7- [4- (1-imidazolyl) phenyl] heptanoate. —%). (Partially reconstituted with ethyl acetate / isopropyl ether. Mp. 77-78 ° C) R ⁴ -CH-(CH2) _n l-Y ¹ Table 4

X ¹

Table 4 (continued)

68-

Table 4 (continued)

 (c ^) t

-Z6-

 ()

-56

-26

 (I ^) ςSenichi 86

eoooo / S8df / iod 8S0 / 98 OAV

66

 (Halla

-00 1- Reference Example 2 2

Under an argon atmosphere, 2-bromo-3,5,6-trimethyl-1,4-dimethoxybenzene (10 g, 4 h! ^! ^ Solution Oml) was cooled to -70 ° C. n-Butyllithium (20% hexane solution) was added dropwise, and the mixture was stirred for 10 minutes at 170 ° C. Subsequently, cuprous bromide (5.7 Og, 40 ol) was added, and then the temperature of the reaction solution was raised to 0 ° C. After the reaction solution was cooled again to 170, crotyl bromide (5.4 g, 40 mmol) was added. After stirring the reaction solution to room temperature, 100 ml of water was added to stop the reaction. The reaction solution was extracted with IPE, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was dissolved in THF (50 ml) and sodium borohydride (1 g) was added. To the reaction mixture was added dropwise 3-boron borate etherate (1.5 ml). After stirring for 1 hour, 50 ml of water was added, and a 3N aqueous solution (50 ml) of constant hydroxylation power was added dropwise. Under cooling, 30% aqueous hydrogen peroxide was added to the reaction solution, and the mixture was stirred as it was for 18 hours. The reaction solution was extracted with IPE. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; IPE) to give 3- (3,5,6-trimethyl-1,4-dimethoxyphenyl) -butan-1-ol. (3 g, 30%) δ 3.6 7 (3 Hs) 3.6 2 (3 H, s) 3.4 9 (2 H, m) 2.2 7 (3 H, s) 2.1 7 (3 H, s) 2.0 2 ( 2 H, m) 1.3 7 (3 H, d, 7 hz) Reference Example 23--Under argon atmosphere, a solution of oxalyl chloride (1 ml, 11 mmol) in dichloromethane (25 ml) was used at -70 °. Cooled to C. To this, a mixed solvent of DMS 0 (1.7 ml, 22 minD and dichloromethane (5 ml)) was added dropwise while maintaining the temperature of the reaction solution at −60 ° C. or lower. A solution of 6-trimethyl-1,4-dimethoxybenzyl) -butane-1-ol (3 g, 11 mmol) in dichloromethane (1 Oml) was added dropwise, and the mixture was stirred at 170 ° C. for 15 minutes. Later, triethylamine (7 ml, 5 O IMIOI) was added dropwise. Thereafter, the mixture was stirred until the temperature of the reaction solution reached room temperature. Water (50 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was extracted with IPE. The organic layer was washed with water, dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 3- (3,5,6-trimethyl-11,4-dimethoxybenzyl) butanal. (2.7g, 90%)

δ 9.6 8 (1 Ht) 3.8 3 (1 H, m) 2.6 7 (3 H, s) 3.6 0 (3 Hs) 2.8 9 (2 H.dd, 2hz, 6 hz) 2.2 7 (3 H ₍ s) 2.16 (6h, s) 1.3 3 (3h, s)

Reference example 2 4

Under an argon atmosphere, DMS 0 (3 Oml) was added to sodium hydride (1 g, 24 mmol, 60% oil dispersion, washed with hexane and dried under reduced pressure), and the mixture was heated and stirred at 80 ° C for 1 hour. did. 'After cooling, 3-carboxylprovided rifenylphosphonium bromide (4.6 g, 11 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature. After stirring for 10 minutes, a THF solution (5 ml) of 3- (3,5,6-trimethyl-1,4-dimethoxyphenyl) butanal (2.7 g, 11 mol) was added dropwise. After the reaction solution was stirred at room temperature for 2 hours, water (50 ml) was added. After washing the organic layer with toluene (100 ml), the aqueous layer was adjusted to pH 4 with 2N hydrochloric acid and extracted with IPE. The organic layer is washed with water, dried, concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography (eluent: I-II). 7 — (1,4 dimethoxy 3,5, 6-Trimethylphenyl) -14-octenoic acid was obtained. (2.2g, 68%)

δ 8.8 0 (1 H, C Ο Ο Η) 5.3 8 (2 H,) 3.6 3 (3 H, s) 3.6 0 (3 H, s) 3.2 δ (1 H, s) 2.4 0 (6 H, m ) 2.2 5 (3 H, s) 2.15 (6 H, s) 1.3 0 (3 Hd, 7 hz)

This was dissolved in ethyl acetate (20 ml), and 5% Pd-C (0.2 g) was added. It was subjected to pressure catalytic reduction. After 6 hours, the catalyst was filtered off. The filtrate was concentrated under reduced pressure to obtain 7- (1,4-dimethoxy-3,5,6-trimethyl) phenyloctanoic acid. (2g, 90%)

δ 9.20 (1 H, C 00 Η), 3.6 5 (6 H, s) 3.2 3 (1 H, m) 2.3 0 (2 H, m) 2.24 (3 H, s) 1.6 β (6 Hm) 1 .2 9 (3 H, d, 7hz)

 Industrial applicability

 The novel quinone derivative according to the present invention has an effect of improving the metabolism of polyunsaturated fatty acids, in particular, an action of inhibiting the production of peroxide fatty acids (antioxidant action) or an action of inhibiting the production of 5-lipoxygenase metabolites. It is useful as a drug, such as an antiallergic agent, a cerebral circulatory system improving agent, and the like. ―

Claims

The scope of the claims

 1. General formula

(Where Rt.R ² is the same or different and represents a hydrogen atom, a methyl group or a methoxy group, or R ¹ and R ² are bonded to each other and R ¹ and R ² are — CH = CH— CH = CH R ³ represents a hydrogen atom or a methyl group, R ⁴ represents an optionally substituted aliphatic group, an aromatic group or a heterocyclic group, and R ⁵ represents a methyl group, a methoxy group, Z represents one C≡C-1,-, a hydroxymethyl group which may be substituted, a carboxyl group which may be esterified or amidated.

Ί "ο :,

 H

CH ₃ CH _£

 C H = C H,

 — 'One-C--Q- ^-or

The group represented by CH ₃ is shown. η represents an integer of 0.0 to 10, πι represents an integer of 0 to 3, and k represents an integer of 0 to 5. However, when m is 2 or 3, a quinone boast represented by Z and 1 (where は may be arbitrarily varied in the repeating unit in []),

2. General formula

(Wherein F ^ .R ² is the same or different and represents a hydrogen atom, a methyl group or a methoxy group, or! ^ And! ^ Are mutually compatible! CH = CH — CH = CH— R ³ represents a hydrogen atom or a methyl group, R ⁺ represents an optionally substituted aliphatic group, aromatic group or heterocyclic group, and R ⁵ represents a methyl group or methoxy group. R ⁶ represents a hydrogen atom, a methyl group, a methoxymethyl group, a benzyl group or a 2-tetrahydropyranyl group. R ⁷ represents a hydrogen atom, a hydroxyl group, a methoxy group, a methoxymethyloxy group, a benzyloquine ′ group, a 2-tetrahydrobilanyloxy group, Z represents one C≡C-1

-C H = C H-, -0-,

Represents a group represented by n represents an integer of 0 to 10, m represents an integer of 0 to 3, and k represents an integer of 0 to 5. However, when m is 2 or 3, Z and can be arbitrarily changed in a few units in []. A general formula characterized by reacting a compound represented by the formula) with an oxidizing agent.

(Wherein each symbol is as defined above).

 3. General formula

(Where RR ² is the same or different and represents a hydrogen atom, a methyl group or a 0-methoxy group, or R ¹ and R ² are bonded to each other and R ¹ and R ² are — CH-CH— CH = CH— R ³ represents a hydrogen atom or a methyl group, R ⁺ represents an optionally substituted lipoprotective group, aromatic group or heterocyclic group, and R ⁵ represents a methyl group, a methoxy group, a substituted Z represents one C≡C, optionally a hydroxymethyl group, a carboxyl group which may be esterified or

CH ₃

 c H = c H-, -o y C-I

 One-way factory

CH ₃

Represents a group represented by η is an integer from 0 to 10, m is an integer from 0 to 3, and k is 0 Indicates an integer from 5 to 5. Provided that when m is 2 or 3, a pharmaceutical composition comprising, as an active ingredient, a compound represented by Z and 1 (wherein, the repeating unit in [] can be arbitrarily changed).