IE48824B1 - Aurone derivatives - Google Patents

Abstract

The substituted aurones correspond to the formula: <IMAGE> where R<1>, R<2>, R<3>, R<4>, R<5> and R<6> = H, halogen, C1-6 alkyl, C 1-6 alkoxy, C3-8 cycloalkyl, optionally substituted phenyl, C1-6 haloalkyl, amido, amino, cyano, hydroxyl, nitro, C2-4 alkenyl, carboxyl, tetrazol-5-yl and -CH=CHCOOH, or R<1> and R<2> together = -CH=CH-CH=CH-, provided that at least one of the radicals R<1>, R<2>, R<3>, R<4>, R<5> and R<6> = carboxyl, tetrazol-5-yl or -CH=CHCOOH. The compounds can be used for the prophylactic chemotherapy of allergic states such as bronchial asthma. [CH644603A5]

Description

This invention relates to novel aurone derivatives possessing valuable pharmacological activity, a process for their production and their use as pharmaceuticals.

In recent years,, extensive efforts have been made to discover new 5 compounds useful in the alleviation of allergic diseases and there is, in particular, a need for therapeutic agents which are effective in treating immediate hypersensitivity conditions such as asthma.

We have discovered certain aurone derivatives possessing the following basic skeleton, which have such useful activity.

According to the present invention there is provided a substituted aurone of formula I in which R1, R^ p.3, ^4, same or different and can each represent hydrogen, halogen, alkyl, alkoxy, Cg_8 cycloalkyl, optionally substituted phenyl, C-^-g haloalkyl, acylamino, substituted carbamoyl, amino, cyano, hydroxy, nitro, C2_4 alkenyl, carboxyl, tetrazol-5-yl or 1 2 -CH=CHCOOH; or in which R and R taken together represent a group of formula -CH=CH-CH=CH-; provided that (1) at least one of R1, R2, R3, R4, R5 and R® is carboxyl, tetrazol-5-yl or -CH=CHCOOH; (2) when one of 1-3 1-3 R is carboxyl in the 5-position, another of R is 1-3 hydrogen and the other of R is hydrogen, alkenyl or C1_g alkyl in the 7-position, then at least one of 4 5 6 R , R and R is other than hydrogen, alkoxy, amino, alkyl, hydroxy or C2_4 alkenyl; and (3) when one of R4-® is hydrogen, hydroxy or nitro in the 2'-position, another of R4 θ is hydrogen, hydroxy, nitro or carboxyl in the 3'-position and the other of R4 ® is hydrogen, hydroxy, nitro, carboxyl or amino in the 4'-position and R4 ® are not all hydrogen, then at least one of r\ R2 and R3 is other than hydrogen; or a pharmaceuticallyacceptable salt or ester thereof.

The compounds of formula I may exist in the (E) - or (2) — form, the (Z)- form being preferred.

A more particular group of compounds is one of formula (X) in which R3·, R2, R3, R4, R5 and R6 have 1 2 the values defined above provided that when R , R and R3 are all hydrogen at least one of R4, R3 and R^ is tetrazol-5-yl or -CH=CHCOOH. Xt is preferred that the benzofuranone ring be substituted and thus a preferred group is one of formula (I) in which at least one of 12 3 R , R and R is other than hydrogen.

A further particular group of compounds is one of formula (I) in which R^, R^, R^, r\ R^ and R^ have the 1 2 values defined above provided that when one of R , R and R^ is carboxyl at least one of R4, R^ and R^ is halogen, C^_g cycloalkyl, optionally substituted phenyl, C1-g haloalkyl, acylamino, substituted carbamoyl cyano, nitro, carboxyl, tetrazol-5-yl or -CH=CHCOOH. It is frequently preferred that at least one of the substituents on the free benzene ring is one such substituent and thus a preferred group is one of formula (I) in which 4 5 6 at least one of R , R and R is halogen, Cg_g cycloalkyl, optionally substituted phenyl, C^_g haloalkyl, acylamino, substituted carbamoyl cyano, nitro, carboxyl, tetrazol-5-yl or -CH=CHCOOH.

An especially preferred group of compounds is one 12 3 of formula (I) in which at least one of R , R and R is other than hydrogen and at least one of R , R and r6 is halogen, Cg_g cycloalkyl, optionally substituted phenyl, C^_g haloalkyl, acylamino, substituted carbamoyl, cyano, nitro, carboxyl, tetrazol-5-yl or -CH=CHCOOH.

The term halogen means especially chlorine, bromine and fluorine. The term C^_g alkyl includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert butyl, pentyl and hexyl, being preferably methyl, ethyl or tert-butyl. The term C^_g alkoxy includes, for example, methoxy, ethoxy, propoxy, butoxy and is pre48824 ferably methoxy. The term Cg_g cycloalkyl is preferably cyclohexyl. The term optionally substituted phenyl includes, for example, phenyl optionally substituted with 1 to 3 substituents selected from methyl, methoxy, halogen and nitro. The term C^_g haloalkyl can be, for example, any of the groups listed for Cj_g alkyl substituted with one to three halo atoms such as fluorine or chlorine and is especially trifluoromethyl. The term C2_4 alkenyl is preferably allyl. The term acylamino includes for example acetamido and the term substituted carbamoyl includes for example N-isopropyl carbamoyl. It is preferred that R1, R2, R3, R4, R5 and R6 be selected from hydrogen, halogen, alkyl, Cj_4 alkoxy, cyclohexyl, trifluoromethyl, N-isopropylcarbamoyl, acetamido, dimethylamino, hydroxy, carboxyl, tetrazol-5-yl or ] 2 -CH=CHCOOH, or R and R together represent -CH=CH-CH=CH-. Other preferred compounds falling within the scope of the aurones of formula (I) are those compounds having one or more of the following characteristics: (a) R3 is alkyl such as methyl (b) R3 is alkoxy such as methoxy (c) R3 is halogen such as chlorine (d) ϊ<1 is Cg_g cycloalkyl such as cyclohexyl 'e' P? is anrno (f) Rl is carboxyl (g) R1 is a 5- or 6- substituent (h) R1 is hydroxyl (i) R2 is hydrogen (j) R3 is hydrogen (k) R4 is carboxyl (l) R4 is tetrazol-5-yl (m) R4 is-CH=CHC00H (n) R5 is hydrogen fi (o) R is hydrogen A particularly preferred group of compounds is one in which R^ is alkyl, carboxyl or halogen, R2 and R3 are hydrogen, R4 is carboxyl or -CH=CHC00H and R5 and R® are hydrogen. Of this group, the compounds in which R4 is alkyl or carboxyl, R2 and R3 are hydrogen, R4 is carboxyl or -CH=CHC00H and R5 and R® are hydrogen are most preferred.

The compounds of formula I can also be in the form of their pharmaceutically-acceptable salts or esters. Such derivatives are encountered, for example, when one or more of the substituents R^, R2, R3, R4, R® and R® are the acid function, carboxyl or -CH=CHC00H. Suitable salts include for example those of mineral bases such as alkali metal hydroxides, especially the potassium or sodium salts, or alkaline earth metal hydroxides, especially the calcium salts, or of organic bases such as amines. Preferred esters are those derived from alkanols, for example, the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxyethyl or ethoxyethyl esters.

The invention also includes a method of preparing aurones of formula (I) which comprises reacting a benzaldehyde of formula (ΠΡ III with (a) a benzofuranone of formula (IV) IV or (b) anysubstituted acetophenone of formula (V) tetrazol-5-yl compound in which X is a leaving group; optionally followed when one or more of R1, R2, R3, c g H , R or R is cyano by reaction with an azide to give the corresponding As indicated above, aurones of formula (I) may be prepared by condensing an appropriately substituted benzaldehyde ΖΠΙ' with ft benzofuranone derivative (IV) as schematically depicted below : (I) Suitable solvents for this reaction include ethereal solvents such as dioxan and tetrahydrofuran and liquid alkanols such as ethanol, hi general, temperature is not critical and is only determinative of the reaction rate. The reaction will proceed at ail temperatures between ambient and the reflux temperature of the reaction mixture, for example, between 25 and 150°C. The reaction is preferably acid or base catalysed. Suitable acid catalysts include mineral acids such as hydrochloric acid and strong organic acids such as p-toluene sulphonic acids, whereas suitable inorganic or organic base catalysts include alkalies such as caustic soda, caustic potash, sodium carbonate or triethylamine. This type of condensation reaction is well known and those skilled in the art will well appreciate’ the nature of the reaction conditions and reagents necessary to produce a particular aurone of formula (I) An alternative process for preparing compounds of formula (I) involves the reaction of anij-substituted acetophenone (V) with an appropriate benzaldehyde (ΙΠ) as depicted schematically below: (I) where X is a leaving group, such as for example halogen, especially chloride or bromide, or the tosyl group. Suitable solvents include ethereal solvents such as dioxan and tetrahydrofuran and liquid alkanols such as ethanol, hi this instance the reaction is preferably base catalysed using a catalyst such as caustic soda, caustic potash or sodium carbonate. Temperatures from 0 to I50°C can be used to effect the reaetion. The reactants of formula (HD, (IV) and (V) are in the main known compounds and can be prepared by well known routes described in the literature.

In addition, compounds of formula (0 in which one of the R groups is tetrazol-5-yl can be derived by preparing the corresponding nitrile and forming the tetrazole therefrom utilising a preferably non-nucleophilic azide, for example trimethylsilyl azide, in a high boiling solvent such as dimethylformamide at temperatures above 100°C.

These reactions will produce the (Z)- isomer which, if desired, can be converted to the corresponding (Eh isomer by photolytie methods which are well know in the art.

The aurones of formula (I) have been shown to be useful in the 5 prophylactic treatment of asthma in mammals. This activity has been demonstrated in guinea pigs using either the Herxheimer test described jn th? Journal of Physiology (London) ] 17, 251 (1952) or the guinea-pig chopped lung test described by Monger and Schild in the Journal of Physiology (London)’ 131. 207 (1956) op Broeklehurst Journal of Physiology (London) (52, 414 (1980), Compounds are also active in the rat peritoneal anaphylaxis test based on an allergic reaction in the peritoneal cavity of the rat, as described by Orange, Stechacbnlte and Austen in Fed.Proe. 28 1710 (1969).

The Herxheimer test is based on an allergic bronchospasm induced in guinea pigs which closely resembles an asthmatic attack in man. The mediators causing the bronchospasm are very similar to those released when sensitised human lung tissue is challenged with an antigen. Compounds of the invention have exhibited activity in the Herxheimer test at dosages ranging from 25 mg/kg to 200 mg/kg.

The compounds of formula (I) may be administered by various routes and for this purpose may be formulated in a variety of forms, although it is a special feature of the compounds of the invention that they are effective when administered orally. Thus the compounds of the invention may be administered by the oral and rectal routes, topically, parenterally, e.g. by injection, in the form of, for example, tablets, lozenges, sub-lingual tablets, sachets, cachets, elixirs, suspensions, aerosols, ointm aits, for example, containing up to 10% by weight of the active compound in a suitable base, soft and hard gelatin capsules, π suppositories, injection solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injection solutions. The nature of the various excipients and additives required to produce such formulations will be well-known to those skilled in the art.

However, some examples of excipients which may be employed in the pharmaceutical formulations of the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidone, cetoBtearyl alcohol, starch, modified starches, gum acacia, io calcium phosphate, cocoa butter, ethoxyiated esters, oil of theobroma, arachis oil, alginates, tragacanth, gelatin, syrup B.P., methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and propellants such as trichloromonofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane. In the case of tablets, a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tabletting machine. For such purpose there may be employed for instance aluminium, magnesium cr calcium stearates, talc or mineral oil.

The invention also includes a pharmaceutical formulation which comprises as an active ingredient a compound of formula (I) or a pharmaceutically-acceptable salt or ester thereof, associated with a pharmaceutically-acceptable carrier therefor. Pharmaceutical formulations can be provided in dosage unit form, each dosage unit preferably containing from 5 to 500 mg. (from 5.0 to 50 mg. in the case of parenteral administration, from 5.0 to 50 mg. in the case of inhalation and from 25 to 500 mg. in the case of oral or rectal administration) of a compound of formula (D. The term unit dosage form, as used in the specification and claims, refers to physically discrete units suitable as unitary dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. ./..- --/ Dosages of from 0.5 to 200 mg/kg per day, preferably f to 20 mg/kg of io active ingredient may be administered, although it will, of course, be understood that the amount of the aurone of formula (I) actually administered will he determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered and the chosen of route of administration and therefore the above preferred dosage range is not intended to limit the scope of the present invention in any way.

The following Examples illustrate the invention.

EXAMPLE ] (Z)-4t-Carboxyl-2-benzylidene-5-methyIbenzofuran-3(2H)-one a)_-Chlort>-2-hydroxy-5-methylacetophenone (8.73g,0.05 mole)[Chem.Ber 41, 4271,(1908)] and 4-carboxybenzaldehyde (7.5g, 0.05 mole) were dissolved in ethanol (100 ml) and the mixture heated to 60°C. Sodium hydroxide (4g, 0.1 mole) in water (20 ml) was then slowly added to the stirred mixture which turned deep red. After 1 hour at 60°C a pale yellow precipitate formed which was then refluxed for a further hour.

The suspension so formed was then cooled to 0°C and acidified with hydrochloric acid (5M\ The resultant pale yellow solid was filtered off, washed with water, dried under reduced pressure and recrystallised from dioxan to yield the title compound as pale yellow needles, m.p. 288-290°C(deeomp.) EXAMPLES 2 TO 5 The following compounds were similarly prepared using the appropriate benzaldehyde and chloroacetophenone. (Z)-2,-Carboxyl-2-benzylidene-5-methylbenzofuran-3(2H)-one m.p. 187-9°C.

(Z)-2,-Carboxyl-2-benzylidene-e-methylbenzofuran-3(2H)-one, m.p. 196-198°C. (decomp.) (Z)-2'-Carboxyl-2-benzylidenenaptho(2,l-b)iuran-3(2H)-one, m.p. 207-208°C.

(Z)-4'-Carboxyl-2-benzylldene-5-isopropylbenzofuran-3(2H)-one, m.p. 262-283°C.

EXAMPLE 6 (Z)-3'-Cart)oxyl-2-benzylldene-5-methoxybenzofliran-3(2H)-one -MethoxybenzofUran-3(2H)-one (6.0g, 0.038 mole) [Annalen 405, 281, (1914)] and 3-carboxybenzaldehyde (5.4g, 0.036 mole) [J.Chem Soc. 4778 (1952)] were dissolved in dioxan (50 ml) and concentrated hydrochloric acid (10 ml) added. The resultant yellow solution was then heated under reflux for 2 hours. On cooling and addition of water (20 ml) a yellow precipitate formed. This material on recrystallization from acetic acid yielded the title compound as yellow needles, m.p. 252-254°C.

EXAMPLES 7 TO 33 The following compounds were prepared using a process similar to that of Example 6 with appropriate variation of the benzofuranone and benzaldehyde. (Z)-2'-Carboxyl-2-benzylidene-6-methoxybenzofuran-3(2H)-one, m.p. 217-220°C (decomp.) (Z)-3'-Carboxyl-2-benzylidene-6-methoxybenzofuran-3(2H)-one, m.p. 258-260°C (decomp.) A (Z)-4'-Carboxyl-2-benzylidene-6-methoxybenzofuran-»3(2H)-one, m.p. 273-275°C (decomp.) (Z)-3'-Carboxyl-2-benzylidene-5-methylbenzofuran-3(2H)-one, m.p. 264-255°C.

(Z)-3’-Carboxyl-2-benzylidene-6-methylbenzofuran-3(2H)-one, m.p. 263-264°C.

(Z)-4'-Carboxyl-2-benzylidene-6-methylbenzofuran-3(2H)-one, m.p. 288-289°C.

(Z)-3'-Carboxyl-4'-hydroxy-2-benzylidene-6-methylbenzofuran-3(2H)-one m.p. 290-291°C.

(Z)-3'-Carboxyl-2-benzylidene-6-chlorobenzo£uran-3(2H)-one, m.p. 278-28O°C.

(Z)-2'-Carboxyl-2-benzylidene-5-chlorobenzofuran-3(2H)-one, m.p. 2O5-2O6°C.

(Z)-3'-Carboxyl-2-benzylidene-5-chlorobenzofuran-3(2H)-one, m.p. 286-288°C.

(Z)-4'-Carboxyl-2-benzylidene-5-chlorobenzofuran-3(2H)-one, m.p.>300°C. (Ζ)-3'-Carboxyl-2-benzylidene-5-ethylbenzofvran-3(2H)-one, m.p. 252°C.

(Z)-4’-[(E)-Carboxyvinyl]-2-benzylidene-5-met)iylbenzofuran--3(2H)-ofleT m.p. 275-276°C.

(Z)-3'-Carboxyl-2-benzylidene-5-cyclohexylbenzoii»an-3(2H)-one, m.p. 252-253°C.

(Z)-4'-Cerboxyl-2-benzylidene-6-diloroben zofuran-3(2H)-one, m.p.>300°C.

(Z)-2'-C arboxyl-2-benzyli dene-δ -chiorobenzofuran-3(2H)-one, m.p, 184°C.

(ZM'-{(E)-2-Carboxy vinyl] -2-benzyli4ene-6-bydroxybenzofuran-3(2H)-one, m.p^300°C (decomp.) (Z)-3'-Carboxyl-2-benzylidene-6-bydroxybenzofuran-3(2H)-one, m.p. 320°C (decomp.) (Z)-2'-CarboxyI-2-benzylidene-e’hydroxybenzofuran-3(2H)-one, m.p. 282-283°c.

(Z)-4'-[(E)-2-CarboxyvinyI]-2’benzyIidene-5,7-dichlorobenzofuran-3(2H)-one, m.p.>300°C.

(Z)-3'-{(E)-2-Carboxyvinyl] -2-bepzy11 dene-5,7-«Hchlorobenzofuran-3-(2H)-one m.p. 300°C (Z)-3'4(E)-2-Carboxyvinyl]-2d3ensylidene-6-hydroxybenzofuran-3-(2H)-one, m.p.^300°C (Z)-3'-[(E)-2~Carboxyvinyl]-=2-benzylidepe-5-methoxybenzofuran-3-(2H)-one, m.p. 242°C.

(Z)-3'-Carboxyl-2-benzylidenenaptho(l,2-blfuran-3(2H)-one, m.p. 276-278°C. 8 8 2 4 (Z)-3'-[(E)-2-Carboxyvinyl)]-2-benzylidenenaphtho-(l,2-b)furan-3(2H)-one, m.p. 280°C.

(Z)-3'-Carboxyl-2-benzylidene-4-hydroxybenzofuran-3(2H)-one, m.p.285-287°C.

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

EXAMPLE 34 (Z)-4’-(5-TetrazoIyI)-2-benzyIidene-i)-ehlorobenzofuran-3(2H)-one 4-Cyanobenzaldehyde (13.1g, OJ mole), ethylene glycol (6.2g OJ mole) and toluene -4-sulphonie acid (19.0 mg, 0.1 m. mole) were refluxed in benzene (100 ml) for 8 hours using a Dean and Stark apparatus. The benzene was then evaporated to dryness to give 4-cyano-(2-l,3 dioxalane) benzene as a waxy colourless solid (m.p. 44-45°C) which was used without further purification.

The above dioxalane (17Jg, 0.1 mole), sodium azide (6.5g, 0 J mole) and lithium chloride (6.5g, 0.15 mole) were refluxed in 2-methoxyethanol (100 ml) for 8 hours. The suspension was then poured into ice and hydrochloric acid (5M). On standing, this solution deposited white crystals of 4-{5-tetrazolyl)-benzaldhyde, m.p. 200°C.

This benzaldhyde and 5-chlorobenzofuran -3(2H)-one[Annalen 2924 405 346] were reacted together using the procedure of Example 6 to yield the title compound which was recrystallised from dimethylformamide, m.p. 260°C (decompL EXAMPLES 35 TO 38 The following compounds were similarly prepared using the appropriate cyanobenzaldhyde and benzoftiranone.

(Z)-3’-(5-Tetrazolyl)-2-benzylidene-5-methoxybenzofuran-3(2H)-one, m.p. 278-280°C (decomp.) (Z)-4'-(5-TetrazoIyI)-2-benzylidene-6-hy*oxybenzofuran-3(2H)-one, m.p. 300°C (decomp.) (Z)-4'-(5-Tetrazolyl)-2-benzylidene-5-methoxybenzofuran-3(2H)-one, m.p. 268-270°C (decomp.) (Z)-3'-(5-Tetrazolyl)-2-benzylidene-5,7-dichlorobenzofuran-3(2H)-one, m.p. 283-285°C (decomp) EXAMPLE 39 (Z)-3'-(5-Tetrazolyl)-2-benzyUdene-5-ethylbenzofuran-3(2H)-one -Ethylbenzofuran-3(2H)-one (3.4g, 0.02 mole) [J. Indian Chem.Soc. 42, 20 (1965)1 X5 and 3-cyanobenzaldehyde (2.62g, 0.02 mole) were dissolved in dioxan (100 ml) and concentrated hydrochloric acid (5 ml) added. The resultant yellow solution was heated under reflux for 2 hours. On cooling, yellow needles of (Z)-3'-cyano-2-benzylidenebenzofuran-3(2H)-one m.p. 162°C formed and were removed by filtration. The aurone (0.5g, 0.0018 mole) and trimethyl silyl azide (lg, 0.086 mole) were refluxed together in dimethylformamide for 6 hours. The cooled solution was poured into ice and hydrochloric acid. The suspension was then heated to 70°C for 30 minutes and after cooling the precipitate was Altered off. This yellow oily solid, after chromatography, yielded the title compound, m.p. 242-243°C. 8 8 2 1 EXAMPLE 40 (zy-21-Carboxvl-2-benzylidene-5-carbomethoxy-6-aminobenzofuran-3-f2P)-one The methyl 3-acetyl-4-hydroxy-6-aminobenzoate (8.0g, 0.038 mole) in dichloromethane (250 ml) was added to trifluoroacetic anhydride (16g, 0.076 mole) and the solution stirred at room temperature of 15 minutes. On evaporation, the pale yellow solution yielded methyl 3-acetyl4_trifluoroacetoxy-6-trifluoroacetamidobenzoate, m.p. 130-131 C Copper (H)bromide (17.0g, 0.076 mole) was suspended in ethyl acetate (300 ml) by rapid stirring. To this suspension was added the benzoate produced above (H.5 g, 0.038 mole) as a solution in ethyl acetate (200 ml) and the resultant mixture was stirred and heated under relux for 3 hours. The pale green cuprous bromide so formed was removed, after cooling, by filtration and the solution evaporated to give a pale yellow solid which was recrystallised from ether/petroleum ether (40-60°C) yielding methyl 3-bromoacetyl-4-trif luoroacetoxy-6-trifluoroacetamidobenzoate as white crystals, m.p. 260-261 C.

This compound (L9g,0-005 mole) and 2-carboxybenzaldehyde (0.75g, .005 mole) in methanol (100 ml) were then heated to 60°C. Sodium hydroxide (0.6g, 0.015 mole) in water (20 ml) was slowly added to the stirred solution. The resultant red solution was heated under reflux for 3 hours and then poured on to ice and hydrochloric acid (5M). The yellow solid so formed was filtered off and dissolved in aqueous sodium bicarbonate solution (10%) at 50°C. The pH of this solution was adjusted to 7 and Amberlite Resin IRA-401 (Amberlite is a registered Trade Mark) in the hydroxyl form added. The resin was then filtered off and washed, firstly vzith water and then with glacial acetic acid. On concentration the acetic acid washings yielded the title compound as bright yellow prisms, m.p. 28O°C (decomp.) EXAMPLE 41 (Z)-3'-Cart)oxyl-2-benzylidene-5,7-dibromo-4-hydroxvbenzofuran-3(2W):one Finely ground copper (Π) bromide (88g, 0.4 mole) was suspended in a 50:50 mixture of ethyl acetate and chloroform (200 ml). 2,6-Dihydroxyacetophenone (lOg, 0.0657 mole) in chloroform (20 ml) was added to the above suspension which was stirred under reflux for 8 hours, hydrogen bromide being evolved. After cooling the copper (D bromide formed in the above reaction was filtered off and the solution evaporated to dryness to give 3,5-dibromo-2,6-dihydroxy.y4>romoacetophenone, m p. 150°C. Thethbromoacetophenone (8.2g, 0.21 mole) and sodium acetate (20 g) were refluxed •10 in 90% ethanol (100 ml) for 15 minutes. On cooling and following the addition of water (100 ml), the yellow solution deposited a greenish solid which was recrystallised from ethanol/water to give ,7-dibromo-4-hydroxybenzofuran-3(2H)-one, m.p. 185°C (decomp.) The benzofuran-3(2H)-one was then reacted with 3-carboxylbenzaldehyde using the procedure described in Example 6 to yield the title compound, m.p.^300°C (decomp.) EXAMPLES 42 AND 43 The following compounds were prepared by a method similar to Example 41 using the appropriate benzaldehyde.

(Z)-4'-Carboxyi-2-benzylidene-5,7-dibromo-4-hydroxybenzofuran-3(2H^one, m.p.^ 300°C.(decomp) (Z)-2tCarboxyI-2-benzyIidene-5,7-dibromo-4-hydroxybenzofuran-3(2H)-one, m.p. 258-260°C EXAMPLE 44 (Z)-4'-((E)-2-Carboxyvinyl1 -2-benzylidene-6-amino-5-cyanobenzofuran-3( 2H)~ one 4-Amino-5-cyano-2-hydroxyacetophenone (J.C.S.Perkin 11979 677) was converted into 4~trifluoroacetamido-5-cyano-2-hydroxyacetophenone(m.p. 214°C) using the procedure described in Example 40.

This acetophenone was then brominated using copper (II) bromide by the method described in Example 4Ito yield 4-trifluoroacetamido-5-cyano-2-hydroxy-bromoacetophenone m.p. 202°C.

The^bromoacetophenon (3.8g 0.011 mole) was dissolved in ethanol 50 ml and excess sodium acetate (lOg) added along with water (10 ml). The mixture was then refluxed for 20 minutes and on cooling deposited an orange solid which was recrystallised from ethanol water to yield orange plates of 6-amino-5-cyanobaizofuran-3(2H)-one, m.p. 270°C (decomp) This benzofuranone was then reacted with (E) 4-formylcinnamic acid using the procedure described in Example 6, the title compound being obtained as orange crystals, m.p^300°C.

EXAMPLE 45 (Z)-3t-Carboxyl-2-benzylidene-5-cvclohexylbenzofuran-3 (2H) -one 4-Cyclohexylrfienol(88g, 0.5 mole) and acetyl chloride (39g, 0.5 mole) were heated together at 170°C for 3 hours. The clear liquid so formed was then cooled to 100°C. and aluminium chloride (133g, l.Omole) added slowly. The brown sticky oil was then heated to 130°C for 5 hours. After cooling, ice and hydrochloric acid were added and the phenol extracted with chloroform. This extract was then evaporated to dryness and the residue steam distilled to give 2-acetyl-4-cyclohexylphenol as a clear ofl. This phenol was then reacted with copper (H) bromide using the procedure described in Example 43. This reaction yielding 2-broraoacetyl-4-cyclohexylphenol as a yellow ofl. This oil was dissolved in ethanol (100 ml), and sodium acetate (44g) and water (20 ml) added.

This solution was then refluxed for 10 minutes, cooled and water added to deposit a brown oil which was extracted with chloroform. On exaporation to dryness the chloroform extract yielded the 5-cyclohexylbenzofuran5 3(2H)-one which was then reacted with 3-carboxybenzaldehyde using the procedure of Example 6 to yield the title compound as yellow crystals, m.p. 252-253°C.

EXAMPLES 46 TO 52 The following compounds were prepared by reaction of the appropriate benzyaldehyde derivative with 5carboxybenzofuran-3-(2H)-one· (Z)-4'-Chloro-2-benzylidine-5-carboxybenzofuran-3-(2H)one, m.p.>300°C.

(Z)-2'-Chloro-4'-dimethylamino-2-benzylidine-5-carboxy15 benzofuran-3(2H)one, m.p. 275°C (decomp). 488 24 (Z)-4'4(E)-2-Carboxyvinyl]-2-benzylidene-5-carboxybenzofuran3-(2H)one, m.p.>300°C.

(Z)-3'-Carboxyl-4,-hydroxy-2-benzylidene-5-carboxybenzofuran-3-(2H)one, m.p.>300°C.

(Z)-4'-Acetamido-2-benzylidene-5-carboxybenzofuran-3-(2H)one, m,p.}300°C.

(Z)-3'-Trifluoromethyl-2-benzylidene-5-carboxybenzofuran-3-(2H)one,. m.p. 264°C.

(Z)-3'-{N“IsopropylcarbaiTioyl) -2-benzylidene-5-carboxy benzofuran—3—(2H)one, m.p. 300°C.

EXAMPLE 53 Z-3' -Carboxy t2-benzylidene^-5-carboxyl-6-hy(3roxy-benzofuran-3- (2H) one. (a) 5-Aeetyl-2,4-dimethoxybenzoic acid (Ber. 41, 1607,1908) (21.1g, 0.094 mole) was stirred in dioxane (200 ml.) at room temperature and bromine (5 ml., ca 0 J mole) was added dropwise. The bromine colour gradually disappeared over 30 minutes and the mixture was then gently warmed in a steambath for 30 minutes, cooled and the dioxane removed in vacuo. The solid product was treated with boiling ethyl acetate, filtered hot and the filtrate evaporated to give -bromoacetyl-2,4-dimethoxybaizoic acid, m.p. 236°C. (b) The product from (a) (2LSg., 0.071 mole) was stirred in dichloromethane (2S0 ml), cooled in an ice bath and boron tribromide (25 ml) added dropwise. The solution was then heated under reflux (water bath) for 4 hours. The mixture was cooled and poured onto ice (1 kg.). After removal of dichloromethane, the resultant pink solid was filtered off, water washed, sucked dry and dissolved in ethanol/water (200/80 ml).

Sodium acetate (25g) was added and the solution warmed at 60°C for 30 minutes.

After cooling and the removal of ethanol in vacuo, further water (150 ml) was added. The solution was cooled in an ice bath and hydrochloric acid solution (5N) added dropwise with stirring to pH2. After overnight storage in a refrigerator the pale yellow crystalline solid was filtered off, water washed and dried to give the title benzofuranone, m.p. 216°C. (c) 5H3adXKy-6-hydrQxybaizofuran-3-(2H)one (5.82 EXAMPLES 54 AND 55 The following compounds were prepared by a similar method to that described in Example 53(c) .

(Z)-3'-Carboxyl-4-hydroxy-2-benzyIidene-5-carboxyl-6-hydroxy benzofiiran-3-<2H)one, m.p. 332°C (decomp.) (Z)-4'-(Tetrazol-5-yl)-2-benzylidene-5-earboxyl-6-hydroxy benzofuran-3-(2H)one. m.p. 327-28°C (decomp.) 488 24 EXAMPLE 56 (Z)-3'-Carboxy8-2.-faenzylidene-5-methoxycarbonyLbenzofuran -2- (2H) one Methyl-3-acetyl-4-hydroxy benzoate (5.39g 0.028 mole) was stirred in dioxan (200 ml) at 40°C and bromine (L5 ml) added dropwise. After 45 minutes the colourless solution was evaporated to give a straw coloured oil which was dissolved in ethanol/water (75 Λ5 ml.). Sodium acetate (6.0g) was added and the solution stirred at room temperature for 5 minutes. The red solution was poured on to ice (lOOg) and extracted via chloroform. Evaporation of the chloroform extract gave -methoxycarbonylbenzofuran-3-(2H) one as an orange red oil( 65% pure by NMR).

This product was immediately dissolved in dioxane (50 ml.), 3-carboxybenzaldehyde (4.5g^ 0.03 mole) added, followed by concentrated hydrochloric acid (10 ml) and the solution heated on a steam bath lor 15 minutes.

The product was recrystallised from dimethylformamide to give the desired aurone, m.p. 280°C.

EXAMPLE 57 (Z)-3'-Carboxyl-2-benzylidene-6-acetamidobenzofuran-3-(2H)-one (a) 3-Aminophenol (54.5g., 0.5 mole) and acetic anhydride (200 ml) were stirred and heated on a steam bath for 2 hours. The straw coloured liquid was evaporated in vacuo to give a viscous oil which was heated to n0°-120°C aluminium chloride (170g. 1.27 mole) being added gradually with stirring. After 30 minutes the solid product was cooled somewhat and carefully decomposed with ice/water (ca 500g.) followed by concentrated hydrochloric acid (200 mL), stirred well and warmed slightly on steam bath. On cooling, the crystalline solid was filtered off, water washed and dried to give the desired compound 2-hydroxy-4-acetamidoacetophenone, m.p. ]40°C. (b) The product from (a) (14.Og 0.072 mole) was dissolved in ethyl acetate (300 ml) and added to a stirred suspension of copper (Π) bromide (32g. 0.143 mole) in ethyl acetate (100 mole). The mixture was heated under reflux for 4 hours, then filtered hot and the filtrate evaporated in vacuo to give an oil which crystallised. This solid was converted to the benzofuranone and reacted with 3-earboxybenzaldehyde (as Example 56). However, during this reaction the product was partially deacylated and it was further reacted with acetic anhydride (20 ml) under reflux to convert to the fully acehylated compound. This reaction mixture was poured onto ice (100 g) and the excess acetic anhydride hydrolysed. The resultant solid was filtered off and recrystallised from glacial acetic acid/water (50% v/v) to give (Z)-3,-carboxyl-2-benzylidene-6-acetamidobenzofuran-3-(2H)one, mq». 305°C (decomp.) EXAMPLE 58 (Z)-4'-Chloro-2-benzTlidene-5-n-butoxycarbonylbenzofuran-3-(2H)one Z-4'-Chloro-2-benzylidene-5-carboxybenzoftiran-3-(2H)one (3.0g. 0.01 mole) was suspended in n-butanol (50 ml), concentrated sulphuric acid (1.5 ml) added dropwise with stirring and the mixture heated under reflux for 5 hours. The resultant yellow solution on cooling deposited yellow fluffy needle crystals of the desired n-butyl ester. The crystals were filtered off, washed with cold n-butanol, then diethylether and dried, m.p. 154°C.

EXAMPLE 59 (E)-4l-Chloro-2-benzylldene-5-n-butoxycarbonylbenzofuran 3-(2 H)one (Z)-4'-Chloro-2-benzylidene-5-nr-butoxycarbonylbenzofuran 3-(2H)one (1.0g' was dissolved in benzene (800 ml) and irradiated in a 1 litre Hanovia photochemical reactor for 15 hours. The solution was evaporated in vacuo to give LOg of solid with m.p. ca 130° and having an E/Z isomer ratio of 75/25 (based on NMR and HPLC). 500 mg of this solid was chromatographed on a Sorbsil (ιλαι Isteitxl Tr.iJt> Mark) silica gel column (200g.) using benzene as the developing solvent and the fractions containing the- faster moving (E)-isaner collected. These tractions were bulked and evaporated to give a yellow crystalline solid; yield 350 mg. of mp 142°C and having an E/Z isaner ratio of 88/12. 200 mg. this solid was recrystallised from dichloromethane/40-60°C petroleum ether (1/3 v/v) to give 130 mg. of crystalline solid of m.p. 142°C and having an E/Z isomer ratio of 92.5/7.5.

The following formulations were prepared using as active ingredient the 10 compound (Z)-3'-carboxyl-2-benzylidene-5chlorobenzofuran-3-{2H)-one, and similar formulations can be prepared with other solid compounds of the invention.

EXAMPLE 60 Hard gelatin capsules were prepared using the following ingredients: Quantity (mg/capsule) Active compound 250 Starch dried 200 Magnesium stearate 10 The above indredients were mixed and filled into hard gelatin capsules 20 EXAMPLE 61 A tablet formula was prepared using the ingredients below: Quantity (mg/tablet) Active compound 250 Cellulose microcrystalline 400 25 Silicon dioxide fumed 10 Stearic acid The components were blended and compressed to form tablets.

EXAMPLE 62 An aerosol solution was prepared containing the following components: Weight % Active ingredient 0.25 Ethanol 29.75 Propellant 22 70 (Chlorodifluoromethane) The active compound was mixed with ethanol and the mixture added to the propellant 22, cooled to -30°C and transferred to a filling device. The required amount was then fed to a stainless steel container and diluted further with a metered amount of propellant. The valve units were then fitted to the container. EXAMPLE 63 A suppository formula was prepared containing 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 in the molten glycol bases and then the mixture was poured into appropriate sippository moulds, to give the active fill weight.

EXAMPLE 64 An ointment was made to the following formula: Active compound 1% by weight White soft paraffin up to 100% The active compound was added to the molten paraffin and then the mixture was allowed to cool.

Claims (27)

1. CLAIMS:1. A compound of the formula in which R^, R 2 , R 3 , R^, R 3 and R^ are the same or 5 different and can each represent hydrogen, halogen, C^_g alkyl, C 1-g alkoxy, C 3 _ g cycloalkyl, optionally substituted phenyl, C^_ g haloalkyl, acylamino, substituted carbamoyl, amino, cyano, hydroxy, nitro, C 2 _^ alkenyl, carboxyl, tetrazol-5-yl or -CH=CHCOOH; or in 1 2 10 which R and R taken together represent a group of formula -CH=CH-CH=CH-; provided that (1) at least one of r\ R 2 , R 3 , rS R 3 and R 3 is carboxyl, tetrazol-51-3 yl or -CH=CHCOOH; (2) when one of R is carboxyl in 1-3 the 5-position, another of R is hydrogen and the 1-3 15 other of R is hydrogen, alkenyl or C^_ g alkyl 4 5 6 in the 7-position, then at least one of R , R and R is other than hydrogen, C 3 _ g alkoxy, amino, Cj_ 6 alkyl, 4-6 hydroxy or C 2 _^ alkenyl; and (3) when one of R is hydrogen, hydroxy or nitro in the 2'-position, another 4-6 20 of R is hydrogen, hydroxy, nitro or carboxyl in the 4-6 3'-position and the other of R is hydrogen, hydroxy, 4-6 nitro, carboxyl or amino in the 4'-position and R 1 2 are not all hydrogen, then at least one of R , R and R 3 is other than hydrogen; or a pharmaceuticallyacceptable salt or ester thereof.

2. A compound according to claim 1 in which at least 12 3 5 one of R , R and R is other than hydrogen.

3. A compound according to either of claims 1 and 2 4. 5 6 in which at least one of R , R and R is halogen, C 3 _ 8 cycloalkyl, optionally substituted phenyl, C^_g haloalkyl, amido, cyano, nitro, carboxyl, tetrazol-5-yl or 10 -CH=CHC00H.

4. A compound according which R 1 is alkyl. to any of claims 1 to 3 in

5. A compound according which R 3, is C 1 _ 4 alkoxy. to any of claims 1 to 3 in 15

6. A compound according which R 3 · is halogen. to any of claims 1 to 3 in

7. A compound according to any of claims 1 to 3 in which R^ is carboxyl.

8. A compound according to any of claims 1 to 7 in 2 3 which R and R are hydrogen.

9. A compound according to any of claims 1 to 8 in which R is carboxyl.

5. 10. A compound according to any of claims 1 to 8 in which R is tetrazol-5-yl.

11. A compound according to any of claims 1 to 8 in which R 4 is -CH=CHCOOH.

12. A compound according to any of claims 1 to 11 in 10 which R 3 and R 6 are hydrogen.

13. A compound of formula I according to claim 1, in 12 3 which at least one of R , R and R is other than 4 5 6 hydrogen and at least one of R , R and R is halogen, Cj_g cycloalkyl·, optionally substituted phenyl, C^_g 15 haloalkyl, acylamino, substituted carbamoyl, cyano, nitro, carboxyl, tetrazol-5-yl or -CH=CHCOOH.

14. A compound according to claim 13 in which R 3- i- s 2 3 4 C^_ 4 alkoxy R and R are hydrogen, R is carboxyl and R 3 and R 3 are hydrogen.

15. (Ζ)-3 *-Carboxyl-2-benzylidene-5-methoxy-benzofuran3(2Η)-one.

16. A compound according to claim 1 substantially as described in any of the foregoing Examples.

17. A process for preparing a compound of formula I according to any of claims 1 to 15 which comprises reacting a benzaldehyde of formula III with (a) a benzofuranone of formula IV or (b) an ω-substituted acetophenone of formula CH 2 X in which X is a leaving group; optionally followed when one or more of R 1 , R 2 , R 3 , R 4 , R 3 and R 3 is cyano by reaction with an azide to give the corresponding tetrazol-5-yl compound.

18. A process for preparing a compound of formula I according to any of claims 1 to 15 which comprises re acting a benzaldehyde of formula of formula in which X is a leaving group.

V

20. A pharmaceutical formula which comprises as an active ingredient a compound according to any of claims 1 to 16 associated. With a pharmaceutically-acceptable carrier thereror. 5

21. A pharmaceutical formulation according to claim 20 in unit’ dosage form.

22. A pharmaceutical formulation according to claim 21 containing from 5 to 500 mg of active ingredient.

23. A pharmaceutical formulation according to claim 6. 10 22 containing from 25 to 500 mg of active ingredient.

24. A compound according to any of claims 1 to 13, for use in the prophylactic chemotherapy of immediate hypersensitivity conditions.

25. A compound whenever prepared by a process according 7. 15 to claim 17,

26. A compound whenever prepared by a process according to claim 18.

27. A compound whenever prepared by a process according to claim 19,