CH616935A5 - Process for the preparation of chromone derivatives - Google Patents

Abstract

5,6-Benzo- gamma -pyrone derivatives of the formula I: <IMAGE> in which the symbols have the meanings given in Patent Claim 1, are prepared by condensation of corresponding 2-methylchromones with aldehydes corresponding to the right-hand moiety of the above formula. 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 5,6-benzo-y-pyrone derivatives of the following general formula

(I)

where n is the number 0 or 1, R is either (a) the cyano group, the carboxyl group or the

~ c

N II / N

NH

Residue, (b) the residue —COR ”, where Ry is the residue —NH OH or one

Rio

\

-Rest,

Rn wherein each of the symbols Rio and Rn represent hydrogen or an alkyl radical having 1 to 6 carbon atoms, or, if Rio represents the hydrogen, Ru also the rest

/

N

-C

\

'—-N

II

N

'NH'

or the group -CH-COOH,

Rl2

^ Rio

• J

\.

- □ ■ -o • -o

25th

or

-f [> R13 '

wherein R13 is an unsubstituted group as defined for R13 above, each of the symbols Ri and R2, which may be the same or different, represents hydrogen or methyl, each of the symbols Rs, R6, R7 and Rs, which may be the same or different can have one of the following meanings, namely (a ') hydrogen, halogen, hydroxy, nitro,

-N

40

Rio

R11

in which Rio and R11 have the meanings given above, (b) a radical of the formula - (0) m ~ Ri3, in which m represents the number 0 or 1 and R13 has the meaning given above, (c ') a radical of the formula -O- CO-R15, in which Ris has the same meaning as indicated above for the symbol R13, or a group of the following formula in which R12 represents the hydrogen atom or an alkyl radical having 1 to 6 carbon atoms, or else Rio and R11 together with the nitrogen atom can be an N-pyrrolidinyl, piperidino or morpholino radical, or (c) the radical COOR13, in which R13 represents an alkyl or alkenyl group having up to 12 carbon atoms, which is either unsubstituted or carries at least one substituent, namely halogen, carboxy, hydroxy, a substituted or unsubstituted phenyl group, the rest

Rio like that

-N \ "

in which Rio and R11 have the above meanings, -OR 14 or -OCORi4, in which Ri4 can be an alkyl radical having 1 to 6 carbon atoms or one of the following radicals ss, in which Rio and R11 have the above meanings, and finally (d;) one Residue of the formula -S-R13, in which R13 has the meaning given above, or R7 and Rs, if they are located on the adjacent carbon atoms, can together form a methylenedioxy, ethylenedioxy or propylenedioxy-60 group, X a phenyl radical or one 5- or 6-membered, heterocyclic, monocyclic radical which is bonded to the rest of the molecule by a carbon atom of the ring and contains a double bond on this carbon atom and has 1 or 2 heteroatoms, namely 65 nitrogen, sulfur and / or oxygen , wherein in those cases where X represents a nitrogen-containing radical, a nitrogen atom may be bonded to an oxygen atom to form an M-oxide, and in which the

5

616 935

is in the 6- or 7-position of the benzopyrone ring.

Pharmaceutically acceptable salts of the compounds of the general formula I can also be prepared according to the invention.

Of course, all conceivable stereoisomers and their mixtures can also be prepared according to the invention.

In 1967, disodium cromoglycat (DSCG) was the first compound to be found to be effective in the treatment of allergic bronchial asthma [J.B.L. Howell and R.E.C. Altounyan Lancet 2, 539 (1967); H. Cairns and co-workers, J. Med. Chem. 15, 583 (1972); J.S.G. Cox and co-workers, Advan. DrugRes. 5, 115 (1970)]. Several other compounds with a similar antiallergic activity have been found in recent years [G.P. Ellis and D. Shwaw, J. Med. Chem. 15, 865 (1972); J.R. Pfister and co-workers, J. Med. Chem. 15, 1032 (1972); D.R. Buckle et al., 16, 1334 (1973); CM. Hall and co-workers, J. Med. Chem. 17, 685 (1974); E.S.K. Assem et al., British Medicai Journal 2, 93 (1974)]; apart from the DSCG already mentioned, none of these new compounds have yet been used clinically.

The following numbering applies to the compounds obtainable according to the invention in which X is the phenyl radical:

20th

iL // ^

W1 '

5 '6'

where Z and the symbol have the above meanings.

In the compounds obtainable according to the invention, the alkyl, alkenyl and alkoxy groups can be branched or straight chains.

If the symbol X is a 5- or 6-membered heterocyclic, monocyclic radical, it will preferably be furyl, thienyl, pyridyl, pyrazinyl or imidazolyl. In those cases in which Ri3 is an alkyl radical substituted by a phenyl radical, this phenyl radical can in turn have one or more substituents from the group consisting of hydroxyl, alkyl, alkoxy, alkenyl or acetyl.

Particularly preferred new compounds which are obtained according to the invention are those of the general formula I in which n is the number 0, R is the carboxyl group or a group of the formula -CONHCH2COOH or -COOR13, in which R13 is one of the following groups:

C1-C6 alkyl, -CH2-CH2N

30th

C2H5

C2H5

-CH2-CH2N

In those cases where X represents a 5-membered, heterocyclic, monocyclic radical, the following numbering applies:

CH3

I.

35 -CH2-COOH, -CH2-O-CO-C-CH3,

I.

CH3

Rs represents hydrogen, allyl or propyl, R «represents the water-40 atom, each of the symbols R7 and Rs, which may be the same or different, either (a) hydrogen or (b) a radical of the formula

45

-N

Rio

R11

where Z represents the heteroatom N, O or S, at which numbering usually begins, while a single * or double bond can be.

In cases where X is a 6-membered heterocyclic, monocyclic radical, the following numbering is used:

tJ V

3 '4

4 «5

so wherein each of the symbols Rio and R11 can denote hydrogen or an alkyl radical having 1 to 6 carbon atoms, or (c) a radical of the following formula - (0) mRt3, where m is 0 or 1 and R13 is an alkyl radical having 1 to 6 Carbon atoms, which may be unsubstituted or have a 55 hydroxyl group or an alkoxy group having 1 to 6 carbon atoms as substituents, means X represents the phenyl, furyl, pyridyl or pyrazinyl radical.

In those cases in which Rs is propyl or allyl, these groups in the compounds of the formula I are preferably in the 8-position. If X represents a phenyl radical, R6 and R7 will preferably denote hydrogen, where Rs does not represent hydrogen and is preferably in the 2'-position of the phenyl nucleus. If m represents the number 0, R13 preferably denotes an alkyl-65 radical with 1 to 3 carbon atoms. If m represents the number 1, the symbol R13 preferably denotes an alkyl radical having 2 to 5 carbon atoms and in particular the propyl, isopropyl, butyl, 1-methylpropyl and 2-methylpropyl radical.

616 935

6

If R13 represents a substituted alkyl radical, this substituent is preferably the hydroxyl or ethoxy group.

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

It is also possible to prepare pharmaceutical preparations which contain a suitable carrier and / or diluent and, as active substance, a compound of the formula I above, in which n, R, Ri, R2, Rs, Rfi, R7, Rs and X have the above meanings.

Preferred examples of compounds which can be obtained according to the invention are the following:

2- (ß-phenyl-vinyl) -chromon-6-carboxylic acid 2- (a-methyl-ß-phenyl-vinyl) -chromon-6-carboxylic acid 2- [ß-2 '- (2-ethoxyethoxy) phenyl- vinyl] -chromon-6-carboxylic acid

2- [ß-2 '- (2-hydroxy-ethoxy) phenyl vinyl] chromone-6-carboxylic acid

2- [ß-2 '- (2-hydroxypropoxy) phenyl vinyl] chromone-6-carboxylic acid

2- [ß-2 '- (3-hydroxypropoxy) phenyl vinyl] chromon-6-car-bonic acid

2- [ß- (2'-pyridyl) vinyl] chromone-6-carboxylic acid

2- [ß- (3'-pyridyl) vinyl] chromone-6-carboxylic acid

2- [ß- (4'-pyridyl) vinyl] chromone-6-carboxylic acid

2- (β-pheny] vinyl) chromone-6-carboxylic acid

2- [ß- (2'-pyrazinyl) vinyl] chromone-6-carboxylic acid and its pharmaceutically acceptable salts, in particular the sodium salts and the chlorohydrates of the esters with diethylaminoethanol and morpholinoethanol as well as the glycol and pivaloyloxymethyl esters.

The 5,6-benzo-Y-pyrone derivatives can be prepared according to the invention by using a compound of the general formula

R- (C)

t

R,

n

Rc in which the symbols have the above meanings, with an aldehyde of the general formula

OHC

6

x l8

■ R,

where the symbols have the above meanings. If desired, a compound of formula I

convert to a 4-thio derivative by treating the product obtained with an agent introducing a sulfur atom, or convert a compound of the formula I into a corresponding 4-thioketal, and this by reaction with a compound of the formula

HS- (CH2) n3-SH

or convert a compound of the formula I into another compound 10 of the formula I in a manner known per se or convert a compound of the formula I into a pharmaceutically acceptable salt or split a mixture of optical isomers obtained in this way into the individual isomers.

The reaction of a compound of formula III with an is aldehyde of formula IV is carried out in the presence of a basic condensing agent, e.g. B. sodium ethoxide, sodium methoxide, sodium hydride, sodium amide or sodium or potassium hydroxide, at a temperature which is preferably in the range from 0 to 100 ° C, and in a solvent, 20 which is preferably made of methanol, ethanol, dioxane or water or a mixture of these.

The possible conversion of a compound of the formula I into a 4-thio derivative can be carried out by treating a solution of this compound in an organic solvent, such as benzene, dioxane, tetrahydrofuran or in a mixture thereof, with P2S5.

The possible conversion of a compound of the formula I into a 4-thioketal by reaction with a compound of the formula HS- (CH2) n3-SH is preferably carried out in the presence of an acidic catalyst, e.g. B. p-toluenesulfonic acid, pyridine hydrochloride, zinc chloride or boron trifluoride etherate, in an inert solvent, e.g. As benzene or toluene, or in the absence of a solvent at a temperature in the range between 20 and 120 ° C.

As mentioned above, 35 compounds of the formula I can be converted into other compounds of the formula I in a manner known per se.

For example, a compound of formula I, wherein R is an esterified carboxy group, e.g. B. represents an alkoxycar-40 bonyl group, by saponification by known methods in corresponding compounds of formula I, wherein R represents the carboxyl group.

(III) For example, a compound of formula I, wherein R represents the cyano group, by acid hydrolysis, 45 z. B. using hydrochloric acid or sulfuric acid, in a compound of formula I, wherein Ri represents the carboxyl group, convert. In a similar manner, compounds of the formula I in which R represents the carboxyl group can be converted by esterification, for example by reacting an alkali metal salt of the acid with the desired alkyl halide, into a compound of the general formula I in which R is a carbalkoxy group.

Free hydroxyl groups can also be converted into ether groups by treatment with, for example, alkyl halides. On the other hand, etherified hydroxyl groups can be treated, for example, with a pyridine salt, e.g. B. the chlorohydrate, or with a strong acid or a Lewis acid in free hydroxyl groups. \ IV) In the case of compounds of the formula I in which X represents a 5- or 6-60-membered nitrogen-containing, heterocyclic, monocyclic radical, the nitrogen atom can be removed by oxidation, e.g. B. with peracids, such as peracetic acid, permaleic acid or per-benzoic acid, are converted into the corresponding N-oxide.

Compounds of the formula I in which R represents the carboxyl group can be prepared in a manner known per se in compounds of the formula I in which R represents the tetrazolyl radical of the following formula

50

55

7

616935

-c H

\ N

convict. This can be done, for example, by the carboxyl group, for example, by reaction with thionyl chloride in the presence of benzene and at the reflux temperature in the corresponding halide, for. B. the chloride is transferred, the halide thus obtained is reacted, for example, with ammonia to form the corresponding amide, the amide thus obtained is dehydrated, for example by means of p-toluenesulfonyl chloride in pyridine, to the nitrite and finally the resulting nitrite is added by means of sodium azide and ammonium chloride in dimethylformamide a temperature between room temperature and 100 ° C implemented.

If one wishes to obtain the compounds of formula I in the form of a salt, one can also use known methods.

The compounds of formula III can be, for example, by acidic cyclization of β-diketones of the general formula

R- (C)

"OH CO-CH

wherein n, R, Ri, R2 and Rs have the above meanings. These latter compounds can in turn by basic condensation of an acetic acid ester, for. B. methyl acetate, ethyl acetate or phenylacetate, with a substituted o-hydroxyacetophenone of the general formula

1 )

R- (C

t

R

CH

2nd

OH

produce, this reaction preferably at a temperature between 20 and 100 ° C in the absence of a solvent or in a solvent such as. As benzene, toluene or dioxane, or a mixture thereof, using, for example, sodium hydride as a condensing agent.

The compounds of formula VII can be prepared, for example, by starting from the corresponding substituted phenols and carrying out a Friedel-Crafts reaction or a Fries rearrangement.

The compounds obtainable according to the invention have antiallergic effects, as can be seen from the fact that they have proven to be useful when tested for passive cutaneous anaphylaxis (PCA) tests in rats according to Goose Y and Blair A.M.Y.N.

(Immunology, 1969 16: 749). They can therefore be used to treat and prevent bronchial asthma, allergic rhinitis, hay fever, nettle fever and dermatoses.

Of particular importance for these compounds is the fact that they also have an antiallergic effect when administered orally.

The following table shows - in comparison with two well-known anti-allergic preparations, namely disodium cromo-glycat (DSCG) and 7-hydroxyethoxyxanthone-2-carboxylic acid (AH 7725; Fullarton J., Martin, LE, and Vardey, C., Int. Arch. All ., 1973, 45:84) - the protective effect of the compounds obtainable according to the invention in rats in the PCA test after oral administration.

table

Inhibitory effect in% compared to the control group

Time span between pre-treatment and determination

connection

Dose (per os, mg / kg)

15

Minutes

30th

Minutes

60

Minutes

120

Minutes

DSCG

50

6.0

5.5

3.2

2.5

AH 7725

50

42.6

14.4

13.3

3.8

2- (ß-phenyl-

vinyl)-

chromon-6-

carboxylic acid

50

69.9

45.8

19.6

16.6

In addition to their anti-allergic action, the compounds obtainable according to the invention reduce the resistance of the airways and increase the elasticity of the lungs. You can therefore for the treatment of respiratory failure, such as. Acute pulmonary insufficiency, as used in rats using Palecek F., Palece-kova M., and Aviado D.M. (Arch. Environ. Health, 1967, 15: 332-342) described results. In the corresponding experiments, the compounds obtainable according to the invention reduce the resistance of the airways and increase the elasticity of the lungs even at a dose of 3 mg / kg (intravenously). At the same dose, they cause a 50% antagonism against the bronchoconstructural effect of serotonin (5-hydro-xytryptamine) and the compound 48/80 (histamine-releasing-the preparation).

In addition, the compounds obtainable according to the invention have antiulcerogenic properties; this is due to their inhibitory effect on the formation of stress ulcers in rats, which in a water bath at 25 ° C for 40 minutes after a change in the method by Takagi K. and Okabe, S. (Jap. of Pharmac., 1968, 18 : 9) are kept. In this experiment, the compounds obtainable according to the invention in a dose of 50 mg / kg (intravenously) bring about a 45% inhibition of the formation of stress ulcers in rats.

The compounds obtainable according to the invention can be administered in the usual way. For example, they can be administered orally or parenterally at daily dosage levels of preferably 0.5 to 15 mg / kg. However, they can also be inhaled, preferably daily doses of 0.5 to 100 mg and more preferably 0.5 to 25 mg of this active substance being inhaled. Finally, they can also be applied topically.

The composition of the pharmaceutical preparations containing one or more compounds obtainable according to the invention, to which pharmaceutically acceptable carriers are added

10th

15

20th

25th

30th

35

40

45

50

55

60

65

616 935

Adding agent or diluent depends, of course, on the type of administration.

The preparations can be prepared in the usual way with the usual ingredients. For example, the compounds obtainable according to the invention can be administered in the form of aqueous or oily solutions or suspensions, aerosols, powders, tablets, pills, gelatin capsules, syrups, creams or lotions for topical applications.

For oral administration, the compounds targeted according to the invention are advantageously incorporated into suitable pharmaceutical preparations. Preparations of this type are preferably tablets, pills and gelatin capsules, which contain the active substance together with diluents, e.g. B. lactose, dextrose, sucrose, mannitol, sorbitol or cellulose, lubricants such as. As silicon dioxide, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols. These preparations can also contain binders, e.g. B. starch, gelatin, methyl cellulose, carboxymethyl cellulose, gum arabic, tragacanth, polyvinylpyrrolidone, grinding agent, e.g. B starch, alginic acid, alginates, sodium starch glycolate, effervescent mixtures, colorants, sweeteners, wetting agents, e.g. As lecithin, polysorbates or lauryl sulfates, and generally non-toxic and pharmacologically ineffective substances, such as those used in pharmaceutical preparations, contain. Such pharmaceutical preparations can be produced in a manner known per se, for example by mixing, granulating, tableting, by coating in a frosting or by methods imparting a film coating.

For the treatment of allergic asthma, the compounds obtainable according to the invention can be administered by inhalation. For this purpose, suitable preparations can consist of a suspension or solution of the active substance, preferably in the form of a salt thereof, in the form of the sodium salt, in water and can be administered with the aid of a conventional atomizer. On the other hand, such preparations can be made from a suspension or solution of an active substance in a conventional liquefied propellant, e.g. B. dichlorodifluoromethane or dichlorotetrafluoroethane exist, such preparations from a pressure vessel, for. B. an aerosol dispenser. If the drug is not soluble in the propellant, it may be necessary to use a cosolvent, e.g. B. ethanol, dipropylene glycol or isopropyl myristate and / or a surface-active agent to add to the preparation to suspend the drug in the propellant medium. Surfactants of this type are the usual means for such purposes, such as. B. nonionic surfactants such as lecithin. The compounds obtainable according to the invention can also be administered in the form of powders with the aid of a suitable insufflation apparatus, in which case the active substance constituents present in finely divided powder form are mixed with a diluent, for. B. lactose can be mixed.

The compounds obtainable according to the invention can also be administered intradermally or intravenously in a manner known per se.

In addition to internal administration, the compounds obtainable according to the invention can also be used for topical applications, for example in the form of creams, lotions or pastes, for dermatological treatments. In the case of such preparations, the active substance can be mixed with customary oil-containing or emulsifying drug carriers.

The invention is illustrated by the following examples.

example 1

A solution consisting of 2-methyl-6-carboethoxychromone (5 g) and 3-pyridyl-carboxyaldehyde (5.5 g) in absolute ethanol (100 ml) is slowly stirred with 0 ° C with a solution of 0 , 5 g of sodium in 50 ml of ethanol. Then the mixture is kept at room temperature for 2 hours, then acidified with acetic acid, concentrated in vacuo and diluted with water, whereupon the precipitate is collected. After crystallization from methanol, this precipitate gives the 6-carbomethoxy-2- (β-3'-pyridyl-vinyl) chromone (3.8 g; mp. 170 to 180 ° C.), which is mixed with a stoichiometric amount of a solution of 1% potassium hydroxide in 95% ethanol is refluxed under reflux temperature for 1 hour. After cooling and diluting with 10 tigers of aqueous, monobasic sodium sulfate, a precipitate is obtained which is collected by filtration and brought to crystallize from a mixture of N, N-dimethylformamide and methanol. 2- (β-3-pyridyl-vinyl) -chromon-6-carboxylic acid (1.8 g;

Mp> 350 ° C); I.R. (KBr): $ c = o (carboxy) 1710 cm x,

970 cm

If you work in an analogous way, you get the following connections:

2- (ß- (2'-Pyridyl-vinyl) -chromon-6-carboxylic acid, 2- (ß-4'-pyridyl-vinyl) -chromon-6-carboxylic acid, 2- (ß-2 /-furyl-vinyl ) -chromon-6-carboxylic acid, 2- (ß-3'-methoxyphenylvinyl) -chromon-6-carboxylic acid, mp. 271-273 ° C;

2- (β-4'-methoxyphenylvinyl) -chromon-6-carboxylic acid, mp 280-282 ° C;

2- (ß-4-methylphenylvinyI) -chromon-6-carboxylic acid, mp> 320 ° C;

2- (ß-4'-fluorophenylvinyl) -chromon-6-carboxylic acid, mp> 300 ° C;

2- (ß-4'-fluorophenylvinyl) -chromon-6-carboxylic acid methyl ester, mp. 193-195 ° C.

Furthermore, the following compound was obtained from the 2-methylchromone-7-carbonate,

2- (phenylvinyl) -chromon-7-carboxylic acid, mp. 272-273 ° C.

Example 2

If the procedure described in Example 1 is followed, 6-carbomethoxy-2- (β-2'-hydroxyphenyl-vinyl) -chromone of melting point 252 to 254 ° C. (after recrystallization from acetone) is obtained from the corresponding starting products. 7 g of this product are dissolved in 35 ml of dimethylformamide and the solution is reacted with 4.2 g of β-ethoxyethyl bromide and 4 g of anhydrous potassium carbonate at 70 ° C. for 24 hours. After cooling, diluting with water and filtering, the collected precipitate is hydrolyzed with a stoichiometric amount of potassium hydroxide (1%) in ethanol (95%) at the reflux temperature for 1 hour. After cooling, diluting with water and acidifying with citric acid, the precipitate is collected and crystallized from a mixture of methanol and benzene. In this way, 2- [ß-2 '- (2-acetoxyethoxy) -phenyl-vinyl] -chromon-6-carboxylic acid (3.6 g; mp. 218 ° C. (decomposition).

If the corresponding vinyl halides are used, the following compounds are obtained:

2- [ß-2 '- (2-Hydroxy-propoxy) -phenylvinyI] -chromon-6-carboxylic acid, mp. 231-235 ° C;

8th

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

9

616 935

2- [β-2 - (3-hydroxypropoxy) phenyl vinyl] chromone-6-carboxylic acid;

2- [ß-2 '- (2-hydroxy-ethoxy) phenyl vinyl] chromone-6-carboxylic acid.

2- (ß-2'-isopropoxyphenylvinyl) -chromon-6-carboxylic acid, s

Mp 246-248 ° C;

and following a similar procedure, the following compounds were obtained from the 3-acetyl-4- (p-benzoyloxy-cinnamoyloxy) -benzoic acid methyl ester: io

2- (β-4'-hydroxyphenylvinyl) -chromon-6-carboxylic acid, mp. 337-338 ° C;

2- (β-4'-hydroxyphenylvinyl) -chromon-6-carboxylic acid methyl ester, mp. 316-317 ° C; 15

2- (ß-4'-isopropoxyphenylvinyl) -chromon-6-carboxylic acid, mp. 245-246C:

Example 3

Following the same procedure as in Example 1, but using other suitable starting materials, the following compounds are obtained.

6-carboxy-2- (β-phenyl-vinyl) chromon, m.p. 273-275 ° C; 6-carboxy-2- (a-methyl-β-phenyl-vinyl) -chromon, mp. 220-222 ° C;

6-carboxy-2- [ß- (4'-fluorophenyl) vinyl] chromone, mp> 320 ° C;

6-carboxy-2- [ß- (3'-pyridyl) vinyl] chromone,

Mp> 350 ° C;

6-carboxy-2- [ß- (4'-methylphenyl) vinyl] chromone, m.p.> 320 ° C.

B

Claims (12)

616 935 2 PATENT CLAIMS 1. A process for the preparation of 5,6-benzo-Y-pyrone derivatives of the following general formula wherein n is 0 or 1, R is either (a) the cyano group, the carboxyl group or the or -c O R 13 NH ' • N II -N Radical, (b) the radical -COR9, in which R9 represents the radical -NHOH or in which R13, an unsubstituted group as defined above for R13, each of the symbols Ri and R2, which may be the same or different, denotes hydrogen or methyl -25 tet, each of the symbols Rs, Rö, R7 and Rs, which may be the same or different, has one of the following meanings, namely (a ') hydrogen, halogen, hydroxy, nitro, one Rio / —N ^ —Rest, R11 wherein each of the symbols Rio and R11 represent hydrogen or an alkyl radical having 1 to 6 carbon atoms, or, if Rio represents the hydrogen, R11 also the radical II or the group -CH-COOH \ NH Rio -N 40 V in which Rio and R11 have the meanings given above, (b) a radical of the formula - (0) m-Ri3, in which m denotes the number 0 or 1 and R13 has the meaning given above, (c ') a radical of the formula -O- CO-R15, in which R15 has the same meaning as indicated above for the symbol R13, or a group of the following formula R12 / Rio in which R12 represents the hydrogen atom or an alkyl radical having 1 to 6 carbon atoms, or Rio and R11 together with the nitrogen atom can be an N-pyrrolidinyl, piperidino or morpholino radical, or (c) represents the radical COOR13 in which R13 is an alkyl - Or alkenyl group having up to 12 carbon atoms, which is either unsubstituted or bears at least one substituent, namely halogen, carboxy, hydroxy, a substituted or unsubstituted phenyl group, the rest Rio -N wherein Rio and R11 have the above meanings, -OR14 or -OCOR14, wherein R14 is an alkyl radical having 1 to 6 carbon atoms, or one of the following radicals: <\. may be -o ■ -o, in which Rio and R11 have the above meanings, and finally (d ') a radical of the formula -S-R13, in which R13 has the above meaning, or else R7 and Rs, if they are appropriate the adjacent carbon atoms, together can form a methylenedioxy, ethylenedioxy or propylenedioxy group, X denotes a phenyl radical or a 5- or 6-membered, heterocyclic, monocyclic radical, 55 which is attached to the rest of the molecule through a carbon atom of the ring is bound and contains a double bond on this carbon atom and has 1 or 2 heteroatoms, namely nitrogen, sulfur and / or oxygen, where, in those cases in which X represents a nitrogen-containing radical, “0 indicates a nitrogen atom with the formation of an N-oxide may be bound to an oxygen atom, and wherein the 3rd 616 935 is in the 6- or 7-position of the benzopyrone ring, characterized in that a compound of the general formula R- (C) (III) 15 wherein the symbols have the above meanings, with an aldehyde of the general formula 6 OHC (IV) 30th X ~ I R. Y r8 where the symbols have the above meanings. 35 2. The method according to claim 1, characterized in that one carries out the reaction in the presence of a basic condensing agent, at a temperature in the range from 0 to 100 ° C and in a solvent. 3. The method according to claim 1, characterized in that obtained process products which carry a free carboxyl group, in pharmaceutically acceptable salts, preferably the sodium salts and the ammonium salts with 2-aminoethanol and 2-amino-2-hydroxymethyl-l, 3-propanediol , transferred. 4. The method according to claim 1, characterized in that obtained esters of diethylaminoethanol and morpholinoethanol are converted into their chlorohydrates. 5. The method according to claim 1, characterized in that one splits an obtained mixture of optical isomers into the individual isomers. 6. The method according to claim 1, characterized in that obtained hydroxy compounds are converted into corresponding ether by treatment with an alkyl halide. 7. The method according to claim 1, characterized in that obtained etherified hydroxyl groups, e.g. B. benzyl ether groups, containing process products by treatment with a pyridine salt, for. B. the chlorohydrate, or with a strong acid or a Lewis acid converted into corresponding hydroxy compounds. 8. The method according to claim 1, characterized in that obtained process products containing a nitrogen-containing, heterocyclic, monocyclic radical X are converted by oxidation into corresponding N-oxides. 9. The method according to claim 1, characterized in that the carboxylic acids obtained are esterified, for example by reacting an alkali metal salt with an alkyl halide. 10. Process for the preparation of compounds of the formula R6 R R, a ß CH = CH- (III) 8th characterized in that according to the method so that the sulfur atom with phosphorus pentasulfide in one Claim 1 produces a compound of formula I and treats it with an agent introducing a sulfur atom. 11. The method according to claim 10, characterized in introduces organic solvents. 12. Process for the preparation of compounds of the formula 616 935 4th wherein n.ì represents the number 2 or 3, characterized in that a compound of the formula I is prepared by the process according to claim 1 and this is reacted with a compound of the formula HS- (CH2) n3-SH. 13. The method according to claim 12, characterized in that the reaction with the compound of the formula HS- (CH2) n3-SH in the presence of an acid catalyst.