JPS6121636B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to substituted 2-vinylchromones, processes for their preparation, and pharmaceutical compositions containing this compound with antiallergic action.

The compound according to the invention has the following formula (): [In the formula, R represents a hydrogen atom or a _C1 - _C12 -alkyl group, _R1 represents a _C2 - _C4 -alkyl group, and _R3 is a group: (Each of R ₆ and R ₇ is independently a hydrogen atom and a group -
(O) _o −R ₈ (in the formula, n represents 0 or 1, R ₈ is C ₁ ~
represents a C ₄ -alkyl group, the alkyl group being unsubstituted or substituted by one or more C ₁ -C ₂ -alkoxy groups or hydroxy groups) .

Further objects of the present invention are pharmaceutically acceptable salts of the compounds of formula () and all possible isomers and mixtures thereof.

In the compounds of the invention, the vinyl moiety may be in the cis- or trans-configuration. That is, the hydrogen atoms of the β-carbon atoms may be on the same side or on opposite sides with respect to the vinyl double bond. cis-
Also included within the scope of the invention are mixtures of the and trans-isomers. Preferably, the vinyl moiety in the compounds according to the invention has a trans-configuration.

The numerical values used to identify the positions of substituents in the R ₃ group are conventional, as exemplified below: Alkyl, alkenyl, alkoxy and alkanoyloxy groups may be branched or straight chain groups.

When R is an unsubstituted _C1 - _C12 alkyl group, R is preferably a _C1 - _C6 alkyl group, especially methyl, ethyl, isopropyl, tert-butyl and hexyl.

R ₁ is advantageously a C ₂ -C ₃ alkyl group, especially an ethyl and propyl group or a C ₃ alkenyl group, especially an allyl group.

When R ₈ is a C ₁ -C ₄ alkyl group, R ₈ is advantageously a methyl or ethyl group.

In particular R ₆ and R ₇ are independently selected from the group consisting of hydrogen, methoxy, methyl and ethyl.

Examples of pharmaceutically acceptable salts are salts with inorganic bases such as sodium, potassium, calcium and aluminum hydroxide, or with organic bases such as lysine, triethylamine, triethanolamine,
dibenzylamine, methylbenzylamine, di-
(2-ethyl-hexyl)-amine, piperidine,
with N-ethyl-piperidine, N·N-diethylaminoethylamine, N-ethylmorpholine, β-phenethylamine, N-benzyl-β-phenethylamine, N-benzyl-N·N-dimethylamine and other acceptable organic amines. salts, and salts with inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid,
and salts with organic acids such as citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, methanesulfonic acid and ethanesulfonic acid. Preferred salts are the sodium and potassium salts, and the hydrochlorides of basic esters, such as diethylaminoethyl and dimethylaminoethyl esters.

In particularly excellent compounds of the present invention, R is a hydrogen atom or an unsubstituted C ₁ to C ₆ alkyl group, R ₁ is an ethyl group, a propyl group, or an allyl group, and R ₃ is unsubstituted or one or A phenyl group substituted by two methyl, ethyl, or methoxy groups, the compound of formula () having a trans configuration in the vinyl moiety, and pharmaceutically acceptable salts thereof.

Examples of particularly excellent compounds of the invention are: 6-carboxy-3-ethoxy-2-trans-styryl-chromone; 6-carboxy-3-ethoxy-2-trans-(2'-methyl- styryl)-chromone; and its pharmaceutically acceptable salts, especially the sodium salt, and its basic esters (e.g. esters with diethylaminoethanol and dimethylaminoethanol) and its _C1 - _C6 alkyl esters, especially the ethyl ester. , isopropyl ester, t-butyl ester and hexyl ester hydrochloride.

The compound of the present invention has the formula (a): A compound of formula (in which R and R ₁ are as defined above) is reacted with an aldehyde of formula (): OHC-R ₃ () in which R ₃ is as defined above, thus forming a compound of formula () [In the formula, the vinyl moiety has a trans configuration], or (b) formula (): [In the formula, R and R ₃ represent the above-mentioned compounds, and R ₂ represents a hydrogen atom] is alkylated, and optionally, the compound of the formula () is converted to another compound of the formula () by a known method. and/or optionally convert the compound of formula () into a pharmaceutically acceptable salt, and/or optionally convert the salt into the free compound, and/or optionally convert the compound of formula In some cases, it can be produced by a method consisting of separating a mixture of isomers into individual isomers.

The reaction of a compound of formula () with an aldehyde of formula () is advantageously carried out in the presence of a basic condensing agent such as sodium ethoxide, sodium methoxide, sodium hydroxide, sodium hydride, sodium amide, such as methanol, ethanol, in a solvent selected from the group consisting of dioxane, water and mixtures thereof, advantageously from about 0 to
Conducted in a temperature range of 120°C.

The alkylation of compounds of formula () is advantageously carried out in conventional manner, for example by converting compounds of formula () into compounds of formula R ₁ -Z, where R ₁ is as defined above and Z represents a chlorine, bromine or iodine atom. ) with a basic reagent such as sodium amide, sodium hydride,
The reaction is carried out in the presence of sodium methoxide, sodium or potassium carbonate at a temperature range of about 0 to about 150°C.

Compounds of formula () can be converted into other compounds of formula () by known methods as described above. For example, compounds of formula () in which -COOR is an esterified carboxy group can be prepared in a solvent such as water or a lower aliphatic alcohol using e.g. sodium or potassium hydroxide and from room temperature to about
Compounds of formula () where -COOR is a carboxy group can be converted to compounds of formula () in which -COOR is a carboxy group by basic hydrolysis at temperatures up to 150 °C, and the same reaction can be carried out with lithium bromide in dimethylformamide at temperatures above 50 °C. It is also possible to implement by processing with. Compounds of formula () in which -COOR is a carboxy group can be prepared, for example, by preparing an alkali salt of an acid in a suitable alkyl halide and an inert solvent such as acetone, dioxane, dimethylformamide, hexamethylphosphortriamide at a temperature of about 0 to 100°C. By reacting within a range, it can be converted into a compound of formula () in which -COOR is an esterified carboxy group, such as a carbalkoxy group.

Any salt formation of the compound of formula (), as well as the conversion of the salt into the free compound and the isolation of the isomer mixture into the single isomer, can be carried out in a conventional manner.
For example, a mixture of arbitrary enantiomers can be isolated into a single enantiomer by salt formation with a suitable active base and subsequent fractional crystallization. To isolate mixtures of cis- and trans-geometric isomers, for example fractional crystallization can be carried out.

Also, the compound of formula () is the compound of formula (): A compound of [wherein R represents the above],
A suitable alkyl or alkenyl halide of the formula: R ₁ -Z, in which R ₁ and Z are as defined above, and a basic reagent such as sodium hydride, sodium methoxy in a solvent such as acetone, dioxane, dimethylformamide. It can be produced by reaction in the presence of carbonate, sodium or potassium carbonate at a temperature range from room temperature to about 120°C.

Compounds of formula () are commercially available products.

A compound of formula () can be prepared by reacting a compound of formula () with an aldehyde of formula () using, for example, the reaction conditions used for the reaction of a compound of formula () with a compound of formula (), such that R ₂ is It can be produced by obtaining a compound of formula () which is a hydrogen atom and whose vinyl moiety has a trans configuration.

Also, the compound of formula () is the compound of formula (): [In the formula, R, R ₂ and R ₃ represent the above, and R ₉ represents a hydrogen atom or a lower alkanoyl group, preferably an acetyl group]. In this case, the cyclization can be advantageously carried out in the presence of an acidic catalyst, such as hydrochloric acid, hydriodic acid, sulfuric acid or formic acid, preferably at a temperature in the range from 20 to 120°C, and the cyclization reaction can be carried out in the presence of an acidic catalyst, for example methanol, ethanol, It is advantageous to carry out in an inert organic solvent selected from the group consisting of dioxane, tetrahydrofuran, benzene, toluene, acetic acid and mixtures thereof.

Furthermore, the compound of formula () is the compound of formula (): The compound [wherein R, R ₂ and R ₃ represent the above] is mixed with hydrogen peroxide in a basic medium, such as sodium methoxide, sodium ethoxide,
It can also be prepared by reaction in the presence of methanol, ethanol, water and mixtures thereof in sodium or potassium hydroxide at temperatures ranging from 0° C. to reflux temperature.

Compounds of formula () are, for example, formula (): It can be produced by acidic hydrolysis of the compound [wherein R represents the above-mentioned compound and _R'9 represents a lower alkanoyl group, for example, an acetyl group]. In this case the compound of formula () is the compound of formula () It can be produced by reacting the compound of the formula [wherein R represents the above-mentioned compound and R' ₉ represents the above-mentioned compound] with an excess amount of acetic anhydride at a temperature ranging from room temperature to reflux temperature.

A compound of formula () is a compound of formula (),
A compound of the formula (): ZOC-CR ₂ =CH-R ₃ ( ) in which R ₂ , R ₃ and Z are as defined above, in a conventional manner, i.e. in an inert solvent such as benzene, toluene, dioxane. in the presence of a base such as pyridine, triethylamine as acid acceptor, in the temperature range from 0 °C to reflux temperature, thus formula (XI): [In the formula, R, R' ₉ , R ₂ and R ₃ represent the above-mentioned compounds] was obtained, and then the compound of the formula (XI) was changed to form the formula () [in the formula, R ₉ is a lower alkanoyl group]. This modification can be prepared by adding a strong base such as sodium, sodium amide, potassium hydroxide or sodium hydroxide or carbonate in an inert solvent such as pyridine, toluene, methyl-ethyl ketone or isopropyl alcohol. Due to the presence of potassium,
Perform at room temperature to reflux temperature. A compound of formula () in which R ₉ is a hydrogen atom can be obtained from a corresponding compound in which R ₉ is a lower alkanoyl group by acidic hydrolysis.

Compounds of formula () are, for example, formula (XII): A compound of [in the formula, R represents the above-mentioned] compound and an aldehyde of the formula (): OHC-CR ₂ =CH-R ₃ () [in the formula, R ₂ and R ₃ represent the above-mentioned] are combined in a solvent. For example in methanol, ethanol, dioxane, water and mixtures thereof,
It can be prepared by reaction in the presence of a basic condensing agent such as sodium ethoxide, sodium hydroxide or potassium hydroxide, sodium carbonate or potassium carbonate at temperatures between 0°C and reflux.

Compounds of formula () are for example [In the formula, R and Z represent the above-mentioned ones, and R ₁₀ represents a known protecting group, such as a _benzyl group]. ' ₉ represents the above compound] triethylamine salt of the compound;
By reacting in a solvent such as acetone, dioxane, dimethylformamide and acetic acid at a temperature range of 0°C to about 100°C, the formula (): A compound of the formula R, R' ₉ and R ₁₀ is as defined above is obtained and then optionally treated in a conventional manner, for example by acidic hydrolysis in the special case of the benzyl fraction, or by hydrogenation. It can be produced by removing the protecting group by decomposition.

The compounds of formulas (), (XII) and () are known compounds and can be produced by conventional methods.

A compound of formula () is a compound of formula (): The compound [wherein R and R ₁₀ represent the above] is prepared in a conventional manner, for example, in chlorine or bromine and an inert solvent such as CH ₂ Cl ₂ , CCl ₄ , acetic acid, or pyridine at 0°C.
React at a temperature range of ~30 °C or CuBr ₂
It can be produced by halogenation by reacting with chloroform-ethyl acetate at reflux temperature.

Expressions (), (), (), (), and ()
The vinyl group in and () may have a cis- or trans configuration, but preferably has a trans configuration.

The compounds according to the invention can be prepared by the Goose.J and Blair AMJN method [“Immunology”].
(Immunology, Volume 16, Page 749, 1969)], as shown by the fact that it is active in the Passive Skin Hypersensitivity (PCA) test in rats.
Has anti-allergic effect. Therefore, the present compounds can be used for the prevention and treatment of bronchial asthma, allergic rhinitis, hay fever, urticaria and skin disease.

Furthermore, the compounds according to the invention have the significant advantage of having high activity as antiallergic agents even when administered orally, as shown in the following table. The following table shows the efficiency of some compounds according to the invention for the compound 6-carboxy-2-trans-styryl-
Chromone (K10210), i.e. Belgian patent no.
It is shown in relation to the most active vinyl-based compound described in No. 823875 (its antiallergic activity is assumed to have a normal value of 1).

Table compound Efficiency (K10210=1) 6-carboxy-3-ethoxy-2-trans-
Styryl-Chromone 20.96 Antiallergic activity, Mota
Law [“Immunology”, Volume 7, No. 681
Goose J., 1964] using homocytotropic antibodies raised in rats by Goose J.
) and Blair AMJN method to determine the degree of inhibition of PCA brought about by IgE. Test compounds were administered orally at three or more doses 15 minutes before challenge. At least 8 rats were used for each dose.

Efficiency is determined by the Finney.DJ method (“Statistical Method in Biological Assay”)
C. Grittin London, p. 118, 1952]. Furthermore, the compounds according to the invention have anticonvulsant action, in particular bronchodilator activity, which is useful for example in the treatment of bronchial asthma. The compounds according to the invention can be administered in the usual manner, for example orally and parenterally, in doses of preferably 0.25 to 15 mg/Kg per day, or by inhalation, preferably 0.25 to 100 mg/Kg per day, especially 0.5
~25 mg/Kg or by topical administration.

Acute toxicity over a 7-day period was measured in rats using the following oral administration method. From the experimental results, it was found that 6-carboxy-3-ethoxy-2-trans-styrylchromone
The LD50 was determined to be >400 mg/Kg.

The nature of the pharmaceutical compositions containing the compounds according to the invention in combination with pharmaceutically acceptable excipients or diluents will depend on the method of administration described above.

The compositions can be formed in a conventional manner using conventional ingredients. For example, the compounds according to the invention can be administered in the form of aqueous or oily solutions or suspensions, aerosols, as well as powders, tablets, pills, gelatin capsules, syrups or creams or topical lotions.

For oral administration, pharmaceutical compositions containing the compounds according to the invention are preferably tablets, pills or gelatin capsules, which contain the active substance in diluents such as lactose, dextrose, sutucarose, mannitol, sorbitol, cellulose;
Lubricants such as silica, talc, stearic acid, magnesium or calcium stearate, and/or
or polyethylene glycol; Foam mixtures may contain dyes, sweeteners, humectants such as lecithin, polysorbates, lauryl sulfate; and non-toxic, pharmacologically inert substances commonly used in pharmaceutical formulations. The abovementioned pharmaceutical preparations can be prepared in a known manner, for example by mixing, granulating,
It can be manufactured by tabletting, sugar coating or film coating.

For allergic asthma, the compounds according to the invention are administered by inhalation. Compositions suitable for this use may consist of a suspension or solution of the active ingredient (advantageously in the form of a salt, eg a sodium salt) in water for administration by means of a conventional nebulizer.
Furthermore, when the composition is administered from a high-pressure vessel or atomizer disperser, it may be a suspension or solution of the active ingredient in a conventional liquid propellant, such as dichlorodifluoromethane or dichlortetrafluoroethane. If the drug does not dissolve in the propellant, co-solvents such as ethanol, dipropylene diglycol, isopropyl myristate, and/or surfactants may be added to the composition to suspend the drug in the propellant vehicle. Such surfactants are necessary and may be any of those commonly used for this purpose, such as non-ionic surfactants such as lecithin. Furthermore, the compounds according to the invention can also be administered in powder form by means of a suitable air inhaler, in which case a finely divided powder of the active ingredient can be mixed with a diluent such as lactose.

Furthermore, the compounds according to the invention can also be administered in conventional manner by intradermal or intravenous injection.

Besides internal administration, the compounds according to the invention can be used in topical compositions such as creams, lotions or pastes for use in skin treatment. For these compositions, the active ingredient can also be mixed with conventional oily or emulsifying vehicles.

Next, the present invention will be described in detail based on Examples, but is not limited thereto.

Example 1 20 g of 5-carbomethoxy-2-benzyloxy-acetophenone (melting point 86-88°C) dissolved in methylene chloride (200 ml) was mixed with bromine (9.8 g) at 10°C.
The reaction was allowed to proceed for 15 minutes. After treatment with 10% sodium sulfite and water, the organic phase was evaporated to dryness. The residue was crystallized from isopropyl ether to give 5-carbomethoxy-2-benzyloxy-ω-bromo-acetophenone (17 g) (mp = 84-86°C), which was dissolved in dimethylformamide (85 ml) and anhydrous. It was reacted with potassium acetate (5.6 g) at 50°C for 2 hours. After cooling and diluting with water, the precipitate is filtered and washed with cold methanol to give 5-carbomethoxy-2-benzyloxy-ω-acetoxy-acetophenone (12.9 g) (mp = 86-87
) was obtained, which was diluted with tetrahydrofuran (40 °C).
ml) and ethanol (20 ml), a few drops of concentrated HCl are added, then the solution is diluted to 5% at atmospheric pressure and room temperature.
Hydrogenation was carried out in the presence of Pd/C (2.5 g) until theoretical hydrogen was consumed. The mixture is filtered to remove the catalyst and the organic solution is evaporated to dryness.
Crude 5-carbomethoxy-2-hydroxy-ω-
Acetoxy-acetophenone (9.2 g) was obtained, which was mixed with dioxane (20 ml) and pyridine (10 g).
ml) and reacted with trans-cinnamoyl chloride (9.4 g) at room temperature for 8 hours. The reaction mixture was diluted with water and acidified to PH4. The precipitate was filtered, dried and treated with methyl-ethyl-ketone (100
ml), anhydrous K ₂ CO ₃ (9.3 g) was added and the mixture was stirred vigorously under reflux for 5 hours. After cooling, the mixture was diluted with hexane (150ml) and filtered. The combined product was dissolved in acetic acid (40 ml) and 57% HI (10 ml).
The mixture was treated under reflux for 4 hours. After cooling, filter the precipitate,
Washed with acetic acid and then with water until neutral. Obtained 6-carboxy-2-trans-styryl-3-hydroxy-chromone (6.1 g) [melting point>
320℃ (decomposition), mass spectrum: m/e308
(M ⁺ ), m/e291, m/e278, m/e263, m/
e231, m/e165, m/e143] was dissolved in dimethylformamide (120 ml) and reacted overnight at 50° C. in the presence of ethyl iodide (5.1 ml) and anhydrous K ₂ CO ₃ (8.4 g). After cooling, the mixture was diluted with water, filtered, washed with water and crystallized from methanol to give 6-carboethoxy-3-ethoxy-2-trans-styryl-chromone (4.65 g) (mp = 126-128°C). was obtained, which was mixed with 1% KOH in 95% ethanol,
(68.5 ml) under reflux for 30 minutes. After cooling the product was acidified with 23% HCl, filtered and
Washing with water until neutral gave 6-carboxy-3-ethoxy-2-trans-styryl-chromone (3.15 g). Melting point = 252-254℃,
IR: δ(C-H)〓C=C〓(Trans) 955cm
^-1 ; NMR (CF ₃ COOD): Vinyl proton δ _H 〓
=7.56(d), δ _H =8.19(d)ppm, J _H = _H =16
Hz.

When treated in a similar manner, the following compound was obtained: 6-carboxy-3-butoxy-2-trans-styryl-chromone, melting point = 192-194°C.
IR: δ(C-H)〓C=C〓(trans) 960cm
^-1 ; Example 2 5- obtained by processing according to Example 1
Carbomethoxy-2-hydroxy-ω-acetoxy-acetophenone (20 g) was heated under reflux in the presence of acetic anhydride (40 ml) and sodium acetate (page 8). The resulting product was diluted with water and ice and extracted with ethyl acetate. 5% organic phase
Washing with Na ₂ CO ₃ then water and evaporation to dryness under vacuum yielded the crude 6-carbomethoxy-3-
Acetoxy-2-methyl-chromone (22.5 g) was obtained which was treated with acetic acid (90 ml) and concentrated HCl (45 ml) for 4 hours under reflux. After cooling the mixture was diluted with water (100 ml).
ml), filtered, washed neutral with water and then hot ethanol to give 6-carboxy-3-hydroxy-2-methyl-chromone (13.5 g), which was diluted with dimethyl Ethyl iodide (28.8 g) in formamide (80 ml) and anhydrous
The reaction was carried out for 20 hours at 50° C. in the presence of K ₂ CO ₃ .
The reaction mixture was diluted with water, filtered and crystallized from methanol to yield 6-carboethoxy-3-ethoxy-2-methyl-chromone (10.3 g),
This was mixed with benzaldehyde (4.95 g) and methanol (50 g) containing sodium methylate (2.4 g).
ml) at room temperature for 20 hours.

The resulting precipitate was filtered and washed with methanol and then water to yield 6-carboethoxy-3-ethoxy-2-trans-styryl-chromone (10.8
g) (melting point = 126-128℃) was obtained, which was reduced to 95%
Hydrolyzed with a solution of 1% KOH in ethanol (185 ml) at reflux temperature for 30 minutes. After cooling the mixture add 23% HCl
After filtering the precipitate and washing with ethanol and water, 6-carboxy-3-ethoxy-2
-trans-styryl-chromone (8.8 g) was obtained. Melting point = 252-254℃, IR: δ (C-H)
〓C=C〓 (trans) 955cm ^-1 ; NMR
(CF ₃ COOD): vinyl proton δ _H =7.56(d),
δ _H 〓′=8.19(d)ppm, J _H 〓 _H 〓=16Hz.

When treated similarly and using the appropriate aromatic aldehyde, the following compound was obtained: 6-carboxy-3-propoxy-2-trans-styryl-chromone, mp = 210-212°C.
IR: δ(C-H)〓C=C〓(trans) 960cm
^-1 ; NMR (CF ₃ COOD); vinyl proton δ _H 〓
=7.49(d), δ _H =8.14(d)ppm, J _H = _H =16
Hz.

6-carboxy-3-butoxy-2-trans-styryl-chromone, melting point = 192-194°C,
IR: δ(C-H)〓C=C〓(trans) 960cm
^-1 ; 6-carboxy-3-ethoxy-2-trans-(2'-methyl-styryl)-chromone, melting point 226
~227°C; 6-carboxy-3-ethoxy-2-trans-(3'-methyl-styryl)-chromone, melting point 221
~222°C; 6-carboxy-3-ethoxy-2-trans-(4'-methyl-styryl)-chromone, melting point 270
~271°C; 6-carboxy-3-ethoxy-2-trans-(2'-ethyl-styryl)-chromone, melting point 211
~212°C; 6-carboxy-3-ethoxy-2-trans-(3'-methoxy-styryl)-chromone, melting point
233-235°C; 6-carboxy-3-butoxy-2-trans-(2'-methyl-styryl)-chromone, melting point 207
~208°C; 6-carboxy-3-butoxy-2-trans-(3'-methyl-styryl)-chromone, melting point 199
~200°C; 6-carboxy-3-butoxy-2-trans-(3'-methoxy-styryl)-chromone, melting point
195-197°C; Example 3 19 g of methyl 3-acetyl-4-hydroxy-benzoate in methanol (250 ml) were reacted with cinnamic aldehyde (37 g) in the presence of sodium methylate (14 g) at room temperature for 18 hours. After concentration to half volume, the reaction mixture was acidified with acetic acid and the precipitate was filtered to give methyl-3-(cinnamylidene-acetyl)-4-hydroxy-benzoate (9 g) (mp = 128-130 °C). , this was mixed with ethanol (470ml) and NaOH (23.5g)
in water (70 ml) containing 36%
Reacted with H ₂ O ₂ for 20 hours at room temperature. After acidification, the precipitate was filtered and washed with water and hot ethanol to yield 6-carboxy-3-hydroxy-2-trans-styryl-chromone (4.5 g) [melting point = 320
°C (decomposition)], which was diluted with propyl bromide (2 g) in dimethylformamide (45 ml).
Treated overnight at 50° C. in the presence of K ₂ CO ₃ (6 g). After diluting with water, filtering and washing with methanol, 6-carbopropoxy-3-propoxy-2
-trans-styryl-chromone (5.2 g) (melting point = 95-97°C) was obtained, which was then dissolved in a solution of 1% KOH (77 ml) in 95% ethanol at reflux temperature.
Hydrolyzed for 30 minutes. After cooling, the mixture was acidified with 23% HCl and the precipitate was filtered and washed with ethanol and water to give 6-carboxy-3-propoxy-2-trans-styryl-chromone (4.1 g).
[Melting point = 210-212℃; IR: δ(C-H)〓C=C
〓(trans)960cm ^-1 ; NMR (CF ₃ COOD);
Vinyl proton δ _H 〓=7.49(d), δ _H 〓=8.14(d)p.
pm, J _H 〓 _H 〓 = 16 Hz] was obtained.

The following compound was obtained by similar treatment: 6-carboxy-3-ethoxy-2-trans-styryl-chromone, melting point 252-254°C, IR:
δ(C-H)〓C=C〓(trans)955cm ^-1 ;
NMR (CF ₃ COOD); Vinyl proton δ _H 〓=
7.56(d), δ _H 〓=8.19(d)ppm, J _H 〓 _H 〓=16
Hz.

6-carboxy-3-butoxy-2-trans-styryl-chromone; melting point = 192-194°C,
IR: δ(C-H)〓C=C〓(trans) 960cm
^-1 ; Example 4 12 g of 6-carboxy-3-ethoxy-2-trans-styryl)-chromone were reacted with thionyl chloride (4 ml) in dichloroethane (80 ml) at reflux temperature for 2 hours. After cooling, the reaction mixture was evaporated to dryness and reacted with an excess amount of absolute ethanol at 50° C. for 1 hour. The mixture was concentrated to a small volume, diluted with water, and filtered to give 6-carboethoxy-3-ethoxy-2-trans-styryl-chromone (9.0
g) was obtained. Melting point = 126-128℃.

The following compound was obtained by similar treatment: 6-carboethoxy-3-ethoxy-2-trans-(2'-methyl-styryl)-chromone, mp.
226-227°C; Example 5 5 g of 6-carboxy-3-ethoxy-2-trans-(2'-methyl-styryl)-chromone was added to 100
The reaction was carried out with NaHCO ₃ (1.25 g) in water (25 ml) at °C until dissolution was complete in the absence of light. A precipitate was obtained when the solution was cooled to 5°C, which was then filtered and washed with ice water to yield 6-carboxy-3-
The sodium salt of ethoxy-2-trans-(2'-methyl-styryl)-chromone (melting point: 300°C or higher (decomposition)) (4.0 g) was produced.

When treated in a similar manner, the following sodium salts of the acids were obtained: Example 6 3-Acetyl-4-acetoxy-benzoic acid methyl ester (16
g) anhydrous _CaCO3 finely dispersed with bromine (10.8 g)
(8.1 g) at 10-15 °C with vigorous stirring.
The reaction was carried out for 20 hours. After treatment with 10% sodium sulfite and water, the organic phase was evaporated to dryness. The crude 3-bromoacetyl-4-acetoxy-benzoic acid methyl ester (20.5 g) thus obtained was dissolved in dimethylformamide (60 ml) and reacted with anhydrous potassium acetate (7.7 g) at room temperature under stirring for 20 hours. Ta.

After dilution with ice water, the precipitate was extracted with ethyl acetate and the solvent was evaporated to dryness in vacuo, yielding crude 3-acetoxyacetyl-4-acetoxy-benzoic acid methyl ester (19 g), which was refluxed for 20 min.
Heat with acetic anhydride (33.2g) and triethylamine (6.58g) for 1 hour. After cooling and diluting with ice water, the precipitate was filtered off and washed with water until neutralized. This gave crude 6-carbomethoxy-3-acetoxy-2-methyl-chromone (17.5g) which was heated under reflux in methanol (200ml) containing potassium hydroxide (4.74g) for 3 hours. After cooling and diluting with ice water, the precipitate was filtered off,
Melting point 218 by washing with water until neutralized
6-Carbomethoxy-3-hydroxy-2-methyl-chromone (7.3 g) at ~220°C was obtained which was mixed with propyl iodide (10.7 g) in dimethylformamide (35 ml) and anhydrous potassium carbonate (8.6 g). )
The reaction was carried out for 24 hours at 50°C under stirring in the presence of . After cooling, the reaction mixture was diluted with ice water, the precipitate was filtered, washed with water until neutralized, then dissolved in ethyl acetate and the solution was passed through a short Al ₂ O ₃ column. After evaporation to dryness in vacuo, the residue is crystallized from ethyl ether to give 6-carbomethoxy-
3-propoxy-2-methyl-chromone (4.1
g), which was dissolved in anhydrous methanol (30 g) containing 2,5-dimethoxy-benzaldehyde (3.7 g).
ml) and added slowly to a solution of sodium methoxide (0.685 g sodium) in absolute methanol (40 ml). The reaction mixture was stirred at room temperature for 20 min.
It kept time. The precipitate is filtered and washed with methanol and water until neutralized, resulting in a 6-
Carbomethoxy-3-propoxy-2-trans-(2'·5'-dimethoxy-styryl)-chromone (3.85 g) was obtained. This was dissolved in a 1% KOH solution in 95% ethanol (66 ml) and heated under reflux for 15 min.
Heated for minutes. After cooling the reaction mixture was diluted with 23% HCl
The precipitate was filtered and washed with ethanol and water until neutralized. Crystallization from ethanol yielded 2.8 g of 6-carboxy-3-propoxy-2-trans-(2'.5')dimethoxy-styryl)-chromone. Melting point 255-256℃ NMR (DMSO-d ₆ ): Vinyl proton δ _H 〓=
7.49(d), δ _H 〓=7.78(d), J _H 〓 _H 〓=16Hz.

By similar treatment using the appropriate aldehyde, the following compounds were obtained: 6-carboxy-3-ethoxy-2-trans-(2'·5'-dimethoxy-styryl)-chromone,
Melting point: 263-265℃; NMR (DMSO-d ₆ ): vinyl proton δ _H 〓=
7.47(d), δ _H 〓 = 7.80(d), J _H 〓 _H 〓 = 16Hz: 6-carboxy-3-ethoxy-2-trans-(2'-methoxy-3'-ethoxy-styryl)-chromone, Melting point: 234-236°C; 6-carboxy-3-ethoxy-2-trans-(2'·3'-dimethoxy-styryl)-chromone,
Melting point: 250-252℃; NMR (DMSO-d ₆ ): vinyl proton δ _H 〓=
7.50(d), δ _H 〓=7.91(d), J _H 〓 _H 〓=16Hz; 6-carboxy-3-ethoxy-2-trans-(2'·5'-dimethyl-styryl)-chromone, melting point: 230-231℃; 6-carboxy-3-propoxy-2-trans-(2',5'-dimethyl-styryl)-chromone,
Melting point: 224-226°C; 6-carboxy-3-ethoxy-2-trans-(2'-methoxy-styryl)-chromone, melting point:
271-272°C; 6-carboxy-3-ethoxy-2-trans-(4'-methoxy-styryl)-chromone, melting point:
261-262°C; 6-carboxy-3-ethoxy-2-trans-(3'-ethoxy-styryl)-chromone, melting point:
234-235°C; 6-carboxy-3-propoxy-2-trans-(3'-methoxy-styryl)-chromone, melting point: 239-241°C; Example 7 6-carboxy-3-propoxy-2-trans-(3'-methoxy-styryl)-chromone dissolved in anhydrous methanol (15 ml) 3-Ethoxy-2-methyl-chromone (1.4 g) and benzaldehyde (0.75 g) are slowly added to a solution of sodium methoxide (obtained from 0.4 g of sodium) in absolute methanol (15 ml) with external cooling. The reaction mixture was kept at room temperature with stirring for 20 hours, then acidified with acetic acid and
Diluted with ice water.

After filtering the precipitate and crystallizing it from methanol,
1.1 g of 6-carboxy-3-ethoxy-3-trans-styryl-chromone with a melting point of 252 DEG -254 DEG C. are obtained.

Example 8 Tablets weighing 150 mg each containing 50 mg of active substance are manufactured as follows: Composition (10 000 tablets) 6-carboxy-3-ethoxy-2-trans-
Styryl-chromone 500 g Lactose 710 g Cornstarch 237.5 g Talcum powder 37.5 g Magnesium stearate 15 g.

Mix half of the 6-carboxy-3-ethoxy-2-trans-styryl-chromone, lactose and cornstarch. Then open the mixture
Pass through a 0.5mm sieve. Suspend cornstarch (18 g) in hot water (180 ml). The resulting paste is used to granulate the powder. Dry the granules and open them
Grind with a sieve having 1.4 mm. remaining starch,
Add talc and magnesium stearate, mix carefully and tablet using 8 mm diameter tableting material.

Example 9 Aerosol formulation 6-carboxy-3-ethoxy-2-trans-
Styryl-chromone 2% Ethanol 10% Lecithin 0.2% Mixture of dichlorodifluoromethane and dichlortetrafluoromethane (70:30 mixture)
amount to be 100%

Claims (1)

[Claims] 1 formula [In the formula, R represents a hydrogen atom or a _C1 - _C12 -alkyl group, _R1 represents a _C2 - _C4 -alkyl group, and _R3 is a group: (Each of R ₆ and R ₇ is independently a hydrogen atom and a group -
(O) _o −R ₈ (in the formula, n represents 0 or 1, R ₈ is C ₁ ~
represents a C ₄ -alkyl group, the alkyl group being unsubstituted or substituted by one or more C ₁ -C ₂ -alkoxy groups or hydroxy groups) or a pharmaceutically acceptable salt thereof. 2 formula: [In the formula, R represents a hydrogen atom or a _C1 - _C6 -alkyl group, _R1 represents an ethyl group or a propyl group, and _R3 is substituted with one or two methyl, ethyl, or methoxy groups. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the vinyl moiety thereof has a trans configuration. 3 6-carboxy-3-ethoxy-2-trans-styryl-chromone, 6-carboxy-3-
is a compound selected from the group of ethoxy-2-trans-(2'-methyl-styryl)-chromones,
A compound according to claim 1 or a pharmaceutically acceptable salt thereof. 4 formula: [In the formula, R represents a hydrogen atom or a _C1 - _C12 -alkyl group, _R1 represents a _C2 - _C4 -alkyl group, and _R3 is a group: (Each of R ₆ and R ₇ is independently a hydrogen atom and a group -
(O) _o −R ₈ (in the formula, n represents 0 or 1, R ₈ is C ₁ ~
represents a C ₄ -alkyl group, the alkyl group being unsubstituted or substituted by one or more C ₁ -C ₂ -alkoxy groups or hydroxy groups) In producing a compound of the formula () or a pharmaceutically acceptable salt thereof, the formula (): A compound of the formula (in which R and R ₁ represent the above) is reacted with an aldehyde of the formula (): OHC-R ₃ () [in the formula, R ₃ represents the above] to obtain the formula () wherein the vinyl moiety has a trans configuration], optionally converting the compound of formula () into another compound of formula () by known methods, and/or optionally converting a compound of formula () into a pharmaceutically acceptable salt, and/or optionally converting the salt into the free compound, and/or optionally separating a mixture of isomers into single isomers; Replacement 2 characterized by
-Production method of vinyl chromone. 5 Formula: [In the formula, R represents a hydrogen atom or a _C1 - _C12 -alkyl group, _R1 represents a _C2 - _C4 -alkyl group, and _R3 is a group: (Each of R ₆ and R ₇ is independently a hydrogen atom and a group -
(O) _o −R ₈ (in the formula, n represents 0 or 1, R ₈ is C ₁ ~
represents a C ₄ -alkyl group, the alkyl group being unsubstituted or substituted by one or more C ₁ -C ₂ -alkoxy groups or hydroxy groups) To obtain a compound of the formula () or a pharmaceutically acceptable salt thereof, the formula (): A compound of formula (2) in which R and R ₃ are as defined above is alkylated to obtain a compound of formula () and/or optionally a compound of formula () is prepared by known methods to obtain a compound of formula ( ), and/or optionally converting the compound of formula () into a pharmaceutically acceptable salt, and/or optionally converting the salt into the free compound, and/or or, as the case may be, a process for the preparation of substituted 2-vinyl-chromones, characterized in that a mixture of isomers is separated into single isomers. 6 Formula: [In the formula, R represents a hydrogen atom or a _C1 - _C12 -alkyl group, _R1 represents a _C2 - _C4 -alkyl group, and _R3 is a group: (Each of R ₆ and R ₇ is independently a hydrogen atom and a group -
(O) _o −R ₈ (in the formula, n represents 0 or 1, R ₈ is C ₁ ~
represents a C ₄ -alkyl group, the alkyl group being unsubstituted or substituted by one or more C ₁ -C ₂ -alkoxy groups or hydroxy groups) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient and/or diluent.