JPH0452253B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD The present invention relates to 1,4-benzoquinone derivatives. Prior Art Asthma is a disease in which patients with high airway hyperresponsiveness cause increased vascular permeability, bronchial smooth muscle contraction, increased secretion, etc. due to external allergens and non-specific stimuli (cold, dry, etc.) to the airways. , a disease that causes breathing difficulties. Currently, multifaceted treatments such as drug therapy, diversion therapy, desensitization therapy, and psychological therapy are being used to treat asthma, but no method with sufficient therapeutic effects has yet been established. Currently, anti-asthmatic drugs commonly used include beta receptor stimulants, xanthine agents, steroids, antihistamines, and chemical transmitter release inhibitors. Although the mechanism of action of these various therapeutic drugs on asthma is not yet clear, it is generally said to be as follows. That is, beta-receptor stimulators increase the enzymatic activity of adenyl cyclase, converting ATP into bronchodilator c-AMP.
change to Xanthine agents dilate the bronchus by inhibiting the activity of phosphodiesterase, which converts c-AMP into 5'-AMP, which has no bronchodilatory effect. Antihistamines act by antagonizing histamine at the histamine _H1 receptor.
Reduces bronchial mucosal edema and swelling caused by increased vascular permeability. Chemical mediator release inhibitors suppress asthma attacks by inhibiting the release of chemical mediators from mast cells. However, these various anti-asthmatic drugs each have their own merits and demerits, and the current situation is that none of them has sufficient therapeutic effects. Additionally, as research into asthma treatment progresses,
As an arachidonic acid derivative, it is a slow-reacting substance of anaphylaxis, which was considered to be the main causative agent of asthma.
(hereinafter abbreviated as "SRS-A") was identified [Chemistry and Biology, Vol. 20, No. 11, 696-698 (1982),
Metabolism, Vol18, No.4, (1981) 307-317, B.
Samuelssonet al, Prostaglandins, 17, 785
(1979), RCMurphy et al, Proc. Nat. Acad.
See Sci. USA, 76, 4275 (1979)]. According to this SRS-A, bronchial mucosal edema, swelling, and bronchial smooth muscle contraction are observed due to increased vascular permeability, which are the main symptoms of asthma [ACPeatfield
et al., Br.J.Pharmacol., 77, 391 (1982), MC
Holroyde et al., Agents Actions, 11, 573
(1981), Z., Marom et al., Am.Rev.Respir.
See Dis., 126, 449 (1982)]. Purpose of the Invention The present inventors have been conducting intensive research on the treatment of asthma and anti-asthmatic drugs for the same, and in the process, the above-mentioned SRS-A was synthesized from arachidonic acid. - Based on the idea that lipoxygenase is involved, and that by inhibiting the activity of 5-lipoxygenase, the production of SRS-A can be suppressed, thereby making it possible to treat asthma. We conducted research on substances that have an inhibitory effect. As a result, the 1,4-benzoquinone derivative represented by the following general formula (1) is useful as a 5-lipoxygenase inhibitor having the desired 5-lipoxygenase inhibitory effect, and its use shows that SRS- A new finding has been obtained that the production of SRS-A can be suppressed and various diseases caused by the production of SRS-A, such as asthma, inflammation, allergies, etc., can be prevented and treated. Structure of the Invention The 1,4-benzoquinone derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1). [In the formula, R ¹ , R ³ , R ⁴ and R ⁶ each represent a lower alkyl group. R ² and R ⁵ represent a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group. A
is a _C5 to _C12 alkylene group or -B-C≡C-D
- indicates a group. Here, B and D are respectively C ₁ to C ₁₀
represents an alkylene group. ] In the above general formula (1), the lower alkyl group includes, for example, a straight or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl group, etc. etc., and examples of the hydroxy lower alkyl group include hydroxymethyl, 2-hydroxyethyl, 2-hydroxyethyl, etc.
-Hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl and the like. Examples of the _C5 to _C12 alkylene group include alkylene groups having 5 or more carbon atoms in the main chain, and specific examples include pantamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, and undecamethylene. ,
Dodecamethylene, 3-methylpentamethylene, 2
Examples include -ethylpentamethylene, 3,4-dimethylhexamethylene, and 2,2-dimethyloctamethylene groups. Examples of _C1 to _C10 alkylene groups include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, 2-methyltetramethylene, and 3-ethylpentamethylene groups. etc. can be mentioned. The 1,4-benzoquinone derivative represented by the above general formula (1) has arachidonic acid 5-lipoxygenase inhibitory action, anti-asthmatic action, etc.
- Useful as a lipoxygenase inhibitor and anti-asthmatic agent. The 1,4-benzoquinone derivative of the present invention can be produced according to various methods, and a preferred example thereof is as follows. [In the formula, R ¹ , R ³ and B are the same as above. R ² ' is a hydrogen atom or a lower alkyl group, X is a halogen atom, E
represents a methoxymethyl group. According to the reaction scheme -, acetylene of general formula (5) can be obtained by reacting dihalogenated alkyl 3 with the compound of general formula (2) and then reacting acetylene with the resulting compound of general formula (4). A derivative is obtained. Furthermore, by reacting the compound of general formula (2) with alkynyl monohalide 6, the acetylene derivative of general formula (5) can be obtained in a one-step reaction. A compound of general formula (2) used as a starting material,
Both alkyl dihalide 3 and alkynyl monohalide 6 are known compounds. In the reaction to obtain compound 4 by reacting compound 2 with alkyl dihalide 3, compound 2 is first reacted with ethers such as tetrahydrofuran and ethyl ether, saturated hydrocarbons such as cyclohexane and n-hexane, ammonia, and hexamethyl phosphoric acid. By dissolving in an organic solvent such as triamide, preferably an anhydrous organic solvent, and cooling preferably to -30 to -100°C, then dropping a strong basic compound to this solution over a period of about 10 minutes to 3 hours, An organometallic compound of Compound 2 is obtained. Examples of strong basic compounds include sec-butyllithium, tert-butyllithium, n-butyllithium-N,N,N',
Examples include alkyl metal bases such as N'-tetramethylethylenediamine, alkali metals or alkali metal compounds such as sodium hydride, sodium, lithium, etc., and these are at least equimolar to Compound 2, preferably equimolar. It is used in an amount of ~2 times the mole. Next, compound 4 is obtained by adding dihalogenated alkyl 3 to the above reaction mixture at least in an equimolar amount, preferably 1.5 to 2.0 times the molar amount of compound 2. The reaction is carried out at room temperature to about 60°C, preferably at room temperature for 2 to 60°C.
This is done by stirring for 20 hours. At this time, by allowing an alkali metal iodide such as sodium iodide or potassium iodide and/or hexamethyl phosphoric acid triamide to be present in the reaction system, the reaction proceeds advantageously, and thus Compound 4 is obtained. . In the reaction to obtain the acetylene derivative represented by the general formula (5) by reacting acetylene with compound 4, first, acetylene is reacted with an ether such as tetrahydrofuran or ethyl ether, a saturated hydrocarbon such as cyclohexane or n-hexane, or ammonia. , dissolved in an organic solvent such as hexamethylphosphoric triamide, preferably an anhydrous organic solvent, and cooled to below 0°C, preferably in a stream of inert gas such as argon, and then a strong basic compound is added to this solution for about 10 minutes. By dropping and stirring for ~3 hours, an alkali metal compound of acetylene is obtained. As the strong basic compound, any of the strong basic compounds used in the reaction to obtain compound 4 from compound 2 can be used, and the amount used may be the same. Next, a solution of Compound 4 obtained above dissolved in the same organic solvent as above is added dropwise to the reaction mixture, and the mixture is stirred at room temperature to about 60°C, preferably room temperature for 1 to 6 hours. At this time, the presence of hexamethylphosphoric acid triamide in the reaction system allows the reaction to proceed advantageously, and thus Compound 5 is obtained. The reaction of reacting compound 2 with compound 6 to obtain compound 5 can be carried out in the same manner as the reaction of reacting compound 2 with compound 3 to obtain compound 4. [In the formula, R ¹ , R ² ', R ³ , R ⁴ , R ⁶ , B, D, X and E are the same as above. R ⁵ ' represents a hydrogen atom or a lower alkyl group. ] The reaction between Compound 5 and Compound 7 is the reaction between Compound 3 and Compound 7.
The reaction is carried out in the same manner as the reaction of compound 4 with compound 4. The demethoxymethylation reaction of Compound 8 is carried out by reacting Compound 8 with an acid in a suitable organic solvent. Examples of the organic solvent include alcohols such as methanol, ethanol, and isopropanol, ethers such as tetrahydrofuran and ethyl ether, saturated hydrocarbons such as cyclohexane and n-hexane, dichloromethane, acetonitrile, and mixed solvents thereof. As the acid, a wide variety of conventionally known acids can be used, including mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, organic acids such as acetic acid, fluoroacetic acid, and oxalic acid, and Lewis acids such as boron fluoride and aluminum chloride. These acids are used in at least equimolar amounts relative to Compound 8. The reaction is preferably carried out in an inert gas such as argon gas or nitrogen gas. Further, the reaction is generally carried out at around room temperature and is completed in about 1 to 4 hours. Compound 9 is thus obtained. The reaction of oxidizing Compound 9 to obtain the compound of the present invention of general formula (1a) is carried out by reacting Compound 9 with an oxidizing agent in a suitable organic solvent. As the organic solvent, a wide variety of organic solvents used in the demethoxymethylation reaction of Compound 8 can be used. As the oxidizing agent, a wide variety of known oxidizing agents can be used as long as it is a mild oxidizing agent, such as air, oxygen, manganese dioxide, etc. The reaction is carried out at room temperature to about 60°C, preferably at room temperature for about 1 to 10 hours. [In the formula, R ¹ , R ² ′, R ³ , R ⁴ , R ⁵ ′, R ⁶ , X and E
is the same as above. A′ represents a C ₅ to C ₁₂ alkylene group. ] The reaction between Compound 2 and Compound 10 can be carried out in the same manner as the reaction between Compound 5 and Compound 7 described above. Further, the demethoxymethylation of Compound 11 and the subsequent oxidation reaction can be carried out in the same manner as the demethoxymethylation of Compound 8 and the oxidation of Compound 9, respectively. [In the formula, R ¹ , R ² ', R ³ , X, E and A' are the same as above. ] The reaction between compound 2 and compound 12 is the reaction between compound 12 and compound 12.
The reaction can be carried out in the same manner as the reaction between compound 2 and compound 3, except that 0.2 to 1 mol, preferably 0.4 to 0.5 mol, is used per 21 mol of compound. Further, the demethoxymethylation of compound 13 and the subsequent oxidation reaction can be carried out in the same manner as the demethoxymethylation of compound 8 and the oxidation of compound 9, respectively. [In the formula, R ¹ , , R ³ , R ⁴ , R ⁶ , X, E and A are the same as above. Y is a hydroxyl-protecting group, n is an integer of 1 to 6, and R ² ″ and R ⁵ ″ represent a lower alkyl group or a hydroxy lower alkyl group. ] Compound 8 obtained by the above reaction scheme - and
and reacting compound 15 with a compound in which R ² ′ and R ⁵ ′ of 11 are both hydrogen atoms [i.e., compound 14],
Then, the corresponding compound 1d is produced by demethoxymethylating the resulting compound 17 in which R ² ″ and R ⁵ ″ are lower alkyl groups, followed by oxidation. In addition, compound 14 is reacted with compound 16, and then hydrolyzed according to a conventional method to obtain further
The corresponding compound 1d is prepared by demethoxymethylating compound 17, in which R ² ″ and R ⁵ ″ are hydroxy lower alkyl groups, followed by oxidation. The reaction between Compound 14 and Compound 15 or Compound 16 is carried out under the same conditions as the reaction between Compound 2 and Compound 3, except that the basic compound is used in a molar amount or more twice that of Compound 15 or 16. I can do it. If the reaction is carried out in the same manner as above using a basic compound in an equimolar amount to Compound 15 or 16, Compound 17 in which one of R ² ″ and R ⁵ ″ is a hydrogen atom is produced. In compound 16, Y
As the protecting group for the hydroxyl group represented by, for example, a tetrahydropyranyl group can be mentioned. Furthermore, in the presence of a Lewis acid, Compound 15 is added with at least an equivalent amount of a lower oxide, a lower ketone, or a lower aldehyde that can easily become an electrophilic reagent, preferably 1 to 2
Hydroxy lower alkylation can also be carried out by acting in equal amounts. Examples of lower oxides include ethylene oxide, examples of lower ketones include acetone, and examples of lower aldehydes include formic acid and acetaldehyde. The compound of the present invention obtained in the above reaction can be isolated by conventional separation means such as column chromatography. Examples of separation columns include silica gel, activated alumina, silver nitrate silica gel, calcium phosphate, activated carbon, Florisil,
Examples include ion exchange resins such as agnesia, styrene polymer resins, DOWEX ion exchange resins, Amberlite ion exchange resins, cellulose ion exchangers, gel filtration carriers, and the like. As the eluent, suitable solvents such as n-hexane, benzene, diethyl ether, chloroform, ethyl acetate, acetone, methanol, ethanol, water, acetic acid aqueous solution, hydrochloric acid aqueous solution, etc. may be used alone, or a mixture thereof may be used. I can do it. After purification by column chromatography, precipitation method, sublimation method, solvent extraction method, dilution method, recrystallization method, high performance liquid chromatography, gas chromatography, droplet countercurrent partition chromatography, thin layer Separation and purification means such as chromatography, distillation, and gel filtration can be used. The compounds of the present invention are usually used in the form of common pharmaceutical preparations. The formulation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, sprays, pills, powders, solutions, suspensions, emulsions,
Examples include granules, capsules, suppositories, and injections (solutions, suspensions, etc.). When forming tablets, a wide variety of carriers known in this field can be used, such as lactose, sucrose, sodium chloride,
Excipients such as glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid,
Water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, dry starch, sodium alginate,
Disintegrants such as agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, white sugar, stearin, cocoa butter, hydrogenated oil, etc. Inhibitors, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, purified talc, stearate, Examples include lubricants such as boric acid powder and polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, a wide variety of conventionally known carriers can be used, such as excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, powdered tragacanth,
Examples include binders such as gelatin and ethanol, and disintegrants such as laminar agar. When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as injections, solutions and suspensions are preferably sterilized and isotonic with blood, and when forming these solutions, emulsions, and suspensions, this agent is used as a diluent. All those commonly used in the field can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, a sufficient amount of salt, glucose, or glycerin may be included in the pharmaceutical preparation to prepare an isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. It's okay. Furthermore, other pharmaceutical agents such as coloring agents, preservatives, perfumes, flavoring agents, and sweeteners may be included in the pharmaceutical preparations, if necessary. In addition, when the above-mentioned 1,4-benzoquinone derivative is in the form of a spray, a wide variety of dispersants and propellants known in this field can be used, and examples of the dispersant include lecithins such as soybean lecithin and egg yolk lecithin. Examples include fatty acids such as oleic acid, linoleic acid, and linolenic acid, and sorbitans such as sorbitan triolate and sorbitan monooleate.
Also, as a propellant, for example, Freon 11, Freon
Examples include normally nonflammable liquefied gases such as 12 and Freon 114. The amount of Compound 1 of the present invention to be contained in a pharmaceutical formulation is not particularly limited and can be appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the pharmaceutical formulation. There are no particular restrictions on the method of administering the above pharmaceutical preparations, and the administration method is determined depending on the various preparation forms, age, sex and other conditions of the patient, and the severity of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acids, and furthermore, if necessary, it is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. Suppositories are administered rectally, and sprays are administered into the bronchi by spraying through the mouth or nose. The dosage of the 5-lipoxygenase inhibitor of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the amount of the compound of general formula (1), which is the active ingredient, is usually Weight 1Kg per day
The amount is preferably about 0.005 to 10 mg, preferably 0.1 to 1 mg. Furthermore, the compound of general formula (1) of the present invention has low toxicity, anticancer effect, biomembrane stabilization effect, mitochondrial electron transport enhancement effect, phosphodieslase inhibition effect, antihypertensive effect, and prevention of cardiac hypertrophy. , has effects such as improving cerebral circulation, protecting against cerebral ischemia, blocking adrenaline-like effects, promoting immunity, and protecting against bacterial infection, etc.; tissue metabolism activator, antihypertensive agent, heart failure treatment agent, cerebral circulation improving agent, analgesic. It is useful as an antiulcer agent, diuretic, immunomodulator, antithrombotic agent, and bacterial infection defense enhancer for the prevention and treatment of hypertension, stroke, heart failure, immunodeficiency, etc. Examples Reference examples, examples, and pharmacological tests are shown below. Reference Example 1 10g of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in tetrahydrofuran.
Dissolve in 300 ml and cool to -78°C in dry ice-acetone solution. Add 35 ml of sec-butyllithium (1.3M cyclohexane solution) dropwise and stir for 30 minutes. 15 ml (0.11 mol) of 1,5-dibromopentane are added dropwise, followed by 12 g of sodium iodide and 20 ml of hexamethylphosphoric triamide. Continue stirring at room temperature for 12 hours. Tetrahydrofuran is removed under reduced pressure and dissolved in 1000 ml of benzene-ether (1:1) mixed solvent. Add 200 ml of water to the organic layer 4 times and 200 ml of saturated saline.
Wash 4 times with water and dehydrate by adding magnesium sulfate. After distilling off the solvent under reduced pressure, silica gel column chromatography (φ8 cm x 30 cm, developing solution ethyl acetate: n-hexane = 1:4, Wako Gel C-200)
1-(5-bromopent-1-yl)-
11.24 g (yield 71.2%) of 2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene was obtained.
This compound is hereinafter referred to as compound _A1 . Characteristics of Compound A ₁ Colorless oil PMR δ ppm (CDC ₃ ) 6.65 (1H, s) 5.17 (2H, s) 5.02 (2H, s) 3.78 (6H, s) 3.58 (3H, s) 3.52 (3H, s) 3.40 (2H, t, J = 6.8Hz) 2.65 (2H, brt, J = 6.8Hz) 1.88 (2H, brm) 1.56 (4H, brm) Replaced with 1,5-dibromopentane in Reference Example 1 above 1-(7-bromohept-1-yl)-
2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene (hereinafter referred to as compound A ₂
) or 1-(9-promononyl-1-yl)-
2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene (hereinafter referred to as compound A ₃
) is obtained. Physical properties of compound A ₂ Colorless oil PMR δ ppm (CDC ₃ ) 6.65 (1H, s) 5.17 (2H, s) 5.02 (2H, s) 3.79 (6H, s) 3.58 (3H, s) 3.53 (3H, s) 3.40 (2H, t, J = 6.8Hz) 2.67 (2H, brt, J = 6.9Hz) 1.82 (2H, brm) 1.2 - 1.65 (8H, brm) Physical properties of compound A ₃ Colorless oil PMR δ ppm (CDC ₃ ) 6.64 (1H, s) 5.17 (2H, s) 5.02 (2H, s) 3.79 (6H, s) 3.59 (3H, s) 3.53 (3H, s) 3.40 (2H, t, J=6.9Hz ) 2.70 (2H, brt, J=6.9Hz) 1.82 (2H, brm) 1.2 to 1.7 (12H, brm) Reference example 2 Cool 100 ml of anhydrous tetrahydrofuran in a dry ice-acetone bath in an argon stream, and dry it. Pass acetylene gas through for 1 hour. Then n-butyllithium (1.6M, n-hexane solution)
Add 9.6ml dropwise and stir. After 15 minutes, 10 ml of the anhydrous tetrahydrofuran solution of Compound A ₁ obtained in Reference Example 1 was added dropwise, 2 ml of hexamethylphosphoric acid triamide was added, and stirring was continued for 12 hours, and the temperature was raised to room temperature. The progress of the reaction is monitored by high performance liquid column chromatography (ODS column, effluent 60% acetonitrile-water, flow rate 1.5 ml/min). The solvent is distilled off under reduced pressure, 400 ml of a mixed solvent of ether:benzene (1:1) is added, and the organic layer is washed four times successively with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, subjected to silica gel column chromatography (φ3 x 10 cm), and 20% ethyl acetate-n
-hexane and 1.71 g of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-3-(6
-heptyn-1-yl)benzene is obtained. This compound is hereinafter referred to as compound _B1 . Physical properties of compound B ₁ Colorless oil PMR δ ppm (CDC ₃ ) 6.64 (1H, s) 5.16 (2H, s) 5.01 (2H, s) 3.78 (6H, s) 3.58 (3H, s) 3.52 (3H, s) 2.67 (2H, brt, J = 7.6Hz) 2.19 (2H, t, d, J ₁ = 7.0Hz, J ₂ = 2.4Hz) 1.92 (1H, t, J = 2.4Hz) 1.7~1.4 (6H, brm) The following compound was obtained by the same method as in Reference Example 2 above. 1,4-dimethoxy-2,5-bis(methoxymethoxy)-3-(8-nonyn-1-yl)benzene This compound is hereinafter referred to as compound _B2 . Physical properties of compound B ₂ Colorless oil PMR δ ppm (CDC ₃ ) 6.63 (1H, s) 5.17 (2H, s) 5.01 (2H, s) 3.78 (6H, s) 3.58 (3H, s) 3.52 (3H, s) 2.67 (2H, brt, J = 7.1Hz) 2.17 (2H, t, d, J ₁ = 6.7Hz, J ₂ = 2.6Hz) 1.93 (1H, t, J = 2.6Hz) 1.7~1.25 (10H, brm) 1,4-dimethoxy-2,5-bis(methoxymethoxy)-3-(10-undecyn-1-yl)benzene This compound is hereinafter referred to as compound _B3 . Physical properties of compound B ₃ Colorless oil PMR δ ppm (CDC ₃ ) 6.63 (1H, s) 5.17 (2H, s) 5.01 (2H, s) 3.78 (6H, s) 3.58 (3H, s) 3.52 (3H, s) 2.67 (2H, brt, J = 2.6Hz) 2.17 (2H, t, d, J ₁ = 6.7Hz, J ₂ = 2.6Hz) 1.93 (1H, t, J = 7.6Hz) 1.7~1.25 (14H, brm) Reference Example 3 1.61 g of the compound B ₁ obtained in Reference Example 2 above was dissolved in 40 ml of anhydrous tetrahydrofuran and cooled in a dry ice-acetone bath in an argon stream.
n-Butyllithium (1.6M, hexane solution)
Add 3.42ml dropwise and stir. After 30 minutes, the above reference example 1
2.23 g of Compound A ₁ obtained above was dissolved in 10 ml of anhydrous tetrahydrofuran, and the solution was added dropwise with stirring. Add 2 ml of hexamethylphosphoric acid triamide dropwise and raise the temperature to room temperature over 12 hours. The solvent was distilled off under reduced pressure, and 400 ml of ether:benzene (1:1) mixed solvent was added.
The organic layer is washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, it was subjected to silica gel column chromatography and developed and eluted by increasing the mixing ratio stepwise from 20% ethyl acetate-hexane to 50% ethyl acetate-hexane.
2.09 g of 2'-(6-dodecynylene)bis[1,4-dimethoxy-3,6-bis(methoxymethoxy)benzene] was obtained. This compound is hereinafter referred to as compound _C1 . Physical properties of compound C ₁ Colorless oil PMR δ ppm (CDC ₃ ) 6.63 (2H, s) 5.17 (4H, s) 5.01 (4H, s) 3.78 (12H, s) 3.58 (6H, s) 3.52 (6H, s) 2.67 (4H, brt, J=7.0Hz) 2.14 (4H, brm) 1.65-1.35 (12H, brm) The following compounds were obtained in the same manner as in Reference Example 3 above. 2,2'-(8-hexadecynylene)bis[1,
4-dimethoxy-3,6-bis(methoxymethoxy)benzene] This compound is hereinafter referred to as compound _C2 . Physical properties of compound C ₂ Colorless oil PMR δ ppm (CDC ₃ ) 6.64 (2H, s) 5.17 (4H, s) 5.01 (4H, s) 3.78 (12H, s) 3.58 (6H, s) 3.53 (6H, s) 2.66 (4H, brt, J = 8.1Hz) 2.12 (4H, t, J = 7.0Hz) 1.6-1.25 (20H, brm) 2,2'-(10-eicocynylene)bis[1,4
-dimethoxy-3,6-bis(methoxymethoxy)benzene] This compound is hereinafter referred to as compound _C3 . Physical properties of compound C ₃ Colorless oil PMR δ ppm (CDC ₃ ) 6.64 (2H, s) 5.17 (4H, s) 5.01 (4H, s) 3.78 (12H, s) 3.58 (6H, s) 3.53 (6H, s) 2.65 (4H, brt, J = 8.2Hz) 2.13 (4H, t, J = 7.0Hz) 1.6-1.2 (28H, brm) Reference Example 4 1,4-dimethoxy- of Reference Example 1 above
2,5-bis(methoxymethoxy)benzene 1g,
Tetrahydrofuran 40ml, sec-butyl lithium (1.3M cyclohexane solution) 3.57ml, 1,5-dibromopentane 0.26ml, sodium iodide 700ml
2,2'-(1,5-pentanediyl)bis[1,4- dimethoxy-3,6
-bis(methoxymethoxy)benzene] 335 mg was obtained. This compound is hereinafter referred to as compound _D1 . Physical properties of compound D ₁ Colorless needle crystals Melting point 67-68℃ PMR δ ppm (CDC ₃ ) 6.64 (2H, s) 5.17 (4H, s) 5.01 (4H, s) 3.78 (6H, s) 3.77 (6H, s) 3.57 (6H, s) 3.52 (6H, s) 2.67 (4H, brt, J=7.3Hz) 1.54 (6H, m) The following compounds were obtained in the same manner as in Reference Example 4 above. 2,2'-(1,6-hexanediyl)bis[1,
4-dimethoxy-3,6-bis(methoxymethoxy)benzene] This compound is hereinafter referred to as compound _D2 . Physical properties of compound D ₂ Colorless powder melting point 59-60℃ PMR δ ppm (CDC ₃ ) 6.63 (2H, s) 5.16 (4H, s) 5.01 (4H, s) 3.78 (6H, s) 3.77 (6H, s) 3.58 (6H, s) 3.53 (6H, s) 2.65 (4H, t, J=7.0Hz) 1.50 (4H, brm) 1.43 (4H, brm) 2,2'-(1,7-heptanediyl)bis[1 ，
4-dimethoxy-3,6-bis(methoxymethoxy)benzene] This compound is hereinafter referred to as compound _D3 . Physical properties of compound D ₃ Colorless oil PMR δ ppm (CDC ₃ ) 6.63 (2H, s) 5.17 (4H, s) 5.01 (4H, s) 3.78 (6H, s) 3.78 (6H, s) 3.58 (3H, s) 3.53 (3H, s) 2.65 (4H, brt, J=7.8Hz) 1.55 (4H, m) 1.39 (6H, m) 2,2'-(1,8-octanediyl)bis[1,
4-dimethoxy-3,6-bis(methoxymethoxy)benzene] This compound is hereinafter referred to as compound _D4 . Physical properties of compound D ₄ Colorless oil PMR δ ppm (CDC ₃ ) 6.63 (2H, s) 5.17 (4H, s) 5.02 (4H, s) 3.78 (12H, s) 3.58 (6H, s) 3.52 (6H, s) 2.66 (4H, t, J = 6.9Hz) 1.6-1.3 (12H, m) 2,2'-(1,9-nonanediyl)bis[1,
4-dimethoxy-3,6-bis(methoxymethoxy)benzene] This compound is hereinafter referred to as compound _D5 . Physical properties of compound D ₅ Colorless oil PMR δ ppm (CDC ₃ ) 6.63 (2H, s) 5.17 (4H, s) 5.01 (4H, s) 3.78 (6H, s) 3.78 (6H, s) 3.58 (6H, s) 3.58 (6H, s) 2.65 (4H, brt, J=7.5Hz) 1.54 (4H, m) 1.4-1.25 (10H, m) 2,2'-(1,10-decanediyl)bis[1,
4-dimethoxy-3,6-bis(methoxymethoxy)benzene] This compound is hereinafter referred to as compound D ₆ . Physical properties of compound D ₆ Colorless oil PMR δ ppm (CDC ₃ ) 6.64 (2H, s) 5.17 (4H, s) 5.02 (4H, s) 3.78 (12H, s) 3.58 (6H, s) 3.53 (6H, s) 2.65 (4H, t, J = 7.0Hz) 1.6-1.2 (16H, m) 2,2'-(1,12-dodecanediyl)bis[1,4-dimethoxy-3,6-bis(methoxymethoxy) Benzene] Hereinafter, this compound will be referred to as a compound.
It is called _D7 . Physical properties of compound D ₇ Colorless oil PMR δ ppm (CDC ₃ ) 6.63 (2H, s) 5.17 (4H, s) 5.01 (4H, s) 3.79 (12H, s) 3.58 (6H, s) 3.53 (6H, s) 2.66 (4H, brt, J = 7.3Hz) 1.56 (4H, m) 1.4-1.2 (16H, m) Reference Example 5 500 mg of the compound C ₁ obtained in Reference Example 3 was mixed with a mixed solvent of 5 ml of tetrahydrofuran and 5 ml of isopropanol. The reaction system was replaced with argon gas three times by degassing under reduced pressure. Hydrogen chloride (20%)
-Tetrahydrofuran-isopropanol solution 1
ml and stirred at room temperature for 12 hours, then further heated to 40°C and reacted for 1 hour to complete the reaction. After distilling off the solvent under reduced pressure, 10 ml of benzene was added and distilled off under reduced pressure to obtain colorless powder 2, 2'-(6-dodecynylene)bis(1,4-dihydroxy-3,6-dimethoxybenzene) is obtained. This compound is hereinafter referred to as compound _E1 . The compound was prepared in the same manner as in Reference Example 5 above.
Compound C ₂ obtained in Reference Example 3 above in place of C ₁ ,
The following compound was obtained using compound _C3 . 2,2-(8-hexadecynylene)bis(1,4
-dihydroxy-3,6-dimethoxybenzene)
This compound is hereinafter referred to as compound _E2 . Physical properties of compound E ₂ Colorless oil PMR δ ppm (CDC ₃ ) 6.43 (2H, s) 5.29 (2H, s) 5.22 (2H, s) 3.82 (6H, s) 3.74 (6H, s) 2.63 (4H, brt, J = 7.6Hz) 2.12 (4H, t, J = 7.0Hz) 1.7~1.2 (20H, brm) 2,2-(10-eicocynylene)bis(1,4-
dihydroxy-3,6-dimethoxybenzene) This compound is hereinafter referred to as compound _E3 . Reference Example 6 The following compounds are obtained using Compounds D ₁ to D ₇ obtained in Reference Example 4 in the same manner as in Reference Example 5 above. 2,2-pentamethylenebis(1,4-dihydroxy-3,6-dimethoxybenzene) This compound will hereinafter be referred to as compound _F1 . Physical properties of compound F ₁ Colorless powder melting point 152-154℃ PMR δ ppm (CDC ₃ ) 6.43 (2H, s) 5.25 (2H, s) 5.19 (2H, s) 3.82 (6H, s) 3.74 (6H, s) 2.66 (4H, t, J=6.7Hz) 1.8-1.2 (6H, brm) 2,2-hexamethylenebis(1,4-dihydroxy-3,6-dimethoxybenzene) This compound is hereinafter referred to as _F2 . 2,2-Heptamethylenebis(1,4-dihydroxy-3,6-dimethoxybenzene) This compound will hereinafter be referred to as compound _F3 . 2,2-octamethylenebis(1,4-dihydroxy-3,6-dimethoxybenzene) This compound will hereinafter be referred to as _F4 . 2,2-nonamethylenebis(1,4-dihydroxy-3,6-dimethoxybenzene) This compound is hereinafter referred to as _F5 . Physical properties of compound F ₅ Colorless powder melting point 100-102℃ PMR δ ppm (CDC ₃ ) 6.43 (2H, s) 5.35 (4H, s) 3.81 (6H, s) 3.74 (6H, s) 2.63 (4H, t, J=7.6Hz) 1.8-1.2 (14H, brm) 2,2-decamethylenebis(1,4-dihydroxy-3,6-dimethoxybenzene) This compound is hereinafter referred to as _F6 . 2,2-dodecamethylenebis(1,4-dihydroxy-3,6-dimethoxybenzene) This compound is hereinafter referred to as _F7 . Reference Example 7 9.8 g of Compound D ₁ obtained in Reference Example 4 above was dissolved in 400 ml of anhydrous tetrahydrofuran in an argon stream, and hexamethylphosphoric triamide was added to this solution.
Add 100 ml and cool in a dry ice-acetone bath. 29.35 ml of sec-butyllithium (1.4M cyclohexane solution) was added dropwise and stirred for 1 hour.
Then, 4.3 ml of methyl iodide is added dropwise, and the mixture is cooled in a dry ice-acetone bath for 12 hours and stirred. The solvent was distilled off under reduced pressure and ether:benzene (1:1)
Mixed solvent 2 was added, and the organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 2,2'-pentamethylenebis[1,4-dimethoxy-3], which is a colorless oil. , 6-bis(methoxymethoxy)-5-methylbenzene)] to obtain 11 g. This compound is hereinafter referred to as compound _G1 . Physical properties of compound G ₁ Colorless needle crystals Melting point 83-84℃ PMR δ ppm (CDC ₃ ) 5.01 (8H, s) 3.73 (6H, s) 3.70 (6H, s) 3.55 (12H, s) 2.61 (4H, brt, J=7.0Hz) 2.19 (6H, s) 1.7-1.4 (6H, brm) 140 mg of Compound D ₁ obtained in Reference Example 4 was dissolved in 5 ml of anhydrous tetrahydrofuran in an argon stream, and hexamethylphosphorus was added to this solution. acid triamide
Add 0.5 ml and cool in a dry ice-acetone bath. Add dropwise 0.23 ml of sec-butyllithium (1.4M cyclohexane solution) and stir for 1 hour. Next, 0.06 ml of methyl iodide is added dropwise, and the mixture is stirred in a dry ice-acetone bath for 12 hours. The solvent was distilled off under reduced pressure and ether:benzene (1:1) mixed solvent 100
ml, the organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, concentrated under reduced pressure,
1,4-dimethoxy-2,5- which is a colorless oil
Bis(methoxymethoxy)-3-methyl-6-[5
-(2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl)pentyl]benzene 100
Get mg. This compound is hereinafter referred to as compound _G2 . Physical properties of compound G ₂ Colorless needle crystals Melting point 76-77℃ PMR δ ppm (CDC ₃ ) 6.70 (1H, s) 5.13 (2H, s) 5.02 (6H, s) 3.76 (6H, s) 3.74 (3H, s) 3.70 (3H, s) 3.56 (9H, s) 3.51 (3H, s) 2.63 (4H, brm) 2.18 (3H, s) 1.8 to 1.3 (6H, brm) Reference Example 8 Same as Reference Example 5 above Compound _G1 obtained in Reference Example 7 was demethoxymethylated by the following procedure to obtain 2,2-pentamethylenebis(1,4-dihydroxy-3,6-dimethoxy-5-methylbenzene). This compound will be referred to as compound H hereinafter. Physical properties of compound H Colorless powder PMR δ ppm (CDC ₃ -DMSO-d ₆ ) 7.35 (2H, s) 7.20 (2H, s) 3.69 (6H, s) 3.65 (6H, s) 2.5 (4H, brm) 2.10 (6H, s) 1.7-1.3 (6H, brm) Reference Example 9 Compound D 1 obtained in Reference Example 4 above _1.1g
(1.8 mmole) was dissolved in a mixed solvent of 20 ml of tetrahydrofuran and 4 ml of hexamethylphosphoric triamide, and cooled to -78°C in a dry ice-acetone bath. Add sec-butyllithium (1.4 mmole/ml) and stir for 1 hour. Add 1 ml of a solution of ethylene oxide in tetrahydrofuran (2.1 mmole/ml), and then add a small amount of BF ₃ -OET ₂ . 4 at -78℃
After stirring for an hour and concentrating under reduced pressure, 300 ml of a benzene-ether (1:1) mixed solvent was added, washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (20 g of silica gel, 40% ethyl acetate-benzene) to obtain 1-(2-hydroxyethyl)-
2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-[5-(1,4-dimethoxy-2,
0.6 g of 5-bis(methoxymethoxy)phenyl)bentyl]benzene was obtained. This compound is hereinafter referred to as compound _I1 . Physical properties of compound I ₁ Amorphous powder PMR δ ppm (CDC ₃ ) 6.60 (1H, s) 5.03 (4H, s) 5.01 (4H, s) 3.80 (3H, s) 3.77 (6H, s) 3.76 (3H, s) 3.55 (3H, s) 3.53 (6H, s) 3.52 (3H, s) 2.95 (2H, t, J=6.0Hz) 2.60 (4H, t, J=6.0Hz) 1.4~1.6 (6H, brm) 4,4'-Pentamethylenebis[1-
(2-hydroxyethyl)-2,5-dimethoxy-
3,6-bis(methoxymethoxy)benzene]
Obtained 0.9g. This compound is hereinafter referred to as compound I ₂ . Physical properties of compound I ₂ Colorless needle crystals Melting point 68-70℃ PMR δ ppm (CDC ₃ ) 5.04 (4H, s) 5.01 (4H, s) 3.79 (4H, t, J = 6.0Hz) 3.76 (6H, s ) 3.75 (6H, s) 3.54 (6H, s) 3.53 (6H, s) 2.96 (4H, t, J=6.0Hz) 2.50 (4H, t, J=6.0Hz) 1.4~1.6 (6H, brm) Implementation Example 1 200 mg of compound F ₁ obtained in Reference Example 6 was added to methanol.
Dissolve in 20 ml, heat to 60°C and pass in oxygen. A small amount of sodium bicarbonate was added, the reaction was terminated in about 1 hour, the solvent was distilled off under reduced pressure, and a yellow oil was obtained by preparative thin layer chromatography on silica gel (2 mm thick, developer: 20% ethyl acetate-benzene). 135 mg of crude 2,2'-pentamethylenebis(3,6-dimethoxy-p-benzoquinone) was obtained, which was crystallized from ethanol water to obtain yellow needles. This compound is hereinafter referred to as compound Ia. Physical properties of compound Ia Yellow needles Melting point 113-115℃ PMR δ ppm (CDC ₃ ) 5.72 (2H, s) 4.04 (6H, s) 3.80 (6H, s) 2.42 (4H, brt, J=7.3Hz) 1.35 (6H, brm) Compounds F ₂ to F ₇ obtained in Reference Example 6 were used in the same manner as in Example 1 to obtain the following compounds. 2,2'-hexamethylenebis(3,6-dimethoxy-p-benzoquinone) This compound will hereinafter be referred to as compound Ib. Physical properties of compound Ib Yellow needle crystals Melting point 120-122℃ PMR δ ppm (CDC ₃ ) 5.72 (2H, s) 4.05 (6H, s) 3.80 (6H, s) 2.42 (4H, t, J = 6.8Hz) 1.5-1.2 (8H, brm) 2,2'-heptamethylenebis(3,6-dimethoxy-p-benzoquinone) This compound is hereinafter referred to as Ic. Physical properties of compound Ic Yellow needles Melting point 77-78℃ PMR δ ppm (CDC ₃ ) 5.72 (2H, s) 4.04 (6H, s) 3.80 (6H, s) 2.41 (4H, t, J = 7.3Hz) 1.5-1.2 (10H, brm) 2,2'-octamethylenebis(3,6-dimethoxy-p-benzoquinone) This compound is hereinafter referred to as compound Id. Physical properties of compound Id Yellow needles Melting point 108-110℃ PMR δ ppm (CDC ₃ ) 5.72 (2H, s) 4.04 (6H, s) 3.80 (6H, s) 2.42 (4H, t, J = 6.8Hz) 1.5-1.2 (12H, brm) 2,2'-nonamethylenebis(3,6-dimethoxy-p-benzoquinone) Hereinafter, this compound will be referred to as a compound.
It is called Ie. Physical properties of compound Ie Yellow columnar crystal Melting point 72-74℃ PMR δ ppm (CDC ₃ ) 5.72 (2H, s) 4.04 (6H, s) 3.80 (6H, s) 2.42 (4H, t, J = 7.6Hz) 1.5 ~1.2 (14H, brm) 2,2'-decamethylenebis(3,6-dimethoxy-p-benzoquinone) This compound is hereinafter referred to as If. Physical properties of compound If Yellow oil PMR δ ppm (CDC ₃ ) 5.72 (2H, s) 4.05 (6H, s) 3.80 (6H, s) 2.42 (4H, t, J = 7.9Hz) 1.6-1.2 (16H, m) 2,2'-dodecamethylenebis(3,6-dimethoxy-p-benzoquinone) This compound will hereinafter be referred to as compound Ig. Physical properties of compound Ig Yellow oil PMR δ ppm (CDC ₃ ) 5.72 (2H, s) 4.04 (6H, s) 3.80 (6H, s) 2.42 (4H, t, J = 7.6Hz) 1.5-1.2 (20H, m) Example 2 Compound E ₁ , Compound E ₂ , Compound obtained in Reference Example 5
Each of E ₃ was oxidized in the same manner as in Example 1 to obtain the following compounds. 2,2'-(6-dodecynylene)bis(3,6-dimethoxy-p-benzoquinone) This compound will hereinafter be referred to as compound a. Physical properties of compound a Yellow oil PMR δ ppm (CDC ₃ ) 5.72 (2H, s) 4.05 (6H, s) 3.79 (6H, s) 2.43 (4H, brt, J=7.0Hz) 2.12 (4H, brt, J=6.7Hz) 1.65~1.2 (12H, brm) 2,2′-(8-hexadecynylene)bis(3,6
-dimethoxy-p-benzoquinone) This compound is hereinafter referred to as compound b. Physical properties of compound b Yellow oil PMR δ ppm (CDC ₃ ) 5.72 (2H, s) 4.05 (6H, s) 3.80 (6H, s) 2.42 (4H, t, J = 7.3Hz) 2.12 (4H, t, J=7.3Hz) 1.7~1.2 (20H, brm) 2,2′-(10-eicosynylene)bis(3,6-
dimethoxy-p-benzoquinone) This compound will hereinafter be referred to as compound c. Physical properties of compound c Yellow oil PMR δ ppm (CDC ₃ ) 5.72 (2H, s) 4.04 (6H, s) 3.80 (6H, s) 2.42 (4H, t, J = 7.3Hz) 2.12 (4H, t, J = 7.3Hz) 1.7-1.2 (28H, brm) Example 3 Compound H obtained in Reference Example 8 was dissolved in 200ml of methanol, and a small amount of sodium bicarbonate was added to the mixture.
Heat to ℃. The reaction was allowed to proceed for 2 hours while passing oxygen, and the solvent was distilled off under reduced pressure, followed by silica gel column chromatography (developing solution: 10% ethyl acetate-n-hexane) to obtain a yellow oil. This was crystallized from ethanol-water to obtain 4.36 g of 2,2'-pentamethylenebis(3,6-dimethoxy-5-methyl-p-benzoquinone) in the form of yellow needles. This compound is hereinafter referred to as . Physical properties of the compound Yellow needle crystals Melting point 84-86℃ PMR δ ppm (CDC ₃ ) 3.99 (12H, s) 2.40 (4H, brt, J=7.3Hz) 1.91 (6H, s) 1.40 (6H, brm) Implementation Example 4 426 mg of compound G ₂ obtained in Reference Example 7 was dissolved in 5 ml of tetrahydrofuran and 5 ml of isopropanol, and 1 ml of 20% hydrogen chloride-tetrahydrofuran-isopropanol (1:1) was added in a nitrogen stream.
Stir at room temperature for 12 hours. After removing the solvent under reduced pressure, a colorless powder is obtained. Methanol 20 without purifying this
ml, add a small amount of sodium bicarbonate, heat to 60°C, stir for 2 hours while passing oxygen, remove the solvent under reduced pressure, and perform preparative thin layer chromatography (developing solution: 40% ethyl acetate-n-hexane). ) to give a yellow powder of 2,5-dimethoxy-3-methyl-
262 mg of 6-[5-(2,5-dimethoxy-p-benzoquinonyl)bentyl]-p-benzoquinone are obtained. Hereinafter, this compound will be referred to as a compound. Physical properties of compound Yellow powder melting point 48-49℃ PMR δ ppm (CDC ₃ ) 5.72 (1H, s) 4.05 (3H, s) 3.98 (6H, s) 3.79 (3H, s) 2.43 (2H, t, J= 7.8Hz) 4.39 (2H, t, J = 7.8Hz) 1.91 (3H, s) 1.45-1.25 (6H, brm) Example 5 402 mg of compound I ₂ obtained in Reference Example 9 was mixed with 4 ml of tetrahydrofuran and 4 ml of isopropanol. Dissolve in a solvent, add 0.8 ml of 20% hydrogen chloride (in tetrahydrofuran-isopropanol (1:1) mixed solvent) under ice cooling, and stir for 5 hours while heating in a 50°C water bath. After concentration, add benzene and perform the concentration operation three times. After dissolving in 10 ml of methanol, add a small amount of sodium hydrogen carbonate and heat on a water bath to 50-60°C while blowing oxygen gas. After 5 hours of reaction, it was overconcentrated, and then subjected to thin layer chromatography (2 sheets of silica gel, 20 x 20 cm, 2 mm thick, ethyl acetate:benzene = 1:1), and crystallized with petroleum ether. '-Pentamethylenebis[2-(2-
hydroxyethyl)-3,6-dimethoxy-p-
Obtain 305 mg of benzoquinone. This compound will hereinafter be referred to as compound a. Physical properties of compound a Yellow needle crystals Melting point 97-99℃ PMR δ ppm (CDC ₃ ) 4.00 (6H, s) 3.96 (6H, s) 3.67 (4H, t, J = 7.5Hz) 2.68 (4H, t, J=7.5Hz) 2.35 (4H, brt, J=6.5Hz) 1.2-1.5 (6H, m) Pharmacological test 5-Lipoxygenase inhibitor in J.Biol,
Chem., 256, 4156-4159, 258, 5754-5758. Preparation of cells: Hartley guinea pigs (body weight 500-650 g) were intraperitoneally administered with 2% casein at a volume of 3/50 of their body weight, and 14 hours after administration, they were exsanguinated to death and placed in Dalpetz choline buffer containing 3 U/ml heparin. (PBS)
(-) Wash the peritoneal cavity with 50 ml to collect infiltrated cells. After washing the cells twice with Dalpetsuko PBS (-),
Suspend in Dalpetsuko PBS (-) containing 1mM CaCl ₂ and 5.5mM glucose to a concentration of 2.5×10 ⁷ cells/ml. Enzyme reaction Add 10 ^-5 M indomethacin to 0.2 ml of the above cell suspension and incubate at 30°C for 2 minutes, then add the test compound at each concentration and incubate for an additional 2 minutes. after that
10 μMionophore A 23187 (Calbiochem-
(manufactured by Behring.), followed by 10 μm ⁻¹⁴ C-arachidonic acid (manufactured by Amersham) to start the reaction. 3
After a minute, add 0.1ml of 0.2M citric acid to stop the reaction.
Add another 1.2 ml of ethyl acetate and shake for 5 minutes. Centrifuge at 3000 rpm for 5 minutes to separate the organic and aqueous layers. 1 ml of the upper organic layer is dehydrated by passing it through a minicolumn packed with sodium sulfate. The dehydrated organic layer is dried under a nitrogen stream. the residue
After dissolving in 60μ of ethyl acetate, the entire volume is applied to a TLC plate (Merck 11845). The plate was prepared using ethyl ether: petroleum ether: acetic acid (50:50:
1v/v) and exposed to X-ray film (LKB
Confirm the location of each metabolite using Ultrafilm ³ H). Scrape each fraction and place it in a scintillation vial.
Add 5 ml of Amersham) and measure the radioactivity using a liquid scintillation counter. The enzyme activity is expressed as the inhibition rate (%) of the production of arachidonic acid into a metabolite [5-hydroxyeicosatetraenoitsucic acid (5-HETE)]. Furthermore, the IC ₅₀ of nordihydroguaialentinic acid (NDGA) in this reaction system
is 1-2 μM. The results are shown in Table 1.

[Table] Pharmacology Test Anderson (Int.Archs Allergy appl.
Immunol., 64 249-258, 1981), 30 mg/Kg of cyclophosphamide was intraperitoneally administered to male Hartley guinea pigs weighing approximately 300 g, and 2 days later, 1 μg of ovalbumin ( (manufactured by Sigma) was intraperitoneally administered together with 10 mg of aluminum hydroxide gel for sensitization. On the 50th day of sensitization, the lungs were removed from exsanguinated guinea pigs, refluxed with 20 ml of Tyrode's solution, and then placed in ice-cold Tyrode's solution. McIlwain tissue
The lungs were sliced into approximately 2 mm squares using a chopper and washed with ice-cold Tyrode's solution. Suspend 400 mg of lung sections in 3.6 ml of Tyrode's solution, pre-incubate at 37°C for 5 minutes, add 4 μ of drug solution dissolved in dimethyl sulfoxide or solvent alone in the case of control, and after 5 minutes add 100 μg/ml. 0.4 ml of ovalbumin was added to release SRS-A for 10 minutes. After cooling the tissue suspension on ice, pass it through gauze and incubate at 2000 rpm for 10 minutes.
The supernatant was collected by centrifugation for a minute. The supernatant was stored frozen at -80°C until bioassay. The amounts of SRS-A and histamine contained in the supernatant were bioassayed using guinea pig ileum pieces. A piece of ileum (2 to 3 cm) from 15 to 25 cm on the oral side of the ileocecal region was removed from a male Hartley guinea pig weighing 400 to 600 g that had been fasted overnight and filled with 10 ml of Tyrode's solution containing 10 ^-7 M atropine sulfate. The tube was suspended in a Magnus tube with air ventilation, and isotonic contraction under a load of 0.5 g was measured using an isotonic transducer (manufactured by Nihon Kohden, TD-112S). Measurements were performed after the reactivity to histamine had stabilized. In the case of histamine, the contraction observed within 30 seconds after addition of the supernatant was used for quantification. Also, SRS-A
In the case of 10 ^-6 M pyrilamine (manufactured by Sigma), the contraction observed within 2 minutes after addition of the supernatant was quantified by comparing it with a standard curve of crude SRS-A derived from lung sections. The results are shown in Table 2.

【table】

[Table] Pharmacological test SRS in rat peritoneal anaphylaxis
A. Histamine Release Inhibition Test Six to seven week old male or female Sprang Dowley rats (Charles River Japan) were divided into groups of 6 rats based on body weight and fasted overnight. Experiments begin with oranges (J. Immumol., 105,
1087-1095, 1970). Rats were sensitized by intraperitoneal injection of a 2-fold dilution of rat anti-ovalbumin serum in an amount of 1 ml/rat. 2 mg of ovalbumin and 2 hours after sensitization.
Anaphylaxis was induced by intraperitoneally administering 5 ml of Tyrode's solution containing 250 μg of heparin sodium. After 5 minutes, the rat was bled to death by hitting the back of the head and making a neck incision. After another 5 minutes, peritoneal fluid was collected from the incision in the rat's abdominal wall, and the collected fluid was
The supernatant was collected by centrifugation at 800 rpm and then 2500 rpm at -80 °C until bioassay.
Store at ℃. The drug was suspended in 5% gum arabic solution and was used to induce anaphylaxis at a rate of 5 ml/Kg.
Administered orally in advance. As a control, only 5% gum arabic solution was administered. The amounts of histamine and SRS-A contained in the collected liquid were measured in the same manner as in the pharmacological test. Bioassay of the collected fluid was performed using guinea pig ileum treated with atropine. An ileum piece (2 to 3 cm) from 15 to 25 cm on the oral side of the ileocecal region was removed from a guinea pig that had been fasted overnight and placed in an organ bath at 32°C filled with 10 ml of Tyrode's solution containing -10 ^-7 M atropine sulfate. Suspended under air ventilation. Isotonic contraction under a load of 0.5 g was recorded on an ink recorder using an isotonic transducer (TD-112S, manufactured by Nihon Kohden). After stabilizing the contraction reaction caused by histamine, the amount of histamine was quantified by observing the contraction that occurred within 30 seconds after adding 0.05 to 0.4 ml of the collection liquid. Also 10−7M pyrilamine (antihistamine)
The amount of SRS-A was determined by converting the contraction observed after adding 0.2 to 0.5 ml of the collected solution into the presence of 5 mg histamine as 1 unit (V) of contractile activity. The antiserum used in this study was obtained by intramuscularly injecting 1 mg ovalbumin into 8-week-old SD rats.
Anti-ovalbumin serum collected on the 14th day after intraperitoneal injection of 100 million killed B. pertussis bacteria, and 48-hour PCA
In the reaction, the titer was 256 times higher, and the titer was reduced to less than 4 times by heat treatment at 56°C for 2 hours. Histamine and
Table 3 shows the inhibition rate of SRC-A.

[Table] Formulation Example 1 Compound Ia 20mg Starch 130mg Magnesium Stearate 10mg Lactose 40mg Total 200mg Tablets of the above composition were prepared in one tablet by a conventional method. Formulation Example 2 Compound Ic 10mg Starch 127mg Magnesium Stearate 18mg Lactose 45mg Total 200mg Tablets of the above composition were prepared in one tablet by a conventional method. Formulation Example 3 Compound a 10 mg Starch 127 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets of the above composition were manufactured in a conventional manner. Formulation Example 4 Compound 1.0g Sorbitan Monoseschelate 3.0g Freon 11 1.5g Freon 12 3.5g Total 9.0g A spray of the above composition was prepared in one cylinder by a conventional method. Production Example 5 Compound 1.0g Oleic acid 3.0g Freon 11 1.25g Freon 12 2.5g Freon 114 1.25g Total 9.0g A spray of the above composition was produced in one cylinder by a conventional method.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ , R ³ , R ⁴ and R ⁶ each represent a lower alkyl group. R ² and R ⁵ represent a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group. A
is a _C5 to _C12 alkylene group or -B-C≡C-D
- indicates a group. Here, B and D are respectively C ₁ to C ₁₀
represents an alkylene group. ] A 1,4-benzoquinone derivative represented by: