5-(ACETAMIDOMETHYL)-3-ARYLDIHYDROFURAN-2-ONE AND TETRAHYDROFURAN-2-ONE DERIVATIVES WITH ANTIBIOTIC ACTIVITY

Abstract: The invention concerns a compound of formula (I) wherein: -A-B- is of the formula >C=CH- or >CHCH2-; R<1> and R<2> are independently hydrogen or fluorine; R<3> and R<4> are independently hydrogen or methyl; D is O, S, SO, SO2 or of the formula R<5>N wherein R<5> is hydrogen or benzyl; or R<5> is of the formula R<6>CO-, or R<6>SO2- wherein R<6> is, for example, amino, or R<6> is of the formula R<7>C(O)O(1-6C)alkyl wherein R<7> is, for example, optionally substituted phenyl or optionally substituted (1-6C)alkyl, or R<6> is of the formula R<8>O-, wherein R<8> is benzyl or optionally substituted (1-6C)alkyl; or R<5> is of the formula R<10>CH(R<9>)(CH2)m- wherein m is 0 or 1, R<9> is, for example, fluoro and R<10> is hydrogen or (1-4C)alkyl; and pharmaceutically-acceptable salts thereof; processes for their preparation; pharmaceutical compositions containing them and their use as antibacterial agents.

Description: 5-(ACETAMID0METHYL)-3-ARYLDIHYDR0FURA -2-0NE AND TETRAHYDR0FURAN-2-0NE DERIVATIVES WITH ANTIBIOTIC ACTIVITY The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing a furanone 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 of 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 ofthe 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 a furanone ring which have 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 Beta-lactams. We have now discovered a class of compounds that is not suggested by the art and which has good activity against a broad range of Gram-positive pathogens including organisms known to be resistant to most commonly used antibiotics. The compounds also possess a particularly favourable toxicological profile. Accordingly the present invention provides a compound of the formula (I): (I) wherein: -A-B- is ofthe formula >C=CH- or >CHCH 2 - R! and R^ are independently hydrogen or fluorine; R3 and R^ are independently hydrogen or methyl; D is O, S, SO, SO 2 or of the formula R^N wherein R^ is hydrogen or benzyl; or R^ is of the formula R 6 CO- or R 6 SO wherein R 6 is amino, (l -4C)alkylamino, di-((l-4C)alkyl)- amino or (l-6C)alkyl optionally substituted by hydroxy, cyano, amino, ( 1 -4C)alkylamino, di-((l-4C)alkyl)amino. or (l -4C)alkylS(O) n ., wherein n is 1 or 2, or R > is ofthe formula R^C(O)O(l-6C)alkyl wherein R? is optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl or optionally substituted (l-όC)alkyl, or R*> is of the formula R^O-, wherein R^ is benzyl or optionally substituted (l -6C)alkyI; or R^ is of the formula R 10 CH(R 9 XCH2) m - wherein is 0 or 1. R 9 is fluoro. cyano. ( 1 -4C)alkoxy, (l-4C)alkyl- sulfonyl, (l-4C)alkoxycarbonyl or hydroxy, (provided that when m is 0, R 9 is not hydroxy) and RlO is hydrogen or (l-4C)alkyl; and pharmaceutically-acceptable salts thereof. In this specification "heteroaryl" means a 5- or 6-membered aryl ring wherein 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulfur. In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain versions only. An analogous convention applies to other generic terms, for example amino(l-4C)alkyl includes 1 -aminoethyl and 2-aminoethyl. Particular optional substituents for carbon atoms in 5- or 6- membered heteroaryl, phenyl and (l-6C)alkyl in R? include, halo, nitro, amino, hydroxy, cyano, (l-4C)alkyl, (1- 4C)alkoxy and (l-4C)alkylS(O) n (wherein n is 1 or 2). Particular optional substituents for nitrogen atoms which can be substituted without becoming quatemised in 5- or 6- membered heteroaryl rings in R? include (1- 4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and ( 1 -4C)alkanoyl. It will be observed that the compounds ofthe present invention have a chiral centre at the C5-position. The 5(R) enantiomer, as shown in formula (IA), is the pharmaceutically-active enantiomer. (IA) The present invention includes the pure 5(R) enantiomer or diastereoisomer and mixtures ofthe 5(R) and 5(S) enantiomers or diastereoisomers, for example a racemic mixture or equal mixtures of diastereoisomers. If a mixture of 5(R) and 5(S) is used, a larger amount (depending on the ratio of the enantiomers or diastereoisomers) will be required to achieve the same effects as the same weight ofthe 5(R) compound. When -A-B- is of the formula >CHCH2- (i.e. when the ring is a 3.4- dihyrofuranone ring) there is also a chiral centre at the 3-position. The present invention relates to both the 3R and the 3S diastereoisomers. Furthermore, some compounds of the formula (I) may have other chiral centres. It is to be understood that certain compounds ofthe formula I can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess antibacterial activity. Suitable values for generic radicals referred to above and hereinafter include those set out below; for (l-6C)alkyl : methyl, ethyl, propyl, isopropyl and tert-butyl: for (l-4C)alkoxy : methoxy. ethoxy, propoxy and tert- butoxy; for (l-4C)alkylS(O)n- methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl; for (l-4C)alkylsulfonyl : methylsulfonyl and ethylsulfonyl; for (l-4C)alkylamino : methylamino and ethylamino; for di-((l-4C)alkyI)amino dimethylamino, N-ethyl-H-methylamino and diethylamino; for (l-6)alkanoyl : formyl. acetyl and propionyl; for ( 1 -4C)alkoxycarbonyl : methoxycarbonyl, ethoxycarbonyl and propoxy carbonyl; for amino( 1 -6C)alkanoyl : aminoacetyl and aminopropionyl; for (l-4C)alkylamino(l-6C)alkanoyl : methylaminoacetyl, methylaminopropionyl and ethylaminoacetyl; for di-(( 1 -4C)alkyl)amino( 1 -6C)alkanoyl dimethylaminoacetyl and dimethylaminopropionyl; for hydroxy(l-6C)alkyl : hydroxymethyl, 1 -hydroxethyl, 2-hydroxyethyl and 3-hydroxypropyl; for amino(l-6C)alkyl : aminomethyl. 1 -aminoethyl, 2-aminoethyl and 3-aminopropyl; for ( 1 -4C)alkylamino( 1 -6C)alkyl : methylaminomethyl and ethylaminomethyl; and for di-(( 1 -2)alkyl)- amino(l-6C)alkyl : dimethylaminomethyl and diethylaminomethy 1. Suitable pharmaceutically-acceptable salts include acid addition salts such as hydrochloride, hydrobromide. citrate, maleate. methanesulfonate. fumarate and salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as sodium, an alkaline earth metal salt for example calcium or magnesium, an ammonium or tetra-(2-hydroxyethyl)ammonium salt, an organic amide salt for example triethylamine, morpholine, M-methylpiperidine, H-ethylpiperidine, procaine, dibenzylamine, M-N-dibenzylethylamine or amino acids for example lysine. There may be more than one or more cation or anion depending on the number of charged functions and the valency ofthe cations or anions. A preferred pharmaceutically-acceptable salt is the sodium salt. However, to facilitate isolation ofthe salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not. The compounds ofthe 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 ofthe formula (I). Examples of pro-drugs include in-vivo hydrolysable esters of a compound ofthe formula (I). An in-vivo hydrolysable ester of a compound ofthe 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-6C)alkoxymethyl esters, for example methoxymethyl; (l-6C)alkanoyloxymethyl esters, for example pivaloyloxymethyl; phthalidyl esters; (3-8C)cycloalkylcarbonyloxy-(l -6C)alkyl esters, for example 1- cyclohexylcarbonyloxyethyl; 1.3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3- dioxolen-2-onylmethyl; and ( 1 -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 ofthe formula (I) containing a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent alcohol. The term includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result ofthe in-vivo hydrolysis ofthe ester breakdown to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropiony loxy methoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyi, phenylacetyl, and substituted benzoyi and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-M-alkylcarbamoyl (to give carbamates). dialkylaminoacetyl and carboxy acetyl. Preferred compounds ofthe invention comprise a compound ofthe formula (I), or a pharmaceutically-acceptable salt thereof, wherein the substituents D, -A-B-, R , R , R and R have the values disclosed hereinbefore or have any ofthe following values : a) -A-B- is of the formula >C=CH2 b) at least one of R^ and R^ is fluorine. c) R3 and R^ are hydrogen. d) D is O, S or of the formula R 5 N wherein R 5 is of the formula R 6 CO- or R 6 SO 2 -. Most preferably D is S or of the formula R^N wherein R^ is of the formula R^SO 2 -, wherein R^ is methyl. e) optional substituents for phenyl in Rl are amino, ( 1 -4C)alkylamino, di(( 1 - 4C)alkyl)amino, amino(l-6C)alkanoyl, (l-4C)alkylamino(l-6C)alkanoyl, di((l- 2C)alkyl)(l-6C)alkanoyl, hydroxy (l-6C)alkyl, amino( 1 -6C)alkyl, (l-4C)alkylamino(l- 6C)alkyl and di((l-2C)alkyl)amino(l-6C)alkyl. f) optional substituents for phenyl in R^ are ( 1 -4C)alkylamino( 1 -6C)alkanoyl and hydroxy (l-6C)alkyl. g) optional substituents for ( 1 -6C)alkyl in R? are hydroxy, cyano. amino. ( 1 - 4C)alkylamino, di((l-4C)alkyl)amino. ( l-4C)alkyl S(O) n (wherein n is 1 or 2). carboxy, (l-4C)alkoxycarbonyl. (l-4C)alkoxy, piperazino and mo holino. h) optional substituents for ( 1 -6C)alky 1 in R are hydroxy, cyano and ( 1 -4C)alkoxy . i) optional substituents for (l-όC)alkyl in R^ are hydroxy, (l-4C)alkoxy, cyano, amino. (l-4C)alkylamino, di((l-2C)alkyl)amino and (l-4C)alkylS(O) n (wherein n is 1 or 2). j) optional substituents for (l-6C)alkyl in R** are hydroxy, (l-4C)alkoxy and cyano. k) 5- or 6-membered heteroaryl rings in R? are unsubstituted. 1) 5- or 6-membered heteroaryl in R? is pyridyl or imidazol-1-yl. m) R 6 is hydroxymethyl or of the formula R 7 C(O)OCH2- n) R is dimethy lamino(l-6C)alkyl. o) R 7 is dimethylaminomethyl. p) R^ is (l-6C)alkyl. Most preferably R^ is methyl. q) R 9 is cyano or fluoro. r) RlO is hydrogen. Therefore, in another aspect ofthe invention preferred compounds ofthe invention comprise a compound ofthe formula (I) wherein : a) -A-B- is of the formula >C=CH- or >CHCH 2 -; R* and R^ are independently hydrogen or fluorine; R3 and R^ are independently hydrogen or methyl; D is O, S, SO, SO 2 or ofthe formula R^N wherein R^ is benzyl; or R^ is ofthe formula R 6 CO- or R 6 SO 2 - wherein R 6 is amino, ( 1 -4C)alkylamino. di-(( 1 -4C)alkyl)-amino or ( 1 - 6C)alkyl optionally substituted by hydroxy, cyano, amino, (l-4C)alky lamino, di-((l- 4C)alkyl)amino, or (l-4C)alkylS(O) n _, wherein n is 1 or 2. or R^ is of he formula R 7 C(O)O(l-6C)alkyl wherein R? is optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl or optionally substituted (l-6C)alkyl, or R^ is ofthe formula R^O-. wherein R^ is benzyl or optionally substituted (l-6C)alkyl; or R^ is ofthe formula R 10 CH(R 9 )(CH2) m - wherein m is 0 or 1. R 9 is fluoro. cyano. ( 1 -4C)alkoxy, ( 1 -4C)alkyl- sulfonyl, (l-4C)alkoxycarbonyl or hydroxy, (provided that when m is 0, R 9 is not hydroxy) and RlO is hydrogen or (l-4C)alkyl; and pharmaceutically-acceptable salts thereof; or b) -A-B- is of the formula >C=CH- ; Rl and R^ are independently hydrogen or fluorine: R3 and R^ are independently hydrogen or methyl; D is O, S, SO, SO 2 or ofthe formula R 5 N wherein R 5 is benzyl; or R 5 is ofthe formula R^CO- or R 6 SO 2 - wherein R 6 is amino, (l-4C)alkylamino, di-((l-4C)alkyl)-amino or (1- 6C)alkyl optionally substituted by hydroxy, cyano. amino, (l-4C)alkylamino, di-((l- 4C)alkyl)amino, or (l-4C)alkylS(O) n _. wherein n is 1 or 2, or R 6 is ofthe formula R 7 C(O)O(l-6C)alkyl wherein R 7 is optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl or optionally substituted (l-6C)alkyl, or R > is ofthe formula R**O-, wherein R** is benzyl or optionally substituted (l-6C)alkyl; or R^ is ofthe formula RlOCH(R 9 )(CH2) m - wherein m is 0 or 1, R 9 is fluoro, cyano, (l-4C)alkoxy, (l-4C)alkyl- sulfonyl, (l-4C)alkoxycarbonyl or hydroxy, (provided that when m is 0, R 9 is not hydroxy) and Rl" is hydrogen or (l-4C)alkyl; and pharmaceutically-acceptable salts thereof; or c) -A-B- is ofthe formula >C=CH- ; Rl and R^ are independently hydrogen or fluorine; R3 and R^ are hydrogen; D is O, S, or ofthe formula R^N wherein R^ is benzyl, or R^ is of the formula R^CO- or R 6 SO 2 - wherein R 6 is amino, (l-4C)alkylamino, di-((l-4C)alkyl)-amino or (l-6C)alkyl optionally substituted by hydroxy, cyano, amino, (l-4C)alkylamino, di-((l- 4C)alkyl)amino, or (l-4C)alkylS(O) n _, wherein n is 1 or 2, or R^ is ofthe formula R 7 C(O)O(l-6C)alkyl wherein R 7 is pyridyl or imidazol-1-yl, phenyl optionally substituted by ( 1 -4C)alkylamino( 1 -6C)alkanoyl and hydroxy( 1 -6C)alkyl; or ( 1 -6C)alkyl optionally substituted by hydroxy, cyano and (l-4C)alkoxy; or R^ is ofthe formula R O-, wherein R8 is benzyl or (l-6C)alkyl optionally substituted by hydroxy, (l-4C)alkoxy and cyano; or R5 is ofthe formula R^CH(R 9 )(CH2) m - wherein m is 0 or 1, R 9 is fluoro or cyano and RlO is hydrogen; and pharmaceutically-acceptable salts thereof; or d) -A-B- is of the formula >C=CH- Rl and R^ are independently hydrogen or fluorine: R and R^ are hydrogen; D is O, S, or ofthe formula R 5 N wherein R 5 is of the formula R 6 CO- or R 6 SO 2 - wherein R 6 is hydroxymethyl or of the formula R 7 C(O)O(l-6C)alkyl wherein R 7 is dimethylamino(l-6C)alkyl: or R<> is of the formula R^O-, wherein R^ is (l-6C)alkyl; or R^ is ofthe formula Rl υ CH(R 9 )(CH2) m - wherein m is 0 or 1. R 9 is fluoro or cyano and R ® is hydrogen; and pharmaceutically-acceptable salts thereof; or e) -A-B- is ofthe formula >C=CH- ; Rl and R^ are independently hydrogen or fluorine; R3 and R^ are hydrogen; D is S, or ofthe formula R^N wherein R^ is ofthe formula R^SO 2 - wherein R*> is (1- 6C)alkyl; and pharmaceutically-acceptable salts thereof. Particular compounds ofthe present invention are: 5R-acetamidomethyl-3-(3-fluoro-4-thiomoφholinophenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-thiomoφholinophenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-thiomoφholinophenyl)furan-2(5H)-one; 5R-acetamidomethy 1-3 -(4-thiomoφhol inopheny 1 )dihydrofuran-2(3 H)-one ; 5R-acetamidomethyl-3-(3.5-difluoro-4-thiomoφholinophenyl)dihydro-furan-2(3H)-one; 5R-acetamidomethyl-3-(3,5-difluoro-4-thiomoφholinophenyl)furan-2(5H)- one; 5R-acetamidomethyl-3-(3-fluoro-4-{ l-oxothiomoφholino}phenyl)dihydrofuran-2(3H)- one; 5R-acetamidomethyl-3-(3-fluoro-4-{ l,l-dioxothiomoφholino}phenyl)dihydrofuran- 2(3H)-one; 5R-acetamidomethyl-3-(4-moφholinophenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-moφholinophenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3,5-difluoro-4-moφholinophenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{ 1-oxothiomoφholino} pheny l)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{ l,l-dioxothiomoφholino}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-moφholinophenyl)furan-2(5H)-one: 5R-acetamidomethyl-3-(3-fluoro-4-moφholinophenyl)furan-2(5H)-one: 5R-acetamidomethyl-3-(3-fluoro-4-piperazinophenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-piperazinophenyl)furan-2(5H)-one: 5R-acetamidomethyl-3-(3,5-difluoro-4-moφholinophenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-methoxycarbonylpiperazin-l- yl}phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(3,5-difluoro-4-{4-methoxycarbonylpiperazin-l- yl}phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(4- {4-methoxycarbonylpiperazin- 1-yl} pheny l)furan- 2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-methoxycarbonylpiperazin- 1 - yl }phenyl)- dihydrofuran-2(3 H)-one ; 5R-acetamidomethyl-3-(3,5-difluoro-4-{4-methoxycarbonylpiperazin-l- yl}phenyl)- dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(4-{4-methoxycarbonylpiperazin- 1-yl} pheny 1)- dihydrofuran-2(3 H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-cyanomethylpiperazin-l- yl}phenyl)- dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-cyanoethyl)piperazin-l-yl}phenyl)dihydrofuran- 2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-methoxycarbonylethyl)piperazin- l-yl}phenyl)- dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-hydroxyethyl)piperazin-l-yl}phenyl)- dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-methoxyethyl)piperazin-l-yl}phenyl)- dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4- {4-acetylpiperazin- 1 -y 1 } pheny 1)- dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-methanesulfmylpiperazin- 1 -yl } phenyl)- dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-methanesulfonylpiperazin-l-yl}phenyl)- dihy drofuran-2(3 H)-one ; 5R-acetamidomethyl-3-(3-fluoro-4- {4-benzoylpiperazin- 1 -y 1 } phenyl)- dihydrofuran-2(3 H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-fluoroethyl)piperazin-l-yl}phenyl)- dihydrofuran-2(3 H)-one ; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(hydroxyacetyl)piperazin-l-yl}phenyl)- dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(3-hydroxypropionyl)piperazin-l-yl}phenyl)- dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3,5-difluoro-4-{4-(hydroxyacetyl)piperazin- 1 -yl }phenyl)- dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(4- { 4-(hydroxyacety l)piperazin- 1 -yl } pheny 1)- dihydrofuran-2(3 H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(4-dimethylaminobenzoyloxymethylcarbonyl)- piperazin- 1 -yl }phenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(4-dimethylaminobenzoyloxymethylcarbonyl)- piperazin-l-yl}phenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(4-{4-benzylpiperazin-l-yl}phenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4- {4-benzylpiperazin- 1 -yl }phenyl)- dihydrofuran-2(3 H)-one ; 5R-acetamidomethy l-3-(4- { 4-benzy loxycarbony lpiperazin- 1 -y 1 } phenyl)- dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(3-pyridylcarbonyloxymethylcarbonyl)- piperazin-1 -yl}phenyl)dihydrofuran-2(3H)-one; 5 R-acetamidomethy 1-3 -(3 -fluoro-4- { 4-(2- { ethoxy } ethoxycarbony loxy- methylcarbonyl)piperazin- 1 -yl } pheny l)dihydrofuran-2(3 H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-{dimethylamino}ethylcarbonyloxymethyl- carbonyl)piperazin-l-yl}phenyI)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-{moφholino}ethylcarbonyloxymethylcarbonyl)- piperazin-l-yl}phenyl)dihydrofuran-2(3H)-one: 5R-acetamidomethyl-3-(3-fluoro-4-{moφholinomethylcarbonyloxymethylcarbonyl- piperazin- 1 -yl } phenyl)dihydrofuran-2(3 H)-one: 5R-acetamidomethyl-3-(3-fluoro-4-{4-(acetoxymethylcarbonyl)piperazin-l-yl}phenyl)- dihydrofuran-2(3 H)-one ; 5R-acetamidomethyl-3-(3-fluoro-4-{ 4-(dimethylaminomethylcarbonyl)piperazin- 1 -yl } - pheny l)-dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-{carboxy}ethylcarbonyloxymethylcarbonyl)- piperazin- 1 -yl}phenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-{methoxycarbonyl}ethylcarbonyloxymethyl- carbony piperazin- 1 -y! } phenyl)dihydrofuran-2(3H)-onε; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(methoxymethylcarbonyloxymethylcarbonyl)- piperazin-l-yl}phenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3,5-difluoro-4-{4-(3-pyridylcarbonyloxymethylcarbonyl)piperazin - 1 -yl } -phenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3,5-difluoro-4-{4-(dimethylaminomethylcarbonyl)piperazin-l-yl} phenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4- { 4-cyanomethy Ipiperazin- 1 - yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-cyanoethyl)piperazin- 1 -yl }phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-benzylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-benzylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-dimethylaminoacetylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethy l-3-(3-fluoro-4- { 4-(2- { methoxycarbonyl } ethyl)piperazin- 1 -yl } phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-hydroxyethyl)piperazin-l-yl}phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-methoxyethyl)piperazin-l-yl}phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-acetylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-methanesulfinylpiperazin-l-yl}phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-methanesulfonylpiperazin-l-yl}phenyl)- furan-2(5H)-one: 5R-acetamidomethyl-3-(4-{4-methanesulfonylpiperazin-l-yl}phenyl)-furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-benzoylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-fluoroethyl)piperazin-l-yl}phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4- { 4-(hydroxyacetyl)piperazin- 1 -yl } phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-acetoxyacetylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(3-hydroxypropionyl)piperazin-l-yl}phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(3,5-difluoro-4- {4-(hydroxyacetyl)piperazin- 1 -yl }phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-hydroxyacetylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(4-dimethylaminobenzoyloxymethyl- carbonyl)piperazin- 1 -yl } pheny l)furan-2(5H)-one; 5R-acetamidomethyl-3 -(3 -fluoro-4- { 4-(4-aminobenzoyloxymethylcarbonyl)- piperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(3-pyridylcarbonyloxymethylcarbonyl)- piperazin- 1 -yl }phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4- {4-(2- { methoxy } ethoxycarbonyloxymethy lcarbonyl)- piperazin- 1 -yl } phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-{dimethylamino}ethylcarbonyloxymethyl- carbonyl)piperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-{moφholino}ethylcarbonyloxymethylcarbonyl)- piperazin- 1 -yl }phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-moφholinomethylcarbonyloxymethylcarbonyl- piperazin-1 -yl} pheny l)furan-2(5H)-one: 5R-acetamidomethyl-3-(3-fluoro-4-{4-acetoxymethylcarbonylpiperazin-l-yl}phenyl)- furan-2(5H)-one: 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-{carboxy}ethylcarbonyloxymethylcarbonyl)- piperazin- 1 -y 1 } phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(2-{methoxycarbonyl}ethylcarbonyloxymethyl- carbonyl)piperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-methoxymethylcarbonyloxymethylcarbonyl- piperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamido-3-(3,5-difluoro-4-{4-(3-pyridylcarbonyloxymethylcarbonyl)piperazin-l-yl}- phenyl)fiιran-2(5H)-one: 5R-acetamido-3-(3,5-difluoro-4-{4-(dimethylaminomethylcarbonyl)piperazin-l-yl}phenyl) -furan-2(5H)-one; 5R-acetamido-3-(3-fluoro-4-{4-(dimethylaminomethylcarbonyl)piperazin-l-yl}phenyl)- furan-2(5H)-one; or the dihydrofuranone compounds listed above as the pure 3R form or as the pure 3S form; or pharmaceutically-acceptable salts thereof. Particular preferred compounds ofthe invention are : 5R-acetamidomethyl-3-(3-fluoro-4-thiomoφholinophenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-acetylpiperazin-l-yl}phenyl)- dihy drofuran-2(3 H)-one ; 5R-acetamidomethyl-3-(3-fluoro-4-moφholinophenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-moφholinophenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-benzylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-methoxycarbonylpiperazin-l-yl}phenyl)furan- 2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-piperazinophenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-methanesulfonylpiperazin-l-yl}phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-benzyloxycarbonylpiperazin-l-yl}phenyl)- dihydrofuran-2(3H)-one: 5R-acetamidomethyl-3-(3-fluoro-4-{4-(hydroxyacetyl)piperazin-l-yl}phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(4-piperazinophenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-acetoxyacetylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-dimethylaminoacetylpiperazin- 1 -yl }phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-thiomoφholinophenyl)furan-2(5H)-one: or the dihydrofuranone compounds listed above as the pure 3R form or as the pure 3S form; or pharmaceutically-acceptable salts thereof. Particular further preferred compounds of the invention are: 5R-acetamidomethyl-3-(3-fluoro-4-thiomoφholinophenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-acetylpiperazin-l-yl}phenyl)- dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-moφholinophenyl)dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-moφholinophenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-benzylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-methoxycarbonylpiperazin-l-yl}phenyl)furan- 2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-methanesulfonylpiperazin-l-yl}phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-benzyloxycarbonylpiperazin-l-yl}phenyl)- dihydrofuran-2(3H)-one; 5R-acetamidomethyl-3-(3-fluoro-4- {4-(hydroxyacetyl)piperazin- 1 -yl Jphenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-acetoxyacetylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-dimethylaminoacetylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-thiomoφholinophenyl)furan-2(5H)-one; or the dihydrofuranone compounds listed above as the pure 3R form or as the pure 3S form; or pharmaceutically-acceptable salts thereof. Particular especially preferred compounds ofthe invention are: 5R-acetamidomethyl-3-(3-fluoro-4-moφholinophenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-benzylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-methoxycarbonylpiperazin-l-yl}phenyl)furan- 2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-methanesulfonylpiperazin-l-yl}phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-{4-(hydroxyacetyl)piperazin-l-yl}phenyl)- furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-acetoxyacetylpiperazin-l-yl}phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(4-{4-dimethylaminoacetylpiperazin- 1 -yl }phenyl)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-thiomoφholinophenyl)furan-2(5H)-one; or pharmaceutically-acceptable salts thereof. Particular further especially preferred compounds ofthe invention are: 5R-acetamidomethyl-3-(3-fluoro-4-moφholinophenyI)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-thiomoφholinophenyl)furan-2(5H)-one; or pharmaceutically-acceptable salts thereof. An especially preferred compound ofthe invention is : 5R-acetamidomethyl-3-(3-fluoro-4-thiomoφholinophenyl)furan-2(5H)-one; or pharmaceutically-acceptable salts thereof. In a further aspect the present invention provides a process for preparing a compound ofthe formula (I) or a pharmaceutically-acceptable salt thereof. The compounds ofthe formula (I) are prepared: (a) when -A-B- is >C=CH-, by eliminating HBr from a related compound wherein -A-B- is >CBr-CH2_; (b) when -A-B- is >C=CH, by oxidising -SPh in a related compound wherein -A-B- is >C(SPh)-CH2-, causing its subsequent elimination; (c) by reacting a compound ofthe formula (IV) with a compound ofthe formula (V); - 11 - (IV) CH3COL (V) d) when D is of the formula R^ and R^ is of the formula R^CO-, by reacting a compound ofthe formula (VI) with a compound ofthe formula R^COl : (VI) e) when D is ofthe formula R^N and R^ is ofthe formula R^SO2-, by reacting a compound ofthe formula (VI) with a compound ofthe formula R S02__.2; f) when D is of the formula R^N and R^ is of he formula R^CH(R 9 )-, by reacting a compound ofthe formula (VI) with a compound ofthe formula RlOCH(R 9 )I_ g) when D is ofthe formula R 5 N and R 5 is ofthe formula R 10 CH(R 9 )CH2-. by reducing a compound ofthe formula (VII): (VII) h) when D is of the formula R 5 N, R 5 is of the formula R 1 °CH(R 9 )CH 2 . and R 9 is not hydroxy. fluoro or (l-4C)alkoxy. by reacting a compound ofthe formula (VI) with a compound ofthe formula R 10 C(R 9 )=CH2; i) when D is of the formula R 5 N and R 5 is of the formula R * 0CH(OH)CH2-, by reacting a compound ofthe formula (VI) with a compound ofthe formula (VIII): 10 CH 2 -CHR (VIII) j) when D is of the formula SO or SO2. by oxidising a compound of the formula (IX): H. (IX) k) when -A-B- is >CH=CH-. by dehydrating the related hydroxy compound wherein -A-B- is >C(OH)-CH 2 -; 1) when D is ofthe formula R 5 N wherein R 5 is hydrogen, by the N-dealkylation of the related compound wherein R is benzyl or ( 1 -4C)alkyl; wherein R 1 , R 2 . R 3 , R 4 . R 6 , R 9 , R 10 . A and B are as hereinabove defined and L. L , L 2 and L 3 are leaving groups and X- is a counter ion: and wherein any functional groups are optionally protected and thereafter if necessary: i) removing any protecting groups; ii) 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 he protecting group in question, such methods being chosen so as to effect removal ofthe 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 preferable 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 ofthe invention. A carboxyl 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, tbutyl); lower alkoxy lower alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl; lower aliphatic acyloxy lower alkyl groups, (eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (eg 1 -methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg p-methoxybenzyl, o^nitrobenzyl, jhnitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl and kbutyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (eg trimethylsilylethyl); 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 hydroxyl protecting groups include lower alkenyl groups (eg allyl); lower alkanoyl groups (eg acetyl): lower alkoxycarbonyl groups (eg kbutoxycarbonyl); lower alkenyloxycarbonyl groups (eg ally loxycarbony 1); aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, jtmethoxybenzyloxycarbonyl, o_nitrobenzyloxycarbonyl, p__nitrobenzyloxycarbonyl); tri lower alkyl/arylsilyl groups (eg trimethylsilyl, tbutyldimethylsilyl, kbutyldiphenylsilyl); aryl lower alkyl groups (eg benzyl); and triaryl lower alkyl groups (eg triphenylmethyl). Examples of amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg p_-methoxybenzyl, nitrobenzyl and 2.4-dimethoxybenzyl, and triphenylmethyl); di-jtanisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg kbutoxycarbonyl); lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl, prmethoxybenzyloxycarbonyl, jtnitrobenzyloxycarbonyl, jtnitrobenzy loxy carbonyl: trialkylsilyl (eg trimethylsilyl and tbutyldimethylsilyl); 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 Qrnitrobenzyloxycarbonyl, photolytically and for groups such as silyl groups, fluoride. Methods appropriate for removal of aryl lower alkyl (eg benzyl) and triaryl lower alkyl (eg triphenylmethyl) protecting groups include hydrogenolysis and Lewis acid catalysed deprotection. For further examples of protecting groups see one ofthe many general texts on the subject, for example, "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons). The conversion of a compound wherein -A-B- is >CBrCH2- into a compound wherein -A-B- is >C=CH- is carried out under conditions known in the art for elimination reactions. Examples of suitable conditons include reacting the compound in an aprotic solvent, such as dimethylformamide. with LiBr/LiCO3. in a temperature range of ambient to 100°C. usually around 60°C. or reacting with dry pyridine in an inert solvent such as toluene, in a temperature range of 40°C to 120°C. usually from 70°C to 90°C. Compounds wherein -A-B- is >CBr-CH2- are conveniently prepared by reacting a compounds of the formula (I) wherein -A-B- is >CHCH2- with a brominating agent. For example, by reacting the compound ofthe formula (I) with N-bromosuccinimide. either in an inert solvent such as carbon tetrachloride or in acetic acid in the presence of catalytic amounts of 2,2'-azobisobutyronitrile (AIBN). The compound in which -A-B- is >C(SPh)CH2- is conveniently converted to the compound in which -A-B- is >C=CH- by oxidising the -SPh group. Oxidation ofthe thio group causes its elimination leaving the >C=CH-group. Standard oxidising agents are known in the art. One should select an oxidising agent which is capable of oxidising the -SPh group but not other groups in the molecule. Preferred oxidising agents for this reaction include potassium peroxymonosulfate (oxone) and sodium periodate. Compounds in which -A-B- is >C(SPh)CH2- are conveniently prepared by reacting the compound ofthe formula (I) in which -A-B- is >CHCH2- with phenyl disulfide in the presence of a base such as potassium carbonate. These procedures for converting -A-B- from >CHCH2 into >C= H- are not only suitable for preparing compounds ofthe formula (I) but also for preparing other furanone intermediates in the preparation of compounds ofthe formula (I). Compounds ofthe formulae (IV) and (V) are reacted together under standard acetylation conditions. For example L may be chloro and the reaction may be performed in the presence of an organic base, such as pyridine or triethylamine, in a temperature range of 0°C to ambient temperature, in an inert organic solvent such as tetrahydrofuran or methylenechloride. Alternatively, CH3COL may be acetic anhydride in which case the reaction may be carried out in the presence of base such as sodium hydroxide under Schotten-Baumann conditions. Compounds ofthe formula (IV) are conveniently prepared by reducing a compound ofthe formula (XI): (XI) wherein RI " R 4 . A and B are as hereinabove defined. Suitable reducing agents include triethylamine/hydrogen sulfide, triphenylphosphine or phosphite ester and hydrogen (in the presence of a catalyst). More specifically a compound ofthe formula (XI) may be converted to a compound ofthe formula (IV) by heating them in an aprotic solvent, such as 1 ,2-dimethoxyethane. in the presence of P(OMe)3 and subsequently heating in 6N aqueous hydrochloric acid, or reacting the compound ofthe formula (XI) with palladium on carbon in a protic solvent such as ethanol. When A-B- is of the formula >C=CH-, hydrogenation may not be suitable and the former method may be more appropriate. For further details on the reduction of azides to amines see USP 4,705,799. Compounds of the formula (IV) in which -A-B- is >CBrCH2, >C(SPh)CH2- or >C=CH- may be prepared from other compounds ofthe formula (IV) in which -A-B- is >CHCH2- or >CBrCH2„ respectively using similar conditions to those described above relating to process a) and b). Compounds ofthe formula (XI) may be prepared using the procedure shown in the Scheme I. The compounds of the formula (X) may be converted to compounds ofthe formula (XI) by reacting it with a source of azide. For example, by reacting the compound of the formula (X) with sodium azide in an inert solvent such as DMF in a temperature range of ambient to 100°C, normally in the region of 50 to 85°C. The hydroxy group in compounds of the formula (XII) is converted to a tosyloxy or mesyloxy group by standard methods known in the art. such as reacting the compounds of the formula (XII) with a tosyl chloride or mesyl chloride group in the presence of a mild base such as triethylamine or pyridine. The protecting group. Rl4. in compounds ofthe formula (XIII) is removed using standard methods known in the art. For example, when R' 4 is benzyl with palladium on carbon. Compounds ofthe formula (XIII) may be prepared by cyclising a compound of the formula (XIV) in a lactone-forming reaction, for example, by heating the compound of the formula (XIII) in aqueous acid in a suitable co-solvent such as THF. DMF or by using a biphasic system. Compounds ofthe formula (XIV) may be formed by reacting together compounds ofthe formulae (XV) and (XVI) in the presence of a strong base, such as lithium diisopropylamide, in an aprotic solvent such as THF in a temperature range of -78°C to O°C. Alternatively, compounds ofthe formula (XII) may be prepared by reacting a compound ofthe formula (XV) with a compound ofthe formula (XVII). Suitable values for R *> include iodo. bromo, mesyloxy and tosyloxy. Compounds ofthe formulae (XV) and (XVII) are conveniently reacted together in DMF or THF, at -70° to ambient temperature, in the presence of a base such as sodium hydride or lithium hexamethyldisilylamide. This provides the raw product ofthe formula (XVIII) which may be converted into a compound ofthe formula (XII) by heating it in an acetic acid/water mixture, at reflux or by treating it with strong hydrochloric acid at ambient temperature. (For example see, GB 2053 196). Compounds ofthe formula (XI) may also be prepared shown in Scheme II. in which the compounds ofthe formula (XI) are formed from a compound ofthe formula (XIX) by reacting the latter compound with a source of azide. such as sodium azide. in an aprotic solvent, such as DMF. The compounds ofthe formula (XX) may be converted into compounds ofthe formula (XIX) by dissolving the former compound in aqueous sodium hydrogen carbonate and subsequently adding iodine in an inert solvent which is miscible with water, such as THF. in a temperature range of -20°C to ambient, normally at 0°C. The compounds ofthe formula (XX) are prepared by deprotonating a compound ofthe formula (XXI) with a strong base, such as lithium diisopropylamide in an aprotic solvent, such as THF and reacting this deprotonated compound with allyl bromide. The deprotonation is carried out at low temeprature. often -78°C: the temperature being allowed to increase after the addition of allyl bromide. Compounds ofthe formulae (XV) and (XXI) can be prepared from a compound ofthe formula (XXIII): (XXIII) At some point in the reaction sequence, preferably the first step, the saturated heterocyclic group is introduced, for example, by reacting the compound ofthe formula (XXIII) with a compound ofthe formula (XXII): (XXII) wherein D, R 3 and R 4 are as hereinabove defined and L 4 is a leaving group. Suitable conditions for this reaction include heating the reagents in an inert organic solvent such as acetonitrile or DMF, in a temperature range of 80-150°C. Suitable values for L 4 include mesyl, tosyl and fluoro. Preferably L 4 is fluoro. The acetyl group may be converted to a carboxymethyl group by reaction with moφholine, in the presence of sulfur, in a temperature range of 100°C-200°C, preferably at reflux. Preferablv the reaction is carried out in the absence of solvent. This forms a moφholinothioacetyl group which may be converted to the carboxymethyl group by treatment with an aqueous base, such as aqueous potassium hydroxide or a strong acid such as concentrated hydrochloric acid, in a temperature range of 80-120°C. The reaction between compounds ofthe formulae (VI) and R^COl is 5 conveniently carried out using similar conditions to those described for the reaction between compounds ofthe formulae (IV) and (V). Preferably L^ is halo and in particular chloro. The acylation ofthe aminomethyl group (similar to the reaction between compounds ofthe formula (IV) and (V)) and the introduction of the R^CO- group onto the piperazine ring (similar to the reaction between compounds ofthe I o formulae (VI) and R^COL I ) may be carried out simultaneously (in one pot) when R^ is methyl. When R 6 is of the formula R 8 O- then R 6 COL J is a suitable formate, preferably a chloroformate (i.e. L is preferably chloro), and the reaction with a compound ofthe formula (VI) is conveniently carried out in the presence of a suitable 15 base such as aqueous sodium hydrogencarbonate solution to give the H- alkoxycarbonylpiperazine or N-benzyloxycarbonylpiperazine compound derived from the starting material of formula (VI). Compounds ofthe formula (VI) and R^SO2L 2 may be reacted together under similar conditions to those described for the reaction between compounds ofthe 20 formulae (IV) and (V). Compounds ofthe formula (VI) and R , 0 CH(R 9 )L 3 are conveniently reacted together under standard alkylation conditions. For example in an aprotic, solvent in the presence of an organic base such as triethylamine or pyridine. in a temperature range of 0-40°C. Suitable values for L 3 include halo, mesyl or tosyl. Preferably L 3 is 25 chloro. Compounds ofthe formula (VII) may be reduced using agents such as sodium borohydride or sodium cyanoborohydride. The compounds of the formula I(VI) may be prepared by reacting a compound of the formula R l υ CH(R 9 )C(=O)H with a compound ofthe formula (VI). wherein R 9 and RlO are as hereinabove defined. 30 The reaction between compounds ofthe formulae (VI) and RlOCH(R 9 )C(=O)H may be carried out under standard conditions known in the art for the formation of an iminium salt, which can be reduced in sill-. For example iminium salt formation and reduction in silu may be carried out in a water-miscible solvent such as ethanol or tetrahydrofuran, in the presence of a reducing agent such as sodium cyanoborohydride (NaCNBH3) under acidic conditions (Synthesis 135, 1975: Org. Prep. Proceed. Int. 11, 201. 1979). Compounds ofthe formula (VI) and R 10 C(R 9 )=CH2 wherein R 9 is other than hydroxy, fluoro or (l-4C)alkoxy are conveniently reacted together under conditions suitable for the reaction known as the 'Michael addition'. For example, in an inert aprotic solvent such as tetrahydrofuran, in the presence of a base, in a temperature range of ambient temperature to 100°C. Compounds ofthe formula (VI) are conveniently reacted with compounds of the formula (VIII) by heating them together in a temperature range of 40-100°C. Compounds of the formula (VI) may be prepared from appropriate intermediates using similar methods to those described in scheme I and scheme II and other processes for the preparation of compounds ofthe formula (I). The piperazine group can be introduced by reacting the appropriate intermediate with a compound of the formula (XXII) wherein D is nitrogen or protected nitrogen. If a protecting group is used it may be removed at a convenient stage later in the reaction sequence. Compounds of the formula (IX) may be oxidised to compounds ofthe formula (I) wherein D is SO or SO2- Suitable oxidising agents for the conversion of D to SO include potassium metaperiodate and peracids such as metachloroperoxybenzoic acid. Stronger oxidising agents, such as oxone may be used to convert D to SO2. The compound in which -A-B- is >C(OH)CH2_ is conveniently converted to the compound in which -A-B- is >C=CH by dehydration. Such dehydration may be achieved by use of suitable acidic conditions, such as the use of toluene-4-sulfonic acid in glacial acetic acid, or the use of phosphorous tribromide in an inert solvent under base-catalysed conditions using a base such as pyridine. Compounds in which -A-B- is >C(OH)CH2_ are conveniently prepared by reacting the compound of formula (I) in which -A-B- is >CHCH2_ with a suitable oxidizing agent. One should select an oxidizing agent which is capable of oxidizing the >CHCH2- group to the >C(OH)CH2- group, but not other groups in the molecule. A preferred oxidizing agent for this reaction is an oxaziridine. such as (lS)(+)(10-camphorsulfonyl)oxaziridine, in the presence of a suitable base, such as potassium bis(trimethylsilyl)amide. The N-dealkylation of a compound ofthe formula (I) wherein D is R N and R 5 is benzyl or ( 1 -4C)alkyl is conveniently achieved by use of a reagent such as 1- chloroethylchloroformate. The reaction is conveniently performed in an inert solvent such as dichloromethane at a temperature in the range 0-40°C. At a convenient stage in the reaction sequence in the preparation of compounds ofthe formula (I) in which -A-B- is >C=CH, intermediates in which -A-B- is >CHCH2- may be converted into intermediates in which -A-B- is >CBrCH2-, >C(SPh)CH2- or >C(OH)CH2- and subsequently >C=CH- if appropriate, using similar reaction conditions to those described for processes a) , b) and k) above. Compounds ofthe formula (IV) and related intermediates can be prepared as a mixture of (R) and (S) enantiomers or diastereoisomers as appropriate, and resolved and/or separated into the desired enantiomer or diastereoisomer using standard methods known in the art. The pure enantiomer or diastereoisomer can be used to prepared compounds ofthe formula (I). In addition, compounds ofthe formula (I) can be prepared as the pure (R) form from a compound ofthe formula (XVI) in the form of the pure (S) enantiomer depicted below: or a compound ofthe formula (XVII) in the form ofthe pure enantiomer depicted below: It will be appreciated that in certain reaction steps it may be necessary to protect functional groups which would otherwise interfere with the reaction. Such protecting groups can later be removed at a convenient point in the reaction sequence. Scheme 1 wherein D, Rl, R 2 , R 3 and R 4 are as hereinabove defined. R' 3 is methyl or p-methylphenyl, R^ 4 is a hydroxy protecting group, R'5 i s hydrogen or alkyl and Rl*> is a leaving group. Scheme II (XXD (XX) wherein D, R , R 2 , R 3 and R 4 are as hereinabove defined. 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 ofthe compound or intermediate using a standard procedure. According to a further feature ofthe invention there is provided a compound ofthe formula I. or a pharmaceutically-acceptable salt thereof, for use in a method of treatment ofthe human or animal body by therapy. According to a further feature ofthe 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 ofthe present invention, or a pharmacetuically-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 ofthe 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 the standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these puφoses 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, emulsions, dispersible powders, suppositories and sterile injectable aqueous or oily solutions or suspensions. In addition to the compounds ofthe 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 improve 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 ofthe 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 mgkg-I to 20 mgkg-I ofthe 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 ofthe 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 ofthe present invention show activity against enterococci. pnenumococci 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 ofthe compounds ofthe 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 IO 4 CFU/spot. Staphylococci were tested on agar. using an inoculum of IO 4 cfu/spot and an incubation temperature of 37°C for 24 hours - standard test conditions for the expression of methicillin resistance. Streptococci and enterococci were tested on agar supplemented with 5% defibrinated horse blood, an inoculum of IO 4 CFU/spot and an incubation temperature of 37°C in an atmosphere of 5% carbon dioxide for 48 hours - blood is required for the growth of some ofthe test organisms. MIC (μg/ml) Organism Example 1 Staphylococcus aureus: Oxford 4 Novb. Res 8 MRQS 8 MRQR 8 Coagulase Negative Staphylococcus MS 2 MR 4 Streptococcus pyogenes C203 8 Enterococcus faecalis 16 Bacillus subtilus 4 Novb. Res = Novobiocin resistant MRQS = methicillin resistant quinolone sensitive MRQR = methicillin resistant quinolone resistant MR = methicillin resistant The invention will now be illustrated by the following examples in which: (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 18-20°C and in air unless otherwise stated or unless the skilled person would appreciate that an inert atmosphere should be used; (iii) column chromatography (by the flash procedure) was performed on Merck Kieselgel silica (Art. 9385); (iv) yields are given for illustration only and are not ncessarily the maximum attainable: (v) the end-products of the formula I have had their structures confirmed by NMR and mass spectral techniques [proton magnetic resonance spectra were determined in D6- DMSO 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 200 MHz or 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: 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; (v) the following abbreviations have been used: DMF is dimethylformamide; THF is tetrahydrofuran; DME is 1.2 -dimethoxyethane; LDA is lithium diisopropylamide; HCl is hydrochloric acid; DMPU is M,N-dimethylpropylene urea; MS is mass spectroscopy; ESP is electrospray; CI is chemical ionization. Example 1: A mixture of 5R-aminomethyl-3R-(3-fluoro-4-thiomoφholinophenyl)- dihydrofuran-2(3H)-one and 5R-aminomethyl-3S-(3-fluoro-4-thiomoφholino- phenyl)dihydrofuran-2(3H)-one (4.3g) was dissolved in a 1 : 1 mixture of THF and water (80ml) and the pH of he mixture adjusted to 10 with 2N sodium hydroxide solution. Acetic anhydride (3.9g) was added dropwise whilst maintaining the temperature at 0°C -5°C. The mixture was allowed to warm to ambient temperature and then stirred for 30 minutes before being extracted with ethyl acetate. The organic phase was washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and then evaporated to give a mixture of 5R-acetamidomethyl-3R-(3-fluoro-4-thiomoφholinophenyl)dihydrofuran-2(3H)-one and 5R-acetamidomethyl-3S-(3-fluoro-4-thiomoφholinophenyl)dihydrofuran-2(3H)-one (1.7g, 36% overall yield from the mixture of 5R-azidomethyl-3-(3-fluoro-4-thiomoφholinophenyl)dihydrofuran-2(3H)-one isomers used to prepare the mixture of 5R-aminomethyl-3-(3-fluoro-4-thiomoφholinophenyl)- dihydrofuran-2(3H)-one isomers used as starting material). A sample of this product mixture was recrystallised from propan-2-ol and the ratio of cis:trans (i.e. 3R:3S) isomers found to be approximately 3: 1. NMR .200MHz. DMSO-D6.: 1.85 (s, 3H). 1.96 (m, 1 H(cis)), 2.44 (m.2H(trans)). 2.59 (m.lH(cis)), 2.73 (m,4H), 3.26 (m,4H), 3.35 (m,2H), 4.06 (m,lH), 4.6 (m,lH), 7.08 (m,3H), 8.18 (m,lH). Microanalysis; C, 57.5; H, 6.10; N, 7.70. CJ7H21FN2O3S requires C, 57.9; H, 6.01; N, 7.95. MS: ESP+ (M+H) = 353. The mixture of 5R-aminomethyl-3R-(3-fluoro-4-thiomoφholinophenyl)- dihydrofuran-2(3H)-one and 5R-aminomethyl-3S-(3-fluoro-4-thiomoφholino- phenyl)dihydrofuran-2(3H)-one used as starting material was obtained as follows:- N,N-Diisopropylethylamine (93g) and then thiomoφholine (74.3g) were added to a solution of 3',4'-difluoroacetophenone (45g) in acetonitrile (200ml), and the mixture refluxed for 90 hours. The mixture was then cooled to 20°C and ice-cold water (200ml) added. The product that precipitated out was filtered and sucked dry before being recrystallised from a mixture of methyl leu-butyl ether and methanol to give 3-fluoro-4-thiomoφholinoacetophenone (28.6g. 41% yield). NMR .200MHz. DMSO-D6.: 2.53(s,3H). 2.78(m,4H). 3.48(m,4H), 7.15(t,lH), 7.7(m,2H). MS: CI+ (M+H)=240. Elemental sulfur (2.35g) and moφholine (6.8g) were added to 3-fluoro-4- thiomoφholinoacetophenone (11.6g), and the mixture refluxed for 10 hours and then allowed to cool overnight. A 1 : 1 mixture of ethyl acetate and iso-hexane (70ml) was added and the mixture refluxed for 15 minutes and then allowed to cool. The product which precipitated on cooling was filtered and dried to give 3-fluoro-4-thiomoφholinophenylthioacetomoφholide (10.6g, 64% yield). NMR .200MHz. DMSO-D6V 2.8 (m.4H), 3.52(m,2H). 3.75(m,4H), 4.3(m,4H), 7.15(m,3H). M-i_ ESP+ (M+H)=341. 3-Fluoro-4-thiomoφholinophenylthioacetomoφholide (14.6g) was refluxed in 10% w/v potassium hydroxide solution (200ml) for 9 hours and the mixture allowed to cool overnight. The mixture was acidified to pH 4 with 2N HCl and then extracted with dichloromethane (4 x 100ml). To this organic phase was added 10% w/v sodium hydroxide solution (200ml) and the mixture stirred for 15 minutes. The organic phase was separated and discarded. The aqueous phase (containing the product) was re-acidified to pH 4 with 2N HCl and extracted with dichloromethane (3 x 200ml). dried over magnesium sulfate and evaporated to yield a solid. The solid was purified by silica gel column chromatography using a mixture of methanol (20%) in dichloromethane as eluant. There was thus obtained 3-fluoro-4-thiomoφholinophenylacetic acid (8.8g, 80% yield). NMR ( 200MHz. DMSO-D6.: 2.7(m,4H). 3.2(m.4H). 3.45(s,2H), 4.1 (broad, IH), 7.0(m,3H). MS: CI+ (M+H)=256. A 2.0M solution of LDA in n-hexane (36ml) was added dropwise to a suspension of 3-fluoro-4-thiomθφholinophenylacetic acid (7.9g) in THF (125ml) whilst maintaining the temperature at -70°C. The mixture was allowed to warm to ambient temperature over 1 hour and then stirred at ambient temperature for a further 15 minutes. The mixture was then cooled back to -70°C and a solution of (S)-(2,2-dimethyl-l,3-dioxane-4)-iodomethane (9g, prepared from (R)-(2.2- dimethyl- l,3-dioxane-4-methanol via the tosylate. cf. J.Amer.Chem.Soc.70, 609 (1948) and J.Org.Chem, 42, 1006 (1977)) in THF (20ml) was added dropwise at -70°C. The mixture was allowed to warm to ambient temperature overnight and then drowned into ice-cold water < 150ml) and the pH adjusted to 4 with 2N HCl. The product so obtained was extracted into dichloromethane (3 x 100ml) and evaporated to yield an oil which was dissolved in THF (50ml). 5N HCl (50ml) was added and the mixture stirred for 5 hours at ambient temperature. The pH ofthe mixture was adjusted to 4 with 2.5N sodium hydroxide solution and the product extracted into ethyl acetate (4 x 50ml), evaporated and purified by silica gel column chromatography using ethyl acetate as eluant. There was thus obtained 5R-hydroxymethyl-3-(3-fluoro-4-thiomoφholinophenyl)dihydrofuran-2(3H)-one (5.8g, 60% yield) as a 1 :1 mixture of cis:trans isomers. NMR ( 250MHz. DMSO-D6V 2.15 (m. lH(cis)). 2.38 (m,2H(trans)), 2.55 (m.lH(cis)), 2.75 (m,4H), 3.25 (m.4H). 3.6 (m.2H). 4.05 (m.lH), 7.05 (m.3H). M£_ CI+ (M+H)=312. Methanesulfonyl chloride (2.5g) was added dropwise to a solution of a 1 :1 mixture of cis:trans isomers of 5R-hydroxymethyl-3-(3-fluoro-4-thiomoφholinophenyl)dihydrofuran- 2(3H)-one (5.3g) in pyridine (50ml) whilst maintaining the temperature at 0°C-5°C. The mixture was stirred at 0°C-5°C for a further 30 minutes, and then allowed to warm to ambient temperature over 1 hour. The mixture was then stirred for a further 1 hour before being drowned into ice-cold water (125ml). Diethyl ether (50ml) was added to this aqueous solution and the mixture stirred for 15 minutes. The product which precipitated was filtered. washed thoroughly with water and then dried to give 5R-methylsulfonyloxy- methyl-3-(3-fluoro-4-thiomoφholinophenyl)dihydrofuran-2(3H)-one (5.7g, 86% yield) as a 1:3 mixture of cis:trans isomers. NMR (250MHz. DMSO-D6.: 2.1 (m,lH (cis)). Ca.2.42 (m,2H (trans)), 2.61 (m,lH (cis)), 2.75 (m,4H). 3.2 (m,4H), Ca.3.25 (s,3H), 4.02 (t.1 H).4.4 (m,2H), 4.85 (m, 1 H), 7.1 (m,3H). Microanalysis: C. 49.5; H, 5.2: N ,3.3. C16H20FNO5S2 requires C. 49.3; H, 5.18; N,3.6. M£ ESP+(M+H)=390. Sodium azide ( 1.2g) and 18-crown-6 (60mg) were added to a solution of a 1 :3 mixture of cis:trans isomers of 5R-methylsulfonyloxymethyl-3-(3-fluoro-4- thiomoφholinophenyl)dihydrofuran-2(3H)-one (5.4g) in DMF (50ml). The mixture was heated at 80°C for 3 hours, cooled to ambient temperature and then drowned into ice-cold water (150ml). The mixture was extracted with ethyl acetate, the organic phase washed with water, dried over magnesium sulfate and evaporated to give 5R-azidomethyl-3-(3-fluoro-4-thiomoφholinophenyl)-dihydrofuran-2(3H)-one as an oil in a 5:1 mixture of cis:trans isomers (100% yield). NMR (200MHz. DMSO-D6V 2.1 (m.lH(cis)), 2.45 (m.2H(trans)), 2.65 (m.lH(cis). 2.74 (m,4H). 3.25 (m. 4H). 3.69 (m.2H), 4.1 (m.lH). 4.78 (m.lH). 7.1 (m.3H). MS: ESP+(M+H)=337. Trimethylphosphite (2g) was added dropwise at 50°C to a solution of a 5: 1 mixture of cis:trans isomers of 5R-azidomethyl-3-(3-fluoro-4-thiomoφholino-phenyl)- dihydrofuran-2(3H)-one (4.6g) in 1.2 -dimethoxyethane (70ml). The mixture was refluxed for 3 hours and then cooled to 60°C. 6N HCl (5ml) and water (5ml) were added, the mixture refluxed for a further 5 hours, and then allowed to cool overnight. The mixture was evaporated to remove the 1 ,2-dimethoxyethane and give the required 5R-aminomethyl-3-(3-fluoro-4-thiomoφholinophenyl)dihydrofuran-2(3H)-one as a mixture of isomers which was used without further purification. Example 2; 2R,3RS-5-Azidomethyl-3-(4-(4-benzyloxycarbonyl- 1 -piperazinyl)-3- fluorophenyl)dihydro-2(3H)-furanone (120 mg) was dissolved in a mixture of glacial acetic acid (10 ml) and water (2 ml), treated with 10% palladium on carbon (120 mg), and hydrogenated at 1 atmosphere for 4.5 hours. The catalyst was filtered off through celite, and washed well with a 4:1 mixture of acetic acid and water. Evaporation ofthe filtrates gave 2R,3RS-5-aminomethyl-3-(4-piperazinyl-3-fluorophenyl)dihydro-2(3H)-furanone as a solid which was used without further purification. MS (Electrospray.: 294 (MH+) The 2R,3RS-5-aminomethyl-3-(4-piperazinyl-3-fluorophenyl)dihydro-2(3H)- furanone was stirred in an ice-bath, in a two phase mixture of water (30 ml), saturated sodium bicarbonate solution (30 ml) and ethyl acetate (30 ml). Acetic anhydride (4 ml) was added in portions over 2 hours, adding solid sodium bicarbonate as required to maintain the pH at 7-8. The mixture was stirred overnight at ambient temperature, and then extracted with ethyl acetate, dried and evaporated. The product was purified by chromatography on silica, using a gradient elution from ethyl acetate to a 1 : 1 mixture of ethyl acetate and methanol. Appropriate fractions were combined to give 2R.3RS-5-acetamidomethyl- 3-[3-fluoro-4-(4-acetylpiperazin-l -yl)phenyl]dihydro-2(3H)-furanone as a gum (60 mg). MS (Elecirospray); 3 8 (MH+) NMR ( COC . 2.04, 2.15 (2s + m. 6.4H); 2.48. 2.71. 2.77 (3dd. 1.6H); 3.04 (m, 4H); 3.28-3.47 (m. IH); 3.63 (t, 2H); 3.74-3.92 (m, 4H); 4.62, 4.75 (2m, IH); 6.03 (t, IH); 6.86-7.05 (m, 3H). The 2R.3RS-5-Azidomethyl-3-(4-(4-benzyloxycarbonyl- 1 -ρiperazinyl)-3- fluorophenyl)dihydro-2(3H)-furanone used as starting material was prepared as follows:- 3,4-Difluoroacetophenone ( 16 g) was added to a suspension of anhydrous piperazine (30 g) in acetonitrile (160 ml), and the mixture stirred under argon at reflux for 5 hours. The mixture was evaporated, and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate. and the solvent evaporated to give 3-fluoro-4- ( 1 -piperazinyl)acetophenone as a solid (20 g) which was used without further purification. NMR (DMSO-D6.: 2.50 (s. 3H); 2.89 (t. 4H); 3.08 (t, 4H): 3.20 (broad. IH); 7.06 (t, I H); 7.62 (dd, IH); 7.72 (dd. IH). MS (Electrospray.: 223 (MH+) 3-Fluoro-4-(l-piperazinyl)acetophenone ( 10 g) was stirred in ethyl acetate (120 ml) under argon at ambient temperature. Di-i≤ri-butyl dicarbonate (12.3 g) in ethyl acetate ( 120 ml) was added dropwise. and the mixture stirred for 17 hours. A small insoluble residue was filtered off. and the solvent evaporated. The residue was triturated with iso-hexane (100 ml ) to give 4-(4-teχ_-butoxycarbonyl-l-piperazιnyl)-3-fluoroacetophenone as a solid (12.7 g). NMR ( MSOd^.: 1.45 (s. 9H); 2.51 (s. 3H); 3.14 (t, 4H); 3.49 (t. 4H); 7.09 (t. IH); 7.64 (dd, IH); 7.74 (dd. IH). MS (CD; 322 (M+) 4-(4-tert-Butoxycarbonyl- 1 -piperazinyl .-3-fluoroacetophenone (27 g), elemental sulfur (4.05 g) and moφholine (12 ml) were mixed and heated to reflux with stirring for 17 hours. After cooling, the solid residue was dissolved in boiling ethyl acetate, and diluted while hot with four parts of hot iso-hexane. The solution was decanted from a gum, and then allowed to crystallise with stirring. The crystals were filtered and washed with a 4: 1 mixture of iso-hexane and ethyl acetate, and then iso-hexane. to give 4-(2-(4-(4-lsrl-butoxycarbonyl- l-piperazinyl)-3-fluorophenyl)-l-thioxoethyl)moφholine (20.6 g). NMR (DMSO-D6.: 1.43 (s, 9H); 2.94 (t, 4H); 3.47 (m, 6H); 3.65 (t, 2H); 3.73 (t, 2H); 4.21 (m, 4H); 6.95-7.25 (m, 3H). MS (Electrospray .: 424 (MH+). 4-(2-(4-(4-tert-Butoxycarbonyl- 1 -piperazinyl)-3-fluorophenyl)- 1 - thioxoethyl)moφholine (I l g) was added cautiously in portions to concentrated hydrochloric acid (55ml, 36%) at ambient temperature. The mixture was refluxed with stirring for 17 hours. After cooling in an ice bath, the mixture was made alkaline (pH 10) with concentrated sodium hydroxide solution, and the total volume adjusted to 250 ml with water. Benzyl chloroformate (I l g) was added dropwise over 30 minutes, maintaining the pH at 10 by the addition of more sodium hydroxide. Stirring was continued at 5°C for 30 minutes, then the temperature allowed to rise to ambient, and stirring continued for 1 hour. The mixture was acidified to pH 3-4. and extracted with ethyl acetate. Acids were back- extracted from the organic layer using 2N sodium carbonate, and the aqueous layer re-acidified to pH 3-4. The aqueous layer was then re-extracted with ethyl acetate, and the organic solution dried over magnesium sulfate. After filtering and evaporation the crude acid was purified by chromatography on silica, using a gradient elution from dichloromethane to a 1 : 1 mixture of dichloromethane and ethyl acetate + 1% acetic acid . Appropriate fractions were combined and recrystallised from a mixture of ethyl acetate and iso-hexane to give 4-(4-benzyloxycarbonyl-l-piperazinyl)-3-fluorophenylacetic acid. NMR ( DMSO- D6.: 2.98 (t, 4H); 3.54, 3.59 (s + 1. 6H); 5.12 (s, 2H); 6.92-7.08 (m, 3H); 7.38 (s. 5H). MS (CD; 73 (MH+) . A solution of LDA was prepared by the dropwise addition of n-butyl lithium (18.3 ml, 1.2M solution in hexane) to a stirred solution of diisopropylamine (3.08 ml) in dry THF (20 ml) at 0°C . The solution of LDA was added to a stirred solution of 4-(4-benzyloxycarbonyl-l-piperazinyl)-3-fluorophenylacetic acid (3.72 g) in dry THF (20 ml), cooled under argon to -70°C. A precipitate formed, which remained on warming to 0°C for 15 minutes. The mixture was re-cooled to -70°C , and treated dropwise with a solution of (S)-2.2-dimethyl-4- iodomethyldioxolane (2.9 g) in dry THF (10 ml). The mixture was allowed to warm to ambient temperature, and stirred for 17 hours. Solvent was evaporated, and the residue treated with sodium dihydrogen phosphate (5%, 200 ml), ethyl acetate (200 ml), and the pH adjusted to 3 with aqueous phosphoric acid. The organic extract was washed with brine, and evaporated to dryness. The crude intermediate dioxolane was dissolved in tetrahydrofuran (50 ml), treated with hydrochloric acid (50 ml, 5M), and stirred at ambient temperature for 3 hours. Organic solvent was removed by evaporation, and the residue extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and brine, dried and evaporated to a gum, which was purified by chromatography on silica using a gradient elution from dichloromethane to a 9: 1 mixture of dichloromethane and methanol. Appropriate fractions were combined to give 2R.3RS-3-(4-(4-benzyloxycarbonyl- 1 -piperazιnyl)-3- fluorophenyl)- 5-hydroxymethyldihydro-2(3H)-furanone (350 mg). NMR fCDCty: 2.20 (broad. IH); 2.34-2.48 (m. IH); 2.57-2.72 (m. IH); 3.04 (t. 4H); 3.67 (t + m, 5H); 3.86 (dd. 0.5H): 3.92-4.05 (m. 1.5H): 4.56-4.65 ( . 0.5H); 4.56-4.75 (m, 0.5H): 5.14 (s, 2H); 6.89-7.05 (m. 3H); 7.35 (m, 5H). MS (Hlectrosprayl: 429 (MH+) 2R,3RS-3-(4-(4-Benzy loxycarbony 1- 1 -piperazinyl)-3-fluorophenyl)-5- hydroxymethyldihydro-2(3H)-furanone (300 mg) was dissolved in dry dichloromethane (3 ml), cooled to 5°C and treated sequentially with triethylamine (141 mg) and methanesulfonyl chloride (120 mg) in dichloromethane (1 ml). Stirring was continued for 10 minutes at 5°C , then 1 hour at ambient temperature. Excess sodium bicarbonate solution and more dichloromethane were added, and the organic layer separated, dried and evaporated to give 2R,3RS-3-(4-(4-benzyloxycarbonyl- 1 -piperazinyl)-3-fluorophenyl)-5- methanesulfonyloxymethyldihydro-2(3H)-fureinone as a gum (320 mg). NMR (QOC\_,J1 2.48-2.84 (2 x m. 2H); 3.05, 3.09 (t + s, 7H); 3.68 (t, 4H); 3.82-3.97 (m. IH); 4.39 (m, IH); 4.51 (td, IH); 4.76 (m. 0.5H); 4.83 (m, 0.5H); 5.16 (s, 2H); 6.82-7.04 ( , 3H); 7.36 (m, 5H). MS (Electrospray); 507 (MH+) 2R,3RS-3-(4-(4-Benzyloxycarbonyl-l-piperazinyl)-3-fluorophenyl)-5- methanesulfonyloxymethyldihydro-2(3H)-furanone (300 mg) was dissolved in DMF (5 ml), treated with sodium azide (58 mg, 0.89 mM) and heated at 80°C for 5 hours under argon. After cooling and dilution with water and brine, the organics were extracted into ethyl acetate (100 ml). The extract was back-washed with water (2 x 50 ml), brine, and dried (magnesium sulfate). Evaporation gave a gum which was purified by chromatography on silica, using a gradient elution from dichloromethane to a 4: 1 mixture of dichloromethane and ethyl acetate. Appropriate fractions were combined to give the required 2R.3RS-5- azidomethyl-3-(4-(4-benzyloxycarbonyl-l-piperazinyl)-3-fluorophenyl)dihydro- 2(3H)-furanone (140 mg). NMR ( CDCI3 : 2.51 fm. IH ) : 2.69 (m, IH); 3.04 (t, 4H); 3.49-3.73, 3.68 (m + t, 6H); 3.86 (dd, 0.6H); 3.97 (dd. 0.4H); 4.64 (m. 0.6H); 4.75 (m, 0.4H); 5.17 (s, 2H); 6.86-7.05 (m, 3H); 7.37 (m, 5H). MS (Ekctrospray): 454 (MH+) Example 3; Trimethylphosphite ( 1 g) was added slowly at 50°C to a solution of a 1:1 3R:3S mixture of isomers of 5R-azidomethyl-3-(3-fluoro-4-moφholinophenyl)-dihydrofuran-2-(3H)-one (2.2g) in 1 ,2-dimethoxyethane (40ml). The mixture was refluxed for 2 hours and then cooled back to 50°C before carefully adding 6N HCl (2.4 ml) and water (2ml). The mixture was refluxed overnight, and then evaporated down to an oily residue, which was taken up in a 1 :1 mixture of THF and water (80ml). The mixture was cooled to 0°C-5°C and sodium hyrdrogencarbonate (6g) added to adjust pH to 8-9. Acetic anhydride (2 ml) was added and mixture stirred at 0°C-5°C for 15 minutes. The mixture was allowed to rise to ambient temperature and stirred for a further 15 minutes. The pH ofthe mixture was re-adjusted to 8 and extracted with ethyl acetate, which was then evaporated to yield an oil. The oil was purified by silica gel column chromatography using as eluant a mixture of methanol (10%) and dichloromethane. There was thus obtained a mixture of isomers of 5R-acetamidomethyl-3-(3-fluoro-4-moφholino- phenyl)dihydrofuran-2-(3H)-one (0.9 g, 39% yield) in a 3R:3S ratio of 1 :2. NMR (200MHz. DMSO-D6.: δl .85 (S, 3H), δl .98 (m, IH (cis)), δ2.44 (m, 2H (trans)), δ2.58 (m, IH (cis)), δ2.98 (t. 4H), δ ca. 3.30 (m. 2H), 63.7 (t, 4H), δ4.07 (m, IH), 64.6 (m,lH), 66.98-7.2 (m. 3H). 68.18 (broad m. IH). MS: ESP+ (M+H)= 337.2 The mixture of isomers of 5R-azidomethyl-3-(3-fluoro-4-moφholinophenyl)- dihydrofuran-2-(3H)-one used as starting material was obtained as follows:- A mixture of 3.4-difluoroacetophenone (50g) and moφholine (56g) was refluxed for 3.5 hours, then cooled to 50°C and acetonitrile (100ml) added. The mixture was stirred until a complete solution was obtained (warming if necessary), water (200ml) was added and the mixture allowed to cool to ambient. The solid formed was collected by filtration and redissolved in dichloromethane (250ml). The dichloromethane solution was washed with water (100ml). separated and evaporated to give 3-fluoro-4-moφholinoacetophenone as a solid (68g, 95% yield). NMR ( 200MHz. DMSO-D6V 62.45 (s, 3H). 63.1 (m. 4H), 63.7 (m, 4H), 67.05 (t, IH), 67.62 (m, 2H). MS: ESP+ (M+H)= 224.2 Moφholine (34g) and elemental sulfur (12.4g) were added to 3-fluoro-4- moφholinoacetophenone (66.6g) and the mixture refluxed for 3 hours. After cooling to 50°C a 1 :1 mixture of ethyl acetate and iso-hexane (200ml) was added and the mixture refluxed for 10 minutes before cooling to ambient temperature and stirring for 30 minutes. The resulting solid was filtered and washed with 1 : 1 mixture of ethyl acetate and iso¬ hexane before being dried to give M-[2-(3-fluoro-4-moφholinophenyl)-l- thioxojethylmoφholine (80g, 83% yield). NMR (200MHz, DMSO-D6); 62.98 (m, 4H), 63.45 (t, 2H),), 63.57-63.8 (m, 8H). 64.21(m, 4H ), 69.4-67.25 (m, 3H). M-il ESP+ (M+H)= 325.3 M-[2-(3-Fluoro-4-moφholinophenyl)-l-thioxo]ethylmoφholine (79g) was refluxed overnight in 5N HCl (300ml). The mixture was then cooled to ambient temperature and the pH adjusted to 10. The aqueous solution was extracted with dichloromethane (3 x 75 ml) and the organic phases discarded. The aqueous phase was then reacidified to pH 4 with concentrated HCl and the resulting solid filtered and dried to give 3-fluoro-4- moφholinophenylacetic acid (25g, 43% yield). NMR ( 200MHz. DMSO-D6.: 62.93 (m. 4H), 63.3 (s, 2H), 63.72 (m, 4H), 64.5 (broad, IH), 66.85-7.05 (m, 3H). MS: ESP+ (M+H)= 240.2. N.N 1 -dimethy lpropylene urea (DMPU) (5ml) was added to a stirred suspension of 3- fluoro-4-moφholinophenylacetic acid (12.5g) in THF (150ml) and the mixture cooled to - 78°C. A 1.5M solution of LDA (77ml) was added dropwise below -70°C and stirred at -78°C for 20 minutes before the mixture was allowed to rise to ambient temperature. The mixture was stirred at ambient temperature for 15 minutes and then cooled back to -78°C and (S)-(2,2-dimethyl-l,3-dioxane-4)-iodomethane (15g) added dropwise below -70°C . The mixture was stirred over a weekend whilst being allowed to warm to ambient temperature. The mixture was then poured into ice-cold water (200ml) and the pH adjusted to 5-6 with concentrated HCl and extracted with ethyl acetate (3 x 100ml). The combined organic phases were evaporated down and the residue taken up in THF (75ml) and 5N HCl (75ml) and stirred ovemight. The pH was adjusted to 4-5 and extracted with ethyl acetate. The organic phase was washed with saturated sodium hydrogencarbonate solution and then evaporated down and the residue purified by silica gel column chromatography using ethyl acetate as eluant. There was thus obtained a mixture of isomers of 5R-hydroxymethyl-3-(3-fluoro-4-moφholinophenyl)dihydrofuran-2- (3H)-one (2.9 g. 19% yield) in a 3R:3S ratio of 1 :1. NMR ( 250MHz. DMSO-D6.: 62.15 (m. 1 H (cis)). δ ca.2.45 (m. 2H (trans)). 62.58 (m. 1 H (cis)). 62.98 (t. 4H). 6 ca.2.65 (m. IH). 63.75 (t. 4H), 64.05 (m,l H). 64.5-4.7 (m. IH). δ ca.5.1 (broad, IH), 66.98-67.18 (m. 3H). MS: ESP+ (M+H)= 296.2. Methanesulfonyl chloride ( 1.4g) was added at 0°C -5°C to a solution of a 1 :1 3R:3S mixture of isomers of 5R-hydroxymethyl-3-(3-fluoro-4-moφholino- phenyl)dihydrofuran-2-(3H)-one (2.8g) in pyridine (50ml). The mixture was allowed to come to room temperature and stirred for 3 hours before being poured into ice-cold water (100ml). The resulting solid was filtered off, and the filtrate evaporated down to an oil, which was triturated with a 1 : 1 mixture of ethyl acetate and iso-hexane. The resulting solid and the filtered off solid were both dissolved in dichloromethane, dried over magnesium sulfate and evaporated to give a mixture of isomers of 5R-methylsulfonyloxymethyI-3-(3- fluoro-4-moφholinophenyl)-dihydrofuran-2-(3H)-one (2.8g, 79% yield) in a 3R:3S ratio of 1:3. NMR ( 200MHz. DMSO-D6.: 62.14 (M, IH (cis)),, 62.5-2.68 (m, 2H (trans) + IH (cis)), 63.0 (m, 4H), 63.26 (s, 3H), 63.27 (S, 3H), 63.76 (m, 4H), 64.02-64.22 (m, IH), 64.48 (m, 2H), 64.75-65.0 (m. IH), 66.98-67.2 (m, 3H). MS: ESP+ (M+H)= 374.1. Sodium azide (lg) was added to a solution of a 1 :3 3R:3S mixture of isomers of 5R- methylsulfonyloxymethyl-3-(3-fluoro-4-moφholinophenyl)-dihydrofuran-2-(3H)-one (2.7g) in DMF (25ml) and the mixture stirred at 80°C for 3 hours. The mixture was then cooled to 15°C, ice-cold water (50ml) added and the product extracted with ethyl acetate. The organic phase was washed with water and then evaporated under reduced pressure to give a mixture of isomers of 5R-azidomethyl-3-(3-fluoro-4- moφholinophenyl)dihydrofuran-2-(3H)-one (2.3g, 100% yield) in a 3R:3S ratio of 1 : 1. NMR (200MHz. DMS -D6V 62.1 (m. 1 H (cis)). 62.43-2.7 (m. 2H (m, 2H (trans)) + m, 1 H (cis)). 63.0 (m. 4H). 63.65-63.8 (m. 6H). 64.1 (m. IH), 64.65-64.9 (m. IH). 56.98-67.22 (m. 3H). MS CI+ (M+H)= 321. Example 4; Potassium carbonate (1.5g) and diphenyl disulfide (0.68g) were added to a solution of a 1 :2 3R:3S mixture of isomers of 5R-acetamidomethyl-3-(3-fluoro-4- moφholinophenyl)dihydrofuran-2-(3H)-one (Example 3) (0.7g) in 1 ,2-dimethoxyethane (50ml), and the mixture refluxed for 5 hours. More potassium carbonate (1.5g) was then added and the refluxing continued for a further 48 hours. The mixture was cooled and poured into 0.5N HCl (44ml) whilst maintaining the temperature below 15°C. The mixture was extracted with ethyl acetate (3 x 50ml), and the combined organic extracts evaporated. The resulting residue was purified by silica gel column chromatography (using as eluant a mixture of methanol (5%) in dichloromethane) to give an oil (0.28g). A solution of sodium periodate (0.283g) in water (5ml) was added to a solution ofthe oil (0.28g) in THF (25ml), and the mixture stirred for 48 hours. The mixture was evaporated and the residue purified on an Isolute column (lOg) using a mixture of acetone (10%) in dichloromethane to remove the early fractions, and a mixture of methanol (3%) and dichloromethane to obtain 5R-acetamidomethyl-3-(3-fluoro-4-moφholinophenyl)furan-2(5H)-one (0.06g, 9% yield) as a solid. NMR (200MHz. DMSO-D6.: 61.77 (s, 3H), 63.08 (m, 4H), 63.45 (m, 2H), 63.75 (m, 4H), 65.2 (m, IH), 67.09 (t, IH), 67.65 (m, 2H), 67.88 (d, IH), 68.1 (broad, IH). MS: FAB (M+H)=335. Example 5: Toluene-4-sulfonic acid (0.4g) was added to a solution of a 1 :2 3R:3S mixture of isomers of 5(R)-acetamidomethyl-3-hydroxy-3-(4- { 4-benzylpiperazin- 1 -yl } -phenyl)dihydrofuran- 2(3H)-one (0.8g) in glacial acetic acid (15ml). and the mixture refluxed for 30 minutes. The acetic acid was removed under reduced pressure and the residue dissolved in a mixture of ethyl acetate and saturated sodium hydrogencarbonate solution. The mixture was stirred for 5 minutes, and the organic phase separated. The aqueous phase was re-extracted with ethyl acetate, the combined organic phases evaporated down and the residue purified on an Isolute column (using a mixture of methanol (10%) in dichloromethane as eluant). There was thus obtained 5R-acetamidomethyl-3-(4-{4-benzylpiperazin-l-yl}phenyl)furan-2(5H)- one (0.71g, 93% yield). NMR ( 300MHz. DMSO-D6.: 61.68 (s. 3H). 62.5 (broad m. 4H), 63.2 (broad s, 4H), 63.25 broad s. 2H), 63.4 (m. 2H). 63.5 (broad s. 2H), 65.18 ( . IH). 66.93 (d. 2H). 67.3 (m, 5H), 67.7 (m, 3H), 68.12 (broad m. IH). MS: ESP+ (M+H)= 406. The mixture of isomers of 5R-acetamidomethyl-3-hydroxy-3-(4-{4-benzylpiperazine-l- yl)phenyl)dihydrofuran-2(3H)-one used as starting material was obtained as follows:- Diisopropylethylamine (31.2g) was added to a suspension of 4-piperazino-acetophenone (52.5g) in dichloromethane (400ml), followed by the dropwise addition of benzyl bromide (28.6ml) at below 15°C. The mixture was then stirred at ambient temperature for 90 minutes and then carefully poured into water (250ml). The organic phase was separated, washed with water and evaporated to give 4-benzylpiperazin-l-ylacetophenone (60.3g, 85% yield). NMR (30QMHZ. DMSO-P6): 62.44 (s, 3H), 62.5 (m, 4H), 63.25 (m. 4H), 63.52 (s, 2H), 66.95 (d, 2H). δ7.34 (m, 5H), 67.79 (d. 2H). MS: ESP+ (M+H)= 295.1. A mixture of 4-benzylpiperazin-l-ylacetophenone(60.3g), elemental sulfur (7.9g) and moφholine (23.2ml) was refluxed for 6 hours and then allowed to cool to 50°C. Ethyl acetate (300ml) was added and the mixture refluxed for a further 1 hour. The mixture was cooled to ambient temperature, and the resulting solid filtered off and dried. There was thus obtained N-[2-{4-(4-benzylpiperazin-l-yl)phenyl}-l-thioxo]ethylmoφholine (45.8g, 57% yield). NMR ( 200MHz. DMSO-D6V 62.5 (m. 4H), 63.1 (m, 4H), 63.4 (t, 2H). 63.52 (s, 2H), 63.58-63.79 (m, 4H). 64.2 (m, 4H), 66.85 (d, 2H). 67.15 (d, 2H), 67.32 (m, 5H). MS: CI+ (M+H)= 396. 1.4-Dioxan (100ml) was added to a stirred suspension of N-[2-{4-(4-benzyl-piperazin-l- yl)phenyl}-l-thioxo]ethylmoφholine (45.7g) in 10% w/v potassium hydroxide solution (250ml). The mixture was thoroughly degassed by bubbling argon through it for 15 minutes, and the mixture then refluxed overnight under argon. The 1 ,4-dioxan was removed under reduced pressure and the pH ofthe aqueous solution adjusted to 1 with concentrated hydrochloric acid at below 20°C. The aqueous mixture was stirred under argon for 1 hour and then neutralised to pH 6.8 with 2.5N sodium hydroxide solution. The resulting solid was filtered and dried to give 4-(4-benzylpiperazin-l-yl)phenylacetic acid (23. lg, 64% yield). NMR ( 250MHz. DMSO-D6V 62.55 (m, 4H), 3.15 (m, 4H), 63.4 (s, 2H), 63.55 (s, 2H), 66.85 (d, 2H). 67.16 (d, 2H), 67.3 (m. 5H). MS: ESP+ (M+H)= 31 1.2. A 1.58M solution of LDA in n-hexane (80ml) was added dropwise to a stirred suspension ofthe 4-(4-benzylpiperazin-l-y Opheny lacetic acid (17g, 0.06M) in THF (400ml) whilst maintaining the temperature below -70°C. The mixture was stirred at -70°C for 1 hour and then allowed to warm to ambient temperature and stirred for a further 30 minutes. The mixture was cooled back to -70°C and (S)-(2.2-dimethyl-1.3-dioxane-4)-iodomethane (15.93g) added dropwise whilst maintaining the temperature below -65°C. The mixture was stirred over a weekend whilst allowing to warm to ambient temperature. The mixture was then poured into ice-cold water (100ml). and then 5N hydrochloric (200ml) added. The mixture was stirred overnight. The pH ofthe solution was adjusted to 7 with 5N sodium hydroxide solution at below 10°C, and then extracted with dichloromethane which was evaporated down to an oil. The oil was purified by silica gel column chromatography using a mixture of methanol (10%) and dichloromethane as eluant. There was thus obtained a mixture of isomers of 5R-3-(4-{4-benzylpiperazin-l-yl}phenyl)-5- hydroxymethyldihydro-2(3H)-furanone (9.5g. 47.5% yield) in a 3R:3S ratio of 1 : 1. NMR (300MHz. DMSO-D6.: 52.1 (m, IH (cis)). 62.3 (m, 2H (trans)), 6 ca. 2.49 (m, IH (cis)), δ ca.2.5 (t, 4H), 63.1 (t, 4H), 3.5 (s, 2H), 63.52 (m, IH), 63.68 (m, IH), 63.97 (m, IH), 64.58 (m, IH), 65.08 (m. IH), 66.88 (d. 2H), 67.08 (d, 2H), 67.28 (m, 5H). MS: ESP+(M+H)= 367. Methanesulfonyl chloride (2.6ml) was added at 0°C-5°C to a stirred solution of a 1 :1 3R:3S mixture of isomers of 5R-3-(4-{4-benzylpiperazin-l-yl}phenyl)-5- hydroxymethyldihydro-2(3H)-furanone (9.4g) in pyridine (100ml). The mixture was stirred for 30 minutes before allowing to rise to ambient temperature and stirring for a further 90 minutes. The mixture was then poured into ice-cold water (250ml) and extracted with dichloromethane. The dichloromethane solution was evaporated down to an oil (lOg). Sodium azide (2g) was added to a solution of this oil (9.2g) in DMF (100ml) and the mixture stirred at 85°C for 3 hours. At the end of this period the mixture was cooled and poured into water (150ml). The product was extracted into ethyl acetate, which was washed with water and then evaporated to give a mixture of isomers of 5R-azidomethyl-3- (4-{4-benzyl-piperazin-l-yl}phenyl)dihydro-2(3H)-furanone as an oil (6.7g, 83% yield) in a 3R:3S ratio of 5:7. NMR (300MHz. DMSO-D6); 62.02 (m. IH (cis)), 62.4 (m, 2H (trans)), δ ca.2.5 (m, 4H). 62.6 (m, IH (cis)). 63.1 (m. 4H). 63.5 (s, 2H). 63.68 (m. 2H), 64.0 (m, IH), 64.72 (m, IH), 66.88 (d. 2H). 67.1 (d, 2H), 67.28 (m, 5H). MS ESP+ (M+H)=392. Trimethylphosphite (2.55g) was added at 50°C to a stirred solution of a 5:7 3R:3S mixture of isomers of 5(R)-azidomethyl-3-(4-{4-benzylpiperazin-l-yl}phenyl)dihydro-2(3H)- furanone (6.7g) in 1 ,2-dimethoxyethane ( 100ml), and the mixture refluxed for 2 hours. The mixture was cooled to 50°C and 6N HCl (5ml) added carefully. The mixture was refluxed for a further six hours and then evaporated down to an oil, which was then taken up in water (50ml) and cooled to 0°-5°C. The pH was adjusted to 9.0 with 2.5N sodium hydroxide solution and acetic anhydride (10ml) added immediately . The mixture was stirred for 30 minutes at 0°-5°C, the pH adjusted to 7.0, and the product extracted with ethyl acetate. The solvent was evaporated to give an oil which was purified by silica gel column chromatography using a mixture of methanol (10%) in dichloromethane as eluant. There was thus obtained a mixture of isomers of 5R-acetamidomethyl-3-(4-{4- benzylpiperazin-l-yl}phenyl)dihydrofuran-2-(5H)-one (3.1 lg, 45% yield) in a 3R:3S ratio of2:3. NMR (300MHz. DMSO-D6.: 61.83 (s, 3H), 61.93 (m, IH (cis)), 62.25 (m, 2H (trans)), δca.2.5 (m, 4H), 62.55 (m, IH (cis)), 63.1 ( , 4H), 63.32 (m, 2H), 63.5 (s, 2H), 63.94 (m, IH), 64.58 (m, IH), 66.88 (d, 2H), 67.1 (d, 2H), 67.24 (m, 5H), 68.1 (m, IH). MS: ESP+ (M+H)= 408. A solution ( 15 wt.%) of potassium bis(trimethylsilyl)amide (26ml) in toluene was added dropwise at below -70°C to a stirred solution of a 2:3 3R:3S mixture of isomers of 5R- acetamidomethyl-3-(4-{4-benzylpiperazin-l-yl}phenyl)- dihydrofuran-2-(5H)-one (6.97g) in THF (100ml). The mixture was stirred at -78°C for 30 minutes and then (1S)(+)(10- camphorsulfonyl)oxaziridine (4.08g) was added and the mixture stirred for a further 1 hour. The mixture was warmed to ambient temperature, and stirred for a further 30 minutes. The mixture was poured at below 10°C into a mixture of 6N hydrochloric acid (3ml) and water (20ml). and then basified to pH 8.0 with saturated sodium hydrogencarbonate solution. The product was extracted into ethyl acetate and purified by silica gel column chromatography using a mixture of methanol ( 10%) in dichloromethane as eluant. There was thus obtained the required starting material mixture of isomers of 5R- acetamidomethyl-3-(4-{4-benzylpiperazin-l-yl}phenyl)-3-hydroxy-dihydrofuran-2(3H)- one as a solid (5.2g. 72% yield) in a 3R:3S ratio of 1 :2. NMR (300MHz. DMSO-D6.: δl .8 (s. 3H). δl .81(s. 3H), 62.18 (m, IH (cis)), δ ca.2.38 (m, 2H, (trans)), 62.63 (m. IH (cis)). 63.18 (broad t. 4H), 6ca. 3.35 (broad m. 4H), 63.5 (s, 2H), 64.28 (m, IH (cis)), 64.7 (m. IH (trans)), 66.28 (broad s. IH (cis)), 66.5 (broad s, IH (trans)), 66.9 (dd, 2H). 67.28 (d, 2H), 67.33 (m, 5H), 68.19 (broad, IH). MS ESP+ (M+H)= 424 Example 6: 1-Chloroethylchloroformate (0.1 lg) was added at 0°C to a solution of 5(R)- acetamidomethyl-3-(4-{4-benzylpiperazine-l-yl}phenyl)furan-2(5H)-one (Example 5) (0.3g) in dichloromethane (15ml). The mixture was stirred at 0°-5°C for 15 minutes and then stirred at 30°C for 30 minutes. The dichloromethane was removed under reduced pressure, and the residue refluxed in methanol (20ml) for 30 minutes before being evaporated down to give a gum. The gum was taken up in water (15ml) and chloroform added. The aqueous phase was separated and cooled to 0°-5°C and the pH adjusted to 8-8.5 with saturated sodium hydrogencarbonate solution. Methyl chloroformate (0.08g) was added immediately and the mixture stirred for 30 minutes. The mixture was re-neutralised with saturated sodium hydrogencarbonate solution and extracted with chloroform. The chloroform was evaporated down and the residue purified by silica gel column chromatography using a mixture of methanol (10%) in dichloromethane as eluant. There was thus obtained 5R-acetamidomethyl-3-(4-{4-methoxycarbonylpiperazin-l- yI}phenyl)furan-2-(5H)-one (170 mg. 60% yield). NMR (200MHz. DMS -D6.: 61.73 (s. 3H), 63.20 ( broad t. 4H). 63.42 (m, 2H), 63.43 (broad t. 4H), 63.62 (s, 3H), 65.17 (m. IH), 66.98 (d, 2H), 67.72 (m, 3H), 68.1 (m, IH). MS: ESP+ (M+H)= 374. Example 7; 1 -Chloroethylchloroformate ( 1.1 g) was added at 0°C -5°C to a stirred solution of 5R- acetamidomethyl-3-(3-fluoro-4-{4-benzylpiperazin-l-yl}phenyl)furan-2-(5H)-one (3g) and the mixture allowed to warm to ambient temperature over 15 minutes. The mixture was then refluxed for 30 minutes. The dichloromethane was removed under reduced pressure and the residue dissolved in methanol and refluxed for a further 90 minutes. The mixture was evaporated to a gum which was triturated with a mixture of ethyl acetate and methanol to give 5R-acetamidomethyl-3-(3-fluoro-4-piperazinophenyl)furan-2-(5H)-one as a solid hydrochloride salt (2.1g, 80% yield). NMR (300MHz. DMSO-D6V 61.75 (s, 3H), 63.24 (broad. 4H). 63.25 (broad , 4H), 63.43 (m, 2H). 65.21 (m. IH). 67.18 (t. IH), 67.62 (s. IH). 67.7 (m. IH). 67.92 (s, IH). 68.18 (m, IH), 69.2 (broad, 2H). MS: ESP+ (M+H)= 334. The 5R-acetamidomethyl-3-(3-fluoro-4-{4-benzylpiperazin-l-yl}phenyl)furan-2-(5H)-one used as starting material was obtained as follows:- 1 -Benzylpiperazine (113.7g) was added to 3,4-difluoroacetophenone (50.4g) and the mixture stirred at 130°C for 3 hours. The mixture was cooled to 50°C and acetonitrile (100ml) added. The mixture was cooled to ambient temperature and poured into water (400ml). The resulting solid was filtered and then re-dissolved in dichloromethane, with filtering to remove any insoluble material. The dichloromethane solution was then washed with water and evaporated to give 4-(4-benzylpiperazin-l-yl)-3-fluoroacetophenone (95.7g, 96% yield) as a solid. NMR (300MHz. CDCL .: 62.51 (s, 3H), 62.62 (broad t. 4H), 63.22 (broad t. 4H). 63.58 (s, 2H), 66.9 (t, IH), 67.3 (m. 5H), 67.62 (m, 2H). MS: ESP+ (M+H)= 313. A mixture of 4-(4-benzylpiperazin-l-yl)-3-fluoroacetophenone (86g), moφholine (31ml) and elemental sulfur (I lg) was refluxed for 6 hours and then cooled to 50°C. Ethyl acetate was added and the mixture refluxed for 30 minutes. The mixture was cooled and filtered, and the solid dried to give N-[2-(4-{4-benzylpiperazin-l-yl}-3-fluorophenyl)-l- thioxojethyl oφholine (70g, 61% yield). _ .62.63 (m, 4H), 63.1 (m. 4H), 63.43 (m, 2H), 63.59 (s, 2H), 63.61 (m, 2H), 63.7 (m, 2H), 64.23 (s, 2H), 64.3(m, 2H), 66.87-67.08 (m, 3H), 67.3 (m, 5H). MS: ESP+ (M+H)= 414. 1.4-Dioxan (200ml) was added to a stirred suspension of M-[2-(4-{4-benzyl-piperazin-l- yl}-3-fluorophenyl)-l-thioxo]ethylmoφholine (70g) in 10% w/v potassium hydroxide solution (300ml), and the mixture thoroughly degassed by bubbling argon through it for 30 minutes. The mixture was then refluxed overnight under an atmosphere of argon. The 1,4- dioxan was removed under reduced pressure and the aqueous phase was extracted with ethyl acetate. The organic phase was then discarded, and the pH ofthe aqueous phase adjusted to 2 with concentrated hydrochloric acid. The mixture was stirred for 30 minutes under argon, and then neutralised to pH 7 with 2.5N sodium hydroxide solution. The resulting solid was filtered and dried to give 4-benzylpiperzin-l-yl-3-fluoro-phenylacetic acid (36.2g. 65% yield). NMR (30MHz. DMSO-D6.: 62.51 (broad. 4H). 62.98 (broad t. 4H), 63.49 (s, 2H), 63.51 (s, 2H), 66.9-67.02 (m. 3H). 67.3 (m. 5H). MS: ESP+ (M+H)=329. A 2.0M solution of LDA in n-hexane (85ml) was added dropwise at below -60°C to a stirred suspension of 4-benzylpiperazin-l-yl-3-fluoro-phenylacetic acid (15.7g) in THF (300ml). The mixture was stirred for 15 minutes and then allowed to rise ambient temperature. The mixture was stirred at ambient temperature for 45 minutes and the mixture then cooled back to -78°C. (S)-(2,2-Dimethyl-l,3-dioxane-4)-iodomethane (12.7g) was added dropwise at below -70°C. and the mixture stirred at -78°C for 4 hours and then at ambient temperature for 48 hours. At the end of this period the mixture was poured onto ice (lOOg) and concentrated hydrochloric acid (100ml) added. The mixture was stirred overnight, and the pH was then adjusted to 8 with 5N sodium hydroxide solution. The mixture was extracted with ethyl acetate which was then washed with saturated sodium hydrogencarbonate solution. Ethyl acetate was removed under reduced pressure and the residue purified by silica gel column chromatography using a mixture of methanol (10%) and dichloromethane. There was thus obtained a mixture of isomers of 5R-3-(4-{4-benzylpiperazin-l-yl}-3-fluorophenyl)-5-hydroxymethyldihydro-2(3H)- furanone (6.6g, 36% yield) in a 3R:3S ratio of 3:4. NMR (200MHz. DMSO-D6V 62.1 (m, IH (cis)). 62.4 (m, 2H (trans)), 62.5 (broad t, 4H), 6 ca. 2.52 (m, IH), 63.0 (broad t, 4H), 63.5 (s, 2H), 63.52 (m, IH), 63.63 (m, IH), 64.05 (m, IH), 64.59 (m, IH), 65.09 (m, IH), 66.94-67.1 (m, 3H), 67.3 (m, 5H). MS: ESP+ (M+H): 385. Methanesulfonyl chloride (2.98g) was added dropwise over 5-10 minutes at 0°C -5°C to a stirred solution of a 3:4 3R:3S mixture of isomers of 5R-3-(4-{4-benzylpiperazin-l-yl}-3- fluorophenyl)-5-hydroxymethyldihydro-2(3H)-furanone (7.7g) in pyridine (75ml). The mixture was stirred for 15 minutes and then allowed to rise to ambient temperature. The mixture was stirred at ambient temperature for a further 2.5 hours, and then poured into ice-cold water ( 100ml). The product was extracted into ethyl acetate, and the ethyl acetate then removed under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of methanol ( 10%) and dichloromethane as eluant. There was thus obtained a mixture of the 3R and 3S isomers of 5R-3-(4-{4-benzylpiperazin-l- yl}-3-fluorophenyl)-5-methanesulfonyioxymethyldihydro-2(3H)-furanone (8.45g, 91% yield) in a 3R:3S ratio of 5:7. NMR (300MHz. DMSO-D6V. 62.09 (M. IH (cis)), 6 ca.2.5 (m, 2H (trans)), δ ca.2.5 (broad t. 4H), 62.66 (m, 1 H (cis)). 63.0 (broad t, 4H). 63.23 (s, 3H). 63.24 (s, 3H), 63.56 (s, 2H), 64.09 (m, IH), 64.43 (m, 2H), 64.84 (m. IH), 66.95-67.14 (m, 3H). 67.3 (m. 5H). MS: ESP+ (M+H)= 463. Sodium azide (2.4g) was added to a solution of a mixture ofthe 3R and 3S isomers of 5R- 3-(4-{4-benzylpiperazin-l-yl}-3-fluorophenyl)-5-methane-sulfonyloxymethyldihydro- 2(3H)-furanone (8.43g) in DMF (50ml), and the mixture stirred at 85°C for 90 minutes. The mixture was cooled to ambient temperature and then poured into water (100ml). The product was extracted with ethyl acetate, which was washed with water and then evaporated down to give a mixture of isomers of 5R-azidomethyl-3-(4-{4- benzylpiperazin-l-yl}-3-fluorophenyl)dihydro-2(3H)-furanone (7.29g, 97.7% yield) in a 3R:3S ratio of 2:3. NMR ( 300MHz. DMSO-D6.: 62.07 (m, IH (cis)), 62.43 (m, 2H (trans)), 62.5 (broad t, 4H), 62.62 (m, IH (cis)), 62.98 (m, 4H). 63.5 (s. 2H), 63.64 (m. 2H). 64.05 (m, IH), 64.78 (m, IH), 66.98-67.13 (m, 3H), 67.3 (m. 5H). MS ESP+ (M+H)= 410. Trimethylphosphite (2.6ml) was added dropwise at 60°C to a solution of a 2:3 3R:3S mixture of isomers of 5R-azidomethyl-3-(4-{4-benzylpiperazin-l -yl}-3- fluorophenyl)dihydro-2(3H)-furanone (7.25g) in 1.2-dimethoxyethane (75ml). The mixture was refluxed for 30 minutes and then cooled to 50°C. 6N hydrochloric acid ( 12ml) was added dropwise and the mixture refluxed for 1 hour. The mixture was then cooled overnight and the dimethoxyethane removed under reduced pressure. Water (15ml) was added to the residue and the pH adjusted to 5-6 with 2.5N sodium hydroxide solution. Acetone (20ml) was added and mixture cooled to 0°C -5°C, and then sodium hydrogencarbonate (6g) added. This was followed by dropwise addition of acetic anhydride (2.2ml) at below 5°C. The mixture was stirred for 15 minutes at 0°C -5°C and then allowed to rise to ambient temperature. The mixture was stirred for a further 30 minutes at ambient temperature and then the product was extracted with ethyl acetate. The ethyl acetate was evaporated and the resulting oil purified by silica gel column chromatography using a mixture of methanol (5%) and dichloromethane as eluant. There was thus obtained a mixture of isomers of 5R-acetamidomethyl-3-(4-{4-benzyl-piperazin- l-yI}-3-fluorophenyl)dihydrofuran-2-(5H)-one (4.6g, 61% yield) in a 3R:3S ratio of 3:5. NMR (300MHz. DMSO-D6V 61.83 (s, 3H). 62.0 (m. IH (cis)), 62.41 (m, 2H (trans)), 62.5 (broad t, 4H). 62.55 (m, IH (cis)), 63.0 (broad t, 4H). 63.39 (m, 2H), 63.5 (s, 2H), 64.02 (m, IH), δ4.6 (m, IH), 66.95-67.1 (m, 3H). 67.28 (m, 5H), 68.16 (m. IH). MS: ESP+ (M+H)= 426. A solution (15 wt.%) of potassium bis(trimethylsilyl)amide in toluene (14.8ml) was added dropwise at equal to or below -70°C to a stirred solution of a 3:5 3R:3S mixture of isomers of 5R-acetamidomethyl-3-(4-{4-benzyl-piperazin-l-yl}-3-fluorophenyl)dihydrofuran-2- (5H)-one (4.3g) in THF (75ml). The mixture was stirred for a further 30 minutes, and then a solution of (lS)(+)-(10-camphor-sulfonyl)oxaziridine (2.3g) in THF (10ml) was added dropwise over 20 minutes at equal to or below -70°C. The mixture was stirred at -78°C for 2 hours and then allowed to warm to ambient temperature. The mixture was carefully added to 6N hydrochloric acid (20ml) and then water ( 10ml) was added. The pH was adjusted to 8 with saturated sodium hydrogencarbonate solution and the product extracted with ethyl acetate. The ethyl acetate was evaporated, and the residue by silica gel column chromatography using a mixture of methanol (10%) and dichloromethane as eluant. There was thus obtained a mixture of isomers of 5R-acetamido-methyl-3-(3-fiuoro-4-{4- benzylpiperazin- 1-yl} pheny l)-3-hydroxydihydrofuran-2(3H)-one (3.4g. 76% yield) in a 3R:3S ratio of 3:8. NMR ( 300MHz. DMSO-D6V 61.82 (s. 3H), 62.2 (m. IH (cis)), 62.41 (m, 2H (trans)), 62.5 (broad t. 4H), 62.65 (m, IH (cis)), 63.0 (broad t, 4H), 63.37 (m, 2H), 63.5 (s, 2H), 64.38 (m, IH (cis)), 64.7 (m, IH (trans)), 66.5 (s, IH (cis)), 66.68 (s, IH (trans)), 67.0 (t, IH), δ7.13(m, 2H), 67.28 (m, 5H), 68.18 (m, IH). ! 0 MS: ESP+ (M+H)= 442. Toluene-4-sulfonic acid (1.6g) was added to a stirred solution of a 3:8 3R:3S mixture of isomers of 5R-acetamido-methyl-3-(3-fluoro-4-{4-benzylpiperazin-l-yl}phenyl)-3- 15 hydroxydihydrofuran-2(3H)-one (3.05g) in glacial acetic acid (25ml). The mixture was refluxed for 1 hour, and then evaporated down to a gum which was taken up in ethyl acetate (100ml) and saturated sodium hydrogencarbonate solution (25ml). The organic phase was separated and re-washed with saturated sodium hydrogencarbonate solution (25ml). The solvent was evaporated to give the required 5R-acetamidomethyl-3-(3-fluoro- 0 4-{4-benzylpiperazin-l-yl}phenyl)furan-2-(5H)-one (3.16g, 99.8% yield) as a solid. NMR (300MHz. DMSO-D6); 61.75 (s, 3H), 62.5 (broad t, 4H), 63.08 (m, 4H), 63.42 (m, 2H), 63.51 (s, 2H), 65.2 (m, IH), 67.07 (t, IH), 67.3 (m, 5H), 67.59 (m, IH), 67.61 (s, IH), 67.88 (d, IH), 68.13 (m, IH). 5 MS: ESP+ (M+H)= 424. Example 8: Sodium hydrogencarbonate (208mg) was added at 0°-5°C to a stirred solution of the 0 hydrochloride salt of 5R-acetamidomethyl-3-(3-fluoro-4-piperazino-phenyl)furan-2-(5H)- one (Example 7) (208mg) in a 1 : 1 mixture of acetone and water ( 15ml). The mixture was stirred for 5 minutes and then methanesulfonyl chloride (0.08g) was added. The mixture was stirred for a further 30 minutes and then brine ( 15ml) was added. The product was extracted with ethyl acetate, and the organic phase evaporated down to a gum which was triturated with ethyl acetate and a few drops of methanol. The resulting solid was filtered and dried to give 5R-acetamidomethyl-3-(3-fluoro-4-{4-methanesulfonylpiperazin-l-yl}- phenyl)furan-2-(5H)-one (178mg, 79% yield). NMR ( 300MHz. DMSO-D6V. 61.75 (s, 3H), 62.91 (s, 3H), 63.14 (broad t, 4H), 63.29 (broad t, 4H), 63.42 (m, 2H), 65.22 (m, IH), 67.1 (t, IH), 67.62 (s, IH), 67.64 (m, IH), δ7.9 (d, IH), 68.12 (broad t, IH). MS: ESP+ (M+H)= 412 Example 9; Acetic anhydride (0.12ml) was added at O°C-5°C to a solution of a 1 :1 3R:3S mixture of isomers of 5R-aminomethyl-3-(4-{4-benzyloxycarbonyl-piperazin-l - yl}phenyl)dihydrofuran-2-(3H)-one (0.46g) in acetonitrile (15ml), and the mixture allowed to warm to ambient temperature. The mixture was stirred for 30 minutes before being evaporated down. The residue was purified by silica gel column chromatography using a mixture of methanol (3%) and ethyl acetate as eluant. There was thus obtained a mixture of isomers of 5R-acetamidomethyl-3-(4-{4-benzyloxycarbonyl-piperazin-l- yl}phenyl)dihydrofuran-2-(3H)-one (250mg, 49% yield) in a 3R:3S ratio of 2:1. NMR (300MHz. DMSO-D6V δl.85 (s, 3H), 62.0 (m, IH (cis)), 62.38 (m, 2H (trans)), 62.59 (m, IH (cis)), 63.1 (broad m, 4H), 63.4 (m, 2H), 63.55 (broad t, 4H), 63.95 (m, IH), 64.57 (m, IH), 65.15 (s, 2H), 66.92 (d, 2H), 67.13 (d, 2H), 67.35 (m, 5H), 68.15 (m, IH). MS: ESP+ (M+H)= 452.4 The mixture of isomers of 5R-aminomethyl-3-(4-{4-benzyloxycarbonyl-piperazin-l- yl}phenyl)dihydrofuran-2-(3H)-one used as starting material was obtained as follows:- A solution of di-I≤Q-butyl dicarbonate (66g) in dichloromethane (100ml) was added dropwise at below 10°C to a stirred solution of 4-piperazinoacetophenone (62g) in dichloromethane (500ml). and the mixture stirred for 1 hour at 10°C. The mixture was poured into water (300ml) and the organic phase separated and re-washed twice with water, and then brine. The dichloromethane and tert-butanol were removed under reduced pressure to give 4-(4-ieH-butyloxycarbonyl-piperazin-l-yl)acetophenone (91.3g, 99.7 %) as a solid. NMR ( 250MH/. DMSO-D6V 61.43 (s, 9H), 62.45 (s, 3H), 63.35 (m. 4H), 63.46 (m, 4H), 66.96 (d, 2H), 67.82 (d, 2H). MS: ESP+ (M+H)= 305.2. A mixture of 4-(4-t£fl-butyloxycarbonyl-piperazin- 1 -yl)acetophenone (86.3g), elemental sulfur (13.6g) and moφholine (37g) was refluxed for 5 hours and then cooled to 50°C. A 1 :1 mixture of ethyl acetate and iso-hexane (200ml) was added and the mixture refluxed for 5 minutes. The mixture was cooled to ambient temperature and the resulting solid filtered and dried to give N-[2-(4-(4-tert-butyloxycarbonylpiperazin-l-yl}phenyl)-1 - thioxojethylmoφholine (80g, 70% yield). NMR ( 200MHz. DMSO-D6.: 61.43 (s, 9H), 63.05 (broad m, 4H), 63.4 (broad m. 6H), 63.6-63.8 (broad m. 4H), 64.2 (m, 4H), 66.9 (d, 2H), 67.19 (d, 2H). MS: CI+ (M+H)= 406. Concentrated hydrochloric acid (300ml) ) was added to a suspension of N-[2-(4-{4-lerl- butyloxycarbonylpiperazin- 1-yl} phenyl)- l-thioxo]ethylmoφholine (50g) in water (100ml) and the mixture refluxed ovemight. At the end of this period the pH of the mixture was adjusted to 10 with 5N sodium hydroxide solution. Benzyl chloroformate (48.2g) was added dropwise at below 10°C. whilst maintaining the pH at 10 with 2.5N sodium hydroxide solution. The mixture was stirred for 2 hours at ambient temperature and the pH then adjusted to 4. The product was extracted into ethyl acetate which was then evaporated down to an oil. The oil was taken up in water (300ml) and the pH again modified to 10 and mixture extracted with ethyl acetate. The ethyl acetate was discarded and the pH ofthe aqueous phase was then brought back to 4. The product was extracted into ethyl acetate, which was evaporated down to a solid. The solid was recrystallised from a mixture of iso¬ hexane and ethyl acetate to give 4-(4-benzy loxycarbony lpiperazin- 1-yl)- phenylacetic acid (16.6g, 38% yield). NMR (200MHz. DMSO-P6); δ3.1 (broad t. 4H), 63.45 (s. 2H). 63.55 (broad t, 4H), 65.11 (s, 2H), 66.9 (d, 2H). 67.1 1 (d. 2H). 67.38 (m, 5H). MS: ESP+ (M+H)= 355.2. Sulfuryl chloride (0.8ml) was added dropwise at 0°-5°C to a stirred solution of 4-(4- benzyloxycarbony lpiperazin- 1-y l)pheny lacetic acid (12g) in methanol (150ml). The mixture was stirred at ambient temperature over a weekend and then evaporated down to an oil, which was dissolved in dichloromethane. The dichloromethane solution was washed with saturated sodium hydrogencarbonate solution and evaporated to give methyl 4-(4- benzyloxycarbonylpiperazin- 1 -y pheny lacetate as a solid ( 1 1.3g, 93% yield). NMR ( 200MHz. DMSO-D6.: 63.08 (broad t, 4H), 63.55 (broad t, 4H + s, 2H), 3.62 (s, 3H), 65.1 (s, 2H), 66.89 (d, 2H), 67.12 (d, 2H), 67.34 (m, 5H). MS: ESP+ (M+H)= 369.2 DMPU (5ml) was added to a stirred solution of methyl 4-(4-benzyloxy-carbonylpiperazin- l-yl)phenylacetate (7.8g) in THF (180ml), and the mixture cooled to -78°C. A 1.5M solution of LDA in n-hexane (15.5ml) was added dropwise at below or equal to -70°C, and the mixture stirred for 20 minutes before being allowed to rise to 0°C. The mixture was stirred for a further 20 minutes and then (S)-(2.2-dimethyl-1.3-dioxane-4)iodomethane (5.6g) was added dropwise at below -70°C and the mixture stirred overnight, whilst warming to ambient temperature. At the end of this period the mixture was cooled to below 10°C and ice-cold water (80ml) added carefully. The pH was adjusted to 7 with 2N hydrochloric acid, and the resulting organic phase isolated. The remaining aqueous phase was re-extracted with ethyl acetate and the combined organic phases evaporated. The residue was dissolved in THF (50ml) and 2N hydrochloric acid (50ml) added. The mixture was stirred at 40°C for 3 hours, and the pH then adjusted to 7 with 5N sodium hydroxide solution. The product was extracted into ethyl acetate, which was evaporated down to give a residue which was purified by silica gel column chromatography using ethyl acetate as eluant. There was thus obtained a mixture of isomers of 5R-hydroxymethyl-3-(4-{4- ben_-yloxycarbonylpiperazin-l-yl}phenyl)dihydrofuran-2(3H)-one (2.8g, 32% yield) as a solid in a 3R:3S ratio of 1 : 1. NMR (200MHz. DMSO-D6 62.12 (m, IH (cis)), 62.35 (m, 2H (trans)), 62.55 (m, IH (cis)), 63.12 (broad t, 4H), 63.53 (broad t, 4H), 63.65 (m, IH), 63.95 (m, IH), 64.6 (m, IH), 65.1 (s, 2H), 66.92 (d, 2H), 67.15 (d, 2H), 67.4 (m, 5H). MS: ESP+ (M+H)=411.2. Methanesulfonyl chloride (0.9g) was added slowly at 0°-5°C to a solution of a 1 : 1 3R:3S mixture of isomers of 5R-hydroxymethyl-3-(4-{4-benzyloxycarbonyl-piperazin- 1 - yl}phenyl)dihydrofuran-2(3H)-one (2.7g) in pyridine (25ml), and the mixture stirred for 1 hour. The mixture was then allowed to rise to ambient temperature and stirred overnight. At the end of this period ice-cold water (30ml) was added and extracted with dichloromethane. The organic phase was separated and evaporated down to give a residue which was purified by silica gel column chromatography using a 3:1 mixture of dichloromethane and ethyl acetate as eluant. There was thus obtained a mixture of isomers of 5R-methylsulfonyloxymethyl-3-(4-{4-benzyloxycarbonylpiperazin-l -yl}phenyl)- dihydrofuran-2(3H)-one (1.85g, 58% yield) as an oil in a 3R:3S ratio of 1 :1. NMR (200MHz. DMS -D6); 62.1 1 (m. IH (cis)). 6 ca.2.5 (m. 2H (trans)), 62.65 (m, IH (cis)), 63.13 (broad t. (4H)). 63.23 (s. 3H). 63.25 (s, 3H), 63.55 (broad t. 4H), 63.9- δ4.24(m, IH), 64.48 (m. 2H). 65.12 (s. 2H), 66.95 (d. 2H), 67.18 (d, 2H), 67.38 (m, 5H). MS ESP+ (M+H)= 489.2. Sodium azide (0.5g) was added to a solution of a 1 :1 3R:3S mixture of isomers of 5R- methylsulfonyloxymethyl-3-(4-{4-benzyloxycarbonylpiperazin-l-yl}phenyl)- dihydrofuran-2(3H)-one (1.8g) in DMF (25ml), and the mixture stirred at 80°C for 3.5 hours. The mixture was then cooled and poured into water. The product was extracted into ethyl acetate, which was washed with water and then removed under reduced pressure to give an oil. The oil was purified by silica gel column chromatography using ethyl acetate as eluant. There was thus obtained a mixture of isomers of 5R-azidomethyl-3-(4-{4- benzyloxycarbonylpiperazin-l-yl}phenyl)dihydrofuran-2(3H)-one (l.Og, 62.5 % yield) in a 3R:3S ratio of 3:4. NMR ( 200MHz. DMSO-D6.: 62.09 (m. IH (cis)), 62.44 (m, 2H (trans)), 62.63 (m, IH (cis)), 63.12 (m, 4H), 63.55 (broad t. 4H), 63.7 (m, 2H), 64.03 (m, IH), 64.77 (m, IH), 65.13 (s, 2H), 66.93 (d, 2H). 67.16 (d, 2H), 67.38 (m. 5H). MS: ESP+ (M+H)= 436.3. Triphenylphosphine (0.6g) was added to a solution of a 3:4 3R:3S mixture of isomers of 5R-azidomethyl-3-(4-{4-benzyloxycarbonylpiperazin-l-yl}phenyl)dihydrofuran-2(3H)-one (0.9g) in THF (25ml). The mixture was stirred at 50°C for 4 hours and then at ambient temperature over a weekend. The THF was removed under reduced pressure and the residue purified by silica gel column chromatography using a mixture of methanol (15%) and dichloromethane as eluant. There was thus obtained the mixture of isomers of 5R- aminomethyl-3-(4-{4-benzyloxycarbonylpiperazin-l-yl}phenyl)dihydrofuran-2(3H)-one (0.46g, 54% yield) in a 3R:3S ratio of 1 : 1 which was used as starting material. NMR (200MHz. DMSQ-D6.: 62.1 (m. IH (cis)). 6 ca.2.35 (m, 2H (trans)), δ ca.2.55 (m, IH (cis)), 62.84 (m. 2H), 63.11 (broad t. 4H). 63.56 (broad t, 4H), 63.98 (m. IH), 64.5 (m, IH), 65.1 (s. 2H), 66.91 (d. 2H). 67.15 (d. 2H). 57.35 (m. 5H). MS FAB+ (M+H)= 410 Example 10: A 2M solution of boron trichloride/methyl sulfide complex in dichloromethane (2ml) was added dropwise to a stirred solution of 5R-acetamidomethyl-3-(3-fluoro-4-{4- benzyloxyacety lpiperazin- 1 -yl }phenyl)furan-2-(5H)one (0.32g) in dichloromethane (50ml), and the mixture stirred at ambient temperature for 30 minutes. Methanol (20ml) was added and the mixture evaporated to dryness. More methanol (50ml) was added and the mixture again evaporated to dryness and the procedure repeated once more. The residue was purified by silica gel column chromatography using a mixture of methanol (10%) and dichloromethane as eluant. There was thus obtained 5R-acetamidomethyl-3-(3-fluoro-4- {4-hydroxyacetylpiperazin-l-yl}phenyl)furan-2-(5H)-one (130mg, 55% yield). NMR ( 300MHz. DMS Q -D6V 51.75 (s, 3H), 63.05 (broad, 4H), 63.43 (m, 2H), 63.5 (broad, 2H), 63.61 (broad. 2H), 64.1 (d, 2H), 64.61 (t, IH), 65.22 (m, IH), 67.09 (t, IH), 67.62 (m, 2H), 57.9 (d, IH), 8.12 (t, IH). MS: ESP+ (M+H)= 392 Tιιe 5R-acetamidome l-3-(3-fluoro-4-{4-ben--yloxyacetylpiperazin-l-yl}pheny0furan-2- (5H)one used as starting material was obtained as follows:- Sodium hydrogencarbonate (370mg) was added to a stirred solution ofthe hydrochloride salt of 5R-acetamidomethyl-3-(3-fluoro-4-piperazino-phenyl)furan-2-(5H)-one (Example 7) (0.37g) in a 2:1 mixture of acetone and water (15ml), and the mixture cooled to 0°C- 5°C. Benzyloxyacetyl chloride (0.24g) was added dropwise and the mixture stirred for 20 minutes before being allowed to rise to ambient temperature and stirring for a further 15 minutes. Water ( 10ml) was added and the solution extracted with ethyl acetate, which was evaporated down and the residue purified by silica gel column chromatography using a mixture of methanol ( 10%) and dichloromethane as eluant. There was thus obtained the required 5R-acetamidomethyl-3-(3-fluoro-4-{4-benzyloxyacetylpiperazin-l- yl}phenyl)furan-2-(5H)one (328mg. 68% yield) as an oily solid. NMR ( 300MHz. DMS Q -D6.: 61.75 (s, 3H). 63.08 (broad, 4H), 63.42 (m, 2H), 63.59 (broad m, 4H), 64.23 (s, 2H), 64.5 (s,2H), 65.21 (m, IH), 67.08 (t, IH), 67.32(m, 5H), 67.63 (m, 2H), 67.9 (d, IH), 68.1 (t, IH). MS: ESP+ (M+H)= 482. Example 11: 1 -Chloroethylchloro formate (1.5ml) was added dropwise at 0°C -5°C to a stirred solution of 5R-acetamidomethyl-3-(4-{4-benzylpiperazin-l-yl}phenyl)furan-2(5H)-one (Example 5) (4.90g) in dichloromethane (50ml). The mixture was allowed to rise to ambient temperature over 15 minutes, and then refluxed for 30 minutes. The bulk ofthe dichloromethane was removed under reduced pressure and the residue dissolved in methanol (50ml), refluxed for 2 hours and then evaporated down to a low volume. The reside was triturated with diethyl ether to give 5R-acetamidomethyl-3-(4- piperazinophenyl)furan-2-(5H)-one as a hydrochloride salt (2.9g, 68% yield). NMR ( 300MHz. DMS Q -D6.: δl.75 (s, 3H), 63.2 (broad, 4H), 63.42 (broad, 6H), 65.18 (m, IH), 67.04 (d. 2H), 67.75 (m, 3H), 68.19 (t, IH), 9.26 (broad, 2H). MS ESP+ (M+H)= 316. Example 12: Sodium hydrogencarbonate (lOOmg) and then acetoxyacetyl chloride (51mg) was added at 0°C-5°C to a stirred solution of the hydrochloride salt of 5R-acetamido-methyl-3-(4- piperazino-phenyl)furan-2-(5H)-one (Example 1 \ ) (l OOmg) in a 2: 1 mixture of acetone and water (9ml). The mixture was stirred at 0°C-5°C for 15 minutes, allowed to rise to ambient temperature and stirred for a further 30 minutes. Water (10ml) was added and the solution extracted with ethyl acetate and dichloromethane. The combined organic extracts were evaporated down and the resulting gum purified on an Isolute column to give 5R- acetamidomethyl-3-(4-{4-acetoxyacetylpiperazin-l-yl}phenyl)furan-2-(5H)-one (100mg, 85% yield). NMR (3Q0MHZ. DMSQ-D6); δl.70 (s, 3H), 62.05 (s, 3H), 63.22 (broad m, 4H), 63.41 (m, 2H), 63.52 (broad m, 4H), 64.79 (s. 2H), 65.13 (m, IH), 66.99 (d, 2H), 67.7 (m, 3H), 68.12 (t. IH). MS: ESP+ (M+H)=416. Example 13; H-Hydroxysuccinimide (73mg), 4-dimethylaminopyridine ( 1 Omg) and 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (123mg) were added to a stirred suspension of H,N-dimethylglycine (66mg) in pyridine (15ml). The mixture was stirred for 15 minutes at ambient temperature and then at 50°C for another 15 minutes. The hydrochloride salt of 5R-acetamidomethyl-3-(4-piperazinophenyl)furan-2-(5H)-one (Example 1 1 ) (150mg) was added and the mixture stirred at ambient temperature ovemight. The mixture was then evaporated down, brine added to the residue and the product extracted with iso-propanol. The bulk ofthe impurities were removed on an Isolute column, and the resulting product was dissolved in methanol. Concentrated hydrochloric acid was added and the resulting solid purified by silica gel column chromatography using a 1 : 1 mixture of methanol and dichloromethane as eluant. There was thus obtained the hydrochloride salt of 5R-acetamidomethyl-3-(4-{4-dimethylaminoacetyl-piperazin-l- yl}phenyl)furan-2-(5H)-one (66mg, 39% yield). NMR ( 300MHz. DMS Q -D6.: δl.75 (S, 3H), 62.79 (s, 3H). 62.8 (s, 3H). 63.22 (m. 2H), 63.3 (m, 2H), 63.41 (m. 2H), 3.48 (m, 2H), 63.63 (m, 2H), 64.33 (broad d. 2H). 65.18 (m. IH). 67.02 (d. 2H). 67.7 (m. 3H), 68.19 (t, IH). 69.7 (m, IH). MS: ESP+ (M+H)=401. Example 14: A catalytic quantity of pyridine (3 drops) was added to a stirred solution of a 3:1 3R:3S mixture of isomers of 5R-acetamidomethyl-3RS-hydroxy-3-(3-fluoro-4- thiomoφholinophenyl)dihydrofuran-2(3H)-one (0.46g) in chloroform (15ml) and the mixture cooled to -5°C. Phosphorous tribromide (300mg) was added and the mixture stirred for 4 hours at -5°C. At the end of this period saturated sodium hydrogencarbonate solution was added until pH 7-8 was reached. The mixture was extracted with chloroform and ethyl acetate and the combined organic phases evaporated. The residue was then purified on an Isolute column using a mixture of methanol (10%) and dichloromethane as eluant. There was thus obtained 5R-acetamidomethyl-3-(3-fluoro-4- thiomoφholinophenyl)furan-2-(5H)-one (0.22g, 50% yield) as a solid. NMR (300MHz. CDC13.: 61.94 (s, 3H), 62.8 (t, 4H), 63.39 (m, 4H), 63.6 (m, IH), 63.72 (complex, IH), 65.12 (m, IH), 65.88 (broad t, IH), 66.91 (t, IH), 67.42 (d, IH), 67.57 (s, IH), 67.59 (m, IH). MS ESP+(M+H)= 351. The 3:1 3R:3S mixture of isomers of 5R-acetamidomethyl-3RS-hydroxy-3-(3-fluoro-4- thiomoφholinophenyl)dihydrofuran-2(3H)-one used as starting material was obtained as follows: - A solution (15 wt %) of potassium bis(trimethylsilyl) amide in toluene (4ml) was added dropwise at below -70°C to a stirred solution of a 3:1 3R:3S mixture of isomers of 5R- acetamidomethyl-3-(3-fluoro-4-thiomoφholinophenyl)-3H-dihydrofuran-2-one (Example 1) (lg) in anhydrous THF (50ml), and the mixture stirred for 30 minutes. (lS)-(+)-(10- CamphorsulfonyOoxaziridine (0.68g) was added and the mixture stirred at -70°C for 2.5 hours, and then allowed to rise to ambient temperature. The mixture was carefully poured into a solution of concentrated hydrochloric acid (0.4ml) in water (20ml). The pH was adjusted to 7.0 with 2.5N sodium hydroxide solution and the product extracted with ethyl acetate. The ethyl acetate was evaporated and the residue purified on an Isolute column using a mixture of methanol ( 10%) and dichloromethane as eluant. There was thus obtained the required mixture of isomers of 5R-acetamidomethyl-3RS-hydroxy-3-(3- fluoro-4-thiomoφholino-phenyl)dihydrofiιran-2(3H)-one (0.8g, 76% yield) in a 3R:3S ratio 3:1. NMR (300MHz. PMSO-D6); 61.81 (s, 3H), 62.2 (m, 2H (cis)), 62.42 (m, 2H (trans)), 62.72 (broad t, 4H), δ3.25 (broad t. 4H), 63.38 (m. 2H), 64.37 (m, IH (cis)), 64.7 (m, IH (trans)), 66.5 (s, IH (cis)), 66.7 (s, IH (trans)), 67.02-67.27 (m, 3H), 68.18 (broad m. IH). MS: ESP+ (M+H)= 369.1 Reference Example: Finely ground potassium carbonate (1.96g) and phenyl disulphide (0.8g) were added to a solution of a 3:1 3R:3S mixture of isomers of 5R-acetamidomethyl-3-(3-fluoro-4-thio- moφholinophenyl)dihydrofuran-2(3H)-one (lg) in 1 ,2-dimethoxyethane (40ml). The mixture was refluxed for two days, cooled and drowned out into 0.6N hydrochloric acid (30ml). The mixture was extracted with ethyl acetate (3 x 50ml), the ethyl acetate layers separated and evaporated down. The product so obtained was purified using a lOg bond-elute column to give a mixture of isomers of 5R-acetamidomethyl-3-phenylthio-3- (3-fluoro-4-thiomoφholinophenyI)dihydrofuran-2(3H)-one (0.3g, 23% yield) in a cis:trans ratio of 1 :2. NMR (25QMHZ. DMSQ- ^ δl .75(s,3H(cis)), 1.8(s,3H(trans)), 2.35 (m, lH(cis)), 2.55 (m,lH(trans)), 2.70 (m,4H), 2.80 (m,lH(trans)), 3.0 (m,lH(cis)), approximately 3.3 (m,4H), approximately 3.35 (m,2H), 4.3(m,lH(cis)), 4.65(m,lH(trans)), 7.25(m,8H), 8.0(t,lH(cis)), 8.1 (UH(trans)). MS: ESP+(M+H)=461.

Claims: CLAIMS 1. A compound of the formula (I): CH NHCCH, (I) wherein: -A-B- is ofthe formula >C=CH- or >CHCH 2 - R' and R2 are independently hydrogen or fluorine; R and R^ are independently hydrogen or methyl; D is O. S, SO, SO 2 or of the formula R^N wherein R^ is hydrogen or benzyl; or R^ is of the formula R 6 CO- or R 6 SO 2 - wherein R 6 is amino, ( 1 -4C)alkylamino, di-(( 1 -4C)alkyl)- amino or (l-6C)alkyl optionally substituted by hydroxy, cyano. amino, ( l-4C)alkylamino, di-((l-4C)alkyl)amino, or (l-4C)alkylS(O) n _, wherein n is 1 or 2, or R > is ofthe formula R?C(O)O( 1 -6C)alkyl wherein R? is optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl or optionally substituted (l-6C)alkyl, or R^ is ofthe formula R^O-, wherein R* is benzyl or optionally substituted (l-6C)alkyl; or R^ is ofthe formula R 10 CH(R 9 )(CH2)m- wherein m is 0 or 1, R 9 is fluoro, cyano, (l-4C)alkoxy, (l-4C)alkyl- sulfonyl, (l-4C)alkoxycarbonyl or hydroxy, (provided that when m is 0, R 9 is not hydroxy) and RO is hydrogen or (l-4C)alkyl; and pharmaceutically-acceptable salts thereof. 2. A compound ofthe formula (I) as claimed in claim 1 wherein : -A-B- is of the formula >C=CH- or >CHCH 2 - R! and R2 are independently hydrogen or fluorine; R3 and R^ are independently hydrogen or methyl; D is O. S, SO, SO 2 or ofthe formula R^N wherein R^ is benzyl; or R^ is ofthe formula R 6 CO- or R 6 SO 2 - wherein R 6 is amino. (l-4C)alkylamino. di-((l-4C)alkyl)-amino or (1- 6C)alkyl optionally substituted by hydroxy. cyano. amino, (l-4C)alkylamino, di-((l- 4C)alkyl)amino. or (l-4C)alkylS(O) n _, wherein n is 1 or 2, or R > is ofthe formula R^C(O)O(l-6C)alkyl wherein R? is optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl or optionally substituted (l-6C)alkyl, or R is ofthe formula R8O-. wherein R^ is benzyl or optionally substituted (l-6C)alkyl; or R^ is of the formula R 10 CH(R 9 )(CH2) m - wherein m is 0 or 1, R 9 is fluoro, cyano, (l-4C)alkoxy, (l-4C)alkyl- sulfonyl, ( 1 -4C)alkoxycarbonyl or hydroxy, (provided that when m is 0, R 9 is not hydroxy) and Rl j s hydrogen or (l-4C)alkyl: and pharmaceutically-acceptable salts thereof. 3. A compound ofthe formula (I) as claimed in claim 1 wherein : -A-B- is ofthe formula >C=CH- ; Rl and R^ are independently hydrogen or fluorine; R3 and R^ are independently hydrogen or methyl; D is O, S, SO, SO 2 or ofthe formula R^N wherein R^ is benzyl; or R^ is ofthe formula R 6 CO- or R 6 SO 2 - wherein R 6 is amino, (l-4C)alkylamino, di-((l-4C)alkyl)-amino or (1- 6C)alkyl optionally substituted by hydroxy, cyano. amino, (l-4C)alk lamino, di-((l- 4C)alkyl)amino. or (l-4C)alkylS(O) n _, wherein n is 1 or 2, or R > is ofthe formula R^C(O)O(l-6C)alkyl wherein R? is optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl or optionally substituted (l-6C)alkyl, or R*> is ofthe formula R^O-, wherein R^ is benzyl or optionally substituted (l-6C)alkyl; or R^ is ofthe formula R 10 CH(R 9 )(CH2) m - wherein m is 0 or 1, R 9 is fluoro, cyano, ( 1 -4C)aIkoxy, (l-4C)alkyl- sulfonyl, (l-4C)alkoxycarbonyl or hydroxy, (provided that when m is 0, R 9 is not hydroxy) and RO i s hydrogen or (l-4C)alkyl; and pharmaceutically-acceptable salts thereof. 4. A compound ofthe formula (I) as claimed in claim 1 wherein : -A-B- is ofthe formula >C=CH- ; R 1 and R^ are independently hydrogen or fluorine; R3 and R^ are hydrogen; D is O. S, or ofthe formula R^N wherein R^ is benzyl, or R$ is of the formula R^CO- or R 6 SO r wherein R 6 is amino. (l-4C)alkylamino. di-((l-4C)alkyI)-amino or (l-6C)alkyl optionally substituted by hydroxy. cyano. amino. (l-4C)alkylamino. di-((l- 4C)alkyl)amino, or (l-4C)alkylS(O) n ., wherein n is 1 or 2, or R*> is of the formula R 7 C(O)O(l-6C)alkyl wherein R 7 is pyridyl or imidazol-1-yl, phenyl optionally substituted by (l-4C)alkylamino(l-6C)alkanoyl and hydroxy(l-6C)alkyl; or (l-6C)alkyl optionally substituted by hydroxy, cyano and (l-4C)alkoxy; or R is ofthe formula R 8 O-, wherein R 8 is benzyl or ( 1 -6C)alkyl optionally substituted by hydroxy, ( 1 -4C)alkoxy and cyano; or R5 is ofthe formula Rl cH(R 9 )(CH2) m - wherein m is 0 or 1, R 9 is fluoro or cyano and Rl is hydrogen; and pharmaceutically-acceptable salts thereof. 5. A compound ofthe formula (I) as claimed in claim 1 wherein : -A-B- is ofthe formula >C=CH- ; Rl and R2 are independently hydrogen or fluorine; R3 and R^ are hydrogen; D is O, S, or ofthe formula R 5 N wherein R 5 is ofthe formula R 6 CO- or R 6 SO 2 - wherein R 6 is hydroxymethyl or ofthe formula R 7 C(O)O(l-6C)alkyl wherein R 7 is dimethylamino(l-6C)alkyl; or R 6 is ofthe formula R 8 O-, wherein R 8 is (l-6C)alkyl; or R 5 is ofthe formula R 10 CH(R 9 )(CH2) m - wherein is 0 or 1, R 9 is fluoro or cyano and R 10 is hydrogen; and pharmaceutically-acceptable salts thereof. 6. A compound ofthe formula (I) as claimed in claim 1 wherein : -A-B- is ofthe formula >C=CH- ; Rl and R.2 are independently hydrogen or fluorine; R3 and R^ are hydrogen; D is S, or ofthe formula R^N wherein R$ is ofthe formula R6SO 2 - wherein R*> is (1- 6C)alkyl; and pharmaceutically-acceptable salts thereof. 7. A compound ofthe formula (I), or a pharmaceutically-acceptable salts thereof, as claimed in claim 1 selected from :- 5R-acetamidomethyl-3-(3-fluoro-4-moφholinophenyl)furan-2(5H)-one and 5R-acetamidomethyl-3-(3-fluoro-4-thiomoφholinophenyl)furan-2-(5H)-one. 8. A process for the preparation of a compound ofthe formula (I) as claimed in claims 1 to 6 which comprises :- (a) when -A-B- is >C=CH-, the elimination of HBr from the related compound wherein -A-B- is >CBr-CH2-; (b) when -A-B- is >C=CH, the oxidation of -SPh in the related compoimd wherein -A-B- is >C(SPh)-CH2-, causing its subsequent elimination; (c) the reaction of a compound ofthe formula (IV) with a compound ofthe formula (V); (IV) CH3COL (V) d) when D is ofthe formula R^N and R^ is ofthe formula R^CO-, the reaction of a compound ofthe formula (VI) with a compound ofthe formula R^COL^ : H (VI) e) when D is ofthe formula R^N and R^ is ofthe formula R^SO2-, the reaction of a compound ofthe formula (VI) with a compound ofthe formula R SO2--2; f) when D is of the formula R 5 N and R 5 is of the formula R l °CH(R 9 )-, the reaction of a compound of the formula (VI) with a compound ofthe formula R^ cH(R )L^; g) when D is of the formula R 5 N and R 5 is of the foπnula R 1 °CH(R 9 )CH2_, the reduction of a compound ofthe formula (VII): H, (VII) h) when D is of the formula R 5 N, R5 is of the formula R 1 °CH(R 9 )CH2. and R 9 is not hydroxy, fluoro or ( 1 -4C)alkoxy, the reaction of a compound of the formula (VI) with a compound ofthe formula R l 0 C(R 9 )=CH2; i) when D is ofthe formula R 5 N and R5 is ofthe formula R 10 CH(OH)CH2-, the reaction of a compound ofthe formula (VI) with a compound ofthe formula (VIII): 10 CH 2 -CHR (VIII) j) when D is ofthe formula SO or SO2 5 the oxidation of a compound ofthe formula (IX): (IX) k) when -A-B- is >CH=CH-, the dehydration ofthe related hydroxy compound wherein -A-B- is >C(OH)-CH 2 -; or 1) when D is of the formula R N wherein R 5 is hydrogen, the N-dealkylation of the related compound wherein R 5 is benzyl or (l-4C)alkyl; wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 9 , R 10 , A and B are as hereinabove defined and L, L 1 , L 2 and ] are leaving groups and X- is a counter ion; and wherein any functional groups are optionally protected and thereafter, if necessary, any protecting groups are removed and, if necessary, a pharmaceutically-acceptable salt formed; and when an optically active form of a compound ofthe 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 ofthe compound or intermediate using a standard procedure. 9. A pharmaceutical composition which comprises a compound ofthe formula (I) or a pharmaceutically-acceptable salt thereof, as claimed in any of claims 1 to 7 and a pharmaceutically-acceptable diluent or carrier. 10. The use of a compound ofthe formula (I) or a pharmacetuically-acceptable salt thereof, as claimed in any of claims 1 to 7 in the manufacture of a novel medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.

Inventors: GRAVESTOCK MICHAEL BARRY, GRAVESTOCK, MICHAEL, BARRY
Applicants: GRAVESTOCK MICHAEL BARRY, ZENECA LTD, GRAVESTOCK, MICHAEL, BARRY, ZENECA LIMITED
Application year: 1996
Main classification: C07D307
IPC codes: A61K31, A61P31, C07D307