GB2030142A

GB2030142A - Aurone derivatives

Info

Publication number: GB2030142A
Application number: GB7931652A
Authority: GB
Original assignee: Lilly Industries Ltd
Current assignee: Lilly Industries Ltd
Priority date: 1978-09-13
Filing date: 1979-09-12
Publication date: 1980-04-02
Also published as: LU81676A1; NL7906823A; US4259340A; FR2436144B1; GB2030142B; DE2936730A1; BE878759A; FR2436144A1

Description

GB 2 030 142 A

Aurone derivatives

5 This invention relates to novel aurone derivatives possessing valuable pharmacological activity, a process 5 for their production and their use as pharmaceuticals.

In recent years, extensive efforts have been made to discover new 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.

10 We have discovered certain aurone derivatives possessing the following basic skeleton, which have such 10 useful activity.

7 -

15 According to the present invention there is provided a substituted aurone of formula I 15

20 ^ 20

in which FT.R^R^R^R5 and R6 are the same or different and can each represent hydrogen, halogen, C-i_6 alkyl, C|.6 alkoxy, C3.8 cycloalkyl, optionally substituted phenyl, haloalkyl, amido, amino, cyano, hydroxy, nitro, C2.4alkenyl, carboxyl, tetrazol-5-yl of-CH=CHCOOH; or in which R1 and R2 taken together represent a group 25 of formula -CH=CH-CH=CH-; provided that a least one of R1,R2,R3,R4,RE and R6 is carboxyl, tetrazol-5-yl or 25 -CH=CHCOOH; or a pharmaceutically-acceptable salt or ester thereof.

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

A more particular group of compounds is one of formula (I) in which R1,R2,R3,R4,R5 and R6 have the values defined above provided that when R1,R2 and R3 are all hydrogen at least one of R4,R5 and R6 is tetrazol-5-yl or 30 -CH=CHCOOH. It is preferred that the benzofuranone ring be substituted and thus a preferred group is one of 30 formula (I) in which at least one of R1,R2 and R3 is other than hydrogen.

A further particular group of compounds is one of formula (I) in which R^^R^R^R5 and R6 have the values defined above provided that when one of R1,R2 and R3 is carboxyl at least one of R4,R5 and R6 is halogen, C3.8 cycloalkyl, optionally substituted phenyl, C-i.e haloalkyl, amido, cyano, nitro, carboxyl, 35 tetrazol-5-yl or-CH=CHCOOH. It is frequently preferred that at least one of the substituents on the free 35

benzene ring is one such substituent and thus a preferred group is one of formula (I) in which at least one of R4,R5 and R6 is halogen, C3.8 cycloakyl, optionally substituted phenyl, haloalkyl, amido, cyano, nitro, carboxyl, tetrazol-5yl or -CH=CHCOOH.

An especially preferred group of compounds is one of formula (I) in which at least one of R1, R2 and R3 is 40 other than hydrogen and at least one of R4,R5 and R6 is halogen, C3.8 cycloalkyl, optionally substituted 40

phenyl, haloalkyl, amido, cyano, nitro, carboxyl, tetrazol-5-yl or -CH=CHCOOH.

The term "halogen" means especially chlorine, bromine and fluorine. The term "C^ alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert butyl, pentyl and hexyl, being preferably methyl, ethyl ortert-butyl. The term "C^g alkoxy" includes, for example, methoxy, ethoxy, propoxy, butoxy and is 45 preferably methoxy. The term "C3.8 cycloalkyl" is preferably cyclohexyl. The term "optionally substituted 45 phenyl" includes, for example, phenyl optionally substituted with 1 to 3 substituents selected from methyl, methoxy, halogen and nitro. The term "C^e haloalkyl" can be, for example, any of the groups listed for "Ci.6 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. It is preferred that R1,R2,R3,R4,R5 and R6 be selected from 50 hydrogen, halogen, C-,.4 alkyl, C^.4 alkoxy, cyclohexyl, trifluoromethyl, N-isopropylcarboxamido, acetamido, 50 dimethylamino, hydroxy, carboxyl, tetrazol-5-yl or-CH=CHCOOH, or R1 and R2 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: 55 55

(a) R1 is 0^4 alkyl such as methyl

(b) R1 is Ci_4 alkoxy such as methoxy 60 (c) R1 is halogen such as chlorine

(d) R1 is C3_8 cycloalkyl such as cyclohexyl

(e)

R1 is amino

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GB 2 030 142 A

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(f) R1 is carboxyl

(g) R1 is a 5-or 6-substituent

5 (h) R1 is hydroxyl 5

(i) R2 is hydrogen

(j) R3 is hydrogen

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(k) R4 is carboxyl

(I) (R4istetrazol-5-yl

15 (m) R4 is -CH=CHCOOH 15

(n) R5 is hydrogen (o) R6 is hydrogen

20 20

A particularly preferred group of compounds is one in which R1 is Ci^ alkyl, carboxyl or halogen, R2and R3 are hydrogen, R4 is carboxyl or-CH=CHCOOH and Rsand R6are hydrogen. Of this group, the compounds in which R1 is alkyl or carboxyl, R2 and R3 are hydrogen, R4 is carboxyl or-CH=CHCOOH and R5 and R6are hydrogen are most preferred.

25 The compounds of formula I can also be in the form of their pharmaceutically-acceptable salts or esters. 25 Such derivatives are encountered, for example, when one or more of the substituents R^R^R^R^R5 and R6 are the acid function, carboxyl or -CH=CHCOOH. 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

30 alkanols, for example, the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxyethyl or ethoxyethyl esters. 30 The invention also includes a method of preparing aurones of formula (I) which comprises reacting a benzaldehyde of formula (III)

35 (OsT hi 35

with (a) a benzofuranone of formula (IV)

40 >C \ ... 40

R'

or (b) an co-substituted acetophenone of formula (V) 45 S 45

0H

R"'

50 50

in which X is a leaving group; optionally followed when one or more of R1,R2,R3,R4,RS or R6 is cyano by reaction with an azide to give the corresponding tetrazol-5-yl compound.

As indicated above, aurones of formula (I) may be prepared by condensing an appropriately substituted benzaldehyde (III) with a benzofuranone derivative (IV) as schematically depicted below:

CIII)

3 GB 2 030 142 A

Suitable solvents forthis reaction include ethereal solvents such as dioxan and tetrhydrofuran and liquid alkanols such as ethanol. In 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 5 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).

10 An alternative process for preparing compounds of formula (I) involves the reaction of anco-substituted acetophenone (V) with an appropriate benzaldehyde (III) as depicted schematically below:

(V)

(i)

(in)

where X is a leaving group, such as for example halogen, especially chloride or bromide, orthetosyl group. Suitable solvents include ethereal solvents such as dioxan and tetrahydrofuran and liquid alkanols such as ethanol. In this instance the reaction is peferably base catalysed using a catalyst such as caustic soda, caustic 25 potash or sodium carbonate. Temperatures from 0 to 150CC can be used to effect the reaction. The reactants of formula (III), (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 (I) 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-30 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 (E)-isomer by photolytic methods which are well know in the art.

The aurones of formula (I) have been shown to be useful in the prophylactic treatment of asthma in 35 mammals. This activity has been demonstrated in guinea pigs using either the "Herxheimer" test described in the Journal of Physiology (London) 7, 251(1952) orthe "guinea-pig chopped lung test" described by Mongar and Schild in the Journal of Physiology (London) 3], 207(1956) or Brocklehurst Journal of Physology (London) 52,414 (1960). 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, Stechschulte and Austen in 40 Fed.Proc.281710 (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. 45 The compounds of formula (I) may be administered by various routes and forthis 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, ointments, for example, containing up to 50 10% by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injection solutions and suspensions in physiologically acceptable media, and sterile packaged powders absorbed 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 55 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, cetostearyl alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated 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, 60 sorbitan sesquioleate and oleyl alcohol and propellants such as trichloromonofluoromethane, dichlorodif-luoromethane and dichlorotetrafluoroethane. In the case of tablets, a lubricant may be incorporated to prevent sticking and binding ofthe powdered ingredients in the dies and on the punch of the tabletting machine. For such purpose there may be employed for instance aluminium, magnesium or calcium stearates, talc or mineral oil.

65 The invention also includes a pharmaceutical formulation which comprises as an active ingredient a

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GB 2 030 142 A

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compound of formula (l) 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 500mg. in the case of oral or rectal 5 administration) of a compound of formula (I). The term "unit dosage form", as used in the specificaton and claims, refers to physically discrete units suitble 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 1 to 20 mg/kg of active ingredient may be 10 administered, although it will, of course, be understood that the amount of the aurone of formula (I) actually administered will be 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.

15 The following Examples illustrate the invention.

Example 1

(Z)-4'-carboxyl-2-benzylidene-5-methyfbenzofuran-3(2H}-one io-Chloro-2-hydroxy-5-methylacetophenone (8.73g, 0.05 mole) [Chem.Ber41,4271, (1908)] and 4-20 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 25 dioxan to yield the title compound as pale yellow needles, m.p. 288-299°C(decomp.)

Examples 2 to 5

The following compounds were similarly prepared using the appropriate benzaldehyde and chloroacetophe-none.

30 (Z)-2'-Carboxyl-2-benzylidene-5-methylbenzofuran-3(2H)-one m.p. 187-9°C

(Z)-2'-Carboxyl-2-benzylidene-6-methylbenzofuran-3(2H)-one, m.p. 196-198°C.(decomp.) (Z)-2'-Carboxyl-2-benzylidenenaptho(2,1-b)furan-3(2H)-one, m.p. 207-208°C. (Z)-4'-Carboxyl-2-benzylidene-5-isopropylbenzofuran-3(2H)-one, m.p. 262-263°C.

35 Examples

(Z)-3'Carboxyf-2-benzylldene-5-methoxybenzofuran-3(2H)-one

5-Methoxybenzofuran-3(2H)-one (6.0g, 0.036 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 40 addition of water (20 ml) a yellow precipitate formed. This material on recrystallizationfrom acetic acid yielded the title compound as yellow needles, m.p. 252-254°C.

Examples 7 to 36

The following compounds were prepared using a process similar to that of Example 6 with appropriate 45 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.) (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. 264-265°C. 50 (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-benzy!idene-6-methylbenzofuran-3(2H)-one m.p. 290-291°C. (Z)-3'-Carboxyyl-4'-hydroxy-2-benzylidenebenzofuran-3(2H)-one, m.p. 268-270°C. (Z)-4'-Carboxyl-2-benzylidenebenzofuran-3(2H)-one, m.p. 274-275°C. 55 (Z)-3'Carboxyl-2-benzylidene-6-chlorobenzofuran-3(2H)-one, m.p. 278-280°C. (Z)-2'-Carboxyl-2-benzylidene-5-chlorobenzofuran-3(2H)-one, m.p. 205-206°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. (Z)-3'-Carboxyl-2-benzylidene-5-ethylbenzofuran-3(2H)-one, m.p. 252°C. 60 (Z)-3'-Carboxyl-2-benzylidenebenzofuran-3(2H)-one, m.p. 259-260°C.

(Z)-4'-[(E)-Carboxyvinyl] -2-benzylidene-5-methylbenzofuran-3(2H)-one, m.p. 275-276°C. (Z)-3'-Carboxyl-2-benzylidene-5-cyclohexylbenzofuran-3(2H)-one, m.p. 252-253°C. (Z)-4'-Carboxyl-2-benzylidene-6-chlorobenzofuran-3(2H)-one, m.p.>300°C. (Z)-2'-Carboxyl-2-benzylidene-6-chlorobenzofuran-3(2H)-one, m.p. 184°C. 65 (Z)-4'-[(E)-2-Carboxyvinyl]-2-benzylidene-6-hydroxybenzofuran-3(2H)-one, m.p.>300°C (decomp.)

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GB 2 030 142 A

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(Z)-3'-Carboxyl-2-benzylidene-6-hydroxybenzofuran-3(2H)-one, m.p. 320°C (decomp.) (Z)-2'-Carboxyl-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)-Carboxyvinyl]-2-benzylidene-5,7-dichlorobenzofuran-3-(2H)-one, m.p. 300°C. 5 (Z)-3'-[(E)-2-Carboxyvinyl]-2-benzylidene-6-hydroxybenzofuran-3-(2H)-one, m.p.>300°C. (Z)-3'-[(E)-2-Carboxyviny!]-2-benzylidene-5-methoxybenzofuran-3-(2H)-one, m.p. 242°C. (Z)-3'-Carboxyl-2-benzylidenenaptho(1,2-b)furan-3(2H)-one, m.p. 276-278°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-hydroxybenzofuran-3(2H)-one, m.p.285-287°C. 10 (Z)-2'-Carboxyl-2-benzylidene-5,7-dibromo-4-hydroxybenzofuran-3(2H)-one, m.p.258-260°C.

Example 37

(Z)-4'-(5-Tetrazofyf}-2-benzyfidene-5-chlorobenzofuran-3(2H)-one

4-Cyanobenzaldehyde (13.1g, 0.1 mole), ethylene glycol (6.2g 0.1 mole) and toluene-4-sulphonic acid (19.0 15 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-(2-1,3 dioxalane) benzene as a waxy colourless solid (m.p. 44-45°C) which was used without further purification.

The above dioxalane (17.1 g, 0.1 mole), sodium azide (6.5g, 0.1 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 20 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 2924405346] were reacted together using the procedure of Example 6 to yield the title compound which was recrystallised from dimethylformamide, m.p. 260°C (decomp).

25

Examples 38 to 41

The following compounds were similarly prepared using the appropriate cyanobenzaldhyde and benzofuranone.

(Z)-3'-(5-Tetrazolyl)-2-benzylidene-5-methoxybenzofuran-3(2H)-one, m.p. 278-280°C(decomp.) 30 (Z)-4'-(5-Tetrazolyl)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one, m.p.300°C(decomp.)

(Z)-4'-(5-Tetrazolyl)-2-benzy!idene-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 42

35 (Z)-3'-(5-Tetrazolyl)-2-benzy/idene-5-ethylbenzofuran-3(2H)-one

5-Ethylbenzofuran-3(2H)-one (3,4g, 0.02 mole) [J. INDIAN Chem.Soc.42,20 (1965)] 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,

40 0.0018 mole) and trimethyl silyl azide (1g, 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 filtered off. This yellow oily solid, after chromatography, yielded the title compound, m.p. 242-243°C.

45 Example 43

(Z)-2'-Carboxyl-2-benzylidene-5-carbomethoxy-6-aminobenzofuran-3-(2H)-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-acetyl-4-acetoxy-6-trifluor0acetamidobenzoate, m.p. 50 130-131°C.

Copper (ll)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 (11.5 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 55 yellow solid which was recrystallised from ether/petroleum ether (40-60°C) yielding methyl 3-bromoacetyl-4-acetoxy-6-trifluoroacetamidobenzoate as white crystals, m.p.260-261°C.

This compound (1.9g,0.005 mole) and2-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 60 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 in the hydroxyl form added. The resin was then filtered off and washed, firstly with water and then with glacial acetic acid. On concentration the acetic acid washings yielded the title compound as bright yellow prisms, m.p. 280°C(decomp.)

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GB 2 030 142 A

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Example 44

(Z)-3'-Carboxyl-2-benzylidene-5,7-dibromo-4-hydroxybenzofuran-3(2H)-one

Finely ground copper (II) bromide (88g, 0.4 mole) was suspended in a 50:50 mixture of ethyl acetate and chloroform (200 ml). 2,6-Dihydroxyacetophenone (1 Og, 0.0657 mole) in chloroform (20 ml) was added to the 5 above suspension which was stirred under reflux for 8 hours, hydrogen bromide being evolved. After cooling the copper (I) bromide formed in the above reaction was filtered off and the solution evaporated to dryness to give 3,5-dibromo-2,6-dihydroxy-a)-bromoacetophenone, m.p. 150°C. The w-bromoacetophernone (8.2g, 0.21 mole) and sodium acetate (20 g) were refluxed 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 10 recrystallised from ethanol/waterto give 5,7-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.)

15 Examples 45and 46

The following compounds were prepared by a method similar to Example 44 using the appropriate benzaldehyde.

(Z)-4'-Carboxyl-2-benzylidene-5,7-dibromo-4-hydroxybenzofuran-3(2H)-one, m.p.> 300°C.(decomp) (Z)-2'Carboxyl-2-benzylidene-5,7-dibromo-4-hydroxybenzofuran-3(2H)-one, m.p. 258-260°C

20

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 11979 3 677) was converted into 4-trifluoroacetamido-5-cyano-2-hydroxyacetophenone(m.p. 214°C) using the procedure described in Example 25 43.

This acetophenone was then brominated using copper (II) bromide by the method described in Example 44 to yield 4-trifluoroacetamido-5-cyano-2-hydroxy-bromoacetophenone m.p.202°C.

The co-bromoacetophenone (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 30 deposited an orange solid which was recrystallised from ethanol water to yield orange plates of 6-amino-5-cyanobenzofuran-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, mp.>300°C.

35 Example 48

(Zj-3'-Carboxyl-2-benzylidene-5-cyclohexylbenzofuran-3(2H)-one

4-Cyclohexylphenol (88g, 0.5 mole) and acetyl chloride (39g, 0.5 mole) were heated together at 170°Cfor3 hours. The clear liquid so formed was then cooled to 100°C. and aluminium chloride (133g, I.Omole) added slowly. The brown sticky oil was then heated to 130°C for 5 hours. After cooling, ice and hydrochloric acid 40 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 oil. This phenol was then reacted with copper (II) bromide using the procedure described in Example 43. This reaction yielding 2-bromoacetyl-4-cyclohexylphenol as a yellow oil. 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 45 brown oil which was extracted with chloroform. On evaporation to dryness the chloroform extract yielded the 5-cyclohexylbenzofuran-3(2H)-one which was then reacted with 3-carboxybenzaldhyde using the procedure of Example 6 to yield the title compound as yellow crystals, m.p. 252-253°C.

Example 49

50 (Zj-3',4',5'-Trimethoxy-2-benzylidene-5-carboxybenzofuran-3(2H)-one

(a) Methyl-4-acetoxybenzoate (126g, 0.65 mole) and aluminium chloride (220g, 1.63 mole) were intimately mixed, stirred and reacted at 160°C by the method of G. Dora et al., Eur.J. Med.Chem 1978 13,33. The crude solid product obtained after acid treatment was stirred with saturated sodium bicarbonate solution and the mixture filtered. The filtrate was carefully acidified to give 3-acetyl-4-hydroxybenzoic acid,

55 which was filtered off, water washed and dried, m.p. 232°C.

The insoluble solid from the above bicarbonate extraction was dissolved in dilute sodium hydroxide (2N) solution and carefully acidified with dilute hydrochloric acid (5N) solution to give methyl 3-acetyl-4-hydroxybenzoate, which after filtration, water washing and drying, had m.p. 90-92°C.

(b) 3-Acetyl-4-hydroxybenzoicacid (24.0g. 0.133 mole) was dissolved in dioxane (400 ml) at40°C and 60 bromine (7.2 ml, 0 14 mole) added dropwise with stirring. The colour soon faded and after 45 minutes the clear supernatant was decanted from some insoluble material and evaporated to give a light straw coloured solid, 3-bromoacetyl-4-hydroxybenzoic acid, m.p. 226°C.

(c) The product from (b) was dissolved in ethanol/water (350/70 ml), sodium acetate (30g) added and the solution stirred at 60°Cfor 10 minutes. The deep orange red solution was cooled to 10°C, stirred, and

65 carefully acidified with 5N hydrochloric acid solution. The resultant bright yellow solution was diluted with

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GB 2 030 142 A

7

an equal volume of water and stored in a refrigerator overnight. The yellow crystalline solid was filtered off, washed with cold water and dried to give 5-carboxybenzofuran-3-(2H)one, with m.p. 204°C(decomp.)

(d) 5-Carboxybenzofuran-3-(2H)one(3,56g., 0.02 mole) and 3,4,5-trimethoxy benzaldehyde (3,92g., 0.02 mole) were dissolved in warm dioxane (50 ml.), concentrated hydrochloric acid (10 ml) added and the 5 mixture stirred and gently heated in a steam bath for 15 minutes. After cooling and the addition of an equal volume of water the yellow crystalline solid was filtered off, washed with water and dried. Recrystallisation from glacial acetic acid gave the title compound, m.p. 290°C.

Examples SO to 60

10 The following compounds were prepared by a method similar to that described in Example 49: (Z)-2-Benzylidene-5-carboxybenzofuran-3-(2H)one, m.p. 280°C. (Z)-4'-Chloro-2-benzylidine-5-carboxybenzofuran-3-(2H)one. m.p.>300°C.

(Z)-2'-Chloro-4'-dimethylamino-2-benzylidine-5-carboxybenzofuran-3(2H)one, m.p. 275°C (decomp) (Z)-4'-Butyl-2-benzylidene-5-carboxybenzofuran-3-(2H)one, m.p. 252°C. 15 (Z)-4'-Dimethylamino-2-benzylidene-5-carboxybenzofuran-3-(2H)one, m.p. 295°C. (Z)-4'-Methoxy-2-benzylidene-5-carboxybenzofuran-3-(2H)one, m.p.300°C. (Z)-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. 20 (Z)-3'-Trifluoromethyl-2-benzylidene-5-carboxybenzofuran-3-(2H)one, m.p. 264°C.

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

Example 61

5-Carboxyl-6-hydroxybenzofuran-3-(2H)one 25 (a) 5-Acetyl-2,4-dimethoxybenzoic acid (Ber. 41,1607,1908) (21.1 g, 0.094 mole) was stirred in dioxane (200 ml.) at room temperature and bromine (5 ml., ca 0.1 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 5-bromoacetyl-2,4-dimethoxybenzoic acid, m.p.236°C. 30 (c) The product from (a) (21.6g., 0.071 mole) was stirred in dichloromethane (250 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 35 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, mp. 216°C.

40 Example 62

(Z)-3'-Carboxyl-2-benzylidene-5-carboxyl-6-hydroxybenzofuran-3-(2H)one

5-carboxy-6-hydroxybenzofuran-3-(2H)one (5,82g, 0.03 mole) was dissolved in dioxane (75 ml), 3-carboxybenzaldehyde (4.50g., 0.03 mole) added, followed by concentrated hydrochloric acid (15 ml). The solution was gently heated on a steam bath for 30 minutes with occasional stirring. The solid mixture was 45 cooled, diluted with an equal volume of water and stored in a refrigerator for 1 hour. The product was filtered off, water washed and dried. Recrystallisation from dimethylformamide gave the desired compound with mp. 335°C(decomp).

Examples 63 and 64

50 The following compounds were prepared by a similar method to that described in Example 62.

(Z)-3'-Carboxyl-4-hydroxy-2-benzylidene-5-carboxyI-6-hydroxy benzofuran-3-(2H)one, m.p. 332°C (decomp.) (Z)-4'-(Tetrazol-5-y-)-2-benzylidene-5-carboxyl-6-hydroxy benzofuran-3-(2H)one, m.p. 327-28°C(decomp.)

Example 65

55 (Z)-3'-Carboxyl-2-benzylidene-5-methoxycarboxybenzofuran-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 (1.5 ml) added dropwise. After 45 minutes the colourless solution was evaporated to give a straw coloured oil which was dissolved in ethanol/water (75/15 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 (1 OOg) and extracted via 60 chloroform. Evaporation of the chloroform extract gave 5-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 for 15 minutes. Work up was as Example 49 with recrystallisation from dimethylformamide to give the desired 65 aurone, mp. 280°C.

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GB 2 030 142 A

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Example 66

(Z)-3'-Carboxyl-2-benzylidene-6-acetamidobenzofuran-3-(2H)-one

(a) 3-Aminopheno! (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 5 to 110°-120°C aluminium chloride (170g.1.27 mole) being added gradually with stirring. After 30 minutes the 5 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 10 (b) The product from (a) (14.0g 0.072 mole) was dissolved in ethyl acetate (300 ml) and added to a stirred 10 suspension of copper (II) 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-carboxybenzaldehyde (as Example 65). However, during this reaction the product was partially deacylated and it was further reacted 15 with acetic anhydride (20 ml) under reflux to convertto the fully acehylated compound. This reaction mixture 15 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, m.p. 305°C (decomp.)

20 Example 67 20

(Z)-4'-Ch/oro-2-benzylidene-5-n-butoxycarbonyl benzofuran-3-(2H)one

Z-4'-Chloro-2-benzylidene-5-carboxybenzofuran-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 25 n-butyl ester. The crystals were filtered off, washed with cold n-butanol, then diethylether and dried, m.p. 25 154°C.

Example 68

(E)-4'-Chloro-2-benzylidene-5-n-butoxycarbony/benzofuran 3-(2H)one 30 (Z)-4'-Chloro-2-benzylidene-5-n-butoxycarbonylbenzofuran 3-(2H)one (1.0g) was dissolved in benzene (800 30 ml) and irradiated in a 1 litre Hanovia photochemical reactor for 15 hours. The solution was evaporated in vacuo to give 1.0g 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 silica gel column (200g.) using benzene as the 35 developing solvent and the fractions containing the faster moving (E)-isomer collected. These fractions were 35 bulked and evaporated to give a yellow crystalline solid; yield 350 mg. of mp 142°C and having an E/Z isomer 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.

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

Example 69

45 Hard gelatin capsules were prepared using the following ingredients: 45

Quantity (mglcapsule)

Active compound Starch dried 50 Magnesium stearate

250 200 10

50

The above indredients were mixed and filled into hard gelatin capsules

Example 70

A tablet formula was prepared using the ingredients below:

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Quantity (mgltablet)

Active compound Cellulose microcrystalline

250 400 10 5

60

60 Silicon dioxide fumed Stearic acid

The components were blended and compressed to form tablets.

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GB 2 030 142 A 9

Example 71

An aerosol solution was prepared containing the following components:

Weight %

5 Active ingredient 0.25

Ethanol 29.75

Propellant22 70

(Chlorodifluoromethane)

The active compound was mixed with ethanol and the mixture added to the propellant 22, cooled to -30°C 10 and transferred to a filling device. The required amount was then fed to a stainless steei container and diluted further with a metered amount of propellant. The valve units were then fitted to the container.

Example 72

A suppository formula was prepared containing 200n mg of the compound using the following ingredients:

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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 20 appropriate suppository moulds, to give the active fill weight.

Example 73

An ointment was made to the following formula:

25 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

30

(1) Acompound of theformula in which R1,R2,R3,R4,R5 and R6 are the same or different and can each represent hydrogen, halogen, C-|.6 alkyl, Ci_6 alkoxy, C3.s cycloalkyl, optionally substituted phenyl, C-,.6 haloalkyl, amido, amino, cyano, hydroxy, nitro, C2.4 alkenyl, carboxyl, tetrazol-5-yl or-CH=CHCOOH; or in which R1 and R2 taken together represent a group of formula -CH=CH-CH=CH-; provided that at least one of R1,R2,R3,R4,R5 and R6 is carboxyl, tetrazol-5-yl or

40 -CH=CHCOOH; or a pharmaceutically-acceptable salt or ester thereof.

(2) A compound according to claim 1 in which at least one of R\R2 and R3 is other than hydrogen.

(3) A compound according to either of claims 1 and 2 in which at least one of R4,R5 and R6 is halogen, C3.8 cycloalkyl, optionally substituted phenyl, C^e haloalkyl, amido, cyano, nitro, carboxyl, tetrazol-5-yl or -CH=CHCOOH.

45 (4) Acompound according to any of claims 1 to 3 in which R1 is CV4 alkyl.

(5) A compound according to any of claims 1 to 3 in which R1 is CV4 alkoxy.

(6) A compound according to any of claims 1 to 3 in which R1 is halogen.

(7) A compound according to any of claims 1 to 3 in which R1 is carboxyl.

(8) A compound according to any of claims 1 to 7 in which R2 and R3 are hydrogen.

50 (9) Acompound according to any of claims 1 to 8 in which R4 is carboxyl.

(10) A compound according to any of claims 1 to 8 in which r4istetrazol-5-yl.

(11) A compound according to any of claims 1 to 8 in which R4 is -CH=CHCOOH.

(12) A compound according to any of claims 1 to 11 in which R5 and R6 are hydrogen.

(13) Acompound according to claim 1 substantially as described in any of the foregoing Examples.

, 55 (14) a process for preparing a compound according to any of claims 1 to 12 which comprises reacting a benzaldehyde of formula

OHC

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with (a) a benzofuranone of formula

10 GB 2 030 142 A

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,2

R'

or (b) anco-substituted acetophenone of formula in which X is a leaving group; optionally followed whenone or more of F^F^R^R^R5 and R6 is cyano by 15 reaction with an azide to give the corresponding tetrazol-5-yl compound.

(15) A process for preparing a compound according to any of claims 1 to 13 which comprises reacting a benzaldehyde of formula

OHC

with a benzofuranone of formula

R'

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(16) A process for preparing a compound according to any of claims 1 to 13 which comprises reacting a benzaldehyde of formula

40 with anco-substituted acetophenone of formula

■CH,X

OH

in which X is a leaving group.

(17) A pharmaceutical formula which comprises as an active ingredient a compound according to any of 50 claims 1 to 13 associated with a pharmaceutically-acceptable carrier therefor.

(18) A pharmaceutical formulation according to claim 17 in unit dosage form.

(19) A pharmaceutical formulation according to claim 18 containing from 5 to 500 mg of active ingredient.

(20) A pharmaceutical formulation according to claim 19 containing from 25 to 500 mg of active 55 ingredient.

(21) Acompound according to any claims 1 to 13, for use as a pharmaceutical.

(22) Acompound according to any of claims 1 to 13, for use in the prophylactic chemotherapy of immediate hypersensitivity conditions such as asthma.

(23) Acompound whenever prepared by a process according to claim 14.

60 (24) Acompound whenever prepared by a process according to claim 15.

(25) A compound whenever prepared by a process according to claim 16.

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Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon Surrey, 1980. Published by the Patent Office, 25 Southampton Buildings, London, WC2A 1AY, from which copies may be obtained.