WO1997021676A1 - Azetidinone compounds for the treatment of atherosclerosis - Google Patents

Abstract

Azetidinone compounds of formula (I) in which inter alia: R?0 is CR4R5-X1-Y1¿ or (CH¿2?)pX?2(CH¿2)qY?2; R4 and R5¿ which may be the same or different is each selected from hydrogen and C¿(1-6)?alkyl, or R?4 and R5¿ may be linked together to form the residue of a C¿(3-7)?cycloalkyl ring; X?1¿ is a linker group and Y1 is optionally substituted C¿(1-12)?alkyl C(2-12)alkynyl, C(2-12)alkynyl, C(3-7)-cycloalkylC(1-8) alkyl or an optionally substituted heteroaryl group; and X?2¿ is a heteroaryl group and Y2 is an optionally substituted aryl group, p is an integer from 1 to 6, q is 0 or an integer from 1 to 6; are inhibitors of the phospholipase A2 enzyme Lp PLA2 and are of use in therapy, for instance in treating atherosclerosis.

Description

AZETIDINONE COMPOUNDS FOR THE TREATEMENT OF ATHEROSCLEROSIS .

The present invenuon relates to certain novel monocyclic β-lactam compounds, processes for their preparation, intermediates useful in their preparation, pharmaceuucal compositions containing them and their use in therapy, in parucular 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 purificauon thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA encoding the enzyme. Suggested therapeuuc uses for mhibitors of the enzyme mcluded atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarcuon, reperfusion injury and acute and chronic inflammation. A subsequent publicauon from the same group further describes this enzyme (Tew D et al, Arteπoscler Thromb Vas Biol 1996:16:591-9) wherein it is referred to as LDL-PLA2. A later patent applicauon (WO 95/09921, Icos Co orauon) and a related publicauon 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 phosphaudylcholine 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 phosphaudylcholine to give lysophosphatidylcholine and an oxidauvely modified fatty acid. Both products of Lp-PLA2 acuon are biologically acuve with lysophosphatidylcholine, a component of oxidised LDL, known to be a potent chemoattractant for cuculaung monocytes. As such, lysophosphaudylchohne is thought play a significant role in atherosclerosis by being responsible for the - accumulauon of cells loaded with cholesterol ester in the arteries. Inhibiuon of the Lp-PLA2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibiuon of the formauon of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis.

The increased lysophosphatidylcholine content of oxidauvely modified LDL is also thought to be responsible for the endothelial dysfuncuon observed in pauents 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 dysfuncuon including diabetes, hypertension, angina pectoπs and after ischaemia and reperfusion. In addition, Lp-PLA2 inhibitors may also have a general applicauon in any disorder that involves acuvated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA₂. 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 neuropsychiauic 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. We have now identified a further series of azetidinone compounds which are distinguished over previous series by tiie substituent at the ring nitrogen and which act as inhibitors of Lp-PLA2-

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

in which:

Rθ is CR^-X-ⁱ-Y¹, CR R5-χ2-γ2_{f or} (CH₂)pX³(CH₂)_qY³;

Rl and R², which may be the same or different, is each selected from hydrogen, halogen or C(i_8)alkyl; R⁴ and R-^ which may be the same or different is each selected from hydrogen and

C(i_6)alkyl, or R⁴ and R⁵ may be linked together to form the residue of a C(3_7) cycloalkyl ring;

X¹ is a linker group and Y¹ is optionally substituted t.^alkyl C(2-i2)*""kenyl.

C(₂-I2)alkynyl, C(₃.7)-cycloalkylC(₁.₈) alkyl; X² is a linker group and Y² an optionally substituted heteroaryl group;

X³ is a heteroaryl group and Y³ is an optionally substituted aryl group, p is an integer from 1 to 6, q is 0 or an an integer from 1 to 6;

Z is O and R³ is C(i„8)alkyl, arylC( ι_4)alkyl or aryl each of which may be opuonally substituted, or Z is S(O)n in which n is 0, 1 or 2 and R³ is C₍i _g₎alkyl, C(3_g₎Cycloalkyl, C(3.g)CycloalkylC(i.6)alkyl, aryl, arylC( i _4)alkyl or heteroarylC(i _4)alkyl each of which may be optionally substituted.

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.

Representative examples of R* and R² include hydrogen, bromo, methyl and ethyl. Suitably, R¹ and R² is each hydrogen or one of R¹ and R² is hydrogen and the other of R¹ and R² is methyl (to give a tra/w-methyl). Preferably, R¹ and R² is each hydrogen.

Representative examples of C(i_g)alkyl for R³ include methyl, n-butyl, t- butyl and n-hexyl, cyclohexyl and cyclohexylmethyl, suitably methyl, n-butyl, t-butyl or n-hexyl. Suitable substituents for the alkyl or cycloalkyl group include halo, hydroxy and carboxy and esters thereof. Representative examples of arylC(j,_4)alkyl for R³ include arylC(i _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 substituents. Suitable substituents include halo, hydroxy, C(i_6)alkyl, C(i_6)alkoxy, arylC(i_6)alkoxy, carboxy and esters thereof, (C ^alkylthio, (Cι_6)alkylsulphinyl, and (Ci^alkylsulphonyl.

Representative examples of aryl for R³ include phenyl and naphthyl. Preferably, the aryl group is optionally substitued phenyl. Suitable substituents for a phenyl or naphthyl ring include halo, hydroxy, C(i_6)alkyl, C(i_6)alkoxy, arylC(i_6)alkoxy, carboxy and esters thereof, (C ι-6)alkylthio, (C i _6)alkylsulphinyl, and (Cι_6)alkylsulphonyl.

Representative examples of heteroaryl group for incoφoration into R^3~ include include pyridyl, pyridyl N-oxide, furanyl, thienyl and thiazolyl. Suitably, the heteroarylalkyi 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 include halo, hydroxy, C(i_6)alkyl, C(i_6)alkoxy, arylC(i _6)alkoxy, carboxy and esters thereof, (Cι-6)alkylthio, (Cι_6)alkylsulphiny{ and (Cι_6)alkylsulphonyl. Preferably, when Z is S(O)n, n is 1 or 2, more preferably 1. Preferably Z is SO and R³ is arylmethyl or heteroarylmethyl, in particular benzyl or furanylmethyl, especially benzyl.

Suitable esters for incoφoraϋon into R³ include pharmaceutically acceptable esters of the formula CO2 . Such esters may be active in their own right and /or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups for incoφoration 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

for instance, methyl, ethyl and propyl, (C2"6)alkenyl, for instance allyl. Further 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.NR^eR^f

-R^dNR^eR^f;

CH(R^a)O.CO.C₆H₄Y⁴COCH(Ri)NH₂ in which:

R^a is hydrogen, (Cι-6)alkyl, in particular methyl, (C3-7)cycloalkyl, or phenyl; R^D is (Cι-6)alkyl, (C₁-₆)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; or

R^a and R*⁵ together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; R^c is (Cι -6)alkyl, (C3-7)cycloalkyl, (Cι-6)alkyl(C3-₇)cycloalkyl;

Rά^* is (C ι -6)alkylene optionally substituted with a methyl or ethyl group;

R^e and Rf which may be the same or different is each (C_j-gjalkyl or aryl (C 1 -4) alkyl, optionally substituted with e.g. hydroxy;

RS is (C-[-₆)alkyl; Rⁿ is hydrogen, (Cι-g)alkyl or phenyl;

Ri is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (Cj. -6)-alkyl, or (Cι -6)alkoxy; and

Y⁴ is oxygen or NH; for instance:

(a) acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)ethyl, and (l-aminoethyl)carbonyloxymethyl;

(b) alkoxy/cycloalkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl and α-ethoxycarbonyloxyethyl; (c) dialkylaminoalkyl, especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethyiaminomethyl or diethylaminoethyl;

(d) acetamido groups such as N,N-dimethylaminocarbonylmethyl, N,N-(2- hydroxyethyDaminocarbonylmethyl;

(e) lactone groups such as phthalidyl and dimethoxyphthalidyl; and

(f) (5-methyl-2-oxo- 1 ,3-dioxolen-4-y l)methyl.

It will be appreciated by those skilled in the art that the values in the further group of examples include those which have previously been proposed for use as pro- drug esters for various penicillin antibiotics such as ampicillin.

Representative examples of R⁴ and R-^ when an alkyl group include methyl. Representative examples of a (C3_7)cycloalkyl ring include cyclopropyl. Suitably, R⁴ and R-^ are both hydrogen or R⁴ is hydrogen and R-^ methyl.

Suitably, X¹ is a direct bond or a group (CH2)_XX⁴ in which X⁴ is CH2O, CO, COO, CONR⁶, CONR⁶CO, or CONHO in which R⁶ is hydrogen or C(i_6₎alkyl, x is 0 (for all except X⁴ =COO) or an integer from 1 to 6. Suitably X⁴ is CONH. Suitably x is 0. Preferably, X¹ is CONH.

Suitably, in Y^**, the alkyl chain is unbranched. Useful such values of Y** include C(6-io) alkyl. preferably C(g_ιo) alkyl or C(3_7)cycloalkylC(5_7) alkyl, preferably cyclohexylC(5_7)alkyl. Representative examples of γl include nonyl and cyclohexylhexyl.

Suitably, X² is:

(a) a direct bond;

(b) a group X⁵(CH₂)_y in which X⁵ is CO, CONR⁶, COO, CONR⁶CO, or CONHO in which R⁶ is hydrogen or C^.^alkyl and y is 0 or an integer from 1 to 12;

(c) a C(μι 2)alkylene chain optionally interupted by X*^;

(d) a group A-B in which A is a direct bond or χ5 and B is a

^cna**ⁿ interupted and or terminated at the end remote from A by one or more groups M selected from O, S(O)n, NR⁶, alkene or alkyne in which R⁶ is hydrogen or C(i_6)alkyl and n is 0, 1 or 2.

Representative examples of X² include CO(CH2)_y, CONH(CH2)_y, COO(CH₂)_y, CONHCO(CH₂)_y, CONHO(CH₂)_y and C_{( 1}.₁₂)alkylene. Preferably, X³ is CO or CONR⁶, more preferably CONH. Preferably, y is 1, 2, 5, 6, 7 or 9, preferably 6. Preferably, X² is CONH(CH₂)6- Representative examples of heteroaryl rings for incoφoration into Y² include pyridyl and pyridyl N-oxide. Suitable substituents for a heteroaryl ring include halo, hydroxy, CQ _g)alkyl and C(i_g)alkoxy. Suitably, Y² is 2-pyridyl or 4- pyridyl, preferably in combination with χl being CONH(CH2)6-

Representative examples of X³ include thiazolyl and oxazolyl, in particular

Suitably, p is 1. Representative - values of q - includXe 0 and 5. Representative examples of aryl rings for incoφoration into Y³ include phenyl and naphthyl. Suitable substituents for the aryl ring include halo, hydroxy, C(i_g₎alkyl and C₍i_g₎alkoxy. Suitably, Y³ is phenyl. Representative examples of X³- Y³ include:

Suitably, R° is CH₂CONHγl in which Y¹ is C(g_ιo) alkyl or cyclohexylC(5_7)alkyl, in particular nonyl or cyclohexylhexyl.

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 R⁴ and R 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, R5=Me, the absolute configuration at the α-carbon (to which R^ is attached) is S.

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, n-propyl, wø-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.

Suitable substituents for an alkyl group include, for example, and unless otherwise defined, halogen, cyano, azido, nitro, carboxy, (Cι_6)alkoxycarbonyl, carbamoyl, mono- or di-(Cι _6)alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(Cτ . 6)alkylsulphamoyl, amino, mono- or di-(Cι_6)alkylamino, acylamino, ureido, (Cι_^6)alkoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, hydroxy, (Ci.gjalkoxy, acyloxy, oxo, acyl, 2-thienoyl, (Cι_6)alkylthio, (Cι _6)alkylsulphinyl, (Cι_6)alkylsulphonyI, 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, (Ci ^alkyl, (C3-7)cycloalkyI, (Cι -6)alkoxy, halo(Cι-6)alkyl, hydroxy, amino, mono- or di-(Cι-6)alkylamino, acylamino, nitro, carboxy, (Cι-6)alkoxycarbonyl, (Ci -gjalkenyloxycarbonyl, (Cι-6)alkoxycarbonyl(Cι-6)alkyl, carboxy(Cι-6)alkyl, (Ci-^alkylcarbonyloxy, carboxy(Cι-6)alkyloxy, (Ci-βtølJcoxycarbonyKC i -^alkoxy, (Cι-6)alkylthio, (Cι-6)alkylsulphinyl, (C ^alkylsul phony 1, sulphamoyl, mono- and di-(C_j-6)- aikylsulphamoyl, carbamoyl, mono- and di-(Cι ^alkylcarbamoyl, and heterocyclyl. When used herein, the term 'heterocyclyl' 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. Preferred compounds of formula (I) include:

N-(6-Cyclohexylhexyl)-(4-benzylsulphinyl-2-oxoazeϋdin-l-yl)acetamide (Diastereoisomer 2);

N-(6-Cyclohexylhexyl)-(4-benzylsulphonyl-2-oxoazetidin-l-yl)acetamide;

N-(Nonyl)-(4-benzylsulphinyl-2-oxoazetidin-l-yl)acetamide (Diastereoisomer 2); and N-(Nonyl)-(4-benzylsulphonyl-2-oxoazetidin- l-yl)acetamide.

Preferred compounds of formula (I) in which, in R^, Y² is heteroaryl, include:

N-(6-(4-Pyridyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin-l-ylacetamide

(Diastereoisomer 2); and

N-(6-(2-Pyridyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin- 1 -ylacetamide (Diastereoisomer 2).

Preferred compounds of formula (I) in which R° is (CH2)pX³(CH2)nY³ include:

(4-(5-Phenylpentyl)thiazol-2-ylmethyl)-4-benzylsulphinyl-2-oxoazetidine.

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 polymoφhic forms of crystalline products. This invention includes within its scope all polymoφhic forms of the compounds of formula (I). Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A (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-PLA2 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 neuropsychiauic 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_j. 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-PLA₂ 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 carτier(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, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, tiie 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 (1).

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 rag 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 prepared by adapting processes previously described for ananlogous compounds in International patent applications WO 96/13484, WO 96/19451 and PCT EP96/02765 (SmithKline Beecham pic). Such processes include treating an azeti (II):

(II) in which:

Rl, R², R³, and Z are as hereinbefore defined; with an alkylating agent of the formula (HI):

R⁷Rθ

(HI) in which R is a suitable leaving group such as halogen or triflate; and

R^is as hereinbefore defined; under alkylating conditions. Suitable alkylating conditions are well known in the art and include carrying out the reaction in the presence of a suitable base such as sodium hydride or potassium hydroxide optionally with a quaternary ammonium salt such tetrabutyl ammonium bromide, in a suitable alkylating solvent such as tetrahydrofuran (THF), and at a temperature in the range - 10 to 0°C. In compounds of formula (I) in which Z is S(O)n, the preceding alkyiation reaction is conveniently effected on compounds in which n is 0.

Compounds of formula (I) in which n is 1 or 2 can be readily prepared from compounds of formula (I) in which n is 0 by treatment thereof with a suitable oxidising agent such as m-chloroperbenzoic acid. Use of chiral oxidising agents such as (+)- or (-)- 1 , 1 '-bi-2-naphthol / titanium wopropoxide (N Komatsu et al, J Org Chem, 1993, 58, 7624-7626) can give diastereo isomeric selectivity, if not chirally pure compounds.

Compounds of formula (I) in which one of R⁴ and R^ is alkyl may also be prepared from corresponding compounds of formula (I) where both R⁴ and R-> are hydrogen by treatment thereof with an alkylating agent under the conditions described above. Such compounds may be obtained by treating a compound of formula (LT) with an alkylating agent of formula (HI) in which both of R⁴ and R⁵ is hydrogen, under alkylating conditions as hereinbefore described.

A second alkyl group for R⁴/R*5 may be introduced by treating a first obtained compound of formula (I) in which one of R⁴ and R⁵ is hydrogen, with an alkylating agent in the presence of a suitable base such as sodium hydride, potassium hydroxide or lithium hexamethyldisilazide, in a suitable alkylating solvent such as tetrahydrofuran (THF), and at a temperature in the range -80 to 10°C.

Compounds of formula (II) in which Z is O may be obtained by treating 4- acetoxyazetidinone, 4-benzoyloxyazetidinone or 4-phenylsulfonylazetidinone with a phenol alcohol HOR³ in the presence of a base such as potassium t-butoxide, in a suitable solvent such as THF at a temperature in the range 0 to 5°C. Compounds of formula (IV) in which Z is S may be obtained by treating 4-acetoxyazetidinone with a thiol HSR³ in the presence of a base such as sodium ethoxide, in a suitable solvent such as ethanol at a temperature in the range 0 to 5°C.

Compounds of formula (IU) may be readily prepared by adapting known synthetic procedures, according to the specific value of X^ . A convenient starting material is an appropriately substituted aryl compound which may then be elaborated to introduce the side chain R⁷CR⁴R⁵ X^{1 2}-. Compounds of formula (I) in which χl denotes a group CONR⁶ or

CONR O may be of the formula (IV):

(IV) in which: Rl, R², R³, R⁴, R⁵ and Z are as hereinbefore defined; with an amine of the formula (V):

NHR Yl

(V) or a hydroxylamine of the formula (VI): NH2OY¹

(VI) in which R⁶ and γl are hereinbefore defined, in the presence of an activating agent such as ethyl chloroformate or dicyclohexylcarbodiimide (DCC), in a suitable solvent such as chloroform or dimethyl formamide, at a temperature in the range -10 to 20°C.

A similar process may be used for preparing a compound of formula (I) in which X² denotes a group CONR⁶(CH₂)_y or CONR⁶O(CH₂)_y, but using an amine NHR⁶(CH₂)_yY¹ or a hydroxylamine NH₂O(CH2)_yγ!. An acid of formula (IV) in which one of R⁴ and R⁵ is hydrogen may be obtained by treating a compound of formula (II) with a corresponding 2-bromo (C1.7) alkanoate ester, under alkylating conditions as hereinbefore described; followed by the hydrolysis of the thus formed intermediate ester using standard conditions. A second alkyl group may be inu-oduced by alkylating of the first formed monoalkyl ester.

Compounds of formula (I) in which χ denotes a group (CH2)_xCOO in which x is an integer from 1 to 6 may be conveniently prepared by transesterifying a compound of formula (VH):

(vn) in which:

R⁷ is methyl; and x, R¹, R\ R\ R", R⁵ and Z are as hereinbefore defined; using conditions well known in the art for such reactions, for instance heating in toluene in the presence of a catalytic amount of sodium methoxide and an alcohol. A compound of formula (VII) in which one of R⁴ and R^ is hydrogen may be obtained by treating a compound of formula (II) with a methyl 2-bromoalkanoate, under alkylating conditions as hereinbefore described. Alternatively, a compound of formula (I) in which χ denotes a group

(CH2)_xCOO in which x is an integer from 1 to 6 may be prepared by treating a compound of formula (IV) in which R⁷ is hydrogen with an alcohol γ θH or an activated derivative thereof, for instance a tosylate.

Compounds of formula (I) in which X 1 is CH2O may be prepared by a suitable ether coupling reaction, for instance treating a compound of formula (VIE):

(vm) in which R** is a halogen or other suitable leaving group such as triflate or tosylate and R¹, R², R³, R⁴, R⁵, x and Z are as hereinbefore defined; with an alcohol γ θH or a suitable salt therof.

In addition, compounds of formula (I) in which Z is S(O)n and n is 0 may be prepared by a process which comprises treating a compound of formula (DC):

(LX) in which RO, R , R², χl and γl are as hereinbefore defined; with an alkylating agent of the formula (X):

R⁸R³

(X) in which R³ and R are as hereinbefore defined; under suitable alkylating conditions, for instance, in a solvent such as acetonitrile, at a temperature in the region 25°C. Compounds of formula (LX) may be obtained from the corresponding 4- acetylthioazetidinone by treatment with silver nitrate and a base in a suitable solvent such as methanol.

Mixtures of diastereoisomeric compounds of formula (I) may be resolved, if so desired, according to procedures well known in the art. For instance sulphoxides (n=l) may be separated by chromatography and/or crystallisation. Chirally pure compounds may be prepared by chiral chromatography, from chirally pure intermediates or by chiral synthesis using chiral reagents or catalysis. Suitable chiral intermediates may be obtained by resolution or chiral induction or by using chiral reagents, in particular natural chiral molecules, according to methods well known to those skilled in the art. For chiral synthesis, a convenient chiral starting material is a penicillin derivative which has the preferred configuration at C-4 of the β-lactam ring. This is illustrated in the following scheme:

The preparation of the starting material (4-methoxybenzyl-6-bromopenicillinate-l- oxide) is described by J. Chem. Soc, Perkin Trans. 1, 1994, 179-188. The present invention will now be illustrated by the following examples. In these, the terms 'diastereoisomer 1' and 'diastereoisomer 2' are used for sulfo xide compounds to refer to the diastereoisomers having R,R/S,S and R,S/S,R configurations, respectively. Such configurations were obtained initially by X-ray analysis of a limited number of compounds and then extrapolated to the remaning compounds on the basis of their H nmr spectra. Unless otherwise specified, all compounds are racemic. Chiral compounds are described as 4R 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.

Preparation 1 Methyl (4-benzylthio-2-oxoazetidin-l-yl)acetate a. 4-(Benzyithio)azetidin-2-one

Sodium (8.1g, 0.35mol) was dissolved in ethanol (250ml) and benzyl mercaptan (45.2g, 0.37mol) added dropwise over 20 minutes keeping the temperature between 20°C - 25°C whilst bubbling nitrogen through the mixture. After 15 minutes, the reaction was cooled to 5°C and a solution of 4-acetoxyazetidin-2-one (45.0g, 0.35mol) in ethanol (50ml) was added dropwise over 15 minutes whilst maintaining the temperature at 5°C. The mixture was stirred at room temperature for 60 minutes and evaporated to dryness under reduced pressure. Water (400ral) was added, the mixture extracted with dichloromethane (2x300ml), the extracts dried (MgSO_ι) and evaporated under reduced pressure to an oil. The oil was cooled to -20°C and titurated with ether (400ml) to give a white solid which was isolated by filtration (50.2g, 79%), m.p. 50-51.0°C. 1H NMR 6 (CDC1₃) 2.86(1H, m, H_3a), 3.30 (IH, m, H_3b), 3.85 (2H, s, SCH₂), 4.68 (IH, m, H₄), 7.31 (5H, m, Ph-H). b. Methyl (4-benzylthio-2-oxoazetidin-l-yl)acetate

To a solution of 4-(benzylthio)azetidin-2-one (5.0g, 25mmol), methyl bromoacetate (4.6g, 30mmol) and tetrabutylammonium bromide (0.9g, 0.28mmol ) in dry THF (150ml) was added powdered potassium hydroxide (1.7g, 30mmol). The resulting mixture was stirred for two hours at room temperature before water (50 ml) was added. The solution was extracted with ethyl acetate (3x150ml portions) and the combined extracts dried (MgSO. ) and evaporated. The residue was purified by flash chromatography on silica gel eluted with petroleum ether 60°-80°:ethyl acetate 4: 1 to give methyl (4-benzylthio-2-oxoazetidin-l-yl)acetate as a yellow oil (5g, 70%).

1H NMR δ (CDCI3) 2.96(1H, dd, J=2.5. 16 Hz H_3a), 3.24,3.99 (each IH, d, J=18.00 Hz, NCH2). ³*⁴ <^1H- ^dd- J=5,12.5 Hz H_3b). ³*70 (3H, s, OCH3). -77 (2H, s, SCH2). 4.92 (IH, m, H4), 7.28 (5H, m. Ph-H) Preparation 2 (4- Benzyl thio-2-oxoazetidin- 1-yl )acetic acid To a solution of methyl (4-benzylthio-2-oxo-azetidin-l-yl)acetate (2.5g, 9.4mmol) in methanol (80ml) was added, dropwise at 0°C, a solution of 1 N sodium hydroxide (9.9ml, 9.9mmol). The reaction was stirred for 1 hr and evaporated to dryness. Water (50 ml) was added and the solution acidified to pH 3 with dilute hydrochloric acid and extracted with ethyl acetate (3x100ml) . The combined extracts were dried (MgSO4), evaporated and the residue purified by recrystallisation (hexane/ether) to give (4-benzylthio-2- oxo-azetidin-l-yl)acetic acid as a white solid (1.3g, 55%), mp 110-111°C. ^!H NMR δ (CDCI3) 2.99 (IH, dd, J=6.87,17.5 Hz, H.3_a). ³-²7, 4.06 (each IH, d, J=18.40 Hz, NCH₂), 3.39 (IH, dd, J=5,15.4 Hz, H_3b). ³-77 (2H, s, SCH2). ⁴*^{9 i} (^1H- ^m> H₄), 7.27 (5H, m, Ph-H). Preparation s: . (4-BenzyIthio-2-oxoazetidin-l-yl)acetic acid a. 4-(Benzylthio)azetidin-2-one

Sodium (8.1g, 0.35mol) was dissolved in ethanol (250ml) and benzyl mercaptan (45.2g, 0.37mol) added dropwise over 20 minutes keeping the temperature between 20°C - 25°C whilst bubbling nitrogen through the mixture. After 15 minutes, the reaction was cooled to 5°C and a solution of 4-acetoxyazetidin-2-one (45.0g,

0.35mol) in ethanol (50ml) was added dropwise over 15 minutes whilst maintaining the temperature at 5°C. The mixture was stirred at room temperature for 60 minutes and evaporated to dryness under reduced pressure. Water (400ml) was added, the mixture extracted with dichloromethane (2x300ml), the extracts dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was cooled to -20°C and titurated with ether (400ml) to give a white solid which was isolated by filtration (50.2g, 79%), m.p. 50-51.0°C. b. MetiιyI-(4-benzy.thio-2-oxoazetidin-l-yl) acetate

To a solution of 4-(benzylthio)azeϋdin-2-one (5.0g, 25mmol), methyl bromoacetate (4.6g, 30mmol) and tetrabutylammonium bromide (0.9g, 0.28mmol ) in dry THF (150ml) was added powdered potassium hydroxide (1.7g, 30mmol). The resulting mixture was stirred for two hours at room temperature before water (50 ml) was added. The solution was extracted with ethyl acetate (3x150ml portions) and the combined extracts dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel eluted with petroleum ether 60°-80°:ethyl acetate 4: 1 to give methyl (4-benzylthio-2-oxoazetidin- l-yl)acetate as a yellow oil (5g, 70%).

1H NMR δ (CDC1₃) 2.96(1H, dd, J=2.5, 16 Hz H_3a). 3.24,3.99 (each IH, d, J=18.00 Hz, NCH₂). ³*⁴ ( H- ^d- J=5.12.5 Hz H_3b). ³-70 (3H, s, OCH3). ³*77 (2H, s, SCH₂). 4.92 (IH, m, H₄), 7.28 (5H, m, Ph-H) c (4-Benzylthio-2-oxoazeridin-l-yl)acetic acid To a solution of methyl (4-benzylthio-2-oxo-azetidin-l-yl)acetate (2.5g, 9.4mmol) in methanol (80ml) was added, dropwise at 0°C, a solution of 1 N sodium hydroxide (9.9ml, 9.9mmoI). The reaction was stirred for 1 hr and evaporated to dryness. Water (50 ml) was added and the solution acidified to pH 3 with dilute hydrochloric acid and extracted with ethyl acetate (3x100ml) . The combined extracts were dried (MgSO4), evaporated and the residue purified by recrystallisation (hexane/ether) to give (4-benzylthio-2-oxo-azetidin- l-yl)acetic acid as a white solid (1.3g, 55%), mp 110-111°C. ^JH NMR δ (CDC1₃) 2.99 (IH, dd, J=6.87,17.5 Hz, H3_a). *²7, 4.06 (each IH, d, J=18.40 Hz, NCH₂), 3.39 (IH, dd, J=5,15.4 Hz, H3t_>). ³*77 (2H, s, SCH2). ⁴*91 (IH, m, H4), 7.27 (5H, m, Ph-H). Preparation 4: 6-(4-Pyridyl)hexylamine

Sodamide (6.63g) was suspended in Uquid ammonia (100ml) and cooled in a cardice/acetone bath. 4-Picoline (7.3ml) was added, the cooling bath removed and the mixture stirred at reflux for 2hrs. The mixture was cooled again and 5- bromopentylamine hydrobromide (18.53g) added and the mixture allowed to reflux for 5 hrs. The mixture was again cooled, quenched with ammonium chloride (lOg) and the solvent allowed to evaporate overnight. The residue was dissolved in water (100ml), made strongly alkaline with NaOH and extracted with CH,C1₂ (2x100ml). The combined organics were partitioned with water at pH7 and the aqueous was washed with CH₂C1₂( 100ml) then basified with NaOH and extracted with CH,C1₂ (2x 100ml), dried over K O, and evaporated to an orange oil. This was purified by vacuum distillation to give the title compound as a colourless oil (4.94g, 37% yield; b.p. 110-120°C/0.5mm)

'H NMR δ (CDCl,) 1.3-1.7 (8H, m, 4 x CH₂), 2.6 (4H, , QLPyr + CH₂NH₂), 7.10 (2H, m, Pyr-3,5H), 8.48 (IH, m, Pyr-2,6H) Preparation 5: 6-(2-Pyridyl)hexylamine Treatment of 2-picoline witii sodamine in liquid ammonia followed by 5- bromopentylamine using the procedure for 6-(4-pyridyl)hexylamine gave the title compound in 38% yield, b.p. 250°C at 0.3 mm Hg Preparation 4: 2-Bromomethyl-4-(5-phenylpentyl)thiazole a. 2-Benxoyloxy-4-(5-phenylpentyl)thiazole

A mixture of benzoyloxylthioacetamide (CA8923f) (2.0g, 0.0102moles) and 1-bromo- 6-phenyl-2-hexanone (2.5g, 0.00929moles) in absolute alcohol (2.5ml) was stiired at reflux for 15 minutes. The reaction was cooled and poured into sat.NaHCO₃ (aq) and extracted with ethyl acetate (2x50ml). The organic extracts were combined, washed with brine, dried (MgSO₄) and evaporated to an orange oil. Purification by column chromatography eluted with 20: 1 to 10:1 P.E.: ethyl acetate gave 2-benxoyloxy-4-(5- phenylpentyl)thiazole as a colourless oil (2.39g, 71%). b. 2-Hydroxymethyl-4-(5-phenylpentyl)thiazole 2-Benxoyloxy-4-(5-phenylpentyI)thiazole (2.29g, 0.00627moles) was treated with 5% ethanolic potassium hydroxide (100ml) and the mixture was heated on a steam bath for 10 minutes. The mixture was reduced in volume to 25ml under reduced pressure, water (100ml) was added and the mixture was reduced to 50ml under reduced pressure. The residue was acidified to pH7 with dilute HCl and extracted with diethyl ether (x2). The organic extracts were combined and washed with sat.NaHCO , brine, dried (MgSO₄) and evaporated to a yellow oil. Purification by column chromatography eluted with 1:1 P.E.: ethyl acetate gave 2-hydroxymethyl-4-(5-phenylpentyl)thiazole as a yellow oil (1.55g, 94%). c 2-Bromomethyl-4-(5-phenylpentyl)thiazole A mixture of 2-hydroxymethyl-4-(5-phenylpentyl)thiazole (1.47g, 0.00562moles) and triphenylphosphine (1.59g, 0.00606moles) in dry CH₂C1₂ (25ml) was cooled to 0°C and treated with solid N-bromosuccinimide (1.08g, 0.00606moles) in portions over 10 minutes maintaining the temperature at 0°C. The cooling bath was removed and the reaction was stirred for lh. Purification by column chromatography eluted with 10:1 to 5:1 P.E.: ethyl acetate gave the product as a colourless oil. The oil was dissolved in diethyl ether and washed with saLNaHCO₃ (aq), brine, dried (MgSO₄) and evaporated to give 2-bromomethyl-4-(5-phenylpentyl)thiazole as colourless oil (1.52g, 83%).

Example 1 N-(6-CydohexyIhexyl)-(4-beιuyIthio-2-oxoazetidin-l-yI)acetamide

A mixture of (4-benzylthio-2-oxoazetidine-lyl)acetic acid (2.06g), 6- (cyclohexyl)hexylamine (1.50g), dicyclohexylcarbodiimide (1.69g) and 1- hydroxybenzotriazole (1.1 lg) in dry dimethylformamide (DMF) (20ml) was stirred at 20°C for 3 hours. Ethyl acetate (50ml) was added, the mixture filtered and the filtrate evaporated to an oil. This oil was taken up in ethyl acetate, washed with aq. NaHCO₃ solution and brine, dried over MgSO₄ and evaporated to an oil which was purified by chromatography on silica gel (40-60 Petroleum ether/ethyl acetate) to give the title compound as a colourless oil (2.89g, 85% yield).

'H NMR δ (CDC1₃) 0.7-1.8 (19H, m, 4 x CH₂ + Cyclohexyl CH, CH₂). 2.95 (IH, dd, J=2, 15 Hz, H3). -25 (2H, m, NHCH₂). ³-³8 (IH, dd, J=5, 15 Hz, H₃), -55, 3.73 (each IH, d, J=17 Hz, NCH₂), ³*^² ( H, s, SCH ), 4.82 (IH, m, H₄), 6.06 (IH, br s, NH), 7.2-7.4 (5H, m, Ph-H) Example 2 N-(6-Cydohexylhexyl)-4-berifcZyIsuIphinyl-2-oxoazetidin-l-ylacetaιnide (Diastereoisomer 1)

N-(6-Cyclohexylhexyl)-4-benzylthio-2-oxoazetidin- 1 -ylacetamide (2.76g) was dissolved in dichloromethane (60ml), cooled to -60°C and a solution of 55-60% m- chloroperbenzoic acid (mCPBA) (1.84g;ca 6.62mM) in dichloromethane (80ml) was added dropwise over 15 mins, then the mixture was stirred at 20°C for 3 hours. The solution was washed with aq. NaHCO/Na.SO₃, water, dried over MgSO, and evaporated to a colourless solid. This was recrystallised three times from EtOAc (cooling to 20°C only) to give the title compound as a colourless solid m.p. 150- PC, (735mg. 26%).

Η NMR δ (CDC1₃) 0.8-1.8 (19H, m, 4 x CH₂ + Cyclohexyl CH, CH₂), 2.95 (IH, dd, J=5, 15 Hz, H₃). *²² (²H. m, NHCH₂). ³-46 (IH, dd, J=2, 15 Hz, H3). 3.72, 4.10 (each IH, d, J=17 Hz, NCH₂). ³-90, 4.06 (each IH, d, J=13 Hz, SOCH₂). 4.53 (IH, m, H4). 6.62 (lH. br s, NH), 7.2-7.5 (5H, m, Ph-H) v ^, 1791 cm^'1

Found: C, 66.4; H, 8.1; N, 6.6%; C2 H3₆N₂O₃S requires: C, 66.6; H, 8.4; N, 6.5% Example 3 N-(6-Cyclohexylhexyl)-(4-benzyIsulphinyI-2-oxoazetidin-l- yl)acetamide (Diastereoisomer 2) The mother liquors from the first two recrystallisations in Example 2 above were combined and evaporated to a solid which was recrystallised from EtOAc, cooling to RT and filtering to remove the first formed solid, then refrigerating to obtain a solid which was recrystallised again from EtOAc to give the title compound as a colourless solid, m.p. 135-7°C, (1.32 g, 46%) 'H NMR δ (CDCI3) 0.8-1.8 (19H, m, 4 x CH₂ + Cyclohexyl CH, CH₂), 2.88 (IH, dd, J=2, 15 Hz, H3), 3.2 (3H, m, H3 + NHCH₂). 3.91, 4.20(each IH, d, J=17 Hz, NCH₂). 4.00, 4.24 (each IH, d, J=13 Hz, SOCH₂). 4.62 (IH, m, H4), 7.2-7.5 (6H, m, Ph-H +

NH); v ^ 1793 cm-¹

Found: C, 66.2; H, 8.2; N, 6.5%; C₂4H3₆N₂O3S requires: C, 66.6; H, 8.4; N, 6.5% Example 4 N-(6-Cyclohexylhexyl)-(4-benzylsulphonyl-2-oxoazetidin-l- y acetamide

N-(6-Cyclohexylhexyl)-(4-benzylsulphinyl-2-oxoazetidin- 1 -yl)acetamide (0.95g) was dissolved in dichloromethane (40ml), a solution of 55-60% mCPBA (0.83g) in dichloromethane (40ml) was added and stirred at 20°C for 1.5 hours. The solution was washed with aq NaHCOJNa_jSO₃ and brine, dried over MgSO₄ and evaporated to a solid. This was purified by chromatography on silica gel (40-60 Pet ether/EtOAc) then recrystallisation from EtOAc to give the title compound as a colourless solid, m.p. 129-30°C, (630 mg, 64%) 'H NMR δ (CDCI3) 0.8-1.8 (19H, m, 4 x CH₂ + cyclohexyl CH, CH,), 3.01 (IH, dd, ^j=2, 15 Hz, H3), 3.12 (IH, dd, J=5, 15 Hz, H3), 3.25 (2H, m, NHCH₂), ³-8 . ³*97 (each IH, d, ^j=17 Hz, NCH₂), ⁴- 5 (2H, s, SO₂CH₂), ⁴-86 (IH, m, H₄), 5.96 (IH, br s, NH), 6.9, 7.4 (5H, m, Ph-H ); v ^ 1796 cm^{" 1}

Found: C, 64.2; H, 7.9; N, 6.4%; C₂4H₃₆N₂O₄S requires: C, 64.3; H, 8.1; N, 6.2% Example 5 N-(Nonyl)-(4-benzyIthio-2-oxoazetidin-l-yl)acetamide Treatment of (4-benzylthio-2-oxoazetidine-lyl)acetic acid with nonylamine under the conditions described for Example 1 gave the title compound as a colourless soild, m.p. 64-65°C, 88% yield

1H NMR δ (CDC1₃) 0.88 (3H, t, J=6.8Hz, CH3), 1.28 (12H, m, 6xCH₂). 1-50 (2H, m, NCH₂CH₂). ²*9³- ²-97 (IH, dd, J=2.4, 15.4Hz, H3). 3.24 (2H, m, NHCH₂). ³-³6, 3.40 (IH, dd, J=5.2, 15.4Hz, H₃), 3.57, 3.72 (each IH, d, J=16.7Hz, NCH₂), ³ _*82 (2H, s, SCH₂). ⁴*81 ( H, m, H4), 6.0 (IH, m, NH), 7.30-7.33 (5H, m, Ph-H); v ^ 1773 cm^{" 1}

Found: C, 67.0; H, 8.4; N, 7.6%; C_2JH₃₂N₂O₂S requires: C, 67.0; H, 8.6; N, 7.4%

Treatment of N-(nonyl)-(4-benzylthio-2-oxoazetidin-l-yl)acetamide with mCPBA as described for Examples 2 and 3 gave the following two compounds (Examples 6 and 7) after separation by crystallisation.

Example 6 N-(Nonyl)-(4-benzyIsulphinyl-2-oxoazetidin-l-yl)acetamide (Diastereoisomer 1)

Colourless solid, m.p. 162-164°C, 22% yield

1H NMR δ (CDCI3) 0.88 (3H, t, J=6.8Hz, CH3), 1.28 (12H, m, 6xCH₂). 1*50 (2H, m,

NCH₂CH2)> *93, 2.97 (IH, dd, J=4.8, 14.8Hz, H3). 3.22 (2H, m, NHCH2). ³*⁴⁴- 3.48 (IH, dd, J=2.0, 14.8Hz, H3). ³-73, 4.10 (each IH, d, J=17.6Hz, NCH₂). ³-90. 4.05 (each IH, d, J=12.8Hz, SOCH₂), 4.53 (IH, m, H4), 6.6 (IH, m, NH), 7.26-7.40 (5H, m, Ph-H); v ^ 1791 cm^"1

Found: C, 64.0; H, 7.8; N, 7.4%; C₂₁H₃₂N₂O₃S requires: C, 64.3; H. 8.2; N, 7.1% Example 7 N-(NonyI)-(4-benzylsulphinyl-2-oxoazetidin-l-yl)acetamide (Diastereoisomer 2)

Colourless solid, m.p. 107-108°C, 34% yield

1H NMR δ (CDCI3) 0.88 (3H, t, J=6.8Hz, CH3), 1.28 (12H, m, 6xCH₂), 1-52 (2H, m, NCH₂CH₂). ²-85, 2.89 (IH, dd, J=2.4, 15.3Hz, H₃), ³-15, 3.19 (IH, dd, J=5.4, 15.3Hz, H3), -26 (2H, m, NHCH₂). 3.91, 4.23 (each IH, d, J=17.1Hz, NCH₂). ⁴*<X 4.20 (each IH, d, J=13Hz, SOCH2), ⁴*62 (IH, m, H₄), 7.2 (IH, m, NH), 7.26-7.40 (5H. ra. Ph-H); v^ 1794 cm^{" 1}

Found: C. 63.9; H, 8.0; N, 7.2%; C₂₁H₃₂N₂O₃S requires: C, 64.3; H, 8.2; N, 7.1% Example 8 N-(Nonyl)-(4-benzylsulphonyl-2-oxoazetidin-l-yl)acetamide Treatment of N-(nonyl)-(4-benzylsulphinyl-2-oxoazetidin-l-yl)acetamide with mCPBA as described for Example 4 gave the title compound as a colourless solid, m.p. 125-126°C, 76% yield

1H NMR δ (CDCI3) 0.88 (3H, t, J=6.8Hz, CH3). 1.28 (12H, m, 6XCH2). 1-50 (2H, m, NCH₂CH₂), 2.97, 3.03 (IH, dd, J=2.4, i5.4Hz. H3), ³*⁰⁹. - 5 (IH, dd, J=5.1, 15.4Hz, H3), -24 (2H, m, NHCH₂), ³-83, 3.98 (each IH, d, J=16.9Hz, NCH₂)- ⁴*³2. 4.39 (each IH, d, J=14.3Hz, SO₂CH₂), 4.85 (IH, m, H*), 5.95 (IH, m, NH), 7.41 (5H, m, Ph-H) v,^ 1796 cm^'1

Found: C, 61.4; H, 7.6; N, 7.0%; C₂₁H₃₂N₂O₄S requires: C, 61.7; H, 7.9; N, 6.9% Example 11 N-(6-( PyridyI)hexyl)^-benzyIthio-2-oxoazetidin-l-ylacetamide A mixture of 4-benzylthio-2-oxoazetidine- lylacetic acid (2.26g), 6-(4- pyridyDhexylamine (1.60g), dicyclohexylcarbodiimide (1.86g) and 1- hydroxybenzotriazole (1.22g) in dry dimethylformamide (20ml) was stirred at 20- 25°C for 3 hrs. Ethyl acetate (50ml) was added, the mixture was filtered and the filtrate evaporated to an oil. This oil was taken up in EtOAc, washed with NaHCO₃, brine, dried over MgSO₄ and evaporated to an orange oil which was purified by chromatography on silica gel (EtOAc/EtOH) to give the title compound as a colourless oil (3.22g. 87% yield)

Η NMR δ (CDC1₃) 1.2-1.7 (8H, m, 4 x CHJ, 2.59 (2H, t, J=8 Hz, CH₂Ph), 2.95 (IH, dd, J=2, 15 Hz. H₃), ³-24 (2H, m, NHCH₂), -37 (IH, dd, J=5, 15 Hz, H,), 3.56, 3.72 (each IH, d, =17 Hz, NCH₂), ³-81 (2H, s, SCH₂), 4.82 (IH, m, HJ, 6.18 (IH, br s, NH), 7.09 (2H, m, Pyr-3,5H), 7.30 (5H, m, Ph-H), 8.47 (IH, m, Pyr-2,6H) Example 12 N-(6-(4-PyridyI)hexyl)-4-benzylsulphinyl-2-oxoazetidin-l- ylacetamide (Dia 1)

N-(6-(4-pyridyl)hexyl)-4-benzylthio-2-oxoazetidin- l-ylacetamide (3.04g)was dissolved in CH₂Cl₂(50ml), cooled to -60°C and a solution of 55-60% m- chloroperbenzoic acid (mCPB A) (2.11 g) in CH₂C1₂ ( 100ml) was added dropwise over 15 mins. The solution was stirred at 20-25°C for 3 hrs then washed with aq NaHCO_j/Na_jSO_j, brine, dried over MgSO₄ and evaporated to a sticky solid. This was recrystallised twice from ethyl acetate to give the title compound as a colourless solid m.p. 167-8°C, (0.90g; 30%) Η NMR δ (CDC1₃) 1.2-1.7 (8H, m, 4 x CH₂), 2.59 (2H, t, J=8 Hz, CH₂Ph), 2.97 (IH, dd, J=5, 15 Hz, H,), 3.23 (2H, m, NHCH₂). 3.47 (IH, dd, J=2, 15 Hz, H₃), 3.68, 4.15 (each IH, d, J=17 Hz, NCH₂), 3.89, 4.07 (each IH, d, J=13 Hz, SOCH₂), 4.50 (IH, m, HJ, 6.75 (IH, br s, NH), 7.10 (2H, m, Pyr-3,5H), 7.25, 7.40 (5H, 2 x m, Ph-H), 8.48 (2H, br s, Pyr-2,6H); v ^ 1792 cm^{" 1} Found: C, 64.4; H, 6.7; N, 9.8%; C^H^N^S requires: C, 64.6; H. 6.8; N, 9.8% Example 13 N-(6-(4-Pyridyl)hexyl)-4-benzylsulphinyI-2-oxoazetidin-l- ylacetamide (95% Dia 2)

The mother liquor from the above recrystallisation in Example 12 was evaporated to a solid which was recrystallised twice from ethyl acatate to give the title compound as a colourless solid, m.p. 109-10°C, (1.41g, 46% yield)

Η NMR δ (CDC1₃) 1.3-1.8 (8H, m. 4 x CH₂), 2.59 (2H, t, J=8 Hz, CH₂Ph). 2.92 (IH, dd, J=2, 15 Hz, H,), 3-25 (3H, m. NHCH₂ +H,), ³-87, 4.27 (each IH, d, J=17 Hz, NCH₂). ³-98, 4.19 (each IH. d. J=13 Hz, SOCH₂), 4.61 (IH, m, HJ, 7.10 (2H, m, Pyr-3,5H), 7.25,7.38 (6H, 2 x m, Ph-H + NH), 8.47 (2H, m, Pyr-2,6H); v <-<, 1793 cm^'1

Found: C, 64.3; H, 6.6; N, 9.8%; C^N^S requires: C, 64.6; H, 6.8; N, 9.8%

Example 14 N-(6-(4-Pyridyl)hexyl)-4-benzylsulphonyI-2-oxoazetidin-l- ylacetamide

N-(6-(4-Pyridyl)hexyl)-4-benzy lsulphinyl-2-oxoazetidin- 1 -ylacetamide (Dia 1 ) (1.15g) was dissolved in CH₂Cl₂(50ml) and a solution of 55-60% CPBA(1.10g;ca 3.5mM) in CH₂Cl₂(50ml) added and stirred at 20-25°C for 3hrs and allowed to stand at 20-25°C for 16 h. mCPBA (0.13g) was added and the solution stirred for a further 3 hrs then washed with aq NaHCO/Na-SO,, brine, dried over MgSO₄ and evaporated to an oil. This oil was chromatographed on silica gel (EtOAc/EtOH) to give the title compound as a solid which was recrystallised from EtOAc/Et.,0 to give a colourless solid m.p. 106-8°C, (0.38g, 31%) 'H NMR δ (CDC1₃) 1.3-1.8 (8H, m, 4 x CH₂). 2.60 (2H, t, J=8 Hz, CH₂Pyr), 3.00 (IH, dd, J=2, 15 Hz. H,), 3.11 (IH, dd, J=5, 15 Hz. H,), 3.25 (2H, m, NHCH₂), 3.86, 3.94 (each IH, d, J=17 Hz, NCH₂), 4.34 (2H, s, SO₂CH₂), 4.83 (IH, m, HJ, 6.10 (IH, br s, NH), 7.10 (2H, m, Pyr-3,5H), 7.41 (5H, m, Ph-H), 8.47 (2H, m, Pyr-6H); v ^ 1797 cm^"1

Found: C, 62.0; H, 6.5; N, 9.5%; C^H^O.S requires: C, 62.3; H, 6.6; N, 9.5% Example 15 N-(6-(4-Pyridyl)hexyl)-4-benzylsulphonyI-2-oxoazetidin-l- yiacetamide N-(pyridyl)oxide N-(6-(4-Pyridyl)hexyl)-4-benzylsulphonyl-2-oxoazetidin- 1 -ylacetamide N- (pyridyl)oxide was also produced in the oxidation of N-(6-(4-Pyridyl)hexyl)-4- benzylsulphinyl-2-oxoazetidin-l-ylacetamide with mCPBA (details in Example 14 above) and was obtained after chromatography and recrystallisation from ethyl acetate as a colourless solid (0.44g, 35%), m.p. 132-4°C. 'H NMR δ (CDCl.) 1.3-1.8 (8H, m, 4 x CHJ, 2.60 (2H, t, J=8 Hz, CH₂Pyr), 3.00 (IH, dd, J=2, 15 Hz. H,), 3.12 (IH, dd, J=5, 15 Hz, H₃), 3.25 (2H, m, NHCH₂), 3.91 (2H, s, NCH₂), 4.36 (2H, s, SO₂CH₂), 4.83 (IH, m, HJ. 6.22 (IH, br s, NH), 7.09 (2H, m, Pyr-3,5H). 7.41 (5H, m, Ph-H), 8.12 (2H, m, Pyr-2,6H); v _c=0 1783 cm^"1 Found; C, 59.6; H, 6.2; N, 9.1%; C_MH₂₉N₃O₅S requires: C, 60.1; H, 6.4; N, 9.1% Example 16 N-(6-(2-Pyridyl)hexyl -berifcZylt ^-2-oxoazetidin-l-ylacetarnide Treatment of of 4-benzylthio-2-oxoazetidine- lylacetic acid with 6-(2- pyridyl)hexylamine, dicyclohexylcarbodiimide and 1 -hydroxybenzotriazole in dry dimethylformamide as described for Example 11 gave the title compound as a colourless oil in 90% yield. Η NMR δ (CDC1₃) 1.3-1.8 (8H, m, 4 x CHJ, 2.77 (2H, t, J=8 Hz, CH₂Pyr), 2.94 (IH, dd, J=2, 15 Hz, HJ, 3.23 (2H, m, NHCH₂), 3.36 (IH, dd, J=5, 15 Hz, HJ, 3.54, 3.75 (each IH, d, J=17 Hz, NCH₂), 3.81 (2H, s, SCH₂), 4.83 (IH, m, HJ, 6.29 (IH, br s, NH), 7.15 (2H, m, Pyr-3,5H), 7.30 (5H, m, Ph-H), 7.59 (IH, m, Pyr-4H), 8.50 (IH, m, Pyr-6H) Examples 17 and 18 were prepared by the methods described for Examples 12 and 13 and Examples 19 and 20 were prepared by the methods described for Examples 14 and 15.

Example 17 N-(6-(2-Pyridyl)hexyI)-4-benzylsulphinyl-2-oxoazetidin-l- ylacetamide (Dia 1)

Colourless solid, m.p. 126-30°C, 30% yield

Η NMR δ (CDCl,) 1.3-1.9 (8H, m, 4 x CH₂), 2.77 (2H, t, J=8 Hz, CH₂Pyr), 2.95 (IH, dd, J=5, 15 Hz, H,), 3.22 (2H, m. NHCH₂), 3.45 (IH, dd, J=2, 15 Hz. HJ, 3.75, 4.09 (each IH, d, J=17 Hz, NCH₂), 3.90, 4.06 (each IH, d, J=13 Hz, SOCH₂), 4.54 (IH, m, HJ, 6.75 (IH, br s, NH), 7.10 (2H, m, Pyr-3,5H), 7.30 (5H, m, Ph-H), 7.59 (IH, m, Pyr-4H), 8.50 (IH, m, Pyr-6H); v _c=0 1791 cm^{" 1} Found: C, 64.5; H, 6.6; N, 9.8%; C^H^O_jS requires: C, 64.6; H, 6.8; N, 9.8% Example 18 N-(6-(2-Pyridyl)hexyI)-4-benzyIsulphinyl-2-oxoa2etidin-l- yiacetamide (92% Dia 2) Colourless solid, m.p. 93-6°C, 20% yield Η NMR δ (CDCl,) 1.3-1.9 (8H, m, 4 x CHJ, 2.78 (2H, t, J=8 Hz, CH₂Pyr), 2.86 (IH, dd, J=2, 15 Hz, HJ, 3.25 (3H, m, NHCH₂ + H,). 3.92, 4.23 (each IH, d, J=17 Hz, NCH,), 4-0, 4.20 (each IH, d, J=13 Hz, SOCHJ, 4.63 (IH, m, HJ, 7.10 (2H, m, Pyr-3,5H). 7.30 (6H, m, Ph-H + NH), 7.58 (IH, m, Pyr-4H), 8.50 (IH, m. Pyr-6H); v _M 1793 cm^'1

Found: C, 64.5; H, 6.7; N, 9.8%; C.JH_j.N.O_jS requires: C, 64.6; H, 6.8; N. 9.8%

Example 19 N-(6-(2-Pyridyl)hexyl)-4-benzylsulphonyl-2-oxoazetidin-l- ylacetamide

Colourless solid, m.p. 116-8°C. 9% yield Η NMR δ (CDCl,) 1.3-1.8 (8H, m.4 x CH₂), 2.78 (2H. t. J=8 Hz. CH₂Pyr), 2.99 (IH, dd, J=2, 15 Hz, H,), 3.11 (IH, dd, J=5, 15 Hz. H,), 3.24 (2H, m, NHCH₂), 3.82, 4.01 (each IH, d, J=17 Hz, NCH₂). 4.36 (2H, s, SO₂CH₂), 4.87 (IH, m, HJ, 6.26 (IH, br s, NH), 7.12 (2H, m, Pyr-3,5H , 7.41 (5H, m. Ph-H), 7.60 (IH, m, Pyr-4H), 8.50 (IH, m, Pyr-6H); v _c=0 1792 cm^{" 1} Found: C, 62.2; H, 6.5; N, 9.4%; C_BUJi₃O_tS requires: C, 62.3; H, 6.6; N, 9.5% Example 20 N-(6-(2.PyridyI)hexyl)-4-benzylsulphonyl-2-oxoazetidin-l- ylacetamide N-(pyridyl)oxide Colourless solid, m.p. 153-4°C, 61% yield 'H NMR δ (CDCl,) 1.3-1.8 (8H, m, 4 x CH₂), 2.96 (3H, m, CH₂Pyr + H₃), 3.13 (IH, dd, J=5, 15 Hz, H,). 3.25 (2H, m, NHCH₂), 3.85, 4.09 (each IH, d, J=17 Hz, NCH₂), 4.38 (2H, s, SO₂CH₂), -92 (IH, m, HJ, 6.61 (IH, br s, NH), 7.2 (3H, m, Pyr- 3.4.5H), 7.41 (5H, m, Ph-H), 8.26 (IH, m, Pyr-6H); v ^ 1793 cm"¹ Found: C, 60.0; H, 6.3; N, 9.1%; C-_jH^N.O_jS requires: C, 60.1; H, 6.4; N, 9.1% Example 21 l-(4-(5-Phenylpentyl)thiazol-2-ylmethyl)-4-benzylthio-2- oxoazetidine

To a mixture of 2-bromomethyl-4-(5-phenylpentyl)thiazole (0.5 g), 4-benzylthio- azetidin-2-one (0.3 g) and tetra-n-butylammonium bromide (0.05 g) in dry tetrahydrofuran (THF), cooled to 10°C, powdered potassium hydroxide (0.096 g) was added. The mixture was warmed to 20°C and stirred for 4 hours. Ethyl acetate and brine were added and the organic solution separated, washed and evapotated to give a brown oil. Chromatography on silica gel using petroleum ether/ethyl acetate gave the title compound as a pale yellow oil (0.48 g, 68% yield). *H nmr δ (CDC1₃) 1.40 (2H, m, CHJ, 1.63-1.75 (4H, m, 2 C U), 2.59 (2H, t, J=7.6 Hz, PhCH,). 2.74 (2H, t, J=7.6Hz, thiazoIvlCH-.). 2.93, 2.97 (IH, dd, J=2.4, 15.2 Hz, Hj), 3.33, 3.37 (IH, dd, J=5.2, 15.2 Hz, HJ, 3.77 (2H, s, SCH--). 4.33, 4.76 (each IH, d, J=16.4 Hz, NCϋϊ), 4.78 (IH, , H₄), 6.83 (IH, s, thiazole-H), 7.14-7.29 (10H, m, 2xPh-H); v ^ 1772 cm ¹

Example 22 l-(4-(5-Phenylpentyl)thiazoI-2-ylmethyl)-4-benzylsulphinyl-2- oxoazetidine (Dia l:Dia 2 22:78) 1 -(4-(5-phenylpentyl)thiazol-2-ylmethyl)-4-benzylthio-2-oxoazetidine (1.1 equiv) was dissolved in CH₂Cl₂(50ml), cooled to -60°C and a solution of 55-60% m- chloroperbenzoic acid (mCPBA) (2.1 lg) in CH₂Cl₂(100ml) was added dropwise over 15 mins. The solution was stirred at 20-25°C for 3 hrs then washed with aq NaHCO Na₂SO₃, brine, dried over MgSO₄ and solvent removed under reduced pressure to give the title compound as a mixture of diastereoisomers in the form of a colourless oil in 87% yield, v _c=0 1785 cm^'1 Found: C, 66.2; H, 6.2; N, 5.9%; C_2SH_2ltN₂θ₂S requires: C, 66.3; H, 6.2; N, 6.2% Example 23 l-(4-(5-Phenylpentyl)thiazol-2-ylmethyl)-4-benzylsulphonyI-2- oxoazetidine

Treatment of l-(4-(5-phenylpentyl)thiazol-2-ylmethyl)-4-benzylsulfinyl-2- oxoazetidine with mCPBA (1.1 equiv) under the conditions described for Example 2 gave the titie compound in the form of a colourless oil in 91% yield. 1H nmr δ (CDCl,) 1.40 (2H, m, £H₂), 1.61-1.73 (4H, m, 2x£H₂), 2.60 (2H, t, J=7.8 Hz, PhC±y, 2.74 (2H, t, J=7.6Hz, thiazolyl£H₂), 3.15 (2H, d, J=4Hz, 2xH₃), 4.35 (2H, m, SO^H,), 4-50, 4.97 (each IH, d, J=16.4 Hz, NCϋ₂), 4.84 (IH, m, HJ, 6.86 (IH, s, thiazole-H), 7.14-7.39 (10H, m, 2xPh-H); v ^ 1792 cm^{" 1}

Found: C, 64.1; H, 6.2; N, 6.0%; C^H^N.O.S requires: C, 64.1; H, 6.0; N, 6.0% Example 24 4-Methylthio-l-((5-phenyloxazol-2-yI)methyl)azetidin-2-one Treatment of 4-methylthioazetidin-2-one with 2-bromomethyl-5-phenyloxazole in the presence of lithium hexamethyldisilazide in THF at -70°C gave the title compound as a yellow gum.

Found: C, 61.3; H, 5.2; N, 10.2%; C_I4H_uN₂O₂S requires: C, 61.3; H, 5.1; N, 10.2% Example 25 4-Methylsulfinyl-l-((5-phenyloxazol-2-yl)methyl)azetidin-2-one Treatment of 4-methylthio-l-((5-phenyloxazol-2-yl)methyl)azetidin-2-one with mCPBA (1 eq) in dichloromethane at -78°C following the procedure of Example 2 gave the titie compound as a mixture of diastereoisomers as a yellow gum. m z 290 (M^*), 227, 158, 103, 77.

Found: C, 56.3; H, 4.9; N, 9.5%; C,₄H₁₄N₂O,S (+ 0.4 H₂O + 0.02 CH₂C1₂) requires: C, 56.2; H, 5.0; N, 9.4%; (solvents identified by nmr) Example 26 4-Methylsulfinyl-l-((5-phenyloxazoI-2-yl)methyI)azetidin-2-one Treatment of 4-methylthio-l-((5-phenyloxazol-2-yl)methyl)azetidin-2-one with mCPBA (2 eq) in dichloromethane at 20°C gave the title as a cream solid Found: C, 54.8; H, 4.7; N, 9.2%; C₁ H₁₄N₂O S requires: C, 54.9; H, 4.6; N, 9.1%;

Biological Data

Screen for Lp-PLA 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 rain 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 Example 3, 7, 8, 13, 18 and 22 had IC50 values in the range 5 to

200nM.

Claims

Claims

1. A compound of formula (I):

in which:

R is CR^ -Y¹, CR⁴R⁵-X²-Y², or (CH₂)pX³(CH₂)qY³;

Rl and R², which may be the same or different, is each selected from hydrogen, halogen or C(i_g)alkyl; R⁴ and R-5 which may be the same or different is each selected from hydrogen and

C(i_6)alkyl, ^{or R4 and R5 ma}y ^De »nked together to form the residue of a C(3_7) cycloalkyl ring;

X¹ is a linker group and Y¹ is optionally substituted C(\.\ 2)alkyl C(2-i2)^aU^ceny¹ _>

C(₂-i2)alkynyl, C(₃.₇)-cycloalkylC(₁.8) alkyl; X² is a linker group and Y² an optionally substituted heteroaryl group;

X³ is a heteroaryl group and Y³ is an optionally substituted aryl group, p is an integer from 1 to 6, q is 0 or an an integer from 1 to 6;

Z is O and R³ is C(i_8)alkyl, arylC(₁_4)alkyl or aryl each of which may be optionally substituted, or Z is S(O)n in which n is 0, 1 or 2 and R³ is C(i_g)alkyl, C(3_8)Cycloalkyl,

C(3_8)cycloalkylC(i_6)alkyl, aryl, arylC(i _4)alkyl or heteroarylC^.^alkyl each of which may be optionally substituted.

2. A compound of formula (I) as claimed in claim 1 in which R and R² is each hydrogen.

3. A compound of formula (I) as claimed in claim 1 or 2 in which Z is SO and R³ is arylmethyl or heteroarylmethyl

4. A compound as claimed in claim 3 in which R³ is benzyl or furanylmethyl.

5. A compound as claimed in claim 4 in which R³ includes a carboxy or ester substituent.

6. A compound as claimed in any one of claims 1 to 5 in which R⁴ and R-5 are both hydrogen or R⁴ is hydrogen and R^ methyl.

7. A compound as claimed in any one of claims 1 to 6 in which: χl is a direct bond or a group (CH₂)_XX⁴ in which X⁴ is CH2O, CO, COO, CONR⁶, CONR^O, or CONHO in which R⁶ is hydrogen or C(i.6)alkyl, x is 0 (for all except X⁴ =COO) or an integer from 1 to 6; or (ii) X² is: (a) a direct bond;

(b) a group χ5(CH₂)_y in which X⁵ is CO, CONR⁶, COO, CONR⁶CO, or CONHO in which R⁶ is hydrogen or C(i_ *,alkyl and y is 0 or an integer from 1 to 12;

(c) a C(i-i2)alkylene chain optionally interupted by X⁵;

(d) a group A-B in which A is a direct bond or X*⁵ 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, NR⁶, alkene or alkyne in which R⁶ is hydrogen or C(i_6)al yl and n is 0, 1 or 2.

8. A compound as claimed in claim 7 in which X¹ is CONH or X² is CONH(CH2)6-

9. A compound as claimed in any one of claims 1 to 8 in which Y¹ is 0(5.10) alkyl, C(3_7)cycloalkylC(5_7) alkyl or Y² is pyridyl or pyridyl N-oxide.

10. A compound as claimed in any one of claims 1 to 9 in which X³ is:

p is 1, q is 0 or 5 and Y³ is optionally substituted phenyl or naphthyl.

11. A compound of formula (I) selected from: N-(6-Cyclohexylhexyl)-(4-benzylthio-2-oxoazetidin- 1 -yl)acetamide;

N-(6-Cyclohexylhexy l)-4-benzylsulphinyl-2-oxoazetidin- 1 -ylacetamide

(Diastereoisomer 1);

N-(6-Cyclohexylhexyl)-(4-benzylsulphinyl-2-oxoazetidin-l-yl)acetamide

(Diastereoisomer 2); N-(6-Cyclohexylhexyl)-(4-benzylsulphonyl-2-oxoazetidin- 1 -yl)acetamide;

N-(T^onyl)-(4-benzylthio-2-oxoazetidin-l-yl)acetamide;

N-(Nonyl)-(4-benzylsulphinyl-2-oxoazetidin-l-yl)acetamide (Diastereoisomer 1);

N-(Nonyl)-(4-benzylsulphinyl-2-oxoazetidin- 1 -yl)acetamide (Diastereoisomer 2);

N-(Nonyl)-(4-benzylsulphonyl-2-oxoazetidin- 1 -yl)acetamide; N-(6-(4-Pyridyl)hexyl)-4-benzylthio-2-oxoazetidin-l -ylacetamide;

N-(6-(4-Pyridyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin-l -ylacetamide (Dia 1);

N-(6-(4-Pyridyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin- 1-ylacetamide (Dia 2);

N-(6-(4-Pyridyl)hexyl)-4-benzylsulphonyl-2-oxoazetidin- 1 -ylacetamide;

N-(6-(4-Pyridyl)hexyl)-4-benzylsulphonyl-2-oxoazetidin- 1 -ylacetamide N- (pyridyl)oxide;

N-(6-(2-Pyridyl)hexyl)-4-benzylthio-2-oxoazetidin-l-ylacetamide;

N-(6-(2-Pyridyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin-l-ylacetamide (Dia 1);

N-(6-(2-Pyridyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin- 1 -ylacetamide (Dia 2);

N-(6-(2-Pyridyl)hexyl)-4-benzylsulphonyl-2-oxoazetidin-l-ylacetamide; N-(6-(2-PyridyI)hexyl)-4-benzylsulphonyl-2-oxoazetidin- 1 -ylacetamide N- (pyridyl)oxide; l-(4-(5-Phenylpentyl)ti iazol-2-ylmethyl)-4-benzylthio-2-oxoazeϋdine; l-(4-(5-Phenylpentyl)thiazol-2-ylmethyl)-4-benzylsulphinyl-2-oxoazeticline ; l-(4-(5-Phenylpentyl)thiazol-2-ylmethyl)-4-benzylsulphonyl-2-oxoazetidine; 4-Methylthio-l-((5-phenyloxazol-2-yl)methyl)azetidin-2-one;

4-Methylsulfinyl-l-((5-phenyloxazol-2-yl)methyl)azetidin-2-one; and 4-Methylsulfιnyl-l-((5-phenyloxazol-2-yl)methyl)azeϋdin-2-one;

12. A pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

13. A compound of formula (I) for use in therapy.

14. The use of a compound of formula (I) as defined in claim 1 in the manufacture of a medicament for treating atherosclerosis.

15. 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, neuropsychiauic disorders such as schizophrenia, and psoriasis.

16. 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.

17. A method as claimed in claim 15 in which the disease state is associated with: (a) the increased involvement of monocytes, macrophages or lymphocytes; (b) the formation of lysophosphatidylcholine and oxidised free fatty acids;

(c) lipid peroxidation in conjunction with Lp PLA2 activity; or

(d) endothelial dysfunction.

18. A process for preparing a compound of formula (I) as defined in claim 1 which comprises treating an azetidone of formula (II):

(II) in which:

Rl, R², R³, and Z are as hereinbefore defined; with an alkylating agent of the formula (IH):

R7Rθ

(Lϋ) in which R⁷ is a suitable leaving group such as halogen or triflate; and Rθ-s as hereinbefore defined; under alkylating conditions.