GB2386893A - (4-Aroylpyrrol-2-yl)methylene substituted azole & azine derivatives and their therapeutic use as antibacterials - Google Patents

Abstract

Compounds of Formula 1 <EMI ID=1.1 HE=55 WI=82 LX=657 LY=596 TI=CF> <PC>[Where: X is O, CHCN, S; Y is O, NH, CH2, S or NHCO; Ar represents an optionally substituted carbocyclic or heterocyclic single or fused aromatic ring system, where for example the ring system can be optionally substituted by one or more groups selected from C1-6 alkyl, halogen, hydroxy, C1-6 alkoxy, nitro and trifluoromethyl, cyano, -CO2H, -CO2R4, CONR4R5; R1 is a H, C1-6 alkyl optionally substituted with one or more hydroxyl, carboxylic acid, carboxamide, halogen, amino or alkylamino groups, or an optionally substituted phenyl or heterocyclic ring Ar as defined previously; R2 is H, C1-6 alkyl optionally substituted with one or more hydroxyl, carboxylic acid, carboxamide, halogen, amino or alkylamino groups; R4 and R5 are independently defined as H, C1-6 alkyl, C1-6 alkylaryl, or Ar as defined previously] 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. pneumoniae, S. aureus and E. faecalis.

Description

RIIODANINE COMPOUNDS AND FIR TEIERAPEUTIC USE

Field of the Invention

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

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 arninoglycoside 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, trunethoprim 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.

The compounds in the invention are structurally novel and inhibit bacterial chorismate synthase enzymes.

For this reason they have utility as antibacterial agents.

Summary of the Invention

This invention relates to heterocyclic compounds, and more specifically to 2,4-disubstituted pyrrole containing compounds and to their pharmaceutical compositions as defined by Formula 1, or a pharmaceutical acceptable salt thereof.

o war y R1,N: Formula 1 Where: X is O. CHCN, S. Y is O. NH, CH2, S or NHCO;

Ar represents an optionally substituted carbocyclic or heterocyclic single or fused aromatic ring system.

This is understood to include benzene, naphthalene, pyridine, imidazole, pyrimidine, furan, oxazole, thiophene, thiazole and the like, and bonded through any ring atom. The ring system can be optionally substituted by one or more groups selected from Cite alkyl, halogen, hydroxy, Clot alkoxy, nitro and trifluoromethyl, cyano, -CO2H, -CO2R4, CONR4R5 R1 is a H. Can aLkyl optionally substituted with one or more hydroxyl, carboxylic acid, carboxamide, halogen, amino or alkylamino groups, or an optionally substituted phenyl or heterocyclic ring Ar as defined previously. R2 is H. Cad alkyl optionally substituted with one or more hydroxyl, carboxylic acid, carboxamide, halogen, amin,,o or aLkylamino groups.

R4 and RS are independently defined as H. Calkyl, Cry alkylaryl, or Ar as defined previously.

Preferred compounds are those where: X is S or O. Y is S. or NH; R1 is H; R2 H. Can aLkyl optionally substituted with one or more hydroxyl, carboxylic acid, carboxamide, halogen, amino or alkylamino groups; Ar is a substituted phenyl ring where the substituent is hydrogen, trifluoromethyl or cyano.

Particularly preferred embodiments of the invention are illustrated in Table 1.

o war art OqR2 R1 INN

Example | R1 R2 X Ar 1 H Me S S Ph 2 H Me S S 2-CF3Ph 3 H Me S S 4-CF3Ph 4 H Me S S 3-CNPh 5 H Me S S 4-CNPh Table 1

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. pneumonias, S. aureus, and E. faecalis. 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 "Cacti atkyl" as used herein refers to straight and branched chain atkyl 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 C, alkyd- . "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 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 clystallisation; resolution via formation of diastereomeric derivatives or complexes which may be separated, for example, by crystatlisation, 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 umnodified enantiomers; or gas-liquid or liquid chromatography on a chirat support such as silica with a bound chiral ligand or in the presence of a chital solvent. It wilt 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 synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer imto another by asymmetric transformation.

When a compound of Formula 1 or a salt thereof contains more than one chisel centre it may exist in diastereomeric forms. The diastereomeric pairs may be separated by methods known to those skilled in the ate, for example, chromatography or crystatlisation and the individual enantiomers within each pair may be separated as described above. The present invention indudes 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, hydrobromic acid, fumaric acid, tartaric acid, citric acid, sulfuric acid, hydiodic acid, rnaleic acid acetic acid, SUCCiDiC acid, benzoic acid, pamoic acid, patmitic 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 lysine or arginine or with orgaruc bases e.g. meglumaine 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 at recognised 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 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 andlor 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 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.

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 phtt atate 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 carboxymethylceltulose, 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 transdermat accelerate such as dimethyl sutphoxide 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 parenterat 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 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 spanugly 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 compounds 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 a heterocycle of the Formula 2 with an aldehyde of Formula 3, wherein X Y. R1, R2, and Ar are as defined previously. This condensation can be carried out in a suitable solvent such as ethanol in the presence of a base such as ammonia, ammonium salts, or piperidine at a temperature range between -BO C to 250 C.

BY H R2 (/'

Formula 2 Formula 3 X Scheme 1 The aldehyde can be prepared by VillsmierHack reaction and a subsequent Friedel Crafts acylation (Scheme 2). A reference to this procedure can be found in S. Massa, M. Artico, F. Corelli, A. Mai, R Di Santo, S. Cortes, M. E. Marongiu, A. Pani, P. La Collar J. Med. Chem, 1990, 33, 2845.

:3 (COCI)2 11 1) AICg / ArCOCI Nl DMF N 2) NaOH /H2O 03 R2 (C;0H2CCH2(CI) Cl R2 N H R2 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 art Procedure for the Preparation of Examples.

Preparation of (5Z)-5-[(4-benzoyl-1-methyl-llI-pyrrol-2-yl)methylene]-2thiozo-1,3-thiazolidin-4-one O.,)- N

CH3 HN$S A solution of N,Nimethylformamide (1.91 mL, 24.66 mmol) in 1,2dichloroethane (50 mL) was cooled to 0 C on an ice bath under an inert atmosphere of nitrogen. A solution of oxalyl chloride (2.15 mL, 24.66 mmol) in 1,2ichloroethane (50 mL) was added dropwise over a period of 20 minutes via a dropping funnel. The reaction was warmed to room temperature and stirred for 15 minutes. The reaction was cooled to 0 C. A solution of N-methylpyrrole (2.18 mL, 24.66 mmol) in 1,2-dichloroethane (50 mL) was added dropwise over a period of 10 minutes via a dropping funnel. The cooling bath was removed and the reaction stirred at room temperature for 20 minutes. Aluminium chloride (7.24 g, 54.25 mmol) was added followed by benzoyl chloride (2.86 mL, 24.66 mmol). The reaction mixture was stirred for 3 hours then poured onto a mixture of ice (250 g) and 50% aqueous sodium hydroxide solution (25 mL). The pH of the reaction mixture was adjusted to pH 7 with concentrated hydrochloric acid and the resulting suspension filtered through celite which was subsequently washed with dichloromethane (2 x 50 mL). The organic phase was isolated, washed with water (3 x 100 mL) and dried over magnesium sulfate. The solvent was removed at reduced pressure. The crude material was purified by flash column chromatography on silica gel elating with a mixture of hexane and ethyl acetate [4: 1]. This afforded 4-benzoyl-1 -methyl-lH- pyrrole-

2-carbaldehyde as a white solid (2.1 g, 9.85 mmol, 40 /O) 4-benzoyl-1methyl-lH-pyrrole-2-carbaldehyde (0.200 g, 0.94 mmol), rhodanine (0.125 g, 0.94 mmol) and ammonium acetate (0.217 g, 2.82 mmol) were reflexed in toluene (50 mL) under a nitrogen atmosphere for 18 hours. The toluene was removed at reduced pressure and the residue boiled in methanol. The methanolic mixture was cooled to room temperature, then on an ice bath. The solid product was collected by vacuum filtration, washed with a minimum amount of cold methanol and dried under vacuum to furnish the desired compound as an orange solid (0.191 g, 0.58 mmol, 62%). LC/MS 327 1M-H]-, 329 [M+H]+. IH NMR (d6-

DMSO) 3.88 (3H, s), 6.81 (1H, s), 7.49 (1H, s), 7.57 (2H, m), 7.65 (1H, m) , 7.79 (1H, m), 7.89 (1H, s), 13.78 (1H, be).

Preparation of (5Z;)-5-({1-methyl 4-[2-(tOfluoromethyl)benzoyl]-lElpyrrol-2-yl}methyleneY2-thioZo-

1,3-thiazolidin Hone F - F -\CH3 HN AS S A solution of N,N dimethylformamide (0.19 mL, 2.40 mmol) in 1,2ichloroethane (15 mL) was cooled to 0 C on an ice bath under an inert atmosphere of nitrogen. A solution of oxalyl chloride (0.21 mL, 2.40 mmol) in 1,2-dichloroethane (15 rnL) was added dropwise over a period of 20 minutes via a dropping funnel. The reaction was warmed to room temperature and stirred for 30 minutes. The reaction was cooled to 0 C. A solution of N-methylpyrrole (0. 21 mL, 2.40 mmol) in 1,2ichloroethane (15 mL) was added dropwise over a period of 10 minutes via a dropping funnel. The cooling bath was removed and the reaction stirred at room temperature for 30 minutes. Aluminium chloride (0.704 g, 5.28 mmol) was added followed by 2-trifluoromethyl benzoyl chloride (0.34 mL, 2.40 mmol). The reaction mixture was stirred for 3 hours then poured onto a mixture of ice (25 g) and 50% aqueous sodium hydroxide solution (2.5 mL).

The pH of the reaction mixture was adjusted to pH 7 with concentrated hydrochloric acid and the resulting suspension filtered through celite which was subsequently washed with dichloromethane (2 x 50 mL). The organic phase was isolated, extracted into dichloromethane (3 x 25 mL) and the combined organic phases dried over magnesium sulfate. The solvent was removed at reduced pressure. The crude material was purified by biotage column chromatography on a silica gel column eluting with a mixture of hexane and ethyl acetate [4: 1]. This afforded 1-methyl-4-t2(trifluoromethyl)benzoyl]-lH-pyrrole-2-carbaldehyde as a yellow solid (0. 083 g, 0.295 mmol, 12%).

1-methyl-4-[2-(trifluoromethyl)benzoyll-lH-pyrrole-2-carbaldehyde (0.083 g, 0.295 mmol), rhodanine (0.039 g, 0.295 mmol) and ammonium acetate (0. 068 g, 0.895 mmol) were reflexed in toluene (10 mL) under a nitrogen atmosphere for 18 hours. The toluene was removed at reduced pressure and the residue recrystallized methanol. The methanolic mixture was cooled to room temperature, then on an ice bath. The solid product was collected by vacuum filtration, washed with a minimum amount of cold methanol and dried under vacuum to furnish a yellow solid (0.010 g, 0.025 mmol, 10%). LC/IVIS 395 [M-H]-, 397 1M+H1+, 419 tM+Na]+. 'H NMR (d6-DMSO) SH 3.83 (3H, s), 6.69 (1H, m), 7.46 (1H, s), 7.60 (1H, d), 7.66 (1H, m), 7.73-7.83 (2H, m), 7.90 (1H, d), 13.80 (1H, be).

Preparation of (5Z)-5-({1-methyl - -[4-(trifluoromethyl)benzoyl]-lHpyrrol-2-yl}methylen*2-thioxo-

1,3-thiazolidin-4-one OF F O44 ION

1 CH3 HNS A solution of N,N-dimethylformamide (0.19 mL,2.40 mmol) in 1, 2ichloroethane (15 rnL) was cooled to 0 C on an ice bath umder an inert atmosphere of nitrogen. A solution of oxalyl chloride (0.21 mL, 2.40 mmol) in 1,2-dichloroethane (15 mL) was added dropwise over a period of 20 minutes via a dropping funnel. The reaction was warmed to room temperature and stirred for 30 minutes. The reaction was cooled to 0 C. A solution of N-methylpyrrole (0.21 rnL, 2.40 mmol) in 1,2ichloroethane (15 mL) was added dropwise over a period of 10 minutes via a dropping funnel. The cooling bath was removed and the reaction stirred at room temperature for 30 minutes. Aluminium chloride (0.704 g, 5.28 mmol) was added followed by 4-trifluoromethyl benzoyl chloride (0.34 mL,2.40 mmol). The reaction mixture was stirred for 3 hours then poured onto a mixture of ice (25 g) and 50% aqueous sodium hydroxide solution (2.5 mL).

The pH of the reaction mixture was adjusted to pH 7 with concentrated hydrochloric acid and the resulting suspension filtered through celite which was subsequently washed with dichloromethane (2 x 50 mL). The organic phase was isolated, extracted into dichloromethane (3 x 25 rnL) and the combined orgamc phases dried over magnesium sulfate. The solvent was removed at reduced pressure. The crude material was purified by biotage column chromatography on a silica gel column eluting with a mixture of hexane and ethyl acetate [4:1]. This afforded 1-methyl-4-[4(trifluoromethyl)benzoyl]-lH-pyrrole-2-carbaldehyde as a yellow solid (0. 130 g, 0.463 mmol, 19%).

1-methyl-4-[4-(trifluoromethyl)benzoyl]-lH-pyrrole-2-carbaldehyde (0.130 g, 0.463 mmol), rhodanine (0.062 g, 0.463 mmol) and ammonium acetate (0. 107 g, 1.388 mmol) were refluxed in toluene (10 mL) under a nitrogen atmosphere for 18 hours. The toluene was removed at reduced pressure and the residue recrystallised metbanol. The metbanolic mixture was cooled to room temperature, then on an ice bath. The solid product was collected by vacuum filtration, washed with a minimum amount of cold methanol and dried under vacuum to furnish an orange solid (0.052 g, 0.130 mmol,45 /O). LC/MS 395 I-H]-, 397 [M+H1+, 419 pvI+Na]+. tH NMR (d6-DMSO) SH 3.88 (3H, s), 6.84 (1H, m), 7.49 (1H, s), 7.92-7.98 (4H, m), B. l l (1H, d), 13.80 (1H, bs).

Preparation of (5Z)-5-({1-methyl-4-[(cyano)benzoyl]-1H-pyrrol-2-yl} methylene)-2-thioKo-1,3-

thia olidinone N i/ _ 0 IN / CH3 HN:'S A solution of N,Ndimethylformamide (0.47 mL, 6.06 mmol) in 1,2-dichloroethane (10 mL) was cooled to 0 C on an ice bath under an inert atmosphere of nitrogen. A solution of oxalyl chloride (0.53 mL, 6.06 mmol) in 1,2-dichloroethane (10 mL) was added dropwise over a period of 20 minutes via a dropping funnel. The reaction was warmed to room temperature and stirred for 30 minutes. The reaction was cooled to 0 C. A solution of N-methylpyrrole (0. 54 rnL, 2.40 mmol) in 1,2-dichloroethane (10 mL) was added dropwise over a period of 10 minutes via a dropping funnel. The cooling bath was removed and the reaction stirred at room temperature for 30 minutes. Aluminium chloride (2.67 g, 20.00 mmol) was added followed by 3<yanomethyl benzoyl chloride (1.00 g, 6.06 mmol). The reaction mixture was stirred for 3 hours then poured onto a mixture of ice (50 g) and 50% aqueous sodium hydroxide solution (5 mL). The pH of the reaction mixture was adjusted to pH 7 with concentrated hydrochloric acid and the resulting suspension filtered through celite which was subsequently washed with dichloromethane (2 x 50 mL). The organic phase was isolated, extracted into dichlorometbane (3 x 50 mL) and the combined organic phases dried over magnesium sulfate. The solvent was removed at reduced pressure. The crude material was purified by biotage column chromatography on a silica gel column eluting with a mixture of hexane and ethyl acetate [4:1]. This afforded 3-[(5-formyl-1-methyl-lH-pyrrol-3- yl)carbonyl]benzonitrile as a yellow solid (0.77 g, 3.23 mmol, 53 /O) 3[(5-formyl-1-methyl-lH-pyrrol-3-yl)carbonyl]benzonitrile (0.100 g, 0.42 mrnol), rhodanine (0.056 g, 0.423 mmol) and ammonium acetate (0.097 g, 1. 26 mmol) were refluxed in toluene (5 mL) under a nitrogen atmosphere for 2 hours. The toluene was removed at reduced pressure and the residue recrystallised methanol. The metbanolic mixture was cooled to room temperature, then on an ice bath. The solid product was collected by vacuum filtration, washed with a minimum amount of cold methanol and dried under vacuum to furnish a brown solid (0.038 g, 0.108 mmol, 26%) LC/MS 352 [M-H]-, 354 [M+H1+, 376 1M+Na]+. H NMR (d6-DMSO) H 3.77 (3H, s), 6.81 (1H, s), 7.42 (1H, s), 7.77 (1H, m), 7.92 (1H, s), 8.09 (2H, m), 8. 18 (1 s), 13.78 (1H, bs).

Preparation of (5Z)-5-(1-methyl 4-[4-(cyano)benzoyl]-1-pycrol-2-yl} methylene)-2-thioxm1,3-

thiazolidinone 0=\ 0 N 1 CH3 HNiS A solution of N,N-dimethylformamide (0. 47 rnL, 6.06 mmol) in 1,2-dichloroethane (10 mL) was cooled to 0 C on an ice bath under an inert atmosphere of nitrogen. A solution of oxalyl chloride (0.53 mL, 6.06 mmol) in 1,2-dichloroethane (10 mL) was added dropwise over a period of 20 minutes via a dropping funnel. The reaction was warmed to room temperature and stirred for 30 minutes. The reaction was cooled to 0 C. A solution of N-methylpyrrole (0.54 rnL, 2.40 mmol) in 1,2ichloroethane (10 rnL) was added dropwise over a period of 10 minutes via a dropping funnel. The cooling bath was removed and the reaction stuTed at room temperature for 30 minutes. Aluminium chloride (2.67 g, 20. 00 mmol) was added followed by 3 cyanomethyl benzoyl chloride (1.00 g, 6. 06 mmol). The reaction mixture was stirred for 3 hours then poured onto a mixture of ice (50 g) and 50% aqueous sodium hydroxide solution (5 rnL). The pH of the reaction mixture was adjusted to pH 7 with concentrated hydrochloric acid and the resulting suspension filtered through celite which was subsequently washed with dichloromethane (2 x 50 mL). The organic phase was isolated, extracted into dichloromethane (3 x 50 mL) and the combined orgauc phases dried over magnesium sulfate. The solvent was removed at reduced pressure. The crude material was purified by biotage column chromatography on a silica gel column eluting with a mixture of hexane and ethyl acetate [4: 1]. This afforded 4-[(5-formyl-1methyl-lH-pyrrol-3-yl)carbonyl]benzonitrile as a brown solid (0.41 g, 1. 72 mmol, 28%).

4-[(5-formyl-1-methyl-lH-pyrrol-3yl)carbonyl]benzonitrile (0.100 g, 0.42 mmol), rhodanine (0.056 & 0.423 mmol) and ammonium acetate (0.097 g, 1.26 mmol) were refluxed in toluene (5 mL) umder a nitrogen atmosphere for 2 hours. The toluene was removed at reduced pressure and the residue recrystallised methanol. The methanolic mixture was cooled to room temperature, then on an ice bath. The solid product was collected by vacuum filtration, washed with a minimum amoumt of cold methanol and dried under vacuum to filrnish a brown solid (0.027 g, 0.076 mmol, 18%). LC/MS 352 [M-H]-, 354 [M+H]+, 376 [M+Na]+. H NMR (d6-DMSO) SH 3.X7 (3H, s) , 6.80 (1H, m), 7.45 (1H, s), 7.89 (lH, s), 7.92 (2H, d), 8.04 (2H, d), 13.72 (1H, bs).

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%) inhibition of the maximal (100%) inhibition occurs. ICso 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 /O) to complete inhibition (100%). The ICso value can be estimated from a plot of % inhibition against concentration of inhibitor, or can be calculated using data fitting programs, such Grafit (Elsevier) or EnzFitter (Biosoft).

Procedure for determining Minimum Inhibitory Concentrations (MIC)s andMinimum Bactericicdal Concentrations (MBC)s on bacteria ICso determinations Compounds (2)-(5) whose structure is given in Table 2 have IC50s in the range 100 nM to 20,uM against Oxford S. aureus, S. pneumonias and E. faecalis.

O:Ar _ N y R1,N No R1 R2 X - Ar 2 H Me S S 2-CF3Ph 3 H Me S S 4-CF3Ph 4 H Me S S 3-CMPh S H Me S S 4-CNPh Table 2

Claims (8)

Claims

1) A compound, for therapeutic use, of Formula 1 o tar Formula 1 O I i\ R2 1 Y R1 AN it Where: X is 0, CHCN, S. Y is 0, NH, CH2, S or NHCO; Ar represents an optionally substituted carbocyclic or heterocyclic single or fused aromatic ring system.

The ring system can be optionally substituted by one or more groups selected from Clot alkyl, halogen, hydroxy, ClaLkoxy, Vitro and trifluoromethyl, cyano, -C02H, -C02R4, C0NR4R5 R1 is a H. Can aLkyl optionally substituted with one or more hydroxyl, carboxylic acid, carboxamide, halogen, amino or allcylamino groups, or an optionally substituted phenyl or heterocyclic ring Ar as defined previously. R2 is H. Cl; alkyl optionally substituted with one or more hydroxyl, carboxylic acid, carboxamide, halogen, amino or allylamino groups.

R4 and R5 are independently defined as H. Clue aLkyl, Clue aLkylayl, or Ar as defined previously.

2) A compound of claim 1, where X is O or S and Y is S 3) A compound of claim 1, selected from: (5Z)-5-[(4-benzoyl-1 -methyl-lH-pyrrol-2-yl) methylene]-2-tbioxo-1,

3 -thiazolidin-4-one, (SZ)-5-({ 1-methyl-4-12(trifluoromethyl)benzoyl]-lH-pyrrol-2-yl}methylene)-2-thioKo-1,3thiazolidin-

4 one, (SZ)-5-({ 1-methyl-4-[4-(trifluoromethyl)benzoyl]-lHpyrrol-2-yl}methylene)-2-tbioKo-1,3-thiazolidin-4 one, (SZ)-5-({ 1-methyl4-[3-(cyano)benzoyl]-lH-pyrrol-2-yl}methylene)-2-thioxo-1,3-tbiazolidin-4one (SZ)-5-({ 1 -methyl-4-[4-(cyano)benzoyl]-lH-pyrrol-2-yl}methylene)-2tbioxo-1,3-tbiazolidin-4-one, 4) A pharmaceutical composition comprising as an active ingredient a compound of any preceding claim, together with a carrier or diluent.

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

6) The use of claim 5, wherein the infection is caused by a gram positive organism.

7) The use of claim 6, wherein the organism is as

S. pneumonias, S. aureus, or E.faecalis.