CS202543B2 - Method of producing novel derivatives of 5,6-benzo-gama-pyrone - Google Patents

Abstract

5,6-Benzogamma -pyrone derivatives of the formula I: <IMAGE> in which the symbols have the meanings given in Patent Claim 1, are prepared by ring closure of corresponding benzoylmethane derivatives of the formula II. <IMAGE> They display antiallergic and antiulcerogenic actions and can be used in particular for the treatment of bronchial asthma and other allergic disorders.

Description

The present invention relates to a process for the preparation of novel 5, 6-benzo-gamma-pyrone derivatives of the general formula I

wherein n and n ^ n are 0 or

R is either cyano, carboxy or a group.

or (b) a -COR 8 group wherein R 8 represents an -NHOH group or a group of formula. Лю ·.

. N ^ * '• ·' \ _R - ·] 1 wherein R and R-θ ₁ and considerable individually is hydrogen or alkyl of 1-6 carbon atoms, _OR where R ^ _Q is hydrogen, ' R ₁ also denotes the group,,.

202543 * · 2 '´ · .. »'. Or a group of the formula -CH-COOH, wherein R 1 represents a hydrogen atom or an alkyl group having 1 to 6 'atoms.

¹ I. '' \ ·· •. . . . ^r 12. Λ. .

alkyl, or R and _Q new or morpholine ne'bo alkenyl - 1, 8 -to 12 together adjacent nitrogen atom form an N-pyrro1idinovou group or / с / group of the formula -COOR, wherein the carbon atoms, optionally substituted with one piperidine atom denotes an alkyl halogen, a carboxy group, a hydroxy group, a logene group, a (C1-C4) alkoxy group, an alkyl group containing from 1 to cyano group, of the general formula I. ^R 10. ... Fennel. optionally a substituent hydroxy group, a carbon atom of 4 and 4 carbon atoms, a nitrOB group wherein R 10a are as defined above, or a -OR 4 alkyl group having 1 to 6 carbon atoms, or a group of formula and / or -O-COR 14 wherein R 14 denotes

or

R ₁ 3 has the above ly hydrogen defined above, R and _R2 »which may be identical or different, represent jednotalkyl having 1 to 4 carbon atoms, hydroxy, nitro, cyano or alkoxy having 1 to 4 carbon atoms, R₆ and R -, which may be the same or different, each represent a hydrogen atom, an alkyl of 1 to 6 carbon atoms, a cycloalkyl of 3 to 8 carbon atoms, an aryl of 6 to 10 carbon atoms, optionally substituted with at least one substituent selected from s 1-4 carbon atoms, nitroacid - and cyano; and R g, which may be the same or different, are a single hydrogen or halogen atom, a hydroxy group, an nitro group, a cyano group, or

wherein R 10 and R 1 are as defined above, or (b) - (O) mR 3 wherein m is 0 or 1 and R is as defined above, or (c), -O-CO-R 5, wherein R 15 is as defined for R 15 or

1g denotes a group

wherein, R 1q and R 1 are as defined above, or a (d) group, -S-R 3, wherein R 3 is as defined above, wherein R 3 is as defined above; and R 8, when bonded to adjacent carbon atoms, optionally together form methylenedioxy, ethylenedioxy or propylladioxy, X is phenyl, or

A 5- or 6-membered heteroeonocyclic residue containing at least one double bond. having 1 to 2 heteroaoons consisting of a nitrogen, sulfur and / or oxygen atom, wherein the nitrogen atom is optionally bonded to an oxygen atom, such as an N-oxide, and the R- (CR 1 R 2) n is in the 6 or 7 position of the benzopyron ring. Excluded from the scope of the present invention are compounds wherein X is phenyl, n and n1 are zero, R8, R8, and R8 are both N and N; R 6 denotes a hydrogen atom or, when in the 3 'or 4' position phenyl, denotes R 8 a hydroxy group, an ethoxy group or an atom of chlorine, bromine or iodine and with another elimination of a group of compounds comprising 6-carboxy-3 ', 4'-methylenedioxyphosphonone, 6-carboxy-7-hydroxyethyl, 6-carboxy-5-ethoxy-4-methoxyphenone, 1-carboxyphenone, [7,4] 6-flavonylacetic acid, 7-flavonylacetic acid, 7-cyanoacids, 7-methoxycarbones, 1-lavon, 7-ethoxycarbonylphenone, 7-carboxameid 1, v-7 6-cyano-6-cyano-7-methoxy-6-cyano-7-methoxy-6-cyano-1-carboxylic acid, and 7,4-diethoxy-6-carboxy-flavone. . , 3. 202543 '

The invention also relates to pharmaceutically acceptable salts of the optical isomers of said compounds.

Examples of pharmaceutically acceptable salts are sodium salts and salts with 2-aminoethanol and 2-amino-2-hydroxymethyl-l, 3-propanediol. Examples of preferred compounds produced by the process of the invention are:

6-karboyy22'-opooPopofyflovon ,.

6-carboxy-2'-propoxyflavone;

--karaoxpyy * -butopyrlavone,

6-kar.booy-2'y / 2-methy0ρroρoxX / _flalon> ·.

6-cfoaopy-2 * 2/1-methyl · 0propoxp0flalone ,.

6-carbopy-2'2 (2-ethoxy-propyl) -flavone, 4-carboxy-1'-ethylthopylethoxide

6-carboxy-2 - / - eydropopropoxpholaluminum,

6-carbonyl-2'2 / 3-hydroxypopropoloflavone, 6-cyano-2222 / 2,3-dihydropyloxypropylphosphone, ‘.

6 · 2karaopp-2'2 / 2 “hpd roxyOatoopOflalon _>

6-carboxp '2' · / - hydro-ymethylpropooy / flalone, - ‘

6-Carbaxp-2 - / - H-Drops --- ™ meho-butapp-flavone, j

6-carbopp-2'-7-hydroxy-3-mithe-batapaplavil,

6-carboop-4 '- / - hydoopypoopoxy Oflalon,

7- karboxo22'yisoρooρopy f lavon ·

7-kaoaopy-2 * y / _{2-metholpoopoxy0fΓflon>}

7-carbopy-2 '- / l-meheypropoxp-flavone, γ-carboxy-2'y / 2-hydroxyypoppopO / lavon,

6-karaooy · 2 * -fmino0l · flon ,.

6-carbopp-2 * -d dmeehp lamirnooiavon ..

6-karaopy-2'y / N2metho1 · 'N' 2SopropylaminoOflone,

62kfraooy-2 “-i with oil naphthalone, ..

6-2karaoPOo222 2'2pooido1 / choomon,. . '

62k (rb ^> ^ 02223'2pyrido1 / chromium mon ₎

6-carbopp-2- / 2-pyridyl-N-opid / chromone;

6-2carbapp-2 '(3'-poridol-N-opium) chromatic,.

6 · 2-caraxoo22- / 2'-fur l / chromon ,.

6 - ^^ γ ^^} ^) ^ ο2 ^ 22 2-yimidazolyl / chromone ,,

6-carbopy-2- / 5-. _т daza lyl / choomon

-'- ppraziny 1 / chromoh ,, ·

6-k and rb exp ---- 4-isoprop-3-ypyrid-1 / chromium.,

6-carboxylic-2- (4 '- {- mercaptopropo-3'-pyridole / chromone), 6-carbo-β-Z-O-methyl-3-oxo-3'-pooidyl / ehomonium.

6-karaoxoo2-24- (3-methylbutyl) pyridyl / choomon, p '

6-karaoxoo2-23 * 2Lsopropoxy-2 * 2porido1 / chromone,

62-caroxy-2- / 3 - (- methylpropoxy --- ” ^, -pyoddylChohomonium,

62kafOaa0-2-2 - ‘/ (lymeehylpropopyO2- '2pooido1 / choOmon,

6-karaoxoo2- / 3 - "(3yme thylbutopy) 2'ypooido _I L / ,, croomon

6-carboxy-4'-3'y (- hydropopropopy) -'-poidol / chromone,

6-kaaBaooo82aflyl2-22'ypyrazinyl / chromone, δ-carbopp-γ-γ-yl-β-pyrimidone,

6-carbopy ---- popp0-2- (2'-porazines 1) chromon.

6-carbooy ~ --poopy1 --- / 3 '-pyr ddpicchoamon,

6-kaoaopp '- (ae ta-phenylvinyl) l .chramon,

6-methyl-β-phenyl-6-methyl-β-phenyl-2-carboxylic acid,

62karbeopo2-2ba t: a-2'2 (- ethooyethopyJfenolvinyl / chromone ^'! 6-karaoxoy2- / attf --'- (- hyiiroxyethopy-fenolvinylcehoamon, · · <..'

6-carbexoy2-2bata-2 * -22eУydopχyp (oepooo) phenylvinylnycone, • 202543 4

6 'carboxy-2- / beta-2 * - (3-hydroxypropoxy) phenylvinyl / chromone,

6-carboxy-2- [eta] - (2 ' -pyridyl) vinyl chloride, [beta] -carbonyl-27 [beta- (3'-pyridyl) vinyl] chromone,

6-carboxy-2-beta- (4'-pyridyl) vinyl7chromone,

7-carboxy-2- (beta) phenylvinyl / chromone

6-carboxy-2-beta- (2'-pyrazinyl) vinyl] chromone, as well as pharmaceutically acceptable salts thereof, especially sodium salts and hydrochloride esters of diethylaminoethanol and morpholinoethanol, as well as glycol esters and pivaloxymethyl esters.

The preparation of the novel 5,6-benzo-gamma-pyrone derivatives of the above general formula (I) by the process according to the invention is characterized in that the compound of the general formula II

wherein n, n 1, R 1, R 2, R 2, R 3, R 4, R 5, R 8, R 7, R 8 and X are as defined above, at a temperature of 20 to 120 ° C, optionally in the presence of acid catalysts; an inert solvent, and the compound of formula I obtained is optionally converted into another compound of formula I, and / or optionally the compound of formula I is converted into a pharmaceutically acceptable salt thereof, and / or optionally the mixture of optical isomers is resolved into individual isomers.

The cyclization of the compound of formula (II) is preferably carried out in the presence of acid catalysts, for example hydrochloric acid, hydrocyanic acid, sulfuric acid, formic acid, at a temperature suitably between 20 and 120 ° C and in an inert solvent selected for example from the group consisting of methanol, ethanol, dioxane, tetrahydrofuran, benzene, toluene, acetic acid and mixtures thereof.

The compound of formula (I) may be converted as described above into another compound of formula (I) by known methods.

For example, a compound of formula I wherein R is cyano may be converted to a compound of formula I wherein R ₁ is a carboxyl group by acid hydrolysis, for example with hydrochloric acid or sulfuric acid.

Similarly, a compound of formula I wherein R is a carboxyl group can be converted to a compound of formula I wherein R is a carboxyl group by esterification, for example, by reacting an alkali acid salt with the desired alkyl halide,

The free hydroxyl groups can be etherified, for example, by treatment with alkyl halides, or the etherified hydroxyl groups can be converted into free hydroxyl groups, for example, by treatment with a pyridine salt, preferably a hydrochloride, or a strong acid or a Lewis acid.

In a compound of formula I wherein X is a nitrogen-containing heteromonocyclic group, the nitrogen atom can be converted to the corresponding N-oxide by oxidation, for example, with a peracid such as peracetic acid, permaleic acid, and perbenzoic acid.

_s S '. A compound of formula I wherein R is a carboxyl group can be converted to a compound of formula I wherein R is a tetrazolyl group of formula

By known methods, for example by converting a carboxyl group to the corresponding halide, preferably chloride, for example by reacting with thionyl chloride in benzene at reflux and then reacting the halide with, for example, ammonia, a corresponding amide is dehydrated to n-itrile, e.g. with p-toluenesulfonyl chloride and pyridine and finally reacting the nitrile with sodium azide and ammonium chloride in dimethylformamide at a temperature ranging between room temperature and 100 ° C.

Also, the possible conversion of the compounds of the formula I into a salt can be carried out by known methods.

_From compounds of formula I have antia1ertičký effect, as evidenced by the fact that they are active in the test of passive cutaneous · anaphylaxis / PSA / rats by Goose and Blair A. Y. Μ. YN (Immunology, 1969, 16: 749). They can therefore be used in the prevention and treatment of bronchial asthma, allergic rhinitis, hay fever, urticaria and dermatoses. ·

An important peculiarity of the novel compounds is that they also exhibit an antiallergic effect also when administered orally.

The following table shows how protective effect is obtained with the compounds of the invention when administered orally in a passive cutaneous anaphylaxis (РСА) test in rats, compared to 2 well known antiallergic drugs, i.e., disodium cromoglycate (DSCG), and АН 7725 i.e., _x- 2-carboxy-7-hydroxyethoxyxanthone / filarton, -Martin, LE, and Vardey, C., Int. Sheet. All., 1973, 45: 84].

Table , ·

7, inhibition compared to control groups at various times after pretreatment

Compound Dose (mg / kg / p. o) 15 min 30 min 60 min 1 20 min DSCG 50 6.0 5.5 3.2 2.5 АН 7725 50 42.6 14.4 .13.3 3.8 6-carboxy-2-isopropoxyflavone 50 ' 82.9 39.5 27.6 24.4 6-carboxy-2- (beta-phenylvinyl) - chromon 50 69.9 45.8 19.6 16.6

In addition to the antiallergic effect, the compounds of the invention are effective in decreasing airway resistance and increasing lung susceptibility and can therefore be used to treat respiratory incapacity, such as acute pulmonary incapacity, as shown in rats obtained by the method described by Paleček. F., Palecekova M. and Aviado DM / Arch.

Environ. Health, 1967, 15, 3332-342]. ',

In these tests, the compounds of the invention, particularly 6-carboxy-2'-isopropoxyflavone, reduce airway resistance and cause lung susceptibility to increase even at a dose as low as mg / kg / L. v.

202543 6. At ‘/ · '

- 'At the same dose' successful antagonizing - (50%) the bronchoconstrictive effect of 5-HT / = 5'-Oydroxytriptamine, i. seiotonins (and compounds 48/80 (drug-inducing drug).

The compounds of the present invention further have an anti-ulcer effect, as evidenced by the test, to prove the effect of ulcer induced pressure in rats that have been subjected to a forced water bath at 25 ° C for 40 minutes. ppdle, adapted to the procedure described by Takagg, K and Okabe, S. / Jap. J. of Pharmaa., 1968, ‘- 18, 9 /. _

In this experiment, the compounds of the invention, and in particular the aqueous salt of 1,6'-carboxy-2'-8-propoxyflavone, produced 45% by weight. water-induced pressure in rats when administered at a dose of 50 mg / kg i.v. ’. . ·,

The compounds of the invention may be administered in a customary manner, for example orally and parenterally in a daily dose of preferably 0.5 to 14 mg / kg or inhaled, preferably in a daily dose of 0.5 to 100 mg, suitably 0.5 to 25 mg. mg or local application.

. The nature of the pharmaceutical compositions containing the compounds of the invention together with the pharmaceutically acceptable salts and diluents will depend, of course, upon the desired route of administration.

The compositions may be manufactured in a conventional manner with the usual ingredients. For example, the compounds of the invention may be administered in the form of aqueous or oily solutions or suspensions, jerkgels, as well as powders, tablets, pills, gelatin oappas, syrups or creams or ectos for topical use.

For oral administration from a compound of the invention, they may be incorporated into a suitable pharmaceutical composition; which are preferably tablets, pills or gelatine capsules which contain the active ingredient together with a diluent, such as lactose, lactose, saccharose, lung, saline, cellulose, maize, for example, silica, maize, stearic acid, magnesium stearate or calcium stearate and / or polyethylene glycol, or may also contain fats, such as starches, gelatin, methylcellulose, carboxyxyme gum, gum arabic, tragacanth, disintegrants, such as starches, dicarboxylic acid, alginates, sodium starch glycolate, foaming mixtures, colorants, sweeteners, smolders, such as -le-polysorbates, lauryl sulphates generally non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. The pharmaceutical preparations may be prepared in a manner known per se, for example by mixing, granulating. tabulation, film coating, or film coating process. ,.

For the treatment of allergic asthma, the compounds of the invention may be administered by isolation. For such use, suitable conditions may include a suspension - or solution of the active ingredient, preferably in the form of a salt, such as sodium salt, in water, for administration - oopoo: Optionally, the occlusion may consist of a suspension or a solution of the active ingredient in a conventional liquid ash, such as a jeans if luormethan or diclor tetrafluorethane, to be fed from a pressurized container, i.e. an aerosol disperser. packaging. - '

When the drug is insoluble in orcpelent ₁ , it may be necessary to add a co-solvent such as ethanol, propylene glycol, isotopes, and / or surfactant to the complex to suspend the drug in the proielestil environment and for this purpose one of the commonly used surfactants, such as non-surfactants, such as &quot; feel &quot;

The compounds of the invention may also be administered in the form of powders by means of a suitable dispensing device, and in this case, the powder particles of the finely divided active ingredient may be mixed with a diluent, such as sucrose.

Further, the compounds of the invention may be administered by intradermal or intravenous injection in the usual manner. '.

In addition to internal, 'served! compounds of the invention may be found. use for topical application, for example as creams, lotions or dermatological pastes. spared. For these compositions, the active ingredient may be admixed with emulsified or emulsifiable excipients.

The following examples illustrate but do not limit the invention.

Example 1 d 1 · -,

A solution consisting of 60 g of diethyl (3-acetyl-4-yloxyoxybenuost). and 120 k of methyl 1/2-isopropoxybenooate / -00 ml dioxane was slowly added by stirring at room temperature to a suspension of -5 g 50% sodium hytiride in 200 ml dioxane. The mixture is kept at 80 ° C for hours, cooled, then diluted with 600 ml of petruelther and then filtered. The collected precipitate was taken up in water, acidified with acetic acid and extracted with ethyl acetate. The organic phase is washed with 5% potassium carbonate and water, evaporated to dryness and crystallized from ethanol to give 70 g (2L · hydroxyl-5-carbomethoxybenzoyl) -122-trifluoromethoxybenzoyl methane (m.p. 105-107 ° C ₎ which is then boiled at with 280 ml of 99% formic acid.

After cooling and diluting with 1 L of water and filtration, the collected precipitate is crystallized. from acetone to give ^x 60 g of 6-carbomethoxy-6-isuprupoxyphosphonate (m.p. 15-155 ° C) which hydrolyze 1.020 g of 1% potassium hydroxide in 95% ethanol at reflux. minutes. The mixture was cooled, the acetic acid okyyelí and ^{u and} h .mu.l in vacuo to obtain a precipitate which is filtered, prumyje with 95% ethanol and water. After ethanol from ethanol, -5 g of 6-kluxux-2'-sopropoxyl isvon is obtained, mp 209-211 ° C.

The following compounds are obtained in the same manner:. . ,,.

6-carboyl-2- (2-propuxylphenone), m.p. Mp 201-203 ° C;

6-Carbonyl-2- (2-methylpropoxy) / phonone, m.p. Mp 193-195 ° C;

6'-carboxy-11'-butyllilon ₎ mp 204-206 ° C.

6 karboxy12'lethox1f Lavon, mp 225-227 ^ч О С ;. - ·

5-carboxy-4'-methuxylphenone, mp 2 65-267 ° C; , ⁶ ^ ^l ^ Albo / - ^1l2, 6 '^ ^l ^ says Methu ^! ^ Fl · AVOL), mp> ³⁰⁰ ° C; Ic ^(K Br): Vm ^- Ukarbux ^{y /} 1715 cm ^-1 ; mon / 1640 cm

6- klrbuxy ~ 2 '- / 1-methyl-propoxy / flavone, mp 186-188 ° ^C ;.

b-carbo-2-allylux-livui, m.p. Mp 193-196 ° C; '.

6-carboxyl-2'-puopuxy-4-chloroflavul, m.p. 300 DEG-302 DEG C .;

6-carbonyl-4-thiisuprups, m.p. Mp 172-174 ° C;

6-Carbonyl-12-iluprupy-fluvun, m.p. 218-221 ° C;

6-carbumelhoxy-2'-propoxyphenyl, m.p. Mp 211-213 ° C;

6 klrbu.melhooy1l2- / 2-meth ^yl Lpropoxy1fl.avul, mp 147-150 ° C;

6-carboxomexy-2 * -alkyloxyphenone, X.t. Mp 111-114 ° C;

6-Carbumetloxy-2 '- [1-methyl-propuxyl] -fluine, m.p. 132-135 ° C.

bycarboxy-N-isuprupyflavun, m.p. Mp 263-265 ° C;

O ^{carbomethoxymethyl-methoxy-2-6} * -dimetlux1flavul, mp 189-192 ° C ;.

6-klrbuxy-3 * - iluprupuxyfllVun, m.p. 235-237 ° C;

6-klrbuxyy4'lisoproρux1fllvun, m.p. 250 DEG-253 DEG C .;

6-carbonyl-4-carbonyl-2,4-dimethoxy-flavone, m.p. 210 DEG-213 DEG C .;

6-kluxux-2,3-dimethoxyphenone, m.p. &Gt; 320 ° C; , '

6-callybutoxy-2-isopropoxy-1-methoxyphenone, m.p. 178-180 ° C;

6-carbuxyr-4'-isopropux-4'-methoxy flavone, m.p. Mp 303-305 ° C;

6-carbomethoxy-oxyl-2-isopropoxy-ethoxy-ethoxy-flun, m.p. 132-134 ° C;

6- karboxy1l2-iluρrupoxy14 '- / 2 l-elhoxyethoxy / fll ^ ox, mp 179-181 ° C Starting with a hydrux ^y 1 - ac-t1lbentoátu, yielding: ·

7-carbuxyl-2-isopropylamine, m.p. Mp 282-284 ° C; mercuric acid; m.p. 122 DEG -124 DEG C .;

6-carboxy-374 "-dimethoxyflavon, mp 302-304 · '- ^O C -'.

In particular, from the 1-3-acetyl-1-4-hydroxybenzoate esters, the following compounds are obtained:

6-Carbethoxy-2-isopropoxyflavone, m.p. Mp 107-108 ° C; ,.

6-carbethoxy-2- (2H-pyrazinyl) chromium, m.p. 168 · to. · 169 ° C.

Example 2. ’'T. · ’\ ./

Solution 54 g of methyl (3-acetyl-4-hydroxybenzoate) and 135 g of methyl (2-benzyloxybenzoate) in water

400 ml of dioxane was added with stirring at room temperature to a suspension of 40 g of 508 sodium hydride in 150 ml of dioxane. The mixture is kept at 70 ° C for 5 hours, then cooled and diluted with petroleum ether and then filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl acetate.

The organic phase is washed with 58 potassium carbonate and water, then evaporated to dryness. After crystallization from methanol, 74 g of (2-hydroxy-5-carbonylethoxy) benzene are obtained, m.p. 95 DEG-97 DEG C., which is then purified. under reflux for 24 hours with 500 ml of 99a formic acid. After cooling and diluting with 500 ml of ethanol, the precipitate was collected by filtration, washed with ethanol, to give 31 g of 6-cardamethoxy-2 ' -hydroxyflavone (m.p. 29 DEG-291 DEG C.), which was then reacted at 150 DEG. m.1 dimethylaminamide with 26 g. of 1-chloro-2-benzoyloxypropane and 18 g of potassium carbonate at 70 ° C-16-1-1. г,. The mixture was cooled, diluted with B00 ml of water, filtered and washed with water to give 45 g 6lkarbáment Уáχy -'- l'-2-bel OA ^ ^ ^ lcxyl LRO] ^ (^ a ^ χl /: _l Lavan that 1.250 g of 1% potassium hydroxide in 95% ethanol were refluxed for 1 hour.

After cooling, the mixture is acidified with acetic acid and concentrated to a vacuum in vacuo and diluted with water, the precipitate obtained is filtered and then washed with water. Crystallization from methylene chloride and ethyl acetate gave 13.5 g of 6-carboxy-2 '- (2-hydroxypropoxy) by fusion, mp 211-213 ° C.

‘. The following compounds were obtained in a similar manner:

6-Carboxy-2 '- (2-hydroxyloxyethoxy) phonone, mp 238-240 ° C;

6-carbonyloxy-2'-1,3-hydroxypiperaphoxyxyflavone, m.p. 215-217 ° C; : '

6-Carboxy-2'-4-hydroxy-3-methylbutoxy / filane. ..

For example, 3 ', 6-carbomethoxyl-2'-hydroxy-oxalate, obtained according to the method described in Example 2, is reacted in 30 ml of dimethylaminamide with 3.5 g of bta-hexoxybromide and 3.2 g of charcoal. Potassium at 80 ° C for 16 hours. The mixture was cooled, diluted with water, filtered and washed with water. ,.

After crystallization from methanol, 4.5 g of 6-carbomethoxy-12,2-ethoxyethoxylate / phthalate are obtained which is hydrolyzed with a solution of 90 ml of 1% potassium hydroxide in 95% ethanol by refluxing for 45 minutes. .

After curing, the acetic acid is washed with acetic acid, diluted with water, filtered and stripped from ethanol. 3.1 g of 6-carboxy-2'-2-ethanol-thoxy / phonone, m.p. 198 DEG-200 DEG C., were separated.

The following compounds are prepared using suitable alkyl halides:

6-carboxy-2-i, s-o-poxyfl and von, mp 208-210 ° C; .

20'2543

6-k-arboxy-2 '- (2-methylpropoxy) flavone, mp 192-194 ° C;

6-carboxy-2- (2-hydroxypropoxy) flavone, mp 210-212 ° C;

6-carboxy-2- (1-methylpropoxx) flavone, mp 186-188 ° C; . . |

6-carboxy-2- (2,3-dihydroxypropoxy) flavone, m.p. 213-216 ° C;

6-carboxy-2'-benzyloxyflavone, mp 288-290 ° C;

6-carboxy-2 '- (1-methyl-2-N, N-dimethylaminoethoxy) flavone, m.p. 120 ° C (dist.); 6-carboxy-2- (2-N, N-dimethylaminoamino) flavone, m.p. 204-206 ° C;

analogously, starting from 6-carbomethoxy-4-hydroxyflavone, the following compounds are obtained: 6-carbooyl-4-methoxy-oxytytoyl / flavone, m.p. 221-223 ° C;

6-carboxy-4 '- (2-hydroxyethoxyphosphonone, mp 309-312 ° C). _y

Example 4

46.2 g of (3-acetyl) -cincinoyloxybenzzoate (t). 97 DEG-99 DEG C., dissolved in 350 ml of ethyl acetate. After. The addition of 37 g of anhydrous potassium carbonate st-mixture maintained at reflux. . ‘

After cooling, the mixture was diluted with 500 ml of petrol and filtered, and the collected precipitate was diluted with water, acidified with acetic acid and extracted with ethyl acetate.

The organic phase was washed with 55% potassium carbonate and water, then evaporated to dryness. After crystallization from methanol, a sufficient 31.2 g of (2-hydroxy-5-carbo-thoybenzoyl) (cinaamoylmethane) m.p. 138 DEG-140 DEG C.), which was refluxed for 15 minutes with 140 ml of 99% formic acid. After cooling, the mixture was diluted with 1 liter of water and filtered, and the collected precipitate was crystallized from acetone to give 27.8 g of 6-larbomeehloxy-2- (beta-phenylvinyl) -hoimone (m.p.). 175 DEG-177 DEG C. which hydrolyzed with 600 ml of 1% potassium hydroxide in 95% of ethanol at reflux for 45 minutes.

After acidification, acidify with acetic acid, evaporate in vacuo, and dilute with water. The compound was collected and washed with water. After glacialization from actton st, 16.1 g of 6-carboxy-2-tert-phenyl-phenylmethyl-chomol, m.p. 273 DEG-275 DEG C., is obtained. .

Using the appropriate methyl esters of 1,3-ethyl-4-hydroxybenzoate, the following compounds are prepared: 6-larbooyl-.alpha.-methyl-.beta.-phenyl-phenyl / lolone, m.p. 220-222 ° C; 6 "catboxy-2-7beta" 2'-methoxyphenylvinyl (lhoomon, m.p. 270 ° C (solid);

b-ka-tjxyy2- [beta- ⁽³ '-pjy-pyridyl) ^vi lУ CHT ^ ^l ^^ a ^ ^{one, i. p.} > ^{350 °} C;

IC / KBr / t ^ c ^«o '/ carboxy-1710 ^{cm -1} *? 0-с / Chrome / 1655 cm ^{-1» 1640} cm ~ \. ¹

6-karbumiehluy-2 / Alla-meehl / ~ ppfenyLviny1 / chrumon, mp 147-151 ° ^C;

6-larbomeehouy2- [beta] - 2'-methylphenylvinyl 1) chromone, mp 186-187 [deg.] C .; .

and analogously, starting from 3-cinnamoyl-4-acttylb-nzuate (mp 91-94 ^° C), the following compounds are obtained:

7- [2- (beta) -phenyl] -hioliol, m.p. 272 DEG -273 DEG C .;

7-larbomethyl-2- (be-8-f-ylvinyl) -human, m.p. Mp 171-172 ° C.

PPřklaaS

Using the method described in Example 4, starting from methyl Q-acetyl-4- (benzoyl-yoyl-yoyl) -benzoate, and hydrolyzing the benzyl-threo group by refluxing for 24 hours with an excess of 99% acid. formic acid, yielding 6-carbomethoxyl-beta-2-l-pyrrolidinylphenol, which after crystallization from acetone has a melting point of 252-254 ° C.

g of this preparation is dissolved in 35 ml of dimethylformamide and treated with 4.2 g of beta-ethoxyethyl bromide and 4 g of anhydrous potassium carbonate at 70 DEG C. for 24 hours. After cooling, it is diluted with water and filtered. the collected precipitate is hydrolyzed. Stoichiometric with 1% potassium hydroxide in 952 ethanol at reflux for 1 hour.

After cooling, diluted with water, okysseí with citric acid, the precipitate was collected and crystallized from methanol and benzene to give 3.6 g 6 ^y kareoxyy2- [beta ^y / "- // ^y eChrxsethoxy / fenylvinyljcroomon, .tt 218 ° C za rozklad ..

Using the appropriate alkyl halides, the following compounds are obtained.

6- oxy ^b ar ^{to s} 2 ^[b eta-2 "- / 2 ^y y ^y rxxy ^p ro ^p ox ^y / ^{F C} en ^yl vinyl chromone, mp ^231-235 ° C ;,

6-carbonitrile ^b oryy2-2 ^b BTA - / '- ^y i8oproprxyftn lvInyl / ch.rαmon ^ mp 246-248 ° C;

6-carbonitrile onxy222 ^{b-3 b} eea -mmthox ^y * ^y yvinyl yen / choDmon, mp 271-273 ° C; 6 kar ^{y b y} oo y2-2 ^b eea ^yl 4'-methoxyphenyl Svinyl ^y / ¢ hroron, mp 280-282 ° C;

6-karЬorX-2-2 / EEA-4'-methslfen vin ^y ^ ^y iC-hormone., Mp> 320 ° C ;.

6-carboxxy ² 2 / beta-4 '' -fluorophinyl vinylchocho, mp> 300 ° C; 6-ka2ermreh oχs ^2-22 / EEA-4'-fUurfein lvin ^{y y} / Cc2roron, mp 193-195 ° C ..

and analogously, starting from methyl 3-acetyl ^y 4 ^y Para ^{y y y} acryryl yyryl arryryl ^y etnort, the following compounds are obtained:

6- [4- [4- (2-methyl-4-hydroxyphenyl) vinyl] cdroomone, mp 337-338 ° C; 6 ^y karbomreh oχ ^{y-222 y b} eta-4 hydroxyftnylvinyl / chroron, mp 316 to 317 ° C; 6-carboxy-4 ooχy222beea ^b * -i8oρroprxsfenylviiylCchooron, mp 245-246 ° C; 6-carboxylic acid-22 / eea-4'-18-proproxyoxyphenylvinylC-hooro, mp 134-136 ° C; ⁶ ar ^{e 2k} ox ^χy 2 ^- [Bee-4 ^'- / ^/ -E ^c hox ^y et ^- OX 7 ^{with phenyl l} vin ^y l ^c -hoorrn, mp. ^{Mp 248-249} ° C; . ·

^6-y ka.rbrmrth oχs2 - 4'27 Bee ^{y 2y} ec0oxyeChrxy / lvis ein ^{y y} ДCchroroi, mp - 146-147 ° C ..

Example 1. and d 6 ·, J

A solution consisting of 16 g S-Reeh / З acets1 ^{y 2 4} -hyУroxyЬenzόátu / and 23 g гь-Ь-lníkotinátu in 100 ml of dioxane. pommlu is added at a temperature to have a stirred suspension of 12 g of 502 sodium hydride in 60 ml of dioxane. The solution is kept at room temperature for 6 hours. The reaction mixture was diluted with 200 ml of petroleum ether and filtered. *

The product obtained is dissolved in water and treated with 8 acetic acid, the precipitate obtained. Wash with water - and crystallize from. m.p. of Senchloride and methanol to give 17.2 g of (22-hydroxy-25-carbethoxyoxy) silicon dioxide. 200 DEG-202 DEG C., which is then treated with 300 ml of ethanol containing 12 N hydrochloric acid at reflux.

After evaporation in vacuo, dilution with water and neutralization with sodium acetate, the precipitate was filtered. 15.1 g of crude 6 karborethoxyy ^{y 2} - / 3 ^'s pyriУs1 / chromone hydrolysed h ^^' with STTC-12 iorttrCcýýr amount of potassium hydroxide in 952 of ethanol under reflux for 1 hour.

After cooling, diluted with 600 ml of water, neuuralizuje acetic acid, the precipitate was collected and crystallized from УImethylrormarIУu 9.8 g karerxyy 6 ^{y 2} - / 3'-pyriУχl / chromrnu / tt> 350 ° C /;

IC / KBr /: ^'C-9 0 / carboxy-1 ⁶⁸ 0 cm' \ '/.Jc^omm/' ¹⁶³⁰ - cm '\ ^{1610 cm "1,} y ^ / ^h, and methyl t ^-

-1.

Dried 770 cm @ -1 ⁶⁹⁶ cm. '

The following compounds were prepared in a similar manner:

6 arboxys ^yk - 2 / ^- * -ps2idSí / chromone, mp> 300 ° C ;, ^{iC / K} Br / ^ - ^ ^ carbonyl xyl / ^{1-7 10} cm ', 9 ^ Mrcmop ¹⁶⁵⁰ cm \ ^ ^c -i ^/ r2t ^- rsu ^b st ^tu o o oi oi n / 768 cm \ 11

6-carboxin-2- (4'-pyridyl) crotin, mp> 350 ° C; CC = (Cg): _{c = 0 (} carboxyl). 1 690 cm² ¹ , cs0 ^ ehrúmon / 1630 cm @ -1, g _e ^ / para- subs titolated pyridine / 825 cm @ -1;

6-carboxen2 '/ 2 th-thienes // crtoπltn, m.p. 301 DEG-304 DEG C .; *

6-C182 (2'-furnace) crmtn, m.p. Mp 330-332 ° C;

6 karboxyn22 / 2 "-pnrazinnl / hhoomtn, mp> 350 0QJ ^iC / _C КВгЛ ^{-g /} carbonyl ^b Ox'yl / ^{1695 cm} '\ ^ Mhromoi ^γ ^ 1. ⁶⁴⁵ cm &lt; 6 &gt; -carboxamide / 2 &apos; (2 &apos; -imidazolyl) chtomone, mp 338 DEG-343 DEG C .;

.alpha.-carboxyl / 1700 cm @ -1;

6-carboxy-2- (2'-isopropyptxy-3 '-pyrrolidine) -cromin, m.p. 285-288 ° C; 6-carboxn22 / 3 * -methxxn2'-pyrimidine / chromont m.p. 322 DEG-324 DEG C .;

6-carboxy-2- (6'-methyl-2'-pyrazine), mp, 320 ° C (dec.), IC (KBr): 9 _n (choomon). '0x0

655 cm c; .

6-1 (m.p. 316 DEG-319 DEG C.);

6-carboxχ-2 * - (3 * -pridridine) / chtooon, m.p. &Gt; 320 ° C, IC (KBr): 9 ° C-0 / chromium / 1635 cm -1;

6-carboϊnetXhoχ ´ · 2 "/ 2 '" pyrIdnl / chtooon,

6-Carbetoxy-2 '/ 3 * η ^) ^ 1 ^;

6 "carbohoxho2-2 / 4-pnrIdnl / chtooon,

6-carbomethoxyl-2- (2'-thienyl) chromene,

6 "karbooethoxχ-2 - / 2 * -furnl / chtόoon, m.p. Mp 226-229 ° C;

m.p. 194 to 196 ° C; m.p. 211 to 213 ' ° c; m.p. 207 to 210 ° C; m.p. 194 to 196 ° C;

6-carbumetoxox-2- / 2 * -prazrazines1 / cУromone, m.p. 232-234 ° C;

6-carbooethoxy-2- (3'-methoxy-2'-pyrrolidyl) chromone, mp 203-205 ° C; 6-carboxyethoxyl-2- (3'-isopropylthio-2'-pyridine) -the, mp 154-157 ° C; 6-carbomethoxy-2 "/ 6"-methylene-2'-pyrazine / chodmon, mp 204-206 ° C; 6-Carbomethyl-2- (5'-methyl) -2'-nitrazone / acetone. _> Mp 240-242 C; 6-karbomethooχn22 / 3 ^{^} -pyridazinnl / _l chtcmtn mp 295-298 ° C.

Example 7

Using the method described in Example 6, starting from m-tert -benzoate _and acetylbenzoate, the following compounds were obtained: 7-carboxoxy- (2'-pyrazinyl) choomon , mp> 340 ° C ^{IR / Kb /:} Co / kaarboxyl / I 705 ^{cm "1,} ·, ^{1640 cm".}

Starting from methyl 3-hydroxy-4-acetylbenzuate, 7-carboxy-2-piperazin-2 ^- yl-hromone, mp 340 ° C, was obtained from thiyl-3-acttyl-4-acetyl-4-acetylbenzylate. 6-Carb 2- (2'-pyrazinyl) - (thunder, mp 168-168 ° C).

Příkklas *

Following the procedure of Example 1, when starting from meehyl- / 3-ethyl acetate / 4 ⁴ -nydroxybtnzoátu / a'vhodného methyl / N-allyl-1 and Ν, Ν / diallllantУ / Anil uj obtained with these. compounds:

6-box (s) “2 '“ dimttУylamlnuϊ: lavun, m.p. Mp 177-18 ° C;

6-carbumethoxyl-2'-N- / thylaminotlavun, m.p. 200-203 ° C; 6 (ka) box-2-N-ethylaminoflavone, m.p. 302-305 ° C;

6 · carbuethoxy-2-N-ethylaminophenone, m.p. Mp 165-168 ° C; 6 karbumethoxχ-2 ' -N, N-dimethylaminof1avon, mp 142-146 ° ^C; 6 ° / ka (boxχ-2 *) inside and outside, mp 238-241 ° C;

6-carbuxy-2-a-alanoflavone, m.p. M.p.> 30.0 ° C. .

202543. 12,

Example 9

Following the procedure of Examples 2 and 3 starting from the intermediates methyl (3-acetyl-4-hydroxy-5-allyl-benzoate). 106 DEG-108 DEG C. and methyl (3-acetyl-4-hydroxy-5-propylbenzoate) m.p. mp 89-91 ° C, prepared according to the method described in J. Pharm., Soc. Japan 74-, 47 (1954), the following compounds are obtained:

6-carboxyl-8-propyl-2'-iopropoxyflavone, mp 205-207 ° C; 6-carboxy-8-a1lyl-2 ^- - / 2-hydroxyythoxyyflavon, mp 242-244 ° C. .

Ppíksa’io. .

Following the procedure of Example 6, starting from the same intermediates as in Example 10, the following compounds were obtained:

6-carboxyxy-8-allyl-2- (3'-pyridyl) chrooop, m.p. 318 DEG-323 DEG C .; 6-carbomethyl-88-proprole- (2'-pyrazpyyl) -cboomon, mp 206-207 ° C.

A portion of 6-carboxxy-2 / 3'-pyrrolidinone suspended in 500 ml of acetic acid was treated with 100 ml of 36Z hydrogen peroxide at reflux for 24 hours. After cooling, diluting with water and filtering, the collected precipitate was crystallized from dimethylformamide to give 5.8 g of 6-carboxy-2- (3'-pyridyl-N-oxide), (mp> 320 ° C), IC). KB'r / 9 _c _O / carboxy ^{1/1 7} 00 cp "\ ^ _ ^c ₀ ^/ /chro°.op ^{/ 1650} cm '\ ^ N ⁰ * ^{1280 CN'} ^ ·

The following compounds are obtained in an analytical procedure:

6-carboxylates - / 2'-uyrides - »- oxide / yhoooon, m.p. &Gt; 300 ° C;

6-carboxy-2- (4'-pyridine-N-oxide / yhoooon), m.p. &Gt; 320 ° C. ‘.

Example 12.

6 g of 6-carboxy-2'-isopropoxyflavone suspended in 75 ml of 1,2-dihydropropane are treated with 6 ml of thirylcyclic acid at reflux temperature for 1 hour.

The solution was then cooled and 15 ml of ammonium hydroxide (28Be) was added with vigorous stirring. After 1 hour after dilution with 300 ml of ethyl ester and filtration, 21 g of 4-carboxylate were obtained. Sophouoxyflavone / t. Ť. 267 DEG-270 DEG C.), which was treated with 37.5 g of p-trifluoromethylphenyl chloride in 33 ml of pyridine, 160 ml of diethylformamide at 90 DEG C. for 8 hours.

After cooling, dilute with 1.5 l of water and filter. The collected precipitate was dried and washed with 300 ml of hot isophropylether to give 15.6 g of 6-cyano-2‘-isopropoxyphenol / t. 172 DEG-175 DEG C., which is then treated with 33 g of sodium azide and 27 g of ammonium chloride in 120 ml of dimethylamide at 100 DEG C. for 4 hours.

After cooling, it is diluted with 600 ml of water, acidified with concentrated hydrochloric acid and filtered. 11 g of 6 ' - [5-tetrazoyl] -2 & apos ^; -pyropropoxyphenol having a melting point of 293 DEG-295 DEG C. are obtained after crystallization from chloroform and ethanol.

Example '11'

The procedure is as described in Example 12, starting from 6-carboxoxide (3 'pyrimidine) made from a redoxide of ethyl ester with ammonia gas in ethanol at 0 ° C. at 6 hours, 6- (5-tetrazolyl) -2- (3'-pyrazole) was obtained in a yield of 85%. .

Using the same method, the following compounds are obtained:

6-75-tetrazoly1-2 - '/ 2'-pyricly] ./ chromone, mp> 300 ° C /roZ^l./ IR / KBr /: ^y gamaNH tetrazole / ^{3100 cm -1; 2,770} 0 cm ^{; ;} ; ^ 1 1 ²⁰ ca ¹ ''

6- (5) tetrazolyl] -2- ^y 2'-py > 310 ° C, (dec.), IC &apos; γ ( ₌ 0) chroma / ⁶³⁰ cm ^{; J} ;

6-kaaboxaaido-2- (2'-pyrrolidinyl) haoaon, m.p. ; 329-331 ° C; Mp 262-264 ° C.

Example _ U ',.

Ha (6.3 g) of 6-kaabloxy-2 '(Sloplopyloxyflavone suspended in 25 ml of benzene sc) was treated with 1.8 ml of tinnyl chloride at reflux for 1 hour. The solution is then evaporated to dryness in vacuo and the residue is dissolved in 45 ml of 1,2-dichloroethane and treated with 2 g of ammonium taazole and 2.7 g of sodium hydrogen carbonate and stirred at room temperature. 3 hours. The precipitate thus obtained is filtered, washed with water and crystallized from dimethylformamide to give 4 g of 6- [5- (ethoxy) -llylcarbonyl] -cddl ( ² ') isopropoxyphenone (mp 275-278 ° C),

Example5

3.2 g of 6-carboxy-2-β-piperopoxyfaavone are treated with 80 ml; of a hot aqueous solution containing 800 mg of sodium hydrogencarbonate. ; Small 'knows undissolved parts; the acid is filtered off and the clear solution; Evaporate in vacuo almost to dryness. Working up with 200 ml of acetone gave 3.1 g of sodium 6 (carboxy-2 ' -L-propropylphosphonone). t> 300; ° C ..

Sodium salts of the following compounds are prepared in a similar manner:. ,. '

6-b ^ar to ^гy y - '/ ^2-y lip ^h roρoyy yl ^{p / f1} and ^outwardly, mp> ³⁰⁰ ° CI 6-b ^ar to ^гy yl-2' - / ^ 1 -math ^hУp after Pгy ^{l y} fla ^al n, ^ t. ^{&Gt; 300} ° ^C;

6- / karboxyy2 ^'/ / 2-h ^yd roxyprlpoxy Ид ™ · ^{y 0; t} . ^t . ^{&Gt; 300} ° ^C; , '6 / K ^and RBO χy ^χ / - / 2' / ^y pyrazíoy1 / ^h omou tt /> 300 ° C. ^y

Example 16

To 5 g of sodium 6,6-carboxy-2'-isopropoxyphaavone prepared according to Example 15, which is suspended in 50 ml of dimethylformamide, is treated with 5 ml of chloromethyl iodide and 1.5 ml. of trimethyl / amine at 70 ° C for 16 hours. The mixture is then diluted, diluted with 500 ml of water, extracted with ethyl acetate / ethyl acetate, and the organic phase is washed with 5% sodium hydrogen carbonate, then with water and finally evaporated to dryness. The residue was crystallized from isopropyl ether to give 3.9 g of 6-carboxylic acid 6-carboxymethyl ester of 6-carboxylic acid polyoxyl (mp 102-10); 104 ^Q Cf-.

By offering the same method, pivalome Ciesyesters of the following compounds are obtained:

6-carboxy] - (2'-pyazazinyl) hlpaline, m.p. Mp 137-142 ° C. .

P ř; i k 1 a; ; d · 17

To 4 g of 6-caaboxy-2'-isoppaopoyylamine salt prepared according to Example 15, which is suspended in 40 ml of dimethylformamide, is treated with 1.25 g / hracracetamide and seeded with drops of tritium at 75 ° C for 24 hours. Dilution with water, acidification with g / taohac acid and filtration yielded 4.2 g of 6-glycamammyl-6-carboxy-2-t -propoyanavone ester (mp 230-232 ° C ⁾ , which was hydrolyzed in 30 ml of acetic acid and 20 ml of 23%. hydrochloric acid at 75 ° C; 1 hour. Dilute with water, filter, crystallize from ethanol and give 3.1 g of glycolate 6 (carbonyl): 1-methyl-1-carboxylic acid. mp 21 ° -212 ° C ^y .

a '

Analogous procedure. · The glycol esters of the 6-carboxyflavones listed at the end of Example 16 are obtained.

Example 18

5.6 g of 2-isopropoxyflavone-6-carbonyl chloride prepared in accordance with Example 14 are dissolved in 50 ml of anhydrous benzene and treated with 4.2 ml of diethylaminoethanol and 1 ml of tri-β-α-α-η at room temperature for 4 hours. The benzene solution was washed with 52% sodium metabisulphite solution and water and evaporated to dryness. The residue was dissolved in 100 ml of acetone, a concentrated solution of concentrated hydrochloric acid was added to give a precipitate of diithylaminoethyl hydrochloride of 6-carboxy-2-isopropoxyflavone. '

5.4 g of the compound, m.p. 215 DEG-217 DEG C., is collected by filtration and washed thoroughly with acetone.

Using the same method, 6-carboxy-2- (2'-pyrazolylmethyl) -ethylthiomethyl ester esters hydrochloride were obtained. 113-115 ° C).

Example '' 19

4.3 g of 2 ' -isopropyloxy-vinyl-6k _and arlyl-thiophene-1-chloro prepared according to Example 14 are dissolved in 40 ml of anhydrous benzene and treated with 3.2 g of N- hydrochloride and 1 ml of pyridine at room temperature for 4 hours. . The benzene solution was washed with a 402 aqueous solution of citric acid, with sodium bicarbonate and water, and then evaporated to dryness. The residue crystallized from acetone gave 3.6 g of 6-carboxy-2'-suopoopoxyphosphoravone (m.p. 133-135 ° C).

Following the procedure of Example 18, the following were obtained.

compounds:

6-2-N, N-dimethylaminoethoxycarbonyl-2'-opropoxy flavone, m.p. 71 to

6- (2-N, N-dimethylaminothoxycarbonyl) -2- (2'-plraziol) -yhoomoo, m.p.

6-2-N, N-pyrrolidoylethoxycarbool17-2'-isopropylphosphine, m.p. 101 ° C;

Mp 116-118 ° C;

1 (01 ° Cj

EXAMPLE 21 21. The 2'-isopropoxyflavoo-6-camphorol chloride prepared by the procedure of Example 17 was treated with an excess of anhydrous ethanol at a lower temperature to give 6-carbethoxy-2'-isopropoxyllavone, m.p. 107-108 ° C.

The 6-carbonyloxy-2- (2 '-pyrazolyl) cronmoo, m.p. 168-169 ° C, was prepared in an yes-like manner.

Example 22 *

Following the procedure of Example 5, starting from methyl 3-acetyl-4- (4'-fluorobenzyloxyl) benzoate, the following compounds were obtained:

6-carboxymethoxy-4'-fluorolavun, t, t. Mp 218-220 ° C; 6-carboxy-4'-fluorophavavoo, m.p. M.p. 297-299 ° C.

Aaologically prepared:

6-kafbomeihУoyy-2-htooflavuo, m.p. 162-163 ° C,

6-caffeine-2-chlorophenyl, m.p. M.p. 277-278 ° C. 6-carboxy-3'-fluoroflavuo, m.p. 314-416 ° C.

. '202543

EXAMPLE 1 a d 23 g of methyl 13-acetyl-4-hydroxybenzoate in 100 ml of dioxane are reacted with 10 g. 2-isopropyloxy-5-methylbenzoyl chloride in the presence of 10 ml of pyridine at temperature for hours. After dilution with water, the precipitate is extracted with ethyl acetate and the organic solution is washed

.. ·. * '’.

5% sodium hydrate and water and then evaporated to dryness to give 13 g -

Acetyl-A-Z 2 isopoopoxy (4'-methylbenzboroxyl) benzoate (oil) which is dissolved in 200 ml of methyl 1-ketone and treated with 22 g of anhydrous potassium carbonate while stirring at reflux temperature for 2 hours. for 4 hours.

After cooling, the reaction mixture was diluted with ice water, extracted with ethyl acetate, the organic solution was washed with water and evaporated to dryness. A residue of 12.7 g is crystallized from methanol to give 8.1 g of (2-hydroxy-5-carbomenhoxybenzoyl) - (2-isopropoxy-5-methylbenzoyl) meethan, m.p. 85-86 ° C, which is refluxed. 15 ml s.30 ml 99% formic acid.

After cooling and diluting with water, the precipitate is extracted with chlorine (MgSO4) and the organic solution is washed with water until neutral and then evaporated to dryness. The residue is crystallized from roethanol to give 6.3 g of 6-carbomethoxy-2'-isopropoxy-1'-methylflavone, m.p. 149-151 ° C, which is hydrolyzed with 1% potassium hydroxide solution in 95 ml of 95% ethanol at reflux temperature. After cooling, the reaction mixture is acidified with 23% hydrochloric acid to pH 3 and the precipitate is filtered off and washed with ethanol and water to give 5.9 g of 6-carboxy-2'-isopropoxy-β-methyl mp 209-210 ° C.

The following compounds can be prepared by annlogic procedures:.

6-Carbonyl-2-nitropropyl-3-methylflavone, m.p. 198 DEG-200 DEG C .;

6-carboxy-2'-isopropoxy-4'-methylphenone, m.p. 296-298 ° C; .

6-carboyl 2 2'-10-propoxy-5'-weight gravone, m.p. 203-205 ° C; 6-carboxy-2-isopropoxy-5-propylflavone, m.p. Mp 236-237 ° C.

Example 1 a d 24

A solution of 6 g of methyl 4-aceny-1-4-hydrateeazate and 12 g of methyl-2-methoxy-5-methylbenzoate in 40 ml of dioxane is slowly added to the 50% slurry of 4.5 g of sodium hydride with stirring at ground temperature. The mixture is kept under stirring at 80 ° C for 3 hours, cooled, then diluted with 100 ml of pelletter and filtered. The precipitate was dissolved in water, washed with acetic acid and extracted with ethyl acetate. (

The organic layer was washed with 5% potassium carbonate and water, then from steam to dryness, and washed with ethanol from ethanol to give 7.9 g of (2-hydroxy-5-carboxymethylaminocarbonyl) - (2-methoxycarbonyl) -. 5-methylthiazolyl (methalal) / t. 145 DEG-147 DEG C., which was then heated to reflux. 15 ml of 99% formic acid. After cooling and dilution with water and filtration, the combined precipitate became ui *. from acetone to give 6 g of 6-carboxymethoxy-2'-methoxy-5-methylphenone, m.p. 154-156 ° C, which is hydrolyzed with 100 ml of a 1% solution. of potassium hydroxide in 95% ethanol at reflux for 30 minutes.

The mixture is cooled, acidified to pH 3 with 23% hydrochloric acid, and the precipitate is filtered off, washed with 95% ethanol and water to give, after crystallization from ethanol, 5.5 g of 6-carboxy-2 &apos; -methyl-5 &apos; -meenylflaerns, nn. to 247 ° C.

Example 1 and d 25. . ' .

20 ml of concentrated hydrochloric acid in 200 ml of acetic acid are added at boiling point to 27 g of (2-hydroxy-5-carboxylic acid-ayraziarylmethane) and the mixture is boiled for 1 hour. After cooling, the precipitate is separated and washed with water and then with ethanol to give 17.8 g of .alpha.-carboxy-2- (2 &apos; -pyrazinyl) omen, n. X &gt; 350 ° C.

The following compounds were prepared in an analogous manner:

6-carboxy-22 / .2' thienyl / chromone _one mp 301-304 ° C

6-carbooyl 22 / 2'-furyl / chromin, m.p. 330-332 ° C,

6-carboxy-22 (2'-imidazolyl) croomone m.p. 338-343 ° C,

6 (ki ^ ihb) -2 (2 ', 2', 2 ', 2', 2 ', 2', 2 ', 2', 2 ', 2', 2 ', 2', 2 ', 2', 2 ', 2', 2', 2'- ’> 300 ° C

6-carboxy- (2 ', 3', 2-idyl) choomoni m.p. > 350 ° C, 6-carboxy (N) -pyridyl / choomoniate m.p. &Gt; 350 ° C; N-carboxy-2-carboxylic acid-pyrazine-1-carboxylic acid m.p. 320 ° C decl

6-carboxy-2 ' ^, 15' ^, methyl / pyrazinyl / homonone mp 316-319 ° C

6-kahboyy-2- 13 * 2-pyridazinyl / hhoomon1 m.p. > 320 ° C. ’

Example 26.

13 g (2) (hydroyy-5 ·) kahboyybeilzool122-soppoopoyybenzoyl (methane) are treated with 10 ml of concentrated hydrochloric acid in 150 ml of ethanol at boiling point for 1 codine. .

After cooling, the precipitate was filtered off with suction and washed with water and ethyl alcohol to obtain

7 g of 6-carbohydrate (m.p. 209 DEG-211 DEG C.).

The following compounds are obtained in an analytical manner:

6-carboxylate / propoylflavone m.p. .201. to 203 ° C

6-carboyy-2 '/ 2-methylpropooy / flavoni m.p. 193-195 ° C

62karboyy22 / butoxyf lavon m.p. 204 až. 206 ° C

6-carboxy-2'-ethoxy / flavone m.p. 225 DEG-227 DEG C. 6-carboxy-4-carboxylate, m.p. 265 DEG-267 DEG.

Example 27.

12 g of (2) hydroxy-5-carboxylate (1) -142-fluorobenzoyl) mechanism are treated with 15 ml of 57Z hydrochloric acid in 95 ml of acetic acid at reflux temperature for 30 minutes. ·

After cooling, the precipitate is filtered off; The mixture is washed with water and ethanol to give

619 g of 6-carbooyl-2'-floflavone, m.p. Mp 299 ° C.

The following compounds are obtained in an analogous manner.

6-carboxy / Gloria avon, m.p. 27 ° C to 278 ° C

6-carb-ooyy2' flnohfl and odors mp 314-311 · ^{C 3} C ^^

Example 28

Following the procedure of Example 25, using the corresponding (2-h) droy (252-carbonybenzoyl) cinnamoylmethane derivatives (h), the following ice-cold compounds were obtained: m.p. 6 (carboyy-2- (beta2-phenylvinyl)) croomoni m.p. 273-275 ° C.

6 karbooyy22 / alia2methyl2bita2ienylvinyl / croomoni mp 220-222 ° C ^6-yl kaabooy ²² Beia 2 ^{and / 2} '' ^{/ i} lnor ⁱ in ^/ I ^/ C ^ omo vinyťJ ^ tt> ³ '0 ° ^C 6-karbooyy22 2beita (3'2β) Ridyl) vinylcromoni m.p. &gt; 350 ° C

HenyVv ^^] tt ^{i> 320} C. ^U

Example 29

9 g · 12-benzyl-2-thiyl-12-benzoyl-1-pyrazinoylmethanate is treated with 90 ml of 99Z formic acid at boiling point ρσ for 3 hours. '

After cooling, the precipitate is filtered off, washed with water and hot ethanol to obtain

4.8 g of 6- (5-tetrazolyl) -2- (2'-pyrazinyl) chromone, m.p. 310 DEG C. (dec.).

By analogy, the following compounds are obtained:

6- (5-tetrazolyl) -2'-pyridylchromone, m.p. > 300. ° C / dec /

IR (KBr): NH (tetrazole) 3 100 cm @ 2 700 cm @ -1, 6 620 6- (5-tetrazolyl) -2'-isopropoxyflavone, mp 293-295 ° C.

Example 30 A solution composed of 8.6 g of 2-N, N-diethylaminomethyl-3-acetyl-4-hydroxybenzoate and 12 g of methyl 2-isopropoxybenzoate in 50 ml of dioxane is slowly added with stirring at room temperature. to a suspension of 5.1 g of sodium methoxide in 20 ml of dioxane.

The mixture was heated at 80 ° C for 5 hours, then diluted with water, acidified with acetic acid and extracted with ethyl acetate.

The organic layer was washed with 5% sodium bicarbonate solution and then with water, evaporated to dryness and then crystallized from ethanol to give 9.1 g of 2-hydroxy-5- (2-N, N-diethylaminoethoxycarbonyl) benzoyl. (2-Isopropoxybenzoyl) methane, which was then heated under reflux for 30 minutes with 45 ml of 99% formic acid.

After cooling and dilution with water and filtration, the separated precipitate is crystallized from isopropyl ether to give 6.9 g of 6- (2-N, N-diethylaminoethoxycarbonyl) -2-isopropoxyphenone, m.p. 76-78. Deň: 32 ° C. This product is then dissolved in 100 ml of acetone. Addition of an 8 thiometric amount of concentrated hydrochloric acid precipitates the corresponding hydrochloride, which is filtered off and washed thoroughly with acetone. 6.5 g of 6- (2-N, N-diethylamino-ethoxycarbonyl) -2'-isopropoxyflavone hydrochloride are obtained, m.p. 215 DEG-217 DEG.

Similarly, the following compounds are obtained:

6- (2-N, N-Dixaethylamino-ethoxycarbonyl) -2'-isopropoxyflavone, m.p. 71-73 ° C; 6- (2-N, -pyrrolidinyl-ethoxycarbonyl) -2'-isopropoxyflavone, m.p. 101-102 ° C; 6- (2-N-morpholino-ethoxycarbonyl) -2'-isopropoxyflavone, m.p. Mp 133-135 ° C.

Example 31

Following the procedure of Example 30 using the appropriate 2-N, N-dialkylaminoethyl esters of 3-acetyl-4-hydroxybenzoate and methylpyrazinoate, the following compounds were prepared:

6- (2-N, N-dimethylamino-ethoxycarbonyl) -2- (2'-pyrazinyl) chromone, m.p. 116-118 ° C; 6- (2-N, N-diethylamino-ethoxycarbonyl) -2- (2'-pyrazinyl) chromone, m.p. Mp 113-115 ° C.

At 1 and d 32

The following compounds were prepared according to the procedure of Examples 30 and 31 and pivaloyloxymethyl-3-acetyl-4-hydroxybenzoate:

6-pivaloyloxymethoxycarbonyl-2-isopropoxyflavone, m.p. 102-104 ° C,

6-pivaloyloxymethoxycarbonyl-2-pyrazinylchromone, m.p. Mp 137-142 ° C.

Claims (6)

A process for the preparation of novel 5,6-benzo-gamma-pyrone derivatives of the general formula I in which n and n are 0 or 1, R is either a (a) cyano, carboxy or a group, or a (-) -CORg group, wherein Rg is -NHOH or a group> ^R10 -ВГ Wherein Rjq and R II represent individually hydrogen or alkyl of · 1-6 carbon atoms or when _{R) 0} represents hydrogen, also represents a group or a group of formula -CH-COOH where _R10 is hydrogen or ^R12 I alkyl s Or ( ₁₀₎ and together with the adjacent nitrogen atom form an N-pyrrolidinyl, piperidine or morpholino group; or (c) a group of the formula -COOR ₁₃ wherein R ^ ₃ denotes an alkyl or alkenyl group having from 1 to 12 carbon atoms. , optionally substituted with at least one halogen atom, carboxy, hydroxy, phenyl, optionally substituted hydroxy, halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, nitro, cyano, ^R 4 ^R 11 wherein R 6 q and R 6 are as defined above, or -OR ₄ and / or -OCOR ₄ , wherein R ₁₄ is alkyl of 1 to 6 carbon atoms, or a group of formula or wherein R 6 is as defined above, R 6 and R _3> which may be identical or different, represent, individually, hydrogen, alkyl of 8 1 to 4 carbon atoms, hydroxy, nitro, cyano or alkoxy of 1 to 4 8 carbon atoms, R₂ and R₃, which may be the same or difference are hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, optionally substituted with at least one substituent selected from hydroxy, halogen, C1-C4 alkoxy carbon atoms, nitro and cyano groups, R 6, R 8, Ry and R 8, which may be the same or different, each represent either a hydrogen atom or a halogen atom, a hydroxy group, a nitro group, a cyano group or a group. above is as hereinbefore 'defined, represents a group as above, or a / b / a - / 0 / m "R (3 where m is 0 or the R (or a / t / -O7CO group -R ₅ wherein R is . or wherein Rq and R1 are as above. meaning wherein R? and Rg metУyl.endIuxnskupInu Mady, '5- or óčlenn.ý heteromunooyklIcký radical ^R x 10' N,. . · '> X _R. R 11 is as defined above, or a (d7) -S-R 8 group, wherein R 11 is, when attached to. adjacent carbon atoms, forming a tri-ethylenedio or propylenedioxy group, X containing at least one double has the above. optionally, L is phenyl or a bond, with 1 to 2 heteroatoms of nitrogen, sulfur and / or oxygen, wherein the βββΐ ^ ΰβ-ΐΐ radical X is a nitrogen atom, optionally the nitrogen atom is bonded to an oxygen atom such as An N-oxide, and a group. R ZCRR / _n ^_ is at position 6 or 7 benzopyronového ring except compounds in which the group X represents phen-l, to 'are zero', Rg, and R? R 6 denotes a hydrogen atom, or R 3 denotes a hydrogen atom or, when in the 3 'or 4' position of a phenyl, R 8 denotes a hydroxy group, a methyl group or a chlorine, bromine or iodine atom, and further exclusion. groups of compounds including 6-Carbonyl-3,4-dendroxy-7-hydroxyhydroxy, 6-carboxy-5-ethoxy-4'-methoxyoxone, 7-Carbonylflavone, (7.4 ") dime thioyl / lav-4-iodine 7-flavonic acid, 7-cyanotlavone, 7-methoxycarbonylbenzone, 7-ethoxycarbonylphenol, 7-carboxamide. flavone, 7-methoxyl-6-cyanotlaeone, 7-methoxy-6-carboxylic acid, 7,4'-dimethoxy-6-cyanoflavone and 7,4-dimethoxy-6-carboxylic acid, and pharmaceutically acceptable salts and optical isomers thereof, wherein the compound of formula (11) is selected in which n, r, R, R, R, R, R, R, R, R,. 'R, Rg and X mail as defined above,' at temperature 20 to 120 ° C, optionally in the presence of acid catalysts and an inert solvent, and the compound of formula I obtained is optionally converted to another compound of formula I, and / or optionally the compound of formula I is converted to a pharmaceutically acceptable salt thereof. , and / or optionally the mixture of optical isomers is resolved into the individual isomers. AND 2. A process according to claim 1 for the preparation of new derivatives 5,6-Benzo-gamma-pyrone of the general formula R denotes either a cyanide of a bisphosphine in which n is zero or 1 carboxy or a group of the formula NH-N or (b) -COR, when Rg denotes -NHOH or a group of the formula ## STR6 ## wherein R @ 1 and R @ 1 are each hydrogen or alkyl having 1 ^to 10, R @ 10 denotes hydrogen; R- optionally a group, 6 carbon atoms, or, NH-- or a group of formula -CH-COOH wherein R 1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or R 1 and forms, with the adjacent nitrogen atom, an N-poro Hin-1, pipeoid Cnovxt or moofolin group, or (c) a group -COOR wherein R 33 is an alkenyl group sl to l2 carbon atoms which is substituted with at least one popřípad.ě halogen, carboxy bopy * gr Inoue hydrxxyfku pi Nou phenyl optionally substUuovanou eodroρo8kupinot, a group of the formula ^R • lo N \ wherein R ₁ and R ₁ are as defined above, by a group of formula -OR- and / or by a group of formula -OCOR-y wherein R 1 -is a C 1 -C 6 -alkyl or a group of the formula or wherein R 1 is Above all, hydrogen has the meaning given above, which is R, which may be the same or part of a methyl group, R, R, R and Rg, which may be the same or different (a) a hydrogen or halogen atom, a hydroxy group, a nitro group or a group of the general formula _Wherein R _1q and R are as defined above, or / b * / m is 0 or l and R 33 is as defined above, or wherein R ₅ is as defined in R 1 or represents a group of the formula - (O) m Wherein R (c) is a group of the formula -O-CO-R-, of the formula. / ^R 1O. . . R. wherein R 8 and R 8 are as defined above, or (d) is as defined above, wherein R 8 and R 8 are as defined above. optionally forming together a methylene group, an ethylene group or a propylene group of the formula -S-R 1 where ^R 13 and R 8 are bonded to adjacent carbon atoms, nu and the radical R- (CRR) is in the 6 or 7 position The benzoic nucleus, except for the compounds excluded in point 1, and the pharmaceutically acceptable salts and optical isomers of the compounds of formula Ia, characterized in that the compound of formula IIa is cloned 21 - ´ .. ·· 202543. in which n, R, R-, Rg, Rg, Rg, R? and Rg are as defined above,. at a temperature of from 20 to 120 ° C, optionally in the presence of acid catalysts and an inert solvent, and the compound of formula Ia obtained is optionally converted to another compound of formula Ia, and / or optionally the compound of formula Ia is converted to a pharmaceutically acceptable salt thereof. , and / or optionally the mixture of optical isomers is resolved into the individual isomers. 3. The process of item 1 for the preparation of novel 5,6-benzo-gamma-pyrone derivatives of formula (Xb) wherein n is zero or 1, R is either cyano, carboxy or formula NH — N II N-N or (b) -COR 8, where R 8 is -NHOH or a group of formula -N Wherein R q and R 6 are each hydrogen or, when R 6 is hydrogen, R 8 is optionally C 1 -C 6 alkyl or a group. NH-N or a group of the formula -CH-COOH, wherein R 6 is hydrogen or an alkyl group having 1 to 6 ^R 12 'carbon atoms, or R 6 and -R 6 together with the adjacent nitrogen atom form N-pyrrolidinylovone, piperidine or morroline, or (c) -COOR 9, wherein -R 6 is an alkyl or alkenyl group of 1 to 12 carbon atoms, optionally substituted with at least one halogen atom, a carboxy group, a hydroxy group, a phenyl group or a hydroxy group substituted with a phenyl group, R1q and Rg are as defined above, a group of the formula -ORg and / or a group of the formula -OCOOg, wherein R- is a C1-C6 alkyl group or a group of formula -о -кэ or where R | ₃ is as defined above, R 1 and R 2, which may be the same or different, denote a single hydrogen atom or a methyl group, R 1 and R 2, which may be the same or different, denote a single hydrogen atom or an alkyl group having 1 to 2 carbon atoms, R R, R ^, R??; and R _gt, which may be the same or different, individually represent a hydrogen or halogen atom, a hydroxyl group, a nitro group or a group of the formula kd "R _10" is zero where ", 5 / ^R 10 -K 'X 1 and R 4 are as defined above, or (b') or 1 and have the above meaning, or as defined in R _1q, or denotes the group / ^R 10 Ir \ _R ^R 11 and rji are as defined above, or A / D * / R and a group of formula ^Ra / с * / group of formula -O-CO-R₁, of the formula wherein R q as hereinbefore defined, wherein R? and, when taken together, a methylenedioxy group, the formula -S-R 6, wherein, when attached to adjacent carbon atoms, they form a polyethylenedioxy or propylenedioxy group, and the residue R-ZCR 4 is in the 6 or 7 position of the benzopyrone. nuclei, dl 1, and pharmaceutically acceptable salts and optical isomers in addition to the compounds excluded in the compounds of formula 1b, characterized in that the compound of formula IIb (IIb) is cycled in which n, R, R ₂ , R 3, R 3, R 3, R 3 ₅ , Rg, Ry, Rg are as defined above, at a temperature of 20 to 20 ° C 120 ° C, optionally in the presence of acid catalysts and an inert solvent, and the compound of formula 1b obtained is optionally converted to another compound of formula 1b, and / or optionally the compound of formula 1b is converted to a pharmaceutically acceptable salt thereof, and / or se. optionally, a mixture of optical isomers resolves into individual isomers. 4. The process of item 1 for the preparation of novel 5,6-benzo-gamma-pyrone derivatives of formula Ic 23 202543 in which n and n is zero or 1, R denotes either a / cyano group, carboxet group or a group formulas / NH — N 4d or (Ь) a -COR 4 group wherein R 4 is -NHOH or a group of the formula wherein R jq and R j are each hydrogen or C 1 -C 6 alkyl, or, when R jq is hydrogen, R j is optionally a group. or a group of the general formula -CH-COOH, wherein R is a hydrogen atom or an alkyl group of 1 to 5 carbon atoms; Or R ( ₁₀₎ and R (6) together with the adjacent nitrogen atom form an N-pyrrolidinyl, piperidine or morpholino group, or (CO) a group -COOR2, wherein R6 is an alkyl or alkenyl group having 1 to 12 atoms carbon * optionally substituted by at least one halogen atom, .karboxyskupinou, hydroxy, phenyl optionally substituted by hydroxy _x Nym the phenyl group of the formula wherein R iq ^and R are as defined above, a group of the formula -OR ^, and / or. -OCOR group of the formula ^ wherein R ^ is an alkyl group having 1 to 6 carbon atoms or a group of the formula or wherein is as defined above, and R _o, which may be identical or different, represent, individually, hydrogen or methyl, R and R 6, which may be the same or different, each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and R 8, which may be the same or different, each represent either a hydrogen atom or a halogen, a hydroxy, a nitro or a group of the general formula ¹ wherein a is as defined above, or (b ') is zero or 1 and R 6 has the meaning given above, or wherein Rj5 is as defined for R _J3 is a group or a group of a formula wherein τη / с / group of formula -O-CO ^_ R¹, formula -N wherein R ^ _q and R ^ are as defined above, wherein R? and if R together form methylenedioxy, or Zd '/ group of the formula -SR ^, wherein R _8> when bound to' adjacent carbon atoms, ethylenedioxy or propylene tvqří 1 alkylenedioxy, 13 AFTER X represents a 5- or 6-membered heteromonocyclic residue with at least one α and β double bond with one or two nitrogen, sulfur and / or oxygen heteroatoms; wherein when X is a nitrogen moiety, optionally a nitrogen atom is bonded to, an oxygen atom to form an N-oxide, is in the 6 or 7 position of the benzopyron nucleus, except for compounds excluded in the tally acceptable salts and optical isomers of compounds of formula Ic, and - / CRjR2 / _n paragraph 1 .a farmaceuvyzbačujících by cyclising a compound of formula IIc / 11с / wherein n Пр R, _R} / & _2, R₂, R₃, R₄, R, R? R ₁ and R ₂ are as defined above, at a temperature of 20 to 120 ° C, optionally in the presence of acid catalysts and an inert solvent, and the compound of formula Ic obtained is optionally converted to another compound of formula Ic, and / or of formula (Ia) is converted to a pharmaceutically acceptable salt thereof, and / or optionally a mixture of optical isomers is resolved into the individual isomers. 5. A process according to claim 1, wherein the acid catalyst is hydrochloric acid, hydroiodic acid, sulfuric acid or formic acid. 6. A process according to any one of claims 1 to 5, wherein the inert solvent is methanol, ethanol, tetrahydrofuran, benzene, toluene, acetic acid and mixtures thereof.