CS214806B2 - Method of making the derivatives of the auron - Google Patents

Description

(54) Method of producing auron derivatives

The substituted aurons of formula I,

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^c , which may be the same or different, each represent a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group (C 6 -C 6) cycloalkyl, (C 3 -C 8) cycloalkyl, (C 1 -C 6) haloalkyl, amide, amino, cyano, hydroxyl, carboxyl, 5-tetrazolyl or formula - CH = CHCOOH, or wherein R ¹ and R ² together represent a group of the formula —CH = CH— —CH = CH—, provided that at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ represents a carboxyl group, A 5-tetrazolyl group or a group of the formula —CH = CHCOOH, and pharmaceutically acceptable salts and esters thereof, are effective in the prophylactic chemotherapy of allergic diseases such as bronchial asthma.

214306

The present invention relates to a process for the preparation of novel auron derivatives having significant pharmacological activity.

In recent years, great efforts have been made to find new compounds useful for alleviating allergic diseases; in particular, there is a need for medicaments that are effective in treating immediate hypersensitivity conditions, such as. is asthma.

The present inventors have found that some auron derivatives having the following structural formula

have such efficiency.

The invention allows the production of new bold aurons of formula I, 0 R * ...... / Ж ) Y> = CH- d3 R (1)

wherein R 1, R ² , R ³ , R ⁴ , R ⁵ and R 6, which may be the same or different, each represent a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, amide, amino, cyano, hydroxyl, carboxyl, 5-tetrazolyl or the group -CH = CHCOOH, or substituents ri and R ² together represent -CH = CH-CH = CH-, with the proviso that at least one of the substituents ri, ^R2, R3, R4, R5 and R6 is -COOH, 5-tetrazolyl or a group of the formula - CH = CHCOOH, and pharmaceutically acceptable salts or esters thereof.

The compounds of formula I may exist in either the (E) - or (Z) -form, with the [Z] -form being more preferred.

A more preferred class of auron derivatives according to the invention are those compounds of formula (I) in which: R 1, R 2, R ³ , R 4, R ⁵ and R 6 are as defined above, but with the proviso that when all three of R 1, R 2 and R 3 are hydrogen, at least one of R 1, R 2, R ³ and R 6 is as defined above. R @ ⁴ , R @ ⁵ and R @ ^c denote a 5-tetrazolyl group or a group of the formula --CH - CHCOOH. It is preferred that in the compounds of the invention the benzofuran ring is substituted, and therefore, those of formula I are preferred wherein _: at least one of R 1, R 2 and R 3. is other than hydrogen.

Another preferred class of auron derivatives of the invention are those compounds of formula I wherein R 1, R 2, R 3, r 4, r 5 and r ₆ are as defined above, but with the proviso that when one of the substituents is present. R @ ¹ , R @ 2 and R @ 3 represent a carboxyl group, at least one of R @ ⁴ R @ ⁵ and R @ ⁶ represents a halogen atom, a C3 -C8 cycloalkyl, a C1 -C6 haloalkyl, an amide group, a cyano group, a carboxyl group 5-tetrazolyl or CH-CHGOOH.

it is often preferred that at least one of the substituents on a single benzene ring is one such substituent, and therefore, those compounds of formula I wherein at least one of R ⁴ , R 5 and R 6 are halogen, a C 3 -C 3 cycloalkyl group are preferred. C-C halogenhaloalkyl, C až-C halogenhaloalkyl, amide, cyano, carboxyl, 5-tetrazolyl, or —CH = CHCOOH.

A particularly preferred class of novel auron derivatives of the invention are those compounds of formula I wherein at least one of R 1, R 2 and R 3 is other than hydrogen and at least one of R ⁴ , R 5 and R 6 is halogen, cycloalkyl C 3 -C 8 haloalkyl of up to 6 carbon atoms; amide, cyano, carboxyl. 5-tetrazolyl or -CH-CHCOOH.

The term "halogen atom" means, in. description. of the present invention means a chlorine, bromine or fluorine atom. The term "alkyl of 1 to 6 carbon atoms" includes, for example, methyl, ethyl, propyl, alkyl, phenylalkyl, phenylalkyl, phenylalkyl, propyl, phenylalkyl, phenylalkyl, phenylalkyl, phenylalkyl, phenylalkyl, phenylalkyl, phenylalkyl, phenylalkyl, phenylalkyl, phenylalkyl. isopropyl, butyl, tertiary butyl, pentyl and hexyl, with methyl, ethyl or tertiary butyl being preferred. The term "C 1 -C 6 alkoxy" includes, for example, methoxy, ethoxy, propoxy, butoxy, preferably methoxy. The term "C 3 -C 8 cycloalkyl" preferably refers to a cyclohexyl group.

Concept. "C 1 -C 6 haloalkyl" means, for example, any of the groups included under the term "C 1 -C 6 alkyl" substituted by one to three halogen atoms such as fluorine or chlorine, and preferably denotes trifluoromethyl.

It is preferred that R 1 · R ² · R ^3, R 4, R 5, _and R c is selected from the group consisting of hydrogen atom. halogen, C 1 -C 4 alkyl, alkoxy. C 1-4 alkyl, cyclohexyl, trifluoromethyl, N-isopropylcarboxamide, acetamido, dimethylamino, hydroxy, carboxyl, 5-tetrazolyl. and -CH = GHCOOH or · when R ¹ and R ² together represent -CH = CH-CH = GH-.

Other preferred auron derivatives included within the scope of Formula I are those having one or more of the following characteristics:

a) R ¹ represents a C 1 -C 4 alkyl group such as a methyl group;

b) R 1 is C 1 -C 4 alkoxy as methoxy;

c) R ¹ represents a halogen atom such as a chlorine atom;

d) R ¹ represents a C 3 -C 8 cycloalkyl group such as a cyclohexyl group;

e) R 1 represents an amino group;

f) R ¹ represents a carboxyl group;

g) R 1 represents a substituent at the 5- or 6- position;

h) R 1 is hydroxyl. a group;

i) R 2 represents a hydrogen atom; jj R3 represents a hydrogen atom;

k) R 4 represents a carboxyl group;

l) R 4 represents a 5-tetrazolyl group;

m) R 4 is -GH = CHCOOH;

n) R ⁵ represents a hydrogen atom; oj · R ⁽ⁱ is hydrogen.

A particularly preferred group of auron derivatives according to the invention are those compounds of formula (I) wherein R @ ¹ is C1 -C4 alkyl, carboxyl or halogen, R @ 2 and R @ ³ are hydrogen, R ^{@ 4} is carboxyl or --CH.dbd.CHCOOH and R5 and R6 are hydrogen. Among these, most preferred are those compounds of formula I wherein R 1 is an alkyl or carboxyl group, R 2 and R 3 are hydrogen, R 4 is a carboxyl group or a group of the formula - CH = CHCOOH · and R 5 and R 6 are hydrogen.

The compounds of the formula I according to the invention can also be used in the form of their pharmaceutically acceptable salts or esters. Such derivatives can be prepared, for example, when one or more of R 1, R 2, R 3, R ⁴ , R 5 and R 6 represent an acidic function, such as a carboxyl group or a group of the formula --CH = CHCOOH. Suitable salts are, for example, salts with inorganic bases, such as alkali metal hydroxides, in particular potassium or sodium salts, or salts with alkaline earth metal hydroxides, in particular calcium salts, or salts with organic bases, such as. amines. As esters, it is advantageous to use esters derived from alkanols having from 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxyethyl or ethoxyethyl esters.

According to the invention, the novel auron derivatives of the formula I can be prepared by substituting a substituted benzaldehyde of the formula III,

in which R ⁴ , R ⁵ and R 6 are as defined above, reacts with benzofuranone

wherein R 1, R 2 and R 3 are as defined above, and optionally in the obtained compound of formula I, the individual groups are converted into other groups within the final meaning of the substituents and / or Salt or ester.

The Aurones of formula (I) are prepared by condensing an appropriately substituted benzaldehyde of formula (III) with a benzofuranone derivative of formula (IV) according to the following reaction scheme:

Suitable solvents for this reaction are ethers, such as dioxane or tetrahydrofuran, or liquid alkanols, such as ethanol. The reaction temperature is not generally critical and determines only the reaction rate. The reaction proceeds well at all temperatures ranging from room temperature to the boiling point of the reaction mixture, for example at 25 to 150 degrees Celsius. Conveniently, the reaction can be catalyzed by acids or bases. Suitable acid catalysts include mineral acids such as hydrochloric acid and strong organic acids such as p-toluenesulfonic acid, and suitable inorganic or organic basic catalysts include, for example, sodium hydroxide, potassium hydroxide, sodium carbonate or triethylamine. This type of condensation reaction is well known and one skilled in the art will readily determine the necessary reaction conditions and the nature of the reagents suitable to obtain the desired auron of Formula I.

Compounds of formula I wherein one of R is a 5-tetrazolyl group can be prepared from the corresponding nitriles by treatment with a preferably non-nucleophilic azide, for example trimethylsilyl azide, in a high boiling solvent such as dimethylformamide at temperatures around 100 ° C.

These reactions give (ZJ-isomers which, if necessary, can be converted to the corresponding (E) -isomers by photochemical methods well known to those skilled in the art.

The inventors have found that aurons of formula I are effective in the prophylactic treatment of asthma in mammals. This activity was found in guinea pig testing of the compounds of the invention using the "Herxheimer test" described in Journal of Physiology (London) 17, 251 (1952), and in the isolated guinea pig lung strips described by Mongar and Schild in Journal of Physiology (London) 3, 207 (1956) or Brocklehurst in Journal of Physiology (London) 52, 414 (1960). The compounds of formula I are also active in the peritoneal assay. Anaphylaxis in rats consisting of monitoring the allergic reaction of the peritoneal cavity in a rat and described by Orange, Stechschulte and Austen in Fed. Why. 28, 1710 (1969).

The Herxheimer test is based on monitoring the effect of test compounds on allergic bronchospasm muscles (guinea pigs) induced in guinea pigs, which are very similar to human asthma attacks. Bronchospasm mediators are very similar to those released when sensitized human lung tissue is stimulated by antigen. The compounds of formula I exhibit efficacy in the Herxheimer test at doses ranging from 25 to 200 mg / kg.

The Aurones of Formula I may be administered by a variety of routes and may be formulated into a variety of dosage forms for this purpose; however, a special property of the compounds of the invention is that they are effective when administered orally. The compounds of formula (I) may be administered orally, rectally, locally or parenterally, for example by injection, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, capsules, elixirs, aerosol suspensions, ointments, e.g. , in the form of soft or hard capsules, suppositories, injectable solutions and suspensions in a physiologically acceptable environment, and sterile packed powders adsorbed to a suitable carrier for the preparation of injectable solutions. The nature of the various excipients and additives required to manufacture said formulations is well known to those skilled in the art.

Examples of suitable additives and excipients which can be used in the pharmaceutical compositions of the present invention include lactose, glucose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffins, white soft paraffin, kaolin, silica powder, cellulose microcrystalline, calcium silicate, silica gel, polyvinylpyrrolidone, cetostearyl alcohol, starch, modified starches, gum arabic, calcium phosphate, cocoa butter, ethoxylated esters, cocoa oil, arachis oil, alginates, tragacanth, gelatin, syrup В. P., methylcellulose, monoxy-acetylenesorbite monolaurate, ethyl lactate, methyl and propylhydroxybenzoate, sorbitan trioleate, sorbitantetraoleate and oleyl alcohol, and suitable propellants include, for example, trichlorofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane. When preparing tablets, glidants may be added to the tablet mixture to prevent sticking and adhering of the sprayed components to the punches and punches of the tabletting machines. For example, aluminum, magnesium or calcium stearate, talc or mineral oils may be used.

The invention also includes pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt or ester thereof as an active ingredient, and a pharmaceutically acceptable carrier. Said pharmaceutical preparations may conveniently be presented in unit dosage form, each unit dose containing preferably 5 to 500 mg of a compound of formula I (5.0 to 50 mg for parenteral administration, 5.0 to 50 mg for inhalation) and up to 500 mg for oral or rectal administration). The term "unit dosage form" as used in the specification and the subject matter of the invention refers to physically discrete individual doses of the formulation suitable as individual human and animal doses, each unit dose containing a predetermined amount of active ingredient, determined to cause the desired therapeutic effect, together with the required pharmaceutical diluent, carrier or vehicle.

Aurons of the formula I can be administered in a total dose of 0.5 to 200 mg of active ingredient per kilogram of patient's weight, preferably at a dose of 1 to 20 mg / kg per day. It will be understood, however, that precise dosages of the compounds of Formula I administered on a case-by-case basis will be determined by the physician based on other serious circumstances such as the condition being treated, the type of compound administered and the route of administration chosen. invention.

The process according to the invention is explained in more detail in the following examples.

Example 1 (Z) -34-carboxy-2-benzylidene-5-methoxybenzofuran-3 (2H) -one

5-Methoxybenzofuran-3 (2H) -one (6.0 g, 0.036 mol) [Annalen 405, 281 (1914)] and 3-carboxybenzaldehyde (5.4 g, 0.036 mol) [J. Chem. Soc. 4778 (1952)) was dissolved in dioxane (50 mL), concentrated hydrochloric acid (10 mL) was added, and the resulting yellow solution was heated to reflux for 2 hours. After cooling the reaction mixture, water (20 ml) was added, the yellow precipitate formed was filtered off and recrystallized from acetic acid. The title compound is obtained as yellow needles, m.p. 252-254 ^° C.

Example 2

The following compounds were prepared as described in Example 1, using the appropriately substituted benzofuranones and benzaldehydes:

(Z) -2‘-carboxy-2-benzylidene-6-methoxybenzofuran-3 (2H) -one, m.p. 217-220 ° C (dec.);

(Z) -3‘-carboxy-2-benzylidene-6-methoxybenzofuran-3 (2H) -one, m.p. 253 DEG-260 DEG C. (dec.);

(Z) -4‘-carboxy-2-benzylidene-6-methoxybenzofuran-3 (2H) -o, n, mp 273-275 ° C (dec.);

(Z) -3‘-Carbonyl-2-benzylidene-5-methylbenzofuran-3 (2H) -one, m.p. 264-265 ° C;

(Z) -3‘-carboxy-2-benzylidene-6-methylbenzofuran-3 (2H) -one, m.p. 263-264 ° C;

(Z) -4‘-Carboxyxy-2-benzylidene-6-methylbenzofuran-3 (2H) -one, m.p. 288 DEG-289 DEG C .;

(Z) -3‘-carboxy-4‘-hydroxy-2-benzylidene-6-methylbenzofuran-3 (2H) -one, m.p. 290-291 ° C;

(Zb 3‘-carboxy-4‘-hydroxy-2-benzylidenebenzofuran-3 (2H) -one, m.p. 268-270 ° C);

¹ * (Z) -4'-carboxy-2-benzylidene-benzofuran-3 (2H) -one, m.p. 274-275 ° C;

(Z) -3‘-carboxy-2-benzylidene-6-chlorobenzofuran-3 (2H) -one, m.p. 278 DEG-280 DEG C .;

(Z) -2‘-carboxy-2-benzylidene-5-chlorobenzofuran-3 (2H) -one, m.p. 205 DEG-206 DEG C .;

(Z) -3‘-carboxy-2-benzylidene-5-chlorobenzofuran-3 (2H) -one, m.p. 286 DEG-288 DEG C .;

(Z) -4‘-carboxy-2-benzylidene-5-chloro benzofuran-3 (2H) -one, m.p. > 300 ° C;

(Z) -3‘-carboxy-2-benzylidene-5-ethylbenzofuran-3 (2H) -one, m.p. 252 ° C;

(Z) -3‘-carboxy-2-benzylidene-benzofuran-3 (2H) -cn, m.p. 259-260 ° C;

(Z) -4 ‘- [(E) -carboxyvinyl] -2-benzylidene-5-methylbenzofuran-3 (2H) -one, m.p. 2-5 DEG-276 DEG C .;

(Z) -3 ^s -k ^R RBO <xy-2-benzylidene-5-cyklohexylbenzofuran-3 (2H) -one, m.p. 252 DEG to 253 DEG C;

[Z) -4 ^{S-carboxy-2-benzylidene-6-chloro-benzofuran-3} (2H) -one, mp> 300 ° C;

(Z) -2‘-carboxy-2-benzylidene-6-chlorobenzofuran-3 (2H) -one, m.p. 184 ° C;

(Z) -4‘ - [(E) -2-Carboxy vinyl] -2-benzylidene-6-hydroxybenzofuran-3 (2H) -one, m.p. > 300 ° C (dec.);

(Z) -3‘-carboxy-2-benzylidene-6-hydroxybenzofuran-3 (2H) -one, m.p. 320 ° C (dec.);

[Z] -2'-carboxy-2-benzylidene-6-hydroxybenzofuran-3 (2H) -one, m.p. 282-283 ° C;

(Z) -4‘ - [(E] -2-carboxyvinyl] -2-benzylidene-5,7-dichlorobenzofuran-3 (2H) -one, m.p. > 300 ° C;

(Z) -3‘ - [(E) -2-carboxyvinyl] -2-benzylide-5,7-dichlorobenzofuran-3 (2H) -one, m.p. > 300 ° C;

(Z) -3‘ - [(E) -2-carboxyvinyl] -2-benzylidene-6-hydroxybenzofuran-3 (2H) -one, m.p. > 300 ° C;

(Z) -3‘ - [(E) -2-carboxyvinyl] -2-benzylidene-5-methoxybenzofuran-3 (2H) -one, m.p. 242 ° C;

(Z) -3‘-carboxy-2-benzylidene naphtho (1,2-b) furan-3 (2H) -one, m.p. 276 DEG-278 DEG C .;

(Z) -3‘ - [(E) -2-carboxyvinyl] -2-benzylidene naphtho (1,2-b) furan-3 (2H) -one, m.p. 280 ° C;

(Z) -3‘-carboxy-2-benzylidene-4-hydroxybenzofuran-3 (2H) -one, m.p. 285 DEG-287 DEG C .;

(Z) -2‘-carboxy-2-benzylidene-5,7-dibromo-4-hydroxybenzofuran-3 (2H) -one, m.p. 258-260 ° C.

Example 3 (Z) -4- (5-Tetrazolyl) -2-benzylidene-5-chlorobenzofuran-3 (2H) -one

A mixture of 4-cyanobenzaldehyde (13.1 g, 0.1 mol), ethylene glycol (6.2 g, 0.1 mol) and tolue-4-sulfonic acid (19.0 mg, 0.1 mmol) was heated. to boiling in benzene (100 mL) for 8 hours using Dean and a Starter Attachment to distill off the solvents. The benzene was then distilled off to give 4-cyano- (2-1,3-dioxalan) benzene as a colorless waxy substance (m.p. 44-45 ° C), which was used in the next step without further purification.

A mixture of the above dioxalane (17.1 g, 0.1 mol), sodium azide (6.5 g, 0.1 mol) and lithium chloride (6.5 g, 0.15 mol) was heated to reflux. in 2-methoxyethanol (100 mL) for 8 hours. The suspension was then poured into a mixture of ice and hydrochloric acid (5 M); Upon standing, colorless crystals of 4- (5-tetrazolyl) benzaldehyde, m.p. 200 DEG C., precipitated.

The latter benzaldehyde was reacted as described in Example 6 with 5-chlorobenzofuran-3 (2H) -one [Annalen 405, 2924, 346]. The title compound is obtained, which after recrystallization from dimethylformamide has a melting point of 260 DEG C. (with decomposition).

Example 4

Following the procedure described in Example 3, but using appropriately substituted cyanobenzaldehydes and benzofuranones, the following compounds were obtained:

(Z) -3- (5-tetrazolyl) -2-benzylidene-5-methoxybenzofuran-3 (2H) -one, m.p. 278 DEG-280 DEG C. (dec.);

(Z) -4- (5-Tetrazolyl) -2-benzylidene-6-hydroxybenzofuran-3 (2H) -one, m.p. 300 DEG C. (dec.);

(Z) -4- (5-Tetrazolyl) -2-benzylidene-5-methoxybenzofuran-3 (2H) -one, m.p. 268-270 ° C (dec.);

(Z) -3‘- (5-Tetrazolyl) -2-benzylidene-5,7-dichlorobenzofuran-3 (2H) -one, m.p. 283-285 ° C (dec.).

Example 5 (Z) -3- (5-Tetriazolyl) -2-benzylidene-5-ethylbenzofuran-3 (2H) -one

To a solution of 5-ethylbenzofuran-3 (2H) -one (3.4 g, 0.02 mol) [J. Indian Chem. Soc. 42, 20 (1965)) and 3-cyanobenzaldehyde (2.62 g, 0.02 mol) in dioxane (100 mL) were added concentrated hydrochloric acid (5 mL) and the resulting yellow colored solution was heated at reflux for 2 h. After cooling, yellow needle crystals of (Z) -3'-cyan-2-benzylidene-benzofuran-3 (2H) -one precipitate which are filtered off; mp 162 ° C.

A mixture of the obtained auron (0.5 g, 0.0018 mol), trimethylsilyl azide (1 g, 0.086 mol) and dimethylformamide was heated at reflux for 6 hours. After cooling, the solution is poured into ice / hydrochloric acid, the suspension obtained is heated at 70 ° C for 30 minutes and the precipitate formed is filtered off. The title compound is obtained in the form of a yellow oil, m.p. 242-243 ° C.

(Z) -4‘- (5-Tetrazolyl) -2-benzylidene-5-methyl (Z) -2‘-carboxy-2-benzylene-5-carbomethoxy-6-aminobenzofuran-3 (2H) -one

Example 6 (Z) -2'-Carboxy-2-benzylidene-5-carbomethoxy-6-aminobenzofuran-3- (2H) -one

A solution of methyl 3-acetyl-4-hydroxy-6-aminobenzoate (8.0 g, 0.038 mol) in dichloromethane (250 mL) was added to trifluoroacetic anhydride (16 g, 0.076 mol) and the solution was stirred at room temperature for 15 minutes. After distilling off the solvent from the yellow solution obtained, methyl 3-acetyl-4-acetoxy-6-trifluoroacetamidobenzoate is obtained, m.p. 130-131 ° C.

The copper (I) bromide (17.0 g, 0.076 mol) was suspended in ethyl acetate (300 mL) with vigorous stirring, and the benzoate prepared above (11.5 g, 0.038 mol) as a solution in ethyl acetate (200 mL) was added. and the mixture was stirred and heated to reflux for 3 hours. The pale green cuprous bromide formed is filtered off and the solvent is distilled off. Recrystallization from ether / petroleum ether (b.p. 40-60 ° C) gave methyl 3-bromoacetyl-4-acetoxy-6-trifluoroacetamidobenzoate as colorless crystals of m.p. 260-261 ° C.

To a solution of the latter compound (1.0 g, 0.005 mol) and 2-carboxybenzaldehyde (0.75 g, 0.005 mol) in methanol (100 mL) at 60 ° C, was slowly added sodium hydroxide solution with stirring. (0.6 g, 0.015 mol) in water (20 mL). The resulting red solution was heated to reflux for 3 hours, then cooled and poured onto ice / hydrochloric acid (5M). The yellow precipitate was filtered off and dissolved in 10% aqueous sodium bicarbonate at 50 ° C. The solution was adjusted to pH 7 and an ion exchange resin [Amberlite iRA-401] in hydroxyl form was added. The resin was then filtered off, washed with water and then glacial acetic acid. After concentration of the acetic acid wash, the title compound crystallizes as shiny yellow prisms, m.p. 280 DEG C. (dec.).

Example 7

The finely divided copper bromide (88 g, 0.4 mol) was suspended in a mixture of ethyl acetate and chloroform - (1: 1, 200 ml), and a solution of 2,6-dihydroxyacetophenone (10 g, 0.0657 - mol) was added. ) in chloroform (20 ml) and refluxed under stirring for 8 hours; hydrogen bromide is released. After cooling the reaction mixture, the precipitated copper (I) bromide is filtered off and the filtrate is evaporated to dryness; is obtained

3,5-Dibromo-2,6-di-hydroxy-1H-bromoacetophenone, m.p.

A mixture of the obtained n-bromo-acetophenone (8.2 g, 0.21 mol), sodium acetate (20 g) and 90% ethanol (100 ml) was heated under reflux for 15 minutes. After cooling, water (100 ml) was added to the reaction mixture, the greenish substance which precipitated from the yellow solution was filtered off and recrystallized from ethanol-water; is obtained

185 DEG C. (dec.) 5,7-dibromo-5-oxoebonzofuran-3 [2H] -one.

The benzofuran-3 (2H) -one thus obtained is then reacted as described in Example 6 with 3-carboxybenzaldehyde to give the title compound, m.p. > 300 DEG C. (dec.). ........

Example

Using the method described in Example 7, using the appropriately substituted benzaldehydes, the following compounds were obtained:

(Z) ‘4 -carboxy-2-benzrlidene-5,7-2-bromo-4-hydroxybenzofuran-3 (2H) -one, m.p. > 300 ° C (dec.);

(Z) -2‘-carboxy-2-beltzylidene-5,7-2-bromo-4-hydroxybenzoCuran-3 (2H) -one, m.p. 258-260 ° C;

Example 9 (Z) -4- [(E) -2-Carboxy vinyl] -2-beezylidee-B-amino-4-cyanobenzofuran-d (2H) -one

4-Amino-5-cyano-2-hydroxy-aetophenone (JC S-Perkin I-1979, 3, 677) was converted to 4-trifluoroacetamido-5-cyano-2-hydroxyacetophenone (m.p. 214 ° C) as described. in Example 6.

Said acetophenone was brominated using copper (I) bromide as described in Example 7 to give 4-trifluoroacetamido-5-cyano-2-hydroxy-brominated tophenone, melting point 202 degrees Celsius.

To a solution of said n -bromoacetophenone (3.8 g, -0.011 mol) in ethanol (50 mL) was added excess sodium acetate (10 g) - and water (10 mL) - and the mixture was heated to reflux for 20 min. reflux condenser. After cooling, an orange solid precipitated, which was filtered off and recrystallized from ethanol. 6-Amino-5-cyanobenzofuran-3 (2H) -one is obtained in the form of -orange plate crystals, m.p. 270 DEG C. (dec.).

The benzoic acid thus obtained was reacted as described in Example 1 with (E) -4-formic cinnamic acid and the title compound was obtained in the form of orange colored crystals, m.p. 300 ° C.

Example 10 (Z) -3‘-Carboxy-2-beezyl-2-ε-5-cyclohexylbenzoCurae-3 (2H) -one

A mixture of? -Cyclohexylphenol (88 g, 0.5 mol) with acetyl chloride (39 g, 0.5 mol) was heated at 170 ° C for 3 hours. The clear liquid obtained was cooled to 100 ° C and aluminum chloride (133 g, 1.0 mol) was slowly added. The brown, sticky-oily liquid was heated at 130 ° C for 5 hours, then cooled, ice and hydrochloric acid were added, and the phenol was taken up in chloroform. The organic extract is evaporated to dryness and the residue is distilled with steam; yield - ^2-acetyl: butyl-4-cyclohexylphenol as -čiré oil.

The phenol was reacted as described in Example 6 with copper (I) bromide. To give 2-brΌ · ^ma, cetyl 4y -cyklohexylfenol as a yellow oil.

The oily product obtained was dissolved in ethanol (100 ml), sodium acetate (44 g) and water (20 ml) were added and the mixture was heated to reflux for 10 minutes. The solution was cooled, water was added and the brown oil which formed was taken up in chloroform. The solvent is distilled off from the chloroform extract and the 5-cyclohexylbenzoCuran-3 (2H) -oe obtained is reacted as described in Example 1 with 3-carboxybeezaldehyde to give the title compound as yellow crystals, m.p. Mp 252-253 ° C.

^Example 1 - ad 11 (Z) -3 ^' , 4', 5'-Trimethoxr-2-benzylidene-5-carboxybenzofuran-3 (2-H) -one

a) Methyl 4-acetoxybenzoate (126 g, 0.65 mol) was thoroughly mixed with aluminum chloride (220 g, 1.63 mol) and the mixture was allowed to react at 160 ° C with stirring as described by G. Dora et al. v Eur. J. Med. Chem. 1978, 13, 33. The reaction product is quenched with acid, the crude product obtained is stirred with a saturated sodium bicarbonate solution and filtered. The filtrate is carefully acidified, the precipitate is filtered off, washed with water and dried; 232-C-3-acetyl-4-hydroxybenzoic acid is obtained.

The insoluble matter after the above extraction with sodium bicarbonate was dissolved in dilute sodium hydroxide solution (2N) and the solution was probably acidified with dilute hydrochloric acid solution (5N) to give methyl 3-acetyl-4-hydroxybenzoate which was filtered off, washed 90-92 ° C.

b) To a solution of 3-acetyl-4-hydroxybenzoronic acid (24.0 g, 0.133 mol) in dioxane (400 mL) at 40 ° C is added dropwise bromine (7.2 mL, 0.14 mol). The orange color of the solution soon disappeared and after 45 minutes the clear solution was decanted from a small amount of insoluble matter and the solvent was distilled off. 3-Bromoacetyl-4-hydroxybenzoic acid is obtained in the form of a pale straw color, m.p. 226 DEG.

c) The product obtained in process b) was dissolved in a mixture of ethanol (350 ml) and water (70 ml), sodium acetate (30 g) was added thereto, and the mixture was heated to 60 ° C with stirring for 10 minutes. The dark orange-red solution was cooled to 10 ° C and carefully acidified with 5N hydrochloric acid with stirring. The clear red solution obtained was diluted with an equal volume of water and stored in a refrigerator overnight. The resulting yellow crystalline solid is filtered off, washed with cold water and dried; 204 DEG C. (with decomposition), 5-carboxybenzofuran-3 (2H) -one.

d) A solution of said 5-carboxybenzofuran-3 (2H) -one (3.56 g, 0.02 mol) and 3,4,5-trimethoxybenzaldehyde (3.92 g, 0.02 mol) in warm dioxane (50 mL). Concentrated hydrochloric acid (10 ml) was added and the mixture was heated in a boiling water bath for 15 minutes with stirring. The solution was cooled, an equal volume of water was added, the precipitated yellow crystalline material was filtered off, washed with water and dried. Recrystallization from glacial acetic acid gave the title compound, m.p. 290 ° C.

Example 12

The following compounds were prepared as described in Example 11:

(Z) -2-benzylidene-5-carboxybenzofuran- (2H) -one, m.p. 280 ° C;

(Z) -4‘-chloro-2-benzylidene-5-carboxybenzofuran-3 (2H) -one, m.p. &gt; 300 ° C;

(Z) -2 ^t -chloroform R-4'-dimethylamino-2-benzylidene-5-karboxybenzof tetrahydrofuran-3 (2H) -one, m.p. 275 DEG C. (decomposition);

(Z) -4‘-butyl-2-benzylidene-5-carboxybenzofuran-3 (2H) -one, m.p. 252 ° C;

(Z) -4‘-Dimethylamino-2-benzylidene-5-carboxybenzofuran-3 (2H) -one, m.p.

295 [deg.] C .;

(Z) -4‘-methoxy-2-benzylidene-5-carboxybenzofuran-3 (2H) -one, m.p. 300 ° C;

(Z) -4- (E) -2-carboxy vinyl-2-benzylidene-5-carboxybenzofuran-3 (2H) -one, m.p. &gt; 300 C;

(Z) -3-carboxy-4 ^{<-hydroxy-2-benzylidene-5-carboxy-benzofuran-3} (2Ή) -one, mp above 300 ° C;

(Z) -4‘-acetamido-2-benzylidene-5-carboxybenzofuran-3 (2H) -one, m.p. &gt; 300 ° C;

(Z) -3‘-trifluoromethyl-2-benzylidene-5-carboxybenzofuran-3 (2H) -one, m.p. 264 ° C;

(Z) -3‘- (N-Isopropylcarboxamido) -2-benzylidene-5-carboxybenzofuran-3 (2H) -one, m.p. 300 ° C.

Example 1 a d 1 3

5-Carboxy-6-hydroxy-benzofuran-3 (2H) -one

a) To a solution of 5-acetyl-2,4-dimethoxybenzoic acid (Ber, 41, 1607, 1908) (21.1 g, 0.094 mol) in dioxane (200 mL) at room temperature, with stirring, was added dropwise bromine (5). ml, about 0.1 mol). The color of the solution caused by bromine slowly disappears over 30 minutes, and then the mixture is heated to gentle boiling on a water bath for 30 minutes. After cooling, the dioxane was distilled off under reduced pressure, the solid residue was taken up in boiling ethyl acetate, the solution was filtered hot and the filtrate was evaporated; 5-bromoacetyl-2,4-dimethoxybenzoic acid, m.p. 236 ° C.

b) The product obtained in a) (21.6 g, 0.071 mol) was dissolved in dichloromethane (250 ml), cooled in an ice bath and boron tribromide (25 ml) was added dropwise with stirring. The solution was refluxed in a water bath for 4 hours, then cooled and poured onto ice (1 kg). After removal of the dichloromethane, the precipitated pink solid was filtered off, washed with water and dried. The product was dissolved in a mixture of ethanol (200 mL) and water (80 mL), sodium acetate (25 g) was added, and the mixture was heated at 60 ° C for 30 min. The solution was cooled, ethanol was distilled off under reduced pressure, and additional water (150 ml) was added to the concentrated solution, cooled in an ice bath ^, and acidified with dilute hydrochloric acid (5N) to pH 2 with stirring. The yellow crystalline solid which precipitated was collected by filtration, washed with water and dried to give the title benzofuranone, m.p. 216 ° C.

Example 14 (Z) -3‘-Carboxy-2-benzylidene-6-carboxy-6-hydroxybenzo'furan-3 (2H) -one

To a solution of 5-carboxy-6-hydroxybenzofuran-3 (2H) -one (5.82 g, 0.03 mol) in dioxane (75 mL) was added 3-carboxybenzaldehyde (4.50 g, 0.03 mol). followed by concentrated hydrochloric acid (15 ml) and the solution was heated, with occasional stirring, in a water bath at moderate boiling for 30 minutes. The solid mixture was cooled, diluted with an equal volume of water and stored in a refrigerator for 1 hour. The precipitated product is filtered off, washed with water and dried. Recrystallization from dimethylformamide gave the title compound, m.p. 335 DEG C. (dec.).

Example 15

The following compounds were prepared as described in Example 14:

(Z) -3‘-carboxy-4-hydroxy-2-benzylidene-5-carboxy-6-hydroxybenzofuran-3 (2H) -one, m.p. 332 DEG C. (dec.);

(Z) -4 '(tetrazol-5-yl) -2-benzyllden-5-carboxy-l ^ - ^ - ^^^ (^ i ox ^i; ^ l ^ i ^] ^ ^ ^ j ^ i ^; furan-3 (2H) -OR ^, mp 327-328 ° C (dec).

Example 16 (Z) -3‘-Carboxy-2-benzylide-5-methoxycarbonylbenzofuran-3 (2H) -one

To a solution of methyl 3-acetyl 4-hydroxybenzoate (5.39 g, 0.028 mol) in dioxane (200 mL) at 40 ° C was added dropwise bromine (1.5 mL). After ~ 45 min, the colorless solution was evaporated to give a straw colored oily product. The material was dissolved in a mixture of ethanol (75 mL) and water [15 mL], sodium acetate (6.0 g) was added, and the mixture was stirred at room temperature for 5 minutes. ice (100 grams), the product was extracted into chloroform and the solvent was distilled off of the organic extract to give 5-methoxycarbonylbenzofuran-3 (2H) -one as an orange-colored oil (65% pure by NMR).

The product obtained was immediately dissolved in dioxane (50 ml), 3-carboxybenzaldehyde (4.5 g, 0.03 mol) was added followed by concentrated hydrochloric acid [10 ml] and the mixture was heated on a boiling water bath for 15 minutes. . After working up the reaction mixture as described in Example 49 and recrystallizing the crude product from dimethylformamide, the desired aura of melting point 280 DEG C. is obtained.

Example 17. (Z) -3 ^t- Carboxy-2-benryllden-6 aceto mido-o-furan-B (2H) -one

a] A mixture of 3-aminophenol [54.5 g, 0.5 mol) with acetic anhydride (200 mL) was heated in a boiling water bath for 2 hours with stirring. Volatile material was distilled off from the straw-colored reaction mixture under reduced pressure and the resulting oily viscous liquid was heated to 110-120 ° C with aluminum chloride (170 g, 1.27 mol), which was slowly added with stirring. After 30 minutes, the solid product cooled somewhat and was carefully quenched with a mixture of Hedu and water (about 500 g). Concentrated hydrochloric acid (200 ml) was then added and the mixture was gently heated on a steam bath. Upon cooling, a crystalline material precipitates, which is filtered off, washed with water and dried. The title compound, 2-hydroxy-4-acetamido-acetophenone, is obtained, m.p. 140 ° C.

b) The product obtained by the above process a) (14.0 g, 0.072 mol) is dissolved in ethyl acetate (300 ml) and the solution is added to the copper bromide suspension (32 g, 0.143 mol) with stirring. in ethyl acetate - (100 mL). The mixture was heated under reflux for 4 hours, then filtered hot and the solvent was distilled off under reduced pressure; an oily residue is obtained, which crystallizes.

The product is converted to benzofuranone and reacted with 3-carboxybenzaldehyde as described in Example 16. However, during the reaction, the substance is partially deacetylated. Therefore, it is allowed to react with. with acetic anhydride (20 ml) at reflux to convert to a fully acetyl compound. The reaction mixture is poured onto ice (100 g) and the excess acetic anhydride is hydrolyzed. The precipitated solid is filtered off and recrystallized from aq. Acetic acid (50% v / v) gave (Z) -3'-carboxy-2-benzylidene-6-acetamldobenzofuran-3 (2H) -one, m.p. 305 ° C (dec.).

Example 1 - a d 18 (Z) -4‘-Chloro-2-benzylidene-5-n-butoxycarborylbenzafuran-3 (2H) -one

To a suspension of (Z) -4‘-chloro-2-benzylidene-5-carbaxybenzofuran-3 (2H) -one [3.0. g, - 0.01 mol) in n-butanol [50 ml] was added dropwise concentrated sulfuric acid (1.5 ml) with stirring and the mixture was heated under reflux for 5 hours. From the resulting yellow colored solution, finely needle-like crystals of the desired n-butyl ester precipitate upon cooling. The crystals are filtered off, washed with cold n-butanol and then with diethyl ether and dried; mp 154 ° C.

Example 19 (E) -4‘-Chloro-2-benzylidene-5-n-butoxycarbonylbenzofuran-3 (2H) -one

A solution of (Z) -4‘-chloro-2-benzylidene-5-one-butoxycarbonylbenzofuran-3 (2H) -one (1.0 g) in benzene (800 mL) was irradiated for 15 hours in a one-liter photochemical reactor. The solvent was distilled off under reduced pressure to obtain 1.0 g of a solid with a melting point of about 130 ° C, which was a mixture of the (E) - and (Z) -isomers in a ratio of about 75:25 (by NMR and HPLC). ).

500 mg of said mixture of isomers is chromatographed on a column of silica gel [Sorbsil] (200 g), eluting with benzene, collecting the fractions of the faster moving (E) -isomer. This fraction was combined, the solvent was distilled off to give a yellow crystalline solid, m.p. 142 ° C, having an E: Z isomer ratio of 88: 12; yield 350 mg.

The concentrate obtained (200 mg) is recrystallized from a mixture of dichloromethane and petroleum ether, b.p. 40-60 ° C (1: 3 by volume). 130 mg of crystalline solid are obtained, m.p. 142 DEG C., having a ratio of (EJ: (Z) -isomer of 92.5: 7.5).

The following therapeutic agents were prepared using (Z) -3‘-carboxy-2-benzylidene-5-chlorobenzofuran-3 (2H) -one as the active ingredient; similarly, preparations containing other compounds of formula I may be prepared.

Example 20

Hard gelatine capsules are prepared using the following ingredients:

Ingredient Quantity (mg / capsule) Active ingredient250 Starch dried200 Magnesium stearate10

The above ingredients are mixed well and the mixture is filled into hard gelatin capsules.

Example 21

Tablets are prepared using the following ingredients:

Ingredient Quantity (mg / tablet) Active ingredient250 Microcrystalline cellulose400 Silicon dioxide10 Stearic acid5

The components are mixed well and compressed into tablets.

Example 22

An aerosol formulation is made using the following components:

Ingredient Amount (% by weight) Active substance 0,25 ethanol '29, 75 Chlorine difluoromethane 70 (propellant 22)

The active ingredient was mixed with ethanol and added to the propellant 22 cooled to -30 ° C. The solution is transferred to a filling machine, the required amount of mixture is filled into stainless steel containers, and the contents are diluted with a further measured amount of propellant. Finally, the vessel is provided with a valve.

Example 23

Suppositories containing 200 mg of an active compound of formula I are prepared using the following components:

Ingredient Quantity Active ingredient 200mg polyethylene glycol 1000 750mg polyethylene glycol 4000 250mg

The active compound is mixed with the molten polyethylene glycol base and the mixture is poured into suitable rosehip molds to provide suppositories of the indicated weight.

Example 1 a d 2 4

The ointment is prepared according to the following formula:

Ingredient active ingredient white soft paraffin

Quantity (% by weight) up to 100%

The active substance is added to the molten paraffin and the mixture is allowed to cool.

Claims (1)

SUBJECT OF THE INVENTION CLAIMS 1. A process for the manufacture of auron derivatives; A compound of formula I wherein R ¹ , R ² , R ³ , R 1, R ^5, and R ⁶ , which may be the same or different, each represent a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group. C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 3 -C 6 haloalkyl, C 3 -C 6 haloalkyl, amide, amino, cyano, hydroxyl, carboxyl, 5-tetrazoles -. or wherein the substituents R ¹ and R ² denote a common group of the formula —CH — CH — CH — CH—, with the proviso that at least one of the substituents R ¹ , R ² , R ^{2 3,} a ^4, R ⁵ and R ^G is carboxyl, 5-tetrazolyl or a group of formula - CH-CHCOOH, and pharmaceutically acceptable salts or esters, characterized in that a substituted benzaldehyde of the formula III, For gve | meaning, state in v R ⁵ and which R Лin by the formula IV, R ^G have the above reactions with benzofurano- > wherein R ¹ , R ² and R ³ have the above mentioned and optionally in the obtained compound of formula (I), the individual groups are converted into other groups within the definitive meaning of the substituents and / or the compound of formula (I) is optionally converted into a pharmaceutically acceptable salt or ester.