FI67080B - FARING REQUIREMENTS FOR THE FARMING OF ACTIVE PHARMACEUTICALS: 6-BENZO-NY-PYRONDERIVAT - Google Patents

Description

--- ANNOUNCEMENT s π non year * W ^ UTLAGGNINGSSKKIFT 67080 Q Pvlentti cyur.n; i, y 10 01 1983 (51) Kv.lt/totCI.3 C 07 D 311/22, 405/04 FINLAND — FINLAND (it ) 37 ^ 2/7 ^ (22) H «k« mlipto * - AiUtaUmri · »27.12.74 (Fi) (23) AHn ^ W-GIW ^ U, 27.12.74 (41) TaNuc HUmIcsI —Mvtto * Mtl« 28/6/75

And the register managed by J. p ** .-

PatMt · och reghtantyralMn v AnaBkan od * d och ttcLakrtfUa paMkarad 28.09.84 (32) (33) (31) fyydtty «cxXfc-ι Bftod peter ** 27.12.73 04.0 / .74, 17.07.74 Itai ia-1talien (IT ) 32089 A / 73, 24777 A / 74, 25244 A / 74 (71) Farmitalia Carlo Erba SpA, Via Carlo Imbonati 24, 20159 Milan, I and 1 (IT) (72) Gianfederico Doria, Milan , Pier Nicola Giraldi, Milan, Francesco Lauria, Milan, Maria LuisaCorno, Milan, Piero Sberze, Varese,

Marcello Tibolla, Milan, I taiia-l talien (IT) (74) Munsterhielm Ky Kb (54) Process for the preparation of new pharmaceutically active 5: 6-benzo) f-pyrone derivatives - Förfarande för framställning av nya, fa rmaceut i This invention relates to a process for the preparation of 5: 6-benzo-γ-pyrone derivatives of general formula (I) wherein O is phenyl which is substituted by fluoro or C 1 -C 4 alkoxy which in turn is unsubstituted or substituted by C 2 -C 4 alkoxy, or R is pyridyl or pyrazinyl which is unsubstituted or substituted by methyl, and pharmaceutically acceptable salts thereof.

In the compounds of the invention, when R is phenyl, the following numbering is used: 2,67080 2 '3 *

Jq. · 6 * 5 'when R is pyridyl (or pyrazinyl 2 heteroatoms) the numbering is as follows: 1' 9 «1» 3 '2' · <>. , 3 »μ» * 4 '5' 5b where Z is the heteroatom from which numbering usually begins.

In the compounds of the invention, the oxy groups may be branched or straight-chain.

Examples of pharmaceutically acceptable salts include sodium salts and salts with 2-aminoethanol and 2-amino-2-hydroxymethyl-1,3-propanediol.

Examples of preferred compounds of the invention are as follows: 6-carboxy-2'-isopropoxy-flavone 6-carboxy-2'-butoxy-flavone 6-carboxy-2 '- (2-ethoxy-ethoxy) -flavone 6-carboxy -H '- (2-ethoxy-ethoxy) -flavone 6-carboxy-2- (2'-pyridyl) -chromone 6-carboxy-2- (3 · -pyridyl) -chromone 6-carboxy-2- (2' -pyrazinyl) chromone and their pharmaceutically acceptable salts, in particular the sodium salts and the hydrochlorides of esters with diethylaminoethanol and morpholinoethanol and of glycol and pivaloxymethyl esters.

The 5: 6-benzo [f] pyrone derivatives can be prepared by a process according to which a) a compound of formula (II) is: [HOOC-^ ClI2 Π i | i (m C (?

X R

3 67080 wherein R is as defined above, is cyclized to give compounds of general formula (I), or b) a compound of formula (III) is O

I] ^ 0? L UiiJ

is reacted with a (C 1 -C 4) alkyl halide which is unsubstituted or substituted by C 2 -C 6 alkoxy to give a compound of formula (I) in which R is phenyl substituted by -alkoxy which in turn is unsubstituted or substituted by C 2 -C 4 alkoxy. and / or the compounds of formula (I) are converted into pivaloxymethyl, glycol, diethylaminoethyl or morpholinoethyl ester, and / or the hydrochloride or maleate of such an ester, and / or the compound of general formula (I) is converted into a pharmaceutically acceptable salt thereof.

The cyclization of a compound of formula (II) is preferably carried out in the presence of acid catalysts such as hydrochloric acid, hydroiodic acid, sulfuric acid, formic acid, preferably at a temperature of 20-120 ° C and in an inert solvent such as methanol, ethanol, ethanol, dioxane, dioxane to-read, acetic acid and mixtures thereof.

The compound of formula (III) can be obtained by cyclizing a compound of formula (IIa) according to method a) 0 l | HOOC (CH2 kJ) CO (Ha) 'cr011 which in turn can be obtained according to the method described for the compound of formula (II).

The free hydroxy groups may be etherified by treatment with e.g. alkyl halides or the etherified hydroxy groups may be converted to free hydroxy groups e.g. by treatment with a pyridine salt, preferably the hydrochloride, or a strong acid or Lewis acid.

The possible salt formation of the compounds of formula (I) can also take place by known methods.

67080

Compounds of formula (II) may be prepared by reacting a compound of formula (IV) 0

II

H 3 C-3 i (IV) to react with a compound of formula (V) is R 1 -COO-R (V) wherein R is as defined above and R 1 is aryl, preferably phenyl, or alkyl.

The reaction between a compound of formula (IV) and a compound of formula (V) is preferably carried out in an organic solvent such as methanol, ethanol, dioxane and pyridine in the presence of a strong base such as sodium methoxide, sodium ethoxide, sodium hydride and room temperature and reflux temperature.

An alternative process for the preparation of compounds of formula (II) comprises reacting a compound of formula (IV) in a known manner with a compound of formula (VI) is M'OC-R (VI) wherein M 'is halogen or hydroxy and R means the same as above to prepare a compound of formula (VII) 0

II

H 2 O 2 / CVCH 3 (VII)

0-C-R

II

o wherein R is as defined above, after which the compounds of formula (VII) are subjected to a rearrangement reaction in an inert solvent, e.g. pyridine, toluene, methyl ethyl ketone, in the presence of a strong base, e.g. sodium, sodium amide, potassium hydroxide, potassium carbonate, at room temperature and reflux. between.

67080 5

Compounds of formula (IV) may be prepared, for example, by starting from suitable substituted phenols by Friedel-Crafts condensation or Fries regrouping.

Compounds of formula (III) may be prepared starting from compounds of formula (VIII)

0 H

HOOC- ^ C = CH-R

| (VIII) wherein R is as defined above, by reacting them with basic condensing agents such as sodium or potassium hydroxide, sodium amide, sodium hydride, sodium or potassium carbonate, potassium acetate, or acids, e.g. hydrohalic acids, sulfuric, phosphoric, with p-toluenesulfonic acid in a solvent, e.g. preferably methanol, ethanol, dioxane, tetrahydrofuran, benzene, toluene, dimethyl sulfoxide, between room temperature and reflux temperature.

Compounds of formula (VIII) may in turn be prepared by condensing a compound of formula (V) with a substituted aldehyde of formula OCH-R (IX) wherein R is as defined above.

The condensation may take place in a solvent such as methanol, ethanol, dioxane, water and mixtures thereof, and in the presence of a basic catalyst such as piperidine, sodium hydroxide, sodium hydride, sodium alkoxide and between room temperature and reflux temperature.

6 67080

The compounds of the invention have antiallergic activity, as evidenced by their activity in the passive cutaneous anaphylaxis (PCA) assay in rats, according to Goose Y and Blair A.M.Y.N. (Immunology, 1969, J5: 749). They can thus be used to prevent and treat bronchial asthma, allergic rhinitis, hay fever, urticaria and dermatosis.

An important property of the new compounds is that they have antiallergic activity even when administered orally.

PHARMACOLOGICAL PROPERTIES

The following table shows the activity values obtained in the PCA experiment in rats after oral administration of the compounds of this invention.

Activity values are expressed as K i values, defined as the dose of active compound (mg / kg) capable of reducing the activity of the serum used for sensitization by:

B

K = - B DR-1 where B = dose of antagonist compound, expressed in mg / kg DR = dose ratio: antilogarithm of the distance between the curves of the serum containing the antagonist and the serum without the antagonist (JH Gaddum et al. Exp. Physiol., 1955, 40 , 49); When K is equal to the antilogarithm, it is independent of both the dose of drug B and the concentration of reagent used for sensitization, pA2 is the negative logarithm of the molar concentration of antagonist compound (A) reduced by half the effect of the stimulating drug.

The lower the Kg value, the higher the antiallergic activity.

The following table compares the antiallergic activity of the compounds of the invention with disodium chromoglycate (DSCG), a known antiallergic drug; in the table the compounds are denoted by the following codes: 67080 K 10149 6-carboxy-2'-isopropoxy-flavone; K 11056 6-carboxy-2'-butoxy-flavone; K 11006 6-carboxy-2 '- (2-ethoxy-ethoxy) -flavone; K 10175 6-carboxy-4 '- (2-ethoxy-ethoxy) -flavone; K 11662 6-carboxy-4'-fluoro-flavone; K 11785 6-carboxy-3'-fluoro-flavone; K 11074 6-carboxy-2- (2'-pyridyl) chromone; K 11054 6-carboxy-2- (3'-pyridyl) chromone; K 11089 6-carboxy-2- (2'-pyrazinyl) -chromone; K 11166 6-carboxy-2- (5'-methyl-2'-pyrazinyl) -chromone; K 11202 6-Carboxy-2- (6, -methyl-2, -pyrazinyl) -chromone.

TABLE I

-------------------------------------------------- --------------------

Compound Pretreatment time Antiallergic activity p.o. - Κβ (mg / kg) DSCG 15 '> 200 K 10149 15' 9.59 K 11056 15 '11.51 K 11006 15' 11.62 K 10175 15 * 14.53 K 11662 15 '5.51 K 11785 15 '16.34 K 11074 15' 8.48 K 11054 15 '15.02 K 11089 15' 5.71 K 11166 15 '10.36 K 11202 15' 9.98! _ _______________________________________________________

Antiallergic activity was determined as inhibition of IgE-mediated PCA according to the method of Goose J. and Blair A.M.J.N. (Immunology, 1969, 16: 749) using homocytotropic antibodies raised in rats according to the method of Mota I., Immunology, 7, 681 (1964).

Test compounds were administered orally 15 minutes before antigen administration and at least 6 rats were used for each assay.

8 67080

The following table shows the protection obtained with the o-orally administered compound of the invention in a PCA test in rats compared to two known antiallergic drugs, namely disodium cromoglycate (DSCG) and AH 7725, i. 2-carboxy-7-hydroxyethoxyxanthone (Fullarton, J., Martin, L.E. and Vardey, C. Int. Arch. All. 1973, 45: 8 * 4).

TABLE II

Compound Dose% inhibition compared to controls (mg / kg / p o) measured after different treatment times of 15 min. 30 min. 60 min. 120 min.

I DSCG 50 6.0 5.5 3.2 2.5 i AH 7725 50 42.6 1 * 4.4 13.3 3.8 6-carboxy-2'-isopropoxy-flavone 50 82.9 39 , 5 27.6 24.4! _______________________________________________________________

In addition to antiallergic activity, these compounds of the invention are effective in reducing airway resistance and increasing pulmonary elasticity, and can therefore be used to treat respiratory insufficiency, such as acute pulmonary insufficiency, as shown by the results obtained in rats using the technique Palek. , Palecekova M., and Aviado DM (Arch. Environ. Health, 1967, 15: 332-342). In these experiments, the compounds of the invention, in particular 6-carboxy-2-isopropoxy-flavone, reduce airway resistance and increase pulmonary elasticity at doses as low as 3 mg / kg / i.v .; at equal doses, they are effective against the bronchoconstrictive effect of (50%) 5-HT (5-hydroxytryptamine, i.e. serotonin) and compound 48/80 (histamine releasing drug).

67080 9

The compounds of the invention further have antiulcer activity, as evidenced by their proven activity in preventing stress-induced gastric ulcers in rats challenged in a 25 ° water bath for 40 minutes according to a method modification described by Tagaki, K. and Okabe, S. (Jap. J. of Pharmac., 1968, 18: 9).

In this experiment, the compounds of the invention, especially the sodium salt of 6-carboxy-2'-isopropoxy-flavone, inhibited 45% of the stress-induced gastric ulcers in rats when administered at doses of 50 mg / kg / i.v.

The compounds of the invention may be administered in a conventional manner, for example orally and parenterally at a daily dose of preferably 0.5 to 15 mg / kg, or by inhalation at a daily dose of preferably 0.5 to 100 mg, more preferably 0.5 to 25 mg , or topically.

The nature of the pharmaceutical compositions containing the compounds of the invention and pharmaceutically acceptable carriers and / or diluents will, of course, depend on the desired route of administration.

The compositions may be prepared in a conventional manner using conventional ingredients. The compounds according to the invention can be administered, for example, in the form of aqueous or oily solutions or suspensions, aerosols and powders, tablets, pills, gelatin capsules, syrups or ointments or lotions for topical use.

For oral administration, the compounds of the invention may be formulated into suitable pharmaceutical compositions, preferably tablets, pills or gelatin capsules, containing the active compound in association with diluents such as lactose, dextrose, sucrose, mannitol, cellbitol; lubricants, for example silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; or they may also contain binders such as starches, gelatin, methylcellulose, carboxymethylcellulose, acacia, tragacanth, polyvinylpyrrolidone, disintegrants such as starches, alginic acid, alginates, sodium starch glycolate; foam-based alloys; coloring agents; sweetening agents; wetting agents; such as 67080 10 for example lecithin, polysorbates, lauryl sulphates; and generally non-toxic and pharmacologically inactive substances used in pharmaceutical preparations. Said pharmaceutical preparations are formed in a conventional manner, for example, by mixing, granulating, tableting, sugar-coating, or film-coating techniques.

For the treatment of allergic asthma, the compounds according to the invention are also administered by inhalation. Suitable compositions for such use may comprise the active ingredient, preferably in the form of a salt, such as the sodium salt, a suspension or solution in water, using a conventional nebulizer for administration. Alternatively, the compositions may be in the form of a suspension or solution of the active ingredient in a conventional liquefied propellant such as dichlorodifluoromethane or dichlorotetrafluoroethane, which is dispensed from a pressure vessel, i. aerosolisäi-container. When the drug is insoluble in the propellant, it may be necessary to add an additional solvent to the composition, such as ethanol, dipropylene glycol, isopropyl myristate, and / or a surfactant to suspend the drug in the propellant, and such a surfactant may be any substance commonly used for this purpose. --ionic surfactant, e.g. lecithin.

The compounds according to the invention can also be used in the form of powders using a suitable blowing device, in which case the fine powders of the active ingredient can be mixed with a diluent such as lactose.

The compounds of the invention may also be administered by intradermal injection or intravenous injection in a conventional manner.

In addition to internal administration, the compounds of the invention may be used in topical compositions, e.g., creams, lotions or pastes for dermatological treatments. For these compositions, the active ingredient may be mixed with conventional oily or emulsifying agents.

67080

The following examples illustrate the invention.

EXAMPLE 1

A solution of methyl 3-acetyl-4-hydroxybenzoate (60 g) and methyl 2-isopropoxybenzoate (120 g) in dioxane (400 ml) was added with stirring at room temperature over 50% sodium hydride. (45 g) in dioxane (200 ml). The mixture was kept at 80 ° C for 4 hours, cooled and then diluted with petroleum ether (600 ml), then filtered. The resulting precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl acetate. The organic phase was washed with 5% potassium carbonate and water, then evaporated to dryness and crystallized from ethanol to give (2-hydroxy-5-carbomethoxy-benzoyl) - (2-isopropoxy-benzoyl) -methane (70 g; m.p. m.p. 105-107 ° C), which was then refluxed for 15 minutes with 99% formic acid (280 mL). After cooling and dilution with water (1 liter) and filtration, the precipitate collected was recrystallized from acetone to give 6-carbomethoxy-21-isopropoxy-flavone (60 g ·, m.p. 154-155 ° C), which was hydrolyzed with 1% with a solution of potassium hydroxide (1. 1.020) in 95% ethanol at reflux for 30 minutes.

The mixture was cooled, acidified with acetic acid, concentrated in vacuo to give a precipitate which was filtered, washed with ethanol (95%) and water to give 6-carboxy-2'-isopropoxy-flavone (45 g; m.p. 209-211 ° C).

By proceeding in a similar manner, the following compounds were obtained: - 6-carboxy-2'-propoxy-flavone, m.p. 201-203 ° C - 6-carboxy-2'-butoxy-flavone, m.p. 204-206 ° C; - 6-carboxy-2'-ethoxy-flavone, m.p. 225-227 ° C; - 6-carboxy-4'-isopropoxy-flavone, m.p. 263-265 ° C; - 6-carboxy-3'-isopropoxy-flavone, m.p. 235-237 ° C - 6-carboxy-2'-isopropoxy-4 '- (2-ethoxy-ethoxy) -flavone, m.p. 179-181 ° C; - 6-carboxy-2 '- (2-ethoxy-ethoxy) -flavone, m.p. 198-200 ° C.

EXAMPLE 2 a) A solution of methyl 3-acetyl-4-hydroxybenzoate (54 g) and methyl 2-benzyloxybenzoate (135 g) in dioxane (400 ml) was added slowly, with stirring, at room temperature 67080 50% of sodium hydride. (40 g) suspension in dioxane (150 ml).

The mixture was kept at 70 ° C for 5 hours, cooled and diluted with petroleum ether, then filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl acetate. The organic phase was washed with 5% potassium carbonate and water, and then evaporated to dryness. After crystallization from methanol, (2-hydroxy-5-carbomethoxy-benzoyl) - (2-benzyloxy-benzoyl) -methane (74 g; m.p. 95-97 ° C) was obtained, which was then refluxed for 24 hours. with% formic acid (500 ml). After cooling and dilution with ethanol (500 ml), the resulting precipitate was filtered and washed with ethanol to give 6-carbomethoxy-2'-hydroxy-flavone (31 g m.p. 290-291 ° C).

b) 6-Carbomethoxy-2'-hydroxy-flavone (5 g) obtained according to the method described in a) above was reacted in dimethylformamide (30 ml) with 3-ethoxyethyl bromide (3.5 g) and potassium carbonate. (3.2 g) at 80 ° C for 16 hours. The mixture was cooled, diluted with water, filtered and washed with water. After crystallization from methanol, 6-carbomethoxy-2 '- (2-ethoxy-ethoxy) -flafonone (4.5 g) was obtained, which was hydrolyzed with a 1% solution of potassium hydroxide (90 ml) in 95% ethanol at reflux temperature. minutes. Cool, acidify with acetic acid, concentrate, dilute with water, filter and crystallize from ethanol to give 6-carboxy-2 '- (2-ethoxy-ethoxy) -flavone (3.1 g; m.p. 198-200 ° C) .

Using the appropriate alkyl halide, the following was prepared: 6-carboxy-2'-isopropoxy-flavone, m.p. 208-210 ° C and starting from 6-carbomethoxy-4'-hydroxy-flavone, respectively: 6-carboxy-4 '- (2-ethoxy-ethoxy) -flavone, m.p. 221-223 ° C.

EXAMPLE 3

A solution of methyl 3-acetyl-4-hydroxybenzoate (16 g) and methyl nicotinate (23 g) in dioxane (100 ml) was added slowly at room temperature with stirring to a 50% suspension of sodium hydride (12 g) in dioxane ( 60 ml). The solution was kept at 80 ° C for 6 hours, cooled and diluted with petroleum ether (200 ml) and filtered. The resulting product was dissolved in water and treated with acetic acid. The resulting precipitate was washed with water and crystallized from methylene chloride / methanol to give (2-hydroxy-5-carbo-13,67080 methoxybenzoyl) -nicotinoyl-methane (17.2 g; m.p. 200- 202 ° C) which was then treated with ethanol (300 ml) containing 1% concentrated hydrogen chloride at reflux for 2 hours. Concentrated in vacuo-diluted with water, neutralized with sodium acetate, then the precipitate was filtered. The crude 6-carbomethoxy-2- (3'-pyridyl) chromone (15.1 g) was hydrolyzed with a stoichiometric amount of 1% potassium hydroxide in 95% ethanol at reflux for one hour. After cooling, dilution with water (600 ml), neutralization with acetic acid, the precipitate was collected and, after crystallization from dimethylformamide, 6-carboxy-2- (3'-pyridyl) -chromone (9.8 g, m.p. 350 ° C) was obtained. ; IR (KBr): δ (carboxy) 1680 cm -1, λ max (chromone) 1630 cm -1, 1610 cm -1, λmax (meta-substituted pyridine) 770 cm -1, 696 cm -1.

By proceeding in a similar manner the following compounds were prepared: 6-carboxy-2- (2'-pyridyl) -chromone, m.p. > 300 ° C; IR (KBr):

Yc_O (carboxy) cm-2 (chromone) 1650 cm-1, (c-H (ortho-substituted pyridine)) 768 cm-1; - 6-carboxy-2- (4'-pyridyl) chromone, m.p. > 350 ° C; IR (KBr): ν max (carboxy) 1690 cm -1, λmax (chromone) 1630 cm -1, λmax (para-substituted pyridine) 825 cm -1; - 6-carboxy-2- (2'-pyrazinyl) -chromone, m.p. > 350 ° C; IR (KBr): V c-g (carboxy) 1695 cm-1, ε-O (chromone) 1645 cm-1; - 6-carboxy-2- (6'-methyl-2'-pyrazinyl) -chromone, m.p. 320 DEG C. (dec.) IR (KBr), .delta. (Carboxy) 1700 cm @ -1, @ @ @ @ @ @ @ @ @ @ @ @ @ N-D - (chromone) - 1655 cm @ -1; chromone, mp 316-319 ° C.

EXAMPLE 4 6-Carboxy-2, -isopropoxy-flavone (3.2 g) was treated with a hot aqueous solution containing sodium bicarbonate (800 mg).

A small insoluble amount of acid was filtered off and the clear solution was concentrated in vacuo to near dryness. Treatment with acetone (200 ml) and crystallization gave 6-carboxy-2'-isopropoxy-flavone 67080 14 sodium salt (3 * 1 g; m.p. 300 ° C).

By proceeding in a similar manner, the following was obtained: the sodium salt of 6-carboxy-2- (2'-pyrazinyl) -chromone, m.p.> 300 ° C.

EXAMPLE 5 The sodium salt of 6-carboxy-2'-isopropoxy-flavone prepared according to Example 4 (5 g) suspended in dimethylformamide (50 ml) was treated with chloromethyl pivalate (5 ml) and triethylamine (1.5 ml) at 70 ° C. at 16 hours. The mixture was then cooled, diluted with water (500 ml), extracted with ethyl acetate and the organic phase washed with 5% sodium bicarbonate, then with water and evaporated to dryness. The residue was crystallized from isopropyl ether to give pivaloxymethyl ester of 6-carboxy-2'-isopropoxy-flavone (3.9 g; m.p. 102-104 ° C).

Using the same procedure, the following was obtained: 6-carboxy-2- (2'-pyrazinyl) -chromone pivaloxymethyl ester, m.p. 137-142 ° C.

EXAMPLE 6

The sodium salt of 6-carboxy-2'-isopropoxy-flavone (4 g) prepared according to Example 4, suspended in dimethylformamide (40 ml), was treated with chloroacetamide (1.25 g) and a few drops of triethylamine at 75 ° C for 24 hours. Cooled, diluted with water, acidified with acetic acid and filtered to give 6-glucolamide ester of 6-carboxy-2'-isopropoxy-flavone (4.2 g; m.p. 230-232 ° C) which was hydrolyzed in acetic acid (30 ml) and In 23% hydrochloric acid (20 ml) at 75 ° C for one hour. Diluted with water, filtered and crystallized from ethanol to give 6-carboxy-2'-isopropoxy-flavone glycol ester (3.1 g; mp 210-212 ° C).

EXAMPLE 7 2'-Isopropoxy-flavone-6-carbonyl chloride (5.6 g) Preparation: 6-Carboxy-2'-isopropoxy-flavone is suspended in benzene and treated with thionyl chloride at reflux, the solution is evaporated to dryness] dissolved in anhydrous benzene. (50 ml) was treated with diethylaminoethanol (4.2 ml) and triethylamine (1 ml) at room temperature for 4 hours. The benzene solution was washed with 5% sodium bicarbonate and water, and then evaporated to dryness. The residue was dissolved in acetone (100 ml); addition of a stoichiometric amount of concentrated hydrochloric acid gave 6-carboxy-2'-isopropoxy-flavone diethylaminoethyl ester hydrochloride. The compound (5.4 g; mp 215-217 ° C) was collected by filtration and washed thoroughly with acetone.

Using the same procedure, the hydrochloride of diethylaminoethyl ester of 6-carboxy-2- (2 * -pyrazinyl) chromone mentioned at the end of Example 5 was prepared, m.p. 113-115 ° C.

EXAMPLE 8 2'-Isopropoxy-flavone-6-carbonyl chloride (4.3 g) dissolved in anhydrous benzene (40 ml) was treated with N-hydroxyethylmorpholine (3.2 g) and pyridine ¢ 1 ml) at room temperature. at 24 hours. The benzene solution was washed with 40% aqueous citric acid, sodium bicarbonate and water and then evaporated to dryness. The recrystallized residue from acetone gave 6-carboxy-2'-isopropoxy-flavone morpholinoethyl ester (3.6 g; m.p. 133-135 ° C).

EXAMPLE 9 (2-Hydroxy-5-carboxy-benzoyl) -pyrazinoyl-methane (27 g) was treated with concentrated hydrochloric acid (20 ml) in acetic acid (200 ml) at reflux for 1 hour. After cooling, the precipitate was collected by filtration and washed with water and then in hot ethanol to give 6-carboxy-2- (2'-pyrazinyl) chromone 17.8 g, m.p. > 350 ° C.

Following a similar procedure, the following compounds were prepared:

6-carboxy-2- (2'-pyridyl) chromone, m.p. > 300 ° C

6-carboxy-2- (3'-pyridyl) chromone, m.p. > 350 ° C

6-carboxy-2- (4'-pyridyl) chromone, m.p. > 350 ° C

6-carboxy-2- (6'-methyl-2'-pyrazinyl) -chromone, m.p. 320 ° C (dec.) 6-carboxy-2- (5'-methyl-2'-pyrazinyl) -chromone, m.p. 316-319 ° C.

EXAMPLE 10 (2-Hydroxy-5-carboxy-benzoyl) - (2-isopropoxy-benzoyl) -methane (13 g) was treated with concentrated hydrochloric acid (10 ml) in ethanol (150 ml) at reflux for 1 hour. After cooling, the precipitate was filtered, washed with water and hot ethanol to give 6-carboxy-2'-isopropoxy-flavone 7.5 g, m.p. 209 to -211 ° C.

67080 16

Correspondingly, the following compounds were obtained: 6-carboxy-2'-propoxy-flavone, m.p. 201-203 ° C; 6-carboxy-2'-butoxy-f corone, m.p. 204-206 ° C *, 6-carboxy-2'-ethoxy-flavone, m.p. 225-227 ° C.

EXAMPLE 11 (2-Hydroxy-5-carboxy-benzoyl) - (4-fluoro-benzoyl) -methane (12 g) was treated with 57% hydrochloric acid (15 ml) in acetic acid (95 ml) at reflux for 30 minutes. After cooling, the precipitate was filtered, washed with water and hot ethanol to give 6-carboxy-U'-fluoro-flavone 6.9 g, m.p. 297-299 ° C.

By a similar procedure were prepared: 6-carboxy-3'-fluoro-flavone, m.p. 314-316 ° C.

EXAMPLE 12 (concerns the preparation of salt)

The 6-carboxy-2'-isopropoxy-flavone-diethylaminoethyl ester hydrochloride (5.95 g) prepared according to Example 7 was treated with an excess of 5% sodium carbonate at room temperature and the resulting free ester was extracted with ethyl acetate. The organic solution was evaporated to dryness *, the residue was crystallized from isopropyl ether to give 3.4 g of 6-carboxy-2'-isopropoxy-flavone-diethylaminoethyl ester (m.p. 76-78 ° C) which was dissolved in acetonitrile. (50 ml) and treated with maleic acid (0.93 g) at room temperature for 1 hour. After the precipitate was filtered, 3.35 g of 6-carboxy-2'-isopropoxy-flavone-diethylaminoethyl ester maleate (m.p. 158-164 ° C) were obtained.

Claims (1)

17 67080 CLAIMS A process for the preparation of novel pharmaceutically active 5: 6-benzo-β-pyrone derivatives of general formula (I) wherein R is phenyl substituted with fluorine or C 2 -C 4 alkoxy. or R 1 is unsubstituted or substituted by C 2-4 alkoxy, or R is pyridyl or pyrazinyl which is unsubstituted or substituted by methyl and their pharmaceutically acceptable salts or pivaloxymethyl, glycol, diethylaminoethyl or morpholinoethyl esters, characterized in that a) a compound of formula (II) is O HOOC-XCH II i (m kvA) H CO nr wherein R is as defined above is cyclized to give a compound of formula (I) or b) a compound of formula (III) is O HOOC (m) is reacted with a C 1 -C 4 alkyl halide which is unsubstituted or substituted by C 2 alkoxy to give a compound of formula (I) in which R is phenyl which is substituted with C2-C1 + alkoxy which in turn is unsubstituted or substituted with C2 alkoxy; and / or, if desired, converting the obtained compounds of formula (I) into pivaloxymethyl, glycol, diethylaminoethyl or morpholinoethyl ester and / or the hydrochloride or maleate of such ester, and / or converting the compound of general formula (I) into a pharmaceutically acceptable salt thereof.