JPH0473436B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to flavone derivatives, more specifically, the general formula () [In the formula, R ¹ represents a lower alkoxy group, and R ² and R ³ each represent an alkoxy group having 1 to 12 carbon atoms. ] Regarding the flavone derivative represented by these and its salt. Disclosure of the Invention The compound of the present invention represented by the above general formula () significantly inhibits arachidonic acid 5-lipoxygenase (hereinafter abbreviated as "5-lipoxygenase"), which is responsible for the biosynthesis of leukotrienes, and inhibits arachidonic acid 5-lipoxygenase. It is useful as a 5-lipoxinase inhibitor (hereinafter referred to as a "5-lipoxinase inhibitor"). Asthma is a condition in which a patient with high airway hyperresponsiveness causes increased vascular permeability, bronchial smooth muscle contraction, increased secretion, etc. due to external allergens or non-specific stimuli (cold, dry, etc.) to the airways, resulting in difficulty breathing. It is a disease that causes 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 the secondary signal transmitter 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 signal transduction effect. Antihistamines reduce bronchial mucosal edema and swelling caused by increased vascular permeability by antagonizing histamine at histamine _H1 receptors. 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,
Slow-reacting anaphylactic substances were considered to be the main causative agents of asthma.
The substance of anaphylaxis (hereinafter abbreviated as "SRS-A") was identified, leading to the discovery of leukotrienes [RCMurphy et al, Proc. Nat. Acad.
Sci.USA, 76 , 4275 (1979), B. Sanmelsson.
Science, 220 , 568 (1983), Shozo Yamamoto, Japan Clinical,
41, 1934 (1983)]. According to this SRS-A, bronchial mucosal edema and swelling and bronchial smooth muscle contraction are observed due to increased vascular permeability, which are the main symptoms of asthma [RPOrange
and KFAusten, Advances in Immunology,
10, 105 (1969), P. Borgeat and P. Sirois, J.
Medicinal Chem., 24 , 121 (1981), Shigekatsu Kono,
[See Katsuya Ohata, Metabolism, 20 , 317 (1983)] The present inventors have been conducting intensive research on the treatment of asthma and anti-asthma drugs for the same, and in the process, the above SRS-A It is synthesized from arachidonic acid, and 5-lipoxygenase is involved in its biosynthesis. By inhibiting the activity of 5-lipoxygenase, the production of SRS-A is suppressed, and this results in the treatment of asthma. Based on the idea that this would be possible, we proceeded with research on substances that have the above-mentioned 5-lipoxygenase inhibitory effect. the result,
The flavone derivative represented by the above general formula () is useful as a desired 5-lipoxygenase inhibitor, and its use allows for the inhibition of arachidonic acid.
It was discovered that SRS-A suppresses the production of SRS-A.
It has been discovered that various diseases caused by the production of -A, such as asthma, inflammation, allergies, etc., can be prevented and treated. The present invention was completed based on the above findings, and its gist is a flavone derivative represented by the general formula () and a salt thereof. The lower alkoxy group defined by R ¹ in the general formula () representing the flavone derivative according to the present invention includes, for example, a methoxy group, an ethoxy group,
propoxy group, isopropoxy group, butoxy group,
Examples include alkoxy groups having 1 to 6 carbon atoms such as pentyloxy group and hexyloxy group. The alkoxy group having 1 to 12 carbon atoms defined as R ² or R ³ includes methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, t-butoxy group, pentyloxy group, hexyloxy group, heptyloxy group , octyloxy group, nonyloxy group, decanyloxy group, undecanyloxy group, dodecanyloxy group, etc. The compound of the above general formula () can be synthesized by various methods, and can be easily produced, for example, by the method shown in the following reaction scheme. [In the formula, R ¹ to ^{R 3} are the same as above. R ⁴ and R ⁵ represent a benzyloxy group, and X represents a halogen atom. ] Publicly known or new general formula () in the above
The esterification reaction between the compound represented by the formula () and the known compound represented by the general formula () is carried out at 0 to 200°C, preferably at 80°C, without a solvent or in a common inert solvent.
The process is completed in about 1 to 8 hours at a temperature of ~130°C. Examples of inert solvents include aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane and heptane; ethers such as dioxane, tetrahydrofuran, and ethyl ether; pyridine, N,N-dimethylaniline, etc. Tertiary amines; dimethylformamide, dimethyl sulfoxide, etc. can be used. The above reaction is more advantageously carried out using a basic compound as dehydrohalogenating agent. Examples of the basic compound include tertiary amines such as triethylamine, tripropylamine, pyridine, quinoline, and N,N-diethylaniline. In addition, the ratio of the compound represented by the general formula () and the compound represented by the general formula () in the above is usually equal to or more, preferably 1 to 1.5 mol, of the latter to 1 mol of the former. In this way, an ester represented by the general formula () is obtained. The transfer reaction of the ester represented by the general formula () takes 2 to 10 hours in the presence of a basic compound in an inert solvent at room temperature to 100°C, which results in an intramolecular transfer reaction (Baker −
Venkataraman reaction) is carried out. Examples of the basic compound include potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium amide. The inert solvent is not particularly limited and can be widely used, such as aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dioxane, tetrahydrofuran, and diethyl ether;
Examples include aliphatic hydrocarbons such as hexane and heptane; and pyridine derivatives such as pyridine and picoline. In the above transfer reaction, the ratio of the basic compound to the compound of general formula () is usually 1
The amount of the latter may be about 1 to 30 moles per mole. In this way, a diketone compound represented by the general formula () is obtained. The ring-closing reaction of the above diketone compound () is carried out at room temperature to 150°C in the presence of a catalyst without a solvent or in a solvent.
It is carried out for about 2 to 15 hours under the temperature conditions of .
Examples of solvents include carboxylic acids such as formic acid, acetic acid, and propionic acid; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as ethyl ether, dioxane, and tetrahydrofuran; and alcohols such as methanol and ethanol. . Examples of the catalyst include sulfuric acid, hydrochloric acid, sodium acetate, potassium acetate, sodium propionate, and potassium propionate. In this way, a flavone derivative represented by the general formula () is obtained. In order to debenzylate the flavone derivative of the general formula () obtained above to obtain the compound of the general formula (), for example, a hydrogenolysis reaction using a catalyst in an inert solvent can be employed. As the catalyst here, a wide range of catalysts commonly used in the past, such as palladium-carbon, can be used, and the amount used is not particularly limited, and may be about the same amount as a normal catalyst. Examples of inert catalysts include alcohols such as methanol and ethanol, ethers such as ethyl ether and tetrahydrofuran, fatty acid esters such as ethyl acetate and ethyl propionate, carboxylic acids such as acetic acid and propionic acid, benzene, toluene, etc. aromatic hydrocarbons and the like. The reduction reaction is usually performed at room temperature to 50°C.
Generally, it takes about 1 to 5 hours to complete. The phosphorylation reaction of the compound of the general formula () thus obtained is carried out by reacting polyphosphoric acid with the compound in the absence of a solvent or in an appropriate solvent. As a solvent, aromatic hydrocarbons such as toluene and xylene, saturated hydrocarbons such as heptane and octane, carboxylic acids such as acetic acid and propionic acid,
Examples include halogenated hydrocarbons such as 1,2-dichloroethane. The amount of polyphosphoric acid to be used is usually at least an equimolar amount, preferably about 5 to 20 times the molar amount of the compound (in terms of phosphoric acid). Polyphosphoric acid can also be used as a solvent, and in this case it is preferable to use it in a large excess amount relative to the compound (). The reaction is usually 60
It is carried out at about 150°C, preferably about 90 to 120°C, and is generally completed in about 20 minutes to 2 hours. In this way, the compound of the present invention represented by the general formula () is produced. The compound of general formula () used as a starting material in the above reaction scheme is a known or new compound, and the compound is produced, for example, according to the following reaction scheme. [In the formula, R ¹ , R ² and R ³ are the same as above, A represents a substituted or unsubstituted phenylsulfonyl group, and B represents a benzyl group. ] First, phenylsulfonyl chloride is allowed to act on a known compound () by a conventional method to protect the hydroxyl group of the compound () to obtain the compound (). Next, compound () was added in an inert solvent at room temperature to 80°C.
After reacting for several hours in the presence of anhydrous aluminum halide in the temperature range of 0.degree. C., the compound () with the methoxy group cleaved is obtained by injecting it into dilute hydrochloric acid. The amount of aluminum halide to be used is preferably 1.5 to 3 times the molar amount of the compound (). The deprotection reaction of the compound () thus obtained is carried out by reacting in anhydrous potassium carbonate-methanol (potassium hydroxide, sodium hydroxide in water-containing methanol or ethanol) at room temperature to 80°C with stirring for 30 minutes to 3 hours. It is done. Compound (XI) is reacted with halogenated phenylmethylene in a conventional manner to obtain compound (XII) in which the hydroxyl group of compound (XI) is protected. Compound (XII) is mixed with acetic acid-hydrochloric acid (preferably 10:
1) Or the compound () is obtained in the same manner as the dealkylation reaction of the above compound () in a Lewis acid such as anhydrous aluminum chloride and an inert solvent. The ether reaction for obtaining compound () from compound () can be carried out by a normal ether reaction. The etherification reaction uses a linear or branched alkyl halide having 1 to 12 carbon atoms as an etherification agent, such as methane bromide, ethane iodide, butane bromide, isopentane chloride, hexane chloride, hexane iodide, It is carried out according to a conventional method using octane chloride, chlorodecane, iodide undecane, bromide dodecane, etc. In the etherification reaction, in the inert solvent used in the esterification reaction in the above reaction scheme, if necessary, a dehydrohalogenating agent such as an amine such as triethylamine, diisopropylethylamine, pyridine, N,N-diethylaniline, etc. Using inorganic salts such as potassium carbonate, sodium carbonate, etc., within the temperature range of room temperature to 150℃,
This process takes about 1 to 24 hours. The amount of etherification agent used is 1 mole of compound ().
The amount is preferably 1.2 to 2 mol, preferably 1.2 to 2 mol. Compound () is thus produced. Finally, compound () is produced by catalytic reduction of compound () or by performing a cleavage reaction with a mineral acid or a Lewis acid. For the catalytic reduction reaction, the same reaction conditions as for the hydrogenolysis reaction of compound () in the above reaction scheme can be adopted. The compound of the present invention obtained in the above reaction scheme can be converted into a pharmacologically acceptable alkali salt by treating it with an alkali such as sodium hydroxide or potassium hydroxide.
Such salts can also be used as active ingredients in the present invention. In each of the above steps, the target compound can be easily isolated and purified by ordinary separation means, such as solvent extraction, dilution, recrystallization, adsorption chromatography, and ion exchange chromatography. Examples include graphite, molecular sieve chromatography, and the like. The thus obtained flavone derivative represented by the general formula () and its salt both have the effect of inhibiting 5-lipoxygenase. The compounds of the present invention are characterized by a long duration of 5-lipoxygenase inhibitory action, low toxicity, and few side effects, and therefore the compounds of the present invention are extremely useful as 5-lipoxygenase inhibitors.
Furthermore, by utilizing their remarkable 5-lipoxygenase inhibitory action, they are promising as preventive or therapeutic agents for symptoms such as asthma, inflammation, and allergies. For example, when the compound of the present invention is administered into a living body, it can exhibit excellent therapeutic effects on symptoms such as asthma, inflammation, and allergy. The compound of general formula () and its salts 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, granules, capsules, suppositories,
Examples include injections (solutions, suspensions, etc.). When forming tablets, a wide variety of carriers known in this field can be used, including excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid. agent, water, ethanol, propanol, simple syrup, glucose solution, starch solution,
Binders such as gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dried starch,
Sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, white sugar, stearin, cocoa butter, hydrogenated oil disintegration inhibitors such as quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, pentonite, colloidal silicic acid, purified talc, Examples include lubricants such as stearate, 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 range of conventionally known carriers can be used, such as excipients such as glucose, lactose, starch, cacao butter, hardened vegetable fat, kaolin, and talc, powdered gum arabic, powdered tragacanth, etc. 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 injectables, solutions and suspensions are preferably sterile and isotonic with blood;
When forming these solutions, emulsions and suspensions, any diluent commonly used in this field can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters. 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, coloring agents, preservatives, fragrances, flavoring agents, sweeteners, and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary. In addition, when the above flavone derivatives and their salts are made into a spray, a wide variety of dispersants and propellants known in this field can be used. Examples of dispersants 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. In addition, as a spray agent, for example, Freon 11, Freon 12,
Examples include normally non-flammable liquefied gases such as Freon 114. The amount of the compound of general formula () or a salt thereof to be contained in a pharmaceutical preparation is not particularly limited and may be appropriately selected within a wide range, but is usually 1 to 70% in a pharmaceutical preparation.
% by weight, preferably from 1 to 30% by weight. 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. Further, the spray is administered to 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, the patient's age, sex and other conditions, the severity of the disease, etc., but the amount of the compound of general formula (), which is the active ingredient, is usually determined per day. weight 1
The amount is preferably 0.1 to 10 mg per kg. Reference examples, examples, pharmacological test results, and formulation examples are listed below. Reference Example 1 Synthesis of 3,4,6-trimethoxy-2-tosyloxyacetophenone 22 g of 3,4,6-trimethoxy-2-hydroxyacetophenone was dissolved in 150 ml of acetone, and 26 g of toluenesulfonyl chloride was finely ground. Add 39 g of potassium carbonate and reflux for 3 hours while stirring. Add water to the reaction mixture, filter out the precipitated crystals, and recrystallize from methanol to obtain mp127~
35.9 g (yield 97%) of 3,4,6-trimethoxy-2-tosyloxyacetophenone was obtained as white needle-like crystals at 129°C. Elemental analysis (as C ₁₈ H ₂₀ O ₄ S) Analysis value C56.89% H5.55% Calculated value C56.83% H5.30% Reference example 2 6-hydroxy-3,4-dimethoxy-2-tosyloxyacetate Synthesis of phenone Add 18 g of 3,4,6-trimethoxy-2-tosyloxyacetophenone to anhydrous aluminum bromide (25
g, 2 molar ratio) in acetonitrile (100 ml) and heated to 50°C for 2.5 hours. reaction mixture
After pouring into 0.1N hydrochloric acid, the acetonitrile is distilled off. The precipitate was recrystallized with a mixed solvent of ethyl acetate and methanol, and heated to mp127-128℃.
6-hydroxy-3, which is a white prismatic crystal of
14.8 g (yield: 86%) of 4-dimethoxy-2-tosyloxyacetophenone was obtained. Elemental analysis (as C ₁₇ H ₁₈ O ₇ S) Analysis value C55.64% H4.83% Calculated value C55.73% H4.95% Reference example 3 of 2,6-dihydroxy-3,4-dimethoxyacetophenone Synthesis 15 g of 6-hydroxy-3,4-dimethoxy-2-tosyloxyacetophenone was added to 150 g of methanol.
ml, add 30g of potassium carbonate to this,
Reflux for 3 hours with stirring. Place the reaction mixture on ice.
After injecting it into hydrochloric acid and washing the precipitated crystals with filtration and water, recrystallization was performed with methanol to obtain mp134~
2,6-dihydroxy- as yellow needle crystals at 135℃
6.5 g of 3,4-dimethoxyacetophenone (yield
75%). Elemental analysis (as C ₁₀ H ₁₂ O ₅ ) Analysis value C56.59% H5.66% Calculated value C56.60% H5.70% Reference example 4 2,6-dibenzyloxy-3,4-dimethoxyacetophenone Synthesis of 6.49 g of 2,6-dihydroxy-3,4-dimethoxyacetophenone was dissolved in 100 ml of DMF (dimethylformamide), and 11.6 ml of benzyl chloride,
Add 38 g of potassium carbonate and reflux for 1 hour while stirring. Water is added to the reaction mixture to dissolve potassium carbonate, and the solvent is distilled off under reduced pressure. After repeating the same operation to remove as much benzyl chloride as possible, the precipitated crystals were filtered and recrystallized with a mixed solvent of ethyl acetate and methanol, mp114-115℃.
White needle-like crystals of 2,6-dibenzyloxy-3,
4-dimethoxyacetophenone 10.36g (yield 86
%). Elemental analysis (as C ₂₄ H ₂₄ O ₅ ) Analysis value C73.58% H6.11% Calculated value C73.45% H6.16% Reference example 5 6-benzyloxy-2-hydroxy-3,4
-Synthesis of dimethoxyacetophenone 10.36 g of 2,6-dibenzyloxy-3,4-dimethoxyacetophenone was dissolved in 200 ml of acetic acid-hydrochloric acid mixture (10:1), and then left at room temperature for 1 hour. Water is added to the reaction mixture, and the precipitated crystals are filtered and washed with water. Recrystallize with a mixed solvent of ethyl acetate and methanol to obtain 6-benzyloxy-2-hydroxy- as yellow needle-like crystals at mp 134-135℃.
7.05 g of 3,4-dimethoxyacetophenone (yield
88%). Elemental analysis (as C ₁₇ H ₁₈ O ₅ ) Analysis value C67.52% H5.99% Calculated value C67.54% H6.00% Reference example 6 2-hexyloxy-6-hydroxy-3,4
Synthesis of -dimethoxy-ω-(3,4-dibenzyloxybenzoyl)acetophenone 6-benzyloxy-2-hydroxy-3,4
-Dimethoxyacetophenone 2g (6.6mmol)
was dissolved in about 30 c.c. of acetone, 7.3 mmol of hexyl iodide (1.1 molar ratio) was added, and the solution was dissolved with stirring.
Reflux for 15 hours. Water was added to the reaction mixture, the precipitated oil was extracted with ether, washed with water, the ether was distilled off, and the residue was thoroughly dried in a desiccator to obtain the crude hexyl ether 6-
Benzyloxy-2-hexyloxy-3,4-
Dimethoxyacetophenone is obtained. The crude hexyl ether is dissolved in about 30 ml of acetic acid-hydrochloric acid mixture (10:2) and heated to 50°C for 30 minutes.
Water was added to the reaction mixture, the produced benzyl chloride was distilled off by steam distillation, the precipitated oil was extracted with ether, washed with water, the ether was distilled off, the oil was dried, and the crude hydroxyacetophene was extracted. Non-isomer 6-hydroxy-2-hexyloxy-3,4-dimethoxyacetophenone is obtained. Crude hydroxyacetophenone and 3,4-
Dibenzyloxybenzoyl chloride 8mmol
(1.2 molar ratio) was dissolved in pyridine and heated at 120°C for 2 hours. The reaction mixture was poured into ice-hydrochloric acid,
The precipitated oil is extracted with ethyl acetate. The ethyl acetate layer is washed with 5% potassium carbonate solution and then with water. After distilling off the ethyl acetate and drying, a crude ester is obtained. Dissolve this ester in 10ml of pyridine, add 5-6g of crushed potassium hydroxide, and stir while stirring.
Heat to 60°C for 3-4 hours. The reaction mixture was poured into ice-hydrochloric acid, and the precipitated oil was extracted with ethyl acetate. The ethyl acetate layer was washed with 5% potassium carbonate and then with water, dried, and then the ethyl acetate was distilled off. The residue was recrystallized from a mixed solvent of ethyl acetate and methanol to give yellow prism crystals of 2-hexyloxy-6-hydroxy-3,
4-dimethoxy-ω-(3,4-dibenzyloxybenzoyl)acetophenone 1.83g (3mmol
A yield of 55% was obtained. Elemental analysis (as C ₃₇ H ₄₀ O ₈ ) Analysis value C72.40% H6.65% Calculated value C72.53% H6.58% Reference example 7 2-dodecyloxy-6-hydroxy-3,4
Synthesis of -dimethoxy-ω-(3,4-dibenzyloxybenzoyl)acetophenone 6-benzyloxy-2-hydroxy-3,4
-Dimethoxyacetophenone 2g (6.6mmol)
The same reaction as in Reference Example 6 was performed from mp79 to
80℃, yellow needle-like crystals of 2-dodecyloxy-6-
Hydroxy-3,4-dimethoxy-ω-(3,4
-dibenzyloxybenzoyl)acetophenone
1.16 g (2 mmol yield 25%) was obtained. Elemental analysis (as C ₄₃ H ₅₂ O ₈ ) Analysis value C74.09% H7.47% Calculated value C74.11% H7.52% Reference example 8 3',4'-dibenzyloxy-5-hexyloxy-6 Synthesis of ,7-dimethoxyflavone 2-hexyloxy-6- obtained in Reference Example 6 above
Hydroxy-3,4-dimethoxy-ω-(3,4
-dibenzyloxybenzoyl)acetophenone
Dissolve 1.6g (2.6mmol) in 15ml of acetic acid, add 1.7g (0.02mol) of anhydrous sodium acetate,
Reflux at 140°C for 2 hours. The reaction mixture was poured into ice water, and the precipitated oil was extracted with ethyl acetate. The ethyl acetate layer was washed with 5% potassium carbonate and then with water, dried, and then the ethyl acetate layer was distilled off. N-hexane was added to the residue, followed by crystallization and filtration to obtain 3',4'-dibenzyloxy-5-hexyloxy-6,7-dimethoxyflavone (yield 92%). Physical properties Melting point 89~90℃ Properties White needle crystal elemental analysis (as C ₃₆ H ₃₆ O ₆ ) Analysis value C74.83% H6.31% Calculated value C74.73% H6.44% Reference example 9 3', 4 Synthesis of '-dibenzyloxy-5-dodecyloxy-6,7-dimethoxyflavone 2-dodecyloxy-6- obtained in Reference Example 7 above
Hydroxy-3,4-dimethoxy-ω-(3,4
-Dibenzyloxybenzoyl)acetophenone was treated in the same manner as in Reference Example 8 and recrystallized from ethyl acetate-hexane to form white needle-like crystals of 3',4'-dibenzyloxy-5-dodecyloxy-6,7 -Dimethoxyflavone was obtained. Melting point 78-79℃ Reference example 10 5-hexyloxy-3',4'-dihydroxy-
Synthesis of 6,7-dimethoxyflavone 1 mmol of 3',4'-dibenzyloxy-5-hexyloxy-6,7-dimethoxyflavone obtained in Reference Example 8 was dissolved in methanol, and 10%
Add palladium-carbon (200 mg) and stir at room temperature.
After hydrogenolysis for an hour, the palladium-carbon was removed, the mother liquor was concentrated, and the residue was recrystallized from methanol-ethyl acetate to give 5-hexyloxy-
3',4'-dihydroxy-6,7-dimethoxyflavone was obtained. Melting point 192-193℃ Properties Yellow needle-like crystals ¹ H-NMR (DMSO-d ₆ ) δppm 9.52 (2H, br.s) 7.38 (1H, d, J = 2.2Hz) 7.36 (1H, dd, J ₁ = 8.2 Hz, J ₂ = 2.2Hz) 7.09 (1H, s) 6.88 (1H, d, J = 8.2Hz) 6.46 (1H, s) 3.93 (3H, s) 3.91 (2H, t, J = 6.5Hz) 3.74 ( 3H, s) 1.73 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.44 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.30 (4H, m) 0.87 (3H, t, J=6.9Hz) UV λ (ethanol, max): 265nm (ε=2.09×
¹⁰⁴ ), 337nm (ε=2.58× ¹⁰⁴ ) λ (ethanol-sodium acetate, max): 263n
m, 318nm, 395nm Reference example 11 5-dodecyloxy-3',4'-dihydroxy-
Synthesis of 6,7-dimethoxyflavone The 3',4'-dibenzyloxy-5-dodecyloxy-6,7-dimethoxyflavone obtained in Reference Example 9 was treated in the same manner as in Reference Example 10, and then re-treated with methanol. Crystallization gave white prismatic 5-dodecyloxy-3',4'-dihydroxy-6,7-dimethoxyflavone. Melting point 150-151℃ ¹ H-NMR (DMSO-d ₆ ) δppm 9.54 (2H, br.s) 7.39 (1H, d, J = 2.2Hz) 7.38 (1H, dd, J ₁ = 8.2Hz, J ₂ = 2.2Hz) 7.11 (1H, s) 6.89 (1H, d, J = 8.2Hz) 6.47 (1H, s) 3.94 (3H, s) 3.93 (2H, t, J = 6.5Hz) 3.74 (3H, s) 1.74 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.45 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.24 (16H, m) 0.85 (3H, t, J = 7.3 Hz) UV λ (ethanol, max): 265nm (ε=2.08×
¹⁰⁴ ), 337nm (ε=2.63× ¹⁰⁴ ) λ (ethanol-sodium acetate, max): 265n
m, 318nm, 395nm Example 1 5-hexyloxy-3'-hydroxy-6,7
Synthesis of -dimethoxy-4'-phosphonooxyflavone 5-hexyloxy-3' obtained in Reference Example 10 above,
4'-dihydroxy-6,7-dimethoxyflavone
500 mg and 19 g of polyphosphoric acid were mixed and heated and stirred at 90°C for 20 minutes. Add 30 g of ice to the reaction mixture and stir to decompose the polyphosphoric acid, then add 10 ml of ethyl acetate.
Add to
It was left for 16 hours. Collect the yellow precipitate and add it to water.
After washing with 10 ml, the residue was air-dried and then dried under reduced pressure to obtain 361 mg of 5-hexyloxy-3'-hydroxy-6,7-dimethoxy-4'-phosphonooxyflavone in the form of yellow needles. Melting point 212-213℃ ¹ H-NMR (DMSO-d ₆ ) δppm 7.80 (1H, br.s) 7.69 (1H, dd, J ₁ = 8.6Hz, J ₂ = 2.2Hz) 7.11 (1H, s) 7.03 ( 1H, d, J = 8.6Hz) 6.55 (1H, s) 3.95 (3H, s) 3.94 (2H, t, J = 6.5Hz) 3.75 (3H, s) 1.75 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.46 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.32 (4H, m) 0.89 (3H, t, J = 6.9Hz) UV λ (ethanol, max): 266nm (ε=2.12×
¹⁰⁴ ), 327nm (ε=2.84× ¹⁰⁴ ) λ (ethanol-sodium acetate, max): 265n
m, 333 nm The chemical structure of the compound obtained above was estimated from the above data. First, in the UV spectrum, there is a significant bathochromic shift accompanying the pH change from the acidic side to the alkaline side of the solution (when a normal flavone has a hydroxyl group at the 4' position, the maximum absorption band around 330 to 350 nm in acidic conditions is alkaline). Since the 4'-position of the flavone skeleton was not observed, it is thought that the 4' position of the flavone skeleton was phosphorylated. Also, when PH titrated with 0.1N sodium hydroxide,
As a result of calculating the consumption amount of 0.1 sodium hydroxide from the titration curve, it was confirmed that one phosphoric acid was bound. Furthermore, it was estimated from the NMR spectrum data that the compound obtained above was 5-hexyloxy-3'-hydroxy-6,7-dimethoxy-4'-phosphonooxyflavone. The NMR spectrum of the obtained compound is shown in Figure 1, the UV spectrum in Figure 2, and the IR spectrum in Figure 3, respectively. Example 2 5-hexyloxy-3'-hydroxy-6,7
-Synthesis of disodium salt of dimethoxy-4'-phosphonooxyflavone 5-hexyloxy-3'- obtained in Example 1 above
360 mg of hydroxy-6,7-dimethoxy-4'-phosphonooxyflavone in 40 ml of methanol and 10 ml of water.
Suspend in 0.1N aqueous sodium hydroxide solution.
Added 14.5ml. The resulting solution was filtered through activated carbon, the liquid was concentrated under reduced pressure, ethanol was added, water was azeotropically removed, and the mixture was dried to give 5-hexyloxy-3'-, which is a hygroscopic pale yellow powder. 390 mg of disodium salt of hydroxy-6,7-dimethoxy-4'-phosphonooxyflavone was obtained almost quantitatively. ¹ H-NMR (D ₂ O) δppm 7.54 (1H, s) 7.25 (1H, d, J = 8.2Hz) 6.77 (1H, s) 6.76 (1H, d, J = 8.2Hz) 6.29 (1H, s) 3.78 (2H, t, J = 6.5Hz) 3.77 (3H, s) 3.71 (3H, s) 1.67 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.34 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.22-1.24 (2H, m) 0.79 (3H, t, J = 7.3Hz) UV λ (ethanol, max): 265nm (logε4.11) λ (ethanol-sodium acetate, max) ):263n
m (logε4.10) λ (ethanol-hydrochloric acid, max): 267nm
(logε4.13) The chemical structure of the compound obtained above was estimated from the above data. First, in the UV spectrum, there is a significant bathochromic shift associated with the pH change from the acidic side to the alkaline side of the solution (usually when there is a hydroxyl group at the 4' position of the flavone,
Since the maximum absorption band around 330 to 350 nm in acidic conditions shifted to around 400 nm when changing to alkaline conditions was not observed, it is thought that the 4' position of the flavone skeleton was phosphorylated. Further, based on the NMR spectrum data and the physical property data of Example 1, the compound obtained above is a disodium salt of 5-hexyloxy-3'-hydroxy-6,7-dimethoxy-4'-phosphonooxyflavone. estimated that. The NMR spectrum and UV spectrum of the obtained compound are shown in FIG. 4 and FIG. 5, respectively. Example 3 5-dodecyloxy-3'-hydroxy-6,7
Synthesis of -dimethoxy-4'-phosphonooxyflavone 5-dodecyloxy-3' obtained in Reference Example 11 above,
4'-dihydroxy-6,7-dimethoxyflavone
50 mg of polyphosphoric acid and 2.5 g of polyphosphoric acid were mixed and treated in the same manner as in Example 1 to obtain yellow needle-like crystals of 5-dodecyloxy-3'-hydroxy-6,7-dimethoxy-
43 mg of 4'-phosphonooxyflavone was obtained. Melting point 191-192℃ ¹ H-NMR (DMSO-d ₆ ) δppm 7.81 (1H, br.s) 7.69 (1H, dd, J ₁ = 8.2Hz, J ₂ = 2.2Hz) 7.11 (1H, s) 7.04 ( 1H, d, J = 8.2Hz) 6.54 (1H, s) 3.95 (3H, s) 3.93 (2H, t, J = 6.5Hz) 3.75 (3H, s) 1.75 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.45 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.24 (16H, m) 0.85 (3H, t, J = 6.9Hz) UV λ (ethanol, max): 266nm (ε=2.20×
¹⁰⁴ ), 326nm (ε=3.08× ¹⁰⁴ ) λ (ethanol-sodium acetate, max): 265n
m, 332 nm The NMR spectrum of the obtained compound is shown in FIG. 6, the UV spectrum is shown in FIG. 7, and the IR spectrum is shown in FIG. 8. Example 4 6-hexyloxy-3'-hydroxy-5,7
-Synthesis of dimethoxy-4'-phosphonooxyflavone 6-hexyloxy-3',4'-dihydroxy-
5,7-dimethoxyflavone 50mg and polyphosphoric acid
2.4 g were mixed and treated in the same manner as in Example 1 to obtain 35 mg of 6-hexyloxy-3'-hydroxy-5,7-dimethoxy-4'-phosphonooxyflavone in the form of yellow needles. Melting point 181-183℃ ¹ H-NMR (DMSO-d ₆ ) δppm 7.80 (1H, br.s) 7.68 (1H, dd, J ₁ = 8.6Hz, J ₂ = 2.2Hz) 7.07 (1H, s) 7.03 ( 1H, d, J = 8.6Hz) 6.55 (1H, s) 3.94 (3H, s) 3.91 (2H, t, J = 6.5Hz) 3.75 (3H, s) 1.68 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.46 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.32 (4H, m) 0.89 (3H, t, J = 6.9Hz) UV λ (ethanol, max): 273nm (ε=2.11×
10 ⁴ ), 329 nm (ε=2.75×10 ⁴ ) λ (ethanol-sodium acetate, max):
270 nm, 333 nm The NMR spectrum of the obtained compound is shown in FIG. 9, the UV spectrum in FIG. 10, and the IR spectrum in FIG. 11, respectively. Example 5 6-dodecyloxy-3'-hydroxy-5,7
-Synthesis of dimethoxy-4'-phosphonooxyflavone 6-dodecyloxy-3',4'-dihydroxy-
5,7-dimethoxyflavone 50mg and polyphosphoric acid
2.9 g were mixed and treated in the same manner as in Example 1 to obtain 38 mg of 6-dodecyloxy-3'-hydroxy-5,7-dimethoxy-4'-phosphonooxyflavone in the form of yellow needles. Melting point 183-185℃ ¹ H-NMR (DMSO-d ₆ ) δppm 7.81 (1H, br.s) 7.70 (1H, dd, J ₁ = 8.2Hz, J ₂ = 2Hz) 7.12 (1H, s) 7.03 (1H , d, J = 8.2Hz) 6.57 (1H, s) 3.94 (3H, s) 3.91 (2H, t, J = 6.5Hz) 3.79 (3H, s) 1.67 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.45 (2H, tt, J ₁ = 6.5Hz, J ₂ = 6.5Hz) 1.24 (16H, m) 0.85 (3H, t, J = 6.9Hz) UV λ (ethanol, max): 266nm ( ε=2.08×
¹⁰⁴ ), 330nm (ε=2.95× ¹⁰⁴ ) λ (ethanol-sodium acetate, max): 266n
m, 333 nm The NMR spectrum of the obtained compound is shown in FIG. 12, the UV spectrum in FIG. 13, and the IR spectrum in FIG. 14, respectively. Example 6 3'-hydroxy-5,6,7-trimethoxy-
Synthesis of 4'-phosphonooxyflavone Mix 50 mg of 5,6,7-trimethoxy-3',4'-dihydroxyflavone and 2.5 g of polyphosphoric acid,
Thereafter, the same procedure as in Example 1 was carried out to obtain 3′-yellow needle-like crystals.
20 mg of hydroxy-5,6,7-trimethoxy-4'-phosphonooxyflavone was obtained. Melting point 218.5-219.5℃ ¹ H-NMR (DMSO-d ₆ ) δppm 7.82 (1H, br.s) 7.71 (1H, dd, J ₁ = 8.9Hz, J ₂ = 2.0Hz) 7.14 (1H, s) 7.04 ( 1H, d, J = 8.9Hz) 6.58 (1H, s) 3.96 (3H, s) 3.81 (3H, s) 3.77 (3H, S) UV λ (ethanol, max): 265nm (ε = 1.97×
¹⁰⁴ ), 327nm (ε=2.48× ¹⁰⁴ ) λ (ethanol-sodium acetate, max): 263n
m, 333 nm The NMR spectrum of the obtained compound is shown in Figure 15, the UV spectrum in Figure 16, and the IR spectrum in Figure 17, respectively. Formulation Example 1 Compound of Example 1 20 mg Starch 130 mg Magnesium Stearate 10 mg Lactose 40 mg Total 200 mg Tablets of the above composition were prepared in one tablet by a conventional method. Formulation Example 2 Compound of Example 1 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 of Example 2 10 mg Starch 127 mg Magnesium stearate 18 mg Lactose 45 mg form 200 mg Tablets containing the above composition were prepared in a conventional manner. Formulation Example 4 Compound of Example 1 1.0 g Sorbitan monoseschelate 3.0 g Freon 11 1.5 g Freon 12 3.5 g Total 9.0 g A spray of the above composition was prepared in one cylinder by a conventional method. Formulation Example 5 Compound of Example 1 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 prepared in one cylinder by a conventional method. [Pharmacological test] Preparation of anti-BPO-BGG guinea pig serum Prepared from penicillin G potassium [manufactured by Meiji Seika Co., Ltd.] and bovine gamma globulin [manufactured by Sigma Co., Ltd.] (benzylpenicilloyl) ₂₉ - bobaine gamma globulin [(BPO) ₂₉ - 1 ml of a Tris-buffered saline solution (PH8.2) containing 1 μg of BGG] and 1 mg of aluminum hydroxide was intraperitoneally administered once a month to female Hartley guinea pigs (weight 250-300 g, Shizuoka Laboratory Animal Agricultural Cooperative) for a total of 8 times. sensitized by injecting Two weeks after the final sensitization, blood was collected from the carotid artery.
BPO-BGG serum was obtained. The titer of this antiserum was evaluated for 7-day passive cutaneous anaphylaxis (7dayPCA).
It was measured by 4000 times. Experimental Asthma Method A guinea pig experimental asthma method was used, which was a modification of the Konzet-Rossler method. In other words, 4 days ago
Add 0.2 ml of BPO-BGG serum to male Hartley guinea pigs [weight 400-600 g, Shizuoka Experimental Animal Agricultural Association]
They were passively sensitized in advance by intravenous administration. The guinea pigs were anesthetized by intraperitoneal administration of 10 to 15 mg of pentobarbital sodium (Abot), and a cannula for drug and antigen administration was inserted into the jugular vein, and a cannula for connecting the tube from the artificial respirator to the trachea. inserted.
After additionally administering approximately 25 mg of pentobarbital intraperitoneally to stop spontaneous breathing, an artificial respirator (Harvard, model 860) was connected to the trachea and the respiratory rate was 4 ml/1 beat, 40 beats/min. I pumped air with it. Airway resistance can be measured by using a Broncospasm transducer [Ugo-
7020] and recorded on recording paper via an amplifier. After the guinea pig's airway resistance becomes almost constant due to artificial respiration, a physiological saline solution (this saline solution 2.5
ml is mepyramine maleate [manufactured by Sigma]
5 mg and cimetidine (manufactured by Sigma) was administered intravenously at a rate of 2.5 ml/Kg, and 20
After a minute, 80 μg/0.5 ml of the antigen solution was administered intravenously to induce a reaction. As a test compound, the compound obtained in Example 1 was intravenously administered at a rate of 5 mg/Kg 2 minutes before the initiation of the reaction. The relationship between the time after antigen administration and the maximum response % was determined, and the results are shown in FIG. The following can be seen from Fig. 18. That is, in the control group, almost no increase in airway resistance was observed 1 minute after the reaction was induced, but it rapidly increased thereafter and reached a nearly constant value after 7 minutes. Airway resistance after 7 minutes was approximately 50% of that at complete tracheal obstruction (maximum response). In contrast, in the group to which the compound obtained in Example 1 was administered, the airway resistance caused by this antigen induction was clearly suppressed, and the suppression rate was 50% or more at any time up to 30 minutes after the reaction induction. Ta.

[Brief explanation of drawings]

Figure 1 shows the NMR of the compound obtained in Example 1.
It is a spectrum diagram. FIG. 2 is a UV spectrum diagram of the compound obtained in Example 1. FIG. 3 is an IR spectrum diagram of the compound obtained in Example 1. FIG. 4 is an NMR spectrum diagram of the compound obtained in Example 2. FIG. 5 is a UV spectrum diagram of the compound obtained in Example 2.
FIG. 6 is an NMR spectrum diagram of the compound obtained in Example 3. FIG. 7 is a UV spectrum diagram of the compound obtained in Example 3. Figure 8 shows
FIG. 3 is an IR spectrum diagram of the compound obtained in Example 3. Figure 9 shows the compound obtained in Example 4.
It is an NMR spectrum diagram. FIG. 10 is a UV spectrum diagram of the compound obtained in Example 4.
FIG. 11 is an IR spectrum diagram of the compound obtained in Example 4. FIG. 12 is an NMR spectrum diagram of the compound obtained in Example 5. 13th
The figure is a UV spectrum diagram of the compound obtained in Example 5. FIG. 14 is an IR spectrum diagram of the compound obtained in Example 5. FIG. 15 is an NMR spectrum diagram of the compound obtained in Example 6. Figure 16 shows the compound obtained in Example 6.
It is a UV spectrum diagram. FIG. 17 shows Example 6
FIG. 2 is an IR spectrum diagram of a compound obtained in FIG. FIG. 18 is a graph showing the relationship between time after antigen administration and maximum response %.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a lower alkoxy group, and R ² and R ³ each represent an alkoxy group having 1 to 12 carbon atoms. ] A flavone derivative represented by these and its salt.