GB2387172A - [(Aryl-/arylthio-)aryl]methylene substituted azole & azine derivatives and their therapeutic use as antibacterials - Google Patents

Abstract

Compounds of Formula 1 <EMI ID=1.1 HE=43 WI=45 LX=694 LY=542 TI=CF> <PC>Where: X is O, CHCN or S; Y is O, NH, CH2, S or NHCO; Z is O, S, NH, or CH=CH; n=0 or 1; Ar is an optionally substituted single or fused carbocyclic or heterocyclic aromatic ring, (where, for example, the aromatic ring may have up to three substituents independently selected from C1-6 alkyl, halogen, hydroxy, C1-6 alkoxy, NO2, CF3, CN, COOH, COOR3, CONR4R5); ```R, R3, R4 and R5 are independently selected from the group consisting of H, or a substituent as claimed or as otherwise described (eg an optionally substituted alkyl, phenyl or heterocycle); R1 and R2 are independently selected from the group consisting of hydrogen, halogen, OH, COOH, CN, substituted or unsubstituted C1-6 alkyl inhibit the chorismate synthase enzyme in the shikimate pathway and may be used as antibacterial agents, eg to treat infections caused by gram positive organisms such as S.aureus.

Description

AZOLE COMPOUNDS AND THEIR TEIERAPEUTIC USE

Field of the Invention

This invention relates to chorismate synthase inhibitory rhodanine analogues, as well as compositions containing the same and to their therapeutic use, particularly those used for treating or preventing infections and diseases associated therewith.

Background 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 sulfonunide drugs. Chorisrnate 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.

Compounds of similar structure to those of the invention have been described previously, but have not been described as chorismate synthase inhibitors nor reported to have antibacterial activity. For example, Patent WO2000010573 claims the general structure shown in Figure 1 as antiviral agents, in which R3 is not hydrogen. /=\ X=S, O or NRa (Ra=H, C1-5 alkyl) ( Y=0 or S; Z=O,S or NRh (Rh=H, alkyl) by,; z Two rings chosen from (un)substituted phenyl; alkylphenyl; R // (un)subsbtuted heterocycles(furan, thiophene, oxazole, \_ 4/ oxadiazole, pyridine, pyrimidine, pyrazole, triazole, // W AX\ pyridazine, 1,3-oxathiolane, thiazole,thiadiazole, imidazole, <I N-R3 tetrazole, pyrrole, triazine R3 C1-10 aliphatic acid, preferred acetic add, propionic acid, y or benzaic acid, or alkylphenyl (substituted or unsubshtuted) Figure 1 Patent W02000032598 claims the general structure shown in Figure 2 as TNF receptor agonists for the treachery of inflammatory disease.

O H W1-W5 together - aliphatic R1 J: I heterocyclic AN: \w5 AWN heteroaromatic R2 Whew/' 2 R1 - H. heteroaromatic, (cyclo)alkyl Figure 2 The compounds described in the invention are novel, and without wishing to be bound by theory, possess a method of action distinct from previously described antibiotics.

Summarv of the Invention This invention relates to compounds, and more specifically to azole al alogues and to their pharmaceutical compositions defined by Formula 1, or a pharmaceutical acceptable salt thereof.

R-Not X Ar n Formula 1 Where: X is O. CHCN or S; Y is O. NH, CH2, S or CHICO; Z is O. S. NH, or CH=CH; n=0 or 1 Ar is an optionally substituted single or fused carbocyclic or heterocyclic aromatic ring. These include but are not limited to phenyl, napthyl, pyridine, quinoline, pyrimidine, imidazole, furan, thiadiazole derivatives.

The bond to the Ar group can be to any of its ring atoms. The aromatic ring may have up to three substituents independently selected from Can aLkyl, halogen, hydroxy, CaLkoxy, NO2, CF3, CN, COOH, COORS, CONR4R5.

R. R3, R4 and R5 are independently selected from a group consisting of substituted or unsubstituted Car alkyl, CH2COOH, substituted or unsubstituted phenyl or heterocycles; R1, R2 are independently selected from the group consisting of hydrogen, halogen, OH, COOH, CN, substituted or unsubstituted Cry alkyl.

Particularly preferred compounds are those where: nisOor l;Xis S orCHCN; YisS;ZisOorS;RisH; end Arisasdefined above.

Particularly preferred compounds are illustrated in Table 1.

Table 1

R-N /)

Y Z X iSAr No | R X _ z n Ar 1 | HS S O 0 3-CF3Ph 2 | HS S S 0 3-BrPh 3 CH2 (2-fury!)S S O O 3-CF3Ph 4 HS S O 0 4-CI-3-NO2Ph 5 HS S S 0 3-CF3Ph 6 H_ S S O 0 2-Cl-3-CF3Ph 7 HS S O 0 3-OCF3Ph 8 HS S O 0 4-CF3Ph H = S S O 0 3-COOH-4-OHPh 10 4-CF3BnS S O 0 3-COOHPh 11 3-ClPhS NH S 0 3- COOHPh 12 HS S O 0 2,6-diCIPh 13 S S O 0 3-COOMePh 14 HS S O 1 3-CF3Ph 15 HS S O 1 4-NO2Ph 16 HS S O 1 2-MePh 17 H1 S S O 1 4-py 18 HS S O 1 6- (3-COOH)Py 19 HS S O 1 2-(3-COOH)Py 20 HS O O 1 2-(3-COOH)Py 21 HO S O 1 2-(3-COOH)Py 22 HS S O 1 2-OHPh 23 H S S O 1 2-OMePh 24 S O O 1 6-3-COOH)Py 25 H S O O 1 6-(3-CONHCH2CH2COOH)Py 26 CH2COOH S S O 1 6 -(3 -COOH)Py 27 S S O 1 2-pyrimidule 28 H CHCN S O 0 3-CF3Ph Compounds of the invention have therapeutic utility as antibacteria1 agents. They are especia11y useful for the treatment of infections caused by gram positive organisms such as S. aureus. In particular, they exhibit inhibition of the enzyme chorisrnate synthase in 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.

Descrintion of the Invention Certain compounds of this invention are preferred The term "C, 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 ten-butyl. "Alkyl" may have the same meaning. "Halogen" means F. Cl, Br or I. "Alkoxy" means Cl alkyl-. "Heterocyclyl" means

a saturated, unsaturated or aromatic ring of 5 to 8 atoms containing one or more heteroatoms such as 0, S or N. and which may be bonded via any C or ring atone 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 for nation of diastereomeric salts or complexes which may be separated, for example, by crystallization; resolution via formation of diastereomeric derivatives or complexes which may be separated, for example, by crystallization, gas- liquid or liquid chromatography; selective reaction with one enantiomer by reaction with an enantiomer-specific reagent, for example, enzymatic 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 chiral 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 1 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 witbin 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 inorgauc or organic acids, e.g. hydrochloric acid, hydrobromic acid, fumaric acid, tartaric acid, citric acid, sulfuric acid, hydiodic acid, maleic acid acetic acid, succinic acid, benzoic acid, pamoic 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 allcali metal hydroxides e.g. sodium hydroxide, with amino-acids e.g. lysine or arginine or with organic bases e.g. meglumaine. It will be appreciated tbat 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, cyclohexanesulphamates, As used hereinafter, the term "active compound" denotes a compound of formula I 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 and/or systemic effect. Thus the therapeutic compositions of the present invention may take the form of any of the known phannacoutical 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 the 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.

s Compositions for oral administration 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 art 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 phthalate.

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 andlor 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 andfor the nose are the known pharmaceutical fonns for such administration, for example aerosols, nebulised solutions or powders.

Metered dose systems, known to those skilled in the art, 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 invention 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 spanngly 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 part 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.

The componds of formula 1 described above can be prepared by the route shown in Scheme 1. The general method of preparation of these compounds is the aldol condensation of azole analogues of the formula 2 with an aldebyde of formula 3, wherein X Y. Z and R. n, Ar are as defined previously. This condensation can be carried out in alcoholic solvents in the presence of a base such as ammonia, ammonium salts, or piperidine, or with a mineral acid catalyst at a temperature range between -80 to 250 C. A particularly favored procedure is the use of anhydrous sodium acetate in glacial acetic acid, with heating at reflex for 1-

24 hours. References to this procedure include: G.R.Newkome and A.Naykak in Advances in Heterocyclic Chemistry, A.RKatritzky and A.J.Boulton, eds., Academic press, New York, NY, Vol 25, Pg83.

R 0): qAr RSIAr formula 2 formula 3 X Scheme 1 The aldehyde can be prepared by Suzuki reaction or by direct nucleophilic substitution on furan or thiophene ring (Scheme 2).

H 73 Ar ArSH/Base H. /j] Suzuki Ha_< at Br ArB(OH)2 g z Ar O O formula 4 Scheme 2 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 an General Procedure for the Preparation of the Examples.

a. Coupling of aldehydes and azole analogues To a solution of the azole analogue of formula 2 (1.0 mmol) in acetic acid (5 ml) was added NaOAc (3. 0 mmol), followed by a solution of the aldehyde of formula 3 (1.0 mmol) in acetic acid (2 mL). The solution was heated for 10-240 minutes, then cooled. The residue was triturated with diethyl ether, the solid collected, washed with ethanol, then with water and dried overnight in a desiccator over P2O5 to give the target compound of formula 1. Compounds were analysed by LCMS and DINER.

b. Aldehydes of formula 3 prepared by Suzuki reactions The mixture of an aryl bromide of formula 4 (1.0 mmol), an atylboronic acid (1.05 mmol) in 5 mL 1-

propanol was stirred at room temperature under nitrogen for 20 minutes, allowing solids to dissolve. The resulting solution was treated with palladium acetate (0.003 mmol), triphenylphosphine (0.009 mmol), 2M sodium carbonate (1.2 mmol), and deionized water (lmL), and heated to reflux under a nitrogen atmosphere for 2-24 hours (reaction monitored by LC/MS). Water (10 mL) was added to the reaction mixture, and stirred open to the atmosphere for 1 hour while cooling to room temperature. The darkened mixture is extracted with ethyl acetate. Combined extracts were washed with 5% sodium bicarbonate, followed by brine, dried over MgSO4, then filtered through celite. The filtrate was concentrated under the reduced pressure to give a yellow solid which was further purified by crystallization from hexane-ethyl acetate. Compounds were analysed by LCMS and HMR c. Aldehydes of formula 3 prepared by direct nucleophilic substitution The mixture of an aromatic thiol (1.0 mmol) and sodium hydride (1.0 mmol) m DMF (5 mL) was stirred at room temperature under nitrogen for 15 minutes, then an aryl bromide of formula 4 was added. The resulting mixture was stirred at room temperature for 1- 12 hours (LC/bIS monitoring the reaction). The reaction mixture was poured into water (if necessary, neutralised to pH7), and extracted with ethyl acetate.

The organic extracts were combined, dried, and concentrated. The crude product was purified by recrystallization in a suitable solvent or by flash column chromatography.

Analytical data for compounds from the invention are given in Table 2.

Table 2

Bacterial chorismate ICso data for compounds of the invention Example No. ICso(pM) SACS SaCS 1i 3 2.3 1.5

4 2.6 0.46

5 5.5 13.5

6 2.1 3.2

7 8.3 22.1

8 118 9 21 10 1.5

11 4.5

12 4.3

13 5.2

14 20 15 11.5

16 12.4

17 8.0 6.0

18 0.56 1.2

19 2.8 2.7

20 9.8 1.6

21 0.6 2.6

22 5.5

23 10.5

24 2.0

25 7.4

26 7.3

27 3.2

28 2.0 4 5

SpCS = Streptococcus pneumonias chorismate synthase, SaCS = Staphlococcus aureus chorismate synthase. 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 /O) inhibition of the maximal (100%) inhibition occurs. IC50 values were determined 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 IC50 value can be estimated from a plot of % inhibition against concentration of inhibitor, or can be calculated using data fitting programs, such Grant (Elsevier) or unfitter (Biosoft).

Claims (9)

f Claims

1. A compound, for therapeutic use, of Formula 1 VS; y R,,N:X

Formula 1 Where: X is O. CHCN or S; Y is O. NH, CH', S or NHCO; Z is O. S. NH, or CH=CH; n=0 or 1 Ar is an optionally substituted single or fused carbocyclic or heterocyclic aromatic ring. These include but are not limited to phenyl, napthyl, pyridine, quinoline, pyrimidine, imidazole, furan, thiadiazole derivatives. The aromatic ring may have up to three substituents independently selected from Cal 6 aLkyl, halogen, hydroxy, C. 6 alkoxy, NO2, CF3, CN, COOH, COOR3, CONR4R5.

R. R3, R4 and R5 are independently selected from the group consisting of H. C, 6 aLkyl optionally substituted with one or more halogen, hydroxy, amino, carboxy, carboxamide groups, optionally substituted phenyl or heterocycles; R1 and R2 are independently selected from the group consisting of hydrogen, halogen, OH, COOH, CN, substituted or unsubstituted C.6 alkyl.

2. A compound of claim 1 where n is 0 or 1, X is S or CHCN, Y is S. Z is O or S. R is H. Ar is substituted and unsubstituted phenyl (optionally substituted by C aLkyl, halogen, OH, C alkoxy, NO2, CF3, CN, COOH, COOR3, CONHR4), pyridine (optionally substituted by C.6 alkyl, halogen, OH, C alkoxy, NO2, CF3, CN, COOH, COOR3, CONHR4), pyrimidine, thiadizole.

3. A compound of daun 1, selected from: (5Z)-2-thioxo-5-({5-[3(trifluoromethyl)phenyl]-2-fuTyl}methylene)-1,3-thiazolidin-4-one (5Z)-5 { [5 -(3 -bromophenyl)-2-furyl] methylene} -2-thioxo- 1, 3 -thiazolidin4-one (5Z)-3-(2-furylmethyl)-2-thioKo-5-({5-[3-(trifluoromethyl)phenyl]-2furyl}methylene)-1,3 thiazolidin-4-one (5Z)-5-{ [5-(4<hloro-3-nitrophenyl) -2-furyl]methylene}-2-thioxo-1,3-thiazolidin-4-one (5Z)-2-thioxo-5-({5-3(trifluoromethyl)phenyl]thien-2-yl}methylene)-1,3-thiazolidin 4-one (5Z)5-({5-[2<hloro-5-(trifluoromethyl)phenyl]-2-furyl}methylene)-2-thioxo-1,3thiazolidin-

4 one

(5Z)-2-thioxo-5-({5-[3-(trifluoromethoxy)phenyl]-2-fulyl}methylene)-1,3thiazolidin-4-one (SZ)-2-thioxo-S-({ 5-[4-(trifluoromethyl)phenyl]-2fuIyllmethylene)-1,3-thiazolidin-one 2-hydroxy-5-{5-[(Z)-(4-oKo-2-thioxo1,3-thiazolidin-5-ylidene)methyl]-2-furyl}benzoic acid 3-[5-((Z)-{4-oXo-2thioxo-3-[4-(trifluoromethyl)benzyl]-1,3-thiazolidin-5-ylidene}methyl)-2 fuyl]benzaic acid 3-(5-{(Z)-[1-(3-chlorophenyl)-5-oxo-2thioxoimidazolidin-4-ylidene]methyl}thien-2-yl)benzOic acid (SZ)-S-{ [5(2,6-dichlorophenyl)thien-2-yl]methylene}-2-thioxo-1,3-thiazolidin-4-one methyl 3-{5-[(Z)-(4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]-2furylibenzoate (2E/Z)-[(SZ)-oxo-

5 ({5-[3-(trifluoromethyl)phenyl]-2-furyl} methylene)-1,3-tbiazolidin-2 ylidene] acetonitrile 5. A compound of claim 1, selected from: (5Z)-2-thioxo-5-[(5-{ [3-(trifluoromethyl)phenyl]thio}2-furyl)methylene]-1,3-thiazolidin-4-one (5Z) -5 -( { 5 - [(4-nitrophenyl) th lo] -2 -f uryl} methylene) -2 -thioxo- 1, 3 -thiazolidin-4 -one (5Z)-5({5-[(2-methylphenyl)thio]-2-furyl}methylene)-2-thioKo-1,3-thiazolidin"one (5Z)-5-{ [S-(pyridin-4-ylthio)-2-furyl]methylene}-2-thioxo-1,3thiazolidin-4-one 6-({5-[(Z)-(4-oKo-2-thioxo-1,3-thiazolidin-5-ylidene) methyl]-2-fuIyl}thio)nicotinic acid 2-({5-[(Z)-(4-oxo-2-thioxo-1,3thiazolidin-5-ylidene)methyl]-2-fuIyl}thio)nicotinic acid 2-({5-[(Z)14oxo-2-thioxo-1,3-oxazolidin-5-ylidene)methyl]-2-furyl}thio)nicotinic acid 2-({5-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-furyl}thio) nicotinic acid (5Z)-5-({5-[(2-hydroxyphenyl)thio]-2-furyl}methylene)-2thioxo-1,3-thiazolidin-4-one (5Z)-5-({5-[(2-methoxyphenyl)thio]-2-furyl} methylene)-2-thioxo-1,3-thiazolidin-4-one 6-({5-[(Z)-(4-oxo-2-thioxo-1,3oxazolidin-S-ylidene)methyl]-2-fulyl}thio)nicotinic acid 3-({ [6-({5-[(Z)(4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]-2-fuIyl}thio)pyridin-3-

yl]carbonyl}amino)propanoic acid trifluoroacetate 2-[(5-{(Z)-[3(carboxymethyl)-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene]methyl}-2-

furyl)thio]nicotinic acid (5Z)-5-{ [5-(pyrinudin-2-ylthio)-2-furyl] methylene}-2-thioxo-1,3 -thiazolidin-4-one

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

7. Use of a compound of any of claims 1 to 5, for the manufacture of a medicament for the treatment of a bacterial infection.

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

9. The use of claim B. wherein the organism is S. aureus.