WO1997031917A1

WO1997031917A1 - Substituted phenyloxazolidinones and their use as antibiotics

Info

Publication number: WO1997031917A1
Application number: PCT/GB1997/000511
Authority: WO
Inventors: Michael John Betts; Stuart Dennett Mills; David Anthony Roberts; Michael Lingard Swain
Original assignee: Zeneca Limited
Priority date: 1996-02-29
Filing date: 1997-02-24
Publication date: 1997-09-04
Also published as: AU1887697A; GB9604301D0

Abstract

The invention concerns a compound of formula (I) wherein, for example: R1 is hydroxy, chloro, fluoro, amino, azido, of the for mula -NHC(=O)Ra wherein Ra is hydrogen or (1-4C)alkyl, of the formula -N(Me)C(=O)Rb wherein Rb is hydrogen, methyl or methoxy or of the formula -NHS(O)¿n?(1-4C)alkyl wherein n is 0, 1 or 2; R?2 and R3¿ are independently hydrogen or fluoro; R?4, R5 and R6¿ are independently selected from hydrogen, (1-4C)alkyl (optionally substituted), halo, trifluoromethyl, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, di-(N-(1-4C)alkyl)carbamoyl, cyano or nitro; and pharmaceutically acceptable salts thereof; and in particular the compounds N-[(5S)-(3-(4-(4-bromoimidazol-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide and N-[(5S)-(3-(4-(4-cyanoimidazol-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide and pharmaceutically acceptable salts thereof; processes for their preparation; pharmaceutical compositions containing them and their use as antibacterial agents.

Description

SUBSTΓΓUTED PHENYLOXAZOLIDINONES AND THEIR USE AS ANTIBIOTICS

The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing an oxazolidinone ring. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.

The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention are regarded primarily as effective against Gram-positive pathogens because of their particularly good activity against such pathogens. Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin resistant staphylococcus (MRSA). methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium.

The major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens.

The present inventors have discovered a class of antibiotic compounds containing an oxazolidinone ring which has useful activity against Gram-positive pathogens including MRSA and MRCNS and, in particular, against various strains exhibiting resistance to vancomycin and against E. faecium strains resistant to both aminoglycosides and clinically used β-lactams. We have now discovered a range of compounds which have good activity against a broad range of Gram-positive pathogens including organisms known to be resistant to most commonly used antibiotics.

Accordingly the present invention provides a compound of the formula (I):

wherein:

R' is hydroxy, chloro, fluoro, (l-4C)alkanesulphonyloxy, amino, azido, (l-4C)alkoxy, (l-4C)alkylthio, (l-4C)alkylaminocarbonyloxy, or of the formula -NHC(=O) R^a wherein R^a is hydrogen, (l-4C)alkoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino, dimethylamino or (l-4C)alkyl or R¹ is of the formula -N(Me)C(=O)R^b wherein R^b is hydrogen, methyl or methoxy or R' is of the formula -NHS(O)_n(l-4C)alkyl wherein n is 0, 1 or 2; R² and R³ are independently hydrogen or fluoro;

R\ R⁵ and R⁶ are independently selected from hydrogen, (l -4C)alkyl, (optionally substituted by trifiuoromethyl, (l-4C)alkyl S(O)_n- (wherein n is 0, 1 or 2), (l-4C)alkoxy, carboxy, (l-4C)alkoxycarbonyl, carbamoyl, N-( 1 -4C)alkylcarbamoyl, di(N-(l-4C)alkyl)carbamoyl, cyano, nitro, amino, N-(l-4C)alkylamino. di(N-(l-4C)alkyl)amino or (l-4C)alkanoylamino), halo, trifiuoromethyl, (l-4C)alkyl S(O)_n (wherein n is 0, 1 or 2). carboxy,

(l-4C)alkoxycarbonyl, carbamoyl, N-(l-4C)alkylcarbamoyl, di(N-(l -4C)alkyl)carbamoyl. (2-4C)alkenyl (optionally substituted by carboxy or (l-4C)alkoxycarbonyl), cyano or nitro; and pharmaceutically acceptable salts thereof.

The term 'alkyl' includes straight chained and branched structures. For example, (l-4C)alkyl includes propyl, isopropyl and t-butyl.

Examples of (l-4C)alkyl include methyl, ethyl, propyl isopropyl and t-butyl; examples of N-(l-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl; examples of di(N-(l-4C)alkyl)carbamoyl include di(methyl)carbamoyl and di(ethyl)carbamoyl; examples of (l-4C)alkylS(O)_n. include methylthio, ethylthio, methylsulphinyl. ethylsulphinyl, methylsulphonyl and ethylsulphonyl; examples of (2- 4C)alkenyl include allyl and vinyl; examples of ( 1 -4C)alkoxy include methoxy, ethoxy and propoxy; examples of (l-4C)alkanoylamino include acetamido and propionylamino; examples of N-(l-4C)alkylamino include methylamino and ethylamino; example of di-(N-(l- 4C)alkyl)amino include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino; examples of ( 1 -4C)alkoxycarbonyl include methoxy carbonyl and ethoxy carbonyl. Examples of halo include fluoro, chloro and bromo. Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N- methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically-acceptable salt is the sodium salt.

However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not. The compounds of the formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the formula (I). Examples of pro-drugs include in-vivo hydrolysable esters of a compound of the formula (I). An in-vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically- acceptable esters for carboxy include (l-όC)alkoxymethyl esters for example methoxymethyl, (l-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, (3-8C)cycloalkoxycarbonyloxy(l-6C)alkyl esters for example l-cyclohexylcarbonyloxyethyl; 1 ,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and (l-6C)alkoxycarbonyloxyethyl esters for example 1 -methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.

An in-vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxy carbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates). dialkylaminoacetyl and carboxy acetyl.

The compounds of the present invention have a chiral centre at the C-5 position. The pharmaceutically active enantiomer is of the formula (I A) :

(IA)

The present invention includes the pure enantiomer depicted above or mixtures of the 5(R) and 5(S) enantiomers, for example a racemic mixture. If a mixture of 5(R) and 5(S) is used, a larger amount (depending up on the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer.

Furthermore, some compounds of the formula (I) may have other chiral centres. Preferably R' is hydroxy, chloro, fluoro, methanesulphonyloxy, amino, azido, methoxy, methylthio, methylaminocarbonyloxy, or of the formula -NHC(=0) R^a wherein R^ais hydrogen, methoxy, amino. chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino. dimethylamino or (l-4C)alkyl or R¹ is of the formula - N(Me)C(=0)R^b wherein R^b is hydrogen, methyl or methoxy or R¹ is of the formula - NHS(0)_π(l-4C)alkyl wherein n is 0, 1 or 2.

More preferably R¹ is hydroxy, chloro, fluoro. methanesulphonyloxy, or of the formula -NHC(=O)R^a wherein R^a is hydrogen, methoxy, amino, chloromethyl. dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl or (l-4C)alkyl or R¹ is of the formula -NHS(0)„(l-4C)alkyl wherein n is 0, 1 or 2.

Yet more preferably R¹ is hydroxy, or of the formula -NHC(=O)R^a wherein R^a is (1 - 4C)alkyl or R¹ is of the formula -NHS(O)_n(l-4C)alkyl wherein n is 0, 1 or 2. Yet more preferably R' is of the formula -NHC(=O)( 1 -4C)alkyl.

Most preferably R¹ is acetamido In another aspect R' is hydroxy.

Preferably one of R² and R³ is hydrogen and the other is fluoro. Preferably R\ R⁵ and R⁶are independently selected from hydrogen, (l-4C)alkyl (optionally substituted by (l-4C)alkoxy or (l-4C)aIkanoylamino) ( 1 -4C)alkylthio, halo, carboxy, (l-4C)alkoxycarbonyl, and carbamoyl.

More preferably R\ R⁵ and R⁶are independently selected from hydrogen, methyl or ethyl (each optionally substituted by methoxy, ethoxy or acetamido), methylthio, ethylthio, chloro, bromo, carboxy, methoxycarbonyl, ethoxycarbonyl and carbamoyl. Most preferably R⁴, R⁵ and R⁶ are independently selected from hydrogen, methyl, ethyl, methoxymethyl, 2-(acetamido)ethyl, methylthio. chloro, bromo, carboxy, methoxycarbonyl and carbamoyl.

Preferably at least two of R\ R⁵ and R⁶ are hydrogen. More preferably, R⁴ and R⁶ are hydrogen and R⁵ is as hereinabove defined. Most preferably R⁴ and R⁶ are hydrogen and R⁵ is cyano or halo (and in particular bromo).

Particular compounds of the present invention include:

N-[(5S)-3-(3-fluoro-4-(imidazol-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide; N-[(5S)-3-(3-fluoro-4-(2-methylimidazol-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide; N-[(5S)-3-(3-fluoro-4-(4-methylimidazol-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide;

N-[(5S)-3-(3-fiuoro-4-(5-methylimidazol-l -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide; N-[(5S)-3-(3-fluoro-4-(4-ethylimidazol-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;

N-[(5S)-3-(3-fluoro-4-(2,4-dimethylimidazol-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide;

N-[(5S)-3-(3-fluoro-4-(2-methylthioimidazol-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide; N-[(5S)-3-(3-fluoro-4-(4-methoxymethylimidazol-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide;

N-[(5S)-3-(3-fluoro-4-(4-bromoimidazol-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide;

N-[(5S)-3-(3-fluoro-4-(4,5-dichloroimidazol-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide;

N-[(5S)-3-(3-fluoro-4-(4-methoxycarbonylimidazol-l-yl)phenyl)-2-oxooxazolidin-5- ylmethyl]acetamide;

N-[(5S)-3-(3-fluoro-4-(4-carboxyimidazol-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide; N-[(5S)-3-(3-fluoro-4-(4-carbamoylimidazol-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide; and

N-[(5S)-3-(3-fluoro-4-(4-(2-acetamidoethyl)imidazol-l-yl)ρhenyl)-2-oxooxazolidin-5- ylmethyljacetamide; and pharmaceutically acceptable salts thereof. The present inventors have recognised that the successful development of suitable antibiotic compounds depends not only on achieving useful antibacterial activity, but also on the compounds possessing a toxicological profile which is acceptable to the host being treated. Many compounds in the art which have useful antibacterial activity also possess toxicity which renders them unacceptable as antibiotics for general use in disease control. The present inventors have now discovered certain compounds of the formula (I) which have useful antibacterial activity and favourably low toxicity. This combination of properties produces a favourable therapeutic ratio. In addition, the compounds also possess a long half- life and so are particularly attractive for pharmaceutical development, for example by permitting a reduced dosage to be administered over a period of time.

Accordingly, in a particularly preferred aspect of the present invention there is provided a compound of the formula (I) in which R¹ is of the formula -NHC(=O)R^a wherein Ra is hydrogen or (l-4C)alkyl (and in particular R¹ is acetamido), R² and R³ are independently hydrogen or fluoro (and in particular one of R2 and R3 is hydrogen and the other is fluoro), R⁴ and R» are hydrogen and R5 is cyano or halo (and in particular bromo); and pharmaceutically-acceptable salts thereof. Thus, preferred compounds of the invention include

N-[(5S)-3-(4-(4-fluoroimidazoI-l-yl)-3-fluorophenyl)-2-oxooxazoIidin-5-ylmethyl]acetamide N-[(5S)-3-(4-(4-chloroimidazol-l -yl)-3-fluorophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide and pharmaceutically-acceptable salts thereof.

An especially preferred compound of the invention is N-[(5S)-3-(4-(4-bromoimidazol-l-yl)-3-fluorophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide and pharmaceutically-acceptable salts thereof.

A particularly preferred compound of the invention is N-[(5S)-(3-(4-(4-cyanoimidazol-l-yI)-3-fluorophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide and pharmaceutically-acceptable salts thereof. In a further aspect the present invention provides a process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The compounds of the formula (I) may be prepared by deprotecting a compound of the formula (II):

(II) wherein R² and R³ are as hereinabove defined. R⁷ is R⁴ or protected R⁴, R⁸ is R⁵ or protected R⁵,

R⁹ is R⁶ or protected R⁶ and R¹⁰ is R¹ or protected R¹ and thereafter if necessary forming a pharmaceutically acceptable salt.

Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake of convenience. in which "lower" signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.

A carboxy protecting group may be the residue of an ester- forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).

Examples of carboxy protecting groups include straight or branched chain

(l-12C)alkyl groups (eg isopropyl, t-butyl); lower alkoxy lower alkyl groups (eg methoxymethyl. ethoxymethyl, isobutoxymethyl; lower aliphatic acyloxy lower alkyl groups, (eg acetoxy methyl, propionyloxymethyl. butyryloxymethyl, pivaloyloxyme hyl); lower alkoxycarbonyl oxy lower alkyl groups (eg 1-methoxycarbonyioxyethyl,

1 -ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg_p-methoxybenzyl, o^nitrobenzyl. r nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl and t^butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (eg trime hylsilylethyl); and (2-6C)alkenyl groups (eg allyl and vinylethyl).

Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, metal- or enzymically-catalysed hydrolysis.

Examples of hydroxy protecting groups include lower alkenyl groups (eg allyl); lower alkanoyl groups (eg acetyl); lower alkoxycarbonyl groups (eg tbutoxycarbonyl); lower alkenyloxycarbonyl groups (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, r methoxybenzyloxycarbonyl, < nitrobenzyloxycarbonyl. r nitrobenzyloxycarbonyl); tri lower alkyl/arylsilyl groups (eg trimethylsilyl, t butyldimethylsilyl, t-butyldiphenylsilyl); aryl lower alkyl groups (eg benzyl) groups; and triaryl lower alkyl groups (eg triphenylmethyl).

Examples of amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg r mefhoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-r anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg tbutoxycarbonyl); lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl, pπmethoxybenzyloxycarbonyl, o^nitrobenzyloxycarbonyl, r nitrobenzyloxycarbonyl; trialkylsilyl (eg trimethylsilyl and trbutyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, metal- or enzymically-catalysed hydrolysis, for groups such as ( iitrobenzyloxycarbonyl, photolytically and for groups such as silyl groups, fluoride. Examples of protecting groups for amide groups include aralkoxymethyl (eg. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl (eg. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl (eg. trimethylsilyl, t-butyldimethylsily, t- butyldiphenylsilyl); tri alkyl/arylsilyloxymethyl (eg. t-butyldimethylsilyloxymethyl, t-butyldiphenylsilyloxymethyl); 4-alkoxyphenyl (eg. 4-methoxyphenyl); 2,4-di(alkoxy)phenyl (eg. 2,4-dimethoxyphenyl); 4-alkoxybenzyl (eg. 4-methoxybenzyl); 2,4-di(alkoxy)benzyl (eg. 2,4-di(methoxy)benzyl); and alk-1-enyl (eg. allyl, but-1-enyl and substituted vinyl eg. 2- phenylvinyl).

Aralkoxymethyl, groups may be introduced onto the amide group by reacting the latter group with the appropriate aralkoxymethyl chloride, and removed by catalytic hydrogenation. Alkoxymethyl, tri alkyl/arylsilyl and tri alkyl/silyl groups may be introduced by reacting the amide with the appropriate chloride and removing with acid, or in the case of the silyl containing groups fluoride ions. The alkoxyphenyl and alkoxybenzyl groups are conveniently introduced by arylation or alkylation with an appropriate halide and removed by oxidation with eerie ammonium nitrate. Finally alk-1-enyl groups may be introduced by reacting the amide with the appropriate aldehyde and removed with acid. For further examples of protecting groups see one of the many general texts on the subject, for example, 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons).

In another aspect of the present invention the compounds of the formulae (I) and (II) and pharmaceutically acceptable salts thereof can be prepared: a) by modifying a substituent in or introducing a substituent into another compound of the formula (I) or (II); b) when R¹ or R¹⁰ is of the formula - NHS(O)_n(l-4C)alkyl, wherein n is 1 or 2, by oxidising a compound of the formula (I) wherein n is 0 or, when n is 2 by oxidising a compound of the formula (I) or (II) wherein n is 1 ; c) when R¹ or R'° is azido, by reacting a compound of the formula (III) with a source of azide:

(III) d) when R¹ or R¹⁰ is amino, by reducing a compound of the formula (I) or (II) wherein

R¹ or R¹⁰ is azido; e) when R¹ or R¹⁰ is of the formula -NHC(=O) R^a, by introducing -C(=O)R^a into a compound of the formula (I) or (II) wherein R¹ or R¹⁰ is amino; f) when R¹ or R¹⁰is of the formula -NHS(O)_n (l-4C)alkyl by introducing -S(O)_n(l- 4C)aikyl into a compound of the formula (I) or (II) wherein R¹ or R¹⁰ is amino; g) when R¹ or R¹⁰ is of the formula -N(Me)C(=O)R^b, by introducing the group - C(=O)R^b into a compound of the formula (IV):

(IV) h) when R' or R¹⁰ is chloro, fluoro, (1 -4C)alkanesulphonyloxy or (1 - 4C)alkylaminocarbonyloxy, from a compound of the formula (I) or (II) wherein R¹ or R^l0 is hydroxy; i) when R¹ or R¹⁰ is chloro, ( 1 -4C)alkylthio or ( 1 -4C)alkoxy, from a compound of the formula (III); j) when R' or R¹⁰ is hydroxy, by reacting a compound of the formula (V) with a compound of the formula (VI):

(V) (VI)

k) when R5 is cyano by the oxidation (dehydrogenation) of a compound of the formula

(I) or (II) wherein R⁵ or R⁸ is azidomethyl; wherein R², R³ and R⁷-R¹⁰ are as hereinabove defined, R¹² is mesyloxymethyl or tosyloxymethyl, R^l3is (l-6C)alkyl or benzyl, and R¹⁴ is (l-6C)alkyl and thereafter if necessary: i) removing any protecting groups; ii) forming a pharmaceutically acceptable salt.

Methods for converting substituents into other substituents are known in the art. For example an alkylthio group may be oxidised to an alkylsulphinyl or alkysulphonyl group, a cyano group reduced to an amino group, a nitro group reduced to an amino group, a hydroxy group alkylated to a methoxy group, a bromo group converted to an alkylthio group or a bromo group to a cyano group.

Compounds of the formula (I) or (II) wherein R' or R'° is -NHS(O)_n(l-4C)alkyl can be prepared by oxidising a compound of the formula (I) or (II) with standard reagents known in the art for the oxidation of a thio group to a sulphinyl or sulphonyl group. For example, a thio group may be oxidised to a sulphinyl group with a peracid such as m-chloroperoxybenzoic acid and oxidising agents such as potassium permanganate will convert a thio group to a sulphonyl group. Compounds of the formula (I) or (II) wherein R¹ or R'° is -NHS( 1 -4C)alkyl can be prepared by reacting compounds of the formula (I) or (II) wherein R' or R¹⁰ is amino with a reagent such as (1 -4C)alkylSCl. A compound of the formula (I) or (II) wherein R' or R¹⁰ is azido may be prepared, for example, by reacting a compound of the formula (III) with sodium azide in an inert solvent such as DMF in a temperature range of ambient to 100°C, normally in the region of 75°C - 85°C. A compound of the formula (III) may be prepared by converting the hydroxy group in a compound of the formula (I) or (II) wherein R' or R¹⁰ is hydroxy into a tosyloxy or mesyloxy group by standard methods known in the art. For example, by reacting the compound of the formula (III) with tosyl chloride or mesyl chloride in the presence of a mild base such as triethylamine, or pyridine.

Suitable reducing agents for reducing azido to amino in a compound of the formula (I) or (II) include triethylamine/hydrogen sulphide, triphenylphosphine or phosphite ester, or hydrogen in the presence of a catalyst. More specifically the reduction of the azido group may be carried out by heating it in an aprotic solvent, such as 1 ,2-dimethoxyethane, in the presence of P(OMe), and subsequently heating in 6N aqueous hydrochloric acid, or reacting it with hydrogen in the presence of palladium on carbon in a protic such as DMF or ethyl acetate. For further details on the reduction of azides to amines see USP 4,705,799. The azido compound may be reduced and converted to a compound of the formula (I) or (II). wherein R' or R'° is acetamido, in situ using acetic anhydride in DMF. When R^a is (l-4C)alkyl, the group -C(=O)(l-4C)alkyl may be introduced into a compound of the formula (I) or (II) wherein R¹ or R¹⁰ is amino by standard acetylation procedures. For example, the amino group may be acetylated to give an acetamido group using the Schotten-Baumann procedure i.e. reacting the compound of the formula (I) or (II) wherein R' or R¹⁰ is amino with acetic anhydride in aqueous sodium hydroxide and THF in a temperature range of 0°C to 60°C , preferably between 0°C and ambient temperature. The acylation may be carried out in situ following the catalytic hydrogenation of a compound of the formula (I) or (II) wherein R¹ or R'° is azido, by performing the hydrogenation in the presence of acetic anhydride (for example using similar methods to those used in example 4). When R is hydrogen, the -CHO group may be introduced into the compound of the formula (I) or (II) wherein R' or R¹⁰ is amino (amino compound) by reacting the latter compound in formic acetic anhydride, in an inert organic solvent such as THF, in a temperature range of 0°C to ambient temperature, or by reacting it with ethyl formate in an inert organic solvent in the temperature range of 50-100°C. When R^a is ( 1 -4C)alkoxy, the -COO( 1 -4C)alkyl group may be introduced into the amino compound by reacting the latter compound with (l-4C)alkyl chloro formate, in the presence of an organic base such as triethylamine, in an organic solvent such as dichloromethane and in a temperature range of 0°C to ambient temperature.

When R^a is amino, the -CONH₂ group may be introduced into the amino compound by reacting the latter compound either with potassium cyanate in aqueous acid (eg hydrochloric acid) in a temperature range of ambient temperature to 80°C or with phenyl carbamate in glyme at reflux.

When R^a is chloromethyl, dichloromethyl, cyanomethyl or methoxymethyl, the -C(=O)R^a group may be introduced into the amino compound by reacting the latter compound with the appropriate acid chloride under standard conditions. The acid chloride may be prepared from the appropriate acid. When R^a is acetylmethyl, the -C(=O)R^a group may be introduced into the amino compound by reacting the latter compound with diketene, in an inert organic solvent such as THF, in a temperature range of 0°C to ambient temperature. Alternatively, the amino compound may be reacted with the appropriate acid anhydride, in dichloromethane or THF, in the presence of an organic base such as triethylamine and in a temperature range of 0°C to ambient temperature, or the amino compound may be reacted with the appropriate acid in the presence of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an organic base such as triethylamine, in an organic solvent such as dichloromethane, in a temperature range of 0°C to ambient temperature. When R^a is methylamino, the -CONHMe group may be introduced into the amino compound by reacting the latter compound with methyl isocyanate in an organic solvent such as THF or acetonitrile, in a temperature range of 0°C to ambient temperature.

When R^a is dimethylamino, the -CONMe₂ group may be introduced into the amino compound my reacting the latter compound with dimethylcarbamoyl chloride and triethylamine in an organic solvent such as THF or acetonitrile, in a temperature range of 0°C to ambient temperature.

Standard reaction conditions for the conversion of a compound of the formula (I) or (II) wherein R' or R¹⁰ is amino to a compound of the formula (I) or (II) wherein R' or R'° is sulphonamido are known in the art. For example, a compound of the formula (I) or (II) wherein R^l or R¹⁰ is amino could for example be converted to a compound of the formula (I) or (II) wherein R¹ or R'°is (l-4C)SO₂NH- by reacting the former compound with a sulphonyl chloride, for example, mesyl chloride, in a mild base such as pyridine.

Alternatively compounds of the formula (I) or (II) wherein R¹ or R¹⁰ is (1- 4C)alkylSO₂NH- or (l-4C)alkylSONH- may be prepared by reacting a compound of the formula (I) or (II) wherein R¹ is amino with a compound of the formula (l-4C)alkylSO₂NHL' or (l-4C)SONHL' wherein L¹ is a phthalimido group.

The phthalimido compound may be prepared by oxidising a compound of the formula (VII):

_ alkyl

(VII) with standard oxidising agents known for the conversion of a thio group to a sulphinyl or sulphonyl group. Compounds of the formula (VII) can be prepared by reacting phthalimide with an alkylthiochloride ((1 -4C)alkylSCl).

The group -C(=O) R^b may be introduced into a compound of the formula (IV) to give the appropriate compound of the formula (I) or (II) wherein R'or R¹⁰ is of the formula -N(Me)C(=O)R^b using similar methods to those described for the introduction of the appropriate -C(=O)R^a group into the compound of the formula (I) or (II) wherein R' or R¹⁰ is amino.

The compound of the formula (IV) may be prepared by reacting a compound of the formula (I) or (II) wherein R¹ or R¹⁰ is amino with formaldehyde and sodium borohydride or sodium cyanoborohydride, in an alcholic solvent such as ethanol or isopropanol, in a temperature range of 0°C to ambient temperature.

A compound of the formula (I) or (II) wherein R¹ or R'° is fluoro may be prepared by reacting a compound of the formula (I) or (II) wherein R¹ or R¹⁰ is hydroxy (hydroxy compound) with a fluorinating agent such as diethylaminosulphur trifluoride in an organic solvent such as dichloromethane in the temperature range of 0^CC to ambient temperature.

When R' or R¹⁰ is chloro, the compound of the formula (I) or (II) may be formed by reacting the hydroxy compound with a chlorinating agent. For example, by reacting the hydroxy compound with sulphinyl chloride in a temperature range of ambient temperature to reflux, optionally in a chlorinated solvent such as dichloromethane or by reacting the hydroxy compound with carbon tetrachloride/triphenyl phosphine in dichloromethane, in a temperature range of 0°C to ambient temperature.

The ( 1 -4C)alkanesulphonyloxy compound may be prepared by reacting the hydroxy compound with (l-4C)alkanesulphonyl chloride in the presence of a mild base such as triethylamine or pyridine. The (l-4C)alkylaminocarbonyloxy compound may be prepared by reacting the hydroxy compound with (l-4C)alkyl cyanate in an organic solvent such as THF or acetonitrile, in the presence of triethylamine, in a temperature range of 0°C to 50°C.

A compound of the formula (I) or (II) wherein R¹ or R¹⁰ is chloro may also be prepared from a compound of the formula (III), by reacting the latter compound with lithium chloride and crown ether, in a suitable organic solvent such as THF. in a temperature range of ambient temperature to reflux. A compound of the formula (I) or (II) wherein R¹ or R¹⁰ is ( 1 - 4C)alkylthio or (l-4C)alkoxy may be prepared by reacting the compound of the formula (III) with sodium thio(l-4C)alkoxide or sodium (l-4C)alkoxide respectively, in an alcohol or THF, in a temperature range of 0°C to reflux. Compounds of the formulae (V) and (VI) are conveniently reacted together in the presence of a strong base such as butyl lithium, lithium bistrirnethylsilylamide, sodium hydride, or lithium diisopropylamide. The reaction is conveniently carried out in an inert solvent such as tetrahydrofuran (THF). dime hylformamide (DMF), N,N'- dimethylpropyleneurea (DMPU) or N-methylpyrrolidone in a temperature range of -78°C to -50°C for the deprotonation and cyclisation. Suitable values for R¹³ include ethyl and benzyl and suitable values for R¹⁴ include ethyl and n-propyl, preferably n-propyl.

A compound of the formula (V) is conveniently prepared by reacting a chloroformate of the formula (C1COOR¹³) with a compound of the formula (VA):

(VA) wherein R², R³ and R⁷-R⁹ are as hereinabove defined. The reaction is conveniently carried out in the presence of an inorganic or organic base such as sodium bicarbonate or an amine base such as dimethylaniline, the former in a solvent such as acetone/water and the latter in an organic solvent such as THF, toluene, DMF or acetonitrile.

A compound of the formula (VA) may be prepared by reducing a compound of the formula (VB):

(VB) wherein R², R³ and R⁷-R⁹ are as hereinabove defined.

Many reduction methods suitable for the reduction of a nitro to an amino group are known in the art. for example catalytic hydrogenation. metal reductions or with reducing agents such as sodium hydrosulphite. Suitable catalysts in catalytic hydrogenation include Raney nickel, platinum metal and its oxide, rhodium, palladium-on-charcoal and Wilkinson^'s catalyst RhCl (Ph,P)₃. Catalyst hydrogenation is conveniently carried out in the temperature range 0°C - 150°C, but preferably at ambient temperature at slightly above atmospheric pressure.

A compound of the formula (VB) is conveniently prepared by reacting together compounds of the formulae (VIII) and (VC):

(VIII) (VC)

wherein R², R³ and R^7"R⁹ are as hereinabove defined and L³ is a leaving group, preferably halo and in particular fluoro.

The reaction between compounds of the formulae (VIII) and (VC) is carried out in the presence of an organic or inorganic base such as sodium bicarbonate, potassium carbonate or an amine base such as diisopropylethylamine, in an inert solvent such as acetonitrile, DMF, DMPU or N-methylpyrroIidone, in a temperature range of 50°C - 150°C.

Compounds of the formula (VIII) may be prepared by introducing substituents into or modifying substituents in a known optionally substituted imidazole ring. Such conversions are well known to the skilled chemist, for example a cyano group may be hydrolysed to a carboxy group which in turn may be converted to a carbamoyl or alkoxycarbonyl group or reduced to a hydroxymethyl group; an amino group may be acylated to an alkanoylamino group; a thio group may be alkylated to an alkylthio group which in turn may be oxidised to an alkylsulphinyl or alkylsulphonyl group and a hydroxyalkyl group may be alkylated to an alkoxyalkyl group.

Alternatively compounds of the formula (VIII) may be prepared using the methods described in Houben-Weyl, Methoden der organischen Chemie, Heterarene III Teil 3. ed E Schaumann (1994), or The Chemistry of Heterocyclic Compounds, Vol 6, Part 1 "Imidazole and its Derivatives" (1953).

The oxidation (dehydrogenation) of a compound of the formula (I) or (II) wherein R5 or R⁸ is azidomethyl may be accomplished by catalytic dehydrogenation (for example, using a Pd/C catalyst) in the presence of a hydrogen-acceptor (for example, 2,5-dimethyl-3- hexyne-2,5-diol) - see Bull.Chem.Soc. Japan, 1976, 49, 506. The reaction is preferably carried out in an inert solvent (for example, ethanol) and at a temperature in the range 50-100 °C. The preparation of the starting materials of the formula (I) or (II) wherein R⁵ or R⁸ is azidomethyl is within the skill of the skilled organic chemist, for example from the corresponding hydroxymethyl compound.

When an optically active form of a compound of the formula (I) is required, it may be obtained, by carrying out one of the above procedures using an optically active starting material or by resolution of a racemic form of the compound or intermediate using a standard procedure.

According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

According to a further feature of the present invention there is provided a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt thereof. The invention also provides the use of a compound of the present invention, or a pharmaceutically-acceptable salt thereof, for use as a medicament; and the use of a compound of the present invention, or a pharmaceutically-acceptable salt thereof, in the manufacture of a novel medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.

In order to use a compound of the formula (I) or a pharmaceutically-acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable diluent or carrier.

The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.

In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain or be co-administered with one or more known drugs selected from other clinically useful antibacterial agents (for example β-lactams or aminoglycosides). These may include penicillins, for example oxacillin or flucloxacillin and carbapenems, for example meropenem or imipenem, to broaden the therapeutic effectiveness against methicillin-resistant staphylococci. Compounds of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein product (BPI) or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.

A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between lOOmg and lg of the compound of this invention.

In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection. Each patient may receive, for example, a daily intravenous, subcutaneous or intramuscular dose of 5 rngkg- to 20 mgkg-I of the compound of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.

Antibacterial Activity The pharmaceutically acceptable compounds of the present invention are useful antibacterial agents having a good spectrum of activity in vitro against standard Gram-positive organisms, which are used to screen for activity against pathogenic bacteria. Notably, the pharmaceutically acceptable compounds of the present invention show activity against enterococci, pneumococci and methicillin resistant strains of S. aureus and coagulase negative staphylococci. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system.

The antibacterial properties of the compounds of the invention may also be demonstrated in vivo in conventional tests.

The following results were obtained on a standard in vitro test system. The activity is described in terms of the minimum inhibitory concentration (MIC) determined by the agar-dilution technique with an inoculum size of 10^ CFU/spot.

The organisms were tested on a standard semi-defined susceptability test medium

(IsoSensitest agar), using an inoculum of 10^ CFU/spot and an incubation temperature of

37°C for 24 hours.

Organism MIC (ug/ml) Example 4 Example 5 Example 6

Staphylococcus aureus:

Oxford 0.5 0.125 0.125 Novb. Res 0.5 0.25 0.25 MRQR 2.0 0.5 4.0 Coagulase Negative Staphylococcus MS 0.25 0.06 0.25

MR 0.5 0.125 0.5 Streptococcus pyogenes

C203 0.5 0.125 0.125 Enterococcus faecalis 1.0 0.25 0.5 Bacillus subtilis 0.5 0.125 0.25

Novb. Res = Novobiocin resistant

MRQR = methicillin resistant quinolone resistant

MR = methicillin resistant

The invention is now illustrated by the following Examples in which unless otherwise stated

i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration; (ii) operations were carried out at ambient temperature, that is in the range 18-26°

(temperatures are in degress Celsius °C) and in air unless otherwise stated, or unless the skilled person would otherwise work under an inert atmosphere;

(iii) column chromatography (by the flash procedure) was performed on Merck Kieselgel silica (Art. 9385) unless otherwise stated; (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) the structures of the end-products of the formula I were confirmed by NMR and mass spectral techniques [proton magnetic resonance spectra were determined in DMSO-D6 unless otherwise stated using a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz, or a Bruker AM250 spectrometer operating at a field strength of 250 MHz; chemical shifts are reported in parts per million downfield from tetramethysilane as an internal standard (δ scale) and peak multiplicities are shown thus: br, broad; s, singlet; d, doublet; dd, doublet of doublets; t, triplet, m, multiplet; fast-atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected];

(vi) intermediates were not generally fully characterised and purity was in general assessed by thin layer chromatographic, infra-red (IR), mass spectral (MS) or NMR analysis; and

(vϋ) in which :-

MPLC is medium pressure chromatography

TLC is thin layer chromatography

DMSO is dimethylsulfoxide

CDC1₃ is deuterated chloroform

MS is mass spectroscopy

ESP is electrospray

CI is chemical ionization

DMF is N,N-dimethylformamide

THF is tetrahydrofuran

Example 1 : (5 ?)-3-(3-Fluoro-4-(imidazol-l-yl)phenyl)-5-hydroxymethyloxazoIidin-2-one l-(4-Benzyloxycarbonylamino-2-fluorophenyl)imidazole (720 mg, 2.31 mM) was dissolved in dry tetrahydrofuran (20 ml) under argon, cooled to -78°, and treated with a solution of n-butyllithium (1.6 M in hexane, 1.6 ml), keeping the temperature below -60°. After stirring for 5 minutes, (Λ)-glycidylbutyrate (0.34 ml, 0.24 mM) was added, and stirring continued at -78° for 30 minutes, before allowing the temperature to rise to ambient over 16 hours. The mixture was diluted with dichloromethane and washed twice with water, then brine. After drying (magnesium sulfate) and evaporation of solvent, the residue was purified by chromatography on silica, eluting with a gradient from 0 to 3% methanol in 9: 1 dichloromethane/acetonitrile. Relevant fractions were combined and evaporated to give the title product (274 mg).

MS (CI): 278 (MH+)

NMR (DMSO-D6) δ: 3.58 (ddd, IH); 3.71 (ddd, IH); 3.90 (dd, IH); 4.13 (t, IH); 4.75 (m, IH); 5.24 (t, IH); 7.1 1 (d, IH); 7.47-7.54 (m, 2H); 7.67 (t, IH); 7.77 (dd, IH); 7.98 (m, IH).

Example 2 : (5R)-3-(3-Fluoro-4-(imidazol-l-yl)phenyl)-5-(4-methylphenylsulfonyl- oxymcthyl)oxazolidin-2-one (5^-3-(3-Fluoro-4-(imidazol-l -yl)phenyl)-5-hydroxymethyloxazolidin-2-one (163 mg, 0.59 mM) was dissolved in pyridine (10 ml) under argon and cooled in an ice-bath. 4-Methyl- phenylsulfonyl chloride (148 mg, 0.88 mM) was added in one portion, and stirring continued at 5° for one hour before allowing the temperature to rise to ambient over 16 hours. The mixture was diluted with iced water, made basic with 2N sodium carbonate, and extracted with ethyl acetate (3 portions). After drying (magnesium sulfate) and evaporation of solvent, the residue was purified by chromatography on silica, eluting with a gradient from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (91 mg). MS (Electrospray): 432 (MH+) NMR (CDCh) δ: 2.45 (s, 3H); 3.96 (dd, IH); 4.13 (t, IH); 4.28 (m, 2H); 4.87 (m. IH); 7.25 (m, 3H); 7.38 (m, 3H); 7.62 (dd, IH); 7.77 (m, 3H). Example 3 : (5R)-Azidomethyl-3-(3-fluoro-4-(imidazol-l-yl)phenyl)oxazolidin-2-one

(5R)-3-(3-Fluoro-4-(imidazol-l-yl)phenyl)-5-(4-methylphenylsulfonyloxymethyl)oxazolidin- 2-one (87 mg, 0.20 mM) was dissolved in dry N,N-dimethylformamide (5 ml), sodium azide (79 mg, 1.21 mM) was added, and the mixture was heated at 75° for 4 hours. The mixture was evaporated to dryness and the residue purified by chromatography on silica, eluting with a gradient from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (43 mg), used without characterisation in the reduction stage above.

Example 4 : N-[(5ι- -3-(3-Fluoro-4-(imidazθ--l-vOphenvO-2-oxooxazolid-n-5- ylmethyljacetamide

(5R)-Azidomethyl-3-(3-fluoro-4-(imidazol-l-yl)phenyl)oxazolidin-2-one (43 mg, 0.14 mM) was dissolved in ethyl acetate (10 ml), and the solution purged with argon. Palladium (10% on carbon, 8 mg) was added, and the mixture stirred at ambient temperature under hydrogen confined in a balloon for 2 hours. Pyridine (0.03 ml, 0.37 mM) and acetic anhydride (0.03 ml, 0.32 mM) were added, and the mixture stirred at ambient temperature for 16 hours. The mixture was filtered through Celite, evaporated to dryness, and purified by chromatography on silica, eluting with a gradient from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (18 mg). MS (Electrospray): 319 (MH⁺)

NMR (DMSO-D6) δ: 1.84 (s, 3H); 3.44 (t, 2H); 3.79 (dd, IH); 4.18 (t, IH); 4.78 (m. I H); 7.12 (d, IH); 7.44 (dm, IH); 7.53 (dd, IH); 7.68 (t, IH); 7.73 (dd, IH); 7.99 (br s, IH); 8.25 (t, IH).

The intermediates for this compound were prepared as follows.

l-(2-Fluoro-4-nitrophenyl^')imidazole

3,4-Difluoronitrobenzene (3.48 ml, 0.031 moles) was dissolved in acetonitrile (100 ml). N,N-diisopropylethylamine (13.7 ml, 0.079 moles), and imidazole (2.35 g, 0.035 moles) added, and the mixture heated to reflux for 16 hours. Solvent was evaporated, and the residue purified by chromatography on silica, eluting with a gradient from 0 to 80% ethyl acetate in hexane. Relevant fractions were combined and evaporated to give the title product (5.8 g), sufficiently pure for use in the next stage. MS (Electrospray): 208 (MH+)

NMR (DMSO-D6) δ: 7.28 (s, IH); 7.37 (dd, IH); 7.63 (dd, IH); 7.97 (br s lH); 8.19, 8.23 (2 x m, 2H).

l-(4-Amino-2-fluorophenvπimidazole l-(2-Fluoro-4-nitrophenyl)imidazole (5.7 g, 0.0275 moles) was dissolved in tetrahydrofuran

(100 ml) and treated with a solution of sodium hydrosulfite (47.9 g, 0.275 moles) in water (200 ml). The mixture was stirred at ambient temperature for 2 hours, cooled in an ice-bath, and carefully neutralised (pH 7) with solid sodium bicarbonate. The aqueous layer was saturated with sodium chloride, and extracted with three portions of dichloromethane. Drying (magnesium sulfate) and evaporation of solvent gave title product as a yellow oil (1.2 g), crystallising on standing. MS (CI): 178 (MH+)

NMR (CDCh) δ: 3.96 (br, 2H); 6.46-6.56 (m, 2H); 7.08-7.15 (m, 3H); 7.68 (d IH).

l-(4-Benzyloxycarbonylamino-2-fluorophenyl)imidazole l-(4-Amino-2-fluorophenyl)imidazole (1.18 g, 0.0067 moles) was dissolved in dry tetrahydrofuran (100 ml) under argon, and cooled to -20°. N.N-Dimethylaniline (1.06 ml.

0.0084 moles) was added, followed by benzyl chloroformate (1.05 ml, 0.0074 moles). The mixture was stirred for 10 minutes at -20°, and the temperature allowed to rise to ambient over 16 hours. The mixture was diluted with ethyl acetate, and washed twice with water, then brine. After drying (magnesium sulfate) and evaporation of solvent, the residue was purified by chromatography on silica, eluting with a gradient from 5 to 15% ethyl acetate in 1 : 1 dichloromethane/hexane. Relevant fractions were combined and evaporated to give the title product (0.73 g). sufficiently pure for use in the next stage.

MS (Electrosprav 312 (MH⁺)

NMR ⁽CDCl3) ^δ: 5.24 (s, 2H); 7.14-7.43 (m, 9H); 7.59 (dd. IH); 7.74 (d, 2H). Example 5 : N-l(5S)-3-(4-(4-Bromoimidazol-l-yl)-3-fluorophenyI)-2-oxooxazolidin-5-yl- methyl|acetamide

(5S)-AzidomethyI-3-(4-(4-bromoimidazol-l-yl)-3-fluorophenyl)oxazolidin-2-one (1 1.8 g) was dissolved in a mixture of acetonitrile (240 ml) and water (24 ml), and stirred at ambient temperature under argon. Triphenylphosphine (16.3 g) was added to give a suspension which slowly dissolved with evolution of nitrogen. Stirring was continue for 60 hours, and solvent removed by evaporation. The residue was partitioned between ethyl acetate (200 ml) and hydrochloric acid (1M, 300 ml). The aqueous layer was separated and washed with ethyl acetate. Further ethyl acetate (200 ml) was added, and the stirred mixture treated cautiously with solid sodium bicarbonate until neutral. A further portion (14 g) of sodium bicarbonate was added, followed by acetic anhydride (4 x 1 ml portions). Stirring was continued for 1 hour, then the mixture concentrated to remove most of the ethyl acetate. The aqueous suspension was shaken with diethyl ether (25 ml), and filtered. The solid was washed with water and a little diethyl ether and dried to give product (1 1.8 g). MS (ES): 397 (MH+) for C₁₅H₁₄BrFN₄O₃

NMR (DMSO-D6 δ: 1.82 (s, 3H); 3.44 (t, 2H); 3.79 (dd, IH); 4.17 (t, IH); 4.77 (m, IH); 7.45 (dm, IH); 7.68 (t, IH); 7.75 (m, 2H); 8.01 (t, IH); 8.22 (t, IH).

The intermediates for this compound were prepared as follows.

4-(4-Bromoimidazol-l-yl)-3-fluoronitrobenzene

3,4-Difluoronitrobenzene (7.9 g) was dissolved in acetonitrile (80 ml), followed by 4- bromoimidazole (7.35 g, see J. Chem. Soc, 1922, 121, 947) and ethyldiisopropylamine (21.7 ml). The mixture was stirred and heated to reflux for 3 days. After cooling, acetonitrile was evaporated, and. the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, then brine, and dried over magnesium sulfate. Evaporation gave crude material (13.5 g) which was recrystallised from ethanol to give a cream solid, mp 155-156° (9.5 g). MS (CI): 286 (MH⁺) for C₉H,BrFN₃O₂

NMR (DMSO-D6) δ: 7.94 (t, IH); 8.07 (dd, IH); 8.25 (m, 2H); 8.45 (dd, IH). 5-Amino-2-(4-bromoimidazol-l-vπfluorobenzene

Stannous chloride dihydrate (34.5 g) was suspended in ethyl acetate (140 ml) and 4-(4- bromoimidazol-l-yl)-3-fluoronitrobenzene (10.9 g) added. The mixture was cautiously heated to boiling, then refluxed 1.5 hours under argon. After cooling in an ice-bath, the mixture was stirred while concentrated aqueous ammonia (30 ml) was added to give a slight excess. The mixture was diluted with further ethyl acetate, filtered through celite, and the residues washed well with ethyl acetate. The combined filtrate and washings were washed twice with water, brine, and dried over magnesium sulfate. Evaporation gave a yellow solid, 9.6 g. MS (CI): 256 (MH⁺) for C₉H₇BrFN,

NMR (DMSO-D6) δ: 5.71, (s, 2H); 6.44 (dd, IH); 6.48 (dd, I H): 7.16 (t, IH); 7.51 (d. lH); 7.78 (d, IH).

5-Benzyloxycarbonylarnino-2-(4-bromoimidazol- 1 -vOfluorobenzene 5-Amino-2-(4-bromoimidazolyl)fluorobenzene_(9.3 g) was dissolved in dry dichloromethane

(150 ml), treated with pyridine (3.67 ml), then stirred under argon while cooling to -20°.

Benzyl chloroformate (5.72 ml) in dichloromethane (20 ml) was added dropwise, keeping temperature down. The mixture was then allowed to warm to ambient temperature overnight, giving a precipitate. The mixture was diluted with 5% aqueous sodium carbonate (200 ml), but the precipitate failed to dissolve. Dichloromethane was mostly evaporated, and the residue diluted with wøhexane. The precipitate was filtered, and filtrate washed with water and isohexane. The dried material was then recrystallised from glacial acetic acid to give a pale yellow solid mp 182-183° (12 g).

MS (ES): 390 (MH⁺) for C₁₇H,₃BrFN₃O, NMR (DMSO-D6) δ: 5.19, (s, 2H); 7.32-7.46 (m, 6H); 7.56 (t, IH); 7.64 (dd, IH); 7 .69

(m, IH); 7.96 (t, IH); 10.24 (s, IH).

(5S)-3-(4-(4-Bromoimidazol-l-yl)-3-fluorophenyl)-5-hvdroxymethyloxazolidin-2-one /-Butanol (2.7 g) and dry tetrahydrofuran (20 ml) were stirred under argon, and cooled to -10°. rt-Butyl lithium (1.6 M in wohexane, 18.3 ml) was added dropwise. the mixture was stirred 10 minutes, then cooled to -70°. A solution of 5-benzyloxycarbonylamino-2-(4-bromoimidazol- l-yl)fluorobenzene (9.5 g) dissolved in dry tetrahydrofuran (125 ml) was added dropwise. After stirring for 30 minutes, a solution of (Λ)-glycidylbutyrate (4.22 g) in dry tetrahydrofuran (10 ml) was added, and stirring continued at -78° for 30 minutes. The temperature was allowed to rise to ambient over 16 hours, then treated with methanol (10 ml), and stirred for 10 minutes. The reaction was diluted with saturated aqueous sodium bicarbonate and extracted twice with tetrahydrofuran (400 ml and 200 ml). Combined organic phases were dried over magnesium sulfate, evaporated, and the residue recrystallised from ethanol. to give product mp 199-200° (6.43 g). MS (ES): 355 (MH+) for C_I3H_πBrFN₃O₃ NMR (DMSO-D6) δ: 3.59 (ddd, IH); 3.71 (ddd, IH); 3.89 (dd, IH); 4.14 (t, IH); 4.76 (m, IH); 5.23 (t, IH); 7.49 (dd, IH); 7.67 (t, IH); 7.74 (t, IH); 7.77 (dd, IH); 8.01 (t, IH).

(5S)-3-(4-(4-Bromoimidazol-l-yl)-3-fluorophenyl)-5-methanesulfonyloxymethyloxazolidin-

2-one (5S)-3-(4-(4-Bromoimidazol-l-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (6.0 g) was dissolved in pyridine (sieve dried, 60ml) with stirring under argon in an ice-bath.

Triethylamine (2.8 ml) was added, followed by dropwise addition of methanesulfonyl chloride (1.43 ml). Stirring was continued for 2 hours as the mixture warmed to ambient temperature. Solvent was evaporated, and the residue stirred vigorously with a mixture of aqueous sodium carbonate (5%, 150 ml) and z^'sohexane (150 ml). The precipitate was filtered, washed well with water and wøhexane, and dried. The solid was taken up in hot acetone, and reprecipitated by addition of wohexane to give pure product, mp 164-165° (6.4 g).

MS (ES): 434 (MH+) for C_l4H₁₃BrFN₃O₅S

NMR (DMSO-D6) δ: 3.25 (s, 3H); 3.88 (dd, IH); 4.25 (t, IH); 4.50 (m, 2H); 5.05 (m, IH); 7.48 (dm, IH); 7.68 (t, IH); 7.71 (m, IH); 7.75 (dd, IH); 8.00 (t, IH).

(5S)-5-AzidomethvI-3-(4-(4-bromoimidazol-l-yl)-3-fluorophenyl)oxazolidin-2-one (5S)-3-(4-(4-Bromoimidazol-l-yl)-3-fluorophenyl)-5-methanesulfonyloxymethyloxazolidin- 2-one (6.2 g) was dissolved in dry N,N-dimethylformamide (75 ml). Sodium azide (1.86 g) was added, and the mixture was heated at 70-80° for 3.5 hours. The mixture was cooled, diluted with water (750 ml) containing sodium bicarbonate (2 g). and extracted with ethyl acetate (2 x 400 ml). Combined organics were washed with water (2 x 150 ml), then brine, and dried over magnesium sulfate. The solution was evaporated to a small volume (-10 ml), and then diluted with wøhexane. Solid was filtered and washed with isohexane to give product (5.2 g). MS (ES): 381 (MH+) for C_I3H₁₀BrFN₆O₂ NMR (DMSO-D6) δ: 3.71 (dd, IH); 3.79 (dd, IH); 3.85 (dd, IH); 4.21 (t, IH); 4.95 ( , IH); 7.50 (dm, IH); 7.69 (t, IH); 7.74 (s, IH); 7.76 (dd, IH); 8.01 (t, IH).

Example 6 : N-[(5S)-3-(4-(4-Cvanoimidazol-l-yl)-3-fluorophenvπ-2-oxooxazolidin-5-yl- methyll acetamide

N-[(5S)-3-(4-(4-Azidomethylimidazol-l-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl- methyl]acetamide (100 mg) was suspended in ethanol (7 ml), 2,5-dimethyl-3-hexyne-2,5-diol (50 mg) and 10% palladium on carbon (50 mg) added. After refluxing 3 hours, the mixture was cooled, and catalyst filtered through celite. The filtrate was evaporated, dissolved in dichloromethane and chromatographed on silica, eluting with a gradient of dichloromethane to ethyl acetate, then ethyl acetate to 10% methanol in ethyl acetate. Relevant fractions were combined and evaporated to give the desired product as a foam (29 mg).

MS (ES): 344 (MH⁺) for C_l6H₁₄FN₃O 3

NMR (DMSO-D6 δ: 1.82 (s, 3H); 3.41 (t, 2H); 3.78 (dd, IH); 4.17 (t, IH); 4.78 (m, IH); 7.48 (dm, IH); 7.72 (t, IH); 7.76 (dd, IH); 8.22 (bit, IH); 8.28 (S, IH); 8.55 (s, IH).

The intermediates for this compound were prepared as follows.

3-Fluoro-4-(4-hydroxymethylimidazol- 1 -vDnitrobenzene 3,4-Difluoronitrobenzene (23.85 g) was dissolved in acetonitrile (180 ml), followed by 4- hydroxymethylimidazole (14.7 g) and ethyldiisopropylamine (65.2 ml). The mixture was stirred and heated to reflux for 2 days. After cooling, acetonitrile was evaporated and the residue was shaken with a mixture of methyl /-butyl ether (200 ml) and water (100 ml), and the solid filtered. After washing with a mixture of methyl /-butyl ether (50 ml) and water (25 ml), the solid was dried in vαcuo at 60° overnight, to give product (26.8 g) mp 157-159°. MS (CI): 237 (MH+) for C₁₀H_gFN₃O₃ NMR (DMSO-D6) δ: 4.57 (d, 2H); 5.18 (t, IH); 7.66 (t, IH); 8.1 1 (t, IH); 8.28 (t, IH); 8.35 (dm, IH); 8. 54 (dd, IH).

3-Fluoro-4-⁽4-/-butyldimethylsilyloxymethylimidazol-l-yl)nitrobenzene 3-Fluoro-4-(4-hydroxymethylimidazol-l-yl)nitrobenzene (26.7 g) and imidazole (15.3 g) were suspended in dry N,N-dimethylformamide (190 ml) and stirred under argon on an ice-bath. /- Butyldimethylsilylchloride (25.5 g) was added in one portion, and stirring continued at ice temperature for 30 minutes, then at ambient temperature overnight. Solvent was evaporated in vacuo at 30°, the residue diluted with water (200 ml) and extracted into ethyl acetate (700 ml). After washing with water (2 x 300 ml), brine, and drying over magnesium sulfate, solvent was evaporated (finally on high vacuum) to give a yellow oil which solidified (39.2 g). This was used in the next stage with no further purification.

NMR (DMSO-D6) δ: 0.00 (s, 6H); 0.82 (s, 9H); 4.55 (s, 2H); 7.44 (m, IH); 7.89 (t, I H); 8.06 (t, IH); 8.14 (dm, IH); 8.33 (dd, IH).

1 -Amino-4-(4-/-butyldimethylsilyloxymethylimidazol- 1 -vDfluorobenzene

3-Fluoro-4-(4-r-butyldimethylsilyloxymethylimidazol-l-yl)nitrobenzene (39.0 g) was dissolved in a mixture of methanol (220 ml) and tetrahydrofuran (890 ml) and stirred under argon in an ice-bath. Ammonium formate (35.2 g) was added, followed by 10% palladium on charcoal (1.6 g), and the mixture allowed to warm to ambient temperature. Stirring was continued for 2 days. TLC showed a trace of remaining starter, so further palladium catalyst (0.5 g) was added, and more ammonium formate (35 g) in portions over 6 hours, before leaving to stir overnight, giving essentially one spot as product. The catalyst was filtered off on celite, the cake washed well with methanol/tetrahydrofuran, and filtrates evaporated to dryness. The residue was partitioned between ethyl acetate (700 ml) and water (200 ml), the organic layers washed with water, brine, and dried over magnesium sulfate. Evaporation gave a yellow oil (36 g), used in the next stage with no further purification. MS (ES): 237 (MH+) for C,₆H₂₄FN₃OSi

NMR (DMSO-D6) δ: 0.04 (s, 6H); 0.85 (s, 9H); 4.56 (s, 2H); 5.63 (s, 2H); 6.45 (dd, IH); 6.48 (dd, IH); 7.12 (t, IH); 7.13 (s, IH); 7.69 (s, IH).

1 -Benzyloxycarbonylamino-4-(4-/-butyldimethylsilyloxymethylimidazol- 1 -vPfluorobenzene l-Amino-4-(4-/-butyldimethylsilyloxymethylimidazol-l-yl)fluorobenzene (36.1 g) was dissolved in dry dichloromethane (450 ml), treated with pyridine (11.3 ml), then stirred under argon while cooling to -20°. Benzyl chloroformate (17.7 ml) in dichloromethane (50 ml) was added dropwise. maintaining the temperature. The mixture was then allowed to warm to ambient temperature over 1 hour, then stirred for a further 1.5 hours. The mixture was diluted with aqueous sodium bicarbonate (250 ml), and the organic layer separated. A further extraction with dichloromethane (200 ml) was made, the combined organic layers dried over magnesium sulfate, and solvent evaporated. The resulting oil was re-evaporated with toluene, and purified by chromatography on silica (500 g) in a sinter column, eluting with a gradient from CH₂C1₂ to 50% EtOAc in CH₂C1₂. Evaporation, then re-evaporation with toluene gave solid product (51 g).

MS (ES): 456 (MH⁺) for C₂₄H₃₀FN₃O₃Si

NMR (DMSO-D6) δ: 0.00 (s, 6H); 0.77 (s, 9H); 4.53 (s, 2H); 5.11 (s, 2H); 7.24-7.40 (complex, 7H); 7.46 (t, IH); 7.53 (dd, IH); 7.79 (s, IH); 10.10 (s, IH).

(5S)-3-(4-(4-/-Butyldimethylsilyloxymethylimidazol-l-yI)-3-fluorophenyl)-5-hvdroxy- methyloxazolidin-2-one

/-Butanol (6.1 g) in dry tetrahydrofuran (50 ml) was stirred under argon at -10°. n-Butyllithium in wohexane (1.6M, 41.3 ml) was added dropwise, the mixture stirred for 10 minutes, then cooled to -70° . A solution of 1 -benzyloxycarbonylamino-4-(4-/- butyldimethylsilyloxymethylimidazol-l-yl)fluorobenzene (25.0 g) in dry tetrahydrofuran (150 ml) was added dropwise over 20 minutes, then stirred for 20 minutes at -70° . (. ?)-glycidylbutyrate (9.5 g) in tetrahydrofuran (10 ml) was added dropwise over 10 minutes, keeping the temperature below -60°. Stirring was continued overnight, allowing the temperature to rise to ambient. Saturated sodium bicarbonate solution (200 ml) was added, and the mixture extracted with ethyl acetate (500 and 200 ml). After drying over magnesium sulfate and evaporation the residue was purified by chromatography on silica, eluting with a gradient from dichloromethane to 20% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give a gum (20.5 g). MS (ES): 422 (MH⁺) for C₂₀H₂₈FN₃O₄Si NMR (DMSO-D6) δ: 0.02 (s, 6H); 0.81 (s, 9H); 3.49 (brd, IH); 3.63 (brd, IH); 3.80 (dd, IH); 4.06 (t, IH); 4.55 (s, 2H); 4.68 (s, IH); 5.14 (brs, IH); 7.30 (s, IH); 7.41 (dm, IH); 7.58 (t, IH); 7.68 (dd, IH); 7.85 (t, IH).

(5S)-3-(4-(4-/-Butyldimethylsilyloxymethylimidazol-l-yl)-3-fluorophenyl)-5-methane- sulfonyloxymethyloxazolidin-2-one

(5S)-3-(4-(4-/-Butyldimethylsilyloxymethylimidazol-l-yl)-3-fluoro-phenyl)-5-hydroxy- methyloxazolidin-2-one (8.0 g) was dissolved in dry dichloromethane (60ml) with stirring under argon in an ice-bath. Triethylamine (3.44 ml) was added, followed by dropwise addition of methanesulfonyl chloride (1.62 ml). Stirring was continued for 2 hours as the mixture warmed to ambient temperature. Aqueous sodium bicarbonate was added, the organic layer separated, and further extracted with dichloromethane. Combined extracts were dried over magnesium sulfate. Evaporation gave a gum (9.4 g), which was dried under high vacuum, and used as such in the next stage. NMR (DMSO-D6) δ: 0.07 (s, 6H); 0.88 (s, 9H); 3.46 (s, 3H); 3.88 (dd, IH); 4.25 (t, IH); 4.49 (m, 2H); 4.61 (s, 2H); 5.06 (m. IH); 7.36 (s, IH); 7.46 (dm, IH); 7.67 (t, IH); 7.84 (dd, IH); 7.94 (t, IH).

(5S)-5-Azidomethyl-3-(4-(4-/-butyldimethylsilyloxymethylimidazol-l-yl)-3-fluorophenyl)- oxazolidin-2-one

(5S)-3-(4-(4-/-Butyldimethylsilyloxymethylimidazol-l -yl)-3-fluorophenyl)-5-methane- sulfonyloxymethyloxazolidin-2-one (13.6 g) was dissolved in dry N,N-dimethylformamide (1 10 ml). Sodium azide (3.53 g) was added, and the mixture was heated at 80° for 3.5 hours. The mixture was cooled, diluted with water (1.1 L) containing sodium bicarbonate (2 g), and extracted with ethyl acetate (2 x 800 ml). Combined organics were washed with water (2 x 300 ml), then brine, and dried over magnesium sulfate. The solution was evaporated to a small volume (-100 ml), and insolubles filtered. The ethyl acetate soluble material was columned on silica (100 g), eluting with ethyl acetate. Product fractions were combined and evaporated to give a gum (10.0 g). MS (ES): 447 (MH⁺) for C₂₀H₂₇FN₆O,Si NMR (DMSO-D6) δ: 0.08 (s, 6H); 0.87 (s, 9H); 3.71 (dd, IH); 3.79 (dd, IH); 3.84 (dd, IH); 4.20 (t, IH); 4.61 (s, 2H); 4.93 (m, IH); 7.36 (s, IH); 7.46 (dm, IH); 7.65 (t, IH); 7.75 (dd, IH); 7.93 (t, IH).

N-[(5S)-3-(4-(4-/-Butyldimethylsilyloxymethylimidazol-l-yl)-3-fluorophenyl)-2- oxooxazolidin-5-ylmethyl^~|acetamide

To (5S)-5-azidomethyl-3-(4-(4-/-butyldimethylsilyloxymethylimidazol-l-yl)-3-fluorophenyl)- oxazolidin-2-one(10.0 g) in ethyl acetate (560 ml) was added triethylamine (13.3 ml), acetic anhydride (4.5 ml), and palladium catalyst (10% on charcoal, 1.5 g), and the mixture hydrogenated at ambient temperature for 17 hours. The mixture was filtered through celite, the celite washed well with ethyl acetate, and the organic layer stirred with a saturated solution of sodium bicarbonate (100 ml) at ambient temperature for 1 hour. The organic layer was separated, dried over magnesium sulfate, and evaporated. Crude product ( 15 g, from two batches) was dissolved in dichloromethane and chromatographed on silica, eluting with a gradient from dichloromethane (100%) to 10% methanol in dichloromethane. Product fractions were combined to give a gum (12.3 g). MS (ES): 462 (MH+) for C₂₂H₃,FN₄O₄Si

NMR (DMSO-D6) δ: 0.00 (s, 6H); 0.81 (s, 9H); 1.77 (s, 3H); 3.36 (t, 2H); 3.71 (dd, IH); 4.08 (t, IH); 4.54 (s, 2H); 4.77 (m, IH); 7.29 (s, IH); 7.38 (dm, IH); 7.59 (t, IH); 7.64 (dd, IH): 7.87 (t, IH); 8.18 (bit, IH).

N-|^"(5S)-3-(3-Fluoro-4-(4-hvdroxymethylimidazol-l-yl)phenyl)-2-oxooxazolidin-5-yl- methyllacetamide

N-[(5S)-3-(4-(4-/-Butyldimethylsilyloxymethylimidazol-l-yl)-3-fluorophenyl)-2- oxooxazolidin-5-ylmethyl]acetamide (6.0 g) was dissolved in a mixture of acetic acid (60 ml), tetrahydrofuran (20 ml) and water (20 ml), and left to stir overnight at ambient temperature.

Solvents were evporated at 40° in vacuo to give a gum. This was dissolved in dichloromethane (25 ml), and dry diethyl ether (100 ml) stirred in. The precipitate was triturated and stirred until properly solid, then filtered, washed with ether, and dried in vacuo to give product (3.7 g).

MS (ES): 349 (MH+) for C₁₆H_]7FN₄0₄ NMR (DMSQ-D6 δ: 1.84 (s, 3H); 3.37 (t, 2H); 3.78 (dd, IH); 4.16 (t, IH); 4.39 (s, 2H);

4.77 (m, IH); 4.97 (brs, IH); 7.34 (s, IH); 7.45 (dm, IH); 7.66 (t, IH); 7.71 (dd, IH); 7.91 (t, IH); 8.22 (brt, IH).

N-[^"(5S)-3-(4-(4-Azidomethylimidazol-l -yl)-3-fluorophenvI)-2-oxooxazolidin-5-yl- methyl^"|acetamide

N-[(5S)-3-(3-Fluoro-4-(4-hydroxymethylimidazol-l-yl)phenyl)-2-oxooxazolidin-5-yl- methyl]acetamide (1.74 g) was suspended in dry dichloromethane (60 ml), diphenyl- phosphoryl azide (2.47 g) and l,8-diazabicyclo[5.4.0]undec-7-ene (1.82 g) were added. The mixture was stirred at ambient temperature for 40 hours, the volume reduced, and the solution chromatographed on silica, eluting with a gradient from dichloromethane to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product as a foam (1.76 g). MS (ES): 373 (MH+) for C₁₆H₁₆FN₇O₃ NMR (DMSO-D6 δ: 1.84 (s, 3H); 3.42 (t, 2H); 3.78 (dd, IH); 4.18 (t, IH); 4.34 (s, 2H);

4.78 (m, IH); 7.25 (dm, IH); 7.59 (s, IH); 7.69 (t, IH); 7.75 (dd, IH); 8.03 (t, IH); 8.23 (brt, IH).

Example 7 : The following illustrate representative pharmaceutical dosage forms containing the compound of Example 1 or 2, or a pharmaceutically-acceptable salt thereof (hereafter compound X). for therapeutic or prophylactic use in humans:

(a) Tablet I mg/tablet Compound X 100

Lactose Ph.Eur 179

Croscarmellose sodium 12

Polyvinylpyrrolidone 6

Magnesium stearate 3 (b) Tablet II me/tablet

Compound X 50

Lactose Ph.Eur 229

Croscarmellose sodium 12

Polyvinylpyrrolidone 6

Magnesium stearate 3

(c) Tablet III mg/tablet Compound X 1

Lactose Ph.Eur 92

Croscarmellose sodium 4

Polyvinylpyrrolidone 2

Magnesium stearate 1

(d) Capsule mg/capsule

Compound X 10

Lactose Ph.Eur 389

Croscarmellose sodium 100 Magnesium stearate 1

(e) Injection I (50 mg/ml)

Compound X 5.0% w/v

Isotonic aqueous solution to 100%

Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl β cyclodextrin may be used to aid formulation. Note The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

IS70149

10FEB97: IGB/KEB

Claims

1. A compound of the formula (I):

(I) wherein:

R¹ is hydroxy, chloro, fluoro, (l-4C)alkanesulphonyloxy, amino, azido, (l-4C)alkoxy, (l-4C)alkylthio, (l-4C)alkylaminocarbonyloxy, or of the formula -NHC(=O) R^a wherein R^a is hydrogen, (l-4C)alkoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino, dimethylamino or (l-4C)alkyl or R¹ is of the formula -N(Me)C(=O)R^b wherein R^b is hydrogen, methyl or methoxy or R' is of the formula -NHS(O)_n(l-4C)alkyl wherein n is 0, 1 or 2; R² and R³ are independently hydrogen or fluoro; R⁴, R⁵ and R⁶ are independently selected from hydrogen, (l-4C)alkyl, (optionally substituted by trifiuoromethyl, (l-4C)alkyl S(O)_n- (wherein n is 0, 1 or 2), (l-4C)alkoxy, carboxy, (l-4C)alkoxycarbonyl, carbamoyl, N-(l-4C)alkylcarbamoyl, di(N-(l-4C)alkyl)carbamoyl, cyano, nitro, amino, N-(l-4C)alkylamino, di(N-(l-4C)alkyl)amino or (l-4C)alkanoylamino), halo, trifiuoromethyl, (l-4C)alkyl S(O)_n (wherein n is 0, 1 or 2), carboxy, (l -4C)alkoxycarbonyl, carbamoyl, N-(l-4C)alkylcarbamoyl, di{N-(l-4C)alkyl)carbamoyl, (2- 4C)alkenyl (optionally substituted by carboxy or (l-4C)alkoxycarbonyl), cyano or nitro; and pharmaceutically acceptable salts thereof.

2. A compound of the formula (I), as claimed in claim 1 , in which R' is of the formula -NHC(=O)Ra wherein R^a is hydrogen or (l-4C)alkyl, R² and R3 are independently hydrogen or fluoro, R⁴ and R⁶ are hydrogen and R5 is cyano or halo; and pharmaceutically- acceptable salts thereof.

3. A compound of the formula (I), as claimed in claims 1 and 2, in which R' is acetamido, one of R2 and R3 is hydrogen and the other is fluoro, R⁴ and R6 are hydrogen and R5 is cyano or halo; and pharmaceutically-acceptable salts thereof.

4. The compound N-[(5S)-3-(4-(4-bromoimidazol-l-yl)-3-fluorophenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide; and pharmaceutically-acceptable salts thereof.

5. The compound N-[(5S)-(3-(4-(4-cyanoimidazol-l-yl)-3-fluorophenyl)-2-oxooxazolidin-5-ylmethyl]- acetamide; and pharmaceutically-acceptable salts thereof.

6. A process for the preparation of a compound selected from claims 4 and 5, which comprises :-

(a) the deprotection of a compound of the formula (II); (b) the modification of a substituent in or the introduction of a substituent into another compound of the formula (I) or (II);

(II)

(c) when R¹ or R¹⁰ is of the formula -NHC(=O)R^a, the introduction of -C(=O)R^a (wherein Ra is methyl) into a compound of the formula (I) or (II) wherein R' or R'°is amino;

(d) when R5 is cyano the oxidation (dehydrogenation) of a compound of the formula (I) or (II) wherein R5 or R⁸ is azidomethyl; wherein R² and R³ are as hereinabove defined, R⁷ is R⁴ or protected R⁴, R⁸ is R⁵ or protected R⁵, R⁹ is R⁶ or protected R⁶ and R¹⁰ is R¹ or protected R¹ and thereafter if necessary: