MXPA98008924A - Azetidinone derivatives for deeterosclero treatment - Google Patents

Abstract

Selected compounds of the formula (I), wherein: R1 is hydrogen or pharmaceutically acceptable corresponding ester or a pharmaceutically acceptable salt thereof: R2 and R3 which may be the same or different, each selected from hydrogen or C1- alkyl 6, optionally substituted; X is a group X 1 (CH 2) m wherein X 1 CO, CONR 4, COO, CONR 4 CO, CONHO 2CH 2 O, wherein R 4 is hydrogen or C 1-6 alkyl and m is 0 to 12, or an alkylene of C1-12 chain optionally interrupted with XY; Y is an optionally substituted aryl group, having the absolute configuration (4R, SS), are inhibitors of the enzyme phospholipase A2 associated with lipoprotein, and are used in the treatment of atherosclerosis

Description

AZETIDINONE DERIVATIVES FOR THE TREATMENT OF ATERQSCLEROS S FIELD OF THE INVENTION The present invention relates to certain novel mannitol complexes of β-lactam * procedures for their preparation intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy * in particular in the treatment of atherosclerosis.

ANTECEDENTS OF THE INVENTION WO 95/00649 (SmithKline Beecham foot) describes the enzyme phospholipase AZ called phospholipase f \ -. associated with lipopratein (Lp-PLA .-.) * the sequencing isolation and purification of the same acid nucleic acids isolated encoding the enzyme * and recombinant host cells transformed with DNA encoding the enzyme. Suggested therapeutic uses for enzyme inhibitors include atherosclerosis * diabetes * rheumatoid arthritis * stroke * myocardial infarction * reperfusion injury and acute and chronic inflation. A subsequent publication of the same group additionally describes this enzyme (Tew D and others * Arterioscler Thramb Vas Biol 199Ó? 16 * 591-9) * where it is referred to as LDL-PLA ^ .. A subsequent patent application (WO 95/09921 * Icos Corporation) and a related publication in Nature (Tjaelker et al. * Vol 374 * April 6, 1995 * 549) * describe the PAF-AH * enzyme that has essentially the same sequence as Lp-PLA-2 * and suggest that it may have potential as a therapeutic protein for regulation of pathological inflammatory events. It has been shown that Lp-PLA ^ is responsible for the conversion of phosphatidylcholine to 1 isophosphatidylcol * during the conversion of low density lipoprotein < LDL) to its oxidized form. It is known that the enzyme hydrolyzes the sn-2 ester of the oxidized phosphatidylcholine to give the isophosphatidylcholine and an oxidatively modified fatty acid. Both products of the Lp-PLAj action are biologically active with lysophosphatidylcholine * a component of oxidized LDL * known as a potent chemoattractant of circulating monocytes. Therefore * lysophosphatidylcholine is considered to have an important role in atherosclerosis * as it is responsible for the accumulation of cholesterol-laden cells in the arteries. Therefore * it is expected that the inhibition of the enzyme Lp-PLAZ will stop the concentration of these lesions enriched with macrophages (by inhibiting the formation of lysophosphatidylcalin and oxidized free fatty acids) * and be useful in the treatment of atherosclerosis. It is also considered that the increased content of lysophosphatidylcholine in oxidatively modified LDL * is responsible for the endothelial dysfunction observed in patients with atherosclerosis. Therefore »the inhibitors of Lp-PLA-, they would be beneficial in the treatment of this phenomenon. An inhibitor of Lp-PLA.-, would also be useful in other disease states that exhibit endothelial dysfunction * including diabetes * hypertension * angina pectoris and after ischemia and reperfusion. In addition * inhibitors of Lp-LA ^ may also have a general application in any disorder involving activated monocytes * macrophages or lymphocytes * since all these cell types express p-PLAjg. Examples of such disorders include Psoriasis. In addition * can Lp-PLA ^ inhibitors have a general application in any disorder involving lipid peroxidation in conjunction with the activity of Lp-PLAS to produce the two harmful products? I isofosfat idi l col ina and fatty acids modified or id ivamente. These conditions include the aforementioned conditions of atherosclerosis * diabetes * rheumatoid arthritis * stroke * myocardial infarction * reperfusion injury and acute and chronic inflammation. Additional conditions like these include different neuropsychiatric disorders such as schizophrenia! (see Psychopharmaclology Bulletin * 31 * 159-165 * 1995). A previous patent application (W096 / 19451 * S ithK'line Beecha pie) describes co-positions of the formula (A); (TO) in which; R * and Rzt which may be the same or different * are each selected from hydrogen * halogen or C < x_ ß) »substituted option lme te * R3 is aryl or arylalkyl of C < t_ ^ > * which may be substituted option lme te * > i is a linking group * Y is an aryl group * optionally substituted * and n is O * 1 or 2. These compounds of formula (A > are inhibitors of Lp-PLAj »* and therefore are expected to be useful in the treatment of atherosclerosis and the other pathological conditions indicated above. WO 97/02242 (S ithKline Beecham foot) describes additional compounds having a substituent such as a methyl on the attached carbon N-1. Also * PCT / EP9? / 055ß7 (SmithKline Eeecham foot) describes prodrugs of compounds of formula (A) in which R3 is a 4-carboalkyl group. The compounds of formula (A) exist in various somatic ether forms. The carbon C-4 * of the f-lactam ring is a chiral center that will give rise to the presence of stereoisomers. In addition * in the compounds of formula (A) wherein n is 1 * which are composed of sulphoxide * the presence of the SO portion will introduce an additional chiral center into the molecule and thus give rise to the existence of more stereoisomers. The preferred compounds of formula (A) are said to be those in which the relative configurations at C-4 and the SO portion are R * S (4R * SS) and S »R (4S * SR) * having the preferred compounds the absolute configuration (4R, SS &.) Consequently, the present invention provides a compound of the formula (I)? a > in which? R1 is hydrogen or a corresponding pharmaceutically acceptable ester or a pharmaceutically acceptable salt thereof * Ra and R3 * which may be the same or different * each is selected from hydrogen or Ctl_fe alkyl > * substituted option you * X is a group X '(CH ^ ^ * in which X' is CO * CONR - ** COO * C0NR? C0 * C0NH0 or Cl-L, 0 * where R "* is hydrogen or alkyl of C <! L_4 > > and is O or an integer from 1 to 12 * or a chain of alkylene from C < X_1S¡ > * optionally interrupted by X '! and Y is an optionally substituted ari * group that has the absolute configuration (4R * SS). The examples represent ivos of X include COCHCHg ^ * - "c? NH (CHa) m * COOICCH ^) ^ * COIMHCO (CHa) m * CQNHO (CH ^)", CH ^ OÍCH ^), ^ and alkylene from C < t_i = 3, > .Preferably * XX is CO * CONR5 * or CHsO * preferably CONH, preferably * m is 1 * 2 »5 * 6 * 7 or 9 * preferably 6. Conveniently * X is CO HÍCHjj ,) ^ or CHszO (CHSi) < s, * preferably CONH (CH--.) A. Conveniently * Rz and R3 are each hydrogen * or Rz is hydrogen and R3 is methyl. Preferably * Rs and R3 are hydrogen each. It will be easily appreciated that when Rz and R3 have different values * the carbon to which they are attached will be chiral. Preferably * the absolute configuration in this carbon is S. In these compounds of formula (D *) the absolute configuration of the preferred enantiomer is (-S-4-R * SS) Conveniently Y is phenyl substituted optionally with up to three substituents Suitable substituents include halogen * hydroxyl * C.sub.1 alkyl and C.sub.12 alkoxy, Preferably * Y is phenyls optionally substituted with halogen * preferably 4- chloro- or 4-fluorophenol * preferably 4-fluorophenyl, conveniently »XY is C0NH (CHse) → Ph (4-F) / < 4-Cl). Suitable pharmaceutically acceptable esters include alkyl esters of < X_A > or alkenyl of C < ss_ < b, » as well as pharmaceutically acceptable in vivo hydrolysable esters. The person skilled in the art will appreciate that the simple esters of alkyl benzoate of c »• - < & > Alkenyl of C < sa_A3, show * if at all »little tendency to fragment in the human body to release the original acid or its salt» although they may be susceptible to in vivo hydrolysis in animals such as rabbits and dogs. Therefore, it is conventionally considered that the term "hydrolysable ester in vivo" does not include such esters. Suitable esters of C ^ ^ alkyl, or alkenyl of C <; as_.A > include ethyl esters and allylic esters. Hydrolysable ester groups which are pharmaceutically acceptable and suitable for incorporation into R1"include those that are readily fragmented in the human body to release the original acid or its salt. Suitable values of R1 for use in hydrolysable stereos in vivo include? -CH < R ~) U.C0.Rte? -CH (R-> C0.NR-R < X -R ^ NR-R ^? «• .Rh Vo and -cH (R »> a.cs.c - YicacH < R? -) NHS in which? R "* is hydrogen» CX_A alkyl »in particular methyl» cycloalkyl of (C - ^.) * Or phenyl * each of which may be optionally substituted if Rt is (C x _) alkyl * alkoxy (C , _6) -alkyl of (Cx_ A) »phenyl * benzyl * cycloalkyl of (C3 _ ^) * alky1 (CaL_ <6,) - cycloalkyl of (C -, *.,.) * 1-aminoalkyl of < C1_ ^) "or 1-alkyl (C1_jS>) aminoalkyl of (C1_ <6,)" each of which may be optionally substituted * or R ** and Rte together form a 1 * 2-phenylene group optionally substituted with one or two methoxy groups. Re is alkyl of C 1_ (fe) »cycloalkyl of (C 3_-) * alkyl (C 1 -el) -cycloalkyl of (C 3 7); Rd is alkylene of (C1_il) r optionally substituted with a methyl or ethyl group * R and R * "'which may be the same or different * is each of them * alkyl of (C1_ < £)) * or arylalkyl of (Ci_4) * optionally substituted with * v.gr. * hydroxyl »R 'is alkyl of (C1_ < s,) * R is hydrogen * alkyl of (Cx_ <6>) or phenyl * R * is hydrogen or phenyl optionally substituted with up to three groups selected from halogen alkyl of (Ct "A) or alkoxy of (C i" ^) i and Y 1 is oxygen or NH. The appropriate values of R * include? (a) acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, benzoyloxymethyl, benzoyloxymethyl, acetoxyethyl, a-pivalai laxiethi, 1- (cyclohexylcarbonyloxy) ethyl, (1-aminoethyl) carbonyloxyeti, 2- methoxyprop-2-ylcarbani laxymethyl * feni Icarbani laximeti lo and 4-metaxyphenylcarboni imet i lo * (b) coxi / cycloalkoxycarboni loxyalkyl groups * such as ethoxycarboni loxymethi and * t-buyloxycarboni loxymethi »cyclohexyl ilox carboni loximeti lo »1- et i lcyclohexi loxi carboni lsximetilo and ot-ethoxy carboni loxiet i lo (c) dialkylaminoalkyl» especially di- (lower alkyl) -aminoalkyl »such as dimethylaminomethyl * dimethylaminoeti or * diethi laminomethyl or diethylmethyl * (d) acetamido talee groups such as NN-dimethyl, minocarbonylmethyl, * N * - (2-hydroxyethyl) aminocarbonyl- methyl? (e) lactone talee groups such as phthalidyl and dimetho iftal idi lo * íf) (5-methyl-2-axo-l * 3-dioxolen-4-yl) meti lo * y () (2-me toxi carbonoi l-E -but-2-en-il) meti it. Representative examples of R1 include? (2-meta i carboni l-E-but-2-en-i l) meti lo »isobutyryl- Axymethyl * 2-methoxyprop-2-ylcabani loximeti lo * feni l carboni l- oi eti lo * 4-meto i feni 1 carboni loxymethi lo »t-but i loxy carbonyl-oxymethyl» cyclohexyl loxycarbon loxymethi * l ~ meti I cyclohexyl - or carboni loximeti what? N > The indocarbonylmethyl-N-di (2-hydroxyeti-1) aminocarbonylmethylloxy and (5-meth i 1-2-oxo-1'-3-dioxolen-4-yl-1-methyl) are especially preferred compounds. formula (I) include (4R »SS) ~ N-C6- (4-fluorophenyl) hex-li l3-4- (4- carbaxibenci Isulfini l) -2-axoazetidin-1-yl) acetamide and pharmaceutically acceptable salts of the same * in particular the sodium salt. Since the compounds of formula (I) are intended for use in pharmaceutical compositions * it will be understood that each of them is provided in substantially pure form * eg * at least 50% pure »conveniently at least 75LX pure» and preference of at least 95% pure (the percentage is based on weight / weight). Impure preparations of the compounds of formula (I) can be used to prepare the purest forms used in pharmaceutical compositions. Although the purity of the intermediates of the present invention is less critical it will be readily understood that the substantially pure form is preferred for the compounds of formula (I). Preferably and when possible * the compounds of the present invention are obtained in crystalline form. When some of the compounds of this invention are let crystallize to recrystallize from organic solvents * the crystallization solvent it may be present in the crystalline product. This invention includes within its scope these solvates. Similarly, some of the compounds of this invention can be crystallized or recrystallized from solvents containing water. In such cases »hydration water can be formed. This invention includes within its scope "stoichiometric hydrates" as well as compounds containing varying amounts of water that can be produced by processes such as lyophilization. Furthermore, different crystallization conditions can lead to the formation of different polymorphic forms of crystalline products. This invention includes within its scope all the polorphic forms of the compounds of formula (I). The compounds of the present invention are inhibitors of the enzyme phosphlipaea A ^, associated with lipoprotein (Lp-PLA2) »and as such are expected to be useful in therapy» in particular in the treatment of atherosclerosis. Therefore * in a further aspect * the present invention provides a compound of formula (I) for use in therapy. The compounds of formula (I) are inhibitors of the production of isofastylcholine by Lp-L jg and therefore may also have a general application in any disorder involving endothelial dysfunction * for example atherosclerosis »diabetes» hypertension »angina of chest »and after ischemia and reperfusion. In addition »the compounds of formula (I) can have a general application in any disorder involving lipid peroxidation in conjunction with enzymatic activity "for example in addition to conditions such as atherosclerosis and diabetes" other conditions such as rheumatoid arthritis * apoplexy »inflammatory conditions of the brain such as Alzheimer's disease * myocardial infarction * reperfusion injury * sepsis and acute and chronic inflammation. Additional conditions as such include several neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin * 32 * 159-165 * 1995). Additional applications include any disorder involving activated monocytes * macrophages or lymphocytes * since all these types of cells express Lp-PLAg. Examples of these disorders include psoriasis. Accordingly * in a further aspect * the invention provides a method of treating a pathological condition associated with the activity of the Lp-PLA ^ enzyme, * this method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor. of the enzyme. The pathological state may be associated with the increased involvement of monocytes * macrophages or lymphocytes »with the formation of lysophosphatidylcholine and oxidized free fatty acids * with peroxidation of lipids in conjunction with Lp-PLA ^ * activity or with endothelial dysfunction. The compounds of the present invention also they may be of use in the treatment of the pathological conditions mentioned above in combination with antihyperic ipidemic agents or antiatherosclerotic or antidiabetic or antianginal or anti-inflammatory or antihypertensive agents. Examples of the above include inhibitors of cholesterol synthesis such as statins »antioxidants such as probucol» insulin sensitizers »calcium channel antagonists» anti-inflammatory drugs such as NSAIDs. In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. Therefore, the present invention provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Suitable pharmaceutical compositions include those that 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, eg, syrups, suspensions or emulsions, tablets, capsules and pastes. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt * in a suitable vehicle or liquid vehicles * for example ethanol * glycerin * non-aqueous solvent * such as for example polyethylene glycol »oils * or water with an agent from * preservative suspension »flavoring or coloring agent. A composition can be prepared in the pharmacy of a tablet using any suitable pharmaceutical carrier routinely used for the preparation of solid formulations. Examples of these vehicles include magnesium stearate »starch» lactose »sucrose and cellulose. A composition in the form of a capsule could be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard vehicles and then introduced into a hard gelatin capsule. Alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier. For example, aqueous gums, celluloses, silicates or oils "and then introduce the dispersion or suspension into a soft gelatin capsule. Typical parenteral compositions consist of a suspension solution of the compound of formula (I) in a sterile pharmaceutically acceptable aqueous vehicle or oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable salve before administration. A typical suppository formulation comprises a compound of formula (I) that is active when administered from this way »with a binder and / or lubricant such as polymeric glycols» gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats. Preferably the composition is in unit dosage form such as a tablet or capsule. Each unit dosed for oral administration preferably contains from 1 to 500 mg (and for parenteral administration it preferably contains 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 1 000 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 Ol mg and 25 mg * of the compound of formula (I) * the compound being administered from one to four times per day. Conveniently * the compounds will be administered during a period of continuous therapy, eg for a week or more. The compounds of formula (I) can be prepared from suitable starting materials by adapting the synthetic procedures well known in the art * with reference to the earlier applications W0 96/19451 and W0 97/02242 (S ith line Beecham pie). Preferred compounds of formula (I) in which X is a C0NH * amide can be prepared by a process which comprises treating a compound of formula (II)? (II), wherein R1 is C (1_?) Alkyl or C < S_A > "And RE and 3 are as defined above in the present * and have the absolute configuration (4R * SS)" with an amine of the formula (III)? H2N (CH2) "Y (III) under suitable conditions of amide formation * by , Example * in the presence of an activating agent such as N * N-dicyclohexy Icarbodiimide and 1-hydraxybenzthiazole in a suitable solvent such as a dry one and then * if necessary », (a) Remove the ester group under suitable conditions of desestirification to form the acid * (b) converting the acid to a pharmaceutically acceptable salt? and / or (c) converting the acid * the suitable salt »the ester or an activated derivative of the acid * into a hydrolysable ester? n -5 live by reaction with a compound of formula (IV)? RlR * (IV) in which? R is a reactive leaving group of esterification "and R1 is as defined hereinabove? under conditions of ester formation. In step (a) above »the free acid can be regenerated from a corresponding compound in which the carboxyl group is protected as an alkyl ester of C < 4_A > or alkenyl of C < 2_ < fc > Using methods well known in the art for the particular protecting group * for example »when it is an allyl group» using palladium-catalyzed dealkylation (tr ifenylphosphine / pyrrole idine / tetrakis-tripheni Ifosphine-palladium (O) in dichloromethane). In step (b) above »salts are prepared by treating the corresponding acid with an appropriate base. Suitable conditions of ester formation for use in step (c) above are well known in the art n and are described for example in Coprehensive Organic Synthesis »Pergamon Press» 1991 »6» 323-380. Suitable conditions for ester formation include? (a) reacting a salt of the acid "for example a sodium salt or tertiary amine such as triethylamine" with a compound of formula (IV) in a polar aprotic solvent such as dimethylformamide »dimethyl sulfoxide or acetonitrile» at moderate temperature » for example on the scale from 0 to 100 ° C? (b) reacting the acid with a compound of formula (IV) in the presence of a base such as an alkali metal carbonate or tertiary amine * in an aprotic polar solvent and temperature as for (a) * (c) reacting the acid can be a compound of formula (IV) in which Rt is a hydroxy lo * group under dehydration conditions * for example the reaction of Mitsunabu which eats an azodicarboxylate and a trivalent phosphorus reagent (Mitsunobu * Synthesis * 1981 * 1) »or (d) reacting an activated derivative of the acid» for example a mixed anhydride »for example a isocarbylcarbonic or methanesulfonic anhydride» or a carbodiimide adduct (DCC) ) »With a compound of formula (IV) in which R? is a hydroxyl group * in the presence of a suitable base such as a tertiary amine * for example triethylamine »in an aprotic solvent such as tetrahydrofuran * at moderate temperature * preferably on a scale from -20 to + 20 ° C * or alternatively in the absence of a base but using a preformed alcohol salt * for example magnesium or lithium alkoxide. Preferred conditions include the use of the sodium salt of the acid in combination with a halide or sulfonate derivative of the compound of formula (IV). The compounds of formula (II) are useful intermediates in the preparation of a compound of formula (I). Consequently * in a further aspect * the present invention provides a composition of formula (II) as defined previously in the present. The compounds of formula (II) are sulfoxides which can be prepared easily by oxidizing a corresponding thio compound of formula (V)? (V) in which R1 * R85 and R3 are as defined hereinabove * and have the absolute configuration (4R) ith a conventional oxidizing agent such as chloroperbenzoic acid (mcpba) or ozone * and then if necessary * isolate the required diastereomer having the desired absolute configuration (4R * SS) * by example by means of fractional crystallization and / or chromatography. The compounds of formula (V) are used to prepare compounds of formula (I). Accordingly * in a further aspect * the present invention provides compounds of formula (V) as defined herein above. The compounds of formula (I) can also be obtained by an alternative process in which the two steps described above are inverted, that is * a compound of formula (V) is first treated with a compound of formula (III) to form the amide bond * and the resulting thio intermediate is then oxidized to the corresponding sulfoxide of formula (II) »preferably using a chiral oxidant system that produces the required isomer with the pre-active product. The compounds of formula (V) having the absolute configuration (4R) can be obtained from the corresponding race compound of formula (VI)? (VI) in which R- "" is a carboxyl protecting group "eg Cti_iS alkyl, > or alkenyl of C < a¡_4 & > * and R58 and R3 are as defined hereinabove by the formation of a diastereomeric salt with a chiral base such as (-) -cinconidine * and then? (a) isolate the preferred diastereomeric salt obtainable by fractional crystallization? and then (b> generating the free enantiammeric acid thereof by means of acidification.The diastereomeric salts formed of a compound of formula (VI) and a chiral base are used to prepare compounds of formula (I). in an additional aspect * the present invention provides said salts. The compounds of formula (VI) can be obtained according to the methods described in previous applications WO 96/19451 and WQ 97/02242 (S ith line Beecham pie). The process described above for the compounds of formula (D * thus as well as an alternative process for preparing the compounds of formula (ID * wherein R2 and R3 are each hydrogen) are summarized in the following scheme * in which R corresponds to CH2C &H ^ .C0¡a 1? OAe re RS- 9n sn (a «** chiral salt» "- NH ha ^ _N V-CO-Ma tí \ ^ ._CO, .H - = * tí CO-H OS COjH The compounds of formula (I) in which Rz is hydrogen and R3 is alkyl * for example methyl »can be prepared canine by means of a corresponding process in which the alkyl group is introduced in a previous step * by alkylating an azetidinone acetate of formula (V I D , (VI D wherein R * ~ is C < 1_ < > > > eg methyl &and R < is as defined above with an alkylating agent under standard alkylation conditions; »Isolate the diastereomers obtained in this manner by fractional crystallization and / or chromatography Conveniently, the compound of formula (VII) can be a single enantiomer» having the required absolute configuration (4R) Suitable alkylating agents include an alkyl iodide * in the presence of a suitable base such as sodium hydrides or potassium hydroxide »optionally with a quaternary ammonium salt such as tetrabutylammonium bromide in a suitable alkylation solvent such as tetrahydrofuran (THF), and at a temperature on the scale of - 10 to 0 ° C. Other suitable conditions include bis (trimethylsilyl) lithium amide in THF * optionally with 1'3-di and il imidazal idin-2-ana * to a temperature of about -70 ° C. The newly formed propyanate ester can then be converted to the corresponding acid * using basic conditions such as aqueous sodium hydroxide in THF "followed by amide bond formation" and after oxidation of the thio group, as described above. The enantiomers can be advantageously isolated by chiral chromatography * for example CLAR using chiral stationary phase »on compueetoe of formula (I) * in the alkyl ester / alkenyl ester stage. The sequences can be easily adapted for other values of X * by reference to previous applications »such as WO 96/19451 and WO 97/02242 (SmithKline Beecham» foot). For example, "compounds of formula (I)" in which the linking group X contains an ether function can be prepared by a suitable ether coupling reaction * for example * when X 'is CH ^ O * by treating a compound of formula (VIII)? (Vffl) wherein R1 * R2 and R3 are as defined above; with a compound of formula (IX)? L3 (CH2), (IX) wherein one of L2 and L3 is a halogen or other suitable leaving group such as triflate or toeilate * and the other is OH or a suitable salt thereof and Y are co or defined above "under standard conditions of ether formation . The ether compound thus formed can then be treated with an oxidizing agent to convert the thio group to a sulfinyl group to give a step of formula (I). If the compound of formula (VIII) is a racemic compound, this will lead to a mixture of diastereoisomers. Oxidation of the thio group will create an additional chiral center "and the resulting diastereoisomers can be separated by fractional crystallization and / or chromatography. The individual enantiomers can then be obtained by chiral chromatography. Suitable compounds of formula can be prepared (VIII) by analogy with the procedures described in WO 97/02242. The compounds of formula (I), which are pharmaceutically acceptable hydrolysable esters in vivo, can be conveniently prepared from the corresponding original acid by a process which involves treat the corresponding original acid or an alkyl ester or activated derivative thereof. The present invention will now be illustrated by the following examples. The chiral compounds are described as 4R or 4S * SR or SS 'where the number 4 describes the center at the C4 position on azetidinone * and the S describes the sulfoxide center. The diastereoisomer 1 derived from a 4R sulfide has the confi ruration 4R »SR. The corresponding diastereomer 2 is 4R * SS. Said confi urations are by extrapolation * based on their * H NMR spectra »from configurations obtained initially by X-ray analysis of a limited number of compounds. The absolute configuration at the chiral alpha carbon »when one of R * 2 and R73 is hydrogen» and the other is methyl »is described as« -R or a-S.

EXAMPLE 1 (R) -N-C6- (4-fluorophenyl) hex-l-il LL3-4- < 4-Alloxycarbonyl-l-benzyl thio) -2-oxoazetidin-1-yl) acetamyl to. 4- (Bromomethyl-1) allyl benzoate 4- (Bromomethyl-1) -benzoic acid (103 g) was suspended 0. 48 moles) in thionyl chloride (200 ml) "and dimethylformamide (i ml) was added. The mixture was heated under reflux until it was clear, evaporated and azeotropically treated with toluene (2 x 150 ml). The resulting oil dissolved in dichloromethane "was added dropwise to a cooled solution of pyridine (42 ml> and allyl alcohol (40 ml) in dichloromethane.The mixture was stirred at room temperature for 1 hour and then washed with 2M hydrochloric acid water. »Sodium acid carbonate solution» and brine The organic solution was dried and evaporated to give allyl 4 ~ (bromomethyl 1) benzoate as a clear oil (98 g »84% yield). * H NMR d ( CDCl 3 > 4.61 (2H »s» CHas) * 4.82 (2H * »CH ^ O), 5.34 (2H» »CHs. CH -) * 6.05 (1H * m * CHCH-g.) * 7.45 (2H * d »Ph-H), 8.03 (2H * d * Ph-H). b. 4- < acetyl thiomethyl l) allyl benzoate Allyl 4- (bromomethyl) benzoate (98 g »0.4 mol) in dry dimethylformamide (100 ml) was added dropwise to a cooled suspension of potassium thioacetate (46 g * 0.4 mol). ) in dry di-i-formamide (200 ml). The cooling bath was stirred and the mixture was stirred overnight. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined extracts were washed with brine and water. The mixture was dried and evaporated to give allyl 4- (acetyl thiomethyl 1) benzoate as an orange oil (100 g * 100% yield). lH NMR d (CDClj,) 2.36 i3H, s * CÜCH3) * 4.13 (2H * s »CU-,), 4.82 (2H * m, CHs-0) * 5.32 (2H * * CH ^ CH) * 6.05 (lH * m, CHCHS!), 7.35 (2H, d * Ph-H) * 7"98 (2H * d * Ph-H). c. 4-f - (al i loxycarbonyl) benzyl thio) azetidin-2-one was added dropwise allyl alcohol (27 ml) in dry tetrahydrofuran (50 ml) was added to a solution of potassium tert-butoxide (4.93 g, O.044 moles) in dry tetrahydrofuran (100 ml). After stirring for 5 minutes, a solution of allyl 4- (acetyl iomethyl) benzoate (10.1 g »0.04 mol) of allyl in dry tetrahydrofuran (100 ml) was added dropwise. After stirring for 15 minutes, a solution of 4-ketoxyazetidin-2-one (5.16 g »0.04 mol) was added dropwise. The mixture was stirred for 1 hour * and evaporated. The residue was separated between ethyl acetate and water * and the aqueous solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried and evaporated. Instant chromatography (silica gel, ethyl acetate-petroleum) gave 4- (4-allyloxycarbonylbenzylthio) azetidin-2-one as an oil (9.1 g »82% yield). lH NMR d (CDCl ^) 2.84 (1H »dd * H3a) * 4.31 (1H * dd» H3b) »3.88 (2H, s» S-CH2) »4.68 (1H, dd» H4), 4.78 (2H, m , CHS20), 5.35 (2H, * CH-.CH -) * 6.05 (lH * m, CHCH: z), 6.07 (lh * br single band * NH) * 7.40 (2H * d »Ph-H)» 8.03 (2H * d, Ph-H). d. 4- < 4- (allylxi arbonyl > benzylthio) -2-oxoazeti din-1-methyl tartrate To a stirring solution of 4- (4- (alkyloxycarbonyl) benzyl thio) azet idin-2-one ( 2.55 g * 9.2 mmoles) * tetrabutyl ammonium bromide (.3 g * 1.02 mmoles) and B Methyl braaacetate (1.06 ml * 11.2 mms) in dry tetrahydrofuran (40 ml) * powdered potassium hydroxide (0.63 g * 11.2 mmolee) was added, keeping the reaction temperature below 30 degrees by a cold water bath . After 2 hours * the mixture was diluted with water and extracted three times with ethyl acetate. The combined extracts were dried (MgSO) and evaporated, and the residue was chromatographed (fine silica * ethyl acetate-petroleum) to give the title compound as a clear oil * in yield of 2.66 g (83%). * H NMR d (CDC1-;-) 2.97 (ÍH * dd * H3a) * 3.26 * 4.07 (each ÍH * CHJSC0 * d) * 3.42 (ÍH * dd * H3b> 3.70 (3H, s * CH30), 3.81 (2H, s * SCHsa!) * 4.83 (2H * m * CHsa.O), 4.93 (lH, dd, H4) »5.35 (2H * m * CHS! CH)» 6.03 (lH, m * CHCHss) * 7.39 (2H * d * Ph-H) * 8.02 (2H * d * Ph-H) and. acid < +/-) - 4- < 4- (al laxicarbonyl) benzylthio > -2-oxoazetidin-1-lactic acid To a solution of 4- (4- (al i loxycarbonyl) benzyl thio) -2- oxoazet idin-li methyl acetate (2.17 g * 6.21 mmol) in tetrahydrofuran (20 ml ) »A 1 molar aqueous solution of potassium hydroxide was added dropwise with cooling (in an ice bath) for 10 minutes. After another 30 minutes * the solution was diluted with water and extracted twice with ether. The aqueous layer was then acidified (dilute hydrochloric acid) with cooling "and the oil that was precipitated was extracted into ether. The combined extracts are dried (MgSO 4 -) and evaporated to a clear oil which was finally crystallized under oil and filtered, washed and dried to give the title compound as white crystals * 1.87 g * 90% yield. * H NMR or (CDCl3) 2.98 (lH »dd, H3a), 3.34» 4.06 (each 1H, CHaíC0 »d)» 3.42 (lH »dd» H3b) »3.82 (2H * s * SCH2!) * 4.82 (2H »M» CH =, 0), 4.92 (1H »dd» H ^ »5.34 (2H» m »--.CH)» 6.03 (HH »m» CHCH¡z) »7.39 (2H» d »Ph-H ) »8.02 (2H, d, Ph-H). £. acid < -) - (R) -4- (4- (al- loxycarbonyl) benzyl) -2- oxoaze i in-1-ilacéticQ They were heated to boiling acid 4- (4- (al i lo carboni) benz l thio) -2-oxoazetidin-1-ylacetic acid (3.41 g »10.2 mmol) and cinchonidine (2.99 g» 10.2 mmol) in ethanol (40 ml) when a clear solution was obtained. Resting for 90 minutes, the crystalline salt which precipitated was filtered and recrystallized from ethanol (20 ml). The solid obtained was stirred vigorously with ether and water while acidifying with dilute hydrochloric acid * and when a complete solution was obtained * the layers were separated, and the aqueous layer was further extracted with ether. The combined extracts were dried (MgSO ^.) And evaporated to an oil * which was crystallized by trituration with clear petroleum to give the title compound as white crystals * m.p. 74-6 ° C »6.7 g * 50% yield. a0 25aC = -24.2 (c 0.7 p / v CHCl3 * 25QC) 4H NMR < 5 (CDCl,) 2.97 (lH * dd »H3a) * 3.26, 4.07 (each lH *) »3.81 (2H, s »SCHz)» 4.83 Í2H » * 4.93 (lH * dd * H4) * 5.35. (2H * m * CH2, CH), 6.03 (lH »m, CHCH2)» 78.39 (2H »d, Ph-H) * 8.02 (2H * d * Ph-H) g. < R) ~ N-C6- < 4-fluarafeni 1) hex-l- ~ il 3-4- (4-alloxycarboni 1-benzylthio) -2-oxoazetidin-1-i Paceta ia To a cooled solution (in an ice bath) of acid (R) -4 - (4- (al i loxycarbonyl) benzyl thio) -2-oxoazet din-li-lactatic (12.51 g * O.0373 mol) * 1-hydroxybenzotriazole hydrated (5.04 g * 0.0373 mol) and 6- (4-fluoropheni) l) hexylamin (O.0373 moles) in dry dried dimethyl ester (150 ml) * dicyclohexycarbodiimide (7.29 g * .0373 moles) was added with stirring. After 20 minutes * the cooling bath was removed * and after another 16 hours * the solvent was evaporated under reduced pressure »and the residue was treated with ethyl acetate * and the insoluble precipitate was filtered and discarded. The filtrate was further diluted with ethyl acetate *, washed with 0.2 M hydrochloric acid, then saturated with sodium hydrogen carbonate * dried and evaporated under reduced pressure. The residue was triturated with ethyl acetate / light petroleum to give the title compound co or white crystals * m.p. 54-7 ° C »17 g * 89% yield. 1H NMR d (CDCl3) 1.30-1.60 (8H * m * 4xCHa :) * 2.55 * (2H * t * J = 7.6 Hz * C! -L, Ph) 2.90 * 2.97 (ΔH »dd * J-2.4, 15.4 Hz »H3t>, 3.23 (2H, m * NHCHs) * 3.35 * 3.41 (1H * dd * J = 5.1 * 15.4 Hz * H3) * 3.53 * 3.78 (each lH * d * J = 16.6 Hz, NCH ^), 3.86 (2H, sSCHss), 4.83 (3H * m, Code * H4), 5.37 (2H, m »CHa = CH), 6.0 (2H,, NH» CHa = CH), Ü. (2H * m »4-FPh-H) * 7.10 (2H * m * 4-FPh ~ H), 7.39 (2H * d * J = 8.3 Hz * 4 ~ C0S? AlilPh ~ H) * 8.02 (2H, d »J = 8.3 Hz» 4-CO ^ .al i IPh-H) EXAMPLE 2 < 4R, SS) -N-C6 ~ < 4-fluorofeni Dhex-l-ilJ ~ 4- < 4- aloxycarbonylbenzylsulfinyl) -2-o; xoagetidin-1-yl) acetamide A solution of (R) -N-C6- (4-fluorophenyl) hex-1-yl 3-4- (4- ~ aloxy carboni Ibencylthio) -2-oxazetidin-1-yl) acetamide (16.36 g) was cooled »0.0319 moles) in dichloromethane (150 ml) at -65 to -70 degrees» and a solution of m-chlorope benzoic acid (6.61 g »0.0383 mol) in dichloromethane (120 ml) was added dropwise with stirring for 20 minutes. . After 1 hour the mixture was washed with saturated sodium metabisulfite solution, then saturated with sodium hydrogen carbonate, dried (MgSO 4) and evaporated to a solid which was recrystallized from ethyl acetate. ethyl to give a mixture of diastereomers 2 and 1 in the ratio of 3? 2. Chromatographic separation (HPLC) gave diastereomer 2 (4R * SS) as a white crystalline solid * m.p. 133-5 ° C * 3.3 g * 20% yield. aD 25 ° C = +74. O (c 0.6% w / v CHCl 3 * 25 ° C) 1 H NMR < 5 (CDCl3) 1.3O-1.60 (8H * m * 4xCH2> »2.56» (2H »t» J = 7.6 Hz * CH2Ph) 2.91 * 2.95 (1H * dd * J = 2.4, 15.2 Hz * H3 > * 3.27 (3H »m» NHCHS2 »H3)» 3.94 * 4.22 (each lH * d * J = 17.2 Hz * NCH ^,) »4.04 * 4.18 (each lH» d »J = 12.8 Hz» S0CHse), 4.65 (lH, m, H ^), 4.84 (2H »m, COa5CHs.), 5.37 (2H, * CHa» CH), 6.0 (1H * »CHβ = CH), 6.95 (3H * m» 4-FP -Hr NH) * ), 7.10 (2H * * 4 ~ FPh-H) * 7.36 (2H, m »4-COaalylPh-H) r 8.09 (2H *» 4-C0ßali IPh-fci).

EXAMPLE 3 < 4R, SR) ~ N ~ [L6- < 4-fluorofeni l) hex-l-il 3 ~ 4- (4'alloylcarbonylbenzylsulfinyl > -2-oxoazetidin-l-yl) acetamide From the HPLC chromatography described in Example 2 above *, the other diastereoisomer (Dia 1 → 4R * SR) co was obtained to a white crystalline solid (1.8 g »11% yield) m.p. 175-7 ° C. a0 25 ° C = • -119.7 (c 0.5% p / v CHCl3, 25 ° C) '-H NMR 5 (CDCl-s) 1.30-1.60 (8H, m * 4xCHz) * 2.55 (2H * t * J = 7.6 Hz * CH ^ Ph) * 2.95 * 2.98 (IH * dd, J = 4.8 * 14.8 * Hz * 3), 3.24 (2H, m * NHCH ^) »3.42, 3.46 (1H * dd * J = 2.4 * 14.8 Hz * H3) * 3.76 * 4.09 (each 1H * d * J = 17.2 Hz * NCH2) * 3.95 * 4.01 (each HH * d, J = 13.2 Hz * S0CH2), 4.59 (HH * m * H4), 4.84 (2H * m »CO ^ CH ^, 5.37 (2H * * CH2 = CH) * 6.0 (1H * * CH: 2 = CH) * 6.53 (1H * m» NH) * 6.95 (2H * m * 4-FPh -H) * 7.10 (2H * m * 4-FPh-H) * 7.36 (2H * d * J = 8 Hz * 4-CO ^ alylPh-H), 8.09 (2H, d, J = 8 Hz, 4- CO ^ al i IPh-H).

EXAMPLE 4 < 4R, SS) -N-C6- < 4-fluorofeni l) hex-l-il 3-4- < 4-- carboxybenzilsulfinyl) -2-QXoazetidin-l-i 1) cetami a A solution of (4R »SS> -N-E6 ~ (4 ~ fluorafeni I) hex-1-i 13-4- (4-halocarboni 1 benz Isulfinyl) -2-oxoazetidin-1-yl) was stirred. acetamide (example 2) (0.185 g »0.35 mmol)» triphenylphosphine (0.092 g »O.35 mmol)» pyrrolidine (0.033 ml »0.4 mmol) and tetrakie trifeni l foefinpalladium (0) (0.012 g» 0.01 mmol) in dichloromethane ( iO ml) under nitrogen for 16 hours. Another 0.012 g (0.01 mmol) of tetrakis triphenyl phosphinpalladium () was added and after four more hours the reaction was concluded. The solution was diluted with water, acidified (HCl to 2N), the layers were separated and the aqueous layer was further extracted with dichloromethane. The combined extracts were dried (MgSO) and evaporated to a yellow oil, which was triturated with ether. A yellow solid was obtained which was filtered and dissolved in a sodium acid carbonate solution. Stirring 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 dichloromethanes, and the extracts were dried (MgSO 4) 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. Mp. 105-7aC »0.1 g» 58% yield. a0 25 ° C = -31.7 (c 0.5% w / v DMSO, 25 ° C) * H NMR < 5 (DMSO) 1.26 (4H, m, 2xCHs,, 1.38 (2H »m» CfcL.,) »1.50 (2H» m, CHL;,) * 2.96 * 2.99 (ÍH * dd * J - 2 * 15" 2 Hz * H- »)» 3.06 (2H * m »NHCH ^)» 3.84 »4.09 (each 1H» d * J «17.2 Hz * NCH ^.), 4.13» 4.31 (each 1H »d» J = 12.8 Hz »SOCH ^)» 4.T4 (1H »» H ^, 7.05 (2H »» 4-FPh-H) »7.19 (2H» m, 4-FPh-H), 7.47.I2H »d» J = 8 Hz , 4-COa-allylPh-H) »7.93 (2H, d» J = 8 Hz »4-COjg.al i IPh-H)» 8.13 (1H * * NH) * 13 (ÍH, bs * COs-Ji) .

EXAMPLE 5 Sodium salt of (-) - < 4R > SS) -N ~ C6- (4-fluorophenyl) hex-l-il -4- < 4- carbo ibencilsul inil) -2-oxoazetidin-i-yl) acetamide A mixture of N-C6- (4-fluorofeni l) hex-1-i 11- - (4- carbaxibenci Isulfini l) -2-oxaazetidin-1-yl) acetamide (0.51 g) and sodium bicarbonate (0.088 g) in water (15 ml) * was treated with sound for 5 minutes * methanol (20 ml) was added and the mixture was treated with sound for another 20 minutes. After filtration * the solution was evaporated to a low volume * diluted with water and lyophilized to give the title compound as a white powder (0.52 g) * m.p. 238-40 ° C. a "= - 31.7 ° (c 0.5 * DMSO).

EXAMPLE & 4R * 5S-N- (6- (4-fluorophenyl) hexyl) -4- < 4- ethoxycarboni Ibenzylsul ini 1) -2-oxoazetidin-1-lacetamide to. Ethyl 4- (bromomethyl) 1-benzoate 4- (Bro ometi 1) benzoic acid (25.75 g, 0.1197 mol) in thionyl chloride (50 ml) was suspended and dimethylformamide (0.25 ml) was added. The mixture was heated under reflux for 25 minutes until it was clear, evaporated and azeotropically treated twice with toluene. The resulting oil was dissolved in dichloromethane (75 ml) and added dropwise over 10 minutes to a solution of absolute alcohol (8.6 ml, 0.1465 moles), pyridine (10.5 ml, 0.1298 moles) in dry dichloromethane (50 ml). And cooled to 10 ° C. The ice bath was stirred »and the reaction was stirred for 45 minutes» and then washed with water »HCl at 2N» water »sodium carbonate acid solution and brine. The organic solution was dried (MgSO ^.) And evaporated to give a mixture of 60? 40 of ethyl 4- (bromomethyl) l benzoate? 4- (clear et i1) ethyl benzoate as an oil (25.6 g »94%). * H NMR 5 (CDCl3) 1.40 (H », CH-.)» 4.40 (2H »m» CH ^ O), 4.50 * 4.61 (2H, 2xs * CH ^ Cl / Br) * 7.45 (2H * m »Ai -H) * 8.01 (2H * m * Aria). b. 4- (ethyl acetyl 1-thiomethyl) benzoate A mixture of 60? 0 of 4- (bromometi 1) benzoate ethyl? 4- (clear eti 1) ethyl benzaate (25.0 g * 0.111 moles) in dry dimethylformamide (150 ml) * cooled to 5 ° C * was treated with potassium thioacetate (13.3 g * 0.117 mmol) * and the temperature rose up to 20 ° C. The reaction was stirred at room temperature for 2 hours, poured into water (250 ml) and extracted with diethyl ether (3x 100 ml). The organic extracts were combined, washed with water, dried (MgSO ^), treated with charcoal and evaporated to give ethyl 4- (acetyl-thiamethyl) benzoate as a brown solid (26.0 g * 99%) * pf 36-37 ° C. * H NMR d (CDCl3) 1.38 (3H * t * J = 7.1Hz »CH-,)» 2.36 (3H * s »COCH--)» 4.14 (2H, s »CH ^ S) * 4.36 (2H * q »CH ^ O)» 7.35 (2H * d, J == 8.2Hz »Ar-H) * 7.97 (2H * d» J = S.2Hz »Ai-H). c, 4- (4- (ethocarbonyl) benzylthio) azetidin-2-one A solution of sodium (1.87 g »0.0813 mol) in absolute alcohol (300 ml) was treated with a solution of 4- (acetyl thiomet 1) ethyl benzoate (19.4 g * 0.0814 mol) in absolute alcohol (75 ml) for 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 (10.Og »0.07745 moles) for 5 minutes. The cooling bath was removed and the reaction was stirred for 2 hours, evaporated to dryness, treated with brine (200 ml) and extracted with ethyl acetate (200 ml »100 ml). The organic extracts were combined * washed with brine * dried (MgSO ^.) and evaporated to a red oil. Purified by flash column chromatography on silica gel, eluted with 3? 1 to 2% petroleum ether at 40 to 60 ° C ethyl acetate to give (4_ (ethaxycarbonyl) benzylthio) azene-2-one as an orange oil (18.64 g, 91%). * H NMR < 5 (CDCl3) 1.38 (3H, t, J = 7.1Hz * CH.,) »2.82, 2.89 (1H, 2xm * H3» 3.29 »3.35 (1H, 2xm» H- »>» 3.88 (2H, s » CH ^ S) »4.37 (2H» q »CHa.0) * 4.70 (1H * m * H *) * 5.70 (lH» bs »NH)» 7.40 (2H * d * J = 8.3Hz * Ar-H) * 8.00 (2H * m * Ar-H) d. < 4- < 4-ethocarbonyl) benzylthio) -2-oxoaze and methyl-1-methyl acetate A stirred solution of 4- (4- (ethoxycarbonyl) encylthio) azetidin-2-ana (217.3 g * 0.819 mol) * bromoacetate of methyl (128.5 g >; 0.84 moles) and tetrabutylammonium bromide (25.8 g, 0.08 mol) in dry THF (900 ml) was cooled in an ice bath at 20 ° C, and added in a hydrogenated portion of finely ground potassium (48.3 g, 0.86 moles). The reaction was treated exothermically at 45 ° C, and allowed to cool again at 30 ° C when the ice bath was stirred and stirring was continued for 1 hour. More potassium hydroxide (2.4 g »0.043 mol) was added, and stirred for minutes when this addition was repeated. After another 30 minutes, the reaction mixture was filtered through hyphla »with more THF. The combined extracts were evaporated until a red oil. Ether (11) was added and stirred well. The ether was decanted and the procedure was repeated. The combined ether extracts were evaporated to give the title compound as a dark brown oil (199.8 g »72% yield). * H NMR d (CDCl3) * 1.40 (3H * t »J = 7Hz». CHUCHU »), 2.98 (HH» dd, J = 2.15 Hz »ü,» 3.26 »4.03 (each HH» d »J = 18 Hz »NCH ^)» 3.42 (lH »dd» J = 5 »15 Hz * t = x) r 3.70 (3H * s * OCfcL,) * 3.81 * (2H * m * SCH-,)» 4.38 (2H * q * J = 7 Hz * OCH-,) * 4.93 (ÍH * m, H ^.), 7.39 (2H, m, Ph-H). and. Or aci (4- (4-ethoxycarbonyl) benzyl thio) -2-oxoaze Idyn ilacé ico-1- (4- (4-etoxicarboni l) l benci thio) -2- oxaazetidin-1-i lacetato methyl (it Dissolves 169.S g, 0.5O3 moles) in THF (750 ml), cooled to 0 ° C * and a solution of potassium hydroxide (29.7 g * 0.529 mol) in water (500 ml) was added for 15 minutes at 0 to 5 ° C * and then the mixture was stirred to 0 ° C for 45 minutes. Ether (11) and water (21) were added and the layers were separated and the aqueous solution was washed with ether (11), then acidified with concentrated hydrochloric acid (55 ml) and extracted with dichloromethane (2x 11). . The combined extracts were washed with brine * dried (MgSO 4) and evaporated to give the title compound as a green solid (128.4 g * 79% yield).

F. Acid (-) - R- (4- < 4-ethoxycarbonyl) benzyl thio) - -oxQazetidin-l- ylacetic acid was dissolved (4 ~ (4-ethoxy carbonyl) benzyl thio) ~ 2-oxoazetidin-l-ilacétí co (46.0 g »0.1422 moles) and (-) cinchonidine (41.88 g * 0.1423 moles) in absolute alcohol (450 ml). The solution was cooled for 1.5 hours »filtered and dried to give the salt as a cream solid (33.15 g). This solid was recrystallized from absolute alcohol (300 ml) to give 23.6 g of the salt which was mixed with water (500 ml) and diethyl ether (500 ml) and acidified with dilute HCl (50 ml). When all the solid had dissolved, the layers were separated and the aqueous layer was extracted with ether (250 ml). The organic extracts were combined * ethyl acetate (100 ml) was added and washed with water * dried (MgSO, -.) * Filtered and evaporated to give R- (4- (4-ethoxycarbonyl) acid) l io) -2-oxoazetidin-1-ylacetic acid as a colorless solid. (10.93 g * 23.8%) p.f. 135-137 ° C. * H NMR < 5 (CDCl3) 1.39 (3H, t * J = 7.1 Hz * CH3) * 2.96 * 3.02 (HH, DD * J = 2.2 * 15.3 H2 »H3), 3.33, 4.05 (each HH, d, J = 18.4 Hz» NCH3eC0! 2H) * 3.40 * 3.46 (1H * dd, J = 5.1 * 15.3 Hz, H3) * 3.82 (2H, 5 »SCH ^)» 4.37 (2H * q * CO ^ CH- ,,) »4.68 (1H * b * CO ^ H), 4.92 (1H * * H?) * 7 * 38 (2H * d »J - 8.2 Hz * Ph-H * 7.99 (2H, d * J = 8.2 Hz * Ph-H) Qj Acid 4R * SR- < 4- < icarbo i 1 4-eta) benci Isulfini 1) 2-oxoazetidin-l-ylacetic acid (diastereoisomer 1) fejs acid 4R * SS- (4- (4-etoxicarbóni 1) benci lsulfini 1-2- oxoazetidin-i-ylacetic acid (diastereoisomer 2) A solution of acid (-) ~ -R ~ (4- (4-ethoxycarbonyl) ethyl) -2-oxoazeti din-1-acetic acid (10.81 g »0.03343 mol) in dry dichloromethane (400 g) was treated. ml) at -700C with ozone until a blue discoloration appeared, the reaction was allowed to warm to room temperature and dichloromethane (50 ml) was added to facilitate stirring, the solution was evaporated to dryness and the resulting solid was mixed with chloroform (200 ml). The colorless solid was collected by filtration to give acid 4R »SR- (4- (4-eto icarbóni l) benci Isulfinil) 2-yn-1-oxoazeti i lacético (4.11 g" 36 %) mp 162-164 ° C. (contains 15.8? 1 diastereomer 1? diastereoisomer 2) * é H NMR (DMSO) 1.33 (3H, t, J = 7Hz, CH3) '2.97' 3.04 (1H dd * J * = 4.8 * 14.8 Hz, H3) * 3.12 »3.16 (ÍH, dd, J = 1.6, 14.8 Hz, H3), 3.83» 4.17 (each 1H, d »J = 18 Hz» NCH ^ CO ^ H) »4.92, 4.24 (IH» d »J = 12.8 Hz »SOCH ^), 4.32 (2H * q, CO ^ CH. ,,) * 4.99 (IH, M * H ^) * 7.48 (2H * d» J = 8.0 Hz »Ph-H)» 7.96 (2H * d * J = 8.0 Hz * Ph-H. The filtrate obtained above was evaporated and mixed with diethyl ether and filtered to give 4R-SS- (4- (4-ethoxycalboni) benzyl isulfini-l-oxoazetidin-1-lactatic acid (6.42%, 56%). ) mp 152-155 ° C (contains 92? 8 diastereoisomer 2? diastereomer 1). lH NMR d (DMSO) 1.33 (3H, t »J = 7 Hz» CH3), 2.97, 3.01 (OH, dd »J = 2.O» 15.5 Hz »H3), 3.35» (1H * M * H3), 3.95 »4.17 (each 1H, d, J = 18.2 Hz »N HjCQs.H, 4.15 (1H * d, 1 of SOCH ^)» 4.32 (3H »m * 1 of SOCH ^» CO ^ CH ^) * 4.82 (1H * * H ^, 7.51 (2H * d * J » 8. 2 Hz »Ph-H). ij (+) -4R »SS-N- < ? - (4-f1uoropheni 1) he i 1) -4- (4-ethoxycarbonj.1-benzylsulfinyl) -2-oxoaz t din-l-ylac tamide 6- (4-fluorophenyl) hexylamine (1.82 g * 0. 00932 moles) in dry dimethylformamide (75 ml) to a mixture of 4R »SS- (4- (4-ethocarbonyl) benzylsulphinyl-2-oxoazetidin-1-ylacetic acid (3.15 g» 0.00928 moles) »N» N »-dicyclohexy Icarbodi imide (1.92 g» O.0 931 moles) and 1-hydroxybenzotriazole (1.25 g 0.00925 moles) The reaction was stirred at room temperature for 3.5 hours »diluted with ethyl acetate (100 ml) and cooled The mixture was filtered to remove the urea and the filtrate was evaporated to dryness The residue was dissolved in ethyl acetate (400 ml) * washed with sodium hydrogen carbonate solution and brine, dried and evaporated to a colorless solid (5.8 g) which was recrystallized from ethyl acetate (125 ml) to give the product (3.0 g) Purification by column chromatography gave 4R acid, SS- (4- (4-etaxycarbanyl)) Isulfini 1-2- oxoazetidin-1-i lacet ico as a colorless solid »155-156aC» 1.8 g * 38% yield. lH NMR < 5 (CDCl3) 1.3-1.6 (11H, * 4x CH.¡. »CH3) * 2.56 (2h * t * J = 7.6 Hz »CHzPh) * 2.89 * 2.96 (ÍH * dd * J = 2.4 * 15.3Hz, H3), 3.25 (3H * m» NHCHß, H-.), 3.94 »4.22 (each 1H» d »J = 17Hz »NCH ^ CO) * 4.03» 4.18 (each HH »d» J = 12Hz »SOCH-J, 4.39 (2H, q, C02CH53!) R 4.65 (1H *» H, 6.9-7.12 (5H * * NH, p -ClPh-H), 7.35 (2H * d »J = 8.3Hz» Ph-H) »8.07 (2H * d * J = 8.3 Hz» Ph-H). An = + 85.2 (c - 0.55 p / v in chloroform at 25 ° C.) Found? C »62.6? H» 6.3; N? 5.4% »Cst? H -3% Fns £.}. aß requires? C, 62.8? H, 64? N, 5.4%.

EXAMPLE 7 C +) - 4R * SS-N - (? - < 4-Chloraphenyl) hexyl) -4- (4-ethoxycarbonyl-1-benzyl-sulphonyl) -2-oxoazetidin-1-ylacetamide The treatment of 4R * SS ~ (4- (4-ethoxycarbonyl) benzylenulfini 1-2-oxoazetidin-1-ylacetic acid with 6- (4-clarofeni 1) hexy lamide »N» N-dicyclohexycarbodiimide and 1- hydraxibenzot iazal in dimethyl the dried pharmacid as described for Example 6 above »followed by the same procedure» gave the title compound as a colorless solid »159-161 ° C» 45% yield. * H IMM d (CDCl 3 ) 1.3-1.6 (11H », 4xCHs ,, CH3), (2H» t, J = 7.6Hz, CH ^ Ph) * 2.89 »2.95 (ÍH * dd, J = 17Hz, NCH ^ CO) * 4.03, 4.18 ( each HH * d * J = 12Hz, SOCHz) * 4.36 (2H * q * C02CHa?), 4.65 (HH * m »H ^.) * 7.04 (HH» m * NH), 7.06-7.26 (4H, m, p-Cl Ph-H), 7.35 (2H, d * J = 8.3 Hz, Ph-H) * 8.07 (2H, d * J = 8.3 Hz * Ph ~ H). a, -, = +83.9 (c = 1.0% w / v in chloroform at 25 ° C) Found? C * 60.9? H »6.1. N »5.2%? Cs, .-, H33 lNa, 0ßS required? C, 60.8? H »6.2? N * 5.3%.

EXAMPLE ß (+) - 4R * SS-N- (6- <4-f1uoro eni 1) hexy1) -4- < 4- eto icarbo ilbencilsul inil) -2-oxoazetidin-l-ylacetamide to. [< 3S * 4R) -4- cetyl thio-3-bromo-2-oxoazetidin-l-p-methoxybenzyl Jacetate Oxygen-treated oxygen was bubbled through a solution of 2-C (3S * 4R) -4 ~ aceti p-Ethoxybenzyl thio-3-bromo-2-oxoazet idin-1-yl 3-3-methylbutyl-2-enoate (Osborne NF et al., J. Chem. Soc., Perkin Trans. 1, 1994 * 179 ) (20.16 g * 0.456 mole) in ethyl acetate (400 ml) at -65 to -70 ° C until a permanent blue solution was obtained. The excess ozone was removed by the passage of oxygen, and then trimethoxyphosphite (53.8 ml, 0.456 moles) was added dropwise. After 15 minutes * the solution was allowed to warm to room temperature * and then stored for 16 hours. The solvents were evaporated * and the residue was re-evaporated twice from toluene * then dissolved in ethyl acetate (300 ml) and stirred vigorously for 1.5 hours with a solution of p-toluenesulfonic acid (2 g). in water (100 ml). After diluting with water * the organic layer was separated * and the aqueous layer was further extracted with ethyl acetate. The The combined extracts were washed successively with saturated aqueous sodium hydrogen carbonate and brine * and then dried (MgSO ^) and evaporated. Purification by flash chromatography (silica * ethyl acetate-petroleum ether) gave the title compound as a light brown oil * in yield of 10.6 g (58%). £ a (3Sr4R) -3-bromo-l- (p-tnetoxibencitoxicarbpnilmetil) -2-oxoazetidin-4-thiolato silver A solution of C (3S * 4R) -4-acet ilt io-3-bromo-2- oxaazetidin-ii p-methoxybenzyllocetate (4.13 g * 0.01 mol) in methanol (90 ml) was added with stirring in dim light to a solution of silver nitrate (2.27 g * O.0133 mol) in methanol (90 ml) ). Triethylamine (1.T7 ml * 0.O133 mol) was then added with cooling on ice * and stirring was continued for 1 hour at 5 to 10 ° C »followed by 30 minutes at room temperature. The mixture was re-cooled (in an ice bath) and the precipitated solid was filtered and washed twice with ice-cold methanol and added with hexane to give the title compound with a yield of 4.6 g (96%). . c. Iodide of 4-carbeto ibenci lo The treatment of 4-carboxybenzyl bromide with thionyl chloride followed by ethanal in pyridine gave a mixture of 4-carbethoxybenzene chloride and bromide which was treated (14.6 g) with iodide Sodium (39.8 g) in acetone (150 ml) at reflux temperature for 20 hours. The mixture was cooled »filtered» and the solvent was evaporated. The residue was taken up in ether (150 ml> and washed with water »aqueous sodium thiosulfate and brine» and dried and evaporated to give the title compound as a pale yellow solid »p" f "61-3 ° C »17.5 g (91% yield).« • H NMR d (CDCl-,) 1.39 (3H »t» J = 7.1 Hz, CH3), 3.37 (2H, q.J = 7.1 Hz, CHa.CH. ,), 4.46I2H, s, CH ^ I) »7.43 (2H, M, 3.5-Ph-H)» 7.96 (H, m »2» 6-Ph-H). d. E (3S * 4R> -4- (4-carbethoxy) benzylthio-3-brorno- -oxoazetidin-l-yl 3 -acetate of P-m toxibention A solution of (3S »4R) -3-bromine was treated -l- (p-methoxybenzyl) icarboni Imet il) -oxoazet idin-4-thiolate silver (2.34 g »0.005 mol) in acetonitrile (20 ml) with a 4-carbetoxybenzyl iodide solution (1.74 g) 0.006 moles (in acetonitrile (10 ml) * and the mixture was stirred in dim light for 2.5 hours The mixture was filtered through hyflo »the filtrate was evaporated and the residue was purified by flash chromatography (silica» ethyl acetate- petroleum ether) * to give the title compound as a white solid * mp 97-9 ° C * 1.60 g (61% yield) 1 H NMR <5 (CDCl-,) 1.39 (3H * t, J- 7.1 Hz, CHZCH3), 3.48, 4.07 (each 1H, d * J = 18 Hz * NCH -,) * 3.80 (5H * s * SCH-. + 0CH3> 4.37 (2H, q »J = 7.1Hz * CH- H--) * 4.61, 4.91 (each ÍH * d * J = 1.6 Hz, Hat-HU, 5.03 * 5.12 (2H * 2Xd * J = l 1.8Hz »0CHa.> 6.89 (2H * m * 3 * 5- (4- CH =, 0Ph) -H), 7 * 26-7.41 (4H * * 2 »6- (4-CO ^ Et) Ph-H + 2» 6- (4-CH, 0Ph) ' H) »8.00 (2H» m, 3.5- (4-CO! 5.Et (Ph-H) eC (3S »4R) -4- (4-car" beto i) benc-sulfinyl-3-bromo-2-oxoazetidin-1-yl-3-acetate-p-methoxybenzyl Diastereomer 2 * 1 75? 25 C (3S) was dissolved , 4R> -4- (4-carbethoxy) benzyl-3-bromo-2-oxoazetidin-1-1-p-methoxybenzyl ether (15.2 g, 0.029 mol) in dichloromethane (40 ml), was cooled to -65o »and a solution of m-chloroperbenzoic acid (8.9 g» 0.029 mol) in dichloromethane (450 ml) was added dropwise with stirring for 20 minutes, the cooling bath was stirred and the mixture was stirred at room temperature. The solution was stirred with a mixture of saturated aqueous sodium sulfite and saturated sodium hydrogen carbonate, and the organic layer was separated, washed with water, dried (MgSO.sub.4) and evaporated to an oil. Hot ethyl acetate (60 ml) was added and after cooling in a freezer overnight, C (3S »4R) -4- (4-carbethoxy) enciulul fini 1-3-bromo-2- was crystallized. axaazetidin-li 1 lacetato of p-metax ibenci gives it a white solid as a mixture of 75? 25 diastereomers (2? 1) »9.94 g (63% yield). * H NMR of the main component? d (CDCl-,) 1.39 (3H * t * J = 7.1Hz * CH-.CH.gt * 3.80 (3H »0CH3) * 4.00-4.2 (3H» m * SOCH ^ + NCH ^), 4.3-4.4 ( 3H * » + NCH--) * 4.50,4.81 (each ÍH * d * J = 18 Hz * NCHj,) * 3.80 (5H * s »SCH-, + 0CH3) * 4.37 (2H * q * J = 7.1Hz * CHaCH3) * 4.61 * 4.91 (each 1H * d »J = 1.7 Hz * H3 + H ^), . 1 (2H, m, 0CHz) 6.88 (2H, m, 3.5- (4-CH30Ph) -H) »7» 26 (4H, m »2» 6- (4-CH30Ph) -H) »7.41 ( 2H »m» 2 »6- (4-C0a, Et (Ph ~ H) .8.00 (2h * M, 3» 5- (4-COSBEt) Ph-H).

F. (4R) -4- (4-carbethoxy) benzyl Isulfini l- -oxoazetidinyl-acetic acid of p-methoxy benzyl Diasterero ero 2 ü (3S, 4R) - - (4-carbethoxy) benci Isulfini 1-3- bromo-2-axoazet idin-1-yl p-m toxi-benzylacetate (8.75 g, 16.25 m oles) by heating in ethanol (400 ml), and a solution of sodium bicarbonate (4.0 g 48 mmoles) was added in water (40 ml). To the cloudy mixture was added Pd at 10% on charcoal (0.5 g), and the hot mixture (initial temperature of 40 ° C) was hydrogenated at 3.5150 kg / cmz at room temperature for two hours. More catalyst (1.0 g) was added, the mixture was heated to 35 aC, and hydrogenated as above for two hours. The mixture was filtered through hyflo and evaporated to give a mixture of toxibenzyl and ethyl p-m esters of the debrominated derivative as a brown oil. This was dissolved in ethanol (50 ml), cooled to 10 ° C and sodium hydroxide was added dropwise to IN (17 ml) for 10 minutes. The mixture was stirred at 10 ° C for 45 minutes, then most of the ethanol was evaporated and the residue was dissolved in dichloromethane and water. The layers were separated and the aqueous solution was washed with dichloromethane * then acidified with concentrated hydroric acid (2 ml) and extracted with dichloromethane. The extracts were dried (MgSO ^.) With the addition of carbon »were filtered through hyfla and evaporated to a black foam. This was dissolved in chloroform and refrigerated overnight. A small amount of solid was filtered and the filtrate was evaporated to a black oil which was solidified under ether to give the title compound as an off-white solid 3.77 g * (68% yield) (ratio of diastereomer 2 to diastereomer 1 94? 6). The chromatographic and spectral characteristics of this material identified it as the same compound prepared in Example 6h. * H NMR < 5 (DMSO) 1.32 (3H * t * J = 7H¡B * CH3), 2.99 (1H »m» H3) »3.33 (ÍH * m »H3) * 3.95 (1H, d, J = 18.2Hz * NCH2), 4.15 (2H, m, NCHaj + S0CHz) * 4.34 (3H »m * S0CHaí + C0S! .CH¡2) * 4.82 (lH, m * H ^)» 7. 51 (2H * d * J = 9.3HZ * Ph-H) * 7.97 (2 * d, J = 8.3Hz * Ph-H) to. acid C < 4R > -4- (4-carbethoxy) benzylsulfinyl-2-oxoazetidin-1-yl-laetic Diastere-2 Also acidic L (4R * SS) -4- (4-carbetaxy) benzylsulfinyl-2-axoazet idin-1- was prepared i Hacétics (Di stereomer 2) by the following procedure? C (3S * 4R) -4- (4-carbethoxy) benz Isulfini 1-3-bromo-2-axoazet idin-1-yl-p-metaxybenzyllacetate (Diastereomer 2? i 75? 25) (4.59 g) was dissolved * 8.52 mmole) in diclarometane (50 ml), cooled in an ice bath * and activated zinc powder (1.11 g »17.05 mmole) was added followed by glacial acetic acid (8 ml). After 1 hour * the mixture was diluted with dichloromethane-water * and the organic layer was washed with saturated aqueous NaHC03 and brine * and dried (MgSO ^) and evaporated to an oil »which was purified by flash chromatography (silica» ethyl acetate-petroleum ether) to give the title compound or an oil which solidified on standing. h. < +) - 4R »SS-N- (- (4-f1uoro eni l) hexi1) -4- (4-ethocarbaryl-benzylsulfinyl) -2-oxoazetidin-l-ylacetamide The treatment of C (4R) -4 acid - (4-carbethoxy) benz Isulfini 1-2-axoazet idin-1-yl lacético with 6- (p-fluorophenyl) he? I lamina under the conditions described for example 6i dio * after chromatography * the title compound with spectral and chromatographic characteristics identical to that prepared in example 6i. a0 25 ° C = +71.9 (c.1.0% w / v CHCl3 * 25 ° C).

EXAMPLE 9 (4R, 5S) -N- (6-C4-luorofeni 13hex-l-il) -4- < 4- (cyclohexloxycarboni loxime i loxycarbonyl) benz Isulfinyl) -2- oxoazetidin-l-yl) acetamide A solution of (4R * SS) -N- (6-C4-fluorophene LJhe? -l-yl) -4- (4-carboxybenzylsulfinyl) -2-oxoazetidi-1-yl) acetamide (see above * 4 g * 0.00819 moles) and carbonate of yadomethacrylamide (3.49 g * 0.0123 moles) in N-met i Ipirrol idinana (40 ml * drying on molecular sieves 4A) was treated with anhydrous potassium carbonate (1.7 g * 0.0123). moles), and stirred for 16 hours at room temperature. The mixture was diluted with water and extracted completely with ethyl acetate, and the combined extracts were washed with 5% aqueous sodium thiosulfate, dried (MgSO 4) and evaporated. The residue was purified by chromatography (silica). fine »ethyl acetate)» and the title compound was obtained as white crystals »mp 105-7 ° C after trituration with ether / light petroleum »4.16 g» 79% yield. * H NMR d (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 (lH, m) * 3.83 and 4.09 (each HH * d) * 4.15 and 4.35 (each HH * d) * 4.58 (lH * m) * 4.85 (lH, m) * 5.95 (2H, s) »7. 5 (2H» m) * 7.05 (2H, m) * 7.18 and 2H *) * 7.5 (2H * d) »7.98 (2H, d)» 8.11 (1H »bt). Found? C »61.6? H» .4? N »4.6%? C33H4iFNS! Oa required? C »61.5? H »6.4JN» 4.3% EXAMPLE ÍO < 4R, SS) -N- < 6-1.4 ~ fluarofenil3hex-l-il) -4- (4- < te? - buti loxica boni lo imeti lo ica bó 1) benci lsul finí l > -2- oxoazetidin-1-il) acetami da A solution of (4R »SS) -N- (6-C4-fluorophenyl-3hex-1-yl) -4- (4-carbaxibenzylsulfi) -2-axoazetidin-1-yl) acetamide (0.2 g» 0.00041 mol) and Iodomethoxide and 1-tert-butyl (0.49 g »0.001 mole) in N-methyl Ipyrrole and dinone (2 ml)» dried over Molecular sieves 4A) »was treated with anhydrous potassium carbonate (0.14 g» 0.001 mol) »and stirred for 16 hours at room temperature. The mixture was diluted with water and completely extracted with ethyl acetate * and the combined extracts were washed with aqueous sodium sulfite * dried (MgSO 4) and evaporated. The residue was crystallized by trituration with clear petroleum to give the title compound as white crystals * m.p. 102-4 ° C * 0.23 g * 92% yield. NMR »H d (DMSO) 1.25-1.52 (17M,) * 2.50 (2H * m), 3.06 (3H * m) * 3.35 (1H * m) * 3.84 and 4.09 (each HH * d) * 4.15 and 4.35 ( every 1H * d) * 4.86 (ÍH,) * 5.90 (2H * s), 7.06 (2H, m) »7.18 (2H») »7.53 (2H» d) »7.97 (2H * d)» 7.99 (1H, bt) found? C »60.1? H »6.3» N, 4.7%? C31H3?, FN- »0ßS requires? C, 60.20? H »6.4í N * EXAMPLE 11 (4R, SS) -N- (6-C4-Fluoro eni l 3hex-li l) -4- (4- (l- neti Icyclohexyloxycarboni loxymethyloxycarbonyl) benz lsu ini l) -2-oxoazetidin-1-i 1) acetami da A solution of < 4R * SS) -N- (6-E4-fluorofeni lhex-1-yl) -4- (4-carboxybenzylsulfinyl) -2- o? Oazeti din-i-yl) ketamide (0.2g * 0.0041 moles) and chloromethyl-1-methyl-1-cyclohexycarbonate (0.2 g, 0.01 mol) in N- and i-pyrrole idana (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 mole) and stirred for 16 hours at room temperature. The mixture was diluted with water and carefully extracted with ethyl acetate, and the combined extracts were washed with aqueous sodium thiosulfate, dried (MgSO 4) and evaporated. The residue was purified by flash chromatography (thin silica »ethyl acetate) and the material thus obtained was crystallized by trituration with ether to give the title compound as white crystals» m.p. 92-3 ° C ».11 g» 41% yield. NMR? 5 (DMSO) 1.25-1.48 (16H »)» 2.00 (2H »m> 2.5 (5H * m) * 3.07 (3H * m) * 3.36 (iH * m), 3.83 and 4.09 (each ÍH * d) * 4.15 and 4.35 (each 1H * d) »4.86 (1H» m) »5.91 (2H, s)» 7.06 (2H »m)» 7.18 (2H, m) »7.54 (2H» d) * 7.98 (2H, d) * 8.11 (ÍH, bt) EXAMPLE 12 < 4R, SS) -N - (? - C4-Fluorophenyl-3-hex-l-yl) -4- (4- (phenylcarbonylloxymethylloxycarbonyl) benzisulfinyl) - - oxoazetiin -l-yl) aceta i da A solution of (4R * SS) -N- (6-C4-fluorofeni 1) hex-l-i l > -4- (4-carboxy benzylsulfinyl) -2-oxoazetidin-1-yl) ace a ida (5g * 0.0102 moles) and benzyloxychloromethane (2.62 g * 0.0154 moles) in N-met i Ipirrol idona (50 ml * dried) on molecular sieves 4A) 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 hours at room temperature. The mixture diluted with water and carefully extracted with ethyl acetate, and the combined extracts were washed with aqueous sodium thiosulfate, dried (MgSO ^) and evaporated. The residue was purified by flash chromatography (thin silica »ethyl acetate) and the material thus obtained was crystallized by trituration with ether to give the title compound as white crystals * m.p. 117-9 ° C »4 g * 52% yield.

NMR? 5 (CDCl-,) 1.33 (4H * m), 1.5-1.62 (4H * m>, 2.56 (2H * t), 2. 95 * (1H * dd) * 3.22 (3H * m) * 3.94 and 4.20 (each HH, d) * 4.04 and 4.16 (each HH, d) »4.65 (HH, m)» 6.25 (2H »s)» 6.94 (3H »m)» 7. 11 (2H »)» 7.37 (2H, d) »7.46 (2H» m) »7.59 (HI, m), 8.1 (4H, m). Found? C, 63.7? H, 5.5? N, 4.5%; C = -3H3aFN-, 0.rS requires: C » 63. 7? H, 5.7? N, 4.5%.

EXAMPLE 13 (4R, SS) -N- < 6-C4-Fluaro-phenyl-3-hex-l-yl- 4- (4- (4-peroxy-phenyl-1-carbonyl-oxoxy-loxycarbonyl) -benzyl-1-yl) -2-oxoazetidin-1-yl) -acetamide A solution of (4R, SS) -N- (6-C4-fluorophenyl 3hex-1-yl) -4- (4-carboxybenzylsulfinyl) -2-a? Aazetidin-1-yl) acetamide (2 g, 0.0041 moles) and 4-methoxybenzoi chloride loximeti lo (2 g »0.01 mol) in N-methyl Ipyrrolidone (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 moles) and stirred for 16 hours at room temperature. The mixture was diluted with water and carefully extracted with ethyl acetate, and the combined extracts were washed with aqueous sodium thiosulfate, dried (MgSO, -) and evaporated. The residue was purified by flash chromatography (thin silica »ethyl acetate) and the material thus obtained was crystallized by trituration with ether, then recrystallized from dichloromethane / light petroleum * to give the title compound as white crystals * m.p. 115-S ° C »1.34 g * 50% yield. NMR * H d (DMSO) 1.23-1.6 (SH * m) * 2.50 22H * m > * 3.02-3.1 (3H * m) * 3.34 (1H, m), 3.8 and 4.09 (each 1H * d) * 3.84 (3H * s> 4.14 and 4.33 (each) »4.85 (IH» m ) »6.17 (2H» s> 7.05 (4H * m) * 7.16 (2H,) »7.52 (2H» d) »7.97 (4H * m > * 8.1 (1H * bt) EXAMPLE 14 < 4R »SS) -N- < 6-C4-riuorophenyl3hex-l-iI) -4- < 4- (isobu iri loxymethi loxycarbonyl) benz Isulfinyl) -2-oxoazetidin-1-yl > cetami da A solution of (4R * SS) -N- (6-C4-fluorofeni l 3hex-l-yl) -4- (4-carboxybenzylsulfinyl) -2-oxoazetidin-l-yl) acetamide (0.2 g * 0.00041 mol) and isobutyloxymethyl iodide (0.23 g »0.001 mol) in N-met i Ipirrol idona (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 room temperature ambient.

The mixture was diluted with water and carefully extracted with ethyl acetate * and the combined extracts were washed with aqueous sodium thiosulfate, dried (MgSO 4) and evaporated. The residue was purified by chromatography (thin silica »ethyl acetate) and the material thus obtained was crystallized by trituration with ether, to give the title compound as white crystals, m.p. 104-6 ° C * 0.14 g * 58% yield. NMR * H d (DMSO) 1.09 (6H, d) »1.25-1.52 (8H»), 2.50 (2H, m), 2.61 (H »m)» 2.97-3.06 (3H »m)» 3.34 (1H »m ) »3.83 and 4.09 (each HH» d) »4.15 and 4.34 (each 1H» d) »4.84 (1H» m) »5.95 (2H, s), 7.06 (2H,)» 7.16 (2H »)» 7.53 ( 2H »d), 7.97 I2H» d), 7.99 (iH »bt) EXAMPLE 15 < 4R, SS) -N- < 6-C4-Fluorophen-I hex-l-yl) -4- < 4- < 2-methoxyprop-2-lcarboni loxymethi loxycarbonyl l) benzyl sulfinyl) -2-oxoazetidin-1-iPacetamide A solution of (4R »SS) -N- (6-C4-fluorofeni l 3hex-l-yl) -4- (4-carbo ibenci lsulfinyl) -2-axoazetidin-l-yl) acetamide (3 g» 0.00614 moles ) and 2-metaxiprap-2-ylcarboni loxymethyl chloride (1.53 g »0.00921 moles) in N-m ti Ipirrol idona (30 ml» dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (1.27 g * 0.00921 moles) and potassium iodide (1.53 g * 0.00921 moles) and stirred for 16 h at room temperature. The mixture was diluted with water and carefully extracted with ethyl acetate, and the combined extracts were washed with aqueous sodium thiosulfate, dried (MgSO 4) and evaporated. The residue was purified by chromatography (fine silica * ethyl acetate) and the material thus obtained as a solution in ethyl acetate was washed additionally with aqueous sodium thiosulfate and then stirred for 10 minutes with SO 2 M and charcoal. discoloration. The solids were filtered and the filtrate was evaporated * and the residue was crystallized by trituration with ether / light oil to give the title compound as white crystals * m.p. 92.4 ° C * 2.6 g »68% yield. NMR lH d (CDCl3 >; 1.34 (4H * m) * 1.45 (6H * s) * 1.58 (4H,) 2.56 Í2H * t), 2.95 (1H, dd) * 3.17-3.37 (3H * m + 3H »s) * 3.96 and 4.10 (each ÍH * d> * 4.05 and 4.22 (every 1H * d) * 4.69 (ÍH * m) * 6.06 (2H * s) * 6.93 (3H * m) * 7.09 (2H,) »7.39 (2H * d) * 8.09 (2H * d).

EXAMPLE 16 < 4R * SS) -N- (6-L4-Fluorof or 13hex-l-yl) -4- (4- <(5-methyl 1-2-0X0-1,3-dioxolen-4-i Dmeti loxycarbonyl ) benci Isulfinil) -2-oxoazetidin-1- i 1) aceta ida A solution of (4R »SS) -N- (6-C4-fluarofeni l 3hex-l-yl) -4- (4-carboxybenzylsulfinyl) -2-oxoaz idin-i-yl) acetamide (5 g» 0.0102 moles) and 4-bromomethyl l-5-meth i ll »3-dioxol-2-one (2.96 g» 0.0154 mol) in N- and i Ipirral idona (50 ml »dried sap molecular sieves 4A) was treated with anhydrous potassium carbonate (2.12 g »0.0154 mol) and stirred for 16 at room temperature. The mixture was diluted with water and carefully extracted with ethyl acetate and the combined extracts were washed with water, brine, dried (MgSO 4) and evaporated. The residue was purified by chromatography (thin silica »ethyl acetate) and the material thus obtained was crystallized by trituration with ether / light petroleum to give the title compound as white crystals» m.p. 84-7 ° C »3.81 g» 62% yield. NMR lH d (CDCl3) 1.24-1.54 (8H * m) * 2.22 (3H, s) * 2.5 (2H *) * 2.95 (ÍH * dd) * 3.05 (2H *) * 3.33 (1H,) * 3.84 and 4.07 (each HH * d) * 4.15 and 4.32 (each HH, d) »4.85 (1H * m) * 5.22 (2H * s), 7.06 (2H * m) * 7.18 (2H *) * 7.51 (2H * d) »7.98 (2H» d) »8.1 (ÍH, bt) Found? C »59.7? H, 5.5? N »4.7%; C-jcH- ^ FN ^ OßS required? C, 60.0? H, 5.5? N »4.7% EXAMPLE 17 < 4R, SS) -N- (6-C4-Fluoro-enyl-3-hex-li-1) -4- (4- ((2-methoxycarbonyl-1-E-but-2-en-yl) methyl-chloro-benzyl) benz-Isulfini 1) -2- oxoazetidin-1- il) acetami A solution of (4R »SS) -N- (6-EL4-fl uoropheni 13hex-1-l) -4- (4-car a i-encylsulfinyl-l) -2-oxoazetidin-1-l) acetamide (0.195 g »0.0004 mol) and E-2-bramaet i lbut-2-enoata de methyl (0.16 g »0.0008 mol) in N-meti Ipirrol idona (2 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (0.11 g, 0.0008 mol) and stirred for 16 at room temperature. The mixture was diluted with water and carefully extracted with ethyl acetate, and the combined extracts were dried (MgSO, -) and evaporated. The residue was purified by chromatography (fine silica, ethyl acetate) and the material thus obtained was crietalized by trituration with ether to give the title compound as micro or white, 0.024 g, 10% yield. NMR * H (CDCl3) 1.25-1.63 (8H, m>, 1.99 (3H * d), 2.56 (2H, t), 2.93 (HI, dd) * 3.17-3.36 (3H *) * 3.79 (3H, s) ), 3.93 and 4.17 (each ÍH d), 3.43 and 4.23 (each 1H, d) * 4.64 (1H, m) * 5.12 (2H * s) * 6.91-7.26 (6H * m) * 7.34 (2H * d) * 8.04 (2H * d) 5 EXAMPLE 18 (4R, SS) -N- < 6-C4-Fluoro-enyl-hex-l-yl) -4- (4- (NN-dimethylaminocarbonylmethylcarbonyl) benzylsil inyl) - 2- oxoazeti in-1-i 1) aceta ida? 0 A solution of (4R * SS) -N- (6-E4-fluorofeni l hex-1-yl) -4- (4-carba ibenzylsulfinil) -2- oxaazetidin-1-yl) ketamide (0.2 g, 0.0004 mole) and a-chloro-N, -d -methyl acetamide (0.17 g »0.001 mole) in N-methi Ipirrol idona (2 ml * dried over molecular sieves 4A) was treated with anhydrous potassium carbonate (0.14 g »0.001 mole) and stirred for 16 h at room temperature.

The mixture was diluted with water and carefully extracted with ethyl acetate, and the combined extracts were dried (MgSO 4) and evaporated. The residue was crystallized by trituration with ether to give the title compound as white crystals * m.p. 141-4aC »0.01 g. NMR * H d (CDCl3) 1.25-1.75 (8H »m> 2" 56 (2H * t) »2.93 (1H, dd) * 2.99 (3H * s) * 3.04 (3H * s) * 3.17-3.36 (3H, m), 3.85-4.25 (4H * 4 xd) »4.65 (1H» m) »4.97 (2H» e), 6.93 (2H, m) »7.10 (3H» m) »7.36 (2H * d) * 8.13 (2H * d).

EXAMPLE 19 < 4R, SS) -N - (»- C4-Fluorophenyl3hex-1-yl) -4- < 4- < N-di- < 2- hi roxietil) aPiinocarboxini Imeti loxicarbonil) benci Isulfinil) -2- oxoazetidin-1-yl) cetamide To a solution of N * N- (1 * i-dihydroxyethyl) -bromaacetamide (1.20 g * 5.3 mmol) in DMF (10 ml) was added (4R »SS) -N- (6-C4-fluorofeni l 3hex -li I) -4- (4-carbsxybenzl-sulfini 1) -2-oxoazetidin-1-yl) acetamide (1.00 g »2.05 mmol) followed by cesium carbonate (1.3 g» 4.0 mmol). The mixture was stirred for 18 hours and then separated between ethyl acetate and 2M hydrochloric acid. The separation of the organic materials followed by the washing with brine, drying (MgSO 4) and concentration, provided the crude product as a white solid. The solids were washed with chloroform, filtered and dried to produce the product as a white solid (0.97. g, 75% p.f. 119-121 ° C. NMR * H d (DMSO, ^) 1.28-1.55 (m »8H), 2.5 (t, J = 12H» 2H), 2.8 (br d, J = 16Hz »1H)» 3.1 (q * J = 10Hz * 2H ) * 3.3-3.7 (m * 9H) * 3.9 (d * J == 27Hz * 1H), 4.1 (d * J = 27Hz * ÍH) »4.15 (d, J = 20Hz * ÍH) * 4.35 (d * J) = 20Hz * 1H) * 4.7 (br »1H) * 4.85 (m * 1H>» 4.95 (br * 1H) »5.2 (s * 2H) * 7.0 (apparent t * J = 14Hz * 2H)» 7.15 (dd) »J = 14» 9 Hz »2H), 7.5 (d * J = 13Hz * 2H), 8.05 (d * J = 13Hz, 2H) * 8.2 (t, J = 8Hz * 1H) EXAMPLE 20 Enantiomers of (R »S / S, R) -l- (2- (6-chlorophenyl) -hexyloxy) eti 1-4- (4-alkoxycarbonyl-1-benz-Isul-inyl) -2-oxoazetidine to. 6- (4- luorophenyl) hexy loxy ethanol Ethylene glycol (41.26 g) and bromide 6- were added. (4-fluorophenyl) hexylo (17.22 g) was added to a solution of sodium hydroxide (2.79 g) in water (2.5 ml) and the mixture was heated at 110 ° C for 24 hours. The mixture was cooled and partitioned between water (150 ml) and diethyl ether (150 ml). The layers were separated and the organic layer was washed with water, brine was dried (MgSO 4) and evaporated to an orange oil. . Purification by column chromatography on silica gel eluted with E5? 13 to El? 13 P.E 40-6O ° C? ethyl acetate gave the product as an orange oil (9.91 g * 62%). b. 6- (4-Fluorophenyl) hexyloxy triflate 6- (4-Fluorophenyl) hexy loxy ethanol (4.0 g) * pyridine (1.43 g) and DMAP (40 mg) were dissolved in dry dichloromethane (30 ml) * cooled to -10 ° C and triflic anhydride (5.6 g) in dry dichloromethane (10 ml) was added over 5 minutes keeping the temperature below 0 ° C. The mixture was stirred at -10 ° C-0 ° C for 60 minutes and then washed with water (50 ml> * brine (50 ml) »dried (MgSO 4) and evaporated to a brown oil (6.17 g * 99%). c. 1- (- (6-Fluorophenyl) hexyloxy) ethyl-4- (4-alloxycarbonylbenzylthio) -2-oxoazetidine A solution of 6- (4-fluoro-phenyl) hexyloxy triflate (7. g) * 4 - (4-ali loxycarbonylbenzyl thio) azetidin-2-one (5.08 g) and tetrabutylammonium bromide (0.59 g) in dry THF (150 ml) was cooled to 15 ° C under nitrogen and treated with potassium hydroxide in powder (1.08 g). The cooling bath was removed and the reaction was stirred for 30 minutes. KOH powder (50 mg) was added and the reaction was stirred at room temperature for 30 minutes. The mixture was filtered through celite and washed with ethyl acetate (100 ml). The filtrate was evaporated to a dark oil and purification by column chromatography by vaporization on silica gel eluted with E3? 23 to El? 13 P.E. 40-60 ° C? ethyl acetate gave the title product as an orange oil (4.65g * 51%).

NMR? d (CDCl3 1.3-1.6 (8H * m * 4xCHa »> 2.55 (2H * t * J« 7. 6Hz * CH-2ph) »2.85» 2.90 (1H »dd» H3) »3.05 (1H * m, 1H), 3.26» 3.32 (IH * dd * J = 4.9 * 15.1Hz »H3)» 3.37-3.68 (5H * m »NCH ^ CHa-» 3.86 (2H »s» SCH ^), 4.76 (1H, »H.-.)» 4.81 (sH, »COseCHjg» 5.36 (eH *, CH = H ^ »6.03 (1H * »CH = CR-») »6.94 (2H, m» p-FPh-H) »7.07 (2H *, p ~ FPh - H) * 7.39 (2H, d * J = 8.3Hz» Ph-H) » 8.01 (2H »d, J = 8.3Hz» Ph-H). d. (R, S / S, R) -l- (2- (6-Fluorophenyl) hexyloxy) ethyl-4- (4-allyloxycarbonylbepcylsulfinyl) -2-oxoazetidine (diast.2) A solution of 1- (2%) -fluorophenyl) hexi loxi) eti 1-4- (4-alloxycarbonyl benzylthio) -2-oxoazetidine (4.58g) in dichloromethane (100 ml) »cooled to -70 ° C was treated with a solution of mcpba (2.0 g) in CHCl 3 (125 ml) by dripping for 1 hour keeping the temperature below -70 ° C. The cooling bath was removed and the reaction was stirred for 1.5 hours, washed with an aqueous solution of 10% sodium hydrogen carbonate (150 ml) + 10% aqueous sodium eulphite (150 ml). The layers were separated and the organic layer was washed with brine, dried (MgSO 4) and evaporated to an oil which solidified on standing. Repeated recrystallizations from diethyl ether (3 times) gave diastereoisomer 2 as a colorless solid (0.8 g »12.2%) mp 73-74 ° C. NMR? < 5 (CDCl3) 1.3-1.6 (8H »» 4xCHE »)» 2.56 (2H »t» J -7.8Hz »CHzPh)» 2.66 »2.69 (ΔH» dd »J = 2.14.8Hz, H-,)» 3.38- 3.68 (7H »m» H3 * NCH ^ CHa »0CHz), 4.07 (2H, s» SOa-L ,,) »4.54 (OH, m» H-) »4.83 (2H * CO ^ CH-X» 5.36 ( 2H »m» CH = CH ".) 6.03 (1H» m » CH "CHa) * 6.94 (2H,» p-FPh-H), 7.10 (2H, »p-FPh-H)» 7.38 (2H, d * J = 8.4Hz * Ph-H) * 8.08 (2H * m , Ph-H). and. < , R / S, S) - < 2- (6-F1 uoropheni 1) hexi lox) et i 1-4- (4-allyloxycarbonylbenzylsulfini l) -2-oxoazetidine (diast.1) A sample of diastereoisomer 1 (containing 21% of dia2) was obtained as a colorless oil * pf 46-50 ° C. NMR * H < 5 (CDCl3) 1.3-1.6 (8H * m * 4 CH-B *) * 2.55 (2H * t J = 8Hz, CHaPh> 2.66 * 2.69 (1H * dd »J = 4.8, 14.8Hz * H3), 3.38-3.68 (7H * m * H3 * CH ^ CH ^ * OCH ^,) * 3.94 (2H, m * SOCH ^) * 4.55 (1H * m, H ^, 4.83 (2h »CO ^ CH ^)» 5.36 (2H »m» CH = CH-,) »6.94 (2H * m, p-FPh-H), 7.10 (2H * m * p-FPh-H), 7.38 (2H, d * J = 8.4Hz, Ph -H) * 8.08 (2H * * Ph-H) Enantiomers of (R * S / S * R) -l- (2- (6-fluorofeni l> hexi lo i) ti 1-4- (4- li loxycarboni l benz Isulfinil) -2-oxoazetidine were separated by HPLC on a Chiracel OD-20MM eluted with 60-40 hexane ethanol. . (+) -! - (2- (6-Fluoropheni Ihexi loxi) eti 1-4- (4-allyloxycarbonyl Ibenzylsulfinyl) -2-oxo-getine (diast.2) 164 mg »colorless solid Pf 52-53 ° C, iammerically pure, E «30 = + 57.5 ° (c = 0.5% w / v in ethanol at 25 ° C) NMR lH d (CDCl3) 1.3-1.6 (8H», 4x0 - ^ * * 2.56 Í2H »t »J - 7.8Hz» CH-.Ph), 2.66 »2.69 (IH» dd »J = 2.14.8Hz * H3) * 3.38-3.68 (7H * m, H3 * NCH ^ -CHa * OCH ^.) * 4.07 (2H * s * S0CH.J.) * 4.54 (H »» H ^ »4.83 (2H» m »CO ^ CH ^, 5.36 (2H, m» CH = CH.-.) »6.03 I1H = CH.-.)» 6.94 (2H * * p-FPh- H) * 7.10 (2H * »p-FPh-H)» 7.38 (2H, d »J-8.4Hz» Ph-H) »8.08 (2H» m, Ph-H). g. (-) i- (2- (6-Fluoropheni 1 (hexyloxy) eti 1-4- < 4- li loxycarbon Ibencylsulfinyl) - -oxoaz tidine (diast.2) 170 mg »colorless solid Pf 51 -53 ° C 99.69% of the desired diastereomer with 0.31% of the other enantiomer present Ea30 - -57.9 ° C (c - 0.4% w / v in ethanol at 25 ° C) NMR? D (CDCl3) 1.3-1.6 (SH » m »4XCK-.»), 2.56 (2H »t, J = 7.8Hz» CH-sPh »2.66, 2.69 (ÍH» dd, J - 2 »14.8Hz» H3), 3.38-3.68 (7H, m, H3 , NCH- »CH1S? * OCH ^)» 4.07 (2H * s * S0CH2) »4.54 (1H * * H ^» 4.83 (2H * CO ^ CH ^ r 5.36 (2H * m * CH = CH.,.) * 6.03 (1H * m * CH = CH ^), 6.94 (2H, m, p ~ lFPh-H), 7.10 (2H, m, p-FPh-H), 7.38 (2H, d, J = 8.4Hz, Ph-H), 8.08 (2H, »Ph-H).

EXAMPLE 21 (R, S / S, R) -l- (2- <6-Fluorof nyl) hexyloxy) ethyl-4- (4-carboni-1-benz-Isulfinyl) -2-oxoazetidine (diast.2) (R »S / S» R) -l- (2- (6-Fluorophenyl) hexyloxy) ethyl-4- (4-allylcarbonyl benzyl Isulfinyl) -oxoazetyl a (220 mg) »triphenylphosphine (11) mg) »tetrakisi tripheni Ifosphine) palladium (O) (15 mg) in dry CH-.Cl.5- (5ml) under nitrogen was treated with pyrrolidine (37μl) and the mixture was stirred at room temperature for 19 hours. Purification by column chromatography by evaporation on silica gel eluted with an elution gradient CHS.sub.2 Cl.sub.2 - »? Aceon? Ci or acetic gave the product as an oil. The oil was dissolved in CH ^Cl-j, (4ml) and diluted with diethyl ether (75ml), washed with water, brine, dried (MgSO ^), filtered and evaporated to an oil that solidified. after cooling Trituration with diethyl ether gave the product as a cream solid 155 mg, 78%) m.p. 95-96 ° C. NMR * H d (CDCl3) 1.25-1.6 (8H, m * 4XCH.J. »)» 2.56 (2H * t * J = 7.6Hz * CHs.Ph * 2.69 * 2.76 * (ÍH, dd, J = 2.1 * 15.1Hz, H-,), 3.10 * 3.17 (IH * dd * J = 5.1 Hz) * 3.37-3.74 (6H * m, NCHa.CH-2 * 0CHa), 4.11 (2H * s * SOC j.) * 4.64 (ΔH * »H ^ * 6.94 (2H» m »p-FPh-H), 7.1O (2H,, p-FPh-H)» 7.41 (2H »d» J = 8Hz »Ph-H)» 8.07 (2H »d» J = SHz »Ph-H).

EXAMPLE 22 (-) - i- < 6-Fluoropheni 1) hexyloxy) ethyl-4- (4-carboxybenzyl Isulfinyl-2-oxoazetine ina (diast.2) (-) -1- (2- (6-Fluoropheyl) hexylaxy) eti l-4- (4- li-laxycarbonyl Ibenzylsulfinyl) -2-oxoazetidine (145 mg) »triphenicum fasphine (7.3 mg)» tetrakis (Ifosphin triphenyl) palladium (0) (10.5mg) in CH-.CI.-dry (4 ml) under nitrogen was treated with pyrrolidine (23.5μl) and the mixture was stirred at room temperature for 6 hours. Pyrrolidine (5μl) was added and the The reaction was stirred at room temperature for 19 hours. Purification by column chromatography by evaporation on silica gel eluted with a gradient of CUjaClj., acetone? Acetic acid gave the title compound as an oil. Trituration with diethyl ether gave the common cream colored solid product (113 mg »85%) m.p. 123-124 ° C * Ctx3D = -53.5 ° (c = 0.5% p / v in ethanal at 25 ° C) NMR * H 6 (DMSO) 1.25-1.6 (8H, m * 4 CH-J *), 2.50 ( 2H, t, CH-2Ph) »2.91, 2.95 (1H, úd r J = 2.15.2Hz) * H3) * 3.22-3.53 (7H * m * H3, NCH-.CH -, * QCH-j)» 4.16 * 4.31 (each ÍH * 2xd * J = OHz * SOCH ^) * 4.73 (ÍH, m * H ^.), 7.0 (2H »m» p-FPh-H) »7.19 (2H», p-FPh-H >; »7.48 (2H, d» J = 8Hz »Ph-H), 7.94 (2H, d, J = 8Hz, Ph-H) EXAMPLE 23 (+) - l- (2- (6-Fluorophenyl) hexyloxy) ethyl-4- < 4- carbonylbenzylsulfinyl) -2-oxoazetidipa (diast.2) (+) -! - (2- (6-Fluarofeni l) hexylaxy) ti 1-4- (4-alloxycarboni Ibenzylsulfini l> -2-oxoaze idine (140 mg) »tripheni Ifosfin (7 mg), tetrakisí trifosine Ifosphine) palladium (0) (10 mg) in CH-jCl-j, dry (4ml) under nitrogen was treated with pyrrolidine (23.5μl) and the mixture was stirred at room temperature for 19 hours. An additional 1.5 mg of catalyst and pyrrolidine (5 μl) was added and the reaction was stirred for 2 hours, diluted with water (25 ml) and CH ^ Cl-, (25 ml) and acidified to Hj, with HCl (2N) . The layers were separated and the aqueous layer was washed with CH-gCl.-, (25 ml). The organic extracts were combined, dried (MgSO 4) and evaporated to a yellow oil. Purification by column chromatography by evaporation on silica gel eluted with a gradient elution of CH.sub.2 Cl.sub.2 acetone.acetic acid gave product as an oil. Trituration with diethyl ether gave the product as a colorless solid (109 mg »84%) m.p. 118 ~ 120 ° C, rt ^ - + 50.0 ° (c = 0.5% w / v in ethanol at 25 ° C) NMR * H d (DMSO) 1.25-1.6 (8H * m * 4xCH -.,) * 2.50 ( 2H, t, CR- »Ph), 2.91 * 2.95 (1H * dd * J = 2» 15.2Hz, H3> 3.22-3.53 (7H, m »H3» NCH ^ aL -. * OCH ^) * 4.16 * 4.31 (each 1H »2xd» J = OHz »S0H-,)» 4.73 (1H * m * H *) * 7.0 (2H * m * p-FPh-H) * 7.19 (2H, m * p-FPh- H) * 7.48 (2H * d * J = 8Hz * Ph-H) * 7.94 (2H * d * J = 8Hz * Ph-H) EXAMPLE 24 Enantiomers of (R, S / S, R) -l- (2- (6-Chloraphenyl) hexyloxy) ethyl-4- (4-allyloxy-arbonylbenz-Isulfini-1) -oxoazetidine to. 6- (4-Chlorophenyl) exi loxy ethanol Ethylene glycol (Sl.lg) and 6- (4-chlorophenyl) hexylo bromide (22.7g) were added to a sodium hydroxide solution (3.46 g) in water (3.1 ml. ) and the mixture was heated at 110 ° C for 24 hours. The mixture was cooled and partitioned between water (300 ml) and diethyl ether (300 ml). The layers were separated and the aqueous layer was washed with ether (150 ml). The organic layers were combined and washed with water, brine, dried (MgSO 4) and they evaporated to a yellow oil. Purification by column chromatography on silica gel eluted with E3? 13 to E2? 13 P.E 40-60 ° C? Ethyl acetate gave the product as a yellow oil (14.13g »67%). b. 6- (4-Chlorophene) l) hexi loti triflate 6- (4-Chlorophene) l) hexyloxy ethanol (7.6 g) »pyridine (2.53 g) and DMAP (79 mg) were dissolved in dry dichloromethane (60 ml)» cooled at -10 ° C »and triflic anhydride (10Og) in dry dichloromethane (20 ml) was added over 7 minutes keeping the temperature low of 0 ° C. The mixture was stirred at 0 ° C for 45 minutes »washed with water (60 ml)» brine (60 ml>) dried (mgS0) and evaporated to a dark oil (11.13 g »97%). c. (2 ~ (6-Clarophenyl) hexyloxy) eti 1-4- (4-ali loxycarbonyl 1-benzyl thio) -2-oxoazetidine A solution of 6- (4-chlorophenyl) hexyloxy triflate (11.1 g) » 4- (4-al i laxicarbani Ibencil tio)) azet idin-2-one (7.69 g) and tetrabutylammonium bromide (0.89 g) in dry THF (200 ml) was cooled to -10 ° C under nitrogen and treated with powdered potassium hydroxide (1.63 g). The cooling bath was removed and the reaction was stirred for 40 minutes. KOH powder (163 mg) was added and the reaction was stirred at room temperature for 1.5 h * and partitioned between brine (60O ml) and ethyl acetate (400 ml). The mixture was filtered through hy-flo and the layers were they separated. The organic layer was dried (MsSO ^.> And evaporated to a dark oil.) Purification by column chromatography by steaming on silica gel eluted with C2? 13 to Cl? 13 PE 40-60? C? Ethyl acetate gave the product as an orange oil (7.28 g * 51%). NMR * H < 5 (CDCl3) 1.3-1.6 (8H * m * 4xCHa ...) »2.55 (2H, t * J = 7.6Hz, CH2Ph) , 2.85, 2.90 (HH, dd, H3), 3.05 (HH, m, 1H), 3.26, 3.32 (1H, dd, J OCHs.), 3.86 (2H, s, SCH-,), 4.76 (ÍH, m, ^) * 4.81 (2H, m COaCH ^), 5.36 (2H * m, CH = CH-,) 6.03 (ÍH , m, CH = CH2) 7.07 (2H, d * J = 8.4Hz * p-ClPh-H), 7.23 (2H * m * p-ClPh-H), 7.39 (2H »d» J = 8.3Hz »Ph -H), 8.01 (2H * d, J - 8.3Hz, Ph-H) d. (R, S / S, R) -l- (2- <6-Chlorophenyl) hexyloxy) ethyl-4- (4-allyloxycarbonylbenzylsulfinyl) -oxoazetidine A solution of l- (2- (6-chlorophenyl) ) hexi loxi) eti 1-4- (4- li loxycarboni lbenci l thio) -2-axaazetidine (7.2 g) in dichloromethane (175 ml> * cooled to -70 ° C) was treated with a mcpba solution (3.0 g) in CH-.CI-, (175 ml) per dropper for 1 hour keeping the temperature below -70 ° C. The cooling bath was removed and the reaction was stirred for 1.5 hours and washed with an aqueous solution. of 10% sodium hydrogen carbonate (200 ml) + 10% aqueous sodium sulfite (200 ml) The layers were separated and the organic layer was washed with brine, dried (MgSO 4) and evaporated to a oil that solidified with rest, repeated recrystallizations from diethyl ether (4 times) gave diastereomer 2 as a colorless solid (O. g, 12.2%). NMR * H c5 (CDCl3) 1.3-1.6 (8H, m »4xCHa,> 2.56 (2H * t J -7.8Hz * CHs-Ph) * 2.66 * 2.69 (lh * dd» J = 2.4 »15.2Hz» H3) »3.07» 3.11 (1H, dd, J = 4.8, 15"2Hz» H3) * 3..37-3.6S (6H, * CH ^ CH-a, OCHjg, 4.07 (2H, s, SOCH ^) , 4.54 (1H * m * H ^) * 4.83 (2H * m »COsaCRj,» 5.36 (2H »m, CH« CH ^) 6.03 (1H, m, CH = CH ^) 7.09 (2H, d, J ~ 8.8Hz, p-ClPh-H), 7.23 (2H, d, J = 8.8Hz * p-ClPLh-H), 7.39 (2H, d, J = 8.4Hz, Ph-H) * 8.07 (2H * m * Ph-H) The previous demineral compound was separated by CLAR on a C iracel 0D-20mm eluted with 80? 20 ethanol? Hexane to give the enantiomers? and. (+) -! - (2- (6-Chlorophenyl) exoxy) ethyl-4- (4-allyloxy-carbonyl-1-benzyl-sulfinyl) -2-oxoazetidine 83 mg * colorless solid. P.f. 57-59 ° C 99.95% of the desired enantiomer with 0.05% of the other enantiomer present. txl ^ = + 52.2 ° (c = 0.28% p / v in ethanol at 25 ° C) NMR? d (CDCl3) 1.3-1.6 (8H * m * 4XCH.3. »)» 2.56 (2H »t» J = 7 »8Hz» CHs-Ph) »2.66 * 2.69 (1H * dd * J = 2.4 * 15.2Hz , H3) * 3.07 * 3.11 (1H * dú r J - 4.8 * 15.2Hz * H3) * 3.37-3.68 (6H, m * NCH ^ CH ^, * 0CHs) * 4.07 (2H * s * S0CH2) * 4.54 ( ÍH * m * H ^ * 4.83 (2H, »CO ^ CH ^.), 5.36 (2H * m * CH = CH ^) 6.03 (ÍH * m * CH = CH--) 7.09 (2H * d, J = 8.8Hz * p-Cl hH) * 7.23 (2H * d * J = 8.8Hz * p-ClPh-H) * 7.39 (2H * d, J = 8.4Hz, Ph-H) - (-) - l- (2- (6-Chloroenyl) hexyloxy) eti 1-4- (4-allyloxycarboni Ibenzylsul inyl) -2-oxoazetidine 103 mg * colorless solid. P.f. 58-59 ° C 99.62% of the desired enantiomer with 0.38% of the other enantiomer present. E «3D = + 61.9 ° (c - 0.06% w / v in ethanol at 25 ° C) NMR * H 5 (CDCl 3) 1.2-1.6 (8H, m * 4xCH2 * >, 2.56 (2H, t * J = 7.8Hz * CH2Ph), 2.66, 2.69 (ÍH, dd, J = 2.4, 15.2Hz, H3), 3.07 * 3.11 (1H, dd * J = 4.8 15.2Hz * H3), 3.37-3.68 (6H * m * N iH-j.) * 3.37-3.68 (6H * »NCH ^ CHa. * 0CH -, * 4.07 (2H * s * SOCH ^), 4.54 (1H,, H, 4.83 (2H,, COßCHß), 5.36 (2H * * CH = CHβ) 6.03 (HH * m * CH = 1) 6.03 (1H, m * CH = CH-.) 7.09 (2H, d, J = 8.8Hz, p-ClPh-H) * 7.23 (2H * d * J = S.dhZ * p-C1 Ph-H), 7.39 (2H, d, J = 8.4Hz, Ph-H), 8.07 (2H,, Ph-H) EXAMPLE 25 (-) - l- (2- (6-Chlorofonyl) hexyloxy) eti 1-4-C-4-carboxybenzyl Isulfinyl) -2-oxoazedine (diast.2) (-) - l- (2- (6-Chlorophenyl) exoxy) ethyl-4- (4-al loxi-carbani Ibenci Isulfinil) -2-o? oaz tidine (86.2 mg) »triphenylphosphine (4.2 mg) > tetrakis (tri-pheni Ifosphine) palladium (0) (6 mg) in CHj.Cl- ,. Dry (2 ml) under nitrogen was treated with pyrrolidine (13.5μl) and the mixture was stirred at room temperature for 19 hours. Purification by column chromatography by vaporization on silica gel eluted with an elution with gradient of CH 2 Cl 2, acetone, acetic acid of the product as an oil. Trituration with diethyl ether gave the title compound as a cream colar solid (59.8nmg, 75%) m.p. 102-102 ° C »E« 30 = 37.32 ° ic = 0.209% w / v in ethanol at 25 ° C) NMR * H d (CDCl 3) 1.25-1.6 (SH »m» 4xCHa! »)» 2.56 (2H, t, J »7.6Hz, CHßPh)» 2.71 »2.74 (HH» dd »J = 2.15Hz, H3), 3.12, 3.15 (HH * dd * J = 5.2 * 15Hz * H3) * 3.38-3.72 (6H * m , NCH ^ CHa., OCH ^), 1H3), 4.09 (2H * m * SOCHj-, 4.60 (1H * m * H4), 7.09 (2H * d * J = 8.8Hz * p-ClPh-H) 7.22 ( 2H * d * J = 8.8Hz, p-ClPh-H) 7.40 (2H * d * J - 8Hz * Ph-H) * 8. S (2H * d, J = 8Hz * Ph-H) EXAMPLE 26 (+) - l- (2- (6-Chlorophenylhexyloxy) ethyl-4- < 4- carboxybenzilsulfinyl) - - oxoazedine (diast. (+) - i ~ (2- (6-Clarophenyl) hexylaxy) ethyl-4- (4-ali lo-i-carboni Ibencylsulfinyl) -2-oxoazedine (65.6 mg) * triphenylphosphine (3.2 mg) * tetrakisí tripheni Ifosfine) palladium (O) (4.6 mg) in dry CHjj.Cl-2 (2 ml) under nitrogen was treated with pyrrolidine (10.3μl) and the mixture was stirred at room temperature for 19 hours. Purification by column chromatography by evaporation on silica gel eluted with a gradient of CH 2 Cl 2 acetone? Acetic acid gave the product as an oil. The azeotropic distillation with water and acetone followed by trituration with diethyl ether gave the product as a solid cream (44.7 mg, 73%) m.p. 104-105 ° C * Eocl0 - + 51.92 ° (c = 0.208% w / v in ethanol at 25 ° C) RMN lH < 3 (CDCl3) 1.25-1.6 (8H * m, XCH-2 *), 2.56 (2H, t, J -7.6Hz * CH ^ Ph) * 2.71 * 2.74 (1H, dd »J = 2.15Hz, H3)» 3.12 »3.15 (1H, dd * J = 5.2 * 15Hz * H3), 3.38-3.72 (6H * m, NCH ^ CH-a, OCH ^), 1H3), 4.09 (2H * m * SOCH ^), 4.60 ( 1H *, H ^), 7.09 (2H * d, J = 8.8Hz, p-ClPh-H) 7.22 (2H * d * J = 8.8Hz * p-ClPh-H) 7.40 (2H * d, J = 8Hz * Ph-H) * 8.OS (2H * d * J = 8Hz, Ph-H) EXAMPLE 27 Cot-S, 4-R, S-S) -N-C6- (4-Fluorophenyl-hexyl-2-C <4- to iloxycarbonyl-benzylisulfinyl-3-2-oxoazetidine-1-yl-1-propionamide to. 4-C (4-A1 i loxycarboni 1) benzyl thio-2-oxo-azetidin-l-ylacetate of R-methyl A suspension of acid R-4-E (4- ali loxycarbonyl) benzyl thio3-2- axaazetidin-li lactic (from the example if * 21.55 g) and anhydrous potassium carbonate (8.88 g) in 1-methyl-2-pyrrole idinone (100 ml) was treated with methyl iodide (10.94 g) and the mixture stirred for 2 hours. Methyl iodide (1.0 g) was added and after 30 minutes the reaction was partitioned between brine (500 ml) and diethyl ether (500 ml). The layers were separated and the aqueous layer was washed with diethyl ether (500 ml). The organic extracts were combined and washed with water (x2) * brine * dried (MgSO ^) and evaporated haeta an orange oil. Purification by column chromatography by evaporation on silica gel eluted with El? 13 PE 40-60 ° C Ethyl acetate gave the title compound as a yellow oil (contains 2% dimethyl ester) (20. Og, 89%). NMR * H 5 (CDCl 3) 2.94 3.01 (1H * dd * J = 2.1 * 15.2Hz, H3>, 3.25 (1H, d * J = 18Hz, 1 of NCHj-X, 3.39, 3.45 (1H * dd, J = 5.1 * 15.2Hz, H3), 3.70 (3H * s »CH3), 3.81 (2H, s, SCH ^)» 4.04 (ÍH, d, J = 18Hz * 1 of NCHa.) * 4.83 (2H, m » »4.93 (ÍH,, 4H), 5.35 (2H * m * CH = CH ^,) * 6.04 (ÍH * m * CH = CH ^) * 7.39 (2H d * J = 8Hz, Ph-H)» 8.02 ( 2H »d, J = SHz, Ph-H) b. 2-C4-C (4-1-yloxy-boni-1) benzl 11-23-oxoazetidin-1-yl 13-propionate of -R, 4-R- and yl 2-C4-C (4- al loxycarbonyl) benzyl thio3-2 -oxoaz tidin-l-il propianata de «- S, 4-R-methyl A solution of 4-C (4-alloxycarboni 1) benz 1 thio3-2-axoazet idin-1-i R-methyl lacetate ( 13.2 g) in dry tetrahydrofuran (250 ml) at -75 ° C under nitrogen was treated with a 1M solution of lithium amide bis (trimethyl isiil) in THF (46.3 ml) for 10 minutes keeping the temperature below - 70 ° C. 1,3-dimethyl imidazole idin-2-ana (30.5 ml) was added maintaining the temperature below -70 ° C. The resulting suspension was stirred at -75 ° C for 30 minutes and then treated with methyl iodide (4.3 ml) for 1 minute and the temperature was raised to -68 ° C. The reaction was stirred for 1.5 hours at -75 ° C and then allowed to warm to -20 ° C for 30 minutes. The reaction was cooled to -75 ° C and quenched with glacial acetic acid (3.5 ml), partitioned between water (300 ml) and diethyl ether (250 ml). The layers were separated and the aqueous layer was washed with diethyl ether (250 ml). The organic extracts were combined, washed with brine (x3), dried (MgSO4) and evaporated to a colored oil. Ratio of 50% R, R (diaA)? 15% starting material? 35% of S, R (day B). Repeated purification by column chromatography by evaporation on silica gel eluted with P.E. 40-60 ° C? Ethyl acetate gave the co-products or oils with color. R * R Diastereoisomer (A) * 3.91 g (29%) (contains 9% day B). NMR * H 5 (CDCl 3) 2.9 (1H * dd, H3) * 3.30 (1H * H3) * 3.75 (3H * s, CH3), 3.88 (2H * s * SCHS) * 4.4 (IH * m * CH) * 4.83 (2H * m, CO ^ CH ^), 4.90 (2H * m * 4H) * 5.35 (2H * m * CH = CH2), 6.04 (IH * m * CH = CHS) * 7.40 (2H d * J = THz * Ph-H) * 8.02 (2H, d * J = 8Hz * Ph-H) R * R Diastereoieómero (B) * 5.36 g (39%) (contains cirto em and 43% of day A). NMR? <; 5 (CDCl3) 2.76 »2.92 (ÍH * dd * J = 24 * 15.2Hz * H3) * 3.28 * 3.33 (1H * dd * J = 5.1 * 15.2 H3) * 3.73 (3H * s * CH3) * 3.85 ( 2H * s * SCHs.) * 3.95 (1H * m * CH) * 4.71 (1H * m * 4H) * 4.83 (2H * m, 4.90 (H, m, 4H) * 5.35 (2H * m * CH = CH -,) * 6.04 (iH * m * CH = CHZ) * 7.40 (2H, d * J = THz, Ph-H) * 8.02 (2H * d, J = THz * Ph-H) c. Acid «-S, 4-R-2-4C4-C (4-allyloxycarbonyl 1) -benzylthio3-2-oxoazetidin-1-yl-3-propionic acid A solution of 2-C4-C (4-allylaxy carboni l> benzi lt io3-2-oxoazetidin-l-yl.}. 'methyl propionate (2.65 g) (mixture of 5% day A (R * R)? 65% of' Me) in THF (50 ml) at 3QC was treated with an IN solution of sodium hydroxide (7.5 ml) for 60 minutes The cooling bath was removed and the reaction was stirred for 30 minutes, 1N NaOH (1.0 ml) was added for 30 minutes and the reaction was stirred then for 30 minutes * was diluted with brine (75 ml) and extracted with diethyl ether (75 ml), the aqueous layer was made acidic with IN HCl and extracted with diethyl ether (2x75 ml). combined * washed with brine * dried (MgSO ^.) and evaporated to give the title compound as an orange oil (2 »5g * 98%) and as a mixture in 5% R, R? 27% R * S? 65 % des «Me. d. oc-S, 4-RN-C6- (4-Fluoropheni 1) hexy 1 -2-C (4-al i loxi-carboni 1) benzyl-thiol-2-oxaazeti in-l-i1propionami at 6- (4- Fluorophenyl) exi lami a (1.55 g) in dry DMF (50 ml) was added to a mixture of 2-C4-alkyloxycarbonyl 1) benzyl thio3-2-oxoazetidyl-1-propionic acid (2.70 g) (top), 1-hydroxybenzotriazole (0.95 g) * N * N '~ dicyclohexy Icarabodi ida (1.46 g) and the mixture was stirred at room temperature for 4 h. The suspension was diluted with diethyl ether (100 ml) and filtered to remove urea. The filtrate was washed with brine * saturated aqueous NaHC03 * dried (MgSO., -.) and evaporated to an oil. Purification by column chromatography by evaporation on silica gel eluted with C2? 1 P.E. 40 ~ 60 ° C ethyl acetate gave the product «- * 4-R diastereomer (B) (contains 10% day A) as an ace e yellow (0.497g * 13.45). NMR? d (CDCl3) 1.25-1.7 (11H, m * xCHar CH3), 2.55 (2H * t, J = 7.6Hz, CHj-sPh), 2.83 * 2.89 (H * dd * H3) * 3.25 (3H, m, NCH) ^ H3), 3.86 (2H, s, SCHjj.) * 4.10 (1H * m, CH), 4.69 (1H, m, 4H), 4.83 (2H, * CO ^ CH ^), 5.4 (2H, m, CH = CH ^) * 6.04 (IH m, CH-CH2) r 6.45 (IH, m »NH), 6.94 (2H,, p-FPh-H> 7.09 (2H * m * p-FPh-H) * 7.39 (2H, d, J = 8Hz * Ph-H) * 8.028 (2H, »Ph-H) Diastereomer A was also isolated 1H NMR d (CDCl3) 1.25-1.7 (11H» »4XCH.2 * CH3) * 2.55 (2H * t * J = 7.6Hz * CH-sPh, 2.78 * 2.85 (HH * dd * J = 2.3, 15.4Hz * H3) * 3.25 (3H * m * NCH-s * H3) * 3.89 (2H * m * SCH2) * 4.05 (ÍH * m * CH) * 4.81 (3H, 4 * CO- H - ,,) * 5.4 (2H * * CH = CHj,), 6.04 (1H * CH = CH2) * 6.48 ( lH * m * NH) * 6.94 (2H, * p-FPh-H) * 7.09 (2H * * p-FPh-H) * 7.39 (2H * d * J = 8Hz * Ph-H) * 8.02 (2H * d * Ph-H). a * oc-S, 4-R, SSN-C6- (4-fluorophenyl-hexyl 3-2-C (4-allyoxi-arbonyl) benzylsulfyl) 3-2-oxoazetidin-i-ylpropyrone a Solution of S * RN-C6- (4-fluorafeni I) he? Il 3-2-C (4-alloxycarbon I) benzyl thio3-2-oxoazetidin-l-ylpropionamide (1.20g) (80? 20DiaB? A) in dichloromethane (25ml) * cooled to -75 ° C * was treated with a solution of mcpba (0.71g) in (25 l> for 1 hour maintaining the temperature at -75 ° C.

Cooling bath was removed and the reaction was stirred for 2 hours, diluted with CH-gCl-, (25ml) * was washed with a 10% aqueous solution of sodium sulfite (50ml) * saturated NaHC03 (50ml) * dried ( MgSO, -.) And evaporated to a colored oil. Purification by flash column chromatography on silica gel eluted with ethyl acetate gave the title compound as a 60-40 mixture of day B2 (aS, 4-R, SS) β day Bl (aS * 4-R, SR ). Purification on Kromasil silica of 5μm (250mm x 4. 6mm) eluted with 50% hexane? 40% ethanol? 10% CHCl3 dia the title compound Diastereoisomera B2? («-S» 4-R »S-S) -N-E6- (4-fluorophenyl) hexy l 3-2-E (4-alloxycarbonyl) benzyl-sulfinyl) 3-2-oxoazetidin- li Ipropionamide as a colorless oil. HH NMR d (CDCl-,) 1.25-1.7 (11H »m» 4xCH2, CH3), 2.55 (2H, t, J = 7.6Hz, CH2Ph), 2.83, 2.89 (1H, dd, J = 2, 15Hz »H3 ) »3.24 (3H» »CHs.» H3), 4.02 (2H »» SOCH ^), 4.44 (1H, m, CH) »4.60 (HI,» 4H), 4.83 (2H, m, CO ^ H ^ * 5.4 (2H, »CH = CH. ,,) * 6.04 (HH» m »CH = CH ^) * 6.85 (HH * m * NH) * 6.94 (2H, m, p- FPh ~ H)» 7.09 (2H, m, p-FPh-H), 7.37 (2H, d, J = 8Hz, Ph-H), 8.08 (2H * d * J = 8Hz * Ph-H).

EXAMPLE 28 ("-S, 4-R, S-S) -N-C- (4-fluorophenyl) hexyl 3-2-C- (4-carboxy-benzylsulfinyl) -2-oxazetidin-1-ylpropionone A solution of (< xS * 4-R * S ~ S) ~ N-E6- (4-fluorophenyl) hexy 13-2-E (4-alloxycarbonyl) lysulfinyl 3-2-oxazetidin-1 -ylpropionamide (day B2) (240mg) * triphenylphosphine (6mg) * tetrakis (triphenylphosphine) palladium (0) (15mg) in CHICHI., dry < 5ml) under nitrogen was treated with pyrrolidine (39μl) and the mixture was stirred at room temperature for 19 hours. The mixture was diluted with CR-jCl-j (50ml) and water (25ml) and acidified with 2N HCl. The layers were separated and the aqueous was washed with (2x50ml). The organic extracts were combined * dried (MgSO 4) and evaporated to a yellow gum. Purification by flash column chromatography on silica gel eluted with a levigation gradient CH-jCHlj;. ? acetone? Acetic acid gave the product as an oil. The oil was dissolved in CH ^ Cls (4ml) and diluted with diethyl ether (75ml) * was washed with water * saline * dried (MgSO ^.) * Filtered and evaporated to a brown foam (123mg * 56%). C «3 = No significant optical rotation (c = 1.1% p / v in CHCl3) 1H NMR a (CDCl3) 1.32-1.6 (13H * * CH3 4xCH2) * 2.55 (2H * t * J = 7.6Hz * CH ^ Ph) * 2.84 * 2.88 (1H * dd * J = 2.4 * 15.2Hz * H3), 3.1-3.3 (3H * * NHCH -, * H3) * 4.04 * 4.10 (2H * 2xd * J = OHz * S0CH.- .), 4.4 (1H * q * CHCH3), 4.68 (1H * »H ^> 6.94 (3H * * NH * pF-Ph- H) * 7.10 (2H *, p-F-Ph-H), 7.39 (2H,, Ar-H), 8.06 (2H,, Ar-H).

EXAMPLE 29 < «-R, 4-R, S ~ R) -y (« -R, 4-R, SS) -N-C6- (4 ~ alkoxyethyl) hexy l 3-2- C (4-alkyloxycarboni) 1) benzylsulfinyl) 3-2-oxoazetidin-1- i 1 ropionami a A solution of (aR »4-R) -N-C6- (4-fluorophenyl) -hexy 13-2-C (4- li-loxycarbonyl) -benzylthio3-2-oxoazet-1-yl-propionamide (1.25 g) (diastereaisomer A) in dichloromethane (25ml), cooled to -75 ° C, was treated with a solution of mcpba (0.75g) in CH ^ Cl ^, (25ml) for 1 hour maintaining the temperature at -75 ° C . The cooling bath was removid and the reaction was stirred for 2 hours, diluted with CH 2 Cl 2, (50ml), washed with a 10% aqueous solution of sadium sulfite (SOml), saturated NaHCO 3 (50ml), water, dried (MgSO ^.) and evaporated to an oil with color. The oil was dissolved in ethyl acetate (7.5ml) and cooled. The resulting solid was combined, washed with diethyl ether and dried to give (-R, 4- R, SR) -N-E6 ~ (4-fluorophenyl) hexyl-2-E (4-alkyloxycarbonyl). ) enci 1- sulfini l) 3-oxaazetidin-l-i I propionamide (day Al) as a solid without color 0.l25g, 9.7%. The filtrate was purified by flash column chromatography on silica gel eluted with ethyl acetate? P.E. 40-60 ° C »R pure * R * and fractions of R were combined and recrystallized from acetate ethyl acetate / diethyl ether to give R »R, R-N-C6- (4-fluorophenyl) hexy l 3-2-C (4-allyloxycarbonyl) benzylsulfinyl) 3-2-oxoazet idin-ii Ipropionamide as a solid without color Í0.195g »15%) * pf 139 ~ 140 ° C? 1 H NMR d (CDCl) 1.25-1.7 (11H * m »4.XCH.;, * CH3), 2.56 (2H, t, J = 7.6Hz, CHa-Ph), 2.79 * 2.83 (1H * dd * J = 5, 15Hz * H3), 3.20 (2H, m, NCHZ), 3.33 * 3.39 (ÍH, dd, J ~ 2, 15Hz, H3), 3.94 (2H, m »SOCHa.) * 4.16 (1H * m * CH ), 4.77 (1H,, 4H), 4.83 (2H,, COa.CH-2) * 5.4 (2H * m * CH = CH ^), 6.04 (IH, m * CH = CH - ,,) * 6.72 ( ÍH * m * NH) * 6.94 (2H * m * p-FPh-H) * 7.09 (2H * m * p-FPh-H) * 7.37 (2H * d * J = SHz * Ph-H), 8.08 ( 2H »d» J = 8Hz »Ph-H). R impure »R» and fractions of S were combined and recrystallized from ethyl acetate / diethyl ether to give (aR »4-R» SS) -N ~ E6- (4-fluorophenyl) hexyl 3-2- C (4-allyloxycarbonyl) benzyl isulfinyl 3-2-oxoazetidin-ti l propionamide as a colorless solid (0.204g »15.8%), mp 102 ° C? HH NMR d (CDCl3) 1.25-1.7 (11H * m, 4xCH2 * CH3) * 2.56 (2H * t * J = 7.6Hz, CHßPh) * 2.83 (HH * dd * H3) * 3.20 (3H * m, NCH, . * H3) * 4.10 (3H * * S0CH2 * CH) * 4.65 (1H * m * 4H) * 4.83 (2H * m, C02CH2) * 5.4 (2H * m * CH = CHa) * 6.04 (1H * m * CH = CH -.) * 6.94 (2H * m * p-FPh-H) * 7.09 (2H * * NH * p-FPh-H), 7.37 (2H »d» J = SHz »Ph-H), 8.08 (2H * d * J = 8Hz * Ph-H). In an analogous manner the following chlorine compounds were prepared from racemic 4-C (4-ali-loxycarbonyl) benzyl-3-oxoazet-1-i-lactatic acid. s; EXAMPLE 30 (-) - (ot-S, 4-R, S-S) -v (+) - («- R, 4 ~ S, S-R) -N-C6 ~ < 4- Chlorophene 1) hexy 13-2-C (4- l i loxycarbonyl) benzylsulfini 13-2-oxoazeti in-i-ylpro-ion to. N-C6- (4-Chlorophenyl) hexy13-2-C (4-ali loxycarbonyl) benzlio3-2-oxoazetidin-1-yl 1 ropionamide A mixture of meth i 1-2- (4-alloxycarbonyl) benzyl 11 3 -3-oxoazetidin-1-yl 3-prapionate (4.87g) * hydroxybenzotriazole (1.88g) * DCC (2.89g) in dry DMF (60ml) was treated with 6- (4-chlorophenyl) hexylate and stirred at room temperature for 6 days. The orange suspension was diluted with diethyl ether (200ml) and filtered to remove the precipitate. The filtrate was washed with NaHCO3 dil. (200ml), saline, dried (MgSO, -,) * and evaporated to an orange oil. Repeated flash column chromatography on silica gel using P.E 40-60 ° C? Ethyl acetate gave? Diastereaisomer A (R * R / S * S) (O.lg, 11%). 1H NMR d (CDCl3) 1.25-1.7 (11H, - m * 4? CH-, * CH3), 2.55 (2H * t * J = 7.6Hz * CH-2Ph) * 2.85 (H * dd, H3) »3.25 (3H, m »NCH2 H3), 3.89 (2H * m» SCH-,) * 4.05 (IH * m * CH) * 4.81 (3H * 4, CO ^ CH.;,) * 5.4 (2H, m * CH = CHa) * 6.04 (1H * * CH = CH ^) * 6.48 (1H * m, NH) * 7.07 (2H, d * J = 8.4Hz * p-ClPh-H> * 7.22 (2H * d * J = 8. SHz * p-ClPh-H), 7.39 (2H * d * J = THz * Ph-H), T.08 (2H * d * Ph-H) diastereomer B (R * S / S * R > (1.63g * 22%) .IH NMR d (CDCl3) 1.25-1.7 (11H,, 4XCH-3. »CH3), 2.55 (2H, t * J T3 = 7.6Hz * CH ^ Ph) * 2.83 * 2.89 (1H * dd, J «2.3 * 15.3Hz * H3), 3.25 (3H, m, NCH2, H3), 3.86 (2H, s, SCH ^.) * 4.10 (HH, m, CH), 4.69 (HH, m * 4H), 4.83 (2H * m * CO-jCH - ») * 5.4 (2H * m * CH = - ^ * 6.04 (1H * m * CH = CHS ) * 6.43 (1H, * NH) * 7.07 (2H * d, J - 8"4Hz * p-ClPh-- H)» 7.22 (2H * d * J «8.8Hz * p-ClPh-H) * 7.39 ( 2H * d * J = THz * Ph-H) * 8.OS (2H, m * Ph-H). b. N-C6- < 4-Chlorophenyl) hexyl 3-2- (4-ali loxycarbonyl) -benzyl-sul in l-2-oxoazeti in-l-yl ropionami a A solution of (R * S / S * R) -N-C6- (4 -chlorophenyl) hexy 13-2- ((4-allylcarbonyl) -benzyl thio) -2-oxoazetidin-1-ylpropionamide (1.60 g) (diastereomer B) in dichloromethane (30 ml) cooled to -75 ° C » was treated with a solution of mcpba (0.92g) in CH-, Cla (30ml) for 45 minutes keeping the temperature below -70 ° C. The cooling bath was removed and the reaction was stirred for 45 minutes * diluted with CHjaCl;., (20ml) * was washed with a 10% aqueous solution of sodium sulfite (50ml) * saturated NaHC03 (SOml) * dried ( MgSO 4) and evaporated to give the title compound as a mixture of stereoisomers as a kneaded oil. (1.6g * 100%). (65%? 35% diastereomer sulfoxide B2? B1). This material was separated by hplc? Sulfoxide dia B2 was separated from day Bi using silica Beckman 15 cm x 4.6 mm eluted with 10? 90 ethanal? Hexane and the subsequent separation of enansiomer of diastereomer B2 used Chiracel 0D-4.6mm eluted with 25? 75 ethanol? ?Ana. c. (-) - (cc-S, 4-R, SS) -N-C6- (4-chlorophenyl) hexyl3-2-C (4- al i lox carbonyl) benzylsulfini 13-2-oxoazeti in-l- lpropionamid ((-) B2) Enantiomerically pure »oil without color * 148mg» C «30 = -4.2 ° (c = 0.4% w / v in CHCl3) 1H NMR d (CDC13) 1.25-1.7 (11H * m * 4XCH-, * CH3), 2.55 (2H, t * J = 7.6Hz * CH-jPh), 2.83, 2.89 (ÍH * dd * J - 2.4 »15.3Hz * H3), 3.24 (3H, m, NCRg, H3), 4.08 (2H, m), 4.60 (1H, m, CH), 4.69 (H * m * 4H), 4.83 (2H * m * CO ^ CHa.), 5.4 (2H * m * CH ~ CHg.) * 6.04 ( 1H * m, CH = CHX * 6.95 (IH * m * NH) * 7.08 (2H * d * J = 8.4Hz, p-ClPh ~ H>, 7.22 (2H * d * J »8.8Hz * p-ClPh -H) * 7.39 (2H * d »J = THz * Ph-H), 8.0T (2H, d, J = THz * Ph-H). d. (+) - (- - R, 4-S, S-R) - C6- (4-chlorophenyl) hexyl -2-C (4-al loxi carbonyl) benz Isulfinyl 3-2-oxoazetidin-l-ylpropionamide < (+) B2) The sample contains 0.83% of the other enansidomer * oil without color * 145mg, Crx3D = + 4.3 ° (c = 0.4% w / v in CHCl3) HH NMR d (CDCl3) 1.25-1.7 (11H, m * 4xCHE * CH3), 2.55 (2H * t * J = 7.6 Hz * CH ^ Ph) * 2.83 * 2.89 (HH * dd * J = 2.4 * 15.3Hz * H3) * 3. 24 (3H * m * NCH ^, H3), 4.08 (2H * m), 4.60 (1H * m * CH), 4.69 (1H, m, 4H), 4.83 (2H, m * CO ^ CH-j.), 5.4 (2H, »CH = CH ^), 6.04 (ÍH, m, CH = CH- ,,), 6.95 (1H, m, NH), 7.08 (2H * d * J = 8.4Hz, p- ClPh-H) * 7.22 (2H * d * J = 8. THz * p-ClPh-H) * 7.39 (2H, d * J = THz * Ph-H) * 8.08 (2H * d * J «THz * Ph-H).

EXAMPLE 31 (-) - (ct-S, 4-R, S-S) -C6- < 4-chlorophenyl) hexyl3-2- < 4- carboxybenzilsulfinyl) -2-oxoaz tidin-l-il ropiona «nida A solution of (~) - (x ~ -S, 4-R, SS) ~ N-C6- (4-chloraphenyl) hexy 13-2-C (4-ali loxycarbonyl) lsulfini l 3-2- oxoazetidin3-2-oxoaz tidin-li lpropionamide (125mg), tripheni Ifasfine (6mg), tetrakiß (tripheni Ifosfin) palladium (O) (Smg) in CH ^ Cl., dry (2ml) under nitrogen was treated with pyrrolidine (19.5 μl) and the mixture was stirred at room temperature for 19 hours. Purification by flash column chromatography eluted with an elution gradient of CH-gCl-s acetone? Acetic acid gave the product as an oil. The oil was dissolved in CH-jClj, (2ml) and diluted with diethyl ether (50ml), washed with »saline (x2)» dried (MgSO ^.) * Filtrate and evaporated to give the title compound as a foam. yellow (104mg * 87%). K »= 3.7 ° (c = 0.5% w / v in CHCl3) HH NMR d (CDCl3) 1.25-1.6 (8H, * 4XCH.- ..), 1.62 (3H, d, J = 7.2 Hz, CH3), 2.55 (2H, t, J = 7.6Hz, CH ^ Ph), 2.86 * 2.89 (IH * dd »J = 2.4, 15.2Hz * H3), 3.20 (3H, m * NCH -» * H3) * 4.06 (2H * m, S0CR-,) »4.45 (1H, m * CH), 4.66 (IH,, 4H), 6.95 (IH, m, NH), 7.08 (2H, d, J = 8.4 Hz, p-CIPh-H ), 7.22 (2H, d, J = 8.THz * p-CIPh-H), 7.39 (2H * d, J = 8HZ * Ph-H) * 8.08 (2H * d * J = 8Hz, Ph-H) EXAMPLE 32 (+) - (ot-R, 4-S, S-R) -N-C6- (4-Chlorophenyl) hexyl -2- (4-carboxy-benzylsulfinyl) -oxoazeti-din-1-yl-1-ropionamide A solution of (+ > - («- R * 4 ~ S * S ~ R) ~ N-C6- (4 ~ chlorophenyl) hexy l -2- (4 ~ al i loxicarboni l) enci l sulfinil 3 -2-oxoazetidin-1-i I propionamide (123 mg), tripheni Ifosphin (6mg), tetrakis (tripheni Ifosphine) palladium (O) (8mg) in dry CH 2 Cl-a (2ml) under nitrogen was treated with pyrrolidine (19.5 μl) and the mixture was stirred at room temperature for 19 hours.Purification by flash column chromatography eluted with an elution gradient CH =, Cl = 1? acetan? acetic acid gave the product co or an oil.The oil was dissolved in HClCl-g (2ml) and diluted with diethyl ether (50ml), washed with ix2 saline), dried (MgSO ^), filtered and evaporated to a yellow foam (lOlmg, 89%) Erx3r > = + 3.3 ° (c = 0.3% p / v in CHCl3) 1H NMR d (CDCl3) 1.25-1.6 (8H, m, 4? CH- ,.), 1.62 (3H, d, J = 7.2 Hz, CH3), 2.55 (2H, t, J = 7.6Hz, CH-, Ph), 2.88 (ÍH, dd, H3), 3.20 (3H, * NCH -, * H3) * 4.06 (2H * m * S0CH -.) * 4.45 (ÍH * m * CH) * 4.69 (1H * * 4H), 6.95 (1H, m, NH), 7.08 (2H, d, J = 8.4 Hz, p-CIPh-H) * 7.22 (2H, d, J = 8.8Hz * p-CIPh-H ) * 7.39 (2H * d * J = 8H2 * Ph-H), 8. OS (2H, d, J = 8Hz * Ph-H). The following racemic compounds were also prepared. These can then be separated into enantromeres by hplc, using a stationary chiral phase, in a manner similar to the separations described here above.

Description 1 (R * S / S * R) ~ l- (2- (6-Chlorophenyl) hexyloxy) eti 1-4- (4-carboxybenzyl Isulfini l) -2-oxoa;: and idine (diast 2) ( R * S / S, R) -l- (2- (6-Chlorophenyl) hexyloxy) ethyl-4- (4-alloxycarbonyl benzylsulfinyl) -2-oxoazetidine (220mg), tripheni Ifasfin (ilmg), tetrakis (triphenylphosphine) palladium (O) (15mg) in dry CH¡-jCls (5ml) under nitrogen was treated with pyrrolidine (37μl) and the mixture was stirred at room temperature for 19 hours. Purification with flash column chromatography on silica gel eluted with a gradient of elution CHs, ClS2? Acetone? Acetic acid gave the product as an oil. The oil was dissolved in CHa-Cl ^ (4ml) and diluted with diethyl ether (75ml) * washed with water * saline * dried (MgSO ^) »filtered and evaporated to an oil that solidified upon cooling. Trituration with diethyl ether gave the title compound as a solid cream (149mg * 75%) m.p. 107-108 ° C 1 H NMR d (CDCl 3) 1.25-1.6 (8H * * 4XCH., ..) »2.56 (2H * t * J = 7.8 Hz * CH ^ Ph) * 2.71 * 2.74 (1H * dd * J = 2 »15.2Hz * H3) * 3.12, 3.15 (1H, dd, J = 5.2, 15.2Hz * H3) * 3.38-3.72 (6H * m, NH ^ CH ^ * OCH ^) * 4.10 (2H * m * SOCH -,) * 4.63 (1H * * H ", 7.09 (2H * d * J = 8» THz * p-CIPh-H) * 7.22 (2H * d * J = T.8HZ »p- IPh-H) , 7.40 (2H, d »J = 8Hz» Ph-H), 8.08 (2H, d, J = 8Hz Ph-H) Description 2 (R »S / S» R) -l- (2- (6-Chlorophenyl) ) hexi loxi) eti 1-4- (4-etaxy carboni Ibencylsulfinyl) -2-oxoazetidine (diast 2) a ,. l- (2- (6-Chlorophenyl) exoxy) ethyl-4- (4-ethoxycarbonyl-benzylthio) -2-oxoazetidine A solution of 6- (4-chlorophenyl) hexyloxy triflate (3.62g) »4 ~ (4 Ethanocarboni Ibencylthio) azetidin-2-one (2.47g) and tetrabutylammonium bromide (0.30g) in dry THF (70ml) was cooled to 10 ° C under nitrogen and treated with powdered potassium hydroxide (0.62g) . The cooling bath was removed and the reaction was stirred for 2 hours. The mixture was divided between saline (200ml) and ethyl acetate (200ml) and filtered through celite. The layers were separated and the aqueous was washed with ethyl acetate (100 ml). The organic extracts were combined, dried (MgSG, -,) and evaporated to a dark oil. Purification by flash column chromatography on silica gel eluted with C2? 13 to El? 13 P.E. 40-60 ° C? ethyl acetate gave the title compound as a yellow oil (2.41g »51%). 1H NMR d (CDCl3) 1.25-1.6 (11H, m »CH3» 4x0- ^., 2.55 (2H, t, J = 7.6 Hz »CH? Ph)» 2.85 (H »dd» H3) »3.05 (1H» m) »3.25» 3.30 (1H, dd, H3) * 3.36-3.72 (5H * m * NCHa. * CHa: * OCH ^) * 3.85 (2H * s * SCH ^), 4.37 (2H * q, J = 7.1Hz * C0ZCH3) * 4.76 (ÍH * m * H ^) * 7.07 (2H * d * J = 8.4 Hz * p-CIPh-H) * 7.22 (2H * m * p-CIPh-H), 7.39 (2H , d * J = 8HZ * Ph-H) * 8.08 (2H * d * J = THz * Ph-H) b_j (R, S / S, R) -l- (2- (6-Chlorophenyl) hexyloxy) eti 1-4- (4-ethoxy-carboni-1-benzylsulfonyl) -2-oxoazetidine (diast 2) A solution of l- (2- (6-Chlorophenyl) hexyloxy) eti 1-4- (4-ethoxy carboni Ibsnci l uncle) - -axaazet idine (2.37g) in dichloromethane (75ml) »cooled to -70 ° C» was treated with a solution of mcpba (l.Og) in CH ^ Cl.-, (75ml) by dripping for 1 hour keeping the temperature below -70 ° C. The cooling bath was removed and the reaction was stirred for 2 hours, washed with a 10% aqueous sodium hydrogen carbonate solution (50ml) + 10% aqueous sodium sulfite (50ml). The layers were separated and the organic layer was washed with saline, dried (MgSO 4) and evaporated to an oil. Recrystallization from diethyl ether (40 ml) gave a colorless solid (0.91 g). Purification by flash column chromatography eluted on silica gel with E2? 13 ethyl acetate? Hexane and recrystallization of the less polar product from diethyl ether (15 ml) gave diastereomer 2 as an uncoloured solid (0.40 g, 0.16 g). %). p.f. 81-82 ° C. HH NMR (CDCl3> 1.25-1.6 (11H * m * CH3 * 4XCH.J,.) * 2.55 (2H * t, J = 7.8Hz * CH ^ Ph) * 2.63, 2.69 (HH, dd, J = 2.2, 15.1Hz, H3) * 3.05, 3.11 (1H, dd »J = 5.1, 15.1Hz * H3) * 3.36-3.74 (6H * m, NCH ^ H ^ * OCH ^) * 3.75 (2H * s, SOCH ^) »4.39 (2H, q, J = 7.1Hz * C0sCH3) 4.54 (1H * m * H ^) * 7.09 (2H * d * J = 8.4 Hz * p-CI hH), 7.22 (2H, m , p-CIPh ~ H), 7.37 (2H * d * J = 8.3HZ * Ph-H) * 8.06 (2H * m * Ph-H) Biological Data i »Lp-PLA inhibition test ^ Enzymatic activity was determined by measuring the rate of renewal of the artificial substrate (A) at 37 ° C in 50 M HEPES pH regulator (acid N-2-hydroxyethylpiperazine-N'- 2-ethanesulfonic acid) containing 150 mM NaCl * pH 7.4.

(TO) The assays were performed on 96-well title plates. Lp, -PLA-, was partially purified by centrifugation in human plasma density gradient. The active fractions were pooled and used as the source of Lp-PLAs »» The enzyme was preincubated at 37 ° C with vehicle or test compound for IO minutes at a total value of 180 μl. The reaction was then initiated by the addition of 20 μM. 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 mixer.

The reaction rate was measured as the proportion of change of absorbency. Results? The compounds of examples 1 and 2, the corresponding carbaxyl acid of (+/-) ~ N-C6- (4 ~ clarafeni I) hex-l-yl-4- (4-carboxybenzyl-sulfinyl) ~ 2-oxoazetidin-l- il) acetamide and the carboxylic acid of (4R, SS) -N-C6- (4-fluarofeni) hex-li 13-4- (4-carboxybenzilsulfinyl) -2-oxoazetidin-1-yl) acetamide had values? CBO in the range of 4 to 20 nM. The compounds of Examples 12, 13 and 14 had IC.sub.o values in the range of 2 to 4 nM. 2- Evaluation of bioavailability Pro-drug esters were evaluated in dog and human liver microsomes according to standard procedures for their ability to be hydrolysates to the original acid. The results are given in the following table.

Acid production -% conversion of the test ester to the original acid by dog or liver microsomes after incubation of a 1 μm test compound for 15 minutes, determined by measurement of the concentration of the original acid produced by HPLC detection of acid (100% = 1 μM of acid produced). The numbers are rounded to the nearest 5%. 3. Stability evaluation The stability was estimated by determining half-lives for the decomposition test compounds in buffer pH 7.5 (SO mM phosphate) and regulator pH 1.2 (USP simulated gastric fluid = NaCl HCl pH 1.2 + pepsin), Initial concentration = 50 μM and monoclonal compound HPLC. The figures rounded to the nearest 0.5 h. Preferred compounds are those that exhibited good conversion from ester to acid in biological systems, while showing good stability in regulators (e.g., examples 9, 11, 12, 15, 16).

Claims (9)

1. NOVELTY OF THE INVENTION
2. CLAIMS 1"A compound of the formula (I)? (i) in which? Rj is hydrogen or a corresponding pharmaceutically acceptable ester or a pharmaceutically acceptable salt thereof? R-, and R3"which may be the same or different" each is selected from hydrogen or Ctl_ < 6,) optionally replaced? X is a group > í t iC s. ') m in which Xr is CO »CONR *» COO »CONR ^ CO, CONHO or CH ^ O * in dande R * is hydrogen or alkyl of CC1_ & > and is 0 or an integer from 1 to 12? or an alkylene chain of Ctl_1¡B > * interrupted optionally with X '* and Y is an arila group * optionally substituted? and having the absolute configuration (4R »SS). 2. A compound according to claim 1, characterized in that R2 and R3 is each hydrogen. R2 is hydrogen and R3 is methyl.
3. 3. A compound of the formula (I) according to claim 1 or 2 »further characterized in that X is C0NH (CHs)" or CHa.0 (CHz) r.
4. 4. - A compound of the formula (I) according to any of claims 1 to 3 * further characterized in that Y is phenyl * optionally substituted with up to three additional substituents.
5. 5. A compound of formula (I) according to any of claims 1 to 4 *. further characterized in that Y is phenyl * optionally substituted with halogen.
6. 6. A compound of formula (I) according to any of claims 1 to 5 * further characterized 0 because the pharmaceutically acceptable ester is an alkyl ester of C < t_ & > or alkenyl C < 2t_ < e, > Or a pharmaceutically acceptable in vivo hydrolysable ester.
7. 7. A compound of the formula (I) according to claim 6 »further characterized in that R1 * for 5 used in a hydrolysable ester in vivo is selected from? - CH (R ») O.C0.Rfc '? -CH (R «) 0.C0.0R '=? -CH (R ~) CQ .NR-R * - »-R ^ NR.R * -? - ~ CH (R «) 0.CO.C £ > H4Y1COCH (Ri) NHS! .5"CH *? VRÍ 5 where? R "is hydrogen * alkyl of Ctl_A>, in particular methyl * cycloalkyl of (C3_ ^) * or phenyl * each of which may be optionally substituted? R" is alkyl of £ < % ~ a, i - ~ alkoxy (C1 _?) alkyl of C < 1_ < & > »Phenyl * benzyl * cycloalkyl of C (3" 7.> * Alkyl (C1_ <) cycloalkyl of C < 3_7. > * 1- aminoalkyl of C < 1_ < > * or i-alkyl (C1_) aminoalkyl of Cti_?> * each of which may be optionally substituted? or R "and Rte together form a l-2-phenylene group optionally substituted with one or two methoxy groups? R ** is C < - «e, > 'cycloalkyl of C < 3_-r > * alkyl (C1_ < 5)) cycloalkyl of C < 3_-r >' * * is alkylene of Ctt_ ?, > * optionally substituted with a methyl or ethyl group? R "and R ^ * which may be the same or different" is each C < i_? > »Or arilalquils of < 1_ ^ > »Optionally substituted with for example» hydroxyl »Rs is C < JL_? > R ^ is hydrogen »C < 1_? > > or phenyl * R1 is hydrogen or phenyl optionally substituted with up to three groups selected from halogen * C < 1_á) > * or alcsxi of C { 1_fe > ? and Y1 is oxygen or NH.
8. 8. A compound of formula (I) selected from? (4R * SS) -N-E6- (4-Fluororopheyl) ex-1-yl 3-4- (4-carboxybenzyl-sulfinyl) -2-oxoazetidin-1-yl > acetamide (and pharmaceutically acceptable salts thereof) in particular the sodium salt)? (4R * SS) ~ N-E6- (4-Fluoroprophenyl) hex-l-il3-4- (4-alloxycarbonyl benzylsulfinyl) -2-oxoazetidin-1-yl) acetamide? (4R * SS) -N- (6- (4-Fluororafe i l) hexi l) -4- (4-etho? I carboni lbenci l- sulfini l) -2-oxoazetidin-l-i lacetamide? (4R * SS> -N ~ (6- (4-Clara-pheni 1) hexy l) -4- (4-ethoxy car onyl benzylsulfinyl) -2-oxoazetidin-li lacetamide? (~) -l- ( 2 ~ (6-Fluarafeni l) hsxi laxi) eti 1-4- (4-carboxibenci Isulfini l) -2-oxoazetid na (diast.2)? (+) - 1-Í2- (6-Fluoropheni l> hexi loxi) et i 1-4- (4-carboxy benci Isulfini 1) - -axo ~ azetidine (diast.2)? (+) -l- (2- (6-Fluarophenyl) hexy loxi) eti 1-4- (4-al loxi carboni Ibenci Isulfini l) -2-oxoazetidine (diast.2)? (-) - l- (2- (6-Fluoropheni l) hexyloxy) eti l-4- (4-alloxycarbonyl-l-benzylsulfinyl) -2-oxoazetidine (diast.2)? (-) - l- (2- (6-Chlorophene) l) hexyloxy) eti 1-4- (4-carbohydrate Isulfinyl) -2-oxo-azetidine (diast.2)? (+) -l- (2- (6-Chlorophenyl) hexyloxy) eti 1-4- (4-carboxybenzyl Isulfini l) -2-oxoazetidine (diast.2)? (+) - l- (2- (6-Chlorophene) l) hexyloxy) eti l-4- (4-al loxycarbonylbenzene-1-eulph nor 1) -2-oxoazetidine? (-) -l- (2- (6-Chlorophene) l) hexyloxy) ethyl-4- (4 ~ al loxicarboni Ibenci Isulfini l >; -2-oxoazetidine? («-S, 4-R, SS) -NC - (4-fluoro-phenyl) -hexy-l- (4- (4-alkylamino) benzyl-n-nyl) 3-2-oxoazetidi-1-propione Going? (? -S * 4-R * S-S) -N-C- (4-Fluaraphenyl) hexy l 3-2-C (4-carboxy benzylsulfinyl) -2-axa-azetidin-1-ylpropione a? (O-R * 4-R * SR) -E6- (4-fluorophenyl) -hexy-l-2-E (4-allyl -lalkyl) -benzyl-Isulfinyl) 3-2-oxoazet idin-1-lpropionam gives ? (O-R * 4-R * SS) -N-E6- (4-Fl uarofeni l) hexy l 3-2-C (4-al loxicarboni 1) benzylsulfinyl) -2-oxoazet idin-l-il - propiona ida? (-) - (aS, 4-R, S ~ S) -N-C6- (4-Chlorophene) 1-hexy-2-E (4-alkyloxycarbonyl) benz-Isulfinyl) 3-2-oxoazet din-1-i 1 - prspione ida ((-) B2)? (-) - (a-S, 4 ~ R, S-S) -E6- (4-Chloro-phenyl) hexy l 3-2-C (4-ca baxibenci Isulfini l) -2-oxaazetidin-1-l- prapianamide? (+) - (O-R * 4-S * SR) -N- 6- (4-Chlorophenyl) hexyl 3-2-C (4-alloxycarbonyl) benzylsulfinyl 3-2-oxoazeti din-l- il-propyamide ((+) B2 >? and (+) - («- R, 4 ~ S * S ~ R) - ~ N-C6- (4-Clarofeni l) -hexi 1 -2-C (- carxonibenci Isulfinil) -2-oxoaze idin-1-i l-propionami da? (4R * S) -N ~ (6 --- C4-Fl uorofeni 13hex-l-il -4- (4-cyclohexyloxycarboni lo? imeti la? icarbani l) benci Isulfinyl) -2-oxo-azetidin-l-yl acetamide? (4R, SS) -N- (- 4-Fluarofeni l 3hex-l-il) -4- (4- ( L-butyloxycarboni loxymethyloxycarbonyl l) benzyl 1-sulfini 1) -2-oxoazetidin-li 1) acetamide? (4R »SS) -N- (6-C4-Fluoropheni l 3he? -l ~ il) -4- (4- (1-methylocyclohexyloxycarboni loxymethi laxycarbonyl) benzylsulfinyl) -2-oxazetidin-i-yl ) acetami da * (4R * SS) -N- (6-C4-F1uorofeni l hex-1-yl) -4- (4- (phenyl-1-carbon-loxi-methyl-laxycarbonyl) benz-Isulfinyl) -2-oxoazetidin-li ) acetami da? (4R * SS > - - (6-E4-Fluorofeni l 3hex-li l) -4- (4- (-methoxyphene-1-carbonyl loxymethyl loxycarbonyl) benz Isulfini l) -2-oxoazetidin-1-yl) acetamide ? (4R, SS) -N- (6-C4-Fluarafe il 3hex-li 1) -4 ~ (4- (iso-but iri loxime i loxi carboni l) benz Isulfinyl) -2-oxoazetidin-l-yl) acetamide ? (4R * S?) - N- (6-C4-Fluorafeni l hex-li l) -4- (4- (2-methoxy-prop-2-yl-carboni-loxymethi-loxycarbonyl) -benzul-leul-fini) -2-oxoazetidin- 1-yl) acetamide? (4R * SS) -N- (6- -Fl uorofe il hex-l-il) -4- (4- ((5-methy1-2-axo-l * 3-diaxal n-4-yl) m ti loxycarboni l) -benzulphulfinil) -2-oxoazetidin-li l) acet mi da * (4R * SS) -N- (6-C4-Fluorafeni l 3hex-li l) -4- (4- ((2 -methoxycarbani lE-but-2-en-yl) methyloxycarboni 1) benzl-1-sulfyl) -2-oxoazetidin-l-yl) -acetamide? (4R * SS) -N- (6 ~ C4-Fluorophenyl 3hex-1-l) -4- (4- (N-N-dimethylaminocarboni Imeti loxycarboni l) benz Isulfini l) -2-oxo- azetidin-1-yl) acetamide? and (4R * SS) -N- (6-4-Fluoropheni 1 hex-l-yl) -4- (4- (NN ~ di- (2-hydroxyethyl) aicarboni Imet i loxycarboni 1) -benzylsulfinyl) - 2-oxaazetidin-1-yl) ceta ida.
9. 9. A pharmaceutical composition comprising a compound of formula (I) as defined in any of the preceding claims, and a pharmaceutically acceptable carrier. I. The use of a composition of formula (I) as defined in claim 1, in the manufacture of a medicament for treating atherosclerosis. 11. A process for preparing a compound of formula (I) in which X is an amide CONH, which comprises treating a compound of formula (ID? (II) in dande R * is C < 4_A > or alkenyl of C < to_? > , and Rz and R3 are as defined in claim 1 * and having the absolute configuration (4R »SS)? with an amine of the formula (III)? Hj, N (CH, -,) "Y (III)" under suitable conditions of amide formation * for example in the presence of such an activating agent or N * N-dicyclohexylcarbodiimide y-hydroxybenzotriazole in a suitable solvent such as dimethylformamide dry * and then, if necessary? (to) lOO Remove the ester group under suitable de-esterification conditions to form the acid? (b) converting the acid to a pharmaceutically acceptable salt? and / or (c) converting the acid, a suitable salt »the ester or an activated derivative of the acid, into a hydrolysable ester in vivo by reaction with a compound of the formula (IV)? RXR "* (IV), wherein" R- * "is a reactive group leaving this formation and R1 is as defined hereinbefore under conditions of ester formation: 12. A compound of formula (V)? (V) 5 wherein R1, Ra and R3 are as defined in claim 1, and having the absolute configuration (4R), having the absolute configuration (4R). * > 13.- A diastereoisomeric salt formed from ? Or a compound of formula (VI)? (VI) 5 wherein R * is a carboxyl protecting group * for example C ^ ^ alkyl, or Ct2 alkenyl "& > * and Rz and R3 are like * Eeta defined in claim 1? and a chiral base. 14. A process for solving an intermediate compound of formula (VI)? 5 (SAW) Wherein R * is a carboxyl protecting group * for example an alkyl of C { 1_A > or alkenyl of CCJZ_fe > * and R2 and R3 are as defined in claim 1? this process comprises the formation of a diastereomeric salt with a chiral base such as (-) -cinconidine.