BETA-LACTAM COMPOUNDS, THEIR PREPARATION AND THEIR USE

Abstract: A compound of formula (I): or a pharmaceutically acceptable salt or cleavable ester thereof, wherein RCONH- represents an organic acylamino group, and E is a carboxy group or a pharmaceutically acceptable salt or C₁₋₁₀ alkyl or substituted C₁₋₁₀ alkyl ester thereof or is a cyano group.

Description: CHEMICAL COMPOUNDS This invention relates to novel ss-lactam antibacterial agents, their preparation and their use, and in particular to 7-oxo-1-azabicyclo[3.2.0]heptanes. The present invention provides the compounds of the formula (I): EMI1.1 and pharmaceutically acceptable salts and cleavable esters thereof wherein RCONH is organic acylamino group, and E is a carboxy group or pharmaceutically acceptable salt or C1 10 alkyl or substituted C1-10 alkyl ester thereof or is a cyano group. Preferably E is a C1-10 al koxycarbonyl or substituted C1,10 alkoxycarbonyl or cyano group. Certain suitable values of E are those of the sub-formulae (L) and (M): C02B1 (L) CO2CHB2B3 (M) wherein B1 is an alkyl group of 1 to 6 carbon atoms optionally substituted by an alkoxy or alkanoyloxy group of 1 to 7 carbon atoms, B2 is an alkenyl or alkynyl group of up to 5 carbon atoms or is a phenyl group optionally substituted by one, two or three atoms or groups selected from fluorine, chlorine, bromine, nitro or alkyl or alkoxy of up to 4 carbon atoms; and B3 is a hydrogen atom, an alkyl group of up to 4 carbon atoms or is a phenyl group optionally substituted by one, two or three atoms or groups selected from fluorine, chlorine, bromine, nitro or alkyl or alkoxy of up to 4 carbon atoms. More suitably B1 is an alkyl group of 1 to 6 carbon atoms. More suitably B1 is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, isopentyl or hexyl group. In particular B1 is a methyl, ethyl or propyl group. A preferred value for B1 is a methyl group. More so table B2 is a hydrogen atom and B3 is a phenyl group optionally substituted by a fluorine, chlorine, bromine, nitro or alkyl or alkoxy of up to .4 carbon atoms. In particular CHB2B3 is a benzyl, methoxybenzyl ethoxybenzyl, nitrobenzyl or chlorobenzyl group. A preferred value for E is a cyano group. Suitably RCONH is an organic acylamino group such as is found in antibacterially effective penicillins and cephalosporins. Thus suitable groups RCONH include those of sub-formulae (a), (b) (c) and (d): EMI3.1 wherein n is 0, 1 or 2; mis 0, 1 or 2; A5 is an alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, cyclohexenyl, cyclohexadienyl, phenyl hydroxyphenyl, thienyl or pyridyl group; X is a hydrogen, bromine or chlorine atom, a carboxylic acid, carboxylate ester, tetrazolyl, azido, hydroxy, acyloxy,amino, acylamino', heterocyclylamino, ureido, guanidino or acylureido group; A6 is an aromatic group such as a phenyl, 2,6-dimethoxyphenyl, 2-alkoxy-1-naphthyl, 3-arylisoxazolyl, isothiazolyl or 3-aryl-5-methylisoxazolyl group; X1 is a CH2OCH2, CH2SCH2 or (CH2)n group; and X2 is an oxygen or sulphur atom. For example, suitable groups RCONH include phenylacetamido, p-hydroxyphenylacetamido, o-hydroxyphenylacetamido, m-hydroxyphenylacetamido, &alpha;-chlorophenylacetamido, &alpha;-bromphenylacetamido, a-carboxyphenylacetamido and esters thereof such as the methylphenyl, indanyl and phenyl esters, &alpha;-azidophenylacetamido, &alpha;-aminophenylacetamido, &alpha;-hydroxy- phenylacetamido, &alpha;-ureidophenylacetamido, &alpha;-guanidino- phenylacetamido, &alpha; ;-(acetylureido)phenylacetamido, &alpha;-acetoxyphenylacetamido, &alpha;-tetrazolylphenylacetamido, acetamido, chloroacetamido, bromoacetamido, propionamido, pyridylacetamido, 2-thienylacetamido, 3-thienylacetamido, 2-thienylpropionamido, 3-thienylpropionamido, &alpha;-chloro (p-hydroxyphenyl)acetamido, &alpha;-bromo(p-hydroxyphenyl) acet2mido, &alpha;-carboxy(p-hydroxyphenyl)acetamido and esters thereof such as the methylphenyl, indanyl and phenyl esters &alpha;-amino(p-hydroxyphenyl)acetamido, &alpha;-hydroxy(p-hydroxyphenyl) acetamido, &alpha;-acetoxy(p-hydroxyphenyl)acetamido, &alpha;-ureido(p- hydroxyphenyl)acetamido, &alpha; ;-guanidino(p-hydroxyphenyl)acetamido, &alpha;-acetylureido(p-hydroxyphenyl)acetamido, phenoxyacetamido, o-hydroxyphenoxyacetamido, m-hydroxyphenoxyacetamido, phydroxyphenoxyacetamido, methoxyacetamido, ethoxyacetamido, &alpha;-amino(p-hydroxy)phenoxyacetamido, &alpha;-aminophenoxyacetamido, &alpha;-acetylphenoxyacetamido, &alpha;-acetyl(p-hydroxy)phenylacetamido, &alpha;-hydroxyphenoxyacetamido, &alpha;-hydroxy(p-hydroxy)-phenylacetamido, &alpha;-carboxyphenoxyacetamido and esters thereof such as, the methylphenyl, indanyl and phenyl esters, &alpha; ;-carboxy(p-hydroxy) phenoxyacetamido and esters thereof such as the methylphenyl, ir.danyl and phenyl esters, phenoxypropionamido, ph2noxybutyramido, benzamido, 2,6-dimethoxybenzamido, 2-ethoxy-1naphthamido, 2-methoxy-1-naphthamido, 2-propoxy-1-naphthamido, 3-phenyl-5-methyl-4-isoxazolylcarboxamido, 3-o-chlorophenyl-5methyl-4-isoxazolylcarboxamido, 3-o,o-dichlorophenyl-5-methyl4-isoxazolylcarboxamido, isothiazolylcarboxamido, 3-o,ofluorochlorophenyl-5-methyl-4-isoxazolylcarboxamido, 3-phenyl4-isoxazolylcarboxamido, 3-o-chlorophenyl-4-isoxazolylcarboxamido, 3-o,o-dichlorophenyl-4-isoxazolylcarboxamido, 3-o,o-fluorochlorophenyl-4-isoxazolylcarboxamido, 1aminocyclohexyl-1-carboxamido, phenylthioacetamido, phenylthiopropionamido, p-hydroxyphenylthioacetamido, and the like. More suitably groups R CON'H include those of the sub-formulae (e) and (f): EMI5.1 wherein R2 is a phenyl, thienyl or phenoxy group; R3 is a hydrogen atom or methyl group; -4 is a phenyl, p-hydroxyphenyl, cyclohexadienyl, or a 5- or 6- membered heteroaryl or heterocyclyl group containing up to 3 hetero atoms selected from sulphur, oxygen and nitrogen, said group being optionally substituted by one two or three substituents selected from hydroxy, amino, halo and C1-6 alkoxy; R5 is a hydroxy, amino or carboxylic acid group or phenyl, methylphenyl, indanyl, or C16 alkyl ester thereof, or amino, ureido, acylamino or acylureido. Examples of suitable groups R include thienyl pyridyl and aminothiazolyl. A particularly preferred group of the sub-formula - (e) is the phenoxyacetamido group. Another particularly. preferred group of the sub-formula (e) is the phenyl acetamido group. Other particularly suitable groups of the formula R CO-NH- include the &alpha;-methylphenoxyacetamido, methyl phenylacetamido, &alpha;-methyl-2-thienylacetamido, &alpha;-methyl-3- thienylacetamido, 2-thienylacetamido, 3-thtenylacetamido, a-hydroxyphenylacetamido, -hydroxy(p-hydroxyphenyl)aceta- mido, &alpha;-hydroxy-2-thienylacetamido, &alpha;-hydroxy-3-thienyl- acetamido, a-aminophenyiacetamido a a-amino ( p-hydroxyphenyl) acetamido, &alpha;-amino-3-thienylacetamido, &alpha;-amino-2-thienyl- acetamido, &alpha;-carboxyphenylacetamido, &alpha; ;-carboxy(p-hydroxy- phenyl)acetamido, &alpha;-carboxy-2-thienylacetamido, &alpha;-carboxy- 3-thienylacetamido, the methyl, ethyl, propyl, butyl, phenyl, methylphenyl or indanyl ester of a-carboxyphenylacetamido, the methyl, ethyl, propyl, butyl, phenyl, methylphenyl or indanyl ester of a-carboxy (p-hydroxyphenylacetamido), the methyl, ethyl, propyl, butyl, phenyl, methylphenyl or indanyl ester of &alpha;-carboxy-2-thienylacetamido, and the methyl, ethyl, propyl, butyl, phenyl, methylphenyl or indanyl ester of a-carboxy-3-thienylacetamido. Suitably the ureido group in either sub-formula (c) or sub-formula (f) is of the formula -NHCONR7R8 wherein R7 is a hydrogen atom or a C1 6 alkyl group and R8 is an organic group, or R7 and R8 together with the nitrogen atom to which they are joined form an optionally substituted heteroaryl or heterocyclyl ring containing 1 or 2 nitrogen atoms. Suitably R8 is C1-6 alkyl or an optionally substituted 5- or 6- membered heteroaryl or heterocyclyl group containing one or two nitrogen atoms. Suitable substituents for R8 and for the rings formed by R7 and R together include one, two or three groups selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, optionally substituted phenyl, oxo, hydroxy optionally substituted such as C16 alkoxy, C2-6 alkenyloxy, C3-6 cycloakyloxy or phenoxy, mercapto optionally substituted such as phenylthio or C1-6 alkylthio; or amino or substituted amino such as C1-6 alkylamino, optionally substituted phenylamino, benzylamino or sulphonylamino for example C1,6 alkyl sulphonylamino or p-aminosulphonylphenylamino. Alternatively two substituents on the ring R8 or on the ring formed by R and 8 together may form the residue of a further carbocyclic or heterocyclic ring. One particularly preferred sub-group of compounds is that of the formula (II): EMI7.1 and pharmaceutically acceptable salts and cleavable esters thereof wherein E and R are as hereinbefore defined, R9 and R10 are independently selected from hydrogen, C1-6 alkyl, halo, amino, hydroxy or C1-6 alkoxy, and R11 is hydrogen or C1-6 alkyl. Suitably R11 is methyl, ethyl, n-propyl, isopropyl, sec-butyl, isobutyl or tert-butyl. Suitably R9 and R10 are independently selected from methyl, ethyl, n-propyl, isopropyl, sec-butyl, isobutyl or tert-butyl. Preferably R9 and R10 are both hydrogen. Preferably R11 is ethyl. A further preferred sub-group of compounds of this invention is that of formula (III): EMI8.1 and pharmaceutically acceptable salts and cleavable esters thereof wherein E' is a methoxycarbonyl or c.yano group, and p is zero or one. Another preferred sub-group of compounds of this invention are those of the formula (IV): EMI9.1 and pharmaceutically acceptable salts and cleavable esters thereof wherein E' is a methoxycarbonyl or cyano group, and B is a cation, hydrogen atom or a benzyl, phenyl, methylphenyl or indanyl group. Yet another preferred sub-group of compounds of this invention is that of the formula (V): EMI9.2 and pharmaceutically acceptable salts and cleavable esters thereof wherein E' is a methoxycarbonyl or cyano group, and R12 is phenyl or p-hydroxyphenyl. A particularly preferred class of compounds of this invention is that of the formula (VI): EMI9.3 and pharmaceutically acceptable salts and cleavable esters thereof wherein E' is a methoxycarbonyl or cyano group. Preferred compounds of this invention include: (2R,5R,6S) sodium 1-aza-3-methoxycarbonyl-6-[D,&alpha;-(4- ethyl-2,3-dioxopiperazine-1-carboxylamino)phenylacetamido] bicyclo[3. 2.O]heptan-7-one-2-carboxylate, (2R,5R,6S)sodium 1-aza-3-methoxycarbonyl-6-phenylacetamido-bicyclo[3.2. heptan-7-one-2-carboxylate, (2R,5R,6S) sodium l-aza3-methoxycarbonyl-6-phenoxyacetamido-bicyclo[3.2.0]heptan 7-one-2-carboxylate , (2R,5R,6S) sodium l-aza-3-methoxycarbonyl-6-tD,2-(2-(^ aminosulphonylanilino)-4-hydroxy- pyrimidyl-5-aminocarbonylamino)-2-(4-hydroxyphenyl) acetamido]bicyclo[3.2. 0]heptan-7-one-2-carboxylate, and (2R,5R,6S) sodium 1-aza-3-methoxycarbonyl-6-[D,2-(2 (4- aminosulphonylanilino) - 4-hydroxypyrimidyl- S-amino- carbonylamino)-2-(phenyl)acetamido]bicyclo[3.2.0]heptan 7-one-2-carboxylate. Suitable pharmaceutically acceptable salts of the compounds of the formulae (I) - (VI) include metal salts for example aluminium, sodium, potassium, calcium and magnesium, and ammonium or substituted ammonium salts. An example of a particularly apt substituted ammonium salt is the'p-toluidine salt. Particularly apt metal salts are the sodium, potassium, calcium and magnesium salts. A preferred salt is the sodium salt. A preferred salt is the potassium salt. The compounds of the formulae (I)-(VI) are aptly in the form of a free carboxylic acid. if a free amino group is present in the group RCONH and the carboxylate is in the form of a free acid then a zwitterion may be formed. For example the compound of the formula (V) may be depicted as a zwitterion. If the group R in the compound of the formula (II) contains an ester group cleavable by hydrogenolysis as hereinbelow described, then a di-acid may be formed. Such di-acids may be presented in the form of a di-salt, suitable pharmaceutically acceptable salts for d carboxy group E being as hereinbefore described. Cleavable esters of the compounds of the present invention include those cleavable by hydrogenolysis and those cleavable by ready hydrolysis in the human body. Suitable esters that are cleavable by hydrogenolysis include benzyl esters wherein the phenyl part is optionally substituted by 2 lower alkyl group of 1 to 6 carbon atoms, a lower alkoxy group of 1 to 6 carbon atoms, a chlorine or bromine atom or a nitro group. Esters cleavable by hydrogenolysis are most useful as intermediates to other compounds of this invention. Suitable esters that are cleavable in the human body, that is to say in-vivo hydrolysable include :those of sub-formulae (g), (h) and (j): -CO-O-CHR1-O-CO-RZ (g) -CO-O-CHR1-O-CO-OR2 (h) EMI11.1 wherein R1 is a hydrogen atom or a methyl group, R2 is an alkyl group of up to 4 carbon atoms or a phenyl or benzyl group and R3 is a -CH=CM-, 1,2-phenylene or 4,5-dimethoxy-1,2-phenylene group. In-vivo hydrolysable esters are those esters which hydrolyse in the human body to produce the parent acid or its salt. Such esters may be identified by administration to a test animal such as a rat or a mouse by intravenous administration and thereafter examining the test animal's body fluids for the presence of the compound of the formula (I) or its salt. Particularly apt in-vivo hydrolysable esters include the acetoxylmethyl, pivaloyloxymethyl, a-acetoxy- ethyl, a-pivaloyloxyethyl, -ethoxycarbonyloxyethyl, phthalidyl and 3 4-dimethoxyphthalidyl ester. A preferred ester group is the phthalidyl ester. Esters of the compounds of the formula (I) if desired, may be presented in the form of their acid addition salts if an amino group is present in either of groups R1 or R2. The acid used to form the salt will most suitably be pharmaceutically acceptable, but nonpharmaceutically acceptable acid addition salts are also envisaged, for example as intermediates in the preparation of the pharmaceutically acceptable salts by ion exchange. Suitable pharmaceutically acceptable acid addition salts include those of inorganic and organic acids, such as hydrochloric, phosphoric, sulphuric, methanesulphonic, toluenesulphonic, citric, malic, acetic, lactic, tartaric, propionic and succinic acid. Most suitably the acid addition salt is provided as a solid and preferably as a crystalline solid. The compounds of the formulae (I)-(VI) are generally provided as racemic mixtures. It is believed that the optical isomer possessing greatest antibacterial activity is that depicted in the compound of the formula (Ia) EMI13.1 and pharmaceutically acceptable salts and in-vivo hydrolysable esters thereof wherein R and E are as defined in relation to a compound of the formula (I). This depicted optical isomer has the configuration 2R, 5R, 6S. The compounds of the formulae (I)-(VI) may be provided with either the R- or S- configuration at C-3 or may be provided as a mixture thereof. The compounds of this invention are preferably provided in substantially pure form contaminated with not more than 25% of impurities, suitably not more than 15% and preferably not more than 5%. Examples of possible impurities include other ss-lactams such as those of European Patent Application Number 81300479.3. Thus in another aspect of this invention there is provided an isolated compound of the formula (I), free of other ss-lactams. In another aspect of this invention there is provided a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof as hereinbefore defined and a pharmaceutically acceptable carrier. Such compositions are normally provided in unit dose form containing from 50 to 500 mg or more usually from 100 to 250 mg of a compound of this invention. The compositions of this invention are usuaily adapted for administration to animals including humans. Such compositions may be formulated in a conventional manner for antibacterial agents, for example in a similar manner to that known from penicillins and cephalosporins. The compounds of this invention may be provided in orally administrable form, for example as tablets or capsules. The compounds of this invention may be provided in a form suitable for administration by injection or infusion, for example in the form of a sterile salt such as the sterile sodium salt sealed in a vial ampoule. It is believed that infections most readily treated by the compounds of this invention are those due to strains of Bacillus, Staphylococcus and Streptococcus. The present invention also provides a process for the preparation of a compound of the formula (I) or pharmaceutically acceptable or cleavable ester thereof which process comprises the reduction of a compound of the formula (VII): EMI15.1 wherein Ra is a hydrogen atom or carboxy-blocking group, E is as defined in relation to formula (I) and G is a group RCONH- wherein R is as defined in relation to formula (I) or G is an azido, amino or protected amino group; and thereafter i) if G is azido or protected amino converting G to amino, ii) acylating any compound wherein G is amino with an N-acylating derivative of a carboxylic acid of the formula (VIII): RCO2H (VIII) wherein R is as hereinabove defined and any group capable of being acylated is optionally protected: iii) converting an ester to form an acid or pharmaceutically acceptable salt, iv) converting an acid or salt to form a cleavable ester. Preferably G is a group RCONH. The reduction of the compound of the formula (VII) may be suitably effected by hydrogenation, preferably in the presence of a transition metal catalyst. The pressure of hydrogen used in the reaction may be low, medium or high but in general an approximately atmospheric or slightly super-atmospheric pressure of hydrogen is preferred. The transition metal catalyst employed is preferably palladium on charcoal or on calcium carbonate. The hydrogenation may be effected in any inert solvent in which the ester is soluble such as aqueous dioxan or the like. If this hydrogenation is performed on a compound of the formula (VII) wherein Ra is a salt-forming cation or hydrogenolysable group and is carried out in the presence of a base then a salt of the compound of the formula (I) is produced. Suitable bases for inclusion include Narc03, KHC03, Na2C03, K2C03, CaC03, MgC03, LiHC03, NH4OCOCH3 and the like. If no base is present then hydrogenation leads to the preparation of an acid within formula (I) which may then be neutralised if desired to yield a salt. Suitable bases which may be used to neutralise acids within formula (I) include Lion, NaOH, NaHC03, KOH, Ca(OH)2 and Ba(OH)2. An alternative method of hydrogenation suitable for use in this procedure is catalytic transfer hydrogenation using a transition metal catalyst. The transition metal catalyst employed is preferably palladium, for example palladium on carbon, palladium on barium sulphate or palladium black. It is preferred to use palladium on carbon, for example 10% palladium on charcoal. Suitable solvents include those in which the compound is soluble, for example ethanol, dimethylformamide, dimethylacetamide and mixtures thereof. In catalytic transfer hydrogenation a hydrogen donor is used (not hydrogen gas). Suitable hydrogen donors include cyclohexene and 1, 4-cyclohexadiene. The reaction is conveniently performed at an elevated temperature suitably between ambient and 100 C, more suitably between 300C and 800C. It is sometimes suitable to perform the reaction at reflux temperature. The term "acylating derivative of a carboxylic acid" includes any N-acylating compound suitable for the performance of analogous reactions with 6-aminopenicillanic acid or 7-aminocephalosporanic acid or salts or esters thereof, for example an acid halide, a mixed anhydride or other reactive derivative such as that produced by the reaction of an acid with an enzyme or a condensation promoting agent such as dicyclohexylcarbodi-imide or its chemical equivalent. Reactive groups present in such acylating agents may be protected in conventional manner. Suitable N-acylating compounds may be summarised by the formula (IX): RCO-W (IX) wherein R is as defined in relation to a compound of the formula (I) and W is a readily displaceable group. Most suitably W is a bromine atom. Preferably W is a chlorine atom. Reduction of the azido group to an amino group may be performed in conventional manner. Suitably G is a protected amino group, which is protected in conventional manner known in the art. Any group R that contains a reactive moiety such as NH2 or CO2H may be suitably protected during the process of this invention. For example an amino group may be reacted with a p-nitrobenzyloxycarbonyl halide to provide a p-nitrobenzyloxycarbonylamino moiety which is cleavable on hydrogenation to yield an amino moiety. Suitable carboxyl-blocking derivatives for the group -CO2R in formulae (VII) include salts, esters, and anhydride derivatives of the carboxylic acid. The derivative is one which may readily be cleaved at a later stage of the reaction. The salts need not be pharmaceutically acceptable. Suitable salts include inorganic salts, for example metal salts such as silver or mercuric salt, or alkali metal salts such as the lithium or sodium salt, and tertiary amine salts. Suitable ester-forming carboxyl-blocking groups are those which may be removed under conventional conditions, and include those of sub-formulae (L)-(M) as hereinbefore defined. Such groups for Ra include benzyl, p-methoxybenzyl, 2,4, 6-trimethylbenzyl, 3, 5-di-t-butyl-4- hydroxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl, 2,2, 2-trichloroethyl, 2,2,2-tribromoethyl, acetonyl, 2-methylallyl, t-butyl, t-amyl, diphenylmethyl, triphenylmethyl, methyl, ethyl, allyl, adamantyl, o-nitrobenzyl, 2-benzyloxphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, methoxymethyl, a silyl, stannyl or phosphorus-containing group, or an in-vivo hydrolysable ester. The carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular Ra group, for example, acid - and base catalysed hydrolysis, or by enzymically - catalysed hydrolysis, photolysis or by hydrogenation. The hydrolysis must of course by carried out under conditions to which the groups on the rest of the molecule are stable. The salts of acids of formula (I) may be converted to esters in conventional manner. Suitable methods include the reaction of an alkali metal salt such as a sodium or potassium salt with a reactive halide or sulphcnate ester such as a bromide, chloride, mesylate or tosylate, for example bromophthalide. Such esterification may be carried out under conventional conditions, for example in dimethylformamide at room temperature. The compounds of the formula (VII) may be prepared by the methods disclosed in European Patent Application 81300479.3 (Publication Number 0034443) which is incorporated herein by reference. Example 1 Benzyl 3,3-Dimethyl-2-nitroacrylate (1) EMI21.1 Benzyl 3,3-dimethylacrylate (80 g) was added dropwise to a well stirred mixture of fuming nitric acid (157 ml. 95%) and water (34 ml) at -20 over 1H, (cf. A.G. Brown and T.C. Smale, J.Chem. Soc. Perkin 1, 65, 1972). After 2h at -20 and warning to 0 for 2h, the reaction mixture was poured Sinto ice (800 ml) and extracted with chloroform (3 x 200 ml). The combined organic extracts were washed successively with water (3 x 200 ml), saturated sodium hydrogancarbonate solution (2 x 350 ml), brine (2 x 200 ml), dried (MgSO4) and evaporated to an oily residue. Chromatography on silica H gave the product (1; 36 g) as an oil, #max. (film) 1715, 1650, 1530, 1370 cm-1; 106 ppm (CDCl3) 1.98 (3H, s), 2.23 (3H, s), 5.20 (2H, s), 7.40 (5H, m). (Found: C, 61.2; H, 5.7; N, 6.0; C12H13NO4 requires C, 61.3; H, 5.5; N, 6.0%). Further elution of the column provided the o-nitro-benzyl 2-nitro-3,3 dimethyl acrylate (2), and p-nitro-benzyl 2-nitro-3,3-dimethyl acrylate (3) 15as white solids (47 g). Ortho isomer (2) #max. (CHCl3) 1755, 1650, 1530, 1350 cm-1; # ppm (CDCl3) 2.03 (3H, s), 2.30 (3H, s), 5.73 (2H, s), 7.4 - 7.8 (4H, m), para isomer (3) #max. (CDCl3) 1735, 1650, 1550, 1350 cm-1; #ppm (CDCl3) 2.03 (3H, s), 2.30 (3H, s), 5.36 (2H, s), 7.52 and 8.30 (4H, ABq, J 9Hz). Example 2 Benzyl 2-Amino-(N-cinnamylidiene)-3,3-dimethyl acrylate (5) EMI22.1 Benzyl 3,3-dimethyl-2-nitroacrylate (; 17.2 g) was converted to benzyl 2-amino-3,3-dimethylacrylate (4; 12.2 g) using the same conditions as for the corresponding methyl ester (A. G. Brown and T. C. Smale, J. Chem. Soc. Perkin I, 65, 1972). #max. (CHCl3) 1710, 1960, 1640 cm-1; # ppm (CDCl3) 1.70 (3H, s), 2.05 (3H, s), 2.8 - 3.7 (2H, m, exch.), 5.17 (2H. s), 7.31 (5E, s). The crude product (4; 80% pure by tlc and nmr) in dry methylene dichlorode (100 ml) was vigorously stirred with trans-cinnamaldehyde (7.72 g) and anhydrous magnesium sulphate (7 g) for (17h. The mixture was filtered, evaporated, and dried = vacuo to give the Schiff base (5) as a red gum (19.7 g); #max. (EtOH) 297 nm (#27600); #max. (CHCl3) 1710, 1675, 1625 cm-1; # (CDCl3) 1.91 (3H, s), 2.00 (3H, s), 5.26 (2H, s), 6.5 - 7.6 (7H, m), and 7.75 (1H, d, J, Example 3 cis 3-Azido-1-(1-benzyloxycarbonyl-2-methylprop-1-enyl)-4-styrylazetidin-2-one (6) EMI23.1 Azidoacetic acid (9.36 g) was dissolved in dry methylene dichloride (80 mi) at 0' under argon and trifluoroacetic anhydride (13.05 ml) added dropwise over 10 min. After 15 min., triethylamine (12.99 ml) in methylene dichloride (20 ml) was carefully added dropwise, over 15 min., and stirring at 0 continued a further 45 min. The solution was transferred under argon to a dropping funnel, cooled to -76', and added over 1h to a mixture of the Schiff base (5) (19.7 g) and triethylamine (12.99 ml) in methylene dichloride (160 ml) at 0 . After a further 1h at 0 the solution was diluted with methylene dichloride, washed successively with water, dilute aqueous sodium hydrogencarbonate, brine, dried (MgSO4) and evaporated. Chromatography of the residne on silica H afforded the product (6; 12.6 g) as a red-orange gum; # (EtOH) 256 nm (#23,400) #max. (CHCl3) 2115, 1760, 1720 cm-1; # ppm (CDCl3) 1.98 (3H, s), 2.21 (3H, s), 4.63 (1H, dd, J 7 and 10Hz), 4.79 (1H, d, J 7Hz), 5.08 and 5.32 (2H, ABq. J 15Hz), 6.11 (1H, dd, J 10 and 20Hz), 6.48 (1H, d, J 20Hz), 7.29 (5H, s), 7.37 (5H, s). (Found: C, 68.4; H 5.5; N, 14.0; C23H22N4O3 requires C, 68.7; H, 5.5; N 13.9%) Example 4 cis 1-(1-Benzyloxycarbonyl-2-methylprop-1-enyl)-3-phenoxyacetamido4-styryl-azetidin-2-one (8) EMI24.1 To the ss-lactam (6; 6.38 g) in dry methylene dichloride (125 ml) at 0 was added triethylamine (2.45 ml). Hydrogen sulphide was bubbled through the mixture for 5 min. and the resulting dark solution stcod at 0 for 1.5H. The solvent was then removed under reduced pressure and the residue re-evaporsted (x 3) from methylene dichloride, to afford the crude amine (7) an an orange solid. With- out further purification, the ss-lactam (7) was dissolved in dry methylene dichloride (60 ml) at -20 and triethylamine (2.45 ml) added, followed by dropwise addition of phenoxyacetyl chloride (2.45 ml) in methylene dichloride (5 ml) over 10 min. The solvent was evaporated and the residne taken up in ethyl acetate', washed successively with water, dilute aqueous sodium bydrogen- carbonate, brine, dried (MgSO4) and evaporated to a gum. Chromatography on silica H provided the product (8; 5.5 g) as a white crystalline solid, m. p. 107 - 108 (ethyl acetate - light petroleum 60 - 80 ), #max. (EtOH) 258 nm (23,200); #max. (CHCl3) 3245, 1755, 1690, 1650 sh, 1630 sh, cm-1; # ppm (CDCl3) 2.05 (3H, s), 2.18 (3H, s), 4.44 (2H, s), 4.67 (1H, dd, J 5 and 8Hz), 5.08 and 5.27 (2H, ABq, J 12Hz), 5.20 (1H, dd, J 5 and 8Hz), 6.04 (1H, dd, J 8 and 16Hz), 6.47 (1H, d, J, 16Hz), 6.7 - 7.5 (10H, m), 7.63 (1H, d, J 8Hz, exch.). (Found: C, 72.7; H 5.9; N, 5.4; C31H30N2O5 requires C, 72.9; H, 5.9; N, 5.5%). Example 4 cis 1-(1-Benzyloxycarbonyl-2-methylprop-1-enyl)-4-(1,1-dimethoxymethyl)-3phenoxyacetamido-azetidin-2-one (10) EMI25.1 Ozonised oxygen was bubbled through a solution of the ss-lactam (8; 3.06 g) in methylene dichloride (30 ml) at -76 for 1.5 h when cleavage of the 4-styryl moisty was complete. Argon was then bubbled through the solution for 20 min followed by the addition of triphenylphosphine (1.56 g) in a little methylene 5 dichloride, and the reaction allowed to reach ambient temperature. After 1.5 h the solvent was removed and the residual aldehyde (9) immediately taken up in metahnol (50 ml) and 2,2-dimethoxypropane (20 ml). The solution was refluxed for 15 h in the presence of ptoluene sulphonic acid as catalyst. The reaction mixture was diluted with ethyl acetate, washed with dilute aqueous sodium 10 hydrogencarbonate, brine, dried (MgSO4) and evaporated to a residual oil. Chromatography on silica H provided the product (10; 26 g) #max, (CHCl3) 3420, 1755, 1715 sh, 1685, 1630 cm-1; # ppm (CDCl3) 2.02 (3H, s), 2.20 (3H, s), 3.22 (6H, s), 4.17 (1H, dd, J 3 and 6 Hz), 4.33 (1H, d, J 3Hz), 4.60 (2H, s), 5.08 and 5.30 (2H, ABq, J 12 Hz)., 5.47 (1H, dd, J6 and 10Hz), 6.8-7.5 (10Hz, m), 15 7.6 (1H, d, J 10 Hz). (Found: C, 64.7; H, 6.2; N, 5.8; C26H30N2O7 requires C, 64.7; H, 6.2; N, 5.(%). Example 6 cis 4-(1,1-Dimethoxymethyl)-1-(1-hydroxy-1-benzyloxycarbonylmethyl)-3-phenoxyacetamido-azetidin-2-one (11) EMI26.1 Ozonised oxygen was bubbled through the ss-lactam (10; 2.4 g) in dry methylene dichloride (20 ml) at -20 for 30 min. Argon was then bubbled through the solution for 10 min, which was then equi- librated with ambient temperature over 45 min. Glacial acetic acid (15 ml) was added, followed by activated zinc dust (3.6 g) portionwise with occasional cooling over 10 min. After 2h at room temperature the mixture was filtered, diluted with ethyl acetate, and washed succesively with water (x 3), saturated aqueous sodium hydrogencarbonate (x 2), brine, dried (MgSO4) and evaporated. Chromatography on silica 9 afforded the less polar isomer (11) (900 mg), #max (CHCl3) 3500, 3420, 1780, 1758 and 1690 cm-1; a (250 ) (CDCl3) 3.31 (3It, s), 3.32 (3H, s), 3.85 (lIt, di J 2.7 and 5,5Hz), 4.24 (1H, d, J 2.7Hz), 4.26 (1H, d, J 10.5 Hz, exch. D2O) 4.47 and 4.55 (2H, ABq, J 14.9Hz), 5.19 and 5.29 (2H, ABq, J 12.1 Hz), 5.52 (1H, dd, J 5.5 and 10.Hz), 5.63 (1H, d, J 10.5Hz, becomes s on D20 exch.) 6.85 - 7.4 (10H, series of n) and 7.51 (1H, d, J 10.5Hz). (Found: C, 60.3; H, 6.0; N 6.1. C23H26N2O8 requires C, 60.3; H, 5.7; N, 6.1%). Further elution provided the more polar isomer (11) (1 g), #max. (CHCl3) 3500, 3415, 1780, 1750 sh and 1690 cm-1; # (250 MHz) (CDCl3) 3.22 (3H, s), 3.35 (3H, s), 4.05 (1H, d, J 6.6Hz, exch. D2O), 4.15 (1H, dd, J 3.9 and 5.5Hz), 4.3 (1H, d, J 3.9Hz), 4.48 and 4.54 (2H, ABq, J 15.2Hz), 5.2 and 5.31 (2H, ABq, J 12.1Hz), 5.43 (1H, d, J 6.6Hz, collapses to s on exch. D2O), 5.51 (1H, dd, J 5.5 and 9.7Hz), 6.9 - 7.4 (bIt,, series of m), and 7.5 (1H, d, J 9.7Hz). (Found: C, 60.2, H, 5.7; N, 6.2%). Example 7 cis 1-[1-Benzyloxycarbonyl-2-methoxycarbonyl-2-triphennylphosphoranylidene-ethyl]-4-(1,1-dimethoxymethyl)-3-phenoxyacetamido-azetidin-2-one (13) EMI28.1 The hydroxy-compound (11) (210 mg) was dissolved in dry tetrahydrofuran (10 ml) and cooled to 20 C. 2,6-Lutidine (74 mg) was added, followed by dropwise addition of thionyl chloride (82 mg) in dry tetrahydrofuran (1 1) during 10 min. After 10 min. the mix- ture was diluted with dry toluene, filtered, and the filtrate was evaporated and dried in vacuo for 15 min. to give (12) as a gum. - The total crude product (12) was dissolved in dry methylene dichloride (10 ml) containing carbomethoxymethylenetriphenylphos phorane (337 mg). The solution was left at room temperature under argon for 40h, then evaporated and the residue chromatographed an silica H to give the prow act (13) as an inseparable mime of isomers (153 mg), # max. (CHCl3) 3390, 1678, 1620cm-1 Example 8 (2RS, 5RS, 6RS) Benzyl 1-Aza-3-methoxycarbonyl-6-phenoxyacetamidobicyclo-[3.2.0]-hept-3-en-7-one-2-carboxylate (14) and cis 1-[(1RS -1-Benzyloxycarbonyl-2-methoxycarbonyl-2-triphenylphosphoranylidene -ethyl]-4-formyl-3-phenoxyacetamido-azetidin-2-one (15) EMI29.1 The azetidinone (13) (54 mg) was dissolved in 95% aqueous trifluoroacetic acid (1 ml) at room temperature, and after 3h. the solution was evaporated, tolnene added and the process repeated (12). The residue was taken up in ethyl acetate and the solution washed successively with aqueous NaHCO3, brine, dried (MgSO4) and evaporated. Chromatography on silica It provided the product (14) (13 mg), # max. (EtOH) 261 (#2332), 268 (2219), 275 cm (1623); # max. (CHCl3) 3410, 1790, 1735 and 1690cm-1; # ppm (CDCl3) 3.65 (3H, s), 4.50 (2H, s), 4..98 (1H, ddd, J 5.5, 3.3 and # 1.5Hz), 5.16 (2E, s), 5.37 (1H, dd, J 3.3 and #1.8Hz), 5.54 (1H, dd, J7 and 5.5Hz), 6.80 (1H, di, J 1.8 and 1.5Hz) and 6.8 - 7.4 (11H, m). (Found: C, 63.7; H, 5.2; N, 5.8. C24H22N2O7 requires C, 64.0; H, 4.9; N, 6.2%). (Found: M+ - CH2Ph+, 359.0879, C17H15N2O7 requires M - CH2Ph+, 359.0873). Further elution of the column provided the aldehyde (15) (35 mg) (contaminated with some triphenylphosphine oxide), # max. (CHCl3) 3375 br, 1760, 1725, 1685 and 1615 cm-1. Example 9 (2SR, 5RS, 6SR) Benzyl 1-Aza-3-methoxycarbonyl-6-phenoxyacetamidobicyclo-[3.2.0]-hept-3-en-7-one-2-carboxylate (16) EMI30.1 The aldehyde (15) (35 mg) (contaminated with triphenyl phosphine oxide) was gently refluxed in ethyl acetate for 5 the solution cooled and evaporated to give an oil. Chromatography on silica H provided the product (16) as an amorphous white solid (15 mg)#max. (EtOH) 261 (e2476), (2517), 275 nm (1982); #max. (CHCl3)3410, 1785, 1735 and 1690 cm-1; 8 ppm (CHDCl3) 3.64 (3H, s), 4.50 (2H,s), 4.83 (2H, m) 5.22 (2H, s), 5.43 (1H, m), 6.79 (1H, m), 7.03 (1H, d,J 7Hz) and 6.8 - 7.4 (10H, m). (Found: C,64.0; H, 5.2; N,5-7; M+ 450-1425. C24H22N2O7 requires C, 64.0:H, 4.9; N, 6.2%, M 450.1433). Example 10 (2RS, 5RS, 6SR) 1-Aza-3-methoxycarbonyl-6-phenoxyacetamido bicyclo [3.2.0]-heptan-7-one-2-carboxylic acid (17) and (2RS, 5RS, 6SR) Methyl 1-Aza-3-methoxycarbonyl-6-phenoxyacetamido -bicyclo [3.2.0]-heptan-7-one-2-carboxylate (18) EMI31.1 The ester (14) (100 mg) was dissolved in dioxan (12 ml) and water (3 ml) and hydrogenated using 10% Pd/C catalyst (50 mg) for 2h# The reaction mixture was filtered, and the filtrate evaporated to dryness, follaweK by re-evaporation from ethnnol, then toluene. Trituration with ethyl gave a white solid (17) (80 mg), #max. (EtOH) 262 (#1644), 268 (1675), 275nm (1279); #amx. (KHr) 3400 br, 1770, 1725 and 1670 cm-1; 8 ppm [(CD3)2SO2] inter alia 1.88 - 2.2 (2R, m), 3.62, 3.64 (s, together 3H), 4.28 (1H, d, J 7Hz). 4.59 (2H, s), 5.58 (1H, dd, J 5 and 9Hz), 6.9 - 7.1 (3H, m), 7.2 - 7.4 (2H,m) and 8.87 (1H, d, J 9 The minimum inhibitory concentration (MIC) of this compound required to inhibit the growth of various bacteria in nutrient broth are tabulated below: : Organism MIC ( g/ml) E. coli 250 Klebsiella aerogenes 250 Proteus mirabilis 62 S. typhimurium 250 - B. subtilis 2 Staph. aureus Oxford < 0.5 Staph. aureus Russell* 62 Strep. faecalis 8 Strep. pyrogenes < 0.5 *ss-lactamase-producing benylpenicillin-resistant strain. The acid (17) (60 mg) was dissolved in ethyl acetate (10 ml) and dimethyl suphixide (2 ml) and an ethereal solution of diazomethane added. Argon was then bubbled through the solution and the reaction mixture washed with water (= 3), brine dried (MgSO4) and evaporated. Chromatography on silica It gave the product (18) (31 mg), #max. (EtOH) 262 (#1070), 268 (1388), 275nm (1195); #max. (CHCl3), 3410, 3350, 1785, 1745 and 1690 cm-1; # ppm (250MHz) (CDCl3) 2.16 (2H, ABq, J 14Hz, higher field arm further coupled, t, J 5Hz; lower field arm further coupled, t, J 8Hz), 3.54 (1H, ddd, J 8, 5 and 3.5Hz), 3.69, 3.72, 3.77, 3.79 (s, together 6H), 4.29 (1H, ddd, J 8, 6 and 5Hz), 4.55, 4.57 (s, together 2H), 4.82 (1H, d, J 3.5Hz), 5.68 (1H, dd, J 9 and 5Hz), 6.8 - 7.4 (5H, series of multiplets) and 8.08 (1H, d, J 9Hz). (Found: M+ 376.1282, C18H20N2O7 requires M 376.1270). Example II N-Cinnamylidene-p-methoxymethoxyaniline (20) EMI33.1 p-Methoxymethoxyaniline (19; T. Fukuyama, R.K. Frank and C.F. Jewell, Jr., J. Amer. Chem. Soc., 1980, 102, 2122) (13.8 g) was dissolved in dry methylene chloride (200 ml) under argon, and cinnamaldehyde (13.3 g) and dry magnesium sulphate (10 g) added. The mixture was stirred at room temperature for 15 h, filtered, and the filtrate evaporated to give a yellow solid (20) (24 g) m.p. 88 - 88.5 (ethyl acetate/light petroleum) #max. (EtOH) 296 (#23,245) and 345 n.m. (23, 206); #max. (CHCl3) 1625 and 1605 cm-1; # p.p.m. (CDCl3) 3.47 (3H, s), 5.16 (2H, s), 6.95 - 7.6 (9H, m), 8.28 (1H, dd, J 2 and 4 Hz). (Found: C, 76.1; H, 6.5; N, 5.0; C17H17NO2 requires C, 76.4; H, 6.4; N, 5.2%). Example 12 cis 3-Azido-1-(p-methoxymethoxyphenyl)-4-ethyl-ezetidin-2-one (21) EMI34.1 The Schiff base (20) (24 g) was converted into (21) (26.1 g) as described in Example 2, m.p. 111 - 112 C; (ethyl acetate/light petroleum) #max. (CHCl3) 2120, 1755 and 1650 cm-1; # ppm (CDCl3) 3.38 (3H, s), 4.7 - 4.95 (2H, m), 5.06 (2H, s), 6.19 (1H, dd, J 7 and 17 Hz), 6.81 (1H, d, J 17 Hz) and 6.9 - 7.5 (9H, m). (Found: C, 65.1; H, 5.1; N, 15.9; C19H18N4O2 requires C, 65.1; H, 5.1; N, 16.0%). Example 13 cis 3-Asido-4-styryl-azetidin-2-one (22) EMI35.1 The lactam (21) (350 mg ) in tetrahydrofuran (10 ml) was cooled to 0 C and ceric ammonium nitrate (274 g) in water (4 ml) added dropwise over 2 - 3 min to the vigorously stirred solution (see ref. in Example II). After 10 min. solid sodium sulphite was added to decolourise the mixture, which was then poured into ethyl acetate and dilute sodium hydrogencarbonate. The organic layer was separated, washed with brine, dried and evaporated. Chromatography of the residue on silica afforded the product (22) (149 mg), m.p. 106 (ethyl acetate/light petroleum)#max. (CHCl3) 3400, 2110, 1775 and 1650 cm-1; #ppm (CDCl3) 4.48(1H, dd, J 4.4 and 7Hz), 4.81 (1h, dd, J 1.8 and 4.4 Bz, becomes d, J 4.4 Hz on i=adiation at d 6.56), 6.19 (1H, dd, J 7 and Hz), 6.56b (1H, s), 6.69 (1H,d, J 16Hz) and 7.2-7.5 (5H, m). (Found: c,61.7; H,25.9; C11H10N4O requires C,61.7; H,4.7; Example 14 cis 3-Phenoxyacetamido-4-styryl-acetidin-2-one (23) EMI36.1 The azide (22) (75 mg)was dissolved in dry methylene chloride (10 ml) at 0 C, and triethylamine (80 mg) added. Hydrogen sulphide was bubbled through the solution for 5 min, and the solution allowed to warm to room temperature. liter 2 h the solvent was evaporated, the residue dissolved in methylene chloride and the process repeated. The crude amine was dissolved in methylene chloride at -10 C and triethylamine (44 mg) aded , followed by phenoxyacetyl chloride (65 mg) in methylene chloride (1 ml). The solution was washed with diluet citric acid, brine, dried and evaporated. Chromatography on silica eluting with methylene chloride/ethyl acetate gave the product (23) (70 mg); m.p. 181-182 (ethyl acetate); #max.(EtOH) 258 a.m. (e 19,200);'max. (Nujol) 3290, 3225, 1780, 1730, and 1680 cm-1; #ppm ([CD3]2SO) (250M Hz) 4.43 (1H, dd, J 8.2 and 5Hz), 4.49 and 4.57 (2H,ddd, J 15Hz), 5.27 (1H, ddd, J 9.2 5 and ca. 0.5 Hz), 6.38 (1H, dd, J 16 and 8.2Hz), 6.65 (1H ,d,J 16Hz), 6.8-7.5 (10H, m), 8.53 (1H, d, J ca. 0.5Hz, exch. D2O) and 8.88(1H, d, J 9.2Hz, exch. D2O). (Found: c,70.8; H,5.7; N,8.5. C19H18N2O5 requires c,70.8; H,5.6; N,8.7%). Example 15 cis-1-(1-Benzyloxycarbonyl-l-hydroxymethyl)-3-phenyoxyacetamido 4-styry- azetidin-2-one (23) EMI37.1 Benzyl glyoxylate (1.23 g) was dissolved in dry benzene (120 ml) and the solution reflured for 1h with provision for the removal of water. The lactam (23)(1.98 g) was then added in dioxan (20 ml) and the reflux continued for a further lh. The solution was cooled to room temperature and triethylamine (62 mg) added. after 2h the solvents were evaporated off and the residue dissolved in toluene (50 ml) and allowed to crystallise at 0 C. Filtration afforded the product (24) as a mixture of isomers (2.23 g) The mother liquors from the crystallisation were evaprorated and chromatographed on silica to give the less polar isomer (24) (385 mg) m.p. 149-152 (ethyl acetate-hexane), #max (CHCl3) 3500, 3415, 1770, 1750, 1690 and 1655 sh cm-1; #ppm 4.25br (s, exch. D2O), 4.38 (2H, s), 4.47 (1H,dd, J 5.5 and 8Hz), 5.27 (2H , AA system ), 5.4 (1H, dd, J 5.5 and 9Hz), 5.42 (1H,s) , 6.03 (1H, dd, J 8 and 16Hz), 5.53 (1H, d, J 16Hz), and 6.7-7.5 (11H,m). (Found: c,69.1; H,5.3; N,5.8%). C28H26N2O6 requires C, 69.1; H, 5.3; N, 5.8%) Further elution provided the more polar isomer (24) (250 mg), m.p. 150-156 (ethyl acetate-hexane); #max. (CDCl3) 3500, 3410, 1770, 1750, 1690 and 1655 cm-1; #ppm (CDCl3) 4.4 (2H, s), latter signal obscures 1H broad singlet, 4.7 (IR, dd, J 5.5 and 8Hz), 4.92 and 5.14 (2H, ABq. J 12Hz), 5.42 (1H, s), 5.45 (1H, dd, J 5.5 and 9Hz), 5.91 (1H, dd, J 8 and 16Hz), 6.68 (1H, D, J 16Hz), and 6.7-7.5 (11H, m). (Found: c,69.4; H,5.5, N,5.7 C28H26N2O6 requires c,69.1, H,5.3; N,5.8%). Example 16 cis-1-[1-Benzyloxycarbonyl-2-methoxycarbonyl-2triphenylphosphjoranylidene ethyl]-3-phenoxyacetamido-4-styrylazetidin-2-one (26) EMI39.1 The hydroxy-compound (24) (0.972 g) was dissolved in dry tetrahydrofuran (20 ml) and cooled to -20 C. 2,6-Lutidine (0.322 g) was added, followed by dropwise addition of thionyl chloride (0.350 g) in dry tetrahydrofuran (2 ml) during 10 min. After 5 min. the mix- ture was diluted with dry toluene, filtered, and the filtrate was evaporated and dried in vacuo for 15 min. to give (25) as an oil. The total crude product (25) was dissolved in dry methylene dichloride (30 ml) containing carbomethoxymethylenetriphenylphosphorane (1.51 g). The solution was stirred at room temperature under argon for 2°h, then evaporated and the residne chromatographed on silica It to give the product (26) (1.35 g) as an inseparable mixture of isomer #max. (Nujol) 3330, 1765, 1760, 1732, 1690, 1685 and 1638 cm-1; (Found: c,72.8; H,3.5. C49H43N2 O7P requires c,73.3; H,5.4; N,3.5%). Example 17 (2RS, 5RS, 6RS) Benzyl 1-Aza-3-methoxycarbonyl-6-phenoxyacetamidobicyclo-[3.2.0]-hept-3-en-7-one-2-carboxylate (14) and cis 1 [(IRS)-l-Benzyloxycarbonyl-2-methoxycarbonyl-2triphenylphosphoranylidene ethyl]-4-formyl-3-phenoxyacetamido -azetidin-2-one (15) EMI40.1 Trifluoracetic acid (2.5 ml) was added to the p-lactam (26) (847 mg) in ethyl acetate (25 ml), and after 10 min. the solution was cooled to -76 and ozonised oxygen bubbled through until a pale blue colour persisted. Argon was passed through the solution for 20 min. followed by the addition of triphenylphosphine (275 mg) in ethyl acetate (1 mi), pre-cooled to -76 . After 45 min. the reaction mixture was transferred to an icebath and carefully neutralised with saturated acueous NaHCO3. The organic phase was separated, washed with brine (s 3), dried (MgSO4) and evaporated to an oil. Chromatography on silica E provided the products(14) (200 mg) and (15) (289 mg) (contaminated with some triphenylphosphine oxide) which were identical to those obtained in Example 8.

Claims: CLAIMS 1. A compound of formula (I): EMI41.1 or a pharmaceutically acceptable salt or cleavable ester thereof, wherein RCONH- represents an organic acylamino group, and E is a carboxy group or a pharmaceutically acceptable salt or C1-10 alkyl or substituted C1-10 alkyl ester thereof or is a cyano group. 2. A compound as claimed in claim 1 wherein E is carboxy or C 1-10 a lkoxycarbonyl 3. A compound as claimed in claim 1 or claim 2 wherein the group RCONH- represents a group of formula (e) or (f): EMI41.2 wherein R2 is a phenyl, thienyl or phenoxy group; R3 is a hydrogen atom or methyl group; R4 is a phenyl, p-hydroxyphenyl, cyclohexadienyl, or a 5- or 6- membered heteroaryl or hetero cyclyl group containing up to 3 hetero atoms selected from sulphur, oxygen and nitrogen, said group being optionally substituted by one two or three substituents selected from hydroxy, amino, halo and C16alkoxy; R5 is a hydroxy, amino or carboxylic acid group or phenyl, methylphenyl, indanyl, or Cl 6alkyl ester thereof, or amino, ureido, acylamino or acylureido. 4. A compound as claimed in claim 3 wherein RCONH represents phenoxyacetamido or phenylacetamido. 5. A compound as claimed in claim 1 selected from: l-Aza-3-methoxycarbonyl-6-[D,-(4-ethyl-2,3- dioXopiperazine-l-carboxylamino)phenylacetamico]- bicyclo[3.2.0]heptan-7-one-2-carboxylic acid; 1-aza-3-methoxycarbonyl-6-phenylacetamido bicyclo[3.2.0]heptan-7-one-2-carbonylic acid; l-aza-3-methoxycarbonyl-6-phenoxyacetamido bicyclo[3.2.0]heptan-7-one-2-carboxylic acid; l-aza-3-methoxycarbonyl-6-[D,2-(2-(4-amino sulphonylanilino)-4-hydroxypyrimidyl-5-amino carbonylamino)-2-(4-hydroxyphenyl)acetamido] bicyclol3.2.0]eDtan-7-one-2-carboxylic acid; l-aza-3-methoxycarbonyl-6-[D,2-(2-(4-amino sulphonylanilino)-4-hydroxypyrimidyl-5-amino carbonylamino)-2-acetamido]bicyclo [3.2.03heptan-7-one-2-carFoxylic acid; ; and pharmaceutically acceptable salts thereof. 6. A process for the preparation of a compound as claimed in claim 1 which process comprises the reduction of a compound of the formula (VII): EMI43.1 wherein Ra is a hydrogen atom or carboxy-blockir.g group, E is as defied in claim 1 and G is a group RCONH- wherein R is as defined in claim 1 or G is an azido, amino or protected amino group; and thereafter: i) if G is azido or protected amino converting G to amino; ii) acylating any compound wherein G is amino with an N-acylating derivative of a carboxylic acid of the formula (VIII): RCO,H (VIII) wherein R is as hereinabove defined and any group capable of being acylated is optionally protected; iii) converting an ester to form an acid or pharmaceutically acceptable salt; iv) converting an acid or salt to form a cleavable ester. 7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as claimed in any one of claims 1 to 5. 8. A compound as claimed in any one of claims 1 to 5 for use as an antibacterial agent.

Inventors: BRANCH, CLIVE LESLIE, PEARSON, MICHAEL JOHN
Applicants: BEECHAM GROUP PLC
Application year: 1982
Main classification: C07D487
IPC codes: A61P31, C07C205, C07D205, A61K31, C07D477, C07F9