JPS6236391A - Novel flavone derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> is lower alkoxy; R<2> and R<3> are 1-12C aloxy) and its salt. EXAMPLE:5-Hexyloxy-3'-hydroxy-6,7-dimethoxy-4'-phosphonoxyflavone. USE:A preventive and remedy for athema, inflammation, allergy, etc. PREPARATION:For example, a well-known or novel compound (e.g., 6-hydroxy-2- hexyloxy-3,4-dimethoxyacetophenone, etc.,) shown by the formula II is reacted with a compound (e.g., 3,4,-dibenzyloxybenzoyl chloride, etc.,) shown by the formula III (R<4> and R<5> are benzyloxy; X is halogen) to give a compound shown by the formula IV and this compound is subjected to rearrangement reaction to give a compound shown by the formula V. Then, this compound is subjected to ring closure, debenzylated, to give a compound shown by the formula VI and this compound is phosphorylated with a solvent amount of polyphosphoric acid preferably at 90-120 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to flavone derivatives, more specifically, flavone derivatives having the general formula (I>(I> This invention relates to flavone derivatives and salts thereof represented by [indicates an alkoxy group].

The compound of the present invention represented by the above general formula (I>) is arachidonic acid 5-lipoxygenase (hereinafter abbreviated as "5-lipoxygenase") which is responsible for the biosynthesis of leukotrienes.
It is useful as an arachidonic acid 5-lipoxygenase inhibitor (hereinafter referred to as "5-lipoxygenase inhibitor").

Asthma is a condition in which a patient with high airway hyperresponsiveness causes vascular permeability, bronchial smooth muscle contraction, secretion, etc. due to external allergens or nonspecific stimuli (cold, dry, etc.) to the airways. It is 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 has yet been established to achieve sufficient therapeutic effects.

Currently, the most commonly used anti-asthmatic drugs are:
These 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.

``In other words, beta-receptor stimulants increase the enzymatic activity of adenyl nicrapi, converting ATP to the secondary signal transmitter C-A.
Change to MP. Xanthine agents dilate the bronchus by inhibiting the activity of phosphogesterase, which prevents the conversion of c-AMP to 5-AMP, which has no signal transduction effect. Antihistamines reduce bronchial mucosal edema and swelling caused by hexagonal 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.

In addition, as research into asthma treatment progresses, slow-reacting anaphylactic substances (31ow reacting substances), which were considered to be the main causative agents of asthma, have become increasingly important.
e of anaphylaxis or less rsR3-AJ
(abbreviated as ) was identified, and biko1~lien was discovered (RoC, Murphy et al, proc
, Nat.

Acad, Sci, USA, 76.4275 (197
9) , B. Sanmelsson, 3ci
ence.

220.568 (1983), Shozo Yamamoto, Japan Clinic,
41, 1934 (1983)].

According to this 5R3-A, edema and swelling of the bronchial mucosa and contraction of bronchial smooth muscle due to increased vascular permeability, which are the main symptoms of asthma, are observed (R, P).

Orange and K, F, Au5ten, A
dvances inl mmunolo (IV, ±0
．． 105 (1969), p.

Borg(!at and p, 5irOiS, J
, MedicinalChem, , 24, 121 (
1981), Shigekatsu Kono, Katsuya Kaidai, Metabolism, 2dan, 317
(1983)) The present inventors have been conducting intensive research on the treatment of asthma and anti-asthmatic drugs for this purpose, and in the process, the above 5R3-A was synthesized from arachidonic acid. Based on the idea that 5-lipoxygenase is involved in its biosynthesis, and that by inhibiting the activity of 5-lipoxygenase, the production of 5R3-A can be suppressed, thereby making it possible to treat asthma. Next, we proceeded with research on the substance that has the above-mentioned 5-lipoxygenase inhibitory effect. As a result, it was discovered that the flavone derivative represented by the above general formula (I>) is useful as a desired 5-lipoxygenase inhibitor, and its use suppresses the production of 5R3-A from arachidonic acid. Said 5R3
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 (I) and a salt thereof.

The general formula (I>
The lower alkoxy group defined by R1 is 1
4 Examples include alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pendeloxy, and hexyloxy groups.

The alkoxy group having 1 to 12 carbon atoms defined as R2 or R3 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,
Examples include undecanyloxy group and dodecanyloxy group.

The compound of the above general formula (I>) can be synthesized by various methods, and can be easily produced, for example, by the methods shown in the following reaction schemes -1 to -2.

[Reaction equation ■]

(II>(III>0(lv) (V) (Vl) (VII) [In the formula, R1 to R3 are the same as above. R4 and R5 represent a benzyloxy group, and X represents a halogen atom.] In the above The esterification reaction between a known or new compound represented by the general formula (II>) and a known compound represented by the general formula (III) is carried out in the absence of a solvent or in a common inert solvent at a temperature of 0 to 200" C1, preferably 80'C~130'C
The process is completed in about 1 to 8 hours under the following temperature conditions. 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-diethylaniline, 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 triethylamine, tripropylamine, pyridine, quinoline, N,
Examples include tertiary amines such as N-diethylaniline. Furthermore, the usage ratio of the compound represented by the general formula (n) and the compound represented by the general formula (III) in the above is as follows:
Generally, the amount of the latter should be equal to or more than 1 mole, preferably 1 to 1.5 moles, per 1 mole of the former. Thus, the general formula (1v)
The ester represented by is obtained.

The transfer reaction of the ester represented by the general formula (1v) is carried out in the presence of a basic compound in an inert solvent at room temperature to 100'C.
It takes about 2 to 10 hours to carry out an intramolecular rearrangement reaction (3aker-V enkataraman
reaction) is carried out. Examples of the basic compound include potassium hydroxide, mono-lithium hydroxide, potassium carbonate, and sodium amide. As an inert solvent,
There are no particular restrictions and it can be widely used, such as aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dioxane, tetrahydrofuran, and diethyl ether; aliphatic hydrocarbons such as hexane and heptane; and pyridine derivatives such as pyridine and picoline. etc. can be exemplified. In the above rearrangement reaction, the ratio of the basic compound to the compound of general formula (1) is usually 1 to 30 molar to 1 mole of the former.
It is sufficient to set it to the maximum level of moles. In this way, a diketone compound represented by general formula (V) is obtained.

The ring-closing reaction of the diketone compound (V) is carried out without a solvent or in a solvent in the presence of a catalyst at a temperature of room temperature to 150°C for about 2 to 15 hours. 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 to lithium propionate, and potassium propionate. Thus, the general formula (
A flavone derivative represented by Vl) is obtained.

In order to debenzylate the flavone derivative of general formula (vl) obtained above to obtain a compound of general formula (VI), for example, a hydrogenolysis reaction using a catalyst in an inert solvent can be employed. Here, as the catalyst, 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 the usual catalyst amount. Examples of inert solvents 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 carried out at room temperature to about 50°C, and generally at 1
It will be completed in about 5 hours.

The phosphorylation reaction of the compound of general formula (Vl) thus obtained is carried out by reacting polyphosphoric acid with the compound in the absence of a solvent or in a suitable solvent.

Examples of solvents include aromatic hydrocarbons such as toluene and xylene, saturated hydrocarbons such as heptane and octane, carboxylic acids such as acetic acid and propionic acid, and halogenated hydrocarbons such as 1°2-dichloroethane. . The amount of polyphosphoric acid used is usually at least an equimolar amount, preferably about 5 to 20 times the molar amount of the compound (VI), in terms of phosphoric acid. Polyphosphoric acid can also be used as a solvent, and in this case it is preferably used in a large excess amount relative to compound (VI). The reaction is usually 60 to 15
It is carried out at about 0°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 (I>) is produced.

The compound of general formula (n) used as a starting material in the above reaction scheme I is a known or new compound,
The compound is produced, for example, according to the following reaction scheme (2).

(Reaction scheme ■) (■) (IX ) (X)
(XI) (XI[)
(XI[l) (XIV)
(n) [In the formula, R1, R2 and R3 are the same as above,
A represents a substituted or unsubstituted phenylsulfonyl group, and B represents a benzyl group. ] First, a known compound (■) is reacted with the phenylsulfonyl chloride method to protect the hydroxyl group of the compound (■) to obtain a compound (IX).

Next, compound (IX) was added to room temperature to 80°C in an inert solvent.
After reacting for several hours in the presence of anhydrous aluminum halide at a temperature range of , the compound (X) in which the methoxy group has been cleaved is obtained by injecting the mixture into dilute hydrochloric acid. Regarding the use of aluminum halide, 1.
It is preferable to use 5 to 3 times the molar amount.

The deprotection reaction of compound (X) obtained in this way was performed in anhydrous potassium carbonate-methanol (potassium hydroxide, sodium hydroxide in water-containing methanol or ethanol) at room temperature to 80 ml.
The reaction is carried out by reacting for 30 minutes to 3 hours under stirring at 'C.

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)
Alternatively, compound (XI[l) is obtained in the same manner as the dealkylation reaction of compound (Vl) in a Lewis acid such as anhydrous aluminum chloride and an inert solvent.

The etherification reaction to obtain compound (X IV ) from compound (XI[I) can be carried out by a conventional Needel 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 addition, the etherification reaction is carried out in the inert solvent used in the esterification reaction in the above reaction scheme ①, if necessary, a dehydrohalogenating agent,
Using amines such as triethylamine, diisopropylethylamine, pyridine, N,N-diethylaniline, and inorganic salts such as potassium carbonate and sodium carbonate,
It is carried out at a temperature of 150'C for about 1 to 24 hours. The use port of the etherification agent is the compound (XII
I> 1 mole or more, preferably 1.2 to 1 mole
The amount is preferably 2 moles. Thus compound (X IV )
is manufactured.

Finally, compound (n) is produced by catalytic reduction of compound (X IV ) or by performing a cleavage reaction with a mineral acid or Lewis acid. For the catalytic reduction reaction, the same reaction conditions as for the hydrogenolysis reaction of compound (VI) in the above reaction scheme (IV) can be adopted.

The compound of the present invention obtained in the above reaction scheme (■) is
By treating this with an alkali such as sodium hydroxide or potassium hydroxide, it can be converted into a pharmacologically acceptable alkali salt.

Such salts can also be used as active ingredients in the red 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 method, dilution method, recrystallization method, adsorption chroma method, etc.
-Graphie, ion exchange chromatography, molecular sieve chromatography, etc. can be exemplified.

The flavone derivatives represented by the general formula (I>) and their salts thus obtained both have the effect of inhibiting 5-lipoxygenase.
- The lipoxygenase inhibitory effect lasts for a long time, has low toxicity, and has few side effects; 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 (I) 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, emulsions, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections. agents (liquid agents, suspension agents, etc.), and the like. When forming tablets, a wide variety of carriers known in this field can be used, such as lactose, sucrose, sodium chloride,
Glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, phosphoric acid Potassium, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride, starch, lactose, etc. Disintegrants, white sugar, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil,
Absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, purified talc, stearate, and phosphoric acid. At the end,
Examples include lubricants such as polyethylene glycol. Zara tablets can be made into conventionally coated tablets, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets, if necessary. When forming into an emulsion, a wide variety of conventionally known carriers can be used, such as excipients such as glucose, lactose, starch, cacao nms hardened vegetable fat, kaolin, 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 an injection, the solution and suspension are preferably sterilized and isotonic with blood, and when formed into the form of a solution, emulsion or suspension, a diluent may be used. All those commonly used in this field can be used, such as water, alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, sufficient salt, glucose or glycerin to prepare an isotonic solution may be included in the iM preparation, and usual solubilizing agents, buffers, soothing agents, etc. may be added. You may. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., 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 lylunic acid, and sorbitans such as sorbitan triolate and sorbitan monoole 1 to 1. Further, as a propellant, for example, Freon 11, Freon 1
2. Normally non-flammable liquefied gas such as Freon 114 can be used as an example.

The amount of the compound of general formula (i) or its salt contained in the 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. Expressed in weight%.

There are no particular restrictions on the method of administering the above pharmaceutical preparations, and the administration may be carried out in a manner depending on the various preparation forms, age, sex and other conditions of the patient, and the severity of the patient. For example, tablets, emulsions, liquids, etc. I
! In the case of suspensions, emulsions, granules and capsules, they are administered orally. In the case of injections, they are administered intravenously either alone or mixed with normal replacement fluids such as glucose or aminacetate, and if necessary, they are administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. . In the case of suppositories, it is administered rectally. Further, the spray is administered to the bronchi by spraying through the mouth or through the throat. .

The dosage of the 5-lipoxygenase inhibitor of the present invention is determined by the usage,
It is selected as appropriate depending on the age, sex and other conditions of the patient, the severity of the disease, etc., but the dose of the compound of the general formula (I>), which is the active ingredient, is usually 0.1 to 10 mg per 1 kc of body weight per day.
It is better to

Reference examples, examples, pharmacological test results, and formulation examples are listed below.

Reference example 1 3.4.6-drimethoxy 2-tosyloxyace 1~
Synthesis of Phenone 3.4. Dissolve 6-drimethoxy-2-hydroxyacetophenone 22Q in 150 mg of acetone, add toluenesulfonyl chloride 26C] and finely ground potassium carbonate 39Q, and flow rapidly for 3 hours with stirring. Water was added to the reaction mixture, the precipitated crystals were filtered, and recrystallized from methanol to give 35.9q of 3.4.6-1 to rimethoxy-2-tosyloxyacetophenone (harvested) of white needle-like crystals at 127-129°C. rate of 97%).

Elemental analysis (as C1B to 12°OaS) Analysis value C5
6,89% H15,55% calculated value C56,83%
H15, 30% Reference Example 2 Synthesis of 6-hydroxy-3,4-dimethoxy-2-1~Syloxyacetophenone 3.4.6-Drimethoxy2-1~Syloxyacetophenone 18CJ with anhydrous aluminum bromide (250,2
molar ratio) in acetonitrile (100 ml) and heated to 50'C for 2.5 hours.

After the reaction mixture was poured into 0.1N hydrochloric acid, the acetonitrile was distilled off. The precipitate was recrystallized with a mixed solvent of ethyl acetate and methanol, and m0127-128
6-Hydroxy-3,4 is a white prismatic crystal at °C
-dimethoxy-2-tosyloxyacetophenone14.
8C1 (yield 86%) was obtained.

Elemental analysis (as C+ 7 H+ 807 S) Analysis value C55,64% H4,83% Calculated value C55,73
%H4,95% Reference Example 3 Synthesis of 2,6-hydroxy-3,4-dimethoxyacetophenone 6-hydroxy-3,4-dimethoxy-2-tosyloxyacetophenone 15C] was dissolved in methanol 150n112
30C1 of potassium carbonate is added thereto, and the mixture is refluxed for 3 hours while stirring. The reaction mixture was poured into ice-hydrochloric acid, and the precipitated crystals were filtered, washed with water, and recrystallized with methanol to give 2,6-hydroxy-3.4 yellow needle-shaped crystals at 134-135°C. -Dimethoxyacetophenone 6.5CI (yield 75%) was obtained.

Elemental analysis (as C+ o Ht 20s) Analysis value C
56,59% H15,66% calculated value C56,60%
1-15.70% Reference Example 4 Synthesis of 2.6-dipenzyloxy-3,4-dimethoxyacetophenone
11.6 mg of benzyl chloride and 38 C1 of potassium carbonate were added, and the mixture was refluxed 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. .4-dimethoxyacetophenone 1
0.36o (86% yield) is obtained.

Elemental analysis (as C24H'2t Os) Analysis value C7
3,58% 16.11% Calculated value C73,45%
H6, 16% Reference Example 5 Synthesis of 6-benzyloxy-2-hydroxy-3,4-dimethoxyacetophenone 2.6-dipenzyloxy-3,4-dimethoxyacetophenone 10.360 was dissolved in acetic acid-hydrochloric acid solution (10: 1)2
After dissolving in 00ynQ, leave it for 1 hour at room temperature. Water is added to the reaction mixture, and the precipitated crystals are filtered and washed with water. Recrystallization is performed using a mixed solvent of ethyl acetate and methanol to obtain 7.05 CI of 6-benzyloxy-2-hydroxy-3,4-dimethoxyacetophenone (yield: 88%) in the form of yellow needle-like crystals at 119134-135°C.

Elemental analysis (as C+ v Ht a Os) analysis value
C67,52% 85.99% Calculated value C67,54%
H6,00% Reference Example 6 Synthesis of 2-hexyloxy-6-hydroxy-3,4-dimethoxy-ω-(3,4-dibenzyloxybenzoyl)acetophenone 6-benzyloxy-2-hydroxy-3,4- Dimethoxyacetophenone 2(j (6,6111 mol)
was dissolved in about 30 cc of acetone, 7.3 mmol of hexyl iodide (1.1 molar ratio) was added, and the mixture was rapidly flowed for about 15 hours with stirring. Water was added to the reaction mixture, the precipitated oil was extracted with ether, washed with water, the ether was distilled off, and the remaining bacteria was thoroughly dried in a desiccator.
Crude hexyl ether 6-benzyloxy-
2-hexyloxy-3,4-dimethoxyacetophenone is obtained.

The crude hexyl ether compound was mixed with acetic acid-hydrochloric acid mixture (10:2
> Dissolve at about 30°C and heat to 50°C for 30 minutes. Water was added to the reaction mixture, the generated 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 hydroxyacetophenone was obtained. 6-hydroxy-2-
Hexyloxy-3,4-dimethoxyacetophenone is obtained.

Crude hydroxyacetophenone and 8 mmO1 (1.2 molar ratio) of 3,4-dibenzyloxybenzoyl chloride are dissolved in pyridine and heated at 120°C for 2 hours.

The reaction mixture was poured into ice-hydrochloric acid, and the precipitated oil was 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 10 liters of pyridine, add 5 to 6 q of ground potassium hydroxide, and heat to 60'C for 30 min without stirring.
Heat for ~4 hours. The reaction mixture was poured into ice-hydrochloric acid,
The precipitated oil is 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 edyl acetate and methanol to give 2-hexyloxy-6-hydroxy- as yellow prism crystals with a mp of 80-81°C.
3,4-dimethoxy-ω-(3,4-dibenzyloxybenzoyl>acetophenone 1.83CI (3mmol
A yield of 55% was obtained.

Elemental analysis (as 037H4o Oa) Analysis value C72
, 40% H6, 65% calculated value C72, 53%'
H6, 58% Reference Example 7 Synthesis of 2-dodecyloxy-6-hydroxy-3,4-dimethoxy-ω-(3,4-dibenzyloxybenzoyl)acetophenone 6-benzyloxy-2-hydroxy-3,4- Dimethoxyacetophenone 2Q (6.6 mmol) was subjected to the same reaction as in Reference Example 6 to obtain mp79-80'C.
1 Yellow button-shaped crystals of 2-dodecyloxy-6-hydroxy-3,4-dimethoxy-ω-(3°4-dibenzyloxybenzoyl)acetophenone 1,160 (2 m
mof yield of 25%) was obtained.

Elemental analysis (as 043Hs 20s) Analysis value C74
,09% 87.47% Calculated value C74,11% 87
．． 52% Reference Example 8 Synthesis of 3',4'-dibenzyloxy-5-hexyloxy-6,7-simethoxyflavone 2-hexyloxy-6-hydroxy-3,4-dimethoxy obtained in Reference Example 6 above -ω-(3,4-dibenzyloxybenzoyl)acetophenone 1.6q (2,6 mmol) was dissolved in acetic acid 15-1.7 g (0,0
2 mol) and refluxed at 130-140°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. Add n-hexane to the residue, crystallize it, and perform t-filtration to obtain 3',4'-dibenzyloxy-5.
-Hexyloxy-6,7-simethoxyflavone was obtained (yield 92%).

Physical properties Melting point 89-90℃ Properties White needle crystal elemental analysis (as 0368360s) Analysis value C74,83% 86.31% Calculated value C74
,73% H6,44% Reference Example 9 Synthesis of 3',4'-dibenzyloxy-5-dodecyloxy-6,7-simethoxyflavone 2-dodecyloxy-6-hydroxy-obtained in Reference Example 7 above 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 give 3' and 4' white needle crystals.
-dibenzyloxy-5-dodecyloxy-6,7-
Cymethoxyflavone was obtained.

Melting point 78-79°C Reference example 10 5-hexyloxy-3',4'-dihydroxy-
Synthesis of 6,7-Simethoxyflavone 1 mmol of 3',4'-dibenzyloxy-5-hexyloxy-6,7-simethoxyflavone obtained in Reference Example 8 was dissolved in methanol, and 10% palladium was added to the solution. -Carbon (200m
After adding (1) and carrying out hydrogenolysis at room temperature for 4 hours, palladium-carbon ? The mother liquor was concentrated, and the residue was recrystallized from methanol-ethyl acetate to obtain 5-hexyloxy-3',4'-dihydroxy-6,7-simethoxyflavone.

Melting point 192-193℃ Properties Yellow needle-like crystals' HNMR (DMSOds > δppm9.52
(2H,br,s>7.38 (IH,d,J=2.2Hz>7.36'(
IH, dd, J+ = 8.2H7゜J2 = 2.2Hz
> 7.09 (1H, s> 6.88 (1H, d, J=8.2Hz>6.46 (
1H,s> 3.93 (3H,s> 3, 91 (2 days, t, J=6.
5 t1z) 3.74 (3H, s) 1.73 (2H, tt, J1=6.5Hz, J2=
6.5Hz> 1.44 (2HStt, J1=6.5Hz, J2
=6. 5 t12> 1.30 (4H, m).

0.87 (3H, t, J=6.9Hz) V λ (ethanol, max): 265r+m (ε
-2,09x10'), 337mm (ε=2.58X
10') λ (ethanol-sodium acetate, max): 26
3mm, 318mm, 395mm Reference example 11 5-dodecyloxy-3',4'-dihydroxy-
Synthesis of 6,7-simethoxyflavone In Reference Example 9, 1q
The 3',4'-dibenzyloxy-5-dodecyloxy-6,7-simethoxyflavone was treated in the same manner as in Reference Example 10 and recrystallized from methanol to obtain white prismatic 5-dodecyloxy-3. ',4'-dihydroxy-6
, 7-dimethoxyflavone was obtained.

Melting point 150-151℃' H-NMR (DMSO-66) δppm9.5
4 (2H,br,s) 7, 39 (1t1.d, J=2.
2Hz>7, 38 (1 to I S dd, J
1 = 8. 2 IZ, J2 =2.
2 G12> 7.11 (1H, s> 6.89 (IH, d, J=8.2Hz>6.47 (
IH, s> 3.94 (3H, s> 3.93 (2H, t, J=6.5l-1z)3,
74 (3t1, S) 1.74 (2H,tt, J+ =6.5Hz, J2
=6.5Hz> 1.45 (2H, tt, J+ =6.5Hz.

J2 = 6.5Hz) 1.24 (16H, m> 0.85 (3H, t%J=7.3Hz) Uv
・λ (ethanol, max
): 265mm (ε='2.08x10'
>, 337mm (ε=2.63X10') λ (ethanol-sodium acetate, max): 26
5mm, 318mm, 395mm Example 1 Synthesis of 5-hexyloxy-3'-hydroxy-6゜7-simethoxy-4'-phosphonooxyflavone 5-hexyloxy-3', 4 prepared in Reference Example 10 above
'-dihydroxy-6,7-dimethoxyflavone 500
Mix ma and polyphosphoric acid 19Cl and heat at 90'C for 20
The mixture was heated and stirred for a minute. After adding 30 g of ice to the reaction mixture and stirring to decompose the polyphosphoric acid, 10 mg of ethyl acetate was added and stirred, and the mixture was left in an ice chamber for 12 to 16 hours as a two-layer liquid. The precipitated yellow precipitate was collected, washed with 10 mQ of water, air-dried, and then dried under reduced pressure to give yellow needle-like crystals of 5-hexyloxy-3'-hydroxy-6,7-simethoxy-4'-phosphonooxy. 361 mg of flavone was obtained.

Melting point 212-213°C' HNMR (DMSO-ds) δppm7.8
0 (1H,br,s) 7, 69 (1t1, dd, J+ =
8. 6 I Z , J2 = 2.2Hz> 7, 11 (1H, s> 7.03 (IH, d, J = 8.6Hz> 6.55 (
IH, S) 3.95 (3H, S> 3.94 (2H, t, J=6.5Hz>3.75
(3H,s> 1, 75 (2H,tt, Lh =6.
5 t I Z , J2 = 6.5H2> 1.46 (2H, ↑t, J+ = 6.5H2, J2
=6. 5 t1z) 1.32 (4H, m> 0.89 (3H, t, J=6.9Hz) UV λ (ethanol, max): 266 nm (ε=2
．． 12X104>, 327nm <6=2.84x
10') λ (ethanol-sodium acetate, max): 26
5 nm, 333 nm The chemical structure of the compound obtained above is estimated from the above data.

First, in the UV spectrum, there is a significant bathochromic shift associated with l) H change from the acidic side of the solution to the alkaline side (usually when water Plt1 is at the 4' position of the flavone, 33
Since the maximum absorption band (2) in the vicinity of 0 to 350 nm shifted to around 400 nm by changing to alkaline conditions was not observed, it is considered that the 4' position of the flavone skeleton was phosphorylated.

Also, when pH was titrated with 0.1N sodium hydroxide,
As a result of calculating the consumption amount of 0.1N sodium hydroxide from the titration curve, it was confirmed that one phosphoric acid was bound.

Furthermore, from the NMR spectrum data, the above compound 19 is 5-hexyloxy-3'-hydroxy-6,
It was estimated to be 7-simethoxy4'-phosboxoxyflavone.

The NMR spectrum of the obtained compound is shown in FIG. 1, the UV spectrum in FIG. 2, and the IR spectrum in FIG. 3, respectively.

Example 2 Synthesis of disodium salt of 5-hexyloxy-3'-hydroxy-6゜7-simethoxy-4'-phosphonooxyflavone 5-hexyloxy-3'-hydroxy-6, 360 mo of 7-simethoxy 4'-phosphonooxyflavone was suspended in 40 mQ of methanol and 10 mo of water, and 14.
Added 5 Peng. The resulting solution is filtered through activated carbon,
2. 5-hexyloxy-3'-hydroxy-6,7-simethoxy-4', which is a hygroscopic pale yellow powder, is obtained by concentrating the 2-liquid solution under reduced pressure, adding 1-polyethanol, azeotropically removing water, and drying it. - 390 mg of disodium salt of phosphonooxyflavone was obtained almost quantitatively.

'HNMR (D20) δppm 7.54 (1H, s> 7.25 (1H, d, J=8.2Hz>6, 77
(1 t1, S 〉 6, 76 (1) 1. d, J=8.
2 t12>6.29 (1H,s>3.78 (2HS t,J=6.5Hz>3.77
(3H, s> 3.71 (3H, s> 1.67 (2H, tt, J+ = 6.5H2゜J2
=6.5l-1z) 1, 34 (2H, tt, J 1 =6.
5 IZ, J2 = 6.5H2) 1.22-1.24 (2H, m> 0.79 (3H, t, J = 7.3Hz) UV λ (ethanol, max): 265 nm (lo
gε 4.11>λ (ethanol-sodium acetate, max): 26
3 nm (log ε 4.10) λ (ethanol-hydrochloric acid, maxi: 267 nm (log
ε 4.13) The chemical composition 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 (usually when the flavone has a hydroxyl group at the 4' position,
Since the maximum absorption band (2) near 50 nm shifted to around 400 nm by changing to alkaline conditions was not observed, it is considered that the 4' position of the flavone skeleton was phosphorylated.

Furthermore, from the NMR spectrum data and the physical property data of Example 1, the compound obtained above was found to be 5-hexyloxy-
It was estimated to be the disodium salt of 3'-hydroxy-6,7-dimethoxy-4'-phosphonooxyflavone.

The NMR spectrum and UV spectrum of the obtained compound are shown in FIG. 4 and FIG. 5, respectively.

Example 3 Synthesis of 5-dodecyloxy-3'-hydroxy-6゜7-simethoxy-4'-phosphonooxyflavone 5-dodecyloxy-3', 4 obtained in Reference Example 11 above
'-dihydroxy-6,7-shifted xiflavone 50I
5-dodecyloxy-3'-
Hydroxy-6,7-simethoxy4'-phosphonooxyflavone 43m.

I got it.

Melting point 191-192℃' HNMR (DMSOds) δppm7.81
(1H,br,s) 7.69 (1H,dd%J1=8.2H2゜J2=
2.2H2) 7. 11 (1H, s> 7.04 (1H, d, J=8.2Hz>6.54 (
1H1s) 3.95 (3HS S) 3.93 (2H, t, J=6.5Hz>3.75 (
3H,s) 1.75 (2H,tt, Jl =e, 5Hz.

J2 = 6.5H2) 1.45 (2H, tt, J+ = 6.5H2, J2
=6.5H2> 1.24 (16H, m> 0.85 (3H, t, J=6.9Hz) UV λ (ethanol, max): 266 nm (ε=
2.20x10'>, 326nm (5=3.08x
10') λ (ethanol-sodium acetate, max): 26
5 nm, 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 Synthesis of 6-hexyloxy-3'-hydroxy-5゜7-simethoxy-4'-phosphonooxyflavone 6-hexyloxy-3',4'-dihydroxy-
5,7-shifted xiflavone 50111 () and polyphosphoric acid 2.40% were mixed and treated in the same manner as in Example 1 to obtain yellow needle-like 6-hexyloxy-3'-hydroxy-
5,7-Simethoxy4'-phosphonooxyflavone 3
5111g was obtained.

Melting point 181-183°C' H-NMR (DMSO-d6) δppm7.
80 (1 to 1. br, s) 7.68 (
1H, dd, Jt = 8.6l-1z, J2 = 2.2
Hz> 7.07 (1H, s) 7.03 (1H, d, J=8.6Hz>6.5!';
(1H,S) 3.94 (3H,s) 3.91 (21-1,t, J=6.5l-1z>3,
75 (3t1, S) 1.68 (2H,tt, Jt =6.5Hz.

J2 =6.5l-1z) 1.46 (2H, tt, Jt =6.5Hz, J2
=6.5Hz> 1.32 (4HSm) 0.89 (3H, t, J=6.9l-1z) UV, 1(1/-l, max): 273nm (ε=
2.11X10'>, 329nm (ε=2.75x
10') λ (ethanol-sodium acetate, max): 27
0 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 Synthesis of 6-dodecyloxy-3'-hydroxy-5゜7-simethoxy-4'-phosphonooxyflavone 6-dozosyloxy-3',4'-dihydroxy-
5,7-shifted xiflavone 50mo and polyphosphoric acid 2
．． 9 g of 6-dozosyloxy-3'-hydroxy-5,7 were mixed and treated in the same manner as in Example 1 to obtain yellow needle-like crystals of 6-dozosyloxy-3'-hydroxy-5,7.
-Simethoxy4'-phosphonooxyflavone 38m (
I got l.

Melting point 183-185°C 1-NMR (DMSO-d6)
δ ppm7.81 (1H, br, s) 7.70 (1H, dd, Jt =8.2Hz.

J2 =2.2H2) 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, Jt =6.5Hz, J2
=6.5H2) 1.45 (2H, ttSJt =6.5Hz.

J2 = 6.5Hz) 1.24 (16H, m) 0.85 (3H, t, J-6, 9H2) UV λ (ethanol, maX > : 266 nm (ε=
2.08X10'>, 330nm (E=2.95
x10') λ (ethanol-sodium acetate, n+ax): 2
66nm, 333nm The NMR spectrum of the obtained compound is shown in Figure 12, UV
The spectrum is shown in FIG. 13, and the IR spectrum is shown in FIG. 14.

Example 6 3'-hydroxy-5,6,7-drimethoxy4'-
Synthesis of phosphonooxyflavone 5.6.7-Trime1~
xy-3',4'-dihydroxyflavone 50!1
10 and 2.5 g of polyphosphoric acid were mixed and treated in the same manner as in Example 1 to obtain 3'-hydroxy-5,6 yellow needle-like crystals.
,7-drimethoxy4'-phosphonooxyflavone 2
It's 0ma@AN.

Melting point 218.5-219.5°C'H-NMR (DMSO-ds) δppm7.
82 (IH, br, s> 7.71 (11-1, dd, J1=8.9H21, J
2=2.0Hz) 7.14 (1f-1,s>7, 04 (1t1, d, J=8.9
) 6.58 (11-1, s) 3.96 (3H, s> 3.81 (3H, s> 3.77 (3H, S) V λ (ethanol, max): 265 nm (ε-
1,97x10'), 327mm (ε=2.48x
10') λ(ethanol-sodium acetate, max > :26
3mm, 333mm 1q Figure 15 shows the NMR spectrum of the compound.
(2) The spectrum is shown in FIG. 16, and the IR spectrum is shown in FIG. 17.

Formulation Example 1 Compound of Example 1 20mg Starch 130m.

Magnesium stearate 10mc + milk
Sugar 40mCl
A total of 200 mg of the above composition was prepared in one tablet using a conventional method.

Formulation Example 2 Compound of Example 1 10ma starch 127mg magnesium stearate 18Il) g total
200+n.

Tablets of the above composition were manufactured in a conventional manner.

Formulation example 3 Compound of Example 2 10m.

Starch 127m.

Magnesium stearate 18m.

A total of 200 mg of the above composition was prepared in one tablet using a conventional method.

Formulation Example 4 Compound of Example 1 1. Oq sorbitan monoseschelate 3.0g Freon 11
1.517L/Sat) 12
3-Double needle 9
．． A spray of the above composition was prepared in one cylinder using the 0Q conventional method.

Formulation Example 5 Compound of Example 1 1. Oci oleic acid 3.0g Freon 11
1.25Cl Freon 12
2.5q7L/2 yu 1 yuyu 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.)
29-Bovine Gamma Gropurine ((BPO) 298G
G) A Tris-buffered saline solution (pH 8, 2>1-) containing 1 μq of aluminum hydroxide and 1 m of aluminum hydroxide was sent to female Hartley guinea pigs [body size 1250-300Q, Shizuoka Experimental Animal 1 Liyokai] once a month. Sensitization was performed by intraperitoneal injection a total of 8 times.

Two weeks after the final sensitization, blood was collected from the posterior oblique artery and anti-BPO-B
GG serum was obtained. The titer of this antiserum was measured by 7-day passive cutaneous anaphylaxis (7-day PCA) and was found to be 4000-fold.

■ Experimental Asthma Method We used an experimental asthma method for guinea pigs, which is a modified version of the Konzetto-Rossler method. That is, 4 days in advance, anti-BPO-BGG serum was administered 0.2 times to male Hartley guinea pigs [body weight 400~
600Q, Shizuoka Experimental Animal Agricultural Association] was passively sensitized in advance by intravenous administration. The guinea pig was anesthetized by intraperitoneally administering 10 to 15 mg of bentoparbital sodium (Abbott), and a cannula for drug and antigen administration was connected to the jugular vein, and a tube from the artificial respirator was connected to the trachea. A cannula was inserted. After intraperitoneally administering approximately 25 mC1 of barbital to stop spontaneous breathing, an artificial respirator @ (Barbard, model 860) was connected to the trachea, and the patient received 4 m12/1 beats and 4 mC1 barbital.
0 beats! ! Air was supplied at a rate of l/min. Airway resistance is determined by connecting the tube branching from the airway to the bronchospasm transtu-
- (Ugo-basile, Model 7020) and recorded on recording paper via an amplifier. After the airway resistance of the guinea pig due to artificial respiration becomes almost constant, a physiological saline solution (2.5 mG of this saline solution)
contains 5 mq of mevilamine maleate (manufactured by Sigma) and 25 mCI of cimetidine (manufactured by Sigma)).
5m+1? /kq, and 20 minutes later, 80 μQ of antigen solution (10.5 m12) was intravenously administered to induce a reaction. As a test compound, the compound obtained in Example 1 was intravenously administered at a rate of 5 mg/kq 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 and reached a nearly constant value after 7 minutes. Airway resistance at J3 after 7 minutes was approximately 50% of that at complete tracheal occlusion (maximum response). On the other hand, in the group to which the compound obtained in Example 1 was administered, the airway resistance caused by antigen induction was clearly suppressed, and the suppression rate was 30% after reaction induction.
It showed 50% or more at any time up to 1 minute later.

[Brief explanation of the drawing]

FIG. 1 is an NMR spectrum diagram of the compound obtained in Example 1. FIG. 2 is a UV spectrum diagram of the compound 1q 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. Fifth
The figure 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. FIG. 8 is an IR spectrum diagram of the compound obtained in Example 3. FIG. 9 is an NMR spectrum diagram of the compound obtained in Example 4. 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. FIG. 13 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
FIG. 3 is a UV spectrum diagram of the compound obtained in Example 6. FIG. 17 is an IR spectrum diagram of the compound obtained in Example 6. FIG. 18 is a graph showing the relationship between time after antigen administration and maximum response %. (and above) ・−・ト“

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a lower alkoxy group, R^2 and R^3
each represents an alkoxy group having 1 to 12 carbon atoms. ] A flavone derivative represented by these and its salt.