JPH0581579B2 - - Google Patents

Description

[Detailed description of the invention]

[Field of Industrial Application] The present invention relates to novel quinone derivatives having therapeutic and preventive effects on bronchial asthma, immediate allergies, various inflammations, arteriosclerosis, infection-based endotoxin shots, and methods for producing the same. The present invention relates to an anti-asthmatic agent and an anti-allergic agent, which can be used in the pharmaceutical field. [Prior Art] Conventionally, it has been considered difficult to effectively treat or prevent bronchial asthma. In recent years, it has been shown to be one of the important chemical mediators of immediate hypersensitivity and asthma.
SRS-A, which has long been known as
It has been revealed that anaphylaxis (slow reacting substance of anaphylaxis) consists of 5-lipoxygenase metabolites of arachidonic acid, that is, leukotrienes. Leukotrienes are potent chemical mediators of allergic or inflammatory reactions, and are thought to primarily cause constriction of the peripheral airways of the lungs, and are associated with the dyspnea associated with bronchial asthma. Furthermore, leukotrienes have the ability to increase capillary permeability and potent migration of leukocytes, and are deeply related to edema and cell infiltration, which are one of the main symptoms of inflammation. It is also thought that the strong vasoconstrictor effect may lead to coronary artery insufficiency and angina pectoris. As the relationship between leukotrienes and pathophysiology has been clarified, the importance of inhibitors of 5-lipoxygenase, which is the initial enzyme in the biosynthetic reaction of leukotrienes, is becoming recognized. . Compounds that already have a 5-lipoxygenase inhibitory effect include flavone compounds, quinone compounds [US Patent No. 4271083, EPC Publication No. 21841, US Patent No. 4358461], and catechol compounds [Clin.
Exp. Pharmacol. Physiol, 8 , 654-655 (1981)],
Phenol, flavone compounds [Biochem.
Biophys.Res.Commun. 116 , 612-618 (1983)],
Acetylene compounds [Enr.J.Biochem. 139 , 577
-583 (1984)], but none of these are fully satisfactory in terms of drug metabolism and absorption kinetics. [Problems to be Solved by the Invention] The present invention provides a novel compound that is less likely to be inactivated by the metabolic system and has excellent long-lasting efficacy compared to known compounds known to have 5-lipoxygenase inhibitory effects. The present invention provides quinone compounds. [Means for solving the problems] The present invention has the following features: 1 General formula

[Formula] (In the formula, R ¹ and R ² are the same or different and represent a hydrogen atom, methyl group, or methoxy group, or R ¹ and
R ² combine with each other and R ¹ and R ² -CH=CH-CH=
Indicates CH−. R ³ is a hydrogen atom or a methyl group,
R ⁴ represents an optionally substituted aromatic group or heterocyclic group, R ⁵ represents an optionally esterified or amidated carboxyl group, and n represents an integer of 2 to 10. ) or a hydroquinone derivative thereof; and 2. An anti-asthmatic or anti-allergic agent comprising a quinone derivative represented by the general formula (2) or a hydroquinone derivative thereof as active ingredients. In the general formula (), examples of the aromatic group represented by R ⁴ include a phenyl group and a naphthyl group. The heterocyclic group is a 5- or 6-membered ring containing one oxygen atom or sulfur atom as a ring constituent atom, and specific examples thereof include thienyl group (2-thienyl, 3-thienyl), furyl group (2-thienyl group), and
-Freel, 3-Freel), etc.
These aromatic groups and heterocyclic groups may have 1 to 5, preferably 1 to 3, substituents at any position on the ring, and examples of such substituents include hydroxyl, fluorine, etc. , halogen atoms such as chlorine and bromine, alkyl groups having 1 to 3 carbon atoms such as methyl and ethyl, alkoxy groups having 1 to 3 carbon atoms such as methoxy and ethoxy, acetyl groups, phenyl groups, p-tolyl groups, m
-Tolyl group, pyridyl group (2-pyridyl, 3-pyridyl), 3-pyridylmethyl group, benzoyl group,
Methylenedioxy group, trimethylene group, 1-imidazolyl group, 1-imidazolylmethyl group

[Formula] can be given. Examples of the esterified carboxyl group represented by R ⁵ include alkoxycarbonyl having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and aryloxy having 7 to 8 carbon atoms such as phenoxycarbonyl. Carbonyl is mentioned. The amidated carboxyl group represented by R ⁵ may be a substituted aminocarbonyl in which the amino group thereof is substituted, or may be a cyclic aminocarbonyl. Substituents for the amino group of substituted aminocarbonyl include, for example, 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 (these may be further substituted at any position on the ring). Examples of amidated carboxyl groups include aminocarbonyl, which may have a substituent such as hydroxyl, amino, nitro, halogen, methyl, methoxy, etc. ~4 mono- or di-alkylaminocarbonyl (methylaminocarbonyl,
ethylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl), phenylaminocarbonyl, substituted phenylaminocarbonyl (p-hydroxyphenylaminocarbonyl, p-methoxyphenylaminocarbonyl, m
-chlorophenylaminocarbonyl), diphenylaminocarbonyl, hydroxyaminocarbonyl, N-hydroxy-N-methylaminocarbonyl, N-hydroxy-N-phenylaminocarbonyl, and the like. Examples of the cyclic aminocarbonyl include morpholinocarbonyl and piperidinocarbonyl. The compound in which R ⁵ in the general formula () is a carboxyl group and its hydroquinone derivative may be, for example, a salt with an alkali metal (eg, sodium, potassium), an alkaline earth metal (eg, calcium, magnesium), or the like. The compound represented by the general formula () according to the present invention is a compound represented by the general formula ()

[Formula] (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n have the same meanings as above, and R ⁶ is a hydrogen atom, methyl group, methoxymethyl group, benzyl group, 2-tetrahydro ( ^R7 represents a hydrogen atom, hydroxyl group, methoxy group, methoxymethyloxy group, benzyloxy group, or 2-tetrahydropyranyloxy group.)
It can be produced by reacting the compound represented by with an oxidizing agent. In the oxidation of the compound represented by the general formula (), the type of oxidizing agent used and reaction conditions differ depending on R ⁶ and R ⁷ in the formula (). A compound in which R ⁶ and R ⁷ are hydrogen atoms in the general formula (), that is, a phenol compound, can be easily converted into a quinone compound () by using Fremy's salt as an oxidizing agent. In this case, the amount of Fremy salt used is about 2 to 4 mol per 1 mol of compound (), and the solvent used is methanol, acetonitrile,
Ethanol, dioxane, 1,2-dimethoxyethane and their water-containing solvents are preferably used. The reaction temperature is 10-80°C, and the reaction time is usually about 2-10 hours. A compound in which R ⁶ is a hydrogen atom and R ⁷ is a hydroxyl group in the general formula (), that is, a hydroquinone compound, is a mild oxidizing agent such as air, oxygen, Flemy's salt, ferric chloride, ferric sulfate, hydrogen peroxide, It can be easily converted into a quinone compound () using peracid or the like. These reactions are usually carried out in the presence of a solvent, such as methanol, acetonitrile, dioxane, 1,2-dimethoxyethane, and a water-containing solvent system consisting of these organic solvents and water. When air or oxygen is used as an oxidizing agent, the pH of the reaction solution is kept from neutral to slightly alkaline (PH7.0 to PH9.0). An appropriate buffer solution (eg, phosphate buffer) is used to maintain the pH. Reaction time starts from -10℃
Reaction times at 30°C are usually up to 24 hours. When ferric chloride, ferric sulfate, Flemy's salt, hydrogen peroxide, peracid (e.g., peracetic acid, m-chloroperbenzoic acid) is used as an oxidizing agent, the amount of the oxidizing agent used is 1 It is preferably about 1 to 4 moles per mole. The reaction temperature is -10°C to 30°C and the reaction time is usually up to 1 hour. Compounds in which R ⁶ is a methyl group, methoxymethyl group, benzyl group, or 2-tetrahydropyranyl group and R ⁷ is a methoxy group, methoxymethyloxy group, benzyloxy group, or 2-tetrahydropyranyloxy group in the general formula () That is, a hydroquinone diether compound can be easily converted into a quinone compound () by using silver oxide (AgO) or ceric ammonium nitrate (hereinafter abbreviated as CAN) as an oxidizing agent. Water or a water-containing organic solvent (e.g. dioxane, acetonitrile) if silver oxide (AgO) is used
It is carried out in the presence of nitric acid at temperatures ranging from -10°C to 30°C. When CAN is used as an oxidizing agent, CAN alone or together with pyridine-2,6-dicarboxylic acid N-oxide, pyridine-2,4-dicarboxylic acid, pyridine-2,4-dicarboxylic acid, This is carried out in the presence of 6-tricarboxylic acid or pyridine-2,6-dicarboxylic acid.
The appropriate mixing ratio of CAN and the above-mentioned pyridine carboxylic acids is usually about 1:1 (mole equivalent). The reaction temperature is about -5°C to 30°C. In the general formula (), R ⁵ is a hydroxyaminocarbonyl group, an N-substituted hydroxyaminocarbonyl group, a carboxyl group, an alkoxycarbonyl group,
A compound which is an aminocarbonyl group or a substituted aminocarbonyl group can be derived from a compound where R ⁵ is a hydroxymethyl group, a carboxyl group, an alkoxycarbonyl group or an acyloxymethyl group by the reaction known per se as shown below. .

[ka] [In the formula, A is

[Formula] (However, R ¹ , R ² , R ³ , R ⁴ and n have the same meanings as above)
, R ⁸ and R ⁹ are C _1-3 alkyl groups (e.g., methyl, ethyl, propyl), R ¹⁰ is C _1-7 lower alkyl groups (e.g., methyl, ethyl, propyl, i-
propyl, butyl, pentyl, hexyl) or aryl group (e.g. phenyl, naphthyl), ^R
and R ¹² represents a hydrogen atom or a group represented by R ¹⁰ ] The quinone compound () thus produced is isolated and collected by known separation and purification means (e.g. chromatography, crystallization method), etc. be able to. The hydroquinone form of the quinone compound () of the present invention has the general formula

[Chemical formula] (wherein, each symbol has the same meaning as above), between the quinone compound and the hydroquinone body, the reaction is easily carried out by a chemical or biochemical oxidation and reduction reaction in the quinone nucleus and the hydroquinone nucleus. Mutual conversion is possible. Since hydroquinone compound (a) is generally easily oxidized by oxygen, air, etc., hydroquinone compound (a) is generally treated as a quinone compound () as a stable compound. Since mutual conversion between hydroquinone compound (a) and quinone compound () is easy chemically and biochemically, quinone compound ()
and hydroquinone compound (a) can be considered to have equivalent properties if they exhibit pharmacological effects under physiological conditions. The quinone compound (a) can be easily converted into the hydroquinone compound (a) by reducing the quinone compound (a) using, for example, a mild reducing agent such as sodium hydrosulfite, acidic sodium sulfite, or sodium borohydride in a conventional manner. can lead to. Quinone compounds () and (a) have an asymmetric center in the alpha (α) carbon of the quinone core side chain in their structure, and therefore some compounds have optical activity. Therefore, the compounds () and (a) of the present invention are meant to include both optically active compounds and racemic compounds. The compounds () and (a) of the present invention contain polyunsaturated fatty acids (linoleic acid, γ-linolenic acid, α-linolenic acid,
Improves metabolism of linolenic acid, arachidonic acid, dihomo-gamma-linolenic acid, eicosapentaenoic acid), especially suppresses the production of peroxidized fatty acids (antioxidant effect) or 5-riboxygenase metabolites (e.g., leukotrienes, 5-hydroxy It has an effect of inhibiting the production of eicosatetraenoic acid, 5-peroxyeicosatetraenoic acid, lipoxins, etc.), and has extremely low toxicity and side effects. Therefore, the compounds () and (a) of the present invention are effective against bronchial asthma, psoriasis, inflammation, immediate allergies, arteriosclerosis, and atherosclerotic arteries in mammals (mice, rats, rabbits, monkeys, horses, humans, etc.). It is expected to have therapeutic and preventive effects on various diseases such as sclerosing, fatty liver, hepatitis, liver cirrhosis, hypersensitivity pneumonitis, immunodeficiency, and decreased resistance to bacterial infection. Cerebral circulatory system improving agent,
It is useful as a drug for preventing coronary arteriosclerosis, an immunomodulating agent, a cell infection defense enhancer, a prostaglandin-thromboxane metabolism improving agent, a therapeutic agent for fatty liver, hepatitis, liver cirrhosis, and hypersensitivity pneumonitis. In addition, when R ⁴ in the general formula () is a group containing an imidazole group, the compound and the hydroquinone form have thromboxane synthase-inhibiting effects in addition to the above-mentioned effects, such as thrombosis, myocardial infarction, cerebral infarction, heart failure, etc. It can also be used as an antithrombotic agent for the prevention and treatment of arrhythmia. The compounds of the present invention have low toxicity and can be used as is or in pharmaceutical compositions mixed with known pharmaceutically acceptable carriers, excipients, etc. [e.g., tablets, capsules (including soft capsules and microcapsules), liquid preparations, injections] It can be safely administered orally or parenterally as a drug or suppository. The dosage varies depending on the subject, route of administration, symptoms, etc., but for example, when administered orally to adult asthma patients, the usual dose is approximately 0.1 mg/Kg to 20 mg/Kg.
mg/Kg body weight, preferably 0.2mg/Kg to 10mg/
It is convenient to administer about 1-2 kg body weight once or twice a day. The compounds () and () of the present invention have a bulky group at the alpha (α) carbon position of the side chain of the quinone core or hydroquinone core, and this characteristic structure makes them less susceptible to inactivation reactions due to in vivo metabolism. Compared to known quinone compounds, it is able to maintain an effective drug concentration in the blood for a longer period of time, and exhibits excellent medicinal efficacy at low doses. Furthermore, when R ⁴ is a functional group containing an imidazole group, it exhibits a dual inhibitory effect simultaneously and specifically on 5-lipoxygenase and thromboxane synthase, which is advantageous for application as a cardiovascular drug. . Compound () can be produced by any of the following methods. Compound (a) has the general formula

[Formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n have the same meanings as above, R ¹³ represents a methoxymethyl group, a benzyl group, a 2-tetrahydropyranyl group, and R ¹⁴ represents a hydrogen atom, a methoxymethyloxy group, a benzyloxy group, or a 2-tetrahydropyranyloxy group. be able to. In compound (), general formula

[Formula] (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n have the same meanings as above, and R ¹⁵ represents a hydrogen atom or a hydroxyl group).

[Formula] (In the formula, each symbol has the same meaning as above.) Compound and general formula

[Formula] (where n and R ⁵ have the same meanings as above,
X ¹ represents a hydroxyl group, an acetoxy group, a lower alkoxy group, or a halogen atom, and R ¹⁶ represents a group represented by R ⁴ or a methoxy group. ) in the presence of an acid catalyst. In addition, among compounds (c), compounds in which R ⁵ is a carboxyl group have the general formula

It can also be obtained by condensing a compound represented by the formula: (wherein R ⁴ has the same meaning as above and n ² represents 2 or 3) in the presence of an acid catalyst. This condensation reaction is carried out using nonpolar solvents (e.g., methylene chloride, chloroform, benzene, toluene, isopropyl ether, 1,2-dichloroethane,
1,1,2,2-tetrachloroethane) in the presence of an acid catalyst (e.g., boron trifluoride ethyl ether complex, aluminum chloride, tin chloride, p-toluenesulfonic acid, D-camphorsulfonic acid, etc.) It is carried out at a temperature range of 10-100°C. This condensation reaction is based on the solubility of the compound () in the solvent and the acid catalyst and the compound () or ().
Because it depends on the reactivity of the reaction catalyst, the compound (),
It is necessary to change it appropriately depending on the combination of () and (). The amount of acid catalyst used is in the range of about 1/20 mole to 3.0 mole based on compound (). This reaction is preferably carried out under anoxic conditions. The reaction under anoxic conditions yields the phenolic or hydroquinone compound (c). Compound (b) has the general formula

[Formula] (wherein R ¹ , R ² , R ³ , R ⁴ and n have the same meanings as above, R ¹⁷ is a methyl group, a benzyl group, a 2-
A tetrahydropyranyl group or a methoxymethyl group, and R ¹⁸ represents a hydrogen atom, a methoxy group, a benzyloxy group, a 2-tetrahydropyranyloxy group or a methoxymethyloxy group. ) by halogenating the compound represented by the general formula

[Formula] (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ¹⁷ , R ¹⁸ and n
has the same meaning as above, and X ² represents a halogen atom. ) is obtained, and then this is reacted with, for example, KCN or NaCN to obtain a nitrile compound,
Furthermore, this was hydrolyzed by a conventional method to form the general formula (
A carboxyl form of the compound d) can be obtained. In addition, compound (d) has the general formula

[Formula] (wherein, R ¹ , R ² , R ³ , R ¹⁷ and R ¹⁸ have the same meanings as above), a compound represented by the general formula X ² −(CH ₂ )− _o Y ² ( ) (wherein, X ² and n have the same meanings as above,
^Y2 is a hydrogen atom, a hydroxyl group, a 2-tetrahydropyranyloxy group, a carboxyl group, or -C( _CH3 )
₂ Indicates the group represented by COOH. ) can be produced by reacting a compound represented by: The reaction between compound () and compound () is performed by converting compound () into a methylene group of a benzyl group as an anion in the presence of a strong base (e.g., n-butyllithium, methyllithium, lithium diisopropylamide, etc.), and adding ω to this reaction. - Compound (d) by reacting the halogenoalkyl derivative ()
is obtained. This reaction was carried out at 0 °C in the presence of tetramethylethylenediamine in anhydrous tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane.
It is carried out at a temperature range from 70℃ to 70℃. Preferred reaction temperature conditions range from room temperature to 65°C. [Effects of the Invention] The novel quinone derivative according to the present invention has an effect of improving the metabolism of polyunsaturated fatty acids, particularly an effect of suppressing the production of peroxidized fatty acids (antioxidant effect) or an effect of suppressing the production of 5-lipoxygenase metabolites, It is useful as a medicine such as an anti-asthma agent and an anti-allergy agent. [Example] Example 1 (Compound No. 1) 2,3,5-trimethylhydroquinone (3.1 g,
D-camphor-10-sulfonic acid (0.1 g) was added to a toluene solution (50 ml) of ethyl 6-acetoxy-6-(2-thienyl)hexanoate (5.6 g, 0.02 mol) and the mixture was heated at 60°C. The mixture was heated and stirred for 6.5 hours. After cooling, add ethanol (100ml) to the reaction solution.
A 10% aqueous ferric chloride solution (20 ml) was added and 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) to give 6-(3,5,6-trimethyl- 1,4-benzoquinon-2-yl)-6-
Ethyl (2-thienyl)hexanoate (5.6g, 76
%)was gotten. The physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. Compounds Nos. 2 to 8 were produced in the same manner as in this example. Example 2 (Compound No. 9) 2,3,5-trimethylhydroquinone (3.1 g,
0.02 mol) and 8-acetoxy-8-phenyl octanoic acid (6.0 g, 0.021 mol) in toluene (80 ml).
In addition to this, boron trifluoride ethyl ether (0.3 ml) was added dropwise at room temperature while stirring. After stirring the reaction solution at room temperature for 4 days, the solvent was distilled off under reduced pressure. Dissolve the residue in tetrahydrofuran (50ml)
A 10% aqueous ferric chloride solution was added to oxidize to the quinone form. The product was extracted twice with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure. The resulting composition was applied to a silica gel column, eluted with isopropyl ether, and the quinone was recrystallized with isopropyl ether to give 8-phenyl-8-(3,5,6- Trimethyl-1,4-benzoquinon-2-yl)octanoic acid (5.8 g, 78%) was obtained. The physical properties and nuclear magnetic resonance spectrum data are shown in Table 1.
This example is based on compound numbers 10 to 19 and 43.
was manufactured. Example 3 (Compound No. 20) 2-Methyl-1,4-naphthohydroquinone (3.6 g, 0.02 mole) and 6-ethoxy-6-(4-
A toluene solution (50 ml) of D-camphor-
10-sulfonic acid (0.1 g) was added, and the mixture was heated and stirred at 60°C for 18 hours. After cooling, the solvent was distilled off under reduced pressure, and then tetrahydrofuran (20 ml) was added. to this
After adding a 10% aqueous ferric chloride solution and stirring for 10 minutes, 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 to give 6-(3-methyl-1,4-naphthoquinon-2-yl)-6-(4-methoxyphenyl)hexanoic acid (3.5 g, 45 %)was gotten.
This product was recrystallized with isopropyl ether.
The 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) 2,3,5-trimethylhydroquinone (3.1 g,
D-camphor-10-sulfonic acid (0.1 g) was added to a toluene solution (60 ml) of 6-hydroxy-6-(4-methoxyphenyl)hexanoic acid (5.0 g, 0.021 mol) and the mixture was heated at 70°C. The mixture was heated and stirred for 20 hours. After distilling off the solvent from the reaction solution under reduced pressure, tetrahydrofuran (50 ml) was added and dissolved, and the mixture was further dissolved for 10 min.
% ferric chloride aqueous solution was added and stirred at room temperature for 10 minutes. The reaction product was extracted with ethyl acetate, and the organic layer was washed with water, dried, and then 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-
1,4-benzoquinon-2-yl)-6-(4-methoxyphenyl)hexanoic acid (5.1 g, 76%) was obtained. The physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. Compound number according to this example
23 to 34 and 44 were manufactured. Example 5 Aluminum chloride (0.7 g, 5.2 mmol) was added to a solution of hydroquinone (0.5 g, 4.5 mmol) and 4-phenylbutyrolactone (0.8 g, 4.9 mmol) in 1,2-dichloroethane (20 ml) at 60°C.
The mixture was heated and stirred for hours. After cooling, 2N hydrochloric acid (40 ml) was added to the reaction solution and stirred for 10 minutes. The reaction solution was extracted with ethyl acetate, the organic layer was washed with water, dried, the solvent was distilled off, and subjected to silica gel column chromatography.
4-phenyl-4-(1,4-dihydroxy-2-phenyl)butyric acid (0.6 g, 49%)
was gotten. Oily substance nuclear magnetic resonance spectrum:
δ2.43 (4H), 4.24 (1H), 6.60 (3H), 7.30 (5H) Example 6 (Compound No. 35) 2,3,5-trimethylhydroquinone (1.5g,
0.01 mol) in 1,2-dichloroethane solution (20
ml) was added with aluminum chloride (1.4 g, 0.01 mol) and heated at 80°C. Add 1,2 4-phenylbutyrolactone (1.6 g, 0.01 mol) to this mixed solution.
-Dichloroethane solution (10 ml) was added dropwise over 2 hours, and the reaction was further carried out under the same conditions for 18 hours.
After cooling, add 2N-hydrochloric acid (40ml) to the reaction solution and
After stirring for a minute, the reaction was extracted with isopropyl ether. The organic layer was washed with water, dried, and the solvent was distilled off.
Dissolve the residue in tetrahydrofuran (30ml) and dilute for 10
% ferric chloride aqueous solution (5 ml) was added and stirred for 10 minutes at room temperature. The reaction was extracted twice with ethyl acetate,
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 to give 4-(3,5,6-trimethyl-1,4-
Benzoquinon-2-yl)-4-phenylbutyric acid (1.2 g, 38%) was obtained. The physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. Compound numbers 36 to 38 were produced according to this example. Example 7 (Compound No. 40) A toluene solution of 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) ( Boron trifluoride diethyl ether (0.25 ml) was added dropwise to the solution (80 ml) at room temperature. 20% reaction solution
After stirring at 50°C for an hour, the mixture was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 ml), a 10% aqueous ferric chloride solution (10 ml) was added, and the mixture was stirred 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 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)-5-phenylvaleric acid (6.5 g, 57 %)was gotten. This product was recrystallized from isopropyl ether-ethyl acetate. The physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. Compound number 39 according to this example
was manufactured. Example 8 (Compound No. 41) 4-phenyl-4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)butanoic acid (1.2 g) was dissolved in ethanol (50 ml), and thionyl chloride ( 0.4 ml) and stirred at room temperature for 4 hours.
After concentrating the reaction solution under reduced pressure, the residue was dissolved in isopropyl ether, the organic layer was washed with water, dried and concentrated under reduced pressure, and subjected to silica gel column chromatography. The target product was eluted with isopropyl ether to give 4-phenyl-4-( 3,5,6-trimethyl-
Ethyl 1,4-benzoquinon-2-yl)butanoate (1.1 g, 84%) was obtained. The 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 numbers 9, 10, 35, 36, according to Reference Example 17,
and 43 were produced. The physical properties and nuclear magnetic resonance spectrum are shown in Table 1. Example 10 (Compound No. 44) Tetrahydrofuran solution of ethyl 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-(2-thienyl)hexanoate (1.7 g, 4.5 mmole) Add 6N hydrochloric acid (10ml) to (10ml),
The mixture was heated and stirred at 70°C for 17 hours. After cooling, isopropyl ether was added and the organic layer was washed twice with water. After drying the organic layer, concentrate under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with isopropyl ether-ethyl acetate (1:1), and recrystallized from isopropyl ether to give 6-(3,5,6
-trimethyl-1,4-benzoquinon-2-yl)-6-(2-thienyl)hexanoic acid (1.1 g,
70%) was obtained. Physical properties and nuclear magnetic resonance spectrum data are shown in Table 1.
It was shown to. Example 11 (Compound No. 45) 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-phenylhexanoic acid (0.7 g, 2 mmole) in 1,2-dichloroethane ( Add thionyl chloride (2 ml) to the solution (10 ml),
The mixture was stirred at 60°C for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in 1,2-dichloroethane (20 ml). Hydroxyamine hydrochloride (0.5 g) was added to this, followed by a saturated aqueous sodium bicarbonate solution (20 g).
ml) and stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction solution to extract the product, and the organic layer was washed with water, dried, and then the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography, eluted with isopropyl ether-ethyl acetate (1:1), and the target product was recrystallized from isopropyl ether-ethyl acetate to give 6-(3,5,6-trimethyl- 1,4
-benzoquinon-2-yl)-6-phenylhexanehydroxamic acid (0.7 g, 96%) was obtained.
The physical properties and nuclear magnetic resonance spectrum are shown in Table 1. Compound numbers 46 to 48 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. Note that the melting point is uncorrected.

【table】

【table】

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【table】

[Table] Example 12 (Compound No. 54) 2,5,6-trimethylhydroquinone 0.76g
(5.0 mmole), 7-(4-chlorophenyl)-7-
Toluene (15 ml) was added to 1.28 g (5.0 mmole) of hydroxyheptanoic acid, heated to 60°C, and stirred. Boron trifluoride ethyl ether 0.19ml (5
x 0.3 mmole) and continued stirring at 60°C for 15 hours. After the reaction, most of the toluene was distilled off, the residue was dissolved in tetrahydrofuran (20 ml), an aqueous solution (10 ml) of 2.7 g (10.0 mmole) of ferric chloride 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 the product. Take out the organic layer, wash with saline, and dry (magnesium sulfate). The ethyl acetate solution was subjected to short silica gel (10 g) column chromatography and eluted with ethyl acetate. Fractions containing the target product were collected and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate/isopropyl ether to give 7-(4-chlorophenyl)-7-(3,5,6-trimethyl-1,4-
benzoquinon-2-yl)heptanoic acid 1.52g (78
%) was obtained.

【table】

[Table] Example 13 (Compound No. 79) Trimethylhydroquinone 0.76g (5.0mmole),
1.45 g (5.0 mmole) of 7-(3-trifluoromethylphenyl)-7-hydroxyheptanoic acid,
Add 2-dichloroethane (15 ml), heat to 80℃, stir, and dissolve boron trifluoride ethyl ether.
0.19 ml (5.0 x 0.3 mmole) was added and stirring was continued at 80°C for 2 hours. After cooling in air, the solvent was distilled off, the residue was dissolved in tetrahydrofuran (15 ml), a solution of 2.7 g (10.0 mmole) of ferric chloride and water (10 ml) 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 for extraction. The organic layer was taken out, washed with brine, dried (magnesium sulfate), and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography and eluted with isopropyl ether.
Fractions containing the target product were collected and concentrated under reduced pressure, and the residue was recrystallized with isopropyl ether/hexane to give 7-
(3-trifluoromethylphenyl)-7-(3,
5,6-trimethyl-1,4-benzoquinone-2
0.50 g (24%) of -yl)heptanoic acid was obtained. Example 14 (Compound No. 86) Trimethylhydroquinone 0.76g (5.0mmole),
7-hydroxy-7-[4-(1-imidazolyl)
Methyl phenylheptanoate 1.51g (5.0mmole)
Add 1,2-dichloroethane (15 ml) to
Warm to ℃ and stir. Drop 1.42 ml (5.0 x 2.3 mmole) of boron trifluoride ethyl ether and heat to 80°C.
Stir for 2 hours. Next, add methanol (15 ml) and stir at 80°C for an additional 2 hours. After air cooling, the solvent was distilled off and the residue was dissolved in tetrahydrofuran (20ml).
Add a solution of 2.7 g (10.0 mmole) of ferric chloride and water (10 ml) and stir at room temperature for 20 minutes. Tetrahydrofuran was distilled off, and chloroform was added to the residue for extraction. The organic layer was taken out, an aqueous sodium bicarbonate solution was added thereto, washed, washed with brine, dried (magnesium sulfate), and chloroform distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate. Fractions containing the target product were collected and the solvent was distilled off under reduced pressure to obtain 7-[4-(1-imidazolyl)phenyl]-
Methyl 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)heptanoate 1.70 g (78
%) was obtained. Example 15 (Compound No. 87) 7-[4-(1-imidazolyl)phenyl]-7
-Methyl (3,5,6-trimethyl-1,4-benzoquinon-2-yl)heptanoate 1.70g
Dissolve (3.92 mmole) in acetic acid (17 ml), add concentrated hydrochloric acid (7.8 ml), and stir at 100°C for 1 hour. Solvent evaporation. Add acetone to the residue and concentrate under reduced pressure. Filter the precipitated crystals. Reconsolidation with ethanol/ethyl ether gives 7-[4-(1-imidazolyl)phenyl]-7
-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)heptanoic acid hydrochloride 1.30g (73
%) was obtained. Example 16 (Compound No. 93) 6-[4-(1-imidazolyl)benzyl]-6
-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)methylhexanoate 3.50g
Dissolve (8.06 mmole) in acetic acid (35 ml), add concentrated hydrochloric acid (16.1 ml), and stir at 100°C for 1 hour. Solvent evaporation. Add acetone to the residue and concentrate under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform/methanol (6:1). Fractions containing the target product were collected and concentrated under reduced pressure, and the residue was crystallized from ethanol/ethyl ether to give 6-[4-(1-imidazolyl)benzyl]-6-(3,5,6-trimethyl-1, 2.94 g (87%) of 4-benzoquinon-2-yl)hexanoic acid were obtained.

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【table】

【table】

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[Table] Esterified with methanol to produce 7-(3,5,
Methyl 6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoate (oil) was obtained. Nuclear magnetic resonance spectrum δ value: 1.1-1.8 (6H),
1.9-2.3 (2H), 1.97 (6H), 2.04 (3H), 2.28 (2H)
，
3.63 (3H), 4.29 (1H), 7.24 (5H) Example 18 Compound number 93 was esterified using methanol in the same manner as in Example 8 to obtain 7-(3,5,
Methyl 6-trimethyl-1,4-benzoquinon-2-yl)-7-(4-methylphenyl)heptanoate (oil) was obtained. Nuclear magnetic resonance spectrum δ value: 1.1-1.8 (6H),
1.9-2.4 (2H), 1.96 (6H), 2.04 (3H), 2.27 (3H)
，
3.63 (3H), 4.23 (1H), 7.04 (2H), 7.17 (2H) Example 19 Compound No. 43 (0.35g, 1.0mmole)
was dissolved in ethyl acetate (7 ml), 5% palladium-carbon (35 mg) was added, and catalytic reduction was carried out for 2 hours at room temperature.
I spent time. The contact was filtered off and the solvent was distilled off.
The residue was recrystallized with ethyl acetate/isopropyl ether to obtain 7-(3,5,6-trimethyl-1,4-hydrobenzoquinon-2-yl)-7-phenylheptanoic acid (0.20 g). Melting point 169-172℃. Example 20 7-(3,5,6-trimethyl-1,4-hydrobenzoquinon-2-yl)-7-(4-fluorophenyl)heptanoic acid was prepared from compound number 51 in the same manner as in Example 18. I got it. Melting point: 167-169°C Example 21 7-(3,5,6-trimethyl-1,4-hydrobenzoquinon-2-yl)-7-(4-methylphenyl) was prepared from compound number 57 in the same manner as in Example 19. ) Heptanoic acid was obtained. Melting point: 172-176℃ Example 22 7.08g (20mmole) of compound number 43 was dissolved in ethyl acetate (142ml), and L-(-)α was dissolved at room temperature.
- 2.57 ml (20 mmole) of phenylethylamine
It was added dropwise in minutes and stirred for an hour. The precipitated crystals were collected and suspended in ethyl acetate (100 ml), 1N hydrochloric acid (30 ml) was added, and the mixture was stirred for 15 minutes. The ethyl acetate layer was taken out, washed with brine, and dried (magnesium sulfate). The solvent was distilled off to obtain a compound in which the (+) form was predominant. By repeatedly subjecting the obtained compound to the above operation four times, a positive optically active form (1.36
g) was obtained. [α] ²² _D = 23.6° (c = 1, chloroform) This product was further recrystallized with ethanol (6.8 ml), the precipitate was filtered off, and the solvent was distilled off. When the residue is crystallized from isopropyl ether, a positive optically active form (+)-7-(3,5,6-trimethyl-
1,4-benzoquinon-2-yl)-7-phenylheptanoic acid (1.10 g) was obtained. Yield 16%,
[α] ²² _D = +24.4° (c = 1, chloroform), melting point 7
9
~82℃ On the other hand, by performing the same operation as above using D-(+)-α-phenylethylamine, a minus optically active form (-)-7 was obtained from 7.08 g of compound number 50.
-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid (1.20 g) was obtained. Yield 17%, [α] ²² _D = −24.4° (
c.
= 1, chloroform), melting point 79-82℃ Example 23 Formulation Example A Capsule (1) Compound No. 57 50mg (2) Finely powdered cellulose 30mg (3) Lactose 37mg (4) Magnesium stearate 3mg Total 120mg (1) , (2), (3) and (4) were mixed and filled into gelatin capsules. B Soft capsules (1) Compound No. 22 50mg (2) Corn oil 100mg Total 150mg (1) and (2) were mixed in a conventional manner and filled into soft capsules. C Tablet (1) Compound No. 43 50mg (2) Lactose 34mg (3) Corn starch 10.6mg (4) Corn starch (glue-like) 5mg (5) Magnesium stearate 0.4mg (6) Calcium carboxymethylcellulose 20mg Total 120mg Regular These were mixed and tableted using a tablet machine according to the method. Example 1 5-lipoxygenase inhibitory effect on RBL-1 cells (rat basophilic
^MCM (mast cell)
suspend in 0.5 ml of medium) and add the test solution (MCM 0.5 ml, arachidonic acid 50 μg,
A-23187 (calcium ionophore, Eli Lilly)
10μg, final concentration of quinone compound 1μM, 0.1μM,
(consisting of 0.01 μM and 0.001 μM) and incubated at 37 °C.
The reaction was carried out for 20 minutes. After reaction, add 4 ml of ethanol
After adding 1,4-dimethoxy-2-methyl-3-(3-methoxypropyl)naphthalene as an internal standard and shaking well, the mixture was left at room temperature for 10 minutes. The mixture was then centrifuged (2000 rpm) for 10 minutes to separate the supernatant. This supernatant was dried under reduced pressure. 0.5ml of 60% aqueous methanol solution in concentrate
added. 100 μl of this solution was subjected to high performance liquid chromatography, and 5-HETE (5-
hydroxyeicosatetraenoic acid) was determined. The absorption of 5-HETE at 237 nm was measured using an ultraviolet absorption monitor. The generation inhibition rate (IE) of 5-HETE is expressed as (1-b/a)×100. a represents the peak height or area value corrected with the peak of the internal standard when not containing a quinone compound, and b represents the peak height or peak area corrected with the peak of the internal standard when containing the quinone compound. [Experimental Results] As shown in Table 2, the results showed a strong 5-HETE production suppressing effect.

【table】

[Table] Experimental Example 2: Effect of immunoglobulin G ₁ on airway constriction response in guinea pigs Male and female Hartley guinea pigs weighing approximately 350 g were treated using the Orange and Moore method (Orange, RPand Moore, EG, J. Immunol.
116, pp. 392-397, 1976), an emulsion (1 ml) consisting of ovalbumin (1 mg) and Freund's complete adjuvant (manufactured by Wako Pure Chemical Industries, Ltd.) was administered intraperitoneally. Sensitization was performed. Three weeks after sensitization, the serum antibody titer of the sensitized guinea pigs was measured to determine the guinea pig's 3-hour cutaneous anaphylaxis (passive cutaneous anaphylaxis).
PCA), and guinea pigs showing PCA positivity in 1000-fold diluted serum were used as sensitized animals. Airway constriction reactions based on antigen-antibody reactions are
Konzett-Rössler, R.
Naunyn−Schmiedeberg′s Arch.exp.Path.
Pharmak, Vol. 195, pp. 71-74, 1940). The guinea pig was fixed in a dorsal position under anesthesia with urethane (1.5g 1Kg, intravenously administered), the trachea was incised, and a ventilator (manufactured by Harvard) was placed through the tracheal cannula.
connected to. The side branch of the tracheal cannula was connected to an airway constriction transducer (model 7020, manufactured by Ugobasil). Air volume per time: 5-7ml, number of air injections: 70 times/
The water pressure (10 cm, H ₂ O) applied to the lungs was applied to the lungs, and the amount of overflowing air was recorded on a Rectigrapy-8S (Sanei Sokki) via a transducer. After intravenously administering 1 mg/Kg of gallamine triethiodide to the animals, 1 mg/Kg of the antigen ovalbumin dissolved in physiological saline was intravenously administered to induce an airway constriction reaction. Airway constriction reactions were recorded for 15 minutes. The drug was suspended in a gum arabic solution for 5 chickens and orally administered 1 hour before antigen administration. Table 3 below shows the results of the suppression rate (%) of the airway constriction reaction caused by immunoglobulin _G1 in guinea pigs. Experimental Example 3 Acute toxicity test on mice (acute toxicity) 1000 mg/Kg of each sample was orally administered to a group of 5 male ICR mice, 5 weeks old, and mortality was measured over 7 days. Representative examples of the above test results are also listed in Table 3.

【table】

[Table] Experimental Example 4 Suppression of lipid peroxide production in rat brain homogenate Brain tissue of male SD rats was dissolved in 5% phosphate buffer.
It was used as a homogenate. After incubating the same homogenate at 37℃ for 1 hour, Ohkawa
[Analytical Biochemistry, 95 , 551, 1979]
The amount of lipid peroxide produced was measured by the thiobarbituric acid method as described in . The test drug was used after being dissolved in dimethyl sulfoxide. The inhibitory effect on lipid peroxide production was compared with the amount produced in the solvent addition group.
Expressed as % inhibition rate.

[Table] Experimental Example 5 Anti-edema effect in experimental cerebral infarction model of sand rats Male sand rats (8 to 10 weeks old) were used. Under light ether anesthesia, the right common carotid artery was ligated for 1 hour to induce experimental cerebral infarction, and then the ligation was removed and reperfusion was performed. One hour after reperfusion, the brain was decapitated and the left and right hemispheres were separated. After measuring the wet weight of each, at 96℃
It was dried for 24 hours and the dry weight was measured. Water content (%) was measured for each brain hemisphere using the following formula. Moisture content (%) = (wet weight - dry weight) x 100/wet weight Symptoms of neurological deficit during ligation-reperfusion were also observed. The drug was orally administered as a gum arabic suspension under anesthesia one hour before common carotid artery ligation.

[Table] Experimental Example 6 Suppression of convulsive seizure induction in an experimental cerebral infarction model in spontaneously hypertensive rats (SHR) Male spontaneously hypertensive (SHR) rats (approximately 22 weeks old) were subjected to bilateral general neck anesthesia under light pentobarbital anesthesia. The arteries were simultaneously ligated to create cerebral ischemia. Thereafter, the behavior of the animals was observed for about 4 hours after they had recovered from anesthesia. The drug was orally administered as a gum arabic suspension one hour before bilateral common carotid artery ligation without anesthesia.

[Table] Experimental Example 7 Airway constriction reaction in guinea pigs due to LTD ₄ LTD ₄ (leukotriene D ₄ ) in guinea pigs
The airway constriction response was measured according to the Konzatt-Roßssler method. Guinea piglet treated with urethane (1.5g/Kg, intraperitoneal administration)
The patient was placed in a dorsal position under anesthesia, and the incised trachea was placed on a ventilator (Harvard apparatus) via a cannula.
rodent respirator). In addition, attach the side plate of the tracheal cannula to an airway constriction transducer (type 7020,
Ugobasile). Air supply volume per time 5-7ml,
The number of air blows was 70 times/min, the load pressure to the lungs was 10 cmH ₂ O, and the amount of overflowing air was recorded via a transducer. The airway constriction response induced by intravenous administration of 10 μg/Kg of LTD ₄ was recorded for 15 minutes. The drug was suspended in 5% gum arabic solution and 1 hour after LTD ₄ administration and
Oral administration 24 hours prior.

[Table] Experimental Example 8 Airway constriction response in guinea pigs due to platelet activating factor (PAF) The airway constriction response in guinea pigs due to PAF (1 μg/Kg, intravenous injection) was measured according to the Konzett-Rossler method. . The following operations were performed in the same manner as in the method for measuring the airway constriction response using leukotriene D ₄ (LTD ₄ ). Drugs are 5%
It was suspended in a gum arabic solution and orally administered 1 hour before PAF administration.

[Table] Reliability Experiment Example 9 Kidney damage in rats due to administration of iron ion-trinitrilotriacetic acid (Fe ³⁺ -NTA) Male SLC-Wistar rats (4 weeks old, weight around 80 g) were used. Animals were provided food and water ad libitum and housed individually in metabolic cages. Body weight, urine volume, and urine protein (Bio-Red method) were measured. On the final day of the experiment, the liver was removed, weighed, and dried.
The weight was measured. The drug was suspended in a 5% gum arabic solution and weighed
1 ml per 100 g was administered orally. Fe ³⁺ −NTA
Awai et al. [Am.J.pathol., 95 , 663-674 (1979)]
Fe ³⁺ −NTA=1:4 (molar ratio) according to the method of
5mg/Kg of iron for 3 days, then 10mg/Kg of iron for 3 days.
Kg was administered intraperitoneally for 9 days.

[Table] Experimental Example 10 Initial vascular hyperpermeability reaction and intrathoracic SRS-A in rat reverse passive Arthus pleurisy
Production Reverse passive Arthus pleuritis in rats was induced using the method of Yamamoto et al. (Agents and actions 5 , 374-377, 1975).
According to the method of That is, 1 ml of a 5 mg/ml ovalbumin (EA) physiological saline solution was administered through the tail vein,
Immediately thereafter, 0.2 ml of rabbit anti-EA antiserum (containing 1 mg of antibody) was intrathoracically administered. For vascular permeability measurement
Immediately before administration of the EA saline solution, 0.5 ml of 1% Evans Blue saline night solution was administered through the tail vein. Thirty minutes after the induction of pleurisy, the animals were exsanguinated to death, and the amount of dye leaked into the pleural cavity was determined. In addition, blood was collected at the time of exsanguination, and the pigment concentration in the serum was determined. (Amount of dye leaking into the thoracic cavity)/(Dye concentration in serum) blood was taken as a parameter of vascular permeability. Measurement of intrathoracic SRS-A production was performed as follows. 30 minutes after the induction of pleurisy, the rats were killed by exsanguination, the thoracotomy was opened, the rats were washed with 2 ml of physiological saline, and 9 ml of the washing solution was added.
of cold ethanol was added. After leaving it in ice water for about 30 minutes, it was centrifuged at 3000 rpm for 10 minutes, and the supernatant was used as a sample.
After evaporating the specimen to dryness under reduced pressure, add 0.5ml of physiological saline.
It was dissolved in water and bioassayed using guinea pig ileum specimens. The amount of SRS-A was determined in terms of leukotriene _D4 . The drug was suspended in 5% gum arabic, and 0.1 ml was administered together with antiserum.

[Table] Reliability rate

[Table] Experimental Example 11 Superoxide anion (O ligation) production of guinea pig peritoneal macrophages Hartley guinea pig (male, 400-450 g)
5 ml of liquid paraffin was administered intraperitoneally, and 4 days later, peritoneal cells were collected by intraperitoneal injection of 15 ml of Hank's buffer, according to the method of Wood, PR.
The peritoneal macrophages were purified (purity: 95% or more). The cell solution was adjusted to 1×10 ⁷ cells/ml. Macrophage 1 x 10 ⁷ cells/ml Luminal 10 ^-5 to 75ml
5 μl of M was added, 1 μg/ml of phorbol myristate acetate (PMA) was added, and O-ligation production was measured by chemiluminescence. The drug was dissolved in 10% dimethyl sulfoxide aqueous solution.

[Table] Experimental Example 12 Production of SRS-A in the peritoneal cavity of rats According to the method of Orange et al., the effect of drugs on the production of SRS-A in the peritoneal cavity of rats was investigated by the following procedure. 2 ml of rat anti-EA antiserum diluted 2 times with physiological saline was intraperitoneally administered to rats.
Two hours later, antigen solution (EA, 2mg/Kg/5ml:
5 ml of Tyrode's nutrition (containing 5 μg/ml heparin and 0.1% gelatin) was administered intraperitoneally. After 15 minutes, the rats were exsanguinated to death under ether anesthesia, and the peritoneal fluid was collected. This peritoneal fluid was centrifuged at 900 g for 5 minutes, and the ethanol-treated supernatant was dried under reduced pressure. This dried product was dissolved in 1 ml of physiological saline, and the amount of SRS-A contained was bioassayed using guinea pig ileum. Drugs are 1%
It was dissolved in a dimethyl sulfoxide saline solution and administered intraperitoneally 1 minute before antigen administration.

[Table] Reference example 1 Suberic acid monoethyl ester (40g,
Add thionyl chloride (40ml) to 0.2mole) and heat at 40℃ 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 on ice. Aluminum chloride (80 g, 0.6 mole) was slowly added to this mixture. The reaction solution was stirred at room temperature for 2 hours and then poured into ice-water (500 ml). Concentrated hydrochloric acid (100 ml) was added to this solution and stirred. 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 on ice. Sodium borohydride (5 g) was added little by little to this solution, and the reaction solution was stirred at room temperature for 1 hour. After decomposing excess reagent 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, and the residue was dissolved in methanol (200
ml) and water (100 ml), sodium hydroxide (15 g) was added thereto, and the mixture was stirred at room temperature. After 2 hours, the reaction solution was concentrated under reduced pressure, and then 2N hydrochloric acid was added to adjust the pH to 4.0, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure to obtain 8-hydroxy-8-phenyl octanoic acid (25 g). Physical properties and nuclear magnetic resonance spectrum data are shown in the table.
Shown in 13. Reference example 2 8-hydroxy-8-phenyl octanoic acid (25
g) was dissolved in dichloromethane (100 ml), acetic anhydride (12 ml), pyridine (25 ml) and dimethylaminopyridine (0.1 g) were added, and the mixture was stirred at room temperature for 3 hours.
The reaction solution was washed with water and then twice with 2N hydrochloric acid.
The organic layer was washed with water, dried, and concentrated under reduced pressure to obtain 8-acetoxy-8-phenyl octanoic acid (21 g). The physical properties and nuclear magnetic resonance spectrum data are shown in Table 13. Reference example 3 Ethanol solution (500 g, 0.19 mole) of ethyl 5-(4-methoxybenzoyl)pentanoate
ml) was cooled on ice, and sodium borohydride (10 g) was gradually added thereto. After 1 hour of reaction, add water (200
ml) and 2N hydrochloric acid (50 ml) were added and 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. Add ethanol (300ml) to the product,
Water (100 ml) and sodium hydroxide (40 g) were added, 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 4.0 with hydrochloric acid and extracted with ethyl acetate.
After washing the organic layer with water, drying, and concentrating under reduced pressure, the residue was subjected to silica gel chromatography and eluted with isopropyl ether-ethyl acetate (1:1). (21g) was then 6-hydroxy-6-
(4-methoxyphenyl)hexanoic acid (20 g) was obtained. Reference example 4 3-benzoylpropionic acid (35g,
Cool an ethanol solution (200 ml) of 0.18 mole) on ice, add sodium borohydride (10 g, 0.26 mole)
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, concentrated under reduced pressure, the residue was dissolved in toluene (300 ml), and D-camphor-
10-sulfonic acid (0.1 g) was added and the mixture was heated under reflux for 1 hour. After cooling, the reaction solution was washed with a saturated aqueous sodium bicarbonate solution and water, and the organic layer was dried and concentrated under reduced pressure to give 4-phenyl-4-butenolide (30
g) was obtained. oily substance. Nuclear magnetic resonance spectrum: δ 2.00−2.80 (4H), 5.42 (1H), 7.32 (5H). 5-phenyl-5-pentanolide was produced from 4-benzoylbutanoic acid in the same manner. oily substance. Nuclear magnetic resonance spectrum: δ 1.30−2.20
(4H), 2.40-2.70 (2H), 5.40 (1H), 7.30 (5H). Reference example 5 1-bromo-2,5-dimethoxy-3,4,6- dissolved in anhydrous tetrahydrofuran (100 ml)
Add n-butyllithium to 10.0 g (38.6 mmole) of trimethylbenzene at -40°C under an argon atmosphere.
Add 24.1 ml (38.6 mmole) of hexane solution dropwise over 10 minutes and stir for an additional 20 minutes. Next, cuprous bromide
Add 3.32g (38.6 x 0.6mmole) and heat to -40 to -20℃
Stir for 1 hour. Then, 6.60 g of benzyl bromide dissolved in tetrahydrofuran (15 ml)
After adding (38.6 mmole), remove the cold bath and
Stir for 1 hour. Cool on ice, add 1N hydrochloric acid (50ml) and stir. Tetrahydrofuran was distilled off under reduced pressure, isopropyl ether was added to the residue, and insoluble matter was filtered off through Hyflo Supercel. Take out the isopropyl ether layer, wash with water, wash with saline,
Dry (magnesium sulfate) and evaporate the solvent. The residual liquid was distilled under reduced pressure to obtain 8.62 g of 1-benzyl-2,5-dimethoxy-3,4,6-trimethylbenzene (83
%) was obtained. bp140~142℃ (0.3mmHg), mp70~
71℃ Similarly, 1-(4-methoxybenzyl-2.5-
dimethoxy-3,4,6-trimethylbenzene,
mp53-54℃ and 1-benzyl-2-methyl-
3,4,5,6-tetramethoxybenzene, bp
148-150℃ (0.3mmHg) was produced. Reference example 6 1 dissolved in anhydrous tetrahydrofuran (70ml)
-benzyl-2,5-dimethoxy-3,4,6-
Trimethylbenzene 7.02g (26.0mmole), 1,
1,2,2-tetramethylethylenediamine 4.32
ml (26 x 1.1 mmole) at 50℃ under argon atmosphere
16.3ml of n-butyllithium hexane solution
(26 mmole) was added dropwise over 10 minutes, and further heated to 50-56℃.
Stir for 20 minutes. Next, 5.80 g (26 mmole) of 3-bromopropanol tetrahydropyranyl ether dissolved in tetrahydrofuran (30 ml)
was added dropwise for 10 minutes and stirred at 50℃ for an additional 10 minutes.
Cool on ice, make acidic by adding 10% phosphoric acid aqueous solution, and extract by adding isopropyl ether. The organic layer was taken out, washed with saturated brine, dried (magnesium sulfate), and the solvent was distilled off. Dissolve the residue in methanol (70 ml) and add 0.25 g of p-toluenesulfonic acid (26 x 1/
20 mmole) and stir at 70℃ for 15 minutes. After air cooling, add sodium hydrogen carbonate aqueous solution to neutralize.
Solvent evaporation. Extract the residue by adding isopropyl ether and water. The isopropyl ether layer was washed with brine, dried (magnesium sulfate), and the solvent was distilled off. The residual solution was purified by silica gel column chromatography (isopropyl ether elution).
(2,5-dimethoxy-3,4,6-trimethylphenyl)-4-phenylbutanol 7.00 g (82
%) was obtained. The physical properties and nuclear magnetic resonance spectrum are shown in Table 14. Reference example 7 1 dissolved in anhydrous tetrahydrofuran (40ml)
-benzyl-2,5-dimethoxy-3,4,6-
Trimethylbenzene 4.05g (15mmole) and 1,
1,2,2-tetramethylethylenediamine 2.49
ml (15 x 1.1 mmole) under argon atmosphere, 50
9.4 ml of n-butyllithium hexane solution at °C
(15 mmole) was added dropwise over 5 minutes and further heated to 50-55℃.
Stir for 25 minutes. Next, 0.98 g of 6-bromohexanoic acid dissolved in tetrahydrofuran (10 ml)
(5.0 mmole) and 0.76 ml (5.0 mmole) of 1,1,2,2-tetramethylethylenediamine were added dropwise over 5 minutes, and the mixture was further stirred at 50°C for 10 minutes. The reaction solution was cooled on ice, made acidic by adding 10% aqueous phosphoric acid solution, and the product was extracted with isopropyl ether. Take out the organic layer and wash with saturated saline. Add 0.5N sodium hydroxide (aqueous solution) (50ml) to the organic layer and extract. Take out the aqueous layer, make it acidic by adding 10% phosphoric acid aqueous solution, and extract by adding isopropyl ether. The isopropyl ether layer was taken out, washed with brine, dried (magnesium sulfate), and the solvent was distilled off to obtain a crude condensate. Meanwhile, methanol (10 ml) was cooled to -10°C.
Add 1.08ml (15mmole) of thionyl chloride dropwise over 10 minutes.
After 10 minutes, the above crude condensate dissolved in methanol (10 ml) was added dropwise over 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 extract the product. The isopropyl ether layer was washed with brine, dried (magnesium sulfate), and the solvent was distilled off. The residual solution was purified by silica gel column chromatography (isopropyl ether/hexane elution) to give 7-(2,5-
dimethoxy-3,4,6-trimethylphenyl)
1.00 g of methyl-7-phenylheptanoate was obtained.
The physical properties and nuclear magnetic resonance spectrum data are shown in Table 14. Reference example 8 4-(2,
3.28 g of 5-dimethoxy-3,4,6-trimethylphenyl)-4-phenylbutan-1-ol
(10.0 mmole) and triethylamine 2.10 ml (10×
1.5 mmole) of methanesulfonyl chloride at -5℃
1.37g (10 x 1.2mmole) of dichloromethane (10
ml) solution was added dropwise over 30 minutes, and the reaction was continued for an additional 20 minutes while stirring on ice. Add cold water to the reaction solution to stop the reaction, take out the dichloromethane layer,
Wash sequentially with cold dilute hydrochloric acid and saline, dry (magnesium sulfate), and evaporate the solvent. Dissolve the residue in acetone (50 ml) and add 4.5 g (10 x 3 mmole) of sodium iodide.
Add and stir at 50℃ for 2 hours. Acetone was distilled off, and isopropyl ether and water were added to the residue to extract the product. The isopropyl ether layer was taken out, washed with brine, dried (magnesium sulfate), and the solvent was distilled off. The residual solution was purified by silica gel column chromatography (hexane/isopropyl ether elution) to give 1-iodo-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-
4.07 g (93%) of 4-phenylbutane was obtained. The physical properties and nuclear magnetic resonance spectrum data are shown in Table 14. Reference example 9 1-iodo-4-(2,5-dimethoxy-3,
0.74 g of sodium cyanide in a solution of 4.19 g (5.0 mmole) of 4,6-trimethylphenyl-4-phenylbutane in dimethyl sulfoxide (30 ml)
(5 x 3 mmole) and stir at 50℃ for 2 hours.
Cool the reaction solution on ice, add isopropyl ether and water, and stir. The isopropyl ether layer was taken out, washed with saline, dried (magnesium sulfate),
Solvent evaporation. The residue was purified by silica gel column chromatography (isopropyl ether/hexane elution) to give 5-(2,5-dimethoxy-
1.65 g (98%) of 3,4,6-trimethylphenyl)-5-phenylvaleronitrile was obtained. The physical properties and nuclear magnetic resonance spectrum data are shown in Table 14. Reference example 10 5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-phenylvaleronitrile
Dissolve 1.01g (3.0mmole) in ethanol (10ml), add 3N sodium hydroxide (10ml), and dissolve at 90%
Stir overnight (15 hours) at °C. After cooling in air, ethanol was distilled off under reduced pressure, isopropyl ether was added to the residue, acidified by adding 10% aqueous phosphoric acid solution, and then extracted. Washed with saline, dried (magnesium sulfate),
After evaporating the solvent and crystallizing the target product from isopropyl ether, 5-(2,5-dimethoxy-3,4,
1.06 g (99%) of 6-trimethylphenyl)-5-phenyl valeric acid mp 142-143°C was obtained. The physical properties and nuclear magnetic resonance spectrum data are shown in Table 14. Reference example 11 15 to 20 minutes while stirring in anhydrous pyridine (20 ml)
2.40 g of chromium trioxide (4.0×
6 mmole) little by little to prepare an orange-yellow porridge-like solution. Add 6-(2,5-dimethoxy-3,4,6-trimethylphenyl)-6- to this solution.
Phenylhexan-1-ol 1.42g
(4.0 mmole) in pyridine (10 ml) and stirred at room temperature overnight (16 hours). Pour the reaction solution into ice water and extract the product with dichloromethane. Take out the dichloromethane layer and evaporate the solvent. Add isopropyl ether and 1N hydrochloric acid to the residue to extract the product. Take out the isopropyl ether layer and wash with saline. Next, add 0.5N NaOH to the isopropyl ether layer.
(50 ml) was added to transfer the product to the aqueous layer. Take out this aqueous layer, add 10% phosphoric acid aqueous solution to make it acidic, and then extract the carboxylic acid with isopropyl ether. The isopropyl ether layer was taken out, washed with brine, dried (magnesium sulfate), and the solvent was distilled off.
The residue was purified by silica gel column chromatography (isopropyl ether elution).
-(2,5-dimethoxy-3,4,6-trimethylphenyl)-6-phenylhexanoic acid 1.07g
(72%). The physical properties and nuclear magnetic resonance spectrum data are shown in Table 14. Reference example 12 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-phenylheptanoic acid 1.99
Dissolve g (5.00 mmole) in methanol (20 ml), add 1N sodium hydroxide (10 ml), and heat at 50°C.
Stir for 2 hours. After cooling in air, methanol was distilled off under reduced pressure, the residue was made acidic by adding 10% phosphoric acid aqueous solution, and the product was extracted with isopropyl ether. The isopropyl ether layer was taken out, washed with brine, dried (magnesium sulfate), and the solvent was distilled off to give 7-(2,
1.92 g (100%) of 5-dimethoxy-3,4,6-trimethylphenyl)-7-phenylheptanoic acid was obtained. The physical properties and nuclear magnetic resonance spectrum data are shown in Table 14. Reference Example 13 9.00 g (30 mmole) of methyl 6-[4-(1-imidazolyl)benzoyl]hexanoate was dissolved in methanol (90 ml) and stirred on ice. Add 0.86g (30 x 0.75mmole) of sodium borohydride,
Ice-cold stirring was continued for 30 minutes. After adding acetone, the solvent was distilled off. Add chloroform and water to the residue and extract. Take out the chloroform layer, wash with saline,
Drying (magnesium sulfate) and evaporation of the solvent gave 9.10 g (100%) of methyl 7-hydroxy-7-[4-(1-imidazolyl)phenyl]heptanoate.
(Partially reconstituted with ethyl acetate/isopropyl ether.mp.77-78℃)

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[Table] Reference example 14 Under argon atmosphere, 2-bromo-3,5,6-
Trimethyl-1,4-dimethoxybenzene (10
g, 40 mmole) in THF (50 ml) was cooled to -70°C. n-Butyllithium (20% hexane solution) was added dropwise and stirred at -70°C for 10 minutes. Subsequently, cuprous bromide (5.70 g, 40 mmole) was added and the temperature of the reaction solution was raised to 0°C. After cooling the reaction solution to -70°C again, crotyl bromide (5.4g,
40 mmole) was added. After stirring the reaction solution until it reached 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 (50ml) and sodium borohydride (1g) was added. 3-fluoroboron etherate (1.5 ml) was added dropwise to the reaction solution. After stirring for 1 hour, add 50ml of water and stir for 3 more hours.
A normal aqueous potassium hydroxide solution (50 ml) was added dropwise.
30% hydrogen peroxide solution was added to the reaction solution under cooling, 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 obtain 3-(3,5,6-trimethyl-1,4-dimethoxyphenyl)-butan-1-ol. (3g, 30%) δ 3.67 (3H), 3.62 (3H, s), 3.49 (2H, m),
2.27 (3H, s), 2.17 (3H, s), 2.02 (2H, m),
1.37 (3H, d, .7Hz) Reference example 15 Oxalyl chloride (1
ml, 11 mmole) in dichloromethane solution (25 ml)
was cooled to -70°C. Add DMSO (1.7ml,
A mixed solvent of 22 mmole) and dichloromethane (5 ml) was added dropwise to the reaction solution while keeping the temperature below -60°C. followed by 3-(3,5,6-trimethyl-1,
A solution of 4-dimethoxybenzyl)butan-1-ol (3 g, 11 mmole) in dichloromethane (10
ml) was added dropwise. After stirring for 15 minutes at -70°C, triethylamine (7 ml, 50 mmol) was added dropwise.
Thereafter, the reaction solution was stirred until the temperature reached room temperature. After adding water (50 ml) to the reaction solution, it was concentrated 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-1,4-dimethoxybenzyl)-butanal was obtained. (2.7g, 90%) δ 9.68 (1H, t), 3.83 (1H, m), 2.67 (3H,
s), 3.60 (3H, s), 2.89 (2H, dd, 2Hz, 6
Hz), 2.27 (3H, s), 2.16 (6H, s), 1.33 (3H,
s) Reference example 16 Sodium hydride (1 g,
DMSO (30 ml) was added to a 24 mmol, 60% oil dispersion (washed with hexane and dried under reduced pressure) and stirred at 80° C. for 1 hour. After cooling, 3-carboxylpropyltriphenylphosphonium bromide (4.6 g, 11 mmole) was added to the reaction mixture, and the mixture was stirred at room temperature. Ten
After stirring for 3 minutes, 3-(3,5,6-trimethyl-1,
4-dimethoxyphenyl)butanal (2.7g,
A THF solution (5 ml) of 11 mmole) 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 (100ml),
The aqueous layer was adjusted to pH 4 with 2N hydrochloric acid and extracted with IPE. The organic layer was washed with water, dried and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: IPF) to give 7-(1,4-dimethoxy-
3,5,6-trimethylphenyl)-4-octenoic acid was obtained. (2.2g, 68%) δ 8.80 (1H, COOH), 5.38 (2H, m), 3.63
(3H, s), 3.60 (2H, s), 3.25 (1H, s), 2.40
(6H, m), 2.25 (3H, s), 2.15 (6H, s), 1.30
(3H, d, 7Hz) Dissolve this in ethyl acetate (20ml) and add 5% PD.
-C (0.2 g) was added and subjected to normal pressure catalytic reduction. After 6 hours, the catalyst was filtered off. Concentrate the filtrate under reduced pressure and
(1,4-dimethoxy-3,5,6-trimethyl)
Phenyl octanoic acid was obtained. (2g, 90%) δ 9.20 (1H, COOH), 3.65 (6H, s), 3.23
(1H, m), 2.30 (2H, m), 2.24 (3H, s), 1.66
(6H, m), 1.29 (3H, d, 7Hz) Reference example 17 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-phenylheptanol (1.85g, 5.0mmole) acetonitrile (12ml),
Ceric ammonium nitrate (8.22 g, 5×
3mmole) 50% acetonitrile water (16ml) solution
Drip over 20 minutes. After continuing ice-cooling and stirring for another 20 minutes, acetonitrile was distilled off under reduced pressure. Add isopropyl ether to the residue and extract. The isopropyl ether layer was taken out, washed with brine, dried (magnesium sulfate), and the solvent was distilled off. The residual solution was purified by silica gel column chromatography (isopropyl ether elution) to give 7-(3,5,6-trimethyl-1,4-
Benzoquinon-2-yl)-7-phenylheptanol (1.53 g, 90%) was obtained.

Claims (1)

[Claims] 1 General formula [Formula] (In the formula, R ¹ and R ² are the same or different and represent a hydrogen atom, a methyl group, or a methoxy group, or R ¹ and
R ² combine with each other and R ¹ and R ² -CH=CH-CH=
Indicates CH−. R ³ is a hydrogen atom or a methyl group,
R ⁴ represents an optionally substituted aromatic group or heterocyclic group, R ⁵ represents an optionally esterified or amidated carboxyl group, and n represents an integer of 2 to 10. ) or its hydroquinone derivative. ^2. The quinone according to claim ₁ , which is represented by the general formula: Derivatives or their hydroquinones. 3 General formula [Formula] (In the formula, R ¹ and R ² are the same or different and represent a hydrogen atom, a methyl group, or a methoxy group, or R ¹ and
R ² combine with each other and R ¹ and R ² -CH=CH-CH=
Indicates CH−. R ³ is a hydrogen atom or a methyl group,
R ⁴ represents an optionally substituted aromatic group or heterocyclic group, R ⁵ represents an optionally esterified or amidated carboxyl group, and n represents an integer of 2 to 10. ) An anti-asthmatic or anti-allergic agent comprising a quinone compound represented by () or its hydroquinone form as an active ingredient.