SE447382B - 2-BENZYLIDEEN-BENZOFURAN-3 (2H) -ON-DERIVATIVE AND PROCEDURE FOR THEIR PREPARATION - Google Patents

Description

15 20 25 30 35 447 382 R 1 and R 2 together represent a group of the formula -CH = CH-CH = CH- and R ", Rs and Rs each mean halo- gene, cycloalkyl having 3 to 8 carbon atoms, haloalkyl having ~ 1-6 carbon atoms, amido, cyano, carboxyl, tetrazol-5-yl or -cn = cHcooH, however, at least one of R1, R2, Ra, RQ, R5 and R5 represent a carboxyl group, tetrazol-5-yl- group or -CH = CHCOOH, or a pharmaceutically acceptable bare salt or ester thereof.

The compounds of formula I may be present in (E) - or the (Z) form, with the (Z) form being preferred.

A special group of associations is one with the formula (I), wherein R 1, R 2, R 3, R 4, R 5 and R 5 have them in the meanings given above, provided that the at least one of R ", R5 and R" means a tetrazol-5-yl- group or -CH = CHCOOH, when R 1, R 2 and Ra atoms. It is preferred that the benzofuranone ring be substituted. and thus a preferred group is one with meln (I), wherein at least one of R 1, R 2 and R 3 means something other than a hydrogen atom.

Another special group of associations is one of formula (I) wherein R 1, R 2, R a, R ", R 5 and R 5 have in the preceding meanings, provided that: when one of R 1, R 2 and R 3 represents a carboxyl group, at least one of R ', R5 and R ° represents halogen, cycloal alkyl of 3 to 8 carbon atoms, haloalkyl of 1 to 6 carbon atoms more, amido, cyano, carboxyl, tetrazol-5-yl or -cH = cHcooH.

An especially preferred group of compounds is one of the formula (IL, wherein at least one of R 1, R 2 and R 3) denotes anything other than a hydrogen atom and at least one of R 2, R 3 and R 6 represent halogen, cycloalkyl of 3 f B carbon atoms, haloalkyl having 1 to 6 carbon atoms, amido, cyano, carboxyl, tetrazol-5-yl or -CH = CHCOOH.

The term "halogen" especially means chlorine, l bromine and fluorine. The term "alkyl of 1 to 6 carbon atoms" includes, for example, methyl, ethyl, propyl, isopropyl, f * 10 15 20 25 30 35 447 382 butyl, t-butyl, pentyl and hexyl, methyl, ethyl or t-butyl is preferred. The term "alkoxy with 1 - 6 carbon atoms "include, for example, methoxy, ethoxy, poxy and butoxy and is preferably methoxy. Expression- a "cycloalkyl of 3 to 8 carbon atoms" denotes preferred desvis cyclohexyl. The term "halogenalkyl" is 1 to 6 carbon atoms "may, for example, refer to any of those for" alkyl with 1 to 6 carbon atoms "indicated groups substituted with 1-3 halogen atoms, e.g. fluorine or chlorine, and cially trifluoromethyl. It is preferred that R1, R2, Ra, R 2, R 5 and R 6 are selected from hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, cyclo- hexyl, trifluoromethyl, N-isopropylcarboxamido, acetamide do, dimethylamino, hydroxy, carboxyl, tetrazol-5-yl and -CH = CHCOOH, or R1 and R2 together mean -CH = CH-CH = CH-.

Other preferred compounds within the scope of the present aurons of formula (I) are the compounds having one or more of the following characteristics: (a) R 1 represents alkyl having 1 to 4 carbon atoms, for example methyl; (b) for example methoxy; (c) (d) for example (e) (f) (9) (hrs) (in) (j) (k) (1) (m) (n) (O) 612010812 'y RJ.

RI RJ. denotes denotes denotes cyclohexyl; RI RI Rl RI denotes denotes * denotes denotes denotes denotes denotes denotes denotes denotes denotes alkoxy having 1 to 4 carbon atoms, halogen, e.g. claws; cycloalkyl having 3 to 8 carbon amino; carboxyl; a 5- or 6-substituent; hydroxyl; hydrogen; hydrogen; carboxyl; tetrazol-5-yl; -CH = CHCOOH; hydrogen; hydrogen. 10 15 20 25 30 35 447 382 An especially preferred group of compounds is one in which R 1 represents alkyl having 1 to 4 carbon atoms, carboxyl or halogen, R 2 and R a represent hydrogen, R represents carboxyl or -CH = CHCOOH and R 5 and R 6 draws hydrogen. In this group, preference is given to compounds in which R 1 represents alkyl or carboxyl, R 2 and Ra means hydrogen, R 'means carboxyl or -CH = CHCOOH and R 5 and R 5 are hydrogen.

The compounds of formula (I) may also have but of pharmaceutically acceptable salts or esters.

Such derivatives are encountered, for example, when one or more of the substituents R 1, R 2, R 3, R ", R 5 and R 5 are acidic function, carboxyl or -CH = CHCOOH. Suitable salts includes, for example, those of mineral bases, e.g. al- potassium metal hydroxides, in particular potassium or sodium salts or alkaline earth metal hydroxides, in particular cium salts, or of organic bases, e.g. amines. Fö- Reduced esters are those derived from alkanols with 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxyethyl or ethoxy- ethyl ester.

The present invention also includes a process for the preparation of aurones of formula (I), which process involves the reaction of a benzaldehyde hyd with the formula 5 R __ (111) ouc i RS with (a) a benzofuranone of the formula 10 15 20 25 30 35 447 382 (IV) Ra or (b) a w-substituted acetophenone of the formula RI CHZX (F) Rz OH Rs wherein X represents an eliminable group: possible consequence, when one or more of R 1, R 2, R a, R ", R 5 or R 5 represents cyano, by reaction with an azide to the corresponding tetra- azol-5-yl compound.

As stated above, aurons of formula (I) prepared by condensation of an appropriate substituent row of benzaldehyde (III) with a benzofuranone derivative (IV) according to the formula RI 122 + onc Rs (IV) (III) (IN) 10 15 20 25 30 35 447 382 Suitable solvents for this reaction are ether solvents, e.g. dioxane and tetrahydrofuran, and liquid alkanols, e.g. ethanol. In general, tempe- temperature is not critical and is only relevant for the tion rate. The reaction proceeds at all temperatures. between ambient temperature and reaction mixture reflux temperature, for example between 25 and 150 ° C. The reaction is preferably acid or base catalyst. lysed. Suitable acid catalysts are mineral acids, for example hydrochloric acid, and strong organic acids, e.g. p-toluenesulfonic acids, and suitable inorganic or organic basic catalysts are alkaline compounds, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate or triethylamine. This type of condensation reaction is well known and those skilled in the art are well aware of the nature of the conditions and reagents necessary for the preparation of a special auron of formula (I).

An alternative method of production of the compounds of formula (I) include reaction of an m-substituted acetophenone (V) with a suitable benzene aldehyde (III) according to the following reaction scheme: 1 o R “ R.

CHZX on R * Ra (V) (III) (IN) wherein X represents an eliminable group, e.g. halogen, especially chloride or bromide, or a tosyl group. _ - .. pnqusw-vw-v-F- fl '' '“' 10 15 20 25 30 35 447 382 Suitable solvents are ether solvents, e.g. di- oxane and tetrahydrofuran, and liquid alkanols for example ethanol. In this case, the reaction is preferably base catalyzed using such a catalyst such as sodium hydroxide, potassium hydroxide or sodium hydroxide carbonate. Temperatures between 0 and 150 ° C can be used for carrying out the reaction. The reactants with meln (III), (IV) and (V) are well known compounds and can are prepared in well-known ways, which are described in raturen.

In addition, compounds of formula (I), wherein one of the R groups is tetrazol-5-yl, obtained by position of the corresponding nitrile and formation of the corresponding tetrazole using a non-nucleophilic azide, e.g. trimethylsilylazide, in a solvent with a high boiling point, e.g. dimethylform- amide, at temperatures above 100 ° C.

These reactions give rise to the (Z) -isomer, which may be transferred to the corresponding (E) - the isomer by photolytic methods, which are well known.

The aurons of formula (I) have been found to be valuable in the prophylactic treatment of asthma in mammals animal. This activity has been demonstrated in guinea pigs with use of the "Herxheimer" test, described in the Journal of nal of Physiology (London) 11, 251 (1952), or test with chopped guinea pig lung ", as described by Mongar and Schild in Journal of Physiology (London) lay, 207 (1956) or Brocklehurst in the Journal of Physiology (London), 414 (1960). The associations are also active in "test with peritoneal anaphylaxis in rats ", which is based on a allergic reaction in the peritoneal cavity of rats, such as described by Orange, Stechschulte and Austen in the Fed. Proc. go, 1710 (1969).

The "Herxheimer" test is based on a pigs induced allergic bronchospasm, which closely resembles one asthmatic attack in a human. The mediators who 10 15 20 25 30 35 447 382 causes bronchospasm, are very similar to those given when sensitized human lung tissue is removed set for an antigen. Compounds of the invention has shown activity in the "Herxheimer" test at doses from 25 mg / kg to 200 mg / kg.

The compounds of formula (I) may be administered in different ways, and for this purpose they can be das in many different forms, although it is a special one characteristics of the present compounds, that they are effective va in oral administration. Thus, the compounds may be added race orally and rectally, externally, parenterally, e.g. give- injection, in the form of, for example, tablets, lozenges sublingual tablets, wafers, solutions, suspensions ions, aerosols, ointments, for example containing up to 10% by weight of the active compound in a suitable ointment base, soft and hard gelatin capsules, suppositories, injection solutions and suspensions in physiological removable media, and sterile packaged powders adsorbed on a carrier material for the preparation of solution for injection nings. The nature of different for the production of such preparations required excipients and additives are well known to those skilled in the art.

Some examples of excipients that can be used used in pharmaceutical preparations, are lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, expanded silicon, oxide, microcrystalline cellulose, calcium silicate, silicon dioxide, polyvinylpyrrolidone, cetostearyl alcohol, starch modified starch, gum arabic, calcium phosphate barrels, cocoa butter, ethoxylated esters, theobroma oil, soil Peanut oil,: alginates, tragacanth, gelatin, syrup, methylcellulose lulose, polyoxyethylene sorbitol monolaurate, ethyl lactate, ethyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan tance violet and oleyl alcohol, and propellants, e.g. trichloromonofluoromethane, dichlorodifluoromethane and di- chlorotetrafluoroethane. When it comes to tablets, one can 10 15 20 25 30 35 447 382 lubricants are incorporated to prevent sticking and sticking the powdered constituents of the tableting the molds and punch of the machine. For such purposes, one can for example, use aluminum, magnesium or calcium stearate, talc or mineral oil.

Pharmaceutical preparations which, as active ingredients, the composition contains a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, together with a pharmaceutically acceptable carrier, can provided in the form of dosage units, each dosage unit preferably contains between 5 and 500 mg (between 5.0 and 50 mg for parenteral administration, between 5.0 and 50 mg by inhalation and between 25 and 500 mg for oral or rectal administration) of a compound containing formula (I). The term "unit dosage form" refers to physical discrete units, which are suitable as dosage units for human humans and animals, each unit containing a specific amount of active material, which is calculated to give the increased therapeutic effect, along with required pharmaceutical diluents, carriers or vehicles. neeer from o, s ri11 zoo mg / kg per day, pre- between 1 and 20 mg / kg active ingredient, may even if it is, of course, a doctor, who is the amount of the dosed amount of auron corresponds to the formula (I) in the light of the relevant circumstances, including the condition to be treated, the choice of compound which to be used and the method of administration chosen, and for the above-mentioned dose range refers to the to limit the present invention.

The following examples illustrate the invention.

Example 1 (Z) -4'-Carboxyl-2-benzylidene-5-methylbenzo- furan-3 (2H) -one --chloro-2-hydroxy-5-methylacetophenone (8.73 g, 0.05 mol) [Chem. Ber. eel, 4271, (1908)] and 4-carboxy- benzaldehyde (7.5 g, 0.05 mol) was dissolved in ethanol (100 ml), and the mixture was heated to 60 ° C. Sodium hydroxide (4 g, 10 15 20 25 30 35 447 382 10 0.1 mol) in water (20 ml) was then added slowly the stirred mixture, which turned deep red. After 1 h at 60 ° C a pale yellow precipitate formed, which then was added for another hour with reflux. The formed sus- the pension was cooled to OOC and acidified with hydrogen chloride acid (SM). The resulting pale yellow solid is filtered. was washed off, washed with water, dried under reduced pressure and recrystallized from dioxane to give kept the title compound as pale yellow needles, m.p. zss - 29 ° C (dec.).

Example 2 - 5 The following compounds were prepared in with the appropriate benzaldehyde and chloro- acetophenones: (Z) -2'-Carboxyl-2-benzylidene-5-methylbenzofu- ran-3 (2H) -one, m.p. 187-198 ° C; (Z) -2'-Carboxyl-2-benzylidene-6-methylbenzofu- ran-szzæn-on, m.p. 196-19 ° C (Sun), (Z) -2'-Carboxyl-2-benzylidene-naphtho (2,1-b) fu- ran-aufn-øn, m.p. 207-200 ° C; (Z) -4'-Carboxyl-2-benzylidene-5-isopropylbenzene sofuran-3 (2H) -one, m.p. 262-263 ° C.

Example 6 (Z) -3'-Carboxyl-2-benzylidene-5-methoxybenzofu- ran-3 (2H) -on 5-methoxybenzofuran-3 (2H) -one (6.0 g, 0.036 mol) [Annals ggå, 281, (1914)] and 3-carboxybenzaldehyde (5.4 g, 0.036 mol) [J. Chem. Soc. 4778, (1952)] was dissolved in di- oxane (50 ml), and concentrated hydrochloric acid (10 ml) sat. The resulting yellow solution was heated under reflux. flöae for 2 h. when cooling and adding water (20 m1) a yellow precipitate formed. This material gave after crystallization from acetic acid the title the unit as yellow needles with a melting point of 252 - 254 ° C. , - «_-_..-.__. _ .. - 10 15 20 25 30 35 447 382 11 Example 7 - 36 The following compounds were prepared in in the same way, they are sewn in Example 6 with the appropriate choice of sofuranone and benzaldehyde: (Z) -2'-Carboxyl-2-benzylidene-6-methoxybenzofu- ran-3 (2H) -one, m.p. 217 DEG-22 DEG C. (Sun.); (Z) -3'-Carboxyl-2-benzylidene-6-methoxybenzofu- ran-3 (2H) -one, m.p. 258-260 ° C (Sun.); (Z) -4'-Carboxyl-2-benzylidene-6-methoxybenzofu- ran-3 (2n) -on, m.p. 273 ° C (Sun.); (Z) -3'-Carboxyl-2-benzylidene-5-methylbenzofuran- 3 (zH) -one, m.p. 264-2 ° C; (Z) -3'-Carboxyl-2-benzylidene-6-methylbenzofuran- 3 (2a) -on, m.p. 263 - 4 ° C; (Z) -4'-Carboxyl-2-benzylidene-6-methylbenzofuran- 3 (2u) -on, m.p. 288-279 ° C; (Z) -3'-Carboxyl-4 '- hydroxy-2-benzylidene-6-methyl tylbenzofuran-3 (2H) -one, m.p. 290-291 ° C; (Z) -3'-carboxyl-4'-hydroxy-2-benzylidenebenzoate furan-3 (2H) -one, m.p. 268 ~ 270 ° C.

(Z) -4'-Carboxyl-2-benzylidenebenzofuran-3 (2H) - on, m.p. 274 DEG-275 DEG C .; (Z) -3'-Carboxyl-2-benzylidene-6-chlorobenzofu- ran-3 (2n) -on, m.p. 278 DEG-288 DEG C .; (Z) -2'-Carboxyl-2-benzylidene-5-chlorobenzofu- ran-3 (2u) -an, m.p. 205 DEG-206 DEG C .; (Z) -3'-Carboxyl-2-benzylidene-5-chlorobenzofu- ran-3 (2n) -on, m.p. 286-2 ° C; (Z) -4'-Carboxyl-2-benzylidene-5-chlorobenzofu- ran-3 (2H) -one, m.p. > 300 ° C; (Z) -3'-Carboxyl-2-benzylidene-5-ethylbenzofuran- 3 (2H) -one, m.p. 2 ° C; (Z) -3'-Carboxyl-2-benzylidenebenzofuran-3 (2H) - on, m.p. 259-260 ° C; (Z) -4 '- [(E) -carboxyvinyl] -2-benzylidene-5-methyl- tylbenzofuran-3 (2H) -one, m.p. 275 DEG-276 DEG C .; 10 15 20 25 30 35 -447 382 12 (Z) -3'-Carboxyl-2-benzylidene-5-cyclohexylbenzene sofuran-3 (2H) -one, m.p. 252 DEG-253 DEG C .; (Z) -4'-Carboxyl-2-benzylidene-6-chlorobenzofu- ran-3 (2H) -one, m.p. > 300 ° C; (Z) -2'-Carboxyl-2-benzylidene-6-chlorobenzofu- ran-3 (2H) -one, m.p. 184 DEG C .; (Z) -4 '- [(E) -2-carboxyvinyl] -2-benzylidene-6- hydroxybenzofuran-3 (2H) -one, m.p. > 300 ° C (Sun.); (Z) -3'-Carboxyl-2-benzylidene-6-hydroxybenzoate furan-3 (2H) -one, m.p. 320 ° C (Sun.); (Z) -2'-Carboxyl-2-benzylidene-6-hydroxybenzoate furan-3 (2H) -one, m.p. 282 DEG-283 DEG C .; (Z) -4 '- [(E) -2-carboxyvinyl] -2-benzylidene-5,7- dichlorobenzofuran-3 (2H) -one, m.p. > 300 ° C; (Z) -3 '- [(E) -2-carboxyvinyl] -2-benzylidene-5,7- dichlorobenzofuran-3 (ZH) -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 DEG C .; (Z) -3'-Carboxyl-2-benzylidene-naphtho (1,2-b) furan- 3 (2H) -one, m.p. 216 DEG-216 DEG C .; (Z) -3 '- [(E) -2-carboxyvinyl] -2-benzylidenenaphtho- (1,2-b) furan-3 (2H) -one, m.p. 280 ° C; (Z) -3'-Carboxyl-2-benzylidene-4-hydroxybenzoate furan-3 (2H) -one, m.p. 285 DEG-287 DEG C .; (Z) -2'-Carboxyl-2-benzylidene-5,7-dibromo-4- hydroxybenzofuran-3 (2H) -one, m.p. 258 - 26000.

Exemgel 37 _ (Z) -4 '- (5-Tetrazolyl) -2-benzylidene-5-chlorobenzene sofuran-3 (2H) -one 4-cyanobenzaldehyde (13.1 g, 0.1 mol), ethylene- glycol (6.2 g, 0.1 mol) and toluene-4-sulfonic acid (19.0) mg, 0.1 mmol) was refluxed at reflux in benzene (100 ml) using a device according to Dean and Stark.

The benzene was then evaporated to dryness to give 10 15 20 25 30 35 wßn-a-v-.f-fyf-w fi h 4247 582 '13 4-cyano- (2-1,3-dioxalane) benzene as a waxy dye dissolved solid (m.p. 44-45 ° C) used without further purification. This 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 refluxed in 2-methoxyethane. zero (100 ml) for 8 hours. The suspension was then poured onto ice and hydrochloric acid (5M). At rest was deposited from this solution white crystals of 4- (5-tetrazolyl) benzaldehyde, m.p. 200 ° C. This benzaldehyde and 5-chlorobenzofuran- 3 (2H) -one (Annals 2924 aga, 346) was reacted using of the procedure of Example 6 to give it the title compound, which was recrystallized from dimethylformamide, m.p. 260 ° C (Sun.).

Example 38 - 41 The following compounds were prepared in using the appropriate cyanobenzaldehyde hyd and benzofuran. IN (Z) -3 '- (5-Tetrazolyl) -2-benzylidene-5-methoxy- benzofuran-3 (2H) -one, m.p. 278-280 ° C (Sun.); (Z) -4 '- (5-tetrazolyl) -2-benzylidene-6-hydroxy- benzofuran-3 (2H) -an, m.p. 300 ° C (Sun.); (Z) -4 '- (5-Tetrazolyl) -2-benzylidene-5-methoxy- benzofuran-3 (2H) -one, m.p. 268 DEG-270 DEG (Sun.); (Z) -3 '- (5-Tetrazolyl) -2-benzylidene-5,7-di- chlorobenzofuran-3 (2H) -one, m.p. 283-285 ° C (Sun.).

Example 42 (Z) -3 '- (5-Tetrazolyl) -2-benzylidene-5-ethyl- benzofuran-3 (2H) -one 5-ethylbenzofuran-3 (2H) -one (3.4 g, 0.02 mol) [J. Indian Chem. Soc. 22, 20 (1965)] and 3-cyanobenzene aldehyde (2.62 g, 0.02 mol) was dissolved in dioxane (100 ml), and concentrated hydrochloric acid (5 ml) was added. The the resulting yellow solution was heated under reflux for 2 hours.

Upon cooling, yellow needles of (Z) -3'-cyano-2-benzene were formed. ylidene benzofuran-3 (2H) -one, m.p. 162 ° C, which were separated by filtration. Aurone (0.5 g, 0.0018 mol) and tri- 10 15 20 25 30 35 '447 382 14 methylsilylazide (1 g, 0.086 mol) was refluxed in dimethylformamide for 6 hours. The cooled solution was poured on ice and hydrochloric acid. The suspension was then heated to 70 ° C for 30 minutes, and after cooling the precipitate was filtered off. ningen. This yellow oily solid gave after chromatography graph the compound indicated in the title, m.p. 242-243 ° C.

Example 43 (Z) -2'-Carboxyl-2-benzylidene-5-carbomethoxy- 6-aminobenzofuran-3 (2H) -one, Methyl 3-acetyl-4-hydroxy-6-aminobenzoate (8.0 g, 0.038 mol) in dichloromethane (250 ml) was added to trifluoro- acetic anhydride (16 g, 0.076 mol), and the solution is stirred at room temperature for 15 minutes. After stripping gave the pale yellow solution methyl-3-acetyl-4-acetoxy-6- trifluoroacetamidobenzoate, m.p. 130-131 ° C.

Copper (II) bromide (17.0 g, 0.076 mol) of suspension was dissolved in ethyl acetate (300 ml) by rapid stirring.

To the suspension was added the benzoate as above (11.5 g, 0.038 mol) as a solution in ethyl acetate (200 ml), and the resulting mixture was stirred and heated at reflux for 3 h. The pale green copper (I) bromide formed was separated after cooling by filtration, and the solution is evaporated to a pale yellow solid, which was recrystallized of ether / petroleum ether (40-60 ° C). Thereby, methyl 3-bromoacetyl-4-acetoxy-6-trifluoroacetamidobenzoate as white crystals, m.p. zeo - 2s1 ° c.

This compound (1.9 g, 0.005 mol) and 2-carboxylate boxibenzaldehyde (0.75 g, 0.05 mol) in methanol (100 ml) was then heated to 60 ° C. Sodium hydroxide (0.6 g, 0.015) mol) in water (20 ml) was slowly added to the stirred solution. The resulting red solution was heated reflux for 3 hours and then poured onto ice and hydrogen chloride. acid (SN). The resulting yellow solid was filtered off and dissolved in an aqueous solution of sodium hydrogencarbonate (10%) at 50 ° C. The pH of this solution was adjusted to 7 and the ion exchanger "Amberlite Resin IRA-401" in hydroxyl form 10 15 20 25 30 35 447 582 15 was added. The resin was then filtered off and washed first with water and then with glacial acetic acid. When concentrating ring, the washing liquid consisting of glacial acetic acid gave it in the title given to the compound as light yellow prisms, m.p. 2 ° C (Sun.).

Example 44 (Z) -3'-Carboxyl-2-benzylidene-5,7-dibromo-4- hydroxybenzofuran-3 (2H) -one Finely ground copper (II) bromide (88 g, 0.4 mol) sus- was suspended in a 50:50 mixture of ethyl acetate and chloroform form (zoo mi). 2,6-ahyaroxyacetophenone (10 g, 0.67 moi) in chloroform (20 ml) was added to the suspension, which was stirred was refluxed for 8 hours, during which time hydrogen bromide was released. After cooling, the copolymer formed in this reaction was filtered. pair (I) of the bromide, and the solution was evaporated to dryness. to give 3,5-dibromo-2,6-dihydroxy-w-bromo- moacetophenone, m.p. 150 ° C. β-bromoacetophenones (8.2 g, 0.21 mol) and sodium acetate (20 g) were refluxed in 90% ethanol (100 ml) for 15 minutes. After cooling and addition of water (100 ml) was precipitated from the yellow solution. a greenish solid which was recrystallized from ethanol / water to give 5,7-dibromo-4-hydro roxybenzofuran-3 (2H) -one, m.p. 185 ° C (Sun.).

The benzofuran-3 (2H) -one was reacted with 3-carboxyl- benzaldehyde using the procedure described in Example 6 procedure, obtaining the title given compound, m.p. > 300 ° C (Sun.).

Examples 45 and 46 The following compounds were prepared with a procedure similar to that of Example 44 using of the applicable benzaldehyde: (Z) -4'-Carboxyl-2-benzylidene-5,7-dibromo-4- hydroxybenzofuran-3 (2H) -one, m.p. > 300 ° C (Sun.); (Z) -2'-Carboxyl-2-benzylidene-5,7-dibromo-4- hydroxybenzofuran-3 (2H) -one, m.p. 258-260 ° C. 10 15 20 25 30 35 447 382 16 Example 47 (Z) -4 '- [(E) -2-carboxyvinyl] -2-benzylidene-6- amino-5-cyanobenzofuran-3 (2H) -one 4-amino-5-cyano-2-hydroxyacetophenone (J.C.S.

Perkin I 1979, Q, 677) was converted to 4-trifluoro- acetamido-5-cyano-2-hydroxyacetophenone (m.p. 214 ° C) with using the procedure described in Example 43.

This acetophenone was then brominated with copper (II) bromide according to the method described in Example 44, 4-trifluoroacetamido-5-cyano-2-hydroxybromoacetamo phenon, m.p. 202 ° C. β-bromoacetophenones (8.3 g, 0.011 mol) dissolved in ethanol (50 ml), and excess sodium acetate (10 g) was added together with water (10 ml). Among- The mixture was refluxed for 20 minutes and then cooling, an orange solid was obtained, which was crystallized was crystallized from ethanol / water to give orange colored plates of 6-amino-5-cyanobenzofuran-3 (2H) -one, m.p. 270 ° C (Sun.). This benzofuranone was reacted with (E) - 4-formyl cinnamic acid by the method described in Example 6, whereby the title compound was obtained as orange crystals, m.p. > 300 ° C.

Example 48 (Z) -3'-Carboxyl-2-benzylidene-5-cyclohexyl benzofuran-3 (2H) -one 4-cyclohexylphenol (88 g, 0.5 mol) and acetyl- chloride (39 g, 0.5 mol) was heated together at 170 ° C The clear liquid formed was cooled to 100 ° C, and aluminum chloride (133 g, 1.0 mol) were added and. The brown sticky oil was heated at 130 ° C below After cooling, ice and hydrochloric acid were added, and the phenol was extracted with chloroform. Extract evaporated to dryness, and the residue was redistilled, to give 2-acetyl-4-cyclohexylphenol as a clear oil. This phenol was reacted with copper (II) bromide below using the procedure described in Example 43, whereby 2-bromoacetyl-4-cyclohexylphenol was obtained as a 10 15 20 25 30 35 447 382 17 yellow oil. This was dissolved in ethanol (100 ml), and sodium acetate (44 g) and water (20 ml) were added. Solution boiled for 10 minutes at reflux, cooled and water was added to precipitate a brown oil, which was extracted cured with chloroform. After evaporation to dryness gave the chloroform extract 5-cyclohexylbenzofuran-3 (ZH) -one, which was then reacted with 3-carboxybenzaldehyde under using the procedure described in Example 6, at the title compound were obtained as yellow crystals, m.p. 252-253 ° C.

Example 49 (Z) -3 ', 4', 5'-trimethoxy-2-benzylidene-5-carboxylate boxibenzofuran-3 (2H) -one (a) Methyl 4-acetoxybenzoate (126 g, 0.65 mol) and aluminum chloride (220 g, 1.63 mol) were mixed intimately, was stirred and reacted at 160 ° C with that of G. Dora et al., Eur. J. Med. Chem. 1978, lay, 33 described procedures. edge. The solid crude product obtained after acidification treatment, stirred with saturated sodium bicarbonate solution. and the mixture was filtered. The filtrate was acidified carefully to give 3-acetyl-4-hydroxybenzoate. acid, which was filtered off, washed with water and dried. kades; m.p. 232 ° C.

The insoluble solid from bicarbonatex the traction was dissolved in dilute sodium hydroxide solution (2M) and was carefully acidified with hydrochloric acid (SM), wherein methyl 3-acetyl-4-hydroxybenzoate was obtained, which after filtration drying, washing with water and drying had a melting point of 90 - 9200. (b) 3-acetyl-4-hydroxybenzoic acid (24.0 g, 0.133 mol) was dissolved in aioxane (400 ml) at 40 ° C, and bromine (7.2 ml, 0.14 mol) was added dropwise with stirring.

The dyeing soon faded and after 45 minutes the decant the clear supernatant was removed from insoluble material and evaporated to give a light gray solid substance, 3-bromoacetyl-4-hydroxybenzoic acid, m.p. 226 ° C. ,,,,, _ ,,, _ ,, ..,., ._ .., _, _..._. ~ _._..-. ~ _-yw-- ~ - » 10 15 20 25 30 35 447 382 18 (c) The product from (b) was dissolved in ethanol / water (350/70 ml), sodium acetate (30 g) was added and dissolved The mixture was stirred at 60 ° C for 10 minutes. The dark The orange-red solution was cooled to 10 ° C, stirred and acidified. was made carefully with SM hydrochloric acid. The obtained the light yellow solution was diluted with an equal volume of water. and was allowed to stand in the refrigerator overnight. The yellow crisis the tallin substance was filtered off, washed with cold water and dried to give 5-carboxybenzofuran 3 (2H) -one with melting point 204 ° C (Sun.). (d) 5-carboxybenzofuran-3 (2H) -one (3.56 g, 0.02 mol) and 3,4,5-trimethoxybenzaldehyde (3.92 g, 0.02 mol) was dissolved in hot dioxane (50 ml), concentrated tea acid (10 ml) was added, and the mixture was stirred and was gently heated in a steam bath for 15 minutes. After cooling and addition of an equal volume of water the yellow crystalline substance was removed, washed with water and dried. Recrystallization from glacial acetic acid gave the title compound, m.p. 290 ° C.

Example 50 - 60 The following compounds were prepared with a procedure similar to that described in Example 49.

(Z) -2-Benzylidene-5-carboxybenzofuran-3 (2H) -one, m.p. 280 ° C; (Z) -4'-chloro-2-benzylidene-5-carboxybenzofuran- 3 (2H) -one, m.p. > 300 ° C; (Z) -2'-chloro-4'-dimethylamino-2-benzylidene-5- carboxybenzofuran-3 (2H) -one, m.p. 275 ° C (Sun.); (Z) -4'-Butyl-2-benzylidene-5-carboxybenzofuran- 3 (2H) -one, m.p. 252 ° C; X2) -4'-dimethylamino-2-benzylidene-5-carboxybenzo furan-3 (2H) Fon, m.p. 295 ° Q; (Z) -4'-Methoxy-2-benzylidene-5-carboxybenzofuran- 3 (2H) -one, m.p. 300 ° C; (Z) -4 '- [(E) -2-carboxyvinyl] -2-benzylidene-5- carboxybenzofuran-3 (2H) -one, m.p. > 300 ° C; 10 15 20 25 30 35 w. ,,.,. ,, _ ,. f --_. _-. V e 447 382 19 (Z) -3'-Carboxyl-4'-hydroxy-2-benzylidene-5- carboxybenzofuran-3 (2H) -one, m.p. > 300 ° C; (Z) -4'-acetamido-2-benzylidene-5-carboxyben- sofuran-3 (2H) -one, m.p. > 300 ° C; (Z) -3'-Trifluoromethyl-2-benzylidene-5-carboxy- benzofuran-3 (2H) -one, m.p. 264 ° C; (Z) -3 '- (N-isopropylcarboxamido) -2-benzylidene- 5-carboxybenzofuran-3 (2H) -one, m.p. 300 ° C.

Exemgel 61 5-Carboxyl-6-hydroxybenzofuran-3 (2H) -one (a) 5-Acetyl-2,4-dimethoxybenzoic acid (Ber. il, 1607, 1908) (21.1 g, 0.094 mol) was stirred in dioxane (200 ml) at room temperature, and bromine (5 ml, about 0.1 mol) was added dropwise. The bromine color gradually disappeared during 30 minutes, and the mixture was then gently warmed in a steam bath for 50 minutes, cooled and liberated from dioxane in vacuo. The solid product was treated with boiling ethyl acetate and filtered hot, and filtered The residue was evaporated to give 5-bromoacetyl-2,4- dimethoxybenzoic acid, m.p. 236 ° C. (b) The product of (a) (21.6 g, 0.071 mol) stirred in dichloromethane (250 ml), cooled on an ice bath, and boron tribromide (25 ml) was added dropwise. Solution was then heated at reflux (water bath) for 4 hours. The mixture was cooled and poured onto ice (1 kg). After removal those of dichloromethane filtered the light red solid of, washed with water, sucked dry and dissolved in zero / water (200/80 ml). Sodium acetate (25 g) was added, heat the solution at 60 ° C for about minutes. After cooling removal of ethanol in vacuo was added to the surface additional water (150 ml). The solution was cooled in an ice bath. and hydrochloric acid (5M) were added with stirring dropwise. to pH 2. After storage overnight in a refrigerator cabinet, the pale yellow crystalline substance was filtered off, was washed with water and dried to give it the title benzofuranone, m.p. 216 ° C. 10 15 20 25 30 35 447 382 20 Example 62 (Z) -3'-Carboxyl-2-benzylidene-5-carboxyl-6- hydroxybenzofuran-3 (ZH) -one 5-Carboxy-6-hydroxybenzofuran-3 (2H) -one (5.82 g, 0.03 mol) was dissolved in dioxane (75 ml), and 3-carboxybenzene aldehyde (4.50 g, 0.03 mol) was added, followed by concentration hydrochloric acid (15 ml). The solution was gently warmed on a steam bath for 30 minutes, stirring occasionally.

The solid mixture was cooled, diluted with an equal volume of water and allowed to stand in the refrigerator for 1 h. was rinsed off, washed with water and dried. Crisis crystallization in dimethylformamide gave the desired compound one with a melting point of 335 ° C (Sun.).

Examples gel 63 and 64 The following compounds were prepared according to a process similar to that described in Example 62.

(Z) -3'-Carboxyl-4-hydroxy-2-benzylidene-5-carboxyl boxi-6-hydroxybenzofuran-3 (ZH) -one, m.p. 33200 (sund.); (Z) -4 '- (tetrazol-5-yl) -2-benzylidene-5-carboxyl- 6-hydroxybenzofuran-3 (2H) -one, m.p. 327 - 328 ° C (Sun.).

Example 65 (Z) -3'-Carboxyl-2-benzylidene-5-methoxycarboxylic acid benzofuran-2 (2H) -one Methyl 3-acetyl-4-hydroxybenzoate (5.39 g, 0.028) mol) was stirred in dioxane (200 ml) at 40 ° C, and bromine (1.5 ml) was added dropwise. After 45 minutes it was evaporated the colorless solution to give a straw yellow oil, dissolved in ethanol / water (75/15 ml) c Sodium acetate. (6.0 g) was added, and the solution was stirred at room temperature. temperature for 5 minutes. The red solution was poured onto ice (100 g) and extracted with chloroform. Evaporation of the chloroform extract gave 5-methoxycarbonylbenzofuran-3 (2H) - as an orange-red oil (purity 65%, NMR). This pro- product was immediately dissolved in dioxane (50 ml), 3-carboxybenzene aldehyde (4.5 g, 0.03 mol) was added first and then concentrated hydrochloric acid (10 ml), and the solution was heated 10 15 20 25 30 35 447 382_ 21 on a steam bath for 15 minutes. The reprocessing took place on (same as in Example 49, and recrystallization in dimethylformamide gave the desired auron, m.p. 280 ° C.

Example 66 (Z) -3'-Carboxyl-2-benzylidene-6-acetamidobenzene sofuran-3 (2H) -one (a) 3-aminophenol (54.5 g, 0.5 mol) and acetic acid acid anhydride (200 ml) was stirred and heated on a steam bath for 2 hours. The straw yellow liquid was evaporated in vacuo, whereby a viscous oil was obtained, which was heated to 100 - 12 ° C. Aluminum chloride (170 g, 1.27 mol) was added gradually. while stirring. After 30 minutes, cool the solid the product slightly and was carefully brought to decomposition with ice / water (500 g), then with concentrated chlorine hydrochloric acid (200 ml), stirred well and warmed slightly steam bath. After cooling, the crystalline substance was filtered of, washed with water and dried to give the desired compound, 2-hydroxy-4-acetamidoacetophenone, m.p. 140 ° C. (b) The product of (a) (14.0 g, 0.072 mol) was dissolved in ethyl acetate (300 ml) and added to a stirred suspension of copper (II) bromide (32 g, 0.143 mol) in ethyl acetate (100 mol). The mixture was heated under reflux in 4 hours, then filtered hot and the filtrate was evaporated in vacuo to give an oil which crystallized.

The solid was converted to benzofuranone and converted to was added with 3-carboxybenzaldehyde (as in Example 65).

During this reaction, however, the product was deacylated partially, and it was further reacted with acetic acid-1 anhydride (20 ml) under reflux for conversion to it fully acetylated compound. This reaction mixture was poured onto ice (100 g), and the excess acetic acid hydride was hydrolyzed. The resulting solid is filtered. was removed and recrystallized from glacial acetic acid / water (50% volume / volume) to give (Z) -3'-carboxyl-2-benzyl- iden-6-acetamidobenzofuran-3 (2H) -one, m.p. 305 ° C (Sun.). 10 15 20 25 30 35 447 382 -22 Exemgel 67 _ (Z) -4'-chloro-2-benzylidene-5-n-butoxycarbonyl- benzofuran-3 (2H) -one (Z) -4'-chloro-2-benzylidene-5-carboxybenzofuran- 3 (2H) -one (3.0 g, 0.01 mol) was suspended in n-butanol (50 ml), concentrated sulfuric acid (1.5 ml) was added dropwise with stirring, and the mixture was heated reflux for 5 h. The resulting yellow solution gave off cooling yellow bulky needle crystals of the desired n- butyl ester. The crystals were filtered off, washed with cold n-butanol, then with diethyl ether and dried. M.p. 1s4 ° c.

Example 68 (E) -4'-chloro-2-benzylidene-5-n-butoxycarbonyl- benzofuran-3 (2H) -one (Z) -4'-chloro-2-benzylidene-5-n-butoxycarbonyl- benzofuran-3 (2H) -one (1.0 g) was dissolved in benzene (800 ml) and irradiated in a 1 liter photochemical reactor (Hanovia) for 15 hours. The solution was evaporated in vacuo to give 1.0 g solid with a melting point of about 130 ° C and an E / Z isomer ratio of 75/25 (based on NMR and HPLC). 500 mg of this solid was chromatographed on a silica cone column (Sorbsil) (200 g) using benzene as developing liquid, and the fractions, which contained the faster (E) isomer, was collected. These factions combined and evaporated to give a yellow crisis. tallint solid; yield 350 mg with a melting point of 142 ° C and an E / Z isomer ratio of 88/12. 200 mg av this solid was recrystallized from dichloromethane role diameter (1/3 volume / volume) at 40 ~ 60 ° C, 130 mg of a crystalline solid_with a molten point of 142 ° C and an E / Z isomer ratio of 92.5 / 7.5.

The following preparations were prepared using reversal of the compound (Z) -3'-carboxyl-2-benzylidene-5- chlorobenzofuran-3 (2H) -one as active ingredient, and similar preparations can be prepared with other solid compounds according to the invention. 10 15 20 25 30 447 382 23 Example 69 Hard gelatin capsules were prepared using of the following ingredients: Amount (mg / kagsel) Active compound 250 Starch, dried 200 Magnesium stearate 10 The indicated ingredients were mixed fi and filled des in hard gelatin capsules.

Example 70 One tablet was prepared using the following ingredients: Amount (mg / tablet) Active compound 250 Cellulose; microcrystalline 400 Expanded silica 10 Stearic acid 5 The ingredients were mixed and pressed tablets.

Example 71 An aerosol solution containing the following constituents were prepared: Weight percentage Active ingredient 0.25 Ethanol 29.75 Fuel 22 70 (chlorodifluoromethane) The active compound was mixed with ethanol and the mixture was added to the propellant, cooled -30 ° C and transferred to a filler. It requires the amount was then transferred to a container of stainless steel and was further diluted with a dosed amount of fuel. The valve was then mounted on the container. 17611 . ... wn - m-u-wwe.

Claims (6)

F? 10 15 20 25 30 447 382 24 Example 72 A suppository preparation was prepared which contained 200 mg of the compound, using the following ingredients: Active compound 200 mg Polyethylene glycol 1000 750 mg Polyethylene glycol 4000 250 mg The active compound was mixed into the molten glycol bases. and then the mixture was poured into suitable molds for suppositories to the desired active fill weight. Example gel 73 An ointment was prepared from the following ingredients: Active compound 1% by weight White soft paraffin to 100% The active compound was added to the molten paraffin, and the mixture was then allowed to cool. Patent claims A compound of the formula RS (I) 10 15 m 25 30 35 ..- Pwwv-w-w. ._...._..._. H ._-._....._-- ~ - 447 382 wherein R1, R2 and Ra are the same or different and each means a hydrogen atom, the halogen atom , alkyl group having not more than 6 carbon atoms, alkoxy group having not more than 6 carbon atoms, cycloalkyl group having not more than 8 carbon atoms, haloalkyl group having 1 to 6 carbon atoms, amido, amino, cyano, hydroxy or carboxyl group, tetrazol-5-yl group or -CH = CHCOOH, or - R 1 and R 2 together represent a group of the formula -CH = Cé-CH = CH, and R 2, R 5 and RE represent a halogen atom, cycloalkyl group having 3 to 8 carbon atoms, haloalkyl group having not more than 6 carbon atoms , amido group, cyano group, carboxyl group, tetrazol-5-yl group or -CH = CHCOOH, however, at least one of R 1, R 2, R 3, R 2, R 5 and R 6 represents a carboxyl group, tetrazol-5-yl group or -CH = CHCOOH; or a pharmaceutically acceptable salt or ester derivative thereof. A compound according to claim 1, in that at least one of R 1, R 2 and k a n - n e t e c k n a d Ra represents a group other than a hydrogen atom. A compound according to claim 1, characterized in that R 1 represents alkyl having not more than 4 carbon atoms, alkoxy having not more than 4 carbon atoms, halogen or carboxyl, R 2 and Ra represent hydrogen, R 2 represents carboxyl, tetrazol-5-yl or - CH = CHCOOH, and R 5 and R 5 represent hydrogen. A compound according to claim 1, characterized in that R 1 represents alkyl having not more than 4 carbon atoms, carboxyl or halogen, R 2 and R a represent hydrogen, R 1 represents carboxyl or -CH = CHCOOH, and R 5 and R 5 represent hydrogen. A compound according to claim 1, for use in prophylactic chemotherapy of immediate hypersensitive conditions, e.g. asthma. 6. A process for the preparation of a compound according to claim 1, wherein a benzaldehyde of the formula 10 is obtained. Reacted with (a) a benzofuranone of the formula R 1 R 2 R 2 (IV) O RS or (b) a w-substituted acetophenone of the formula O R 1 R 2 CH 2 X ( V) OH Ra wherein X represents an eliminable group, optionally when one or more of the groups R1, R2, Ra, R ', Rs and R6 represent cyano, followed by reaction with an azide to the corresponding tetrazol-5-yl compound.