MONOCYCLIC BETA-LACTAME DERIVATIVES FOR TREATMENT OF ATHEROSCLEROSIS

Abstract: Compounds of formula (I) are prodrugs of the corresponding compounds in which CO2R<3> is CO2H. These are inhibitors of the phospholipase A2 enzyme Lp-PLA2 and of use in treating atherosclerosis.

Description: MONOCYCLIC BETA-LACTAME DERIVATIVES FOR TREATMENT OF ATHEROSCLEROSIS The present invention relates to certain novel monocyclic β-lactam compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy, in particular in the treatment of atherosclerosis. WO 95/00649 (SmithKline Beecham pic) describe the phospholipase A2 enzyme Lipoprotein Associated Phospholipase A2 (Lp-PLA2), the sequence, isolation and purification thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA encoding the enzyme. Suggested therapeutic uses for inhibitors of the enzyme included atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. A subsequent publication from the same group further describes this enzyme (Tew D et al, Arterioscler Thromb Vas Biol 1996: 16;591-9) wherein it is referred to as LDL-PLA2. A later patent application (WO 95/09921 , Icos Corporation) and a related publication in Nature (Tjoelker et al, vol 374, 6 April 1995, 549) describe the enzyme PAF-AH which has essentially the same sequence as Lp-PLA2 and suggest that it may have potential as a therapuetic protein for regulating pathological inflammatory events. It has been shown that Lp-PLA2 is responsible for the conversion of phosphatidylcholine to lysophosphatidylcholine, during the conversion of low density lipoprotein (LDL) to its oxidised form. The enzyme is known to hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid. Both products of Lp-PLA2 action are biologically active with lysophosphatidylcholine, a component of oxidised LDL, known to be a potent chemoattractant for circulating monocytes. As such, lysophosphatidylcholine is thought play a significant role in atherosclerosis by being responsible for the accumulation of cells loaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis. The increased lysophosphatidylcholine content of oxidatively modified LDL is also thought to be responsible for the endothelial dysfunction observed in patients with atherosclerosis. Inhibitors of Lp-PLA2 could therefore prove beneficial in the treatment of this phenomenon. An Lp-PLA2 inhibitor could also find utility in other disease states that exhibit endothelial dysfunction including diabetes, hypertension, angina pectoris and after ischaemia and reperfusion. In addition, Lp-PLA2 inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 . Examples of such disorders include psoriasis. Furthermore, Lp-PLA2 inhibitors may also have a general application in any disorder that involves lipid peroxidation in conjunction with Lp-PLA2 activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids. Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995). International patent applications WO 96/13484, WO 96/19451 and PCT EP96/02765 (SmithKline Beecham pic) describe a series of azetidinone derivatives which are inhibitors of Lp PLA2. Compounds disclosed therein having a terminal carboxyl substituent at C4 were found to have good activity in in vitro assays of Lp-PLA2 activity. It was however found that, in in vivo animal models, the activity of these carboxyl compounds when given orally was compromised by a poor pharmacokinetic profile. This problem was not overcome by using the simple alkyl or alkenyl ester derivatives also disclosed therein. It has been found that this problem may be overcome by using more sophisticated ester derivatives as 'pro-drugs'. Accordingly, the present invention provides a compound of formula (I): in which: R.1 and R~, which may be the same or different, is each selected from hydrogen, halogen or C( 1 . 8 )alkyl; R.3 is a pharmaceutically acceptable in vivo hydrolysable ester; R and R^ which may be the same or different is each selected from hydrogen, Cπ _6)alkyl, Cn^alkenyl, aryl, aryl(Cι_4)alkyl and heteroaryl(Cι_4)alkyl each of which may be optionally substituted or R^ and R^ may be linked together to form the remainder ofa (C3_7)cycloalkyl ring; X is a linker group; Y is an optionally substituted aryl group; and l\ is O and 7X is Cπ .gjalkyl, arylC ]_,_nalkyl or aryl each of which may be optionally substituted, or - 2 Zl is S(O)n in which n is 0, 1 or 2 and Z is C^j.g^alkyl, Cπ-8) c y c l oa ^ c yl' C ( -3.8)cycloalkylCn _6)alkyl, aryl, arylCπ_4)alkyl, heteroaryl or heteroarylCn.4)alkyl each of which may be optionally substituted; and excluding compounds in which: (a) R and R^ is each hydrogen, Z^ is S(O)n in which n is 0, 1 or 2 and Z^ is Cπ _8)alkyl, Cp.g^cycloalkyl or C(3_g)cycloalkylCπ _5)alkyl; or (b) R^ is Cπ _6)alkyl or C -ό^lkenyl. Compounds of formula (I) are inhibitors of Lp-PLA2 and as such are expected to be of use in treating atherosclerosis and the other disease conditions noted elsewhere. Such compounds are found to act as inhibitors of Lp-PLA2 in in vitro assays and have an improved pharmacokinetic profile in in vivo assays. Representative examples of R^ and R^ include hydrogen, bromo, methyl and ethyl. Suitably, R* and R^ is each hydrogen or one of Rl and R2 is hydrogen and the other of R 1 and R^ is methyl (to give a trαrø-methyl). Preferably, VTS and R^ is each hydrogen. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups for incorporation in R^ include those which break down readily in the human body to leave the parent acid or its salt. Examples of suitable values for R^ include: -CH(R a )O.CO.R b ; -CH(R a )O.CO.OR c ; -CH(R a )CO.NReRf -RdNR e R f ; -CH 2 ORg; R 0 O Y 'l 1 iCOCH(R i )NH 2 ; and in which: R a is hydrogen, (Cι-6)alkyl, in particular methyl, (C3-7)cycloalkyl, or phenyl, each of which may be optionally substituted; R b is (Cι-6)alkyl, (Cj-6)alkoxy(Cι-6)alkyl, phenyl, benzyl, (C3-7)cycloalkyl, (Cι-6)alkyl(C3-7)cycloalkyl, l-amino(Cι-6)alkyl, or l-(Cι-6alkyl)amino(Cι-6)alkyl, each of which may be optionally substituted; or R a and R D together form a 1 ,2-phenylene group optionally substituted by one or two methoxy groups; R c is (Cι-6)alkyl, (C 3 - 7 )cycloalkyl, (C 1 - 6 )alkyl(C 3 -7)cycloalkyl; R^ is (Cj-6)alkylene optionally substituted with a methyl or ethyl group; R e and R^ which may be the same or different is each (Cι-6)alk l; or aryl(Cι-4) alkyl, optionally substituted with e.g. hydroxy; Rg is (Cι-6)alkyl; Rh is hydrogen, (Cι-6) lkyl or phenyl; R' is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (Cι-6)-alkyl, or (Cι-6)alkoxy; and γl is oxygen or NH; for instance: (a) acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl, 1 -(cyclohexylcarbonyloxy)ethyl, ( 1 -aminoethyl)carbonyloxymethyl, 2-methoxyprop-2- ylcarbonyloxymethyl, phenylcarbonyloxymethyl and 4-methoxyphenyl- carbonyloxymethyl; (b) alkoxy/cycloalkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, t- butyloxycarbonyloxy methyl, cyclohexyloxycarbonyloxymethyl, 1- methylcyclohexyloxycarbonyloxymethyl and α-ethoxycarbonyloxy ethyl; (c) dialkylaminoalkyl, especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; (d) acetamido groups such as N,N-dimethylaminocarbonylmethyl, N,N-(2- hydroxyethyl)aminocarbonylmethyl; (e) lactone groups such as phthalidyl and dimethoxyphthalidyl; (f) (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl; and (g) (2-methoxycarbonyl-£-but-2-en-yl)methyl. Representative examples of R^ include: (2-methoxycarbonyl-E-but-2-en-yl)methyl, isobutyryloxymethyl, 2-methoxyprop-2- ylcarbonyloxymethyl, phenylcarbonyloxymethyl, 4-methoxyphenyl-carbonyloxymethyl, t-butyloxycarbonyloxymethyl, cyclohexyloxy-carbonyloxymethyl, 1- methylcyclohexyloxycarbonyloxymethyl, N,N-dimethylaminocarbonylmethyl, and (5- methyl-2-oxo- 1 ,3-dioxolen-4-yl)methyl. - 4 - SU6STITUTE SHEET (RULE 26) Representative examples of R^ and R$ when an alkyl group include methyl. Representative examples of a (C3_7)cycloalkyl ring include cyclopropyl. Suitably, R^ and R^ are both hydrogen or R^ is hydrogen and R^ methyl. Suitably, X is: (a) a direct bond; (b) a group X"(CH2) m in which X' is CO, CONR 6 , COO, CONR 6 CO, or CONHO in which R 6 is hydrogen or Cπ _6)alkyl and m is 0 or an integer from 1 to 12; (c) a Cπ _i2) a lkylene chain optionally interupted by X'; (d) a group A-B in which A is a direct bond or X' and B is a C(i_i2)alkylene chain interupted and/or terminated at the end remote from A by one or more groups M selected from O, S(O)n, NR 6 , alkene or alkyne in which R 6 is hydrogen or Cπ _6)alkyl and n is 0, l or 2. Representative examples of X include CO(CH2) m , CONH(CH 2 ) m , COO(CH2) m , CONHCO(CH 2 ) m , CONHO(CH 2 ) m and C(i_ι 2 )alkylene. Preferably, X' is CO or CONR 6 , more preferably CONH. Preferably, m is 1 , 2, 5, 6, 7 or 9, preferably 6. Preferably, X is CONH(CH 2 )6- Further representative examples of X when X represents a group A-B include A'(CH 2 ) a CH=CH(CH 2 )b, A'(CH 2 ) a C ≡ C(CH 2 ) b or A'(CH 2 ) a (O) c (CH 2 ) b (O) d in which A' is a direct bond or CONR 6 , a is an integer from 1 to 12, b is 0 or an integer from 1 to 12 such that a+b < 12, suitably < 6, c is 0 or 1 and d is 1 or c is 1 and d is 0, with the proviso that if c and d are both 1 , then b ≥ 1. Suitably, Y is a benzene ring, optionally substituted by up to three further substituents. Suitable substituents include halo, hydroxy, Cπ.g^alkyl and Cπ _g)alkoxy. Preferably, Y is phenyl optionally substituted by halo, preferably fluoro or chloro, preferably at the 4-position. Representative examples include methyl, n-butyl, t-butyl and n-hexyl, cyclohexyl and cyclohexyl methyl, suitably n-butyl, t-butyl or n-hexyl. Suitable substituents for the alkyl or cycloalkyl group in Z^, in addition to CO2R^, include halo and hydroxy. Representative examples of arylCπ _4)alkyl for Z^ include arylCπ_3)alkyl, preferably arylCH2- Representative examples of the aryl group include phenyl and naphthyl, preferably phenyl. Suitable examples include benzyl, 2-phenylethyl and 3-phenylpropyl in each of which the phenyl ring may be optionally substituted by up to two extra substituents, in addition to CO2R^. Suitable extra substituents include halo, hydroxy, C^.g-yalkyl, C(i_6)alkoxy, arylC^j. ^alkoxy, (Cι-6)alkylthio, (C].6)alkylsulphinyl, and (Cι_6) a ^ c ylsulphonyl. Representative examples of aryl for Z^ include phenyl and naphthyl. Preferably, the aryl group is optionally substitued phenyl. Suitable substituents for a phenyl or naphthyl ring, in addition to CO2R^, include halo, hydroxy, Cπ _6)alkyl, Cπ_6) a ^oxy, arylC(i_6)alkoxy, (Cι-6)alkylthio, (Cι_6)alkylsulphinyl, and (Cι_6)alkylsulphonyl. Representative examples of heteroaryl group for incorporation into lX include pyridyl, pyridyl N-oxide, furanyl, thienyi and thiazolyl. Suitably, the heteroarylalkyl group is heteroarylC(i_3)alkyl, more suitably heteroarylmethyl. Preferred values include optionally substitued pyridylmethyl, furanylmethyl, thienylmethyl or thiazolylmethyl. Suitable substituents for a heteroaryl ring, in addition to CO2R , include halo, hydroxy, C(i_6)alkyl, C(i_6)alkoxy. Preferably, when Z* is S(O)n, n is 1 or 2, more preferably 1. Preferably l\ is SO and Z^ is arylmethyl or heteroarylmethyl, in particular benzyl or furanylmethyl, especially furan-2-ylmethyl. include: -SOCH 2 -( O )— C0 2 R 3 and -SOCH 2 - _ - C0 2 R 3 more preferably: It will be readily appreciated by the skilled person that C-4 of the β-lactam ring is a chiral centre which will give rise to the presence of stereoisomers. The present invention encompasses all such stereoisomers. An additional chiral centre will be introduced in compounds of formula (I) in which Z^ is SO. The present invention encompasses all such stereoisomers. A further chiral centre will be introduced when R 4 and R5 are not the same. This will give rise to the existence of extra stereoisomers. The present invention encompasses all such stereoisomers. In preferred compounds of formula (I), the absolute configurations at C-4 and the SO moiety are R and S respectively. In preferred compounds of formula (I) when R4=H, R^=Me, the absolute configuration at the α-carbon (to which R^ is attached) is S. Representative compounds of formula (I) include: N-(6-(4-chlorophenyl)hex-l-yl)-4-((4-(cyclohexyloxycarbonyloxy-methyloxycarbonyl) benzylsulphinyl)-2-oxoazetidin- 1 -y l)acetamide; N-(6-(4-chlorophenyl)hex-l-yl)-4-((4-(phenylcarbonyloxymethyl-oxycarbonyl)benzyl sulphiny l)-2-oxoazetidin- 1 -y l)acetamide; (4R, S5)-N-(6-[4-Fluoropheny l]hex- 1 -yl)-4-(4- (cyclohexyloxycarbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l- yl)acetamide; (4R, S5 -N-(6-[4-Fluorophenyl]hex-l -yl)-4-(4-(tert- butyloxycarbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l-yl)acetamide; - 6 - SU6STITUTE SHEET (RULE 26) (AR, S5)-N-(6-[4-Fluorophenyl]hex- 1 -yl)-4-(4-( 1 - methylcyclohexyloxycarbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l- yl)acetamide; (AR, S5)-N-(6-[4-Fluorophenyl]hex- 1 -yl)-4-(4- (phenylcarbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin- 1 -yl)acetamide; (AR, S5 -N-(6-[4-Fluorophenyl]hex-l -yl)-4-(4-(4- methoxyphenylcarbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l- yl)acetamide; (AR, S5)-N-(6-[4-Fluorophenyl]hex- 1 -yl)-4-(4- (isobutyryloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin- 1 -yl)acetamide; (AR, S5)-N-(6-[4-Fluorophenyl]hex- 1 -yl)-4-(4-(2-methoxyprop-2- ylcarbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin- 1 -yl)acetamide; (AR, S5)-N-(6-[4-Fluorophenyl]hex- 1 -yl)-4-(4-((5-methyl-2-oxo- 1 ,3-dioxolen-4- yl)methyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin- 1 -yl)acetamide; (AR, S5)-N-(6-[4-Fluorophenyl]hex- 1 -yl)-4-(4-((2-methoxycarbonyl-£-but-2-en- yl)methyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin- 1 -yl)acetamide; and (AR, S5)-N-(6-[4-Fluorophenyl]hex-l-yl)-4-(4-( N-N- dimethylaminocarbonylmethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l- yl)acetamide. Preferably, compounds of formula (I) are prodrugs of N-(6-[4-fluorophenyl]hex- 1 - yl)-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin-l-yl)acetamide. The preparation of this is described as Example 166 of WO 96/19451 (SmithKline Beecham pic). Particularly preferred compounds of formula (I) are prodrugs of (AR,SS) N-(6-[4- fluorophenyl]hex- 1 -yl)-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin- 1 -yl)acetamide; in particular a compound selected from: (AR, S5)-N-(6-[4-Fluorophenyl]hex- 1 -yl)-4-(4- (cyclohexyloxycarbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l- yl)acetamide; (AR, S5)-N-(6-[4-Fluorophenyl]hex- 1 -yl)-4-(4-( 1 - methylcyclohexyloxycarbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l- yl)acetamide; (AR, S5)-N-(6-[4-Fluorophenyl]hex-l -yl)-4-(4- (phenylcarbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l-yl)acetamide; (AR, S5)-N-(6-[4-Fluorophenyl]hex-l -yl)-4-(4- (isobutyryloxymethyloxycarbonyl)benzylsulphinyI)-2-oxoazetidin- 1 -yl)acetamide; and (AR, SS)-N-(6-[4-Fluorophenyrjhex-l -yl)-4-(4-(2-methoxyprop-2- ylcarbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l-yl)acetamide. When used herein, the term 'alkyl' and similar terms such as 'alkoxy' includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, rc-propyl, /so-propyl, n-butyl, .sec-butyl, wo-butyl, t-butyl, n-pentyl and «-hexyl. Suitable substituents for an alkyl group include, for example, and unless otherwise defined, halogen, cyano, azido, nitro, carboxy, (Cι_6)alkoxycarbonyl, carbamoyl, mono- - 7 - SUBSTITUTE SHEET (RULE 23 or di-(Cι _6)alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(C i _5)alkylsulphamoyl, amino, mono- or di-(Cι _6)alkylamino, acylamino, ureido, (C].6)alkoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, hydroxy, (Cι_6)alkoxy, acyloxy, oxo, acyl, 2-thienoyl, (Cι.6)alkylthio, (C j _6)alkylsulphinyl, (Cι_6)alkylsulphonyl, hydroxyimino, (Cι_6)alkoxyimino, hydrazino, hydrazono, benzohydroximoyl, guanidino, amidino and iminoalkylamino. When used herein, the term 'aryl' includes, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents. Suitable substituents for an aryl group include, for example, and unless otherwise defined, halogen, cyano, (C \ -6)alkyl, (C3-7)cycloalkyl, (C \ -6)alkoxy, halo(C i -6)alkyl, hydroxy, amino, mono- or di-(C \ -6)alkylamino, acylamino, nitro, carboxy, (C j -6)alkoxycarbonyl, (C \ -6)alkenyloxycarbonyl, (C \ -g)alkoxycarbonyl(C \ -6)alkyl, carboxy(Cι -6)alkyl, (Ci"6)alkylcarbonyloxy, carboxy(C j -6)alkyloxy, (C j -6)alkoxycarbonyl(C \ -6)alkoxy, (C \ -6)alkylthio, (C \ -^alkylsulphinyl, (C i -6)alkylsulphonyl, sulphamoyl, mono- and di-(C i -6)-alkylsulphamoyl, carbamoyl, mono- and di-(Cι-5)alkylcarbamoyl, and heterocyclyl. When used herein, the term 'heterocyclyl 1 includes aromatic and non-aromatic single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents. Suitably the heterocyclic ring comprises from 4 to 7, preferably 5 to 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. When substituted, a heteroaryl or a heterocyclyl group may have up to three substituents. Suitable such substituents include those previously mentioned for an aryl group as well as oxo. When used herein, the terms 'halogen' and 'halo' include fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo and iodo, respectively. Since the compounds of the present invention, in particular compounds of formula (I), are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I). Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form. When some of the compounds of this invention are allowed to crystallise or are recrystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. In addition, different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products. This invention includes within its scope all polymorphic forms of the compounds of formula (I). Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A2 (Lp-PLA2) and as such are expected to be of use in therapy, in particular in the treatment of atherosclerosis. In a further aspect therefore the present invention provides a compound of formula (I) for use in therapy. The compounds of formula (I) are inhibitors of lysophosphatidylcholine production by Lp-PLA and may therefore also have a general application in any disorder that involves endothelial dysfunction, for example atherosclerosis, diabetes, hypertension, angina pectoris and after ischaemia and reperfusion. In addition, compounds of formula (I) may have a general application in any disorder that involves lipid peroxidation in conjunction with enzyme activity, for example in addition to conditions such as atherosclerosis and diabetes, other conditions such as rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, myocardial infarction, reperfusion injury, sepsis, and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31 , 159-165, 1995). Further applications include any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 . Examples of such disorders include psoriasis. Accordingly, in a further aspect, the present invention provides for a method of treating a disease state associated with activity of the enzyme Lp-PLA 2 which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor of the enzyme. The disease state may be associated with the increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidised free fatty acids; with lipid peroxidation in conjunction with Lp PLA2 activity; or with endothelial dysfunction. Compounds of the present invention may also be of use in treating the above mentioned disease states in combination with anti-hyperlipidaemic or anti-atherosclerotic or anti-diabetic or anti-anginal or anti-inflammatory or anti-hypertension agents. Examples of the above include cholesterol synthesis inhibitors such as statins, anti- oxidants such as probucol, insulin sensitisers, calcium channel antagonists, and anti- inflammatory drugs such as NSAIDs. In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Suitable pharmaceutical compositions include those which are adapted for oral or parenteral administration or as a suppository. The compounds of formula (I) which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, poly vinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. A typical suppository formulation comprises a compound of formula (I) which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats. Preferably the composition is in unit dose form such as a tablet or capsule. Each dosage unit for oral administration contains preferably from 1 to 500 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I). The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I), the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more. Compounds of formula (I) may be conveniently prepared by a process which compromises treating the corresponding parent acid of formula (II) (II) in which R , R^, R3, X, Y, z\ ^d TT- are as hereinbefore defined; or a corresponding salt, (Cι.g)alkyl ester or activated derivative thereof; with a compound of formula (III): R 3 R 7 (III) in which: R is a reactive esterifying leaving group; and R3 is as hereinbefore defined; under ester forming conditions. Suitable ester forming conditions are well known in the art and are described in, for instance, Comprehensive Organic Synthesis, Pergamon Press, 1991, 6, 323-380. Suitable ester forming conditions include: (a) reacting a salt of the acid of the formula (II), for instance, a sodium or a tertiary amine salt such as triethylamine, with a compound of formula (III), in a polar aprotic solvent such as dimethyl formamide, dimethyl sulphoxide or acetonitrile, at moderate temperature, for instance in the range 0 to 100°C; (b) reacting the acid of formula (II) with a compound of formula (III) in the presence of a base such as an alkali metal carbonate or a tertiary amine, in a polar aprotic solvent and temperature as for (a); (c) reacting the acid of formula (II) with a compound of formula (III) in which R? is a hydroxyl group, under dehydrating conditions, for instance the Mitsunobu reaction employing an azodicarboxylate and a trivalent phosphorus reagent (Mitsunobu, Synthesis, 1981, 1); or (d) reacting an activated derivative of the acid of formula (II), for instance a mixed anhydride, for instance an wo-butylcarbonic or a methane sulphonic anhydride or a carbodiimide (DCC) adduct, with a compound of formula (III) in which R? is a hydroxyl group, in the presence of a suitable base such as a tertiaryamine, for instance, triethylamine, in an aprotic solvent such as tetrahydrofuran, at a moderate temperature, preferably in the range -20 to +20°C, or alternatively, in the absence of a base but using a preformed salt of the alcohol, for instance the magnesium or lithium alkoxide. Preferred conditions include the use of the sodium salt of the acid of formula (II) in combination with a halide or sulphonate derivative of the compound of formula (III). The preparation of compounds of formula (II) is described in International patent applications WO 96/13484, WO 96/19451 and PCT EP96/02765 (SmithKline Beecham pic). Preferred compounds of formula (I) are prodrugs of the compound of formula (II) in which R 1 = R 2 = hydrogen; Z 1 Z 2 CO2H is SOCH2C6H4CO2H; R 4 = R 5 = hydrogen; X is CONH(CH2)6 and Y is C^I F and having the preferred (AR,SS) configuration, namely (AR,SS) N-(6- [4-fluorophenyl]hex- 1 -y l)-4-(4-carboxybenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide. This may be prepared by analogy with processes previously described in WO 96/19451 02765 (SmithKline Beecham pic). In particular, a key step is the resolution of the early stage intermediate of formula (IV): SCH 2 C 6 H 4 — C0 2 R* N u — CC00 22 HH (IV) in which R* is carboxy protecting group, for instance aCπ _6)alkyl or C(2_6)alkenyl; via the formation of a diastereoisomeric salt with a chiral base such as (-)-cinchonidine. The preferred diastereoisomeric salt may be obtained by fractional crystallisation and the enantiomeric free acid regenerated therefrom by acidification. This may be then converted through to a compound of formula (II) by analogy with processes hereinbefore described. In the final step, the free acid may be regenerated from a corresponding compound in which the carboxy group is protected as a Cπ .g^alkyl or C(2-6) a lkenyl ester; using methods well known in the art for the particular protecting group, for instance, when an allyl group, using palladium catalysed de-allylation - 12 - SUflSTITUTE SHEET RULE (triphenylphosphine/ pyrrolidine/ tetrakis triphenyl-phosphinepalladium(O) in dichloromethane). The present invention will now be illustrated by the following examples. Unless otherwise specified, all compounds are racemic. Chiral compounds are described as AR or S, SR or S where the 4 describes the centre at the C4 position in the azetidinone and the S describes the sulfoxide centre. General methods for the preparation of reagents 1. Iodomethyicyclobexyl carbonate CICH2OCOCI + C 6 H n OH → ClCH 2 OCO2C 6 H n Chloromethyl chloroformate is treated with cyclohexanol in dichloromethane/pyridine as generally described in the reference: Y. Yoshimura et al., J. Antibiot., 1987, 40(1), 81-90. Subsequent conversion of the chlorides to the iodides is a simple "Finkelstein reaction" well known to those skilled in the art. 2. (Benzoyloxy)iodomethane PhCO2H + CISO2OCH2CI → PI1CO2CH2CI This general route is described by the reference: E. Binderup et al., Synthetic Commun. , 1984, 14(9), 857-64. Subsequent conversion of the chlorides to the corresponding iodides uses the Finkelstein reaction as before. Preparations Preparation 1 - (4R, SS)-N-[6-(4-Fluorophenyl)hex-l-yl]-4-(4- carboxybenzylsulphinyl)-2-oxoazetidin-l-yI)acetamide (a) (+/-)-Methy 1 4-(4-(AHyloxy carbonyl)benz lthio)-2-oxoazetidin- 1 - lacetate To a stirring solution of 4-(4-(allyloxycarbonyl)benzylthio)azetidin-2-one (2.55 g, 9.2 mmol), tetrabutylammomum bromide (0.33 g, 1.02 mmol) and methyl bromoacetate (1.06 ml, 11.2 mmol) in dry tetrahydrofuran (40 ml) was added powdered potassium hydroxide (0.63 g, 11.2 mmol) keeping the reaction temperature below 30 by means of a cold water bath. After 2 h, the mixture was diluted with water and extracted three times with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated and the residue chromatographed (fine silica, ethyl acetate-petrol) to give the title compound as a clear oil, yield 2.66 g (83%). Η NMR δ (CDC1 3 ) 2.97 (IH, dd, H3a), 3.26, 4.07 (each IH, CH2CO, d), 3.42 (IH, dd, H3b), 3.70 (3H, s, CH3O), 3.81 (2H, s, SCH2), 4.83 (2H, m, CH2O), 4.93 (IH, dd, H4), 5.35 (2H, m, CH2CH), 6.03 (IH, m, CHCH 2 ), 7.39 (2H, d, Ph-H), 8.02 (2H, d, Ph-H) b. (+/-)-4-(4-(AllyloxycarbonyI)benzylthio)-2-oxoazetidin-l-ylacetic acid To a solution of methyl 4-(4-(allyloxycarbonyl)benzylthio)-2-oxoazetidin-l-ylacetate (2.17 g, 6.21mmol) in tetrahydrofuran (20 ml) was added dropwise with cooling (ice bath) over 10 min a 1 molar aqueous solution of potassium hydroxide. After a further 30 min, the solution was diluted with water and extracted twice with ether. The aqueous layer was then acidified (dil. hydrochloric acid) with cooling and the oil which precipited was extracted into ether. The combined extracts were dried (MgSO4) and evaporated to a clear oil which eventually crystallised under petrol and was filtered, washed and dried to give the title compound as white crystals, 1.87 g, 90% yield Η NMR δ (CDCI3) 2.98 (IH, dd, H3a), 3.34, 4.06 (each IH, CH .2 CO, d), 3.42 (IH, dd, H3b), 3.82 (2H, s, SCH2), 4.82 (2H, m, CH2O), 4.92 (IH, dd, H4), 5.34 (2H, m, CH2CH), 6.03 (IH, m, CHCH 2 ), 7.39 (2H, d, Ph-H), 8.02 (2H, d, Ph-H) c. (-)-(R)-4-(4-(Allyloxycarbonyl)benzylthio)-2-oxoazetidin-l -ylacetic acid 4-(4-(Allyloxycarbonyl)benzylthio)-2-oxoazetidin-l-ylacetic acid ( 3.41 g, 10.2 mmol) and cinchonidine (2.99 g, 10.2 mmol) in ethanol (40 ml) were heated to boiling when a clear solution was obtained. On standing for 90 min, the crystalline salt which had precipitated was filtered off, and recrystallised from ethanol (20 ml). The solid obtained was stirred vigorously with ether and water whilst acidifying with dil. hydrochloric acid, and when complete solution was obtained the layers were separated and the aqueous layer further extracted with ether. The combined extracts were dried (MgSO4) and evaporated to an oil which crystallised on trituration with light petrol to give the title compound as white crystals, m.p. 74-6°C, 6.7 g, 50% yield a D 25 = -24.2 (c. 0.7 w/v CHC1 3 , 25°C) Η NMR δ (CDC1 3 ) 2.97 (IH, dd, H3a), 3.26, 4.07 (each IH, CH 2 CO, d), 3.42 (IH, dd, H3b), 3.70 (3H, s, CH3O), 3.81 (2H, s, SCH2 4 -83 (2H, m, CH. 2 O), 4.93 (IH, dd, H4), 5.35 (2H, m, CH2CH), 6.03 (IH, m, CHCH 2 ), 7.39 (2H, d, Ph-H), 8.02 (2H, d, Ph-H) d. (R)-N-[6-(4-Fluorophenyl)hex-l-yl]-4-(4-alloxycarbonyIbenzylthio)-2- oxoazetidin-l-yl)acetamide To a cooled (ice bath) solution of (R)-4-(4-(allyloxycarbonyl)benzylthio)-2-oxoazetidin- 1-ylacetic acid (12.51 g, 0.0373 mol), 1 -hydroxybenzotriazole hydrate (5.04 g, 0.0373 mol) and 6-(4-fluorophenyl)hexylamine (0.0373 mol) in dry dimethylformamide (150 ml) was added with stirring dicyclohexylcarbodiimide (7.29 g, 0.0373 mol). After 20 min the cooling bath was removed, and after a further 16 h, the solvent was evaporated under reduced pressure and the residue treated with ethyl acetate and the insoluble precipitate filtered off and discarded. The filtrate was further diluted with ethyl acetate, washed with 0.2 M hydrochloric acid, then saturated sodium hydrogen carbonate, dried and evaporated under reduced pressure. The residue was triturated with ethyl acetate/light petrol to give the title compound as white crystals, m.p. 54-7°C, 17 g, 89% yield Η NMR δ (CDCI3) 1.30-1.60 (8H, m, 4xCH 2 ), 2.55 (2H, t, J=7.6 Hz, CH 2 Ph), 2.90, 2.97 (IH, dd, J-2.4, 15.4 Hz, H 3 ), 3.23 (2H, m, NHCH 2 ), 3.35, 3.41 (IH, dd, J=5.1, 15.4 Hz, H 3 ), 3.53, 3.78 (each IH, d, J=16.6 Hz, NCH 2 ), 3.86 (2H, s, SCH 2 ), 4.83 (3H, m, CO 2 CH 2 , H 4 ), 5.37 (2H, m, CH 2 =CH), 6.0 (2H, m, NH, CH 2 -CH), 6.94 (2H, m, 4-FPh- H), 7.10 (2H, m, 4-FPh-H), 7.39 (2H, d, J=8.3 Hz, 4-CO 2 allylPh-H), 8.02 (2H, d, J=8.3 Hz, 4-CO 2 allylPh-H) e. (4Λ, S5)-N-[6-(4-FIuorophenyl)hex-l-yl]-4-(4-alloxycarbonylbenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide A solution of (R)-N-[6-(4-fluorophenyl)hex- 1 -yl]-4-(4-alloxycarbonylbenzylthio)-2- oxoazetidin-l-yl)acetamide (16.36 g, 0.0319 mol) in dichloromethane (150 ml) was cooled to -65 to -70 and a solution of m-chloroperbenzoic acid (6.61 g, 0.0383 mol) in dichloromethane (120 ml) added dropwise with stirring over 20 min. After 1 h, the mixture was washed with saturated sodium metabisulphite solution, then saturated sodium hydrogen carbonate, then dried (MgSO4) and evaporated to a solid which was recrystallised from ethyl acetate to give a mixture of diastereoisomers 2 and 1 in the ratio 3:2. Chromatographic separation (HPLC) gave diastereomer 2 (AR, SS) as a white crystalline solid, m.p. 133-5°C, 3.3 g, 20% yield α D 25°c = +74.0 (c. 0.6% w/v CHC1 3 , 25°C) Η NMR δ (CDC1 3 ) 1.30-1.60 (8H, m, 4xCH 2 ), 2.56 (2H, t, J=7.6 Hz, CH 2 Ph), 2.91, 2.95 (lH, dd, J=2.4, 15.2 Hz, H 3 ), 3.27 (3H, m, NHCH 2 , H 3 ), 3.94, 4.22 (each IH, d, J=17.2 Hz, NCH 2 ), 4.04, 4.18 (each IH, d, J=12.8 Hz, SOCJJ 2 ), 4.65 (lH, m, H 4 ), 4.84 (2H, m, CO 2 CH 2 ), 5.37 (2H, m, CH 2 =CH), 6.0 (IH, m, CH 2 =CH), 6.95 (3H, m, 4-FPh-FJ, NH),), 7.10 (2H, m, 4-FPh-H), 7-36 (2H, m, 4-CO 2 allylPh-H), 8.09 (2H, m, 4-CO 2 allylPh-H). f. (AR, SS)-N-[6-(4-Fluorophenyl)hex-l-yl]-4-(4-carboxybenzylsulphinyl)-2- oxoazetidin- 1 -yl)acetamide A solution of (AR, S5)-N-[6-(4-Fluorophenyl)hex-l-yl]-4-(4-alloxycarbonylbenzyl- sulphinyl)-2-oxoazetidin-l-yl)acetamide (0.185 g, 0.35 mmol), triphenylphosphine (0.092 g, 0.35 mmol), pyrrolidine (0.033 ml, 0.4 mmol) and tetrakis triphenyl- phosphinepalladium(O) (0.012 g, 0.01 mmol) in dichloromethane (10 ml) was stirred under nitrogen for 16 h. A further 0.012 g (0.01 mmol) of tetrakis triphenylphosphinepalladium(O) was added and after a further 4 h the reaction was complete. The solution was diluted with water, acidified (2N HCl), the layers separated and the aqueous layer further extracted with dichloromethane. The combined extracts were dried (MgSO4)and evaporated to a yellow oil, which was triturated with ether. A yellow solid was obtained which was filtered off and dissolved in sodium hydrogen carbonate solution. Shaking with ether gave an emulsion which was separated by treatment with ethyl acetate and centrifugation. The aqueous layer was then acidified (2N HCl) and extracted with dichloromethane, and the extracts dried (MgSO4)and evaporated. The residue was triturated with ether to give a white solid which was filtered, washed and dried to give the title compound as a white solid, m.p. 105-7°C, 0.1 g, 58% yield α D 25°c = -31.7 (c. 0.5% w/v DMSO, 25°C) Η NMR δ (DMSO) 1.26 (4H, m, 2xCH 2 ), 1.38 (2H, m, CH 2 ), 1.50 (2H, m, CH 2 ), 2.96, 2.99 (IH, dd, J=2, 15.2 Hz, H 3 ), 3.06 (2H, m, NHCH 2 ), 3.84, 4.09 (each IH, d, J=17.2 Hz, NCH 2 ), 4.13, 4.31 (each IH, d, J=12.8 Hz, SOCH 2 ), 4.84 (IH, m, H 4 ), 7.05 (2H, m, 4-FPh-H), 7.19 (2H, m, 4-FPh-H), 7.47 (2H, d, J=8 Hz, 4-CO 2 allylPh-H), 7.93 (2H, d, J=8 Hz, 4-CO 2 allylPh-FJ), 8.13 (IH, m, NH), 13 (IH, bs, CO 2 H). Preparation 2 - 4R, SS-N-(6-(4-Fluorophenyl)hexyI)-4-(4- ethoxycarbonylbenzylsulphinyl)-2-oxoazetidin-l-ylacetamide a. Ethyl 4-(bromomethyl)benzoate 4-(Bromomethyl)benzoic acid (25.75g, 0.1197moles) was suspended in thionyl chloride (50ml) and dimethylformamide (0.25ml) was added. The mixture was heated under reflux for 25 minutes until clear, evaporated and azeotroped with toluene (x2). The resulting oil was dissolved in dichloromethane (75ml) and added dropwise over 10 minutes to a solution of absolute alcohol (8.6ml, 0.1465moles), pyridine (10.5ml, 0.1298moles) in dry dichloromethane (50ml), cooled to 10°C. The ice bath was removed and the reaction was stirred for 45 minutes , then washed with water, 2NHC1, water, sodium hydrogen carbonate solution and brine. The organic solution was dried (MgSO4) and evaporated to give a mixture of 60:40 ethyl 4-(bromomethyl)benzoate: ethyl 4- (chloromethyl)benzoate as an oil (25.6g, 94%) IH nmr δ (CDCI3) 1.40 (3H, m, CH3), 4.40 (2H, m, CH2O), 4.50, 4.61 (2H, 2xs, CH2C1 Br), 7.45 (2H, m, Ar-H), 8.01 (2H, m, Ar-H) b. Ethyl 4-(acetylthiomethyl)benzoate 60:40 Ethyl 4-(bromomethyl)benzoate: ethyl 4-(chloromethyl)benzoate (25.0g, 0.111 moles) in dry dimethylformamide (150ml), cooled to 5°C, was treated with potassium thioacetate (13.3g, 0.117moles) and the temperature rose to 20°C. The reaction was stirred at room temperature for 2 hours, poured into water (250ml) and extracted with diethyl ether (3x100ml). The organic extracts were combined, washed - 16 - SUeSTITUTE SHEET (RULE 26) with water, dried (MgSO4), charcoaled and evaporated to give ethyl 4- (acetylthiomethyl)benzoate as a brown soild (26.0g, 99%), m.p. 36-37°C. iH nmr δ (CDC1 ) 1.38 (3H, t, J=7.1Hz, CH3), 2.36 (3H, s, COCH3), 4 14 ( 2H > s > CH2S), 4.36 (2H, q, CH2O), 7.35 (2H, d, J = 8.2Hz, Ar-H), 7.97 (2H, d, J= 8.2Hz, Ar-H) c. 4-(4-(Ethoxycarbonyl)benzylthio)azetidin-2-one A solution of sodium (1.87g, 0.0813moles) in absolute alcohol (300ml) was treated with a solution of ethyl 4-(acetylthiomethyl)benzoate (19.4g, 0.0814moles) in absolute alcohol (75ml) over 3 minutes. The reaction was stirred at room temperature for 30 minutes, cooled to -5°C and treated with a solution of 4-acetoxyazetidin-2-one (lO.Og, 0.07745moles) over 5 minutes. The cooling bath was removed and reaction was stirred for 2 hours, evaporated to dryness and treated with brine (200ml) and extracted with ethyl acetate (200ml, 100ml). The organic extracts were combined washed with brine, dried (MgSO4) and evaporated to a red oil. Purified by flash column chromatography on silica gel eluted with 3:1 to 1 :2 petroleum ether 40-60°C:ethyl acetate to give 4-(4- (ethoxycarbonyl)benzylthio)azetidin-2-one as an orange oil (18.64g, 91%). !H nmr δ (CDCI3) 1.38 (3H, t, J=7.1Hz, CH3), 2.82, 2.89 (IH, 2xm, H3), 3.29, 3.35 (IH, 2xm, H3), 3.88 (2H, s, CH2S), 4.37 (2H, q, CH2O), 4.70 (IH, m, H4), 5.70 (lH,bs, NH), 7.40 (2H, d, J = 8.3Hz, Ar-H), 8.00 (2H, m, Ar-H) d. Methyl (4-(4-ethoxycarbonyl)benzylthio)-2-oxoazetidin-l -ylacetate A stirred solution of 4-(4-(ethoxycarbonyl)benzylthio)azetidin-2-one (217.3g,0.819mol), methyl bromoacetate (128.5g,0.84mol) and tetrabutylammonium bromide (25.8g,0.08mol) in dry THF (900ml) was cooled in an ice bath to 20°C and finely ground potassium hydroxide (48.3g, 0.86mol) was added in one portion. The reaction exothermed to 45°C and was allowed to cool back to 30°C when the ice bath was removed and stirring continued for lhr. More potassium hydroxide (2.4g, 0.043mol) was added and stirred 30mins when this addition was repeated. After a further 30mins, the reaction mixture was filtered through hyflo, washing with more THF. The combined organics were evaporated to a red oil. Ether (11) was added an shaken well. The ether was decanted and the process repeated. The combined ether extracts were evaporated to give the title compound as a dark red oil (199.8g, 72% yield) 'H NMR δ (CDCI 3 ), 1.40 (3H, t, J=7Hz, CH2CH3), 2.98 (IH, dd, J=2, 15 Hz, H 3 ), 3.26, 4.03 (each IH, d, J=18 Hz, NCH 2 ), 3,42 (IH, dd, J=5, 15 Hz, H 3 ), 3.70 (3H, s, OCH 3 ), 3.81, (2H, m, SCH2), 4.38 (2H, q, J=7 Hz, OCH 2 ), 4.93 (IH, m, H,), 7.39 (2H, m, Ph-H ), 7.99 (2H, m, Ph-H )■ e. (4-(4-Ethoxycarbonyl)benzylthio)-2-oxoazetidin-l-ylacetic acid Methyl (4-(4-ethoxycarbonyl)benzylthio)-2-oxoazetidin- 1 -ylacetate ( 169.8g,0.503mol) was disolved in THF (750ml), cooled to 0°C and a solution of potassium hydroxide (29.7g, 0.529mol) in water (500ml) was added over 15min at 0 - 5°C then the mixture was stirred at 0°C for 45mins. Ether (11) and water (21) were added, the layers separated and the aqueous washed with ether (11), then acidified with cone hydrochloric acid (55ml) and extracted with dichloromethane (2 x 11). The combined extracts were washed with brine, dried (MgSO4) and evaporated to give the title compound as a green solid (128.4g, 79% yield). f. (-)-R-(4-(4-Ethoxycarbonyl)benzylthio)-2-oxoazetidin-l-ylacetic acid 4-(4-Ethoxycarbonyl)benzylthio)-2-oxoazeyidin-l-ylacetic acid (46.0g, 0.1422moles) and (-)-cinchonidine (41.88g, 0.1423moles) were dissolved in abolute alcohol (450ml). The solution was cooled for 1.5 hours, filtered, and dried to give the salt as a cream solid (33.15g). This solid was recrystallised from absolute alcohol (300ml) to give 23.6g of salt which was mixed with water (500ml) and diethyl ether (500ml) and acidified with dilute HCl (50ml). When all the solid had dissolved the layers were separated and the aquous layer was extracted with ether (250ml). The organic extracts were combined, ethyl acetate (100ml) was added and washed with water, dried (MgSO4), filtered and evaporated to give R-(4-(4-ethoxycarbonyl)benzylthio)-2-oxoazetidin-l -ylacetic acid as a colourless solid. (10.93g, 23.8%) m.p. 135-137°C. a D = -23.5 (c = 0.46 w/v in chloroform at 25°C) Η NMR δ (CDC1 3 ) 1.39 (3H, t, J=7.1Hz, CH3), 2.96, 3.02 (IH, dd, J =2.2, 15.3 Hz, H3), 3.33, 4.05 (each IH, d, J=18.4 Hz, NCH2CO 2 H), 3.40, 3.46 (IH, dd, J- 5.1, 15.3 Hz, H3), 3.82 (2H, s, SCH2), 4.37 (2H, q, CO 2 CH 2 ), 4.68 (IH, b, CO 2 H), 4.92 (IH, m, H4), 7.38 (2H, d, J=8.2Hz, Ph-H), 7.99 (2H, d, J=8.2Hz, Ph-H) g. 4R,SR-(4-(4-Ethoxycarbonyl)benz Isulphinyl)-2-oxoazetidin- 1 -ylacetic acid (diastereoisomer 1) h. 4R,S5-(4-(4-Ethoxycarbonyl)benzyisulphinyI)-2-oxoazetidin-l-ylacetic acid (diastereoisomer 2) A solution of (-)-Λ-(4-(4-ethoxycarbonyl)benzylthio)-2-oxoazetidin- 1 -ylacetic acid (10.81g, 0.03343moles) in dry dichloromethane (400ml) at -70°C was treated with ozone until a blue colouration appeared. The reaction was allowed to warm to room temperature and dichloromethane (50ml) was added to aid stirring. The solution was evaporated to dryness and the resulting soild was mixed with chloroform (200ml). The colourless solid was collected by filtration to give 4Λ,Si?-(4-(4-ethoxycarbonyl)benzylsulphinyl-2- oxoazetidin-1 -ylacetic acid (4.1 lg, 36%) m.p.162-164°C. (contains 15.8:1 dial :dia2) Η NMR δ (DMSO) 1.33 (3H, t, J=7Hz, CH3), 2.97, 3.04 (IH, dd, J=4.8,14.8Hz, H3), 3.12, 3.16 (IH, dd, J= 1.6, 14.8Hz, H3), 3.83, 4.17 (each IH, d, J= 18Hz, NCH.2CO 2 H), 4.92, 4.24 (IH, d, J = 12.8Hz, SOCH2), 4.32 (2H, q, CO 2 CH 2 ), 4.99 (IH, m, H4), 7.48 (2H, d, J=8.0Hz, Ph-H), 7.96 (2H, d, J=8.0Hz, Ph-H) The filtrate from the above was evaporated, mixed with diethyl ether and filtered to give 4/?,S5-(4-(4-ethoxycarbonyl)benzylsulphinyI-2-oxoazetidin-l -ylacetic acid (6.42, 56%) m.p. 152-155°C. (contains 92:8 dia2:dial) 'H NMR δ (DMSO) 1.33 (3H, t, J=7 Hz, CH3), 2.97, 3.01 (IH, dd, J=2.0,15.5Hz, H3), 3.35 (IH, m, H3), 3.95, 4.17 (each IH, d, J= 18.2Hz, NCH2CO2H), 4.15 (IH, d, I of SOCH2 4.32 (3H, m, 1 of SOCH2, CO 2 CH ), 4.82 (IH, m, H4), 7.51 (2H, d, J=8.2Hz, Ph-H), 7.97 (2H, d, J=8.2Hz, Ph-H) i. (+)-4R, S5-N-(6-(4-Fluorophenyl)hexyl)-4-(4-ethoxycarbonyIbenzyIsulphinyl)-2- oxoazetidin-1-ylacetamide 6-(4-Fluorophenyl)hexylamine (1.82g, 0.00932moles) in dry dimethylformamide (75ml) was added to a mixture of AR,SS -(4-(4-ethoxycarbonyl)benzylsulphinyl-2-oxoazetidin-l- ylacetic acid (3.15g, 0.00928moles), N,N,-dicyclohexylcarbodiimide (1.92g, 0.00931 moles) and 1-hydroxybenzotriazole (1.25g, 0.00925moles). The reaction was stirred at room temperature for 3.5 hours, diluted with ethyl acetate (100ml) and cooled. The mixture was filtered to remove urea and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate (400ml), washed with sodium hydrogen carbonate solution, brine, dried and evaporated to a colourless solid (5.8g) which was recrystallised from ethyl acetate (125 ml) to give the product (3.0g). Purification by column chromatography gave AR,SS -(4-(4- ethoxycarbonyl)benzylsulphinyl-2-oxoazetidin-l -ylacetic acid as a colourless solid, 155- 156°C, 1.8 g, 38% yield Η NMR δ (CDC1 3 ) 1.3-1.6 (1 IH, m, 4xCH2, CH3), 2.56 (2H, t, J = 7.6Hz, C Ph), 2.89, 2.96 (IH, dd, J=2.4,15.3Hz, H3), 3.25 (3H, m, NHCH2, H3), 3.94, 4.22 (each IH, d, J=17Hz, NCH2CO), 4.03, 4.18 (each IH, d, J=12Hz, SOCH2), 4.39 (2H, q, CO2CH2X 4.65 (IH, m, H4), 6.9-7.12 (5H, m, NH,p-ClPh-H), 7.35 (2H, d, J=8.3Hz, Ph-H), 8.07 (2H, d, J=8.3Hz, Ph-H) a D = +85.2 (c = 0.5% w/v in chloroform at 25°C) Found: C, 62.6; H, 6.3; N, 5.4%; C2 7 H33FN2O5S requires: C, 62.8; H, 6.4; N, 5.4% Example 1 - N-(6-(4-chlorophenyl)hex-l-yl)-4-((4-(cyclohexyloxycarbonyloxy- methyloxycarbonyl) benzylsulphinyl)-2-oxoazetidin-l-yl)acetamide A solution of N-(6-(4-chlorophenyl)hex- 1 -yl)-((4-carboxybenzylsulphinyl)-2- oxoazetidin- 1 -yl)acetamide (diastereoisomer 2) (Example 130, WO 96/19451 , SmithKline Beecham, lOOmg, 0.2mmol) in methanoi (10ml) was treated with a solution of sodium hydrogen carbonate (17mg, 0.2mmol) in water (0.5ml). After lOmins, the reaction mixture was evaporated to dryness and the residue azeotroped with toluene (3 x 10ml), titurated with ether, dried and dissolved in 1 -methylpyrrolidin-2-one (1ml). The resulting solution was treated with iodomethylcyclohexyl carbonate (68mg, 0.24mmol) at room temperature for 2h. The mixture was subjected to aqueous extractive workup and the crude product purified by flash chromatography using 9:1 CH 2 Cl 2 :MeOH as the eluting solvent. Evaporation of the appropriate fractions gave the title compound as a white solid (70mg, 54%), mp 87°C. Η NMR δ (CDCI3) 1.33-1.37 (7H,m), 1.49-1.58 (7H,m), 1.75 (2H, m), 1.90 (2H,m), 2.56 (2H, t, J= 7.6Hz), 2.96 (IH, dd, J= 15.2, 2.4Hz), 3.20-3.35 (3H, m), 3.93 and 4.23 (each IH, d, J=17.2Hz), 4.03 and 4.12 (each IH, d, J=13.2Hz), 4.66 (2H, m), 6.00 (2H, s), 6.93 (IH, bt), 7.08 (2H, d, J=8.4Hz), 7.23 (2H, d, J=8.4Hz), 7.34 (2H, d, J=8.4Hz), 8.09 (2H, d, J=8.4Hz). Found: C, 59.74; H, 6.15: N, 4.33%. C^H^Cl^OgS requires: C, 59.94; H, 6.25; N, 4.24%. Example 2 - N-(6-(4-chlorophenyl)hex-l-yl)-4-((4-(phenylcarbonyloxymethyl- oxycarbonyl)benzyI sulphinyl)-2-oxoazetidin-l-yl)acetamide A solution of N-(6-(4-chlorophenyl)hex-l -yl)-((4-carboxybenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide (diastereoisomer 2) (200mg, 0.4mmol) in 1 -methylpyrrolidin- 2-one (1ml) was treated with potassium carbonate (280mg, 2mmol) and benzoyloxyiodomethane (200mg, O.δmmol) and the resulting mixture stirred for 16h. The mixture was subjected to aqueous extractive workup and the crude product purified by flash chromatography using a) ethyl acetate and b) ethyl acetate:methanol (95:5) as the eluting solvents. Evaporation of the appropriate fractions gave an oil which crystallised upon tituration with ether to give the title compound as a white solid (240mg, 93%), mp 126°C. 'H NMR δ CDC^) 1.33 (4H, m), 1.51 (4H, m), 2.55 (2H, t, J=7.7Hz), 2.95 (IH, dd, J =15.4, 2.2Hz), 3.20-3.32 (3H, m), 3.97 and 4.21 (each IH, d, J=20.8Hz), 4.15 and 4.19 (each IH, d, J=18.2Hz), 4.63 (IH, m), 6.25 (2H, s), 6.90 (IH, bt), 7.07 (2H, d, J=8.4Hz), 7.21 (2H, d, J=8.4Hz), 7.36 (2H, d, J=8.0Hz), 7.46 (2H, d, J=8.0Hz), 7.63 (IH, m), 8.08 (2H, m). Example 3 (4R, SS)-N-(6-[4-Fluorophenyl]hex-l-yl)-4-(4- (cyclohexyloxycarbonyloxymethyloxycarbonyl)benzylsulphinyI)-2-oxoazetidin-l- yl)acetamide A solution of (AR, S5)-N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide (see above, 4 g, 0.00819 mol) and iodomethyl cyclohexyl carbonate (3.49 g. 0.0123 mol) in N-methylpyrrolidinone (40 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (1.7 g, 0.0123 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with 5% aq. sodium thiosulphate, dried (MgSO4) and evaporated. The residue was purified by chromatography (fine silica, ethyl acetate) and the title compound obtained as white crystals m.p.l05-7°C after trituration with ether/light petrol, 4.16 g, 79% yield 1H NMR δ (DMSO) 1.23-1.51 (14H, m), 1.64 (2H, m), 1.84 (2H, m), 2.51 (2H, m), 3.04 (3H, m), 3.35 (IH, m), 3.83 and 4.09 (each IH, d), 4.15 and 4.35 (each IH, d), 4.58 (IH, m), 4.85 (IH, m), 5.95 (2H, s), 7.05 (2H, m), 7.18 (2H, m), 7.53 (2H, d), 7.98 (2H, d), 8.11 (IH, bt). Found: C, 61.6; H, 6.4; N,4.6%; C 3 3H 41 FN 2 O 8 S requires: C, 61.5; H, 6.4; N, 4.3% Example 4 (4R, S5 -N-(6-[4-Fluorophenyl]hex-l-yl)-4-(4-(tert- butyIoxycarbonyloxymethyIoxycarbonyI)benzyIsulphinyl)-2-oxoazetidin-l- yl)acetamide A solution of (AR, S5)-N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide (0.2g, 0.00041 mol) and iodomethyl tert-butyl carbonate (0.49 g. 0.001 mol) in N-methylpyrrolidinone (2 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (0.14 g, 0.001 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with aq. sodium sulphite, dried (MgSO4) and evaporated. The residue was crystallised by trituration with light petrol to give the title compound as white crystals m.p.102-4°C, 0.23 g, 92%yield Η NMR δ (DMSO) 1.25-1.52 (17H, m), 2.50 (2H, m), 3.06(3H, m), 3.35 (IH, m), 3.84 and 4.09 (each IH, d), 4.15 and 4.35 (each IH, d), 4.86 (IH, m), 5.90 (2H, s), 7.06 (2H, m), 7.18 (2H, m), 7.53 (2H, d), 7.97 (2H, d), 7.99 (IH, bt) Found: C, 60.1 ; H, 6.3; N, 4.7%; C 31 H3 9 FN 2 O 8 S requires: C, 60.2; H, 6.4; N, 4.5% Example 5 (4R, SS)-N-(6-[4-Fluorophenyl]hex-l-yl)-4-(4-(l- methylcyclohexyloxycarbonyloxymethy!oxycarbonyl)benzylsulphinyl)-2- oxoazetidin-l-yl)acetamide A solution of (AR, S5)-N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide (0.2g, 0.00041 mol) and chloromethyl 1 -methylcyclohexyl carbonate (0.21 g. 0.001 mol) in N-methylpyrrolidinone (2 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (0.14 g, 0.001 mol) and potassium iodide (0.166 g, 0.001 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with aq. sodium thiosulphate, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (fine silica, ethyl acetate) and the material thus obtained crystallised by trituration with ether, to give the title compound as yield white crystals, m.p. 92-3°C, 0.11 g, 41% yield iH NMR δ (DMSO)1.25-1.48 (16H, m), 2.00 (2H, m), 2.5 (5H, m), 3.07 (3H, m), 3.36 (IH, m), 3.83 and 4.09 (each IH, d), 4.15 and 4.35 (each IH, d), 4.86 (IH, m), 5.91 (2H, s), 7.06 (2H, m), 7.18 (2H, m), 7.54 (2H, d), 7,98 (2H, d), 8.11 (IH, bt) Example 6 (4R, SS)-N-(6-[4-Fluorophenyl]hex-l-yl)-4-(4- (phenylcarbonyloxymethyloxycarbonyl)benzyisuIphinyl)-2-oxoazetidin-l- yl)acetamide A solution of (AR, S5)-N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide (5 g, 0.0102 mol) and benzoyloxychloromethane (2.62 g. 0.0154 mol) in N-methylpyrrolidinone (50 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (2.12 g, 0.0154 mol) and potassium iodide (2.55 g, 0.0154 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with aq. sodium thiosulphate, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (fine silica, ethyl acetate) and the material thus obtained crystallised by trituration with ether to give the title compound as white crystals, m.p.117- 9°C, 4 g, 52% yield !H NMR δ (CDC1 3 ) 1.33 (4H, m), 1.5-1,62 (4H, m), 2.56 (2H, t), 2.95, (IH, dd), 3.22 (3 H, m), 3.94 and 4.20 (each IH, d), 4.04 and 4.16 (each IH, d), 4.65 (IH, m), 6.25 (2H, s), 6.94 (3H, m), 7.1 1 (2H, m), 7.37 (2H, d), 7.46 (2H, m), 7.59 (IH, m), 8.1 (4H, m) Found: C, 63.7; H,5.5; N, 4.5%; C 3 3H 35 F 2 O 7 S requires:C, 63.7; H, 5.7; N, 4.5% Example 7 (4R, SS)-N-(6-[4-FIuorophenyl]hex-l-yl)-4-(4-(4- methoxyphenylcarbonyloxymethyloxycarbonyI)benzylsulphinyI)-2-oxoazetidin-l- yl)acetamide A solution of (AR, SS)-N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide (2 g, 0.0041 mol) and 4-methoxybenzoyloxymethyl chloride (2 g. 0.01 mol) in N-methylpyrrolidinone (20 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (1.38 g, 0.01 mol) and potassium iodide (1.66 g, 0.01 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with aq. sodium thiosulphate, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (fine silica, ethyl acetate) and the material thus obtained crystallised by trituration with ether, then recrystallised from dichloromethane/light petrol, to give the title compound as white crystals, m.p. 115-8°C, 1.34 g, 50% yield iH NMR δ (DMSO) 1.23-1.6 (8H, m), 2.50 (2H, m), 3.02-3.1(3H, m), 3.34 ( IH, m ), 3.8 and 4.09 (each IH, d), 3.84 (3H, s), 4.14 and 4.33 (each IH, d), 4.85 (IH, m), 6.17 (2H, s), 7.05 (4H, m), 7.16 (2H, m), 7.52 (2H, d), 7.97 (4H, m), 8.1 (IH, bt) Example 8 (4R, SS)-N-(6-[4-Fluorophenyl]hex-l-yl)-4-(4- (isobutyryloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l-yl)acetamide A solution of (AR, SιS)-N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide (0.2g, 0.00041 mol) and isobutyryloxymethyl iodide (0.23 g. 0.001 mol) in N-methylpyrrolidinone (2 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (0.14 g, 0.001 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with aq. sodium thiosulphate, dried (MgSO4) and evaporated. The residue was purified by chromatography (fine silica, ethyl acetate) and the material thus obtained crystallised by trituration with ether, to give the title compound as white crystals, m.p. 104-6°C, 0.14 g, 58% yield iH NMR δ (DMSO)1.09 (6H, d), 1.25-1.52 (8H, m), 2.50 (2H, m), 2.61 (IH, m), 2.97- 3.06 (3H, m), 3.34 (IH, m), 3.83 and 4.09 (each IH, d), 4.15 and 4.34 (each IH, d), 4.84 (IH, m), 5.95 (2H, s), 7.06 (2H, m), 7.16 (2H, m), 7.53 (2H, d), 7.97 (2H, d), 7.99 (IH, bt) Example 9 (4R, S-S)-N-(6-[4-Fluorophenyl]taex-l-yl)-4-(4-(2-methoxyprop-2- ylcarbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l-yl)acetamide A solution of (AR, S5)-N-(6-[4-Fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide (3 g, 0.00614 mol) and 2-methoxyprop-2- ylcarbonyloxymethyl chloride ( 1.53 g. 0.00921 mol) in N-methylpyrrolidinone (30 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate 1.27 g, 0.00921 mol) and potassium iodide (1.53 g, 0.00921 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with aq. sodium thiosulphate, dried (MgSO4) and evaporated. The residue was purified by chromatography (fine silica, ethyl acetate) and the material thus obtained as a solution in ethyl acetate further washed with aq. sodium thiosulphate then stirrred for 10 min with MgSO4 and decolourising charcoal. The solids were filtered off and the filtrate evaporated, and the residue crystallised by trituration with ether/light petrol to give the title compound as white crystals m.p. 92-4°C, 2.6 g, 68% yield *H NMR δ (CDC1 3 ) 1.34 (4H, m), 1.45 (6H, s), 1.58 (4H, m), 2.56 (2H, t), 2.95 (IH, dd), 3.17-3.37 (3H, m + 3H, s), 3.96 and 4.10 (each IH, d), 4.05 and 4.22 (each IH, d), 4.69 (IH, m), 6.06 (2H, s), 6.93 (3H, m), 7.09 (2H, m), 7.39 (2H, d), 8.09 (2H, d) Example 10 (4R, SS)-N-(6-[4-Fluorophenyl]hex-l-yl)-4-(4-((5-methyl-2-oxo-l,3- dioxolen-4-yl)methyloxycarbonyl)benzylsulphinyI)-2-oxoazetidin-l-yl)acetamide A solution of (AR, S5)-N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide (5 g, 0.0102 mol) and 4-bromomethyl-5-methyl-l,3-dioxol- 2-one (2.96 g. 0.0154 mol) in N-methylpyrrolidinone (50 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (2.12 g, 0.0154 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by chromatography (fine silica, ethyl acetate) and the material thus obtained crystallised by trituration with ether/light petrol to give the title compound as white crystals, m.p. 84-7°C, 3.81 g, 62% yield. Η NMR δ (CDCI3) 1.24-1.54 (8H, m), 2.22 (3H, s), 2.5 (2H, m), 2.95 (IH, dd), 3.05 (2H, m), 3.33 (IH, m), 3.84 and 4.07 (each IH, d), 4.15 and 4.32 (each IH, d), 4.85 (IH, m), 5.22 (2H, s), 7.06 (2H, m), 7.18 (2H, m), 7.51 (2H, d), 7.98 (2H, d), 8.1 (IH, bt) Found: C, 59.7; H, 5.5; N, 4.7%; C 3 oH3 3 FN 2 O 8 S requires:C, 60.0; H, 5.5; N, 4.7% Example 11 (4R, S5)-N-(6-[4-Fluorophenyl]hex-l-yl)-4-(4-((2-methoxycarbonyI-.E- but-2-en-yl)methyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l-yl)acetamide A solution of (AR, SιS)-N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide (0.195 g, 0.0004 mol) and methyl E-2-bromomethylbut-2- enoate (0.16 g. 0.0008 mol) in N-methylpyrrolidinone (2 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (0.1 1 g, 0.0008 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts dried (MgSO4) and evaporated. The residue was purified by chromatography (fine silica, ethyl acetate) and the material thus obtained crystallised by trituration with ether to give the title compound as white microprisms, 0.024 g, 10% yield iH NMR δ (CDCI3) 1.25-1.63 (8H, m), 1.99(3H, d), 2.56 (2H, t), 2.93 (IH, dd), 3.17- 3.36 (3H, m), 3.79 (3H, s), 3.93 and 4.17 (each IH, d), 3.43 and 4.23 (each IH, d), 4.64 (IH, m), 5.12 (2H, s), 6.91-7.26 (6H, m), 7.34 (2H, d), 8.04 (2H, d) Example 12 (4Λ, S5)-N-(6-[4-Fluorophenyl]hex-l-yl)-4-(4-( N-N- dimethylaminocarbonylmethyloxycarbonyI)benzylsulphinyl)-2-oxoazetidin-l- yl)acetamide A solution of (AR, SιS)-N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide (0.2 g, 0.0004 mol) and α-chloro-N,N-dimethyl acetamide (0.17 g. 0.001 mol) in N-methylpyrrolidinone (2 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (0.14 g, 0.001 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts dried (MgSO4) and evaporated. The residue was crystallised by trituration with ether to give the title compound as white cryatals, m.p. 141-4°C, O.Ol g l H NMR δ (CDCI3) 1.25-1.75 (8H, m), 2.56 (2H, t), 2.93 (IH, dd), 2.99 (3H, s), 3.04 (3H, s), 3.17-3.36 (3H, m), 3.85-4.25 (4H, 4 x d), 4.65 (IH, m), 4.97 (2H, s), 6.93 (2H, m), 7.10 (3H, m), 7.36 (2H, d), 8.13 (2H, d). Biological Data 1. Screen for Lp-PLA2 inhibition. Enzyme activity was determined by measuring the rate of turnover of the artificial substrate (A) at 37 °C in 50mM HEPES (N-2-hydroxyethylpiperazine-N'-2- ethanesulphonic acid) buffer containing 150mM NaCl, pH 7.4. (A) Assays were performed in 96 well titre plates. Lp-PLA2 was partially purified by density gradient centrifugation of human plasma. Active fractions were pooled and used as the source of Lp-PLA2- The enzyme was pre- incubated at 37 °C with vehicle or test compound for 10 min in a total volume of 180 μl. The reaction was then initiated by the addition of 20 μl lOx substrate (A) to give a final substrate concentration of 20 μM. The reaction was followed at 405 nm for 20 minutes using a plate reader with automatic mixing. The rate of reaction was measured as the rate of change of absorbance. Results: The compounds of Examples 1 and 2, the corresponding carboxylic acid (+/-)-N-[6-(4- chlorophenyl)hex- 1 -yl]-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin- 1 -yl)acetamide and the carboxylic acid (AR, S5)-N-[6-(4-fluorophenyl)hex-l-yl]-4-(4- carboxybenzylsulphinyl)-2-oxoazetidin-l-yl)acetamide had IC50 values in the range 4 to 20 nM. 2. Evaluation of Bioavailability The pro-drug esters were evaluated in dog and human liver microsomes according to standard procedures for their ability to be hydrolysed to the parent acid. The results are given in the table below. Acid production - % conversion of test ester to parent acid by dog or liver microsomes after incubation of 1 μm test compound for 15 min, determined by measuring the concentration of parent acid produced by HPLC detection of acid (100% = IμM acid produced). Figures are rounded to nearest 5%. 3. Evaluation of stability Stability was estimated by determining half lives for decomposition test compound in pH 7.5 buffer (50 mM phosphate) and pH 1.2 buffer (USP simulated gastric fluid = NaCl/HCl pH 1.2 + pepsin). Initial concentration = 50 uM and compound monitored by HPLC. Figures rounded to nearest 0.5 h. Preferred compounds are those exhibiting good conversion of ester to acid in biological systems, while showing good stability in buffers (e.g. examples 3, 5, 6, 9, 10).

Claims: Claims 1. A compound of formula (I): (I) in which: Rl and R2, which may be the same or different, is each selected from hydrogen, halogen or C(i_8)alkyl; R is a pharmaceutically acceptable in vivo hydrolysable ester; R and R^ which may be the same or different is each selected from hydrogen, C(i-6)alkyl, C(2-6) alken yl> aryl. aryl(Cι _4)alkyl and heteroaryl(C \ _4)alkyl each of which may be optionally substituted or R^ and R^ may be linked together to form the remainder of a (C3_7)cycloalkyl ring; X is a linker group; Y is an optionally substituted aryl group; and lS is O and Z^ is C(i_8)alkyl, arylC(i_4)alkyl or aryl each of which may be optionally substituted, or C(3_8)cycloalkylC( \ _6)alkyl, aryl, arylC( \ _4)alkyl, heteroaryl or heteroarylC( \ _4)alkyl each of which may be optionally substituted; and excluding compounds in which: (a) R4 and R^ is each hydrogen, l\ is S(O)n in which n is 0, 1 or 2 and l is C(i _8)alkyl, C(3_g)cycloalkyl or C(3_g)cycloalkylC(i_6)alkyl; or (b) R 3 is C(i.6)alkyl or C(2_6)alkenyl. 2. A compound as claimed in claim 1 in which ) is selected from: -CH(R a )O.CO.R ; -CH(R a )O.CO.OR c ; -CH(R a )CO.NR e R f -RdNR e R f ; -CH 2 ORg; CH 2 R h COCH(R i )NH 2 ; and in which: R a is hydrogen, (C \ -6)alkyl, in particular methyl, (C3-7)cycloalkyl, or phenyl, each of which may be optionally substituted; R b is (Cι-6)alkyl, (Cι-6)alkoxy(Cι-6)alkyl, phenyl, benzyl, (C3-7)cycloalkyl, (Cι-6)alkyl(C3-7)cycloalkyl, l-amino(Cι-6)alkyl, or l-(Cι-6alkyl)amino(Cι-6)alkyl, each of which may be optionally substituted; or R a and R^ together form a 1 ,2-phenylene group optionally substituted by one or two methoxy groups; R c is (Cι-6)alkyl, (C 3 -7)cycloalkyl, (C 1 - 6 )alkyl(C3- 7 )cycloalkyl; Rd is (Cj-6)alkylene optionally substituted with a methyl or ethyl group; R e and R^ which may be the same or different is each (Cj^alkyl; or aryl(Cι-4) alkyl, optionally substituted with e.g. hydroxy; Rg is (C 1 - 6 )alkyl; Rh is hydrogen, (C]-6)alkyl or phenyl; R' is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (Cι-g)-alkyl, or (C \ -6)alkoxy; and γl is oxygen or NH. 3. A compound as claimed in claim 1 or 2 in which R3 is selected from: (2-methoxycarbonyl-E-but-2-en-yl)methyl, isobutyryloxymethyl, 2-methoxyprop-2- ylcarbonyloxymethyl, phenyl-carbonyloxymethyl, 4-methoxyphenylcarbonyloxymethyl, t-butyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1- methylcyclohexyloxycarbonyloxymethyl, N,N-dimethylaminocarbonylmethyl, and (5- methyl-2-oxo- 1 ,3-dioxolen-4-yl)methyl. 4. A compound as claimed in any one of claims 1 to 3 in which R^ and R^ is each hydrogen. 5. A compound as claimed in any one of claims 1 to 4 in which R^ is hydrogen and R$ is methyl or R 4 and R^ is each hydrogen. 6. A compound as claimed in any one of claims 1 to 5 in which X is: (a) a direct bond; (b) a group X'(CH2)m n which X' is CO, CONR 6 , COO, CONR 6 CO, or CONHO in which R 6 is hydrogen or C(j .g^alkyl and m is 0 or an integer from 1 to 12; (c) a C(i_i2)alkylene chain optionally interupted by X'; (d) a group A-B in which A is a direct bond or X' and B is a (i_i2)al ylene chain interupted and/or terminated at the end remote from A by one or more groups M selected from O, S(O)n, NR 6 , alkene or alkyne in which R 6 is hydrogen or and n is 0, l or 2. 7. A compound as claimed in claim 6 in which X is CO(CH2) m , CONH(CH2) m , COO(CH 2 ) m , CONHCO(CH 2 ) m , CONHO(CH 2 ) m , C (1 . 12 )alkylene, A'(CH )aCH=CH(CH 2 )b, A'(CH 2 )aC≡C(CH 2 )b or A'(CH 2 )a(O) c (CH 2 )b(O)d in which A' is a direct bond or CONR 6 , a is an integer from 1 to 12, b is 0 or an integer from 1 to 12 such that a+b < 12, suitably < 6, c is 0 or 1 and d is 1 or c is 1 and d is 0, with the proviso that if c and d are both 1 , then b > 1. 8. A compound as claimed in claim 6 or 7 in which m is 1 , 2, 5, 6, 7 or 9, preferably 6. 9. A compound as claimed in any one of claims 1 to 8 in which X is CONH(CH2)6- 10. A compound as claimed in any one of claims 1 to 9 in which Y is a benzene ring, optionally substituted by up to three further substituents. 11. A compound as claimed in any one of claims 1 to 10 in which Y is phenyl substituted at the 4-position by halo. 12. A compound as claimed in any one of claims 1 to 11 in which l\ is SO. 13. A compound as claimed in any one of claims 1 to 12 in which l is benzyl. 14. A compound as claimed in any one of claims 1 to 13 in which is: 15. A compound as claimed in any one of claims 1 to 14 which is a prodrug of N-(6-[4- fluorophenyl]hex-l -yl)-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin- 1 -yl)acetamide or N- (6-[4-chlorophenyl]hex- 1 -y l)-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin- 1 - yl)acetamide. 16. A compound as claimed in any one of claims 1 to 15 which has the stereochemistry 4Λ and, if Z 1 is SO, SS. 17. A compound of formula (I) as defined in claim 1 selected from: N-(6-(4-chlorophenyI)hex-l-yl)-4-((4-(cyclohexyloxycarbonyloxy-methyloxycarbonyl) benzylsulphinyl)-2-oxoazetidin-l -yl)acetamide; and N-(6-(4-chlorophenyl)hex-l-yl)-4-((4-(phenylcarbonyloxymethyl-oxycarbonyl)benzyl sulphinyl)-2-oxoazetidin- 1 -y I)acetamide. 18. A pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. 19. A compound of formula (I) for use in therapy. 20. The use of a compound of formula (I) as defined in claim 1 in the manufacture of a medicament for treating atheroscelrosis. 21. The use of a compound of formula (I) as defined in claim 1 in the manufacture of a medicament for treating diabetes, hypertension, angina pectoris, after ischaemia, reperfusion, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury, sepsis, and acute and chronic inflammation, inflammatory conditions of the brain such as Alzheimer's Disease, neuropsychiatric disorders such as schizophrenia, and psoriasis. 22. A method of treating a disease state associated with activity of the enzyme Lp-PLA2 which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor of the enzyme. 23. A method as claimed in claim 22 in which the disease state is associated with the increased involvement of monocytes, macrophages or lymphocytes. 25. A method as claimed in claim 22 in which the disease state is associated with the formation of lysophosphatidylcholine and oxidised free fatty acids. 26. A method as claimed in claim 22 in which the disease state is associated with lipid peroxidation in conjunction with Lp PLA2 activity. 27. A method as claimed in claim 22 in which the disease state is associated with endothelial dysfunction. 28. A process for preparing a compound of formula (I) as defined in claim 1 which process comprises treating an azetidone of formula (II): CD in which Rl, R^, X, Y, z , and ZT- are as hereinbefore defined; or a corresponding salt, (Cι_g)alkyl ester or activated derivative thereof; with a compound of formula (III) : R3R7 (III) in which: R ' is a reactive esterifying leaving group and R3 is as hereinbefore defined; under ester forming conditions.

Inventors: DHANAK DASHYANT, HICKEY DEIRDRE MARY BERNADETTE, IFE ROBERT JOHN, LEACH COLIN ANDREW, TEW DAVID GRAHAM, DHANAK, DASHYANT, HICKEY, DEIRDRE, MARY, BERNADETTE, IFE, ROBERT, JOHN, LEACH, COLIN, ANDREW, TEW, DAVID, GRAHAM
Applicants: DHANAK DASHYANT, HICKEY DEIRDRE MARY BERNADETTE, IFE ROBERT JOHN, LEACH COLIN ANDREW, SMITHKLINE BEECHAM PLC, TEW DAVID GRAHAM, DHANAK, DASHYANT, HICKEY, DEIRDRE, MARY, BERNADETTE, IFE, ROBERT, JOHN, LEACH, COLIN, ANDREW, TEW, DAVID, GRAHAM
Application year: 1996
Main classification: C07D205
IPC codes: A61K31, A61P3, A61P9, A61P19, A61P25, A61P29, A61P43, C07D205, C07D405