GB2386891A - Antibacterial benzofuran-2H-3-ones - Google Patents

Abstract

A compound, for therapeutic use, eg. antibacterial, of Formula 1 <EMI ID=1.1 HE=44 WI=62 LX=759 LY=613 TI=CF> R1, R2 are independently selected from the group consisting of hydrogen, C1-6 alkyl, where alkyl may be optionally further substituted with halogen, hydroxy, cyano, trifluoromethyl, -CO2R4, C1-6 alkoxy. R1 and R2 together may also represent a bridging group -(CR4R5)n- where n is one or two and R4 and R5 are as defined below. Ar represents a carbocyclic or heterocyclic, single or fused aromatic ring. This includes benzene, naphthalene and heterocycles containing one or more heteroatoms selected from O, N or S such as pyridine, pyrimidine, furan, oxazole, thiazole, indole acridine and the like. The bond to the Ar group may be from any ring atom. Furthermore, the aromatic ring may be optionally substituted by one or more groups R3 independently chosen from: H, C1-8alkyl, C2-8alkenyl, C1-8alkyl-OH, C1-4alkylaryl, C1-4alkylCO2R4, -CO2R4, -CONR4R5, -CN, -CF3, -SO2R4, phenyl, R1-substituted phenyl, heterocyclyl, halogen, hydroxyl, C1-8alkoxy, arylC1-8alkoxy -NH2, - NHR4,-N(R4)COR5, -NR4R5, NO2 and SR4 Wherein R4 and R5 are independently defined as: H, C1-8alkyl, C2-8alkenyl, C1-4alkylaryl, C1-4alkylCO2R4, aryl or taken together R4 and R5 are -C1-6alkyl- And aryl is defined as: Phenyl, or heterocylyl optionally substituted by C1-4alkyl, -OH, -OCH3, -CO2R4, halogen or -CF3. Independent of use, most of the above compounds are claimed.

Description

238689 1

BENZOFIJRAN-2H-3-ONE COMPOUNDS AND THEIR THERAPEUTIC IJSE

Field of the Invention

This invention relates to benzofuranone analogues which inhibit bacterial chorismate synthase, and to their therapeutic use as antibiotics.

BackEround to the Invention Several chemical classes of compound are known that possess considerable antibacterial activity, and these have proven of immense value in the treatment of bacterial diseases and infection. They include among others, the penicillins, the cephalosporins, the aminoglycoside antibiotics, vancomycin analogues and the sulfonamide drugs.

The mechanism of action of a number of known antibiotics is by the direct inhibition of enzymes of essential bacterial biosynthetic pathways. These include, amongst others, trimethoprim and the sulfonamide drugs.

Chorismate synthase, an enzyme in the shikimate pathway has been shown to be essential for bacterial viability (EP0913480). Compounds that inhibit this enzyme could therefore be useful antibacterial agents.

WO99/04789 discloses compounds of formula A as antibacterial or antifungal agents.

o R2\ R3 Formula A Wherein R1, R2 and R3 are independently H. OH, Br, Cl, I, amino, thiol, nitro, C-4 alkoxy, C1-4 aenyloxy, C2 alkoxyalkyleneoxy, C1.4 alkylthio, C3. 18 alkyl, or C3-18 alkenyl; or two adjacent Rs, taken together, are a C2-18 bivalent moiety containing at least one oxgen atom, substituted or disubstituted with A or B. or both, A being H. OH, Br, Cl, I, amino, or thiol, and B being H. Cl-10 aLkyl, C2-18 alkenyl. and X is aLkyl, cycloaLicyl, or optionally substituted ar, I or heterocyclyl ring However, no compounds were exemplified containing the (2Z)-2-benzylidene, 7ihydroxy-1-

benzofuran-3(2H)-one substructure so their identification as inhibitors of bacterial chorismate syntheses is novel. The compounds described in the invention are structurally distinct from previously synthesised antibiotics.

Summarv of the Invention This invention relates to compounds, and more specifically to benzofuIan-2H-3-one analogues and to their pharmaceutical compositions defined by Formula 1, or a pharmaceutically acceptable salt thereof. The compounds and their pharmaceutically acceptable salts are claimed as the active ingredients in medicines for the treatment of bacterial infection in man and animals.

O R1' Formula 1 R1, R2 are independently selected from the group consisting of hydrogen, C, aLicyl, where alkyl may be optionally further substituted with halogen, hydroxy, cyano, trifluoromethyl, -CO2R4, Can alkoxy. R1 and R2 together may also represent a bridging group CR4R5)nwhere n is one or two and R4 and R5 are as defined below.

Ar represents a carbocyclic or heterocyclic, single or fused aromatic ring. This includes benzene, naphthalene and heterocycles containing one or more heteroatoms selected from O. N or S such as pyridine, pyrimidine, futan, oxazole, tbiazole, indole acridine and the like. The bond to the Ar group may be from any ring atom. Furthermore, the aromatic ring may be optionally substituted by one or more groups R3 independently chosen from: H. Cl.8 alkyl, C2.R alkenyl, Cal e alkyl-OH, CI.4 aLkylaryl, C} 4 aLkylCO2R4, -CO2R4, -CONR4R5, -CN, -CF3, -SO2R4, phenyl, Rl-substituted phenyl, heterocyclyl, halogen, hydroxyl, Cat salkoxy, aIylC.gallcoxy -NH2, NHR4, -NR4R5, NO2 and SR4 Wherein R4 and R5 are independently defined as: H. Cal galkyl, C2ealkenyl, C,alkylaryl, ClaLsylCO2R4, awl or taken together R4 end R5 are-Clalkyl And awl is defined as: Phenyl, or heterocylyl optionally substituted by CI.4 ethyl, -OH, -OCH3, -CO2R4, halogen or -CF3 Preferred compounds are those where: R1 amd R2 are H. Cal; alkyl, or together R1 and R2 are a methylene bridge; Ar is phenyl, preferably substituted with one or more amino, carboxyl, nitro, trifluoromethyl, hydroxy or Can alkoxy groups.

Particularly preferred compounds are illustrated in Table 1.

R2o JO- JO T R1 Compound S T H H OH H N(Et)2 H H H H 1-Pvlrole 3 H H H COOH H

4 H H H H H

5 H H OH H OCH3

6H H OH H H

7H H H CF3 H

8H H OH OCH3 H

9H H NO2 H H

1O -C]]2- OH_ H OCH3

11H H OH H O(CH2hCH3 12H H OH H O(CH2hCH3 13H H OH H O(CH2)5CH3 _

14H H OH H O(CH2)2CH3

15H H OH H OCH2Ph 16H H OH O(CH2)zCH(CH3)2 17, H H OH H O(CHz)30H 18H H OCHzCOOH H OCH2COOH 19H H OCHzCOOH H H _ 20H H OH H O(CHz\OH 21H H _ OH H OCH2COOH

22OCH3 OCH3 H H H

23_ OCH3 OCH3 OH H O(CHzhCOOH _ Compounds of the invention have therapeutic utility as antibacterial agents. They are especially useful for the treatment of infections caused by gram positive organisms such as S. aureus. In particular, they exhibit inhibition of the enzyme chorismate synthase in the shikimate pathway which has been shown to be essential for bacterial viability (EP0913480). The compounds and their pharmaceutically acceptable salts are claimed as the active ingredients in medicines for the treatment of bacterial infection in man and animals. Description of the Invention

Certain compounds of this invention are preferred.

The term "C,4 alkyl" as used herein refers to straight and branched chain alkyl groups having up to 6 C atoms. Examples are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. "Alkyl" may have the same meaning. "Halogen" means F. Cl, Br or I. "Alkoxy" means Cl4, alkyl-O-. "Heterocyclyl" means a saturated, unsaturated or aromatic ring of 5 to 8 atoms containing one or more heteroatoms such as O. S or N. and which may be bonded via any C or ring atom.

Compounds of formula 1 may contain one or more chiral centres and exist in optically active forms. When a compound of formula 1 or a salt thereof contains a single chiral centre (for example sec-butyl) it may exist in two enantiomeric forms. The present invention includes individual enantiomers and mixtures of these enantiomers. The enantiomers may be obtained by methods known to those skilled in the art Such methods typically include resolution via formation of diastereomeric salts or complexes which may be separated, for example, by crystallisation, resolution via formation of diastereomeric derivatives or complexes which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography; selective reaction with one enantiomer by reaction with an enantiomer-specific reagent, for example, enymatic esterification, oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography on a chiral support such as silica with a bound chira ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation processes described above, at least one further step will subsequently be required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into another by asymmetric transformation.

When a compound of formula I or a salt thereof contains more than one chiral centre it may exist in diastereomeric forms. The diastereomeric pairs may be separated by methods known to those skilled in the art, for example, chromatography or crystallisation and the individual enantiomers within each pair may be separated as described above. The present invention includes each diastereomer of compounds of formula 1 and mixtures thereof.

Some compounds of formula 1 may exist in the form of solvates, for example, hydrates, which also fall within the scope of the present invention.

The compounds of formula 1 may form organic or inorganic salts, for example, the compounds of formula 1 may form addition salts with inorganic or organic acids, e.g. hydrochloric acid, hydrobronuc acid, fumaric acid, tartaric acid, citric acid, sulfuric acid, hydiodic acid, rnaleic acid acetic acid, succinic acid, benzoic acid, parnoic acid, palmitic acid, dodecanoic acid and acidic amino-acids such as glutamic acid.

Such compounds of formula 1 may form base addition salts, for example, with alkali metal hydroxides e.g. sodium hydroxide, with amino-acids e.g Iysine or arginine or with organic bases e.g. meglurnaine. It will be appreciated that such salts, provided that they are pharmaceutically acceptable may be used in therapy in place of compounds of formula 1. Such salts are prepared by reacting the compound of formula 1 with a suitable acid or base in a conventional manner. Such salts may also exist in the form of solvates, for example, hydrates. The present invention includes each salt and any solvate thereof.

Certain compounds of formula 1 or salts thereof may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.

"Pharmaceutically acceptable salts" are acid addition salts which can be prepared by any of the art recogmsed means. Typical acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, acetate, propionate, lactate, malate, succinate, tartrate, and cyclohexanesulphamates.

As used hereinafter, the term "active compound" denotes a compound of formula 1 including pharmaceutically acceptable salts thereof. In therapeutic use, the active compound may be administered orally, rectally, parenterally, topically, ocularly, aurally, nasally, intravaginally or to the buccal cavity, to give a local andfor systemic effect. Thus the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention.

Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions of the invention may contain 0.1-99% by weight of active compound. The compositions of me invention are generally prepared in unit dosage form. Preferably the unit dosage of active ingredient is 1-500 ma. The excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.

Compositions for oral admirustration are preferred compositions of the invention and there are known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions.

Tablets may be prepared from a mixture of the active compound with fillers such as lactose or calcium phosphate, disintegrating agents, for example maize starch, lubricating agents, for example magnesium stearate, binders for example microcrystalline cellulose or polyvinyl pyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods. The tablets may, if desired be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate. The tablets may be formulated in a manner known to those skilled in the aft so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate ptthalate.

Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and if desired, provided with enteric coatings in a known manner. The tablets and capsules may conveniently each contain 0.1 to 1000 mg (for example 10 ma, 50 ma, 100 ma, 200 ma, 400 ma, 600 ma, or 800 ma) of the active compound. Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example sunflower oil.

The active compound may be formulated into granules with or without additional excipients. The granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion. The granules may contain disintegrants (for example a pharmaceutically acceptable

effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.

Compositions for topical administration are also preferred compositions of the invention. The pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A suitable cream may be prepared by incorporating the active compound in a topical vehicle such as petrolatum and/or light liquid paraffin, dispersed in an aqueous medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil, petrolatum and/or a wax e.g. paraffin wax or beeswax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent e.g. basified Carbomer BP, in the presence of water. Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. A suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as described above, together with a potential transdermal accelerate such as dimethyl sulphoxide or propylene glycol.

Compositions of the invention suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with hard fat, synthetic glycerides or polyethylene glycol bases.

Compositions of the invention suitable for parenteral administration are known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.

Compositions of the invention suitable for inhalation via the mouth and/or the nose are the known pharmaceutical forms for such administration, for example aerosols, nebulised solutions or powders.

Metered dose systems, known to those skilled in the aft, may be used.

Compositions suitable for application to the buccal cavity include slow dissolving tablets, troches, chewing gum, gels, pastes, powders, mouthwashes or rinses.

The compounds of the present imvention may also be administered by continuous infusion either from an external source, for example by intravenous infusion, or from a source of the compound placed within the body, internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be a) liquid such as an oily solution or suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or b) solid in the form of an implanted support for example of a synthetic resin of waxy material for the compound to be infused. The support may be a single body containing the entire compound or a series of several bodies each containing pa t of the compound to be delivered. In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.

Scheme 1 shows the preparation of compounds of formula 1 by aldol condensation of benzofuranone analogues of formula 2 with aldehydes of formula 3 in which R1, R2 and Ar are as defined previously.

Literature methods for this conversion are given by R. S. Varma et al, Tetrahedron Letters, 1992, 33, 5937-

5940 or are referenced therein. The condensation can be carried out in alcoholic solvents in the presence of an acid catalyst such as HCI or A1203 or alternatively with a base such as an alkali metal hydroxide ammonia, ammonium salts, or piperidine, in a temperature range between 80 to 250 C. A particularly favored procedure is the use of hydrochloric acid in ethanol, with heating at reflex for 1-24 hours.

R2o + tar R2'0kAr R1' 0 formula 2 formula 3 R1

Scheme 1 The benzofuranone of formula 2 can be prepared by a two-step procedure involving (in either order) O-

aLkylation and Friedel Crafts acylation of a phenol of formula 4 with an electrophile of formula 5. X represents a suitable leaving group, preferably, but not exclusively, halide, tosylate or mesylate, and R6 represents an acid or ester group CO2R4 or a cyanide group. O-aLkylation may be carried out using an appropriate alkylating agent, in a suitable solvent such as DMF or THF, with or without the presence of a suitable base, at a temperature between 0 C and 25 C for 1 to 48 hours. The Friedel-Crafts acylation reaction can be carried out in a suitable solvent, such as dichloromethane or chloroberzene, at a temperature between 0-250 C, preferably in the presence of a Lewis acid catalyst such as aluminiuTn chloride, zinc chloride or a dehydrating agent such as sulphuric acid I X R2o R1'0 H R1

formula 4 formula 5 formula 2 Scheme 2 Benzofuranones of formula 1 may also be synthesized by alkylation of other benzofuranones of formula 1 wherein either or both R1 or R2 is H. This can be carried out using an appropriate aLkylating agent, in a suitable solvent such as DMF or THF, with or without the presence of a base, at a temperature between -

80 C and 25 C for 1 to 48 hours.

Aldehydes of formula 3, where Ar is a 2-hydroxy-4-aLkoxy phenyl group, can be prepared by treatment of 2,4-dihydroxybenzaldehyde with an appropriate alkylating agent, in a solvent such as DMF or THF, with or without the presence of a suitable base, at a temperature between -80 C and 25 C for 1 to 48 hours.

The reactions described herein will be generally understood by one of ordinary skill in the art The starting materials are available or can readily be prepared by one of ordinary skill in the art.

General Procedure for the Preuaration of Examples.

a Coupling of aldehydes and benzofuranone analogues To a solution of a benzofuranone analogue of formula 2 (1.0 mmol) in concentrated hydrochloric acid (2 mL) /EtOH (8 rnL) was added an aldehyde of fonnula 3 (1.0 mmol) under nitrogen. The solution was heated to reflux for between 10 and 240 minutes, then cooled. The reaction mixture was poured into water and the resulting solid collected and dried in a vacuum oven. Where necessay, compounds were furer purified by recrystallization or by flash chromatography and then analysed by I-CMS and 'HNMR b. 4Alkoxysalicaldehyde Analogues A mixtme of 2,4-dihydroxybenzaldehyde (lOnunol), an alkyl halide (lOmmol) and sodium carbonate (10 mmol) in dry DMF was heated to reflux for 18 hours under nitrogen. The reaction mixture was cooled poured into water and acidified with 2M HCl(aq). The aqueous solution was extracted with ethyl acetate and the organic layers were washed with brine, dried over magnesium sulfate and evaporated under

reduced pressure. The crude products were purified by column chromatography and analysed by LCMS and 'HNMR.

c. 5,6-Dim ethoxybenzofu ranone An alogues To a solution of an appropriate 2-benzylidene,7-dihydroxybenzofuranone (lmmol) in DMF was added sodium hydride (2mmol) and methyl sulfate (2 mmol) and heated to reflux under nitrogen for 4 hours. The solution was cooled, poured into water, and acidified with 2M HCI. The resulting solid was isolated by filtration, dries in a vacuum oven and analysed by LCMS, NMR.

Measurement of ICso The inhibitory effect of a compound can be described by an IC50 value, that is the concentration of inhibitor at which half (50 /0) inhibition of the maximal (100%) inhibition occurs. IC50 values were detenTined by measuring the extent of inhibition over a range of concentrations of the compound, preferably a range where the degree of inhibition varied from no inhibition (0%) to complete inhibition (100%). The IC5,, value can be estimated from a plot of % inhibition against concentration of inhibitor, or can be calculated using data fitting progams, such Grafit (Elsevier) or EnzFitter (Biosoft).

Results of IC50 determinations S R2o0 T OR1 Compound Ri R2 S T IC50 _ SpCI I H H OH H N(Eth _ 3 9 2 H H H H l-Pyrrole 5 5 3 H H H COOH H 2 8

4 H H H H 3 5

5 H H OH H OCH3 0.70

6 _ H H OH H H 0.80

7 H H H CF3 H 7.2

8 _ H H OH OCH3 H 1.7

9 H H NO2 H H 2.0

10 -C] Ir OH H OCH3 6.4 11 H H OH H OBu 0 45 12 H H OH H _ OPent 0 22 13. H H OH H OHex 0.32 14 H H OH H OPr 0.51 15 H H OH H OBn 1.0 16 H H OH H OiPent 0.58 17 H _ H OH H O(CHzhOH 2.5 18 H H OCH2COOH H H 1.8

H H OH H O(CHl)4OH 0.86 20 H H OH H OCH2COOH 2.6

21 OCH3 OCH3 H H H 6.1

22 OCH3 OCH3 OH H O(CHzhCOOH 15 Et=Ethyl, Bu=n-butyl, Pent=n-pentyl, Hex=n-hexyl, Pm-n-Propyl, Bn=Benzyl, iPenPisopentyl.

SpCl=Streptococcuspneumoniae chorismate synthase

Claims (8)

Claims

1. A compound, for therapeutic use, of Formula 1 o JAr R1 To Formula 1 R1, R2 are independently selected from the group consisting of hydrogen, C, alkyl, where alkyl may be optionally further substituted with halogen, hydroxy, cyano, trifluoromethyl, -CO2R4, Cab alkoxy. R1 and R2 together may also represent a bridging group CR4R5)n- where n is one or two and R4 and R5 are as defined below.

Ar represents a carbocyclic or heterocyclic, single or fused aromatic ring. This includes benzene, naphthalene and heterocycles containing one or more heteroatoms selected from O. N or S such as pyridine, pyrimidine, furan, oxazole, thiazole, indole acridine and the like. The bond to the Ar group may be from any ring atom. Furthermore, the aromatic ring may be optionally substituted by one or more groups R3 independently chosen from: H. C,.g aLkyl, C2 8 alkenyl, C, 8 alkyl-OH, C, 4 aL'cylaryl, C,.4 aLkylCO2R4, -CO2R4, -CONR4R5, -CN, -CF3, -SO2R4, phenyl, Rl-substituted phenyl, heterocyclyl, halogen, hydroxyl, C 3alkoxy, alylC,.8alkoxy -NH2, NHR4,-N(R4)COR5, -NR4R5, NO2 and SR4 Wherein R4 and R5 are independently defined as: H. C, 8alkyl, C28aLcenyl, C4alkylaryl, C 4aLkylCO2R4, aryl or taken together R4 end R5 are-C,alkyl And aTyl is defined as: Phenyl, or heterocylyl optionally substituted by C, 4 alkyl, -OH, -OCH3, -CO2R4, halogen or -CF3

2. A compound of claim 1, independent of use, excluding: (2Z)-2-[4-(diethylamino)-2-hydroxybenzylidene]-6,7-dihydroxy-1 benzofuran-3(2H)-one (2Z)-2-benzylidene-6,7-dihydroxy- 1 -benzofuran-3(2H) -one (2Z)-6,7 dibydroxy-2-(2-nitrobenzylidene)-1-benzofuran-3(2H)-one (2Z) -6,7ihydroxy-2-(2-hydroxybenzylidene)- 1 -benzofuran-

3 (2H)-one (2Z)-2benzylidene-6,7-dimethoxy-1-benzofuran-3(2H)-one 3. A compound of claim 1 where R1 and R2 are hydrogen, methyl or methylene bridge; Ar is phenyl substituted with amino, carboxyl acid, nitro, trifluoromethyl, hydroxy or C 8 alkoxy groups.

4. A compound of claim 1, selected from: (2Z)-2-[4-(diethylamino)-2hydroxybenzylidene]-6,7-dihydroxy- 1-benzofuran-3(2H)-one

(2Z)-6,7-dihydroxy-2-(4-pyrrolidin-1-ylbenzylidene)-1-benzofuran-3(2H)one 3-[(Z)-(6,7-dihydroxy-3-oxo-1-benzofuran-2(3H)-ylidene)methyl]benzoic acid (2Z)-2-benzylidene-6,7-dihydroxy-1-benzofuran-3(2H)-one (2Z)-6,7dihydroxy-2-(2-hydroxy-4-methoxybenzylidene)-1-benzofuran-3(2H)-one (2Z)6,7-dihydroxy-2-(2-hydroxybenzylidene)-1-benzofuran-3(2H)-one (2Z)-6,7dihydroxy-2-[3-(trifluoromethyl)benzylidene]-1-benzofuran-3(2H)-one (2Z)6,7-dihydroxy-2-(2-hydroxy-3-methoxybenzylidene)-1-benzofuran-3(2H)-one (2Z)-6,7 dibydroxy-2-(2-nitrobenzylidene)-1-benzofuran-3(2H)-one (7Z)-7(2-hydroxy-4-methoxybenzylidene)furol2,3-e] [1,3]benzodioxol(7H)-one (2Z)2-(4-butoxy-2-hydroxybenzylidene)-6,7-dihydroxy-1-benzofuran-3(2H)-one (2Z)-6,7 dihydroxy-2-[2-hydroxy-4-(pentyloxy)benzylidene]-1-benzofuran3(2H)-one (2Z)-2-[44hexyloxy)-2-hydroxybenzylidene]-6,7 dihydroxy-1benzofuran-3(2H)-one (2Z)-6,7-dihydroxy-2-(2-hydroxy-4-propcxybenzylidene) -1-benzofuran-3(2H)-one (2Z)-2-[4-(benzyloxy)-2-hydroxybenzylidene]-6,7 dihydroxy-1-benzofuran-3(2H)-one (2Z)-6,7 dibydroxy-2-[2-hydroxy - -(3methylbutoxy)benzylidene]-1-benzofuran-3(2H)-one (2Z)-6,7-dihydroxy-2-L2hydroxy 4-(3-hydroxypropoxy)benzylidene]-1-benzofuran-3(2H)-one {2-[(Z)46, 7-dihydroxy-3-oxo-1-benzofuran-2(3H)-ylidene)methyl]phenoxy}acetic acid (2Z)-6,7ihydroxy-2-[2-hydroxy 4-(4-hydroxybutoxy)benzylidene]-1benzofuran-3(2H)-one {4-[(Z)-(6,7-dihydroxy-3-oxo-1-benzofuran-2(3H)ylidene)methyl]-3-hydroxyphenoxy}acetic acid (2Z)-2-benzylidene-6,7dimethoxy-1 -benzofuran-32H)-one 4-{4-[(Z)-(6,7-dimethoxy-3-oxo-1benzofuran-2(3H)-ylidene)methyl]-3-hydroxyphenoxy}butanoic acid

5. A pharmaceutical composition comprising as an active ingredient a compound of any preceding claim, together with a carrier or diluent

6. Use of a compound of any of claims 1 to 4, for the manufacture of a medicament for the treatment of a bacterial infection.

7. The use of claim 6, wherein the infection is caused by a gram positive organism.

8. The use of claim 7, wherein the organism is S. aureus.