NO882652L - Acyl. - Google Patents

Description

The present invention relates to acyl derivatives with the general formula

wherein X is -OCO-, -SCO-, -NHCO- or -OCONH-, is an acyl group; R 2 is hydrogen or lower alkoxy; and R3s

wherein R4,<R>41 and R411 are independently hydrogen or COR20O' wherein R200 is straight chain or branched lower alkyl, A and B are halogen, a, b, x, y and z are independently 0 (when a hydrogen atom is present at a ring position) or 1, except that at least two of x, y and z are always 1, and m is 0 or an integer from 1-8, as well as readily hydrolyzable esters and pharmaceutically acceptable salts of these compounds, and hydrates of the compounds of formula In or of their esters

or salts.

As used herein, the terms "lower alkyl" and "alkyl" mean both straight and branched chain saturated hydrocarbon groups having 1-8, and preferably 1-4, carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, tertiary butyl etc.

As used herein, the term "lower alkoxy" or "alkoxy" means a straight chain or branched hydrocarbonoxy group, wherein the "alkyl" moiety is a lower alkyl group as defined above. Examples include methoxy, ethoxy, n-propoxy and the like.

The term "halogen" or "halo" as used herein denotes all four forms, which are chlorine, bromine, iodine and fluorine, unless otherwise specified.

The term "acyl" used in connection with R 1 refers to all organic radicals which are derived from an organic acid, such as a carboxylic acid, by removal of the hydroxyl group. Although the R 1 group may be one of many acyl radicals, certain acyl groups are preferred, as described below.

By the term "aryl" is meant a substituted or unsubstituted aromatic component, such as phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl etc., in which said aryl group can have 1-3 suitable substituents, such as halo (fluorine, chlorine, bromine etc) ., hydroxy etc.

By the term "lower alkanoyl" or "alkanoyl" as used herein is meant a component of formula

wherein R 25 is hydrogen or C 1 -C 8 lower alkyl. Examples of such groups are acetyl, formyl, propionyl, n-butyryl etc.

With the expression "substituted phenyl" is meant phenyl mono- or di-substituted by e.g. halo (eg chlorine, bromine, fluorine etc), lower alkyl, amino, nitro or trifluoromethyl.

By the term "substituted alkyl" is meant a "lower alkyl" component which is substituted with e.g. halo (e.g. chlorine, fluorine, bromine etc), trifluoromethyl, amino, cyano etc.

By the term "lower alkenyl" or "alkenyl" is meant straight-chain or branched hydrocarbon groups having 2-6 carbon atoms and containing an olefinic double bond, i.e. radicals to compounds of the formula CnH2n, in which n is 2-6, e.g. allyl, vinyl etc.

By the term "aralkyl" is meant a hydrocarbon group having both aromatic and aliphatic structures, it is a hydrocarbon group in which a lower alkyl hydrogen atom is substituted by a monocyclic aryl group, e.g. by phenyl, tolyl etc.

The term 5-, 6- or 7-membered heterocyclic ring containing 1-4 nitrogen, oxygen and/or sulfur atoms is intended to represent the following groups: a 6-membered nitrogen-containing heteroring, e.g. pyridyl, piperidyl, piperidine, N-oxide-pyridyl, pyrimidyl, piperazinyl, pyridazinyl, N-oxide-pyridazinyl etc, a 5-membered pyrazolyl, pyrrolidinyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1.2.4- thiadiazolyl , 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,2 ,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl etc. and others. Each of these heterorings can further be substituted, and as substituents are mentioned e.g. lower alkyls such as methyl, ethyl, n-propyl etc, lower alkoxys such as methoxy, ethoxy etc, halogens such as chlorine, bromine etc, halogen-substituted alkyls such as trifluoromethyl, trichloroethyl etc, amino, mercapto, hydroxy, carbamoyl or carboxy -group etc

With the term "cyclolower alkyl" or "cycloalkyl" is meant a 3-6 membered saturated carboxylic part, e.g. cyclopropyl, n-cyclobutyl, n-cyclohexyl etc. "Cyclolaverealalkenyl" or "cycloalkenyl" means corresponding 3-7-membered unsaturated carboxylic components such as cyclohexenyl.

Exemplary acyl groups are those groups that have been used recently to acylate (3-lactam antibiotics, including 6-aminopenicillin acids and derivatives, and 7-aminocephalosporanic acid and derivatives; see, e.g., Cephalo- sporins and Penicillins, published by Flynn, Academic Press

(1972), Belgian Patent 866,038, published October 17, 1978, Belgian Patent 867,994, published December 11, 1978, U.S. U.S. Patent 4,152,432, issued May 1, 1979. patent 3,971,778, issued July 27, 1976 and U.S. patent 4,173,199, issued October 23, 1979. Portions of these references describing various acyl groups are incorporated herein by reference. The following list of acyl groups is presented to further exemplify the term "acyl", without intending to limit the term to only those groups set forth:

(a) Aliphatic groups having the formula

wherein R 5 is alkyl, cycloalkyl; alkoxy; alkenyl; cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio or cyanomethylthio groups.

(b) Carbocyclic aromatic groups having the formula

wherein n is 0, 1, 2 or 3; R 8 , R 7 and R 8 are each independently hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or aminomethyl; and R is amino, acylamino, hydroxy, a carboxyl salt, protected carboxy such as

benzyloxycarbonyl, formyloxy, azido or a sulfosalt, and M is a cation.

Preferred carbocyclic aromatic acyl groups include those having the formula

(R90 is preferably an amino group, a hydroxy group or a carboxyl or sulfo salt).

Examples of other acyl groups suitable for the present invention are sulfophenylacetyl, hydroxysulfonyloxyphenylacetyl, sulfamoylphenylacetyl, (phenoxycarbonyl)phenylacetyl, (p-tolyloxycarbonyl)phenylacetyl, formyloxyphenylacetyl, carboxyphenylacetyl, formylaminophenylacetyl, benzyloxycarbonylphenylacetyl, 2-(N,N- dimethylsulfamoyl)-2-phenylacetyl, 2-bromo-2-thienylacetyl etc.

(c) Heteroaromatic groups of formula

wherein n is 0, 1, 2 or 3; Rqq is as defined above; and R 101 is a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and/or sulfur atoms. Exemplary heterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl and tetrazolyl. Examples of substituents are halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl with 1-4 carbon atoms or alkoxy with 1-4 carbon atoms.

Preferred heteroaromatic acyl groups include those of the above formulas, where R is 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyridin-2-yl, 2-amino-1,3, 4-thiadiazol-5-yl, 2-thienyl, 2-furanyl, 4-pyridinyl or 2,6-dichloro-4-pyridinyl.

(d) [[(4-substituted-2,3-dioxo-1-piperazinyl)carbonyl]-amino]arylacetyl groups of formula

wherein Rm is lower alkyl, hydroxy-lower alkyl or a

aromatic group (including carboxylic aromatics), such as those of formula

wherein Rg, R7 and Rg are as previously defined and heteroaromatics are included within the definition of R^oi'°9 R120 is lower alkyl, substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups), e.g. 4-lower alkyl (preferably ethyl or methyl)-2,3-dioxo-1-piperazinecarbonyl-D-phenylglycyl. (e) (Substituted oxyimino)arylacetyl groups of formula

wherein Rx is as defined above and R130 is hydrogen, lower alkyl, C3-C7-cycloalkyl, carboxy<y->C^-Cy-cycloalkyl or substituted lower alkyl [in which the alkyl group is substituted with one or more halogen, cyano-, nitro- , amino-, mercapto-, lower alkylthio-, aromatic group (as defined by Rui), carboxy-, (including salts thereof), carbamoyl-, lower alkoxycarbonyl-, phenylmethoxycarbonyl-, diphenylmethoxycarbonyl-, hydroxy-lower alkoxyphosphinyl-, dihydroxyphosphinyl-, hydroxy( phenylmethoxy)phosphinyl, di-lower oxyphosphinyl substituents].

Examples of

groups are 2-[(2-chloroacetamidothiazol-4-yl)-2-[(p-nitro-

benzyloxycarbonyl]methoxyimino]acetyl, 2 - (2-chloroacetamido-thiazol-4-yl)-2-methoxyiminoacetyl, 2-(2-aminothiazol-4-yl)-2-isopropoxyiminoacetyl, 2-(2-aminothiazol-4-yl) )-2-methoxyiminoacetyl, 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetyl, 2-thienyl-2-methoxyiminoacetyl, 2-furyl-2-methoxyiminoacetyl, 2-(4-hydroxyphenyl)-2- methoxyiminoacetyl, 2-phenyl-2-methoxyiminoacetyl, 2-phenyl-2-hydroxyiminoacetyl, 2-thienyl-2-hydroxyiminoacetyl, 2-thienyl-2-(dichloroacetyloxyimino)-acetyl, 2-[4-(γ-D-glutamyloxy) phenyl]-2-hydroxyiminoacetyl, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyimino-acetyl, 2-(5-chloro-2-chloroacetamidothiazol-4-yl)-2-methoxy- iminoacetyl, 2-(5-chloro-2-aminothiazol-4-yl)-2-methoxyimino-acetyl, 2-[2-(t-butoxycarbonyl)isopropoxyimino]-2-(2-sulfoaminothiazol-4-yl)acetyl, 2-[2-(t-butoxycarbonyl)iso-propoxyimino]-2-( 2-triphenylmethylaminothiazol-4-yl)acetyl, 2-(2-chloroacetamidothiazol-4-yl)-2-isopropoxyiminoacetyl, 2-methoxyimino-2- (2-sulfoaminothiazol-4-yl)acetyl, 2-[(2-aminothiazole). -4-yl)-2-carboxymethoxyimino]acetyl, 2-[2-(2-mesyl-aminothiazol-4-yl)-2-isopropoxyiminoacetyl, 2-(2-imino-3-mesyl-4-thiazolin-4- yl)-2-isopropoxyiminoacetyl, 2-[(2-aminothiazol-4-yl)-2-(carboxyisopropoxyimino)acetyl etc.

(f) (Acylamino)arylacetyl groups of formula

wherein<R>in is as defined above and R140 is

(wherein Rg, R7, Rg and n are as previously defined), hydrogen, lower alkyl, substituted lower alkyl, amino, lower alkylamino, di-lower alkylamino, (cyano-lower alkyl)amino,

hydrazino, lower alkyl hydrazino, aryl hydrazino and acyl hydrazino.

Preferred (acylamino)arylacetyl groups of the above formula include those groups in which R 140 is amino or acylamino. Those groups in which Rm is phenyl or 2-thienyl are also preferred.

(g) (Substituted acyloxyimino)arylacetyl groups of formula

wherein R 1 and R 140 are as defined above, and R 22 and R 23 are independently selected from the group consisting of hydrogen and lower alkyl, or R 22 and R 23 joined with the carbon atom to which they are attached to form a C 3 -C 7 carbocyclic ring, e.g. cyclopropyl, n-cyclobutyl or n-cyclopentyl.

Preferred (substituted acyloxyimino)arylacetyl groups of the above formula include those groups in which R 140 is amino. Those groups in which Rm is 4-thiazolyl are also preferred.

(h) [[[3-substituted-2-oxo-1-imidazolidinyl]carbonyl]-amino]arylacetyl groups of formula

wherein Rm is as defined above and R^5 is hydrogen, lower alkylsulfonyl, arylmethyleneamino (ie -N=CHR^iiwherein Rm is as defined above), -COR^g (wherein R^g is hydrogen, lower

alkyl or halogen substituted alkyl), aromatic group (as defined by Rm above), lower alkyl or substituted lower alkyl (wherein the lower alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups).

Preferred [[[3-substituted-2-oxo-1-imidazolidinyl]carbonyl]amino]arylacetyl groups of the above formula include those in which Rm is phenyl or 2-thienyl. Those groups in which R 5 is hydrogen, methylsulfonyl, phenylmethyleneamino or 2-furylmethyleneamino are also preferred.

A preferred connection class is formula

wherein X, R 2 and R 3 are as above, R 20 is an amino protecting group, e.g. triethyl or chloroacetyl, or preferably hydrogen; and R 21 is hydrogen, lower alkyl or a group of formula

wherein<R>22 and<R>23 are as defined above.

Even more preferred are compounds of formula II, in which <R>20 is hydrogen, and <R>21 is methyl or a group of formula

wherein R22 and R23 are selected from the group consisting of hydrogen and methyl. Another preferred compound class has the formula

wherein X, R 2 and R 3 are as above, R-^g is hydrogen, lower alkyl, amino, lower alkylamino, arylamino or acylamino, and<R>20'R22°9<R>23 is as defined above.

Preferably is

the groupings on the sight form, i.e. the Z form, or as mixtures, in which the sight form dominates. Another preferred compound class is that of formula

in which X, R2 and R3 are as above.

Compounds with formula are also preferred

wherein X, R2, R3,<R>ui and<R>120 are defined as above.

Easily hydrolyzable esters of compounds of formula I are understood to mean compounds of formula I, where the carboxy group(s) (i.e. the 2-carboxy group) is present in the form of easily hydrolyzable ester groups. Examples of such esters, which may be of the usual type, are lower alkanoyloxy alkyl esters (e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester), lower alkoxycarbonyloxyalkyl esters (e.g. methoxycarbonyloxymethyl . Other esters (eg benzyl and cyanomethyl esters) can also be used.

Examples of salts of compounds of formula I are alkali metal salts such as the sodium and potassium salts, the ammonium salt, alkaline earth metal salts such as the calcium salt, salts with organic bases such as salts with amines (e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, alkylamines or dialkylamines), which also salts with amino acids such as e.g. salts with arginine or lysine.

The compounds of formula I, as well as their salts and readily hydrolyzable esters, can be hydrated. The hydration may be induced during the manufacturing process, or may occur gradually as a result of the hygroscopic properties of an initially anhydrous product.

The aforementioned acyl derivatives are prepared according to the present invention by

(a) to react a compound of formula

wherein X and R 3 are as above, and the carboxy group and/or the amino group may be present in protected form, with an acid of formula R^COOH, wherein R^ is as above, or thereof with a reactive functional derivative, or (b) in the preparation of a carboxylic acid of formula I to convert an ester of formula wherein R-L, R 2 and R 3 are as above, and R is a carboxylic acid protecting group, to the carboxylic acid of formula I, or (c) in the preparation of a compound of formula I, in which R^ contains an amino substituent, or an ester or a salt thereof, to cleave off the amino protecting group in the substituent R^q of a compound of formula wherein R2 and R3 are as above, and R^o is an acyl group containing a protected amino group, or of an ester or salt thereof, or (d) in the preparation of a compound of formula I in which X is -OCO- or -SCO-, reacting a compound of formula in which R-1 is as above and Y is a leaving group, or a ester or salt thereof, with a salt of a carboxylic acid n R3COQH, wherein R3 is as above and Q is 0 or S, or (e) in the preparation of a compound of formula I, wherein X is -OC0- or -OCONH-, to react a compound of formula wherein R]_ and R2 is as above, or an ester or salt thereof, with a compound of formula R3COZ, R3NHCOZ or R3NCO, wherein R3 is as above, and Z is an acyl activating group, or (f) in the preparation of a compound of formula I, in which X is -NHCO-, to react a compound of formula in which R-L and R2 are as above, and A is the anion of an acid, or an ester or salt thereof, with an acid of formula R3-COOH, in which R3 is as above, or (g ) in the preparation of a readily hydrolyzable ester of a compound of formula I, to subject a carboxylic acid of formula I to a corresponding esterification, or (h) in the preparation of salts or hydrates of a compound of formula I, or hydrates of said salts, to converting a compound of formula I into a salt or hydrate or into a hydrate of said salt.

The reaction of compounds XVIII with the acids R^COOH, or their reactive functional derivatives according to design (a) can be carried out using methods known per se. The carboxy group in compounds XXVIII can be protected, e.g. by esterification to form an easily cleavable ester, such as a silyl ester (eg, the trimethylsilyl ester). The carboxy group can also be protected in the form of one of the previously mentioned easily hydrolyzable esters. Furthermore, the carboxyl group can be protected by salt formation with an inorganic or tertiary organic base, such as triethylamine. Amino groups present in the groups R^ can be protected. Possible protecting groups are e.g. protecting groups that can be cleaved by acid hydrolysis (e.g. the tert. butoxycarbonyl or trityl groups), or by basic hydrolysis (e.g. the trifluoroacetyl group). Preferred protecting groups are the chloroacetyl, bromoacetyl and iodoacetyl groups, especially the chloroacetyl group. The latter protecting groups can be cleaved off by treatment with thiourea. The 7-amino group in compounds XVIII can be protected, e.g. by a silyl protecting group, such as the trimethylsilyl group.

Examples of reactive functional derivatives of acids with the formula R^COOH are halides (i.e. chlorides, bromides and fluorides), azides, anhydrides, especially mixed anhydrides with strong bases, reactive esters (e.g. N-hydroxysuccinimide esters) and amides (eg, imidazolides).

By reacting a 7-amino compound of formula XVIII with an acid of formula R^COOH or a reactive functional derivative thereof, e.g. a free acid of formula R^COOH is reacted with a previously mentioned ester of a compound of formula XVIII in the presence of a carbodiimide, such as dicyclohexylcarbodiimide, in an inert solvent, such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide , and then the ester group can be cleaved off. Oxazolium salts (eg N-ethyl-5-phenyl-isoxazolium-3'-sulfonate) can be used instead of carbodiimides in the preceding reaction.

According to another embodiment, a salt of an acid of formula XVIII (eg, a trialkylammonium salt such as the triethylammonium salt) is reacted with a reactive functional derivative of an acid of formula R^COOH, as previously mentioned, in an inert solvent (e.g. one of the previously mentioned

the solvents).

According to a further embodiment, an acid halide, preferably the chloride, of an acid of formula R^COOH is reacted with an amine of formula XVIII. The reaction is preferably carried out in the presence of an acid-binding agent, e.g. in the presence of aqueous base, preferably sodium hydroxide, or in the presence of an alkali metal carbonate, such as potassium carbonate, or in the presence of a lower alkylamine, such as triethylamine. It is preferred to use water, freely chosen with the addition of an inert, organic solvent, such as tetrahydrofuran or dioxane. The reaction can also be carried out in an aprotic, organic solvent, such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoric acid triamide. When a silylated compound of formula XVIII is used, the reaction is carried out in an anhydrous medium.

Advantageous alternatives for acylation, where an amino group present in group R₂ does not need to be protected, include the use of a 2-benzthiazolyl thioester or a 1-hydroxybenzotriazole ester of the acid R₂COOH. For example, the 2-benzthiazolyl thioester can be reacted with compound XVIII in an inert organic solvent, such as a chlorinated hydrocarbon, e.g. methylene chloride, in acetone, ethyl acetate or in a mixture of such solvents with water. The 1-hydroxybenzotriazole ester can be used by reacting the acid R^COOH with 1-hydroxybenzotriazole and a carbodiimide, especially N,N'-dicyclohexylcarbodiimide or N,N'-diisopropylcarbodiimide, in an inert, organic solvent, preferably methylene chloride, dimethylformamide, tetrahydrofuran , acetonitrile or ethyl acetate.

The reaction of a 7-amino compound of formula XVIII with an acid of formula R^COOH, or a reactive functional derivative thereof, can usually be carried out at room temperature between about -5-40°C and +60°C, e.g. at room temperature. The deprotection of the esters XIX according to design (b) is brought about by using agents which are compatible with the ester protecting group used. As ester protecting groups R, you can use an ester precursor that can easily be converted into a free carboxyl group under mild conditions, examples of such an ester protecting group are e.g. t-butyl, p-nitrobenzyl, benzhydryl, allyl etc. The residues of the easily hydrolyzable esters mentioned above as end products can also be used. For example, the following reagents and their corresponding compatible esters have been used: p-nitrobenzyl removed by hydrolysis in the presence of sodium sulfide at about or below 0°C to room temperature in a solvent such as dimethylformamide (aqueous); t-butyl removed by reacting with trifluoroacetic acid in the presence of anisole at about 0°C to room temperature with or without a carbon solvent, such as methylene chloride; or allyl removed by a palladium(0)-catalyzed transallylation reaction in the presence of sodium or potassium salt to 2-ethylhexanoic acid, see e.g. J. Org. Chem. 1982, 47, 587.

The removal of the amino protecting group in substituent R^O to a compound XX (or an ester or salt thereof)

according to design (c) gives corresponding compounds of formula I (and esters and hence salts) bearing a free amino group. Possible amino protecting groups are those used in peptide chemistry, such as an alkoxycarbonyl group, e.g. t-butoxycarbonyl etc, a substituted alkoxycarbonyl group, e.g. trichloroethoxycarbonyl etc, a substituted aralkyloxycarbonyl group, e.g. p-nitrobenzyloxycarbonyl, an aralkyl group, such as trityl or benzhydryl, or a haloalkanoyl group, such as chloroacetyl, bromoacetyl, iodoacetyl or trifluoroacetyl.

Preferred protecting groups are t-butoxycarbonyl (t-BOC) and trityl.

The amino-protecting groups can be cleaved off by acid hydrolysis (e.g. the t-butoxycarbonyl or trityl group) or by basic hydrolysis (e.g. the trifluoroacetyl group). The chloroacetyl, bromoacetyl and iodoacetyl groups are split off by treatment with thiourea.

Amino-protecting groups which can be removed by acid hydrolysis are preferably removed by means of a lower alkane carboxylic acid which can be halogenated. In particular, formic acid or trifluoroacetic acid is used. The acid hydrolysis is usually carried out at room temperature, although it can be carried out at a slightly higher or slightly lower temperature (eg a temperature in the range of about 0°C to +40°C). Protecting groups which are cleavable under basic conditions are usually hydrolysed with dilute aqueous caustic soda at 0°C to 30°C. Chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be cleaved off by using thiourea in acidic, neutral or basic medium at about 0°C to 30°C.

The reaction of compounds XXI, or esters or salts thereof, with the salts of compounds R3COQH according to embodiment (d) is preferably carried out in a non-hydroxyl solvent, such as dimethylformamide, methylene chloride or N,N'-dimethylacetamide. Other non-hydroxyl solvents can also be used. Suitable salts for compounds R3COQH are e.g. sodium, potassium, cesium, tetrabutylammonium or tetramethylammonium. Hal is a halogen, preferably bromine or iodine. The reaction can also be carried out in aqueous bicarbonate with one of the aforementioned salts of compounds R3COQH. The reaction is preferably run at about 0°C to 80°C at about room temperature as preferred.

The reaction of compounds XXII with compounds R3COZ, R3NHCOZ or R3NCO according to embodiment (e) is carried out as illustrated below in schemes II and V.

The reaction of compounds XXIII and their esters and salts with the acids R 3 COOH according to embodiment (f) is illustrated below in Scheme IV.

In order to prepare an easily hydrolyzable ester of the carboxylic acid of formula I according to embodiment (g) in the preparation provided by the present invention, a carboxylic acid of formula I is preferably reacted with a corresponding halide, preferably an iodide, which contains the desired ester group. The reaction can be accelerated by means of a base, such as an alkali metal hydroxide, an alkali metal carbonate, or an organic amine, such as triethylamine. The esterification is preferably carried out in an inert, organic solvent, such as dimethylacetamide, hexamethylphosphoric acid triamide, dimethylsulfoxide or especially dimethylformamide. The reaction is preferably carried out at a temperature in the range of around 0-40°C.

The preparation of the salts and hydrates of compounds of formula I, or the hydrates of said salts, according to embodiment (h) in the preparation provided by the present invention, can be carried out by methods known per se, e.g. by reacting a carboxylic acid of formula I, or a salt thereof, with an equivalent amount of the desired base, suitably in a solvent, such as water or an organic solvent (eg ethanol, methanol, acetone 0.1). The temperature at which the salt formation is carried out is not critical. The salt formation is usually carried out at room temperature, but can also be carried out at a temperature slightly above or below room temperature, e.g. in the range 0°C to +50°C.

The production of the hydrates usually occurs automatically during the manufacturing process or as a result of the hygroscopic properties of an initially anhydrous product. For the controlled preparation of a hydrate, a totally or partially anhydrous carboxylic acid of formula 1, or salts thereof, can be exposed to a moist atmosphere (eg at about +10°C to +40°C).

In the following reaction schemes, compounds X in scheme I, XIII in scheme III, XVI in scheme IV and XVII in scheme V, can

R3 (as defined above) be hydroxyaryl or alkanoyl esters thereof. In the case of alkanoyl esters, the conversion of the corresponding hydroxyaryl can be achieved using an alcohol and a base, preferably methanol and sodium bicarbonate.

Processes that can serve as examples to obtain products according to the invention are the following reaction schemes:

wherein R-L, R2 and R3 are as defined above.

In the reaction scheme above, depending on the selected carboxylic acid protecting group (R) and the halogen used, the double bond in the cephem ring can be *3 or ±2 with respect to the sulfur atom due to isomerization. The mixed product may be purified, if necessary, to only the desired isomer by formation of the sulfoxide (IX) and then reduction of this compound or purification by separation of the two components.

Form I

VI - » VII + VIII

The compound of formula VI, which is known or prepared by analogy (see, e.g., U.S. Patent No. 4,406,899 and U.S. Patent No. 4,266,049), is reacted with the salt of the selected carboxylic acid. The reaction is carried out as described above for process alternative (d).

VII -> X

The compound of formula VII is then deprotected as described above for process alternative (b) by forming a carboxylic acid of formula X, or a mixture thereof with the corresponding *2-isomer.

VIII -> IX

If isomerization of the double bond occurs, the compound of formula VIII is then oxidized, e.g. with a peracid, such as meta-chloroperbenzoic acid, in a solvent, such as methylene chloride, at a reaction temperature of about -s-20°C to 40°C, preferably about 0°C.

IX -> VII

The compound of formula IX is then reduced to the desired final product of formula VII using one of a variety of reactions, e.g. to treat with phosphorus trihalide in dimethylformamide or trifluoroacetic anhydride in the presence of sodium iodide in acetone/methylene chloride. The reaction temperature for both of the above-mentioned reactions can lie at around 0°C to +20°C, with around 0°C being preferred.

wherein R, R-j_, R2 and R3 are defined as above.

Form II

XI -> VII + VIII

The compound of formula XI, which is known or prepared by referring to the methods described in the Journal of Antibiotics, 1981, 3_4, 1300, is reacted with a compound of formula R 3 -CO-Z, wherein Z is an acyl activating group. Halogen is preferred as activating group Z.

(where R 10 is C 1 -C 3 alkyl).

The reaction is carried out in a solvent, such as methylene chloride, at a reaction temperature of about +20 to 100°C, preferably at about 25°C. The double bond in the cephem ring of the product formed may be *3 or ±2 with respect to the sulfur atom due to isomerization. The mixed product can be purified to only one isomer, as described for reaction core I, by conventional separation or by oxidation with a peracid to form the sulfoxide (IX) and subsequent reduction of this compound to the protected ester (VII).

wherein Ri f R2°9R3 is as defined above, and Ac represents CH3CO-.

Form III

XII - » XIII

The compound of formula XII, or a salt thereof, is reacted stepwise in aqueous sodium bicarbonate with a compound of formula ASCO-R3, wherein R3 is as before and A is a cation, preferably sodium, at a temperature of about 25-100°C, preferably 40-60°C, to form the desired end product (XIII).

The compound of formula XIII can also be prepared according to reaction scheme I, in which the selected acid is R3COSH.

wherein Ac, A, R-L, R2 and R3 are as defined above.

Form IV

XII ■ » XIV

The compound of formula XII is reacted with an azide salt (sodium or potassium) in an aqueous base, such as sodium bicarbonate, at a temperature of about 25-100°C, preferably 40-60°C.

XIV -> XV

The azide (XIV) is reduced with hydrogen and a catalyst, such as palladium or platinum, or preferably with metallic tin and hydrochloric acid, at a temperature of about 0-

50°C, preferably 20-35°C.

XV -> XVI

The amide bond is formed by standard methods by coupling an amine with an acid as in peptide chemistry (see, e.g., Synthesis, 1972, page 453), preferably using dicyclohexylcarbodiimide and N-hydroxybenzotriazole or triphenylphosphine and a diaryl disulfide (e.g. 2 ,2'-dibenzothiazolyl disulfide), at a reaction temperature of about 0-50°C, preferably 20-35°C, and in an inert solvent, e.g. dimethylformamide or dimethylsulfoxide.

wherein R, R]_, R 2 and R 3 are as defined above.

Form V

XI - > XVII

The compound of formula XI is reacted with a compound of formula O=C=N-R3 or ZCONHR3 with or without a base (eg pyridine, picoline or lutidine), wherein R3 is as above, and Z is an acyl activating group, as defined in reaction scheme II. The reaction is carried out in a solvent, e.g. methylene chloride, at a temperature of about 0-60°C, and preferably at 25°C. The compound of formula XVII can then be deprotected, if desired, according to the procedure described in reaction scheme I.

Compounds of formula I containing the moieties

(cf. above) exist preferably as synforms. Such synforms can be achieved by using starting materials which basically contain groupings on the synform. Alternatively, a syn/anti mixture obtained can be separated into corresponding syn and anti forms by usual methods, e.g. by recrystallization or by chromatographic methods, using a suitable solvent or solvent mixture.

Compounds of formula I, their salts and esters and hydrates of these compounds possess antibiotic, especially bactericidal, activity and can be used as agents in the fight against bacterial infections (including urinary tract infections and respiratory infections) in mammalian species, e.g. dogs, cats, horses etc. and humans. These compounds exhibit activity against a wide range of both gram-negative and gram-positive bacteria.

The in vitro activity of compounds according to the present invention, as measured by the minimal inhibitory concentration in micrograms/ml using the Agar well diffusion method, the Agar dilution method or the soup dilution method against a varying spectrum of gram-positive and gram-negative organisms, is as follows : Compound A: [6R-[6 alpha, 7 beta(Z)]]-7-[[(2-amino-4- thiazoly1)(methoxyimino)acetyl]amino]-3-[[(3,4-dihydroxybenzoyl)oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2- carboxylic acid monosodium salt

Compound B: [6R-[6 alpha, 7 beta(Z)]]-3-[[[3,4-bis-(acetyloxy)benzoyl]oxy]methyl]-7-[[[2-amino-4- thiazolyl][(2-amino-2-oxoethoxy)-imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt

Compound C: [6R-[6 alpha, 7 beta(Z)]]-[[(2-amino-4-thiazolyl)(1-carboxy-1-methylethoxy)imino]-acetyl]amino]-3-[[ (3,4-Dihydroxybenzoyl)-oxy]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid disodium salt

Compound D: [6R-[6 alpha, 7 beta(R<*>)]]-7-[[[[(4-ethyl-2,4-dioxo-1-piperazinyl)carbonyl]amino]-phenylacetyl]amino ]-3-[[(3,4-dihydroxy)-benzoyl]oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt. In the fight against bacterial infections in mammals, a compound according to the invention (more precisely, a compound of formula I, or a corresponding hydrolyzable ester or pharmaceutically acceptable salt or hydrate) can be administered to a mammal in an amount of about 5 mg/kg/day to about 500 mg/kg/day, preferably about 10 mg/kg/day to 100 mg/kg/day, most preferably about 10 mg/kg/day to about 55 mg/kg/day.

All administration methods that have been used in the past to deliver penicillins and cephalosporins to the site of infection are also expected to be able to be used for compounds of the present invention. By way of illustration, such administration methods include oral, e.g. tablets or capsules, parenteral, e.g. intravenous or intramuscular, and enteral administration.

The cephalosporin derivatives obtained by the present invention can be used as drugs, e.g. in the form of pharmaceutical preparations containing them together with a miscible pharmaceutical carrier. This carrier may be an organic or inorganic, inert carrier suitable for enteral or parenteral administration, such as e.g. water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be produced in solid form (e.g. as tablets, coated pills, suppositories or capsules), or in liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations can be sterilized and/or can contain auxiliary substances, such as preservatives, stabilisers, wetting or emulsifying agents, salts to vary the osmotic pressure, anesthetics or buffers. The pharmaceutical preparations may also contain other therapeutically valuable substances. The carboxylic acids of formula I as well as their salts and hydrates are particularly suitable for parenteral administration, and for this purpose they are preferably prepared as freeze-dried or dried powders for dilution with common agents, such as water or isotonic sodium chloride solution, as well as dissolution media such as such as propylene glycol. The readily hydrolyzable esters or ethers of formula I are also suitable for enteral administration.

In the following examples, chemical shifts in NMR spectra are presented as 6, and band positions in infrared (IR) spectra are presented as cm"^.

Example 1

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-( acetoxymethyl)-7- amino- 8- oxo- 5- thia- l- azabicyclo[ 4. 2♦ 0] oct- 2- one - 2- carboxylic acid 1, 1- dimethyl ethyl ester

To 200 ml of ice-cold dioxane was added 10 ml of concentrated H 2 SO 4 , followed by 21.78 g (80.0 mmol) of 7-aminocephalosporinic acid in one portion. The mixture was cooled to +50°C and 50 ml of liquid isobutylene (condensed separately under argon) was added. The pressure bottle was sealed and the mixture was stirred overnight (about 1.3-1.4 kg/cm 2 ). The mixture was then cooled to +50°C and the bottle was opened. The contents were slowly poured into NaHCO 3 (100 g in 1500 ml H 2 O) with stirring. The solution was extracted (3 x 500 mL) with ethyl acetate, and the combined organic extracts were washed with brine and dried with MgSO 4 . Removal of the solvent under vacuum gave a yellow-orange oil. Trituration with petroleum ether (boiling point 30-60°C) gave a solid which was filtered and dried. The yield was 17.1 g (65%) and was used without further purification.

NMR (CDCl 3 ): 1.55 (s) 9 H (t-bu); 2.07 (s) 3 H (OAc); 3.33, 3.54 (d of d, J = 10 Hz) 2 H (CH 2 S); 4.75, 5.02 (d of d, J = 20 Hz) 2 H (CH 2 O); 4.72 (d, J = 10 Hz) 1 H (C 6 ); 4.91 (d, J = 10 Hz) 1 H (C 7 ).

Example 2

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-( acetoxymethyl)-7-[[( methoxyimino)[ 2-( tritylamino)- 4- thiazolyl]- acetyl]-amino]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester

13.94 ml (0.1 mol ) triethylamine, and the mixture was mechanically stirred until a clear solution was formed (about 45 min.). After complete dissolution, 20.6 g (0.1 mol) of N,N-dicyclohexylcarbodiimide and 13.5 g (0.1 mol) of 1-hydroxybenzotriazole were added, and the mixture was stirred at room temperature for 2 hours. A solution of 32.8 g (0.1 mol)

[6R-[6 alpha, 7 beta(Z)]]-3-(acetoxymethyl)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-Dimethylethyl ester (from Example 1) in 250 ml of anhydrous dichloromethane was added, and the resulting solution was stirred for 16 hours at room temperature. The precipitate was removed by filtration and the filtrate was washed successively with 2 x 250 ml = 500 ml saturated aqueous sodium bicarbonate and 2 x 250 ml = 500 ml saturated aqueous sodium chloride and dried over sodium sulfate. Removal of dichloromethane gave the crude product as a gummy oil which was purified by initial liquid chromatography (0-10% EtOAc in CH 2 Cl 2 ) to give 57.2 g (76%) of a pale yellow solid.

NMR (CDCl 3 ): 1.54 (s) 9 H (t-bu) 2.09 (s) 3 H (OAc); 3.35, 3.56 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.08 (s) 3 H (OCH 3 ); 4.86, 5.04 (d of d, J = 14 Hz) 2 H (CH 2 O); 5.04 (d, J = 6 Hz) 1 H (C 6 ); 5.93 (d of d, J = 6 Hz J = 10 Hz), 1 H (C 7 ); 6.71 (s) 1 H (thiazole); 6.91 (d, J = 10 Hz) 1 H (NH); 7.08 (s) 1 H (NH); 7.30 (s) 15 H (CPh 3 ).

Example 3

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-( iodomethyl)- 7-[[( methoxyimino)[ 2-( tritylamino)- 4- thiazolyl]- acetyl] amino]-8- oxo - 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester

To a stirred solution of 23.8 g (0.0316 mol) [6R-[6 alpha,

7 beta(Z)]]-3-(acetoxymethyl)-7-[[(methoxyimino)[2-(trityl-amino )-4-thiazolyl]-acetyl]amino]-8-oxo-5-thia-l- azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester (from Example 2) in 250 ml of anhydrous dichloromethane (distilled from P2C>5) at room temperature was added, in three successive steps with 10 minute intervals, 2.0 mL (0.014 mol),

2.0 ml (0.014 mol) and 1.5 ml (0.0105 mol) of iodotrimethylsilane. After the last addition, the mixture was stirred at room temperature for 2 hours, and then a final addition was made

portion with 0.5 mL (0.0035 mol, total amount added is 1.3 equivalents) of iodotrimethylsilane. After stirring for a further 30 min. the solvent was removed at 0°C under vacuum (ice bath) to form a gum which was dissolved in 250 ml of ethyl acetate (precooled to 0°C). The ethyl acetate solution was washed (all solutions were pre-cooled to about 0°C) successively with 3 x 125 ml = 375 ml cold 10% aqueous sodium thiosulfate, 125 ml saturated aqueous sodium bicarbonate, 2 x 125 ml saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed at 0°C under vacuum to give a gum which was directly purified by initial liquid chromatography (EtOAc/n-hexane/methylene chloride, 1:4:6) to give the desired iodomethylcephalosporin (15.4 g, 59%) as a pale yellow solid. Unreacted starting material (5.0 g) was also detected, so that the yield based on reacted starting material is 75%.

NMR (CDCl 3 ): 1.56 (s) 9 H (t-bu); 3.51, 3.76 (d of d, J = 20 Hz) 2 H (CH 2 S); 4.11 (s) 3 H (OCH 3 ); 4.30, 4.44 (d of d, J = 10 Hz) 2 H (CH 2 I); 5.03 (d, J = 6 Hz) 1 H (C 6 ); 5.89 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.72 (m) 2 H (thiazole, NH), 7.02 (s) 1 H (NH); 7.30 (s) 15 H (CPh 3 ). IR (KBr): 3385, 3285, 1787, 1717, 1681, 1524, 701.

Example 4

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[( 3, 4- bis( acetyloxy) benzoyl) oxy] methyl3- 8- oxo- 7-[[[ 2-[( triphenylmethyl )-amino]- 4- thiazolyl]( methoxyimino) acetyl] amino]-5-thia-l-azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester

To a solution of 6.98 g (0.085 mol) [6R-[6a, 7(3 ( Z) [ [ 3-(iodo-methyl)-7-[[[(methoxyimino)-2-[(triphenylmethyl)amino ]-4-thiazolyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester (from Example 3) in 100 ml of dry dimethylformamide (DMF) was added dropwise to a stirred solution of 2.29 g (0.088 mol) sodium (3,4-diacetoxy)benzoate in 100 ml dry DMF (previously dried for 1 h over 4 Å molecular sieves) under argon at room temperature. The reaction mixture was stirred for 3 hours, and the solvent was removed under vacuum. The oily residue was dissolved in 100 mL of CH2Cl2/EtOAc (9:1) and passed through a short silica gel column. The appropriate fractions were combined to give 7.25 g impure material Further purification using initial chromatography (n-hexane/EtOAc, 5:4) gave 3.9 g (42%) of a

cream-colored solid.

NMR (CDCl 3 ): 1.44 (s) 9 H (t-bu); 2.27 (s) 3 H (OAc); 2.29 (s) 3 H (OAc) 3.63, 3.73 (d of d, J = 10 Hz) 2 H (CH 2 S); 3.81 (s) 3 H (OCH 3 ); 4'91'5'19 (d of d, J = 16 Hz) 2 H (CH 2 O); 5.13 (d, J = 6 Hz) 1 H (C 6 ); 5.99, 6.01 (d of d, J = 6 Hz, J = 6 Hz) 1 H (C 7 ); 6.68 (s) 1 H (thiazole) 7.2-7.4 (m) 15 H (CPh 3 ); 7.44 (d, J = 9 Hz) 1 H (Ar); 7.84 (s) 1 H (Ar); 7.91 (d, J = 9 Hz) 1 H (Ar); 8.86 (s) 1 H (NH); 9.59 (d, J = 10 Hz) 1. H (NH). IR (KBr): 3300, 1778, 1772, 1682. UV (EtOH): A max 23 4 (e = 36,500); MS: m/z 932 (M+H).

Example 5

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[( 3, 4- dihydroxybenzoyl) oxy] methyl]- 8- oxo- 7-[[[ 2-[( triphenylmethyl)-amino ]- 4- thiazolyl]( methoxyimino) acetyl] amino]- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester

Following the procedures and conditions described in Example 4, 374 mg (2.12 mmol) sodium 3,4-dihydroxybenzoate in 80 mL DMF added to 1.65 g (2.0 mmol) [6R-[6a, 7(3 (Z)]]-3-(iodo-methyl)-7-[[[(methoxyimino)-2-[(triphenylmethyl)amino]-4-thiazolyl]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester in 50 mL DMF, followed by stirring for 1.5 h, afforded 1.71 g (50%) of a cream solid after silica gel chromatography (99:1CH2Cl2/MeOH).

NMR (CDCl 3 ): 1.22 (s) 9 H (t-bu); 3.30, 3.54 (d of d, J = 16 Hz) 2 H (CH 2 S); 3.82 (s) 3 H (OCH 3 ); 4.04 (br s) 2 H (OH); 5.07 (d, J = 6 Hz) 1 H (C 6 ); 5.24, 5.32 (d of d, J = 12 Hz) 2 H (CH 2 O); 5.95 (d of d, J = 6 Hz, J = 10 Hz), 1 H

(C7); 6.77 (s) 1H (thiazole); 6.87 (d, J = 6 Hz) 1 H (Ar); 7.30 (s) 15 H (CPh 3 ); 7.49 (m) 3 H (Ar). IR (KBr): 3290, 1791, 1690, 1522, 702. UV (EtOH): A max 260 nm (e = 23,200); MS: m/z 848 (M+H).

Example 6

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[( 2, 3- dihydroxybenzoyl) oxy]- methyl]- 8- oxo- 7-[[[ 2-[( triphenylmethyl)- amino]- 4- thiazolyl]( methoxyimino) acetyl] amino]- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester

Following the procedures and conditions described in Example 4, 35.3 mg (0.20 mmol) sodium 2,3-dihydroxybenzoate in 5 mL DMF added to 157 mg (0.19 mmol) [6R-[6a, 70(Z )]]-3-(iodo-methyl)-7-[[[(methoxyimino)-2-[(triphenylmethyl)amino]-4-thiazolyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester in 5 mL DMF, followed by stirring for 2 h 15 min, gave 111 mg (69%) of an off-white solid after silica gel chromatography (0-10%EtOAc in CH2C12)•

NMR (CDCl 3 ): 1.59 (s) 3 H (t-bu); 3.48, 3.68 (d of d, J = 20 Hz) 2 H (CH 2 S); 4.07 (s) 3 H (OCH 3 ); 5.10 (m) 2 H (C 6 , 1/2 CH 2 O); 5.48 (d, J = 14 Hz) 1 H (1/2 CH 2 O); 5.99 (m) 1 H (C 7 ); 6.67 (br s) 1 H (OH) 6.72-6.88 (m) 3 H (thiazole, 2 Ar) 7.02 (br s) 1 H; 7.16 (d of d, J = 10 Hz) 1 H (NH) 7.28 (s) 15 H (CPh 3 ); 10.71 (s) 1 H (OH). IR (KBr): 3400, 1789, 1722, 1688, 700. UV (EtOH): Å max 240 nm (e = 33,900); MS: m/z 848 (M+H).

Example 7

Preparation of [ 6R-[ 6 alpha, 7 beta( Z) 33- 3-[[( 3, 4, 5- tris-( acetyloxy) benzoyl) oxy]- methyl]- 7-[[[( methoxyimino)[ 2 -( triphenylmethyl) amino]- 4- thiazolyl] acetyl] amino]- 8- oxo- 5- thia- l-azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester

Following the procedures and conditions described in Example 4, 59 mg (0.195 mmol) of sodium 3,4,5-triacetoxybenzoate in 2 ml of DMF added to 160.8 mg of [5R-[5a, 7(3(Z) ] ]- 3-(iodo-methyl)-7-[[[(methoxyimino)-2-[(triphenylmethyl)amino]-4-thiazolyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0 ]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester in 2 mL DMF, followed by stirring for 2 h, gave 64.1 mg (33%) of a cream solid after silica gel chromatography (0-15% EtOAc in CH2Cl2).

NMR (CDCl 3 ): 1.52 (s) 9 H (t-bu); 3.37, 3.59 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.06 (s) 3 H (OCH 3 ); 5.02, 5.38 (d of d, J = 7 HZ) 2 H (CH 2 O); 5.05 (d, J = 6 Hz) 1 H (C 6 ); 5.95 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.70 (d, J = 10 Hz) 1 H (NH); 6.72 (s) 1 H (thiazole; 6.98 (s) 1 H (NH); 7.29 (s) 15 H; (CPh3); 7.77 (s) 2 H (Ar). IR ( KBr): 3340, 1788, 1722, 1690, 701. UV (EtOH): Å max 235 nm (e = 32,750); MS: m/z 990 (M + H).

Example 8

Preparation of [ 6R-[ 6 alpha, 7 beta( Z) 3]- 3-[[ 2-( 3, 4- dihydroxy-phenyl) acetoxymethyl3- 7-[[( methoxyimino)[ 2-[( triphenylmethyl ) amino3- 4- thiazolyl3 acetyl] amino]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0 3oct- 2- ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester

Following the procedures and conditions described in Example 4, 76 mg (0.400 mmol) 2-(3,4-dihydroxyphenyl)acetic acid sodium salt in 4.0 mL DMF added to 328.7 mg (0.400 mmol) [6R-[6a , 7(3( Z ) ] ]-3-( iodomethyl )-7-[ [[ (methoxyimino)-2-[(triphenylmethyl)amino]-4-thiazolyl]acetyl]amino]-8-oxo-5-thia -1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethyl ethyl ester in 4 mL DMF, followed by stirring for 2 h 30 min gave 215 mg (62%) of a cream-colored solid substance after silica gel chromatography (0-20% EtOAc in CH2Cl2).

NMR (DMSO-d 6 ): 1.44 (s) 9 H (t-bu); 3.23-3.45 (m) 4 H (CH 2 S, CH 2 CO); 3.80 (s) 3 H (OCH 3 ); 4'65>4/95 (d of d, J = 14 Hz) 2H (CH 2 O); 5.11 (d, J = 4 Hz) 1 H (C 6 ); 5.69 (d of d, J = 4 Hz, J = 10 Hz) 1 H (C 7 ); 6.46-6.65 (m) 3 H (Ar); 6.69 (s) 1H (thiazole; 7.19-7.37 (m) 15H (CPh3); 8.80 (s) 1H (OH); 8.86 (s) 1H (NH); 6.88 (s) 1 H (OH); 9.57 (d, J = 10 Hz) 1 H (NH). IR (KBr): 3390, 1788, 1723, 1662, 702. UV (EtOH): A max 225 nm (e = 19,900); MS: m/z 861 (M + H).

Example 9

Preparation of (6R-trans)-3-[[[(3,4-bis(acetyloxy)benzoyl]oxy]methyl]-8-oxo-7-[(phenoxyacetyl)amino]-5-thi-1-azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester

Following the procedures and conditions described in Example 4, 2.33 g (8.95 mmol) of sodium 3,4-diacetoxybenzoate in 100 ml of DMF added to 4.75 g (8.95 mmol) of (6R-trans)-3 -(iodomethyl)-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester in 50 mL DMF, followed by of stirring for 2 h gave 3.36 g (58.5%) of a cream-colored solid after silica gel chromatography (6:4 n-hexane/EtOAc).

NMR (CDCl 3 ): 1.56 (s) 9 H (t-bu); 2.33 (s) (6 H) (2 OAc); 3.41, 3.63 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.60 (s) 3 H (OCH 3 ); 5.06, 5.40 (d of d, J = 14 Hz) 2 H (CH 2 O); 5.07 (d, J = 6 Hz) 1 H (C 6 ); 5.97 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.98 (d, J = 8 Hz) 1 H (Ar); 7.09 (d, J = 10 Hz) 1 H (NH); 7.12-7.40 (m) 5 H (Ar); 7.90 (s) 1 H (Ar); 7.98 (d, J = 8 Hz) 1 H (Ar).

Example 10

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 7-[[( 2- amino- 4-thiazolyl)( methoxyimino) acetyl] amino]- 3-[[[( 3, 4- bis( acetyloxy) benzoyl)] oxy] methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0]-oct- 2- ene- 2- carboxylic acid monosodium salt

A solution of 1.90 g (2.04 mmol) [6R-[6 alpha, 7 beta(Z)]]-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]-methyl]-8 -oxo-7-[[[2-[(triphenylmethyl)amino]-4-thiazolyl](methoxyimino)acetyl]-amino]-5-thia-1-azabicyclo[4.2.0]oct-2-en-2- carboxylic acid 1,1-dimethylethyl ester (from Example 4) in 38 ml of dry methylene chloride was cooled to 0°C in an ice/water bath and treated with 3.8 ml of anisole, followed by 37.5 ml of trifluoroacetic acid. The reaction mixture was stirred at 0°C for 6 hours, and the volatiles were removed under vacuum. The oil formed was taken up in 40 ml of ethyl acetate and washed with 9 portions (40 ml each) of 1% aqueous sodium bicarbonate. Fractions 4-7, containing the UV actives, were combined and passed through a short column of C^g reversed phase silica gel using water to remove excess NaHCC>3, followed by 25% acetonitrile in water to remove the organic the substance. The appropriate fractions were combined and freeze-dried to give 760 mg of crude material. The lyophilized material was further purified using initial reverse phase chromatography (0-30% acetonitrile) to give 580 mg (43%) of a white powder.

NMR (DMSO- dg ): 2.29 (s) 3 H (OAc); 2.30 (s) 3 H (OAc); 3.26, 3.60 (d of d, J = 16 Hz) 2 H (CH 2 S) 3.84 (s) 3 H (OCH 3 ); 4.95, 5.21 (d of d, J = 10 Hz) 2 H (CH 2 O); 4.97 (d, J = 6 Hz) 1 H (C 6 ); 5.53 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.69 (s) 1 H (thiazole); 7.19 (s) 1 H (NH), 7.39 (d, J = 8 Hz) 1 H (Ar); 7.80 (s) 1 H (Ar) 7.87 (d, J = 8 Hz) 1 H (Ar); 9.51 (d, J = 8 Hz) 1 H (NH). IR (KBr): 3350, 1769, 1715, 1685, 1610; MS: m/z 656 (M+H). UV (H20): A max = 235 nm (e = 26,500). HRMS calcd (M + H) for C25<H>23NaN5-<0>11S2: 656.0733. Found: 656.0732.

Example 11

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 7-[[( 2- amino- 4-thiazoly1)( methoxyimino) acetyl] amino 3 - 3-[[( 3, 4- dihydroxybenzoyl) oxy ] methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2-ene- 2- carboxylic acid monosodium salt

By following the procedures and conditions described in Example 10, 52.3 mg (0.092 mmol) [6R-[6 alpha, 7 beta(Z)]]-3-[[(3,4-dihydroxybenzoyl)oxy]methyl]- 8-oxo-7-[[[2-[(triphenylmethyl)amino]-4-thiazolyl3(methoxyimino)acetyl]amino 3-5-thia-1-azabicyclote 4.2.0]oct-2-ene-2-carboxylic acid 1 ,1-Dimethylethyl ester (Example 5) in 1 ml CH 2 Cl 2 and 100 µl anisole, treated with 1 ml trifluoroacetic acid (TFA), followed by stirring for 3 h 40 min, gave 11.3 mg (32%) of a white powder after reversed phase chromatography (0-30% acetonitrile in water).

NMR (D 2 O): 3.47, 3.73 (d, J = 18 Hz) 2 H (CH 2 S); 3.98 (s) 3 H (OCH 3 ); 4.89, 5.11 (d of d, J = 10 Hz) 2 H (CH 2 O); 5.21 (d, J = 6 Hz) 1 H (C 6 ); 5.80 (d, J = 6 Hz) 1 H (C 7 ); 6.91 (d, J = 8 Hz) 1 H (Ar); 7.00 (s) 1 H (thiazole); 7.48 (s) 1 H (Ar); 7.52 (d, J = 8 Hz) 1 H (Ar). IR (KBr): 3320, 1762, 1680, 1610, 1530. MS: m/z 572 (M + H). UV (H 2 O): ^ max = 260 nm (e = 21,800). HRMS calcd (M + H) for C 21<H>19<->NaN 5 O 9 S 2 : 572.0522. Found: 572.0533.

Example 12

Preparation of ( 6R- trans)- 3-[[[ 3, 4- bis( acetyloxy) benzoyl3-oxy3methyl 3- 8- oxo- 7-[( phenoxyacetyl) amino3- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid monosodium salt

By following the procedures and conditions described in Example 10, 129 mg (0.201 mmol) of (6R-trans)-3-[[[3,4-bis(acetyloxy)benzoyl3oxy]methyl]-8-oxo-7-[( phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester (Example 9) in 2.5 ml CH 2 Cl 2 and 220 µl anisole, treated with 2 .2 ml of TFA, followed by stirring for 6 h 30 min., gave 42 mg (34%) of a white powder after

reverse phase chromatography (0-30% acetonitrile in water).

NMR (D 2 O): 2.37 (s) 6 H (2 OAc); 3.42, 3.70 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.96, 5.16 (d of d, J = 12 Hz) 2 H (CH 2 OCO); 5.11 (d, J = 6 Hz) 1 H (C 6 ); 6.70 (d, J = 6 Hz) 1 H (C 7 ); 7.01 (d, J = 8 Hz) 1 H (Ar); 7.05 (M) 1 H (Ar) 7.32-7.43 (m) 4 H (Ar) 7.92 (s) 1 H (Ar) 8.00 (d, J = 8 Hz) 1 H (Year)

(CH2OAr overshadowed by HOD). IR (KBr): 3450, 1782, 1718, 1692, 1608. MS: m/z 607 (M + H). UV (H20): A max = 236 nm (e = 13,400). HRMS calcd (M + H) for C27H24NaN2011<S>2<:>607.0999. Found: 607,1007.

Example 13

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 7-[[( 2- amino- 4-thiazoly1)( methoxyimino) acetyl] amino]- 3-[[[( 2, 3- dihydroxy- phenyl) carbonyl] oxy] methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0]- oct- 2- ene- 2- carboxylic acid monosodium salt

By following the procedures and conditions described in Example 10, 100 mg (0.118 mmol) [6R-[6 alpha, 7 beta(Z)]]-3-[[(2,3-dihydroxybenzoyl)oxy]methyl]-8- oxo-7-[[[2-[(triphenylmethyl)amino]-4-thiazolyl](methoxyimino)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1 ,1-Dimethylethyl ester (Example 6) in 3.0 mL of CH 2 Cl 2 and 300 µl of anisole, treated with 3.0 mL of TFA, followed by stirring for 6 hours, gave 28.2 mg (42%) of a white powder after inversion phase chromatograph in (0-30% acetonitrile in water).

NMR (D 2 O): 3.30, 3.57 (d of d, J = 16 Hz) 2 H (CH 2 S); 3.78, (s) 3 H (OCH 3 ); 4.78, 5.02 (d of d, J = 12 Hz) 2 H (CH 2 OCO); 5.04 (d, J = 6 Hz) 1 H (C 6 ); 5.66 (d, J = 6 Hz) 1 H (C 7 ); 6.64 (m) 1 H (Ar); 6.81 (s) 1 H (thiazole); 6.91 (d, J = 8 Hz) 1 H (Ar); 7.24 (d, J = 6 Hz) 1 H (Ar). IR (KBr): 3350, 1765, 1672, 1612. MS: m/z 572 (M + H). UV (H20): A max 245 nm (e = 21,400), A max 298 nm (e = 8,600). HRMS calcd (M + H) for C21<H>19<N>aN509S2: 572.0522. Found: 572.0505.

Example 14

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[ 3, 4, 5- tris-( acetyloxy) benzoyl] oxy]- methyl]- 7-[[( 2- amino- 4 - thiazolyl)-( methoxyimino) acetyl] amino]- 8- oxo- 5- thia- l- azabicyclo-[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid monosodium salt

By following the procedures and conditions described in Example 10, 160 mg (0.161 mmol) of [6R-[6 alpha, 7 beta(Z)]]-3-[[3,4,5-tris(acetyloxy)benzoyl]oxy] methyl]-7-[[(methoxyimino )[2-[(triphenylmethyl)amino]-4-thiazolyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene -2-carboxylic acid 1,1-dimethylethyl ester (Example 7) in 3.2 mL CH 2 Cl 2 and 300 µl anisole, treated with 3.0 mL TFA, followed by stirring for 6 h 30 min, gave 69 mg (60%) of a white solid after reverse phase chromatography (0-30% acetonitrile in water).

NMR (D 2 O): 2.38 (s) 3 H (OAc); 2.39 (s) 3 H (OAc); 3.51,

3.78 (d of d, J = 16 Hz) 2 H (CH 2 S); 5.00, 5.21 (d of d, J = 12 Hz) 2 H (CH 2 O); 5.24 (d, J = 6 Hz) 1 H (C 6 ); 5.82 (d, J = 6 Hz) 1 H (C 7 ); 7.03 (s) 1 H (thiazole); 7.79 (s) 2 H (Ar). IR (KBr): 3360, 1772, 1718, 1675, 1610. MS: m/z 714 (M + H). UV (H20): A max = 234 nm (e = 18,100). HRMS calcd (M + H) for<C>27<H>25NaN5<0>13<S>2: 714.0788. Found: 714.0745.

Example 15

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 7-[[( 2- amino- 4-thiazolyl)( methoxyimino) acetyl] amino]- 3-[[ 2-( 3, 4- dihydroxy -phenyl) acetoxy] methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2-ene- 2- carboxylic acid monosodium salt

By following the procedures and conditions described in Example 10, 175 mg (0.203 mmol) of [6R-[6 alpha, 7 beta(Z)]]-3-[[2-(3,4-dihydroxyphenyl)-acetoxy]methyl] -7-[[(Methoxyimino) [2-[(triphenylmethyl)amino]-4--thiazolyl]acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene -2-carboxylic acid 1,1-dimethylethyl ester (Example 8) in 3.5 mL CH 2 Cl 2 and 3 50 µl anisole, treated with 3.5 mL TFA, followed by stirring for 6 h, gave 22 mg (19%) of a white solid left

reverse phase chromatography (0-30% acetonitrile in water).

NMR (D 2 O): 3.27, 3.49 (d of d, J = 16 Hz) 2 H (CH 2 S); 3.62 (s) 2 H (CH 2 O); 4.00 (s) 3 H (OCH); 5.00 (d, J = 12 Hz) 1 H (1/2 CH 2 O) (second doublet overshadowed by HOD); 5.17 (d, J = 6 Hz) 1 H (C 6 ); 5.82 (d, J = 6 Hz) 1 H (C 7 ); 6.75 (d, J = 8 Hz) 1 H (Ar); 6.86 (s) 1 H (Ar); 6.90 (d, J = 8 Hz) 1 H (Ar); 7.04 (s) 1 H (thiazole). IR (KBr): 3340, 1763, 1670, 1610. MS: m/z 586 (M + H), 564 (M + H free acid). UV (H 2 O): sh 230 nm (e = 16,900), sh 260 nm (e = 13,300). HRMS calcd (M + H) for <C>22H21NaN509S2: 586.0678. Found: 586.0641.

Example 16

Preparation of (6R-trans)-7-amino-3-[[[3,4-bis(acetyloxy)-benzoyl]oxy]methyl]-8-oxo-5-thia-l-azabicyclo[ 4. 2. 0 ] oct- 2-ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester monohydrochloride

A solution of 1.66 mL (20.0 mmol) of pyridine in 60 mL of dry CH 2 Cl 2 under argon was cooled to 0°C in an ice-water bath and treated with 4.16 g (20.0 mmol) of PCI 5 . The mixture was stirred at 0°C for 45 min. To this was added dropwise a solution of 8.80 g of (6R-trans)-3-[[[3,4-bis(acetyloxy)-benzoyl]oxy]methyl]-8-oxo-7-[(phenoxyacetyl) amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester (Example 9) in 40 ml of dry CH2Cl2 over 20 min. The reaction mixture was stirred at 0°C for 1 hour 30 minutes, followed by an addition of 24 ml of 1-propanol added dropwise. Stirring was maintained for 1 hour, then treated with 60 ml of H 2 O and stirred for 40 min. The volatile components were removed under reduced pressure. The remaining aqueous solution was treated with 300 mL of Et 2 O with vigorous stirring to precipitate the product as a white crystalline solid, 5.28 g (71%).

NMR (DMSO-d 6 ): 1.49 (s) 9 H (t-bu); 2.32 (s) 3 H (OAc); 2.33 (s) 3 H (OAc); 3.78, 3.87 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.97 (m) 1 H (C 6 ); 5.24 (m) 3 H (C 7 , CH 2 O); 7.47

(d, J = 8 Hz) 1 H (Ar); 7.85 (s) 1 H (Ar); 7.92 (d, J = 8 Hz) 1 H (Ar); 9.05 (br) 3 H (NH3+). IR (KBr): 3400, 1778, 1772. UV (EtOH): A max 238 nm (e = 15,580).

Example 17

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[[ 3, 4- bis-( acetyloxy) benzoyl] oxy] methyl]- 7-[[[( 2- amino- 4- thiazolyl)-[ 1, l- dimethyl- 2-( 1, 1- dimethylethoxy)- 2- oxoethoxy] imino]-acetyl] amino]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester

A suspension of 1.00 g (1.84 mmol) (6R-trans)-7-amino-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-8-oxo-5-thia -1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester monohydrochloride (Example 16) in 25 mL of CH 2 Cl 2 was washed thoroughly with 25 mL of a sodium bicarbonate/saturated sodium bicarbonate mixture (4:1). The organic solution was separated and dried over MgSO 4 . To this solution was added in one portion 1.10 g (2.30 mmol) S-2-benzothiazol-yl-2-amino-alpha-[(Z)-[1-(tert.butoxycarbonyl)-1-methylethoxy ]imino]thio-4-thiazole acetate. The resulting solution was stirred for 16 h, and the solvent was removed under vacuum. The residue was chromatographed on silica gel using n-hexane/ethyl acetate (1:1) and then ethyl acetate as eluents to give 1.16 g (77%) of a cream colored substance.

NMR (CDCl 3 ): 1.41 (s) 9 H (t-bu); 1.52 (s) 9 H (t-bu); 1.56 (S) 3 H (CH 3 ); 1.58 (s) 3 H (CH 3 ); 2.29 (s) 6 H (2 OAc); 3.38, 3.59 (d of d, J = 18 Hz) 2 H (CH 2 S); 5.04 (m) 2 H (C 6 , 1/2 CH 2 O); 5.38 (d, J = 12 Hz) 1 H (1/2 CH 2 O); 6.01 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.10 (s) 2 H (NH 2 ); 6.88 (s) 1 H (thiazole); 7.25 (d, J = 12 Hz) 1 H (NH); 7.68 (d, J = 8 Hz) 1 H (Ar), 7.82 (s) 1 H (Ar); 7.91 (d, J = 8 Hz) 1 H (Ar). IR (KBr): 3300, 1782, 1722, 1688, 1535. MS: m/z 818 (M + H). UV (EtOH): A max 235 nm (e = 28,450).

Example 18

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[[ 3, 4- bis-( acetyloxy) benzoyl] oxy]- methyl]- 7-[[[[( 2- amino- 2- oxoethoxy) imino]- 4- thiazolyl] acetyl] amino]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester

A suspension of 234 mg (0.430 mmol) of (6R-trans)-7-amino-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester monohydrochloride in 10 mL of CH 2 Cl 2 was washed with 10 mL of a sodium bicarbonate solution/saturated NaHCl solution (4:1). The organic solution was separated and dried with MgSO 4 . This solution was added dropwise to a solution of 157 mg (0.400 mmol) of S-(2-benzothiazolyl)-Z-aminothio-4-thiazole-glyoxylate-O-(carbamoylmethyl)oxime in 5 mL of CH 2 Cl 2 and 8 mL of dry DMF. Stirring was maintained for 3 hours, and the solvent was removed under vacuum. The residue was chromatographed (0-10% MeOH in CH2C1H2) to give 220 mg (70%) of a cream

fabric.

NMR (CDCl 3 ): 1.51 (s) 9 H (t-bu); 2.28 (s) 3 H (OAc); 2.29 (s) 3 H (OAc); 3.48, 3.51 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.60, 4.81 (d of d, J = 18 Hz) 2 H (CH 2 CON); 4.96, 5.37 (d of d, J = 12 Hz) 2 H (CH 2 O); 5.10 (d, J = 6 Hz) 1 H (C 6 ); 5.83 (br) 2 H (NH 2 ) 5.83 (br) 2 H (NH 2 ) 6.01 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.76 (s) 1 H (thiazole); 7.27 (d, J = 8 Hz) 1 H (Ar); 7.85 (s) 1 H (Ar); 7.93 (d, J = 8 Hz) 1 H (Ar). IR (KBr): 3450, 3350, 1778, 1720, 1680, 1532. MS: m/z 733 (M + H). UV (EtOH): \ max 236 nm (e = 29,700).

Example 19

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[[ 3, 4- bis-( acetyloxy) benzoyl3oxy] methyl3- 7-[[( 2- amino- 4- thiazolyl)[( 1-carboxy- 1- methylethoxy) imino] acetyl] amino]- 8- oxo- 5- thia- 1-azabicyclof 4. 2. 0] oct- 2- ene- 2- carboxylic acid disodium salt

By following the procedures and conditions described in Example 10, 247 mg (0.301 mmol) [6R-[6 alpha, 7 beta(Z)]]-3-

[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-7-[[[(2-amino-4-thiazolyl)[1,1-dimethyl-2-(1,1-dimethylethoxy)-2 -oxoethoxy]-imino]acetyl]amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester (Example 17) in 2.5 ml CH 2 Cl 2 and 250 µl of anisole, treated with 2.5 mL of TFA, followed by stirring for 7 hours, gave 61.2 mg (27%) of a white solid after reverse phase chromatography (0-30% acetonitrile in water).

NMR (DMSO-d 6 ): 1.30 (s) 3 H (CMe 2 ); 1.37 (s) 3 H (CMe 2 ); 2.20 (s) 3 H (OAc); 2.21 (s) 3 H (OAc); 3.49 (d, J = 18 Hz) 1 H (1/2 CH2S, second half overshadowed by HOD); 4.87, 5.23 (d of d, J = 12 Hz) 2 H (CH 2 O); 4.96 (d, J = 6 Hz) 1 H (C 6 ); 5.60 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.66 (s) 1 H (thiazole); 7.11 (br) 3 H (NH, NH 2 ); 7.37 (d, J = 8 Hz) 1 H (Ar); 7.78 (S) 1 H (Ar); 7.85 (d, J = 8 Hz) 1 H (Ar). IR (KBr): 3400, 1770, 1718, 1672, 1608. MS: m/z 650 (M + H). UV (EtOH): A max 235 nm (e = 20,000). HRMS calcd (M + H) for<C>28<H>25NaN5<0>13S2: 772.0584. Found: 772.0543.

Example 20

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 7-[[[( 2- amino- 4-thiazolyl)[ 1- carboxyl- l- methylethoxy] imino] acetyl] amino]- 3-[ [( 3, 4- dihydroxybenzoyl) oxy] methyl]- 8- oxo- 5- thia- 1- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid disodium salt

A solution of 220 mL (0.227 mmol) [6R-[6 alpha, 7 beta(Z)]]-3- t[[(3,4-bis(acetyloxy)benzoyl]oxy]methyl]-7-[[[ (2-amino-4-thiazolyl)[1,1-dimethyl-2-(1,1-dimethylethoxy)-2-oxoethoxy]-imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester (Example 17) in 10 mL CH 2 Cl 2 and 1 mL anisole was stirred at 0° C. while 10 mL TFA was added. Stirring was maintained at 0° C. for 6 hours, and the volatile components were removed under reduced pressure. To the oily residue was added 5 mL of EtOAc, 5 mL of saturated NaHCO 3 , and 5 mL of methanol, and the biphasic mixture was stirred for 30 min. The solution was concentrated under reduced pressure to a volume of about 5 mL, to which 5 mL of EtOAc and 5 mL of saturated sodium bicarbonate were added. The solution was stirred for 15 min. The aqueous layer was separated to give 60 mg (33%) of a white solid after invert phase chromatography (0-20% acetonitrile in water).

NMR (DMSO-d 6 ): 1.40 (s) 3 H (CMe 2 ); 1.49 (s) 3 H (CMe 2 ); 3.31, 3.49 (d of d, J = 16 Hz) 2 H (CH 2 S); 4.96, 5.04 (d of d, J = 12 Hz) 2 H (CH 2 O); 5.05 (d, J = 6 Hz) 1 H (C 6 ); 5.68 (m) 1 H (C 7 ); 6.73 (ra) 2 H (Ar, thiazole); 7.18 (br) 2 H (NH 2 ); 7.27 (d, J = 8 Hz) 1 H (Ar); 7.34 (s) 1 H (Ar); 11.70 (d, J = 10 Hz) 1 H (NH). IR (KBr): 3350, 1762, 1670, 1598. MS: m/z 666 (M + H). UV (EtOH): Å max 218 nm (e = 25,050), A max 262 nm (e = 17,600). HRMS calcd (M + H) for<C>24<H>21<N>5<0>11S2Na: 666.0553. Found: 666.0619.

Example 21

Preparation of [ 6R-[ 6 alpha, 7 beta( S*)]]- 3-[[[ 3, 4- bis-( acetyloxy) benzoyl] oxy] methyl]- 7-[[ a[[( 4- ethyl - 2, 3- dioxo-l-piperazinyl) carbonyl] amino] phenylacetyl] amino]- 8- oxo- 5- thia-l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid 1, 1 - dimethyl ethyl ester

A suspension of 275 mg (0.506 mmol) of (6R-trans)-7-amino-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-8-oxo-5-thia-1-azabicyclote 4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester monohydrochloride in 10 mL CH 2 Cl 2 was washed with 10 mL of a mixture of sodium chloride/saturated NaHCO 3 (4:1). The organic solution was separated from and dried over MgSO 4 . This solution was added to a solution of activated ester (prepared by adding 69 mg (0.506 mmol) of N-hydroxybenzotriazole, followed by 104 mg (0.506 mmol) of 1,3-dicyclohexylcarbodiimide, to a solution of 161 mg (0.506 mmol) of a -[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]araino]phenyl-acetic acid in 10 ml of dry THF and stirred for 45 min.). The solution was stirred for 16 hours, filtered, and the solvent was removed under vacuum. The residue was chromatographed (EtOAc) to give 250 mg (61%) of a cream-colored material.

NMR (CDCl 3 ): 1.20 (t, J = 3 Hz) 3 H (Et) 1.52 (s) 9 H (t-bu); 2.32 (s) 6 H (2 OAc) 3.2-3.7 (m) 6 H (CH 2 S, Et, 1/2 NCH 2 CH 2 N) 3.93 (m) 1 H (1/4 NCH 2 CH 2 N); 4.11 (m) 1 H (1/4

NCH 2 CH 2 N); 4.91 (d, J = 6 Hz) 1 H (C 6 ); 5.00, 5.30 (d of d, J = 14 Hz) 2 H (CH 2 O); 5.58 (d, J = 8 Hz) 1 H (NCHCPh); 5.84 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.83 (d, J = 10 Hz) 1 H (NH); 7.20-7.35 (m) 6 H (Ar); 7.80 (s) 1 H (Ar); 7.89

(d, J = 8 Hz) 1 H (Ar); 10.04 (d, J = 8 Hz) 1 H (NH). IR (KBr): 3320, 1780, 1718, 1688. UV (EtOH): inf. 225 nm (e = 23,300), inf. 270 nm (e = 10,900).

Example 22

Preparation of [ 6R-[ 6 alpha, 7 beta( S*)]]- 3-[[[ 3, 4- bis-( acetyloxy) benzoyl] oxy] methylj- 7-[[ a[[( 4- ethyl- 2, 3- dioxo-l-piperazinyl) carbonyl] amino] phenylacetyl] amino]- 8- oxo- 5- thia-l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid monosodium salt

By following the procedures and conditions described in Example 10, 100 mg (0.124 mmol) [6R-[6 alpha, 7 beta(S<*>)]]-3-[[[3,4-bis(acetyloxy)benzoyl] oxy]methyl]-7-[[a[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2. 0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester (Example 21) in 5 mL CH 2 Cl 2 and 500 µl anisole, treated with 5 mL TFA, followed by stirring for 5 h, gave 48 mg (50%) of a white solid after reverse phase chromatography (0-30% acetonitrile in water).

NMR (DMSO-d 6 ): 1.08 (t, J = 8 Hz) 3 H (NEt); 2.31 (s) 6 H (2 OAc); 3.21-3.60 (m) 6H (CH2S, NEt, 1/2 NCH2CH2N) 3.91 (m) 2H (1/2 NCH2CH2N); 4.92 (d, J = 6 Hz) 1 H (C 6 ); 4.95, 5.25 (d, J = 12 Hz) 2 H (CH 2 O); 5.57 (m) 1 H (C 7 ); 5.75 (d, J = 8 Hz) 1 H (NCHCPh); 7.26-7.48 (m) 6 H (Ar); 7.82 (s) 1 H (Ar); 7.89 (d, J = 8 Hz) 1 H (Ar); 9.41 (d, J = 8 Hz) 1 H (NH) 9.86 (d, J = 10 Hz) 1 H (NH). IR (KBr): 3420, 3305, 1772, 1715, 1682, 1610. UV (EtOH): Å max 230 nm (e = 22,600). HRMS calcd (M + H) for C34H33NaN5013<S:>774.1693. Found: 774.1729.

Example 23

Preparation of [ 6R-[ 6 alpha, 7 beta( S*)]]- 7-[[ g[[( 4- ethyl-2, 3- dioxo- l-piperazinyl) carbonyl] amino] phenylacetyl] amino]-3 -[[( 3, 4- dihydroxy) benzoyl] oxy] methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid monosodium salt

By following the procedures and conditions described in Example 20, 150 mg (0.186 mmol) [6R-[6 alpha, 7 beta(S<*>)]]-3-[[[3,4-bis(acetyloxy)benzoyl] oxy]methyl]-7-[[a[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2. 0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester (Example 21) in 5 mL CH 2 Cl 2 and 500 µl anisole, treated with 5 mL TFA, followed by stirring with a mixture of EtOAc, saturated aqueous NaHCO 3 and MeOH (1 :1:1), gave 68 mg (53%) of a white solid after reverse phase chromatography (0-20% acetonitrile in water).

NMR (DMSO-d 6 ): 1.01 (t, J = 8 Hz) 3 H (NEt); 3.14, 3.39 (d of d, J = 18 Hz) 2 H (CH 2 S); 3.30-3.60 (m) 4 H (NEt, 1/2 NCH 2 CH 2 N); 3.85 (m) 2 H (1/2 NCH 2 CH 2 N); 4.80, 5.08 (d of d, J = 12 Hz) 2 H (CH 2 O); 4.83 (d, J = 6 Hz) 1 H (C 6 ); 5.48 (m) 1 H (C 7 ); 5.61 (d, J = 8 Hz) 1 H (NCHCPh); 6.69 (d, J = 8 Hz) 1 H (Ar); 7.16-7.41 (m) 7 H (Ar); 9.33 (br) 1 H (NH) ; 9.78 (d, J = 8 Hz) 1 H (NH). IR (KBr): 3400, 3300, 1762, 1712, 1680, 1603. MS: m/z 690 (M + H). UV (EtOH): A max 263 nm (e = 17,900). HRMS calcd (M + H) for C30<H>29<N>5<O>11-SNa: 690.1482. Found: 690.1517.

Example 24

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[[ 3, 4- bis-( acetyloxy) benzoyl] oxy] methyl]- 7-[[[ 2- amino- 4- thiazolyl ][( 2-amino- 2- oxoethoxy) imino] acetyl] amino]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid monosodium salt

By following the procedures and conditions described in Example 10, 200 mg (0.272 mmol) of [6R-[6 alpha, 7 beta(Z)]]-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl ]-7-[[[2-amino-4-thiazolyl][(2-amino-2-oxoethoxy)imino]acetyl]amino]-8-oxo- 5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylic acid 1,1-dimethylethyl ester (Example 18) in 4 mL CH 2 Cl 2 and 400 µl anisole, treated with 4 mL TFA, followed by stirring for 6 h, gave 40 mg (21%) of a white, solid after reversed phase chromatography (0-30% acetonitrile in water).

NMR (DMSO-d 6 ): 2.28 (s) 3 H (OAc); 2.29 (s) 3 H (OAc); 3.57 (d, J = 18 Hz) 1 H (1/2 CH2S, 1/2 CH2S overshadowed by HOD); 3.99 (s) 2 H (CH 2 ON); 4.94, 5.27 (d of d, J = 12 Hz) 2 H (CH 2 OCO); 5.01 (d, J = 6 Hz) 1 H (C 6 ); 5.60 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.84 (s) 1 H (thiazole); 7.10 (s) 2 H (NH 2 ); 7.28 2 H (NH 2 ); 7.41 (d, J = 8 Hz) 1 H (Ar); 7.84 (s) 1 H (Ar); 7.89 (d, J = 8 Hz) 1 H (Ar). IR (KBr): 3440, 1768, 1710, 1710, 1678, 1610. MS: m/z 699 (M + H). UV (H2O): X max 234 nm (e = 26,260). HRMS calcd (M + H) for <C>26H26NaN6012s2: 699.0791. Found: 699.0822.

Example 25

Preparation of ( 6R- cis )- 3-[[( aminocarbonyl) oxy] methyl]- 7- methoxy- 8- oxo- 7-( 2- thienylacetyl)- amino- 5- thi- l- azabicyclo-[ 4. 2 .Ojoct- 2-ene- 2- carboxylic acid (4-nitrophenyl) methyl ester

To 3.75 g (8.30 mmol) of p-nitrobenzyl bromide in 100 ml of dry DMF was added 3.75 g (8.30 mmol) of (6R-cis)-3-[[(aminocarbonyl)oxy]methyl]- 7-Methoxy-8-oxo-7-[(2-thienylacetyl)-amino-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt. The mixture was stirred for 2 hours 30 minutes, and 100 ml of ethyl acetate was added. The solution was washed with brine, dried with MgSO 4 , and the solvent was removed under vacuum. The residue was chromatographed on silica gel using ethyl acetate/n-hexane as eluent (1:1, then 2:1). The obtained material was crystallized from ethyl acetate/n-hexane to give 3.4 g (72%).

NMR (CDCl 3 ): 3.31, 3.49 (d of d, J = 18 Hz) 2 H (CH 2 S); 3.44 (s) 3 H (OCH 3 ); 3.79 (s) 2 H (CH 2 CON); 4.67 (br). 2 H (NH 2 ); 4.82, 5.12 (d of d, J = 14 Hz) 2 H (CH 2 O); 5.03 (s) 1 H (C 6 ); 5.31, 5.60 (d of d, J = 14 Hz) 2 H (CH 2 Ar); 6.44

(s) 1 H (NH); 6.99 (m) 2 H (thiophene); 7.25 (m) 1 H (thiophene); 7.56 (d, J = 8 Hz) 2 H (Ar); 8.19 (d, J = 8 Hz) 2 H (Ar).

IR (KBr): 3465, 3335, 1785, 1728, 1698, 1522, 1348.

Example 26

Preparation of (6R)-3-(iodomethyl)-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thi-1-azabicyclo[4.2.0]oct-2-ene - 2-carboxylic acid (4 nitrophenyl) methyl ester

To 3.0 g (5.33 mmol) (6R-cis)-3-[[(aminocarbonyl)oxy]-methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5 -thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (4-nitrophenyl)-methyl ester (Example 25) in 75 ml of CH 2 Cl 2 at room temperature was added 1.40 ml (10.3 mmol) of trimethylsilyl iodide. The mixture was stirred for 30 min. and then washed with aqueous NaHCO 3 and dried with MgSO 3 . The solvent was removed under vacuum and the residue was chromatographed on silica gel (EtOAc/n-hexane 2:3) to give 2.88 g (86%) of a pale yellow solid.

NMR (CDCl 3 ): 3.45, 3.60 (d of d, J = 16 Hz) 2 H (CH 2 S); 3.49 (s) 3 H (OCH 3 ); 3.94 (s) 2 H (CH 2 CON); 4.36, 4.50 (d of d, J = 8 Hz) 2 H (CH 2 I); 5.07 (s) 1 H (C 6 ); 5.36, 5.46 (d of d, J = 16 Hz) 2 H (CH 2 Ar); 6.46 (s) 1 H (NH); 7.05 (m) 2 H (thiophene); 7.30 (m) 1 H (thiophene); 7.65 (d, J = 8 Hz) 2 H (Ar); 8.27 (d, J = 8 Hz) 2 H (Ar).

Example 27

Preparation of ( 6R- cis )- 3-[[[ 3, 4- bis( acetyloxy) benzoyl]-oxy] methyl]- 7- methoxy- 8- oxo- 7-[( 2- thienylacetyl) amino]- 5- thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (4 nitro-phen<y>Dmethyl ester

To 1.90 g (3.02 mmol) (6R-cis)-3-(iodomethyl)-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid 4-nitrophenyl)methyl ester (Example 26) in 15 ml of dry DMF at 0°C was added 0.78 g (3.00 mmol) of sodium 3,4-diacetoxybenzoate in one portion. The solution was stirred for 30 min, and 100 mL of EtOAc was added. The resulting solution was washed with brine (3 x 50 mL), dried over MgSO 4 , and the solvent was removed in vacuo. Chromatography (n-hexane/EtOAc, 1:1) gave 1.30 g (58%) of a mixture of ±2- and ^3-isomers. This substance was dissolved in 30 mL of CH 2 Cl 2 at 0°C, and 400 mg (2.32 mmol) of m-chloroperbenzoic acid was added in one portion. The mixture was stirred at 0°C for 2 hours, washed with aqueous NaHCO 3 solution, dried over MgSO 4 and the solvent was removed in vacuo. Crystallization from EtOAc-n-hexane (5:2) afforded 870 mg (66%) of a single sulfoxide isomer. The mother liquor was chromatographed on silica gel (EtOAc/CH 2 Cl 2 , 1:1) to give 320 mg (24%) of the isomeric sulfoxide. The combined sulfoxides (1.19 g, 90%) were reduced by dissolving them in 5 mL of dry DMF at +20°C and adding 0.34 mL of PBr 3 , followed by stirring for 1 hour. Removal of the solvent followed by silica gel chromatography (EtOAc/n-hexane 1:1) afforded 967 mg (83%) of the title compound.

NMR (CDCl 3 ): 2.29 (s) 6 H (2 OAC); 3.33, 3.54 (d of d, J = 18 Hz) 2 H (CH 2 S) 3.44 (s) 3 H (OCH 3 ); 3.88 (s) (CH2CON); 4.98 (d, J = 12 Hz) 1 H (1/2 CH 2 O); 5.04 (s) 1 H (C 6 ); 5.34 (m) 3 H (1/2 CH 2 O, CH 2 ); 6.40 (s) 1 H (NH); 6.99 (m) 2 H (thiophene); 7.24 (m) 2 H (thiophene, Ar); 7.54 (d, J = 8 Hz) 1 H (Ar); 7.78 (s) 1 H (Ar); 8.87 (d, J = 8 Hz) 1 H (Ar); 8.16 (d, J = 8 Hz) 1 H (Ar). IR (KBr): 3325, 1775, 1722, 1700, 1520, 1348. MS: m/z 740 (M + H).

Example 28

Preparation of ( 6R- cis )- 3-[[[ 3, 4- bis( acetyloxy) benzoyl]-oxymethyl]- 7- methoxy- 8- oxo- 7-[( 2- thienylacetyl) amino]- 5-thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid monosodium salt

To a solution of 100 mg (0.135 mmol) (6R-cis)-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-7-methoxy-8-oxo-7-[(2- thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester in 5 ml of THF was added 100 ml of 5% Pt/C. The mixture was hydrogenated at 3.5 kg/cm 2 for 48 hours. The mixture was filtered to remove the catalyst and the solvent was removed under vacuum. The residue was poured into 3 mL of EtOAc and 3 mL of 2% aqueous NaHCO 3 solution and stirred vigorously for 15 min. The aqueous layer was separated and chromatographed (reverse phase, 0-30% acetonitrile in water) to give 45 mg (53%) of a white solid after lyophilization of the appropriate fractions.

NMR (DMSO-d 6 ): 2.32 (s) 6 H (2 OAc); 3.19, 3.59 (d of d, J = 18 Hz) 2 H (CH 2 S); 3.49 (s) (OCH 3 ); 3.79, 3.89 (d of d, J = 16 Hz) 2 H (CH 2 CO); 4.98, 5.17 (d of d, J = 14 Hz) 2 H (CH 2 O); 5.00 (s) 1 H (C 6 ); 6.96 (m) 2 H (thiophene); 7.38 (m) 1 H (thiophene); 7.45 (d, J = 8 Hz) 1 H (Ar); 8.84 (s) 1 H (Ar); 8.91 (d, J = 8 Hz) 1 H (Ar); 9.41 (s) 1 H (NH). IR (KBr): 3400, 1770, 1618, 1612. MS: m/z 672 (M + H). UV (EtOH): A max 236 nm (e = 16,620). HRMS calcd (M + H) for<C>26H24NaN2<0>11S2: 627.0719. Found: 627.0676.

Example 29

Preparation of ( 6R- cis )- 3-[[( 3, 4- dihydroxybenzoyl) oxy]-methyl]- 7- methoxy- 8- oxo- 7-[( 2- thienylacetyl) amino]- 5- thia- 1- azabicyclof 4. 2. Q] oct- 2- ene- 2- carboxylic acid monosodium salt

To a solution of 65 mg (0.104 mmol) (6R-cis)-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-7-methoxy-8-oxo-7-[(2- thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (Example 28) in 4 ml of saturated aqueous NaHCO 3 solution was added 1 ml of methanol. The solution was stirred at room temperature for 1 hour. The methanol was removed under reduced pressure and the remaining aqueous solution was chromatographed (reverse phase, 0-20% acetonitrile in water) to give 52 mg (92%) of a white solid after lyophilization of the appropriate fractions.

NMR (DMSO-d 6 ): 3.11 (d of d, J = 18 Hz) 1 H (1/2 CH 2 S, other 1/2 overshadowed by HOD); 3.37 (s) 3 H (OCH 3 ); 3.78, 3.87 (d of d, J = 16 Hz) 2 H (CH 2 O); 4.83, 5.01 (d of d, J = 12 Hz) 2 H (CH 2 O); 4.98 (s) 1 H (C 6 ); 5.40 (br) 3 H (2 OH, NH); 6.38, 6.95 (m) 1 H (Ar); (m) 2 H (thiophene); 7.11 (s) 1 H (Ar); (d, J = 8 Hz) 1 H (Ar); 7.36 (m) 1 H (thiophene). IR (KBr): 1762, 1675, 1610. MS: m/z 543 (M + H). UV (EtOH): A max 222 nm (e = 15,960), Å max 265 nm (e = 10,280). HRMS calcd (M + H) for C22<H>2o<N>209s2Na: 543.0508. Found: 543.0506.

Example 30

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[[ 3, 4- bis-( acetyloxy) benzoyl] amino] methyl]- 7-[[( 2- amino- 4- thiazolyl )-( methoxyimino) acetyl] amino]- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2-ene- 2- carboxylic acid monosodium salt

To a solution of 61.3 mg (0.258 mmol) of 3,4-diacetoxybenzoic acid in 10 ml of dry DMF was added 68 mg (0.258 mmol) of triphenylphosphine, followed by 86 mg of 2,2'-dibenzothiazolyl disulfide. Complete dissolution occurred within 20 min., and the solution was then stirred for 10 min. To this solution was added dropwise a solution of 100 mg (0.206 mmol) [6R-[6 alpha, 7 beta(Z)]]-3-(aminomethyl)-7-[[(2-amino-4-thiazolyl) (Methoxyimino)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydrochloride salt and 150 µl triethylamine in 5 mL dry DMF. The resulting solution was stirred for 3 hours, and the solvent was removed under vacuum. To the residue were added 5 ml of ethyl acetate and 5 ml of 2% aqueous NaHCO 3 solution. The biphasic mixture was stirred rapidly for 15 min, and the aqueous layer was separated and chromatographed (reverse phase, 0-30% acetonitrile in water) to give 62 mg (45%) of a white solid.

NMR (DMSO-d 6 ): 2.30 (s) 6 H (2 OAc); 3.21, 3.54 (d of d, J = 18 Hz) 2 H (CH 2 S); 3.82 (s) 3 H (OCH 3 ); 3.99 (d of d, J = 12 Hz, J = 4 Hz) 1 H (1/2 CH 2 N); 4.05 (d of d, J = 12 Hz) 1 H (1/2 CH 2 N); 4.95 (d, J = 6 Hz) 1 H (C 6 ); 5.52 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.72 (s) 1 H (thiazole); 7.20 (s) 2 H (NH 2 ); 7.36 (d, J = 8 Hz) 1 H (Ar); 7.70 (s) 1 H (Ar); 7.75 (d, J = 8 Hz) 1 H (Ar); 9.20 (br) 1 H (NH), 9.49

(d, J = 10 Hz) 1 H (NH). IR (KBr): 3360, 1763, 1645, 1612. MS: m/z 655 (M + H). UV (EtOH): A max 228 nm (e = 21,250). HRMS calcd (M + H) for C25<H>25NaN6O10<S>2: 655.0893. Found: 655.0886.

Example 31

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[[( 3, 4-dihydroxy) benzoyl] amino] methyl]- 7-[[( 2- amino- 4- thiazolyl)( methoxyimino) acetyl ] amino]- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2-carboxylic acid monosodium salt

By following the procedures and conditions described in Example 29, 20 mg (0.031 mmol) of [6R-[6 alpha, 7 beta(Z)]]-3-[[[3,4-bis(acetyloxy)benzoyl]amino]methyl ]-7-[[2-amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt (Example 30 ) in 1 ml saturated aqueous NaHCO 3 solution and 500 µl methanol gave 10 mg (60%) of a white substance after chromatography in (reversed phase, 0-20% acetonitrile in water) and freeze-drying.

NMR (D 2 O): 3.38, 3.67 (d of d, J = 18 Hz) 2 H (CH 2 S); 3.99 (s) 3 H (OHCH 3 ); 4.13, 4.39 (d of d, J = 14 Hz) 2 H (CH 2 N); 5.21 (d, J = 6 Hz) 1 H (C 6 ); 5.30 (d, J = 6 Hz) 1 H (C 7 ); 6.75 (d, J = 8 Hz) 1 H (Ar); 7.02 (s) 1 H (thiazole); 7.22 (m) 2 H (Ar). HRMS calcd (M + H) for C21H19NaN608S2<:>571.0862. Found: 571.0646.

Example 32

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 7-[[( 2-amino- 4-thiazolyl)( methoxyimino) acetyl] amino]- 3-[[( 3, 4- dihydroxy)- benzoyl) thiomethyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene-2- carboxylic acid monosodium salt

To a suspension of 2.03 g (8.0 mmol) of 3,4-bis(acetyloxy)-benzenecarbutioic acid in 80 ml of H 2 O was added 2.02 g (24.0 mmol) of NaHCO 3 . The resulting solution was stirred at 50°C for 15 min. To this was added a solution of 3.82 g

(8.0 mmol) 3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo-[ 4.2.0]oct-2-ene-2-carboxylic acid monosodium salt in 20 mL H2O. The reaction mixture was stirred at 50°C for 18 h, cooled, filtered and chromatographed (C18, 0-20% CH 3 CN in H 2 O) to give 1.55 g (29%) after lyophilization.

NMR (D 2 O): 3.35, 3.75 (d of d, J = 18 Hz) 2 H (CH 2 S); 3.86, 4.23 (d of d, J = 14 Hz) 2 H (CH 2 SCO); 3.98 (s) 3 H (OCH<3>); 5.19 (d, J = 6 Hz) 1 H (C 6 ); 5.79 (d, J = 6 Hz) 1 H (C 7 ); 6.96 (d, J = 8Hz) 1 H (Ar); 7.01 (s) 1 H (thiazole); 7.45 (s) 1 H (Ar); 7.52 (d, J = 8 Hz). IR (KBr): 3345, 1770, 1695, 1600. UV (H20): A max 203 nm (e = 36,500), X max 230 nm (e = 32,000), Å max 250 nm (e = 24,000). HRMS calcd (M + H) for<C>2i<H>19NaN5O8S3: 588.0294. Found: 588.0287.

Example 3 3

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[( 3, 4- bis-( acetyloxy) benzoyl) thio] methyl]- 8- oxo- 7-[[[ 2-[ ( triphenylmethyl) amino] - 4- thiazolyl] ( methoxyimino) acetyl] amino]- 5- thia- 1-azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester

Following the procedures and conditions described in Example 4, 61 mg (0.220 mmol) of 3,4-bis(acetyloxy)benzenecarbothioic acid monosodium salt in 2 mL of dry DMF was added to 171 mg (0.208 mmol) of [6R-[6 alpha , 7 beta(Z)]]-3-(iodomethyl)-7-[[2-(methoxyimino)-2-[2-(tritylamino)-4-thiazolyl]-acetyl]-amino]-8-oxo-5 -thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester in 2 mL DMF, followed by stirring for 3 hours, gave 112 mg (57%) of a cream-colored substance after silica gel chromatography ( 9:1 CH2Cl2/MeOH).

NMR (CDCl 3 ): 1.54 (s) 9 H (t-Bu); 2.31 (s) 6 H (2 OAc); 2.32, 2.62 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.05, 4.30 (d of d, J = 10 HZ) 2 H (CH 2 SCO); 5.02 (d, J = 6 Hz) 1 H (C 6 ); 5.90 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ) 6.68 (d, J = 10 Hz) 1 H (NH) 6.70 (s) 1 H (thiazole ); 6.99 (br s) 1 H (NH) 7.26 (s) 16 H (CPh 3 , Ar); 7.81 (s) 1 H (Ar); 7.86 (d, J = 8 Hz) 1 H (Ar). IR (KBr): 1780, 1715, 1665. UV (EtOH): A max 214 nm (e = 36,000), A max 267 nm (e = 29,750). MS: m/z 948 (M+H).

Example 34

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 7-[[( 2- amino- 4-thiazolyl)( methoxyimino) acetyl] amino]- 3-[[[( 3, 4- bis( acetyloxy) benzoyl] thio] methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct-2- ene- 2- carboxylic acid monosodium salt

By following the procedures and conditions described in Example 10, 208 mg (0.219 mmol) of [6R-[6 alpha, 7 beta(Z)]]-3-[[(3,4-bis(acetyloxy)benzoyl)thio]methyl ]-8-oxo-7-[[[2-[(triphenylmethyl)amino]-4-thiazolyl](methoxyimino)acetyl]-amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene -2-carboxylic acid 1,1-dimethylethyl ester (Example 33) in 4 mL CH 2 Cl 2 and 500 µl anisole, treated with 4 mL TFA, followed by stirring for 5 h and then worked up according to Example 31, gave 77 mg (52%) of a white powder after reverse phase chromatography (0-20% acetonitrile in water).

NMR (D 2 O): 2.40 (s) 6 H (2 OAc); 3.39, 3.73 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.01 (s) 3 H (OCH 3 ); 3.96, 4.39 (d of d, J = 14 Hz) 2 H (CH 2 SCO); 5.21 (d, J = 6 Hz) 1 H (C 6 ); 5.81 (d, J = 6 Hz) 1 H (C 7 ); 7.03 (s) 1 H (thiazole) 7.45 (d, J = 8 Hz) 1 H (Ar); 7.89 (s) 1 H (Ar); 8.98 (s) 1 H (Ar). UV (H20): A max 237 nm (e = 20,200), A max 275 nm (e = 17,000). MS: m/z 672 (M+H).

Example 3 5

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[[( 3, 4- bis-( acetyloxy)- 2, 5- dichloro)- benzoyloxy]- methyl]- 7-[[ ( methoxyimino )[ 2-[( triphenylmethyl) amino]- 4- thiazolyl] acetyl] amino]- 8-oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid 1 , 1-dimethylethyl ester

Following the procedures and conditions described in Example 4, 87 mg (0.264 mmol) of 3,4-bis(acetyloxy)-2,5-dichloro-benzoic acid sodium salt in 2 ml of DMF added to 208 mg (0.253 mmol) [6R -[6 alpha, 7 beta(Z)]]-3-(iodomethyl)-7-[[2-(methoxyimino)-2-[2-(tritylamino)-4-thiazolyl]-acetyl]amino]-8- oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester in 2 mL DMF, followed by stirring for 4 h, gave 176 mg (70%) after silica gel chromatography ( 9:1 CH2Cl2/MeOH).

NMR (CDCl 3 ): 1.50 (s) 9 H (tBu); 2.36 (s) 6 H (2 OAc); 2.36, 2.60 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.03 (s) 3 H (OCH3) 5.01 (m) 2 H (1/2 CH2O, C6) 5.38 (d, J = 14 Hz) 1 H (1/2 CH2O) 5.92 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7); 6.68 (m) 2 H (NH, thiazole) 7.12 (s) 15 H (CPh 3 ); 7.81 (s) 1 H (Ar).

Example 36

Preparation of [ 6R-[ 6 alpha, 7 beta( Z)]]- 7-[[( 2- amino- 4-thiazolyl'( methoxyimino) acetyl] amino]- 3-[[[( 3, 4- bis( acetyloxy) - 2 , 5- dichlorobenzoyl] oxy] methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid monosodium salt

A solution of 146 mg (0.146 mmol) [6R-[6 alpha, 7 beta(Z)]]-3-[[[3,4-bis(acetyloxy)-2,5-dichlorobenzoyl]oxy]-methyl]- 7-[[(methoxyimino)[2-[(triphenylmethyl)amino]-4-thiazolyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1 ,1-dimethylethyl ester (Example 35) in 4.6 ml of 70% aqueous formic acid was stirred for 3 hours at room temperature. The solvent was removed under vacuum and the residue chromatographed on silica gel (0-100% EtOAc in CH 2 Cl 2 ) to give 80.7 mg (72%) of detritylated material. A solution of 39 mg (0.051 mmol) of this substance in 1.4 mL CH 2 Cl 2 and 100 µl anisole was cooled to 0°C and treated with 1.2 mL TFA. The reaction mixture was stirred for 6.5 hours at 0°C, and the solvent was removed under vacuum. The oily residue was dissolved in 1 ml of acetone and added to 50 ml of n-hexane with stirring. The precipitate formed was filtered and dissolved in 0.5 mL EtOAc and treated with 9.0 mg (0.054 mmol) 2-ethyl sodium n-hexanoate. The precipitate was collected and dried to give 7 mg (19%) of a white substance.

NMR (D 2 O): 2.30 (s) 6 H (2 OAc); 3.30, 3.60 (d of d, J = 18 Hz) 2 H (CH 2 S); 3.82 (s) 3 H (OCH 3 ) 4.80 (d, J = 12 Hz) 1 H (1/2 CH 2 O); 5.06 (ra) 2 H (1/2 CH 2 O, C 6 ); 5.66 (d, J = 6 Hz) 1 H (C 7 ); 6.84 (s) 1 H (thiazole); 7.91 (s) 1 H (Ar).

Example 37

Preparation of [( 6R- trans )- 3-[[[[[ 3, 4- bis(acetyloxy)-phenyl] amino] carbonyl] oxy] methyl]- 7-[[( 1, 1- dimethylethoxy)-carbonyl] amino]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid- diphenyl raethyl ester

To a solution of 160 mg (0.8 mmol) of 3,4-bis(acetyloxy)-phenyl isocyanate in 7 ml of dry methylene chloride was added 0.2 ml of pyridine, followed by the addition of 198 mg (0.4 mmol) (6R -trans)-3-[hydroxymethyl]-7-[[(1,1-dimethylethoxy)-carbonyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2 -carboxylic acid diphenyl methyl ester under argon at room temperature. The reaction mixture was stirred for 5 hours and the solvent removed under vacuum. The residue was taken up in EtOAc, and the organic solution was washed with dilute HCl and dried over anhydrous Na 2 SO 4 . The crude product was purified by silica chromatography (EtOAc/n-hexane, 1:1) to give 250 mg (84%) of a white substance.

NMR (CDCl 3 ): 1.46 (s) 9 H (t-bu); 2.28 (s) 6 H (2 OAc); 3.43, 3.64 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.84, 5.18 (d of d, J = 12 Hz) 2 H (CH 2 O); 4.95 (d, J = 6 Hz) 1 H (C 6 ); 5.68 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 5.23 (d, J = 10 Hz) 1 H (NH); 6.62 (s), 1 H (thiazole, Ar); 7.0 (s) 1 H (CH Ar 2 ); 7.14 (s) 2 H (Ar); 7.36 (m) 1 H (Ar). IR (KBr): 3340, 1773, 1722, 1530, 700.

Example 38

Preparation of [ 6R-[ 6 alpha, 7 beta( Z) 3]- 3-[[[[[ 3, 4- bis-( acetyloxy) phenyl] amino] carbonyl] oxy] methyl]- 7-[[( 2 - amino- 4-thiazolyl)( methoxyimino) acetyl] amino]- 8- oxo- 5- thia- 1- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid monosodium salt

A solution of 233 mg (0.31 mmol) [(6R-trans)-3-[[[[[3,4-bis-(acetyloxy)phenyl]amino]carbonyl]oxy]methyl]-7-[[( 1,1-Dimethylethoxy)carbonyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid diphenyl methyl ester from Example 37 in 5 ml of dry 1, 2-Dichloroethane was cooled to 0°C in an ice/water bath and treated with 0.6 mL of anisole, followed by 4 mL of trifluoroacetic acid. The reaction mixture was stirred at 0°C for 5 hours, and the volatiles were removed under vacuum. The residue was precipitated with anhydrous diethyl ether and filtered. The solid (130 mg) in 10 mL of dry methylene chloride and 0.1 mL of triethylamine was added at 0°C to 106 mg (0.33 mmol) of s-(2-benzo-thiazolyl)-(Z)-aminothio-4 -thiazole-glyoxylate-o-(methyl)-oxime and 5 ml of acetone. The mixture was stirred under argon at room temperature for 15 hours. The solvents were removed under vacuum and the residue was added to 5 mL of EtOAc and 10 mL of 1% aqueous NaHCO 3 solution. The aqueous solution was purified by C 3 reversed phase chromatography (0-20% acetonitrile in water) to give 39 mg (20%) of the desired product.

NMR (DMS0-d6): 2.23 (s) 3 H (OAc); 2.26 (s) 3 H (OAc); 3.24, 3.50 (d of d, J = 18 Hz) 2 H (CH 2 S); 3.84 (s) 3H

(OCH3); 4.90, 4.98 (d of d, J = 12 Hz) 2 H (OCH 2 ); 5.0 (d, J = 6 Hz) 1 H (C 6 ); 5.60 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.78 (s) 1 H (thiazole); 7.18 (d, J = 8 Hz) 1 H (Ar); 7.32 (d of d, J = 3 Hz, J = 8 Hz) 1 H (Ar) 7.44 (d, J = 3 Hz) 1 H (Ar); 7.30 (br s) 2 H (NH 2 ); 9.56 (br d, J = 10 Hz), 1 H

(NH). IR (KBr): 3330, 1762, 1672, 1732 inf. 1612.

Example 39

Preparation of [ 6R-[ 6 alpha, 7 beta( Z) 33- 3-[[[[[ 3, 4- bis-( acetyloxy) phenyl] amino] carbonyl] oxy] methyl 3 - 7-[[[ 2- amino-[( 2- amino- 2- oxoethoxy) imino- 4- thiazolyl3acetyl] amino3- 8-oxo- 5- thia- l- azabicyclo[ 4. 2. 0 3oct- 2- en- 2- carboxylic acid monosodium salt

By following the procedures and conditions described in Example 38, 233 mg (0.31 mmol) of [(6R-trans)-3-[[[[[3,4-bis(acetyloxy)phenyl]amino]carbonyl]oxy]methyl ]-7-[[(1,1-dimethyl-ethoxy ) carbonyl ]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0 3oct-2-ene-2-carboxylic acid diphenyl methyl ester (from example 37 ) in 5 mL of dry 1,2-dichloroethane and 0.6 mL of anisole was treated with 4 mL of trifluoroacetic acid, followed by reaction with 87 mg (0.22 mmol) of s-(2-benzothiazolyl)-Z-aminothio-4-thiazole -glyoxylate-O-(carbamoylmethyl)oxime. Purification by C₂8 reversed phase chromatography (0-20% acetonitrile in water) gave 48 mg (23%) of a white substance.

NMR (DMSO-d 6 ): 2.23 (s) 3 H (OAc); 2.26 (s) 3 H (OAc); 3.24, 3.52 (d of d, J = 16 Hz) 2 H (CH 2 S); 4.42 (s) 2 H (CH 2 CON); 4.93 (s) 2 H (OCH 2 ); 5.03 (d, J = 6 Hz) 1 H (C 6 ); 5.64 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.87 (s) 1 H (thiazole); 7.17 (d, J = 9 Hz) 1 H (Ar); 7.32 (d of d, J = 3 Hz, J = 9 Hz) 1 H (Ar); 7.35 (br s) 2 H (NH 2 ); 7.42 (d, J = 3 Hz) 1 H (Ar); 9.75 (d, J = 10 Hz) 1 H (NH); 10.15 (br s) 1

H (NH).

Example 40

Preparation of [( 6R- trans)- 3-[[[( 3, 4- bis( acetyloxy) benzoyl] thiojmethyl3- 8- oxo- 7-[( phenoxyacetyl) amino]- 5- thia- 1- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester

Following the procedures and conditions described in Example 4, 230 mg (0.832 mmol) of 3,4-bis(acetyloxy)benzenecarbothioic acid sodium salt in 5 mL of DMF added to 411 mg (0.775 mmol) of [6R-[6 alpha, 7 beta(Z)33-3-(iodomethyl)-7-[(phenoxyacetyl)amino3-8-oxo-5-thia-1-azabicyclo[4.2.0 3 oct-2-ene-2-carboxylic acid 1, 1 dimethyl ethyl ester in 5 ml DMF, followed by stirring for 2.5 hours, gave 206 mg (40%) of a white substance after silica gel chromatography (9:1 CH 2 Cl 2 /EtOAc).

NMR (CDCl 3 ): 1.44 (s) 9 H (t-Bu); 2.42 (s) 6 H (2 OAc);

3.35, 3.61 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.00, 4.29 (d of d, J = 12 Hz) 2 H (CH 2 SCO); 4.55 (s) 3 H (OCH 3 ); 5.01 (d, J = 6 Hz) 1 H (C 6) 5.91 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7); 6.90 (d, J = 8 Hz) 1 H (Ar); 7.00 (m) 1 H (Ar); 7.2, 7.3 (m) 3 H (Ar); 7.79 (s) 1 H (Ar); 7.86 (d, J = 8 Hz) 1 H (Ar). IR (KBr): 3320, 1780, 1712, 1692, 1662. UV (EtOH): ^max 248 nm (e = 17,000), A max 274 nm (e = 1850).

Example 41

Preparation of ( 6R- trans)- 7- amino- 3-[[[ 3, 4- bis(acetyloxy)-benzoyl] thio] methyl]- 8- oxo- 5- thia- 1- azabicyclo[ 4. 2. 0 ] oct- 2- ene-2- carboxylic acid 1, 1- dimethyl ethyl ester monohydrochloride

By following the procedures and conditions described in Example 16, 147 mg (0.223 mmol) of (6R-trans)-3-[[[(3,4-bis(acetyloxy)benzoyl]thio]methyl]-8-oxo-7- [(phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester (Example 48) in 0.7 mL CH 2 Cl 2 was added to 27 µl (0.333 mmol ) pyridine and 61.7 mg (0.296 mmol) PCI5 to give 70.5 mg (56%) of a white powder.

NMR (DMSO-d 6 ): 1.53 (s) 9 H (t-Bu); 2.30 (s) 3 H (OAc); 2.31 (s) 3 H (OAc); 3.54, 3.83 (d of d, J = 18 Hz) 2 H (CH 2 S); 3.96, 4.33 (d of d, J = 12 Hz) 2 H (CH 2 SCO); 5.17 (d, J = 6 Hz) 1 H (C 6 ); 5.22 (d, J = 6 Hz) 1 H (C 7 ); 7.48 (d, J = 8 Hz) 1 H (Ar); 7.84 (s) 1 H (Ar); 7.88 (d, J = 8 Hz) 1 H (Ar). IR (KBr): 1780, 1712, 1668. UV (EtOH)

A max 277 nm (e = 16,760).

Example 42

[ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[( 3, 4- dihydroxybenzoyl) oxy]-methyl]- 7-[[[ 2- amino- 4- thiazolyl][( 2- amino - 2- oxoethoxy)-imino] acetyl] amino]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2-ene- 2- carboxylic acid monosodium salt

By following the procedures and conditions described in Example 20, 350 mg (0.477 mmol) [6R-[6 alpha, 7 beta(Z)]]-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl ]-7-[[[2-amino-[(2-amino-2-oxoethoxy)imino]-4-thiazolyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct -2-ene-2-carboxylic acid 1,1-dimethylethyl ester in 5 mL CH 2 Cl 2 and 500 µl anisole, treated with 5 mL TFA, followed by stirring the residue with EtOAc, MeOH and saturated NaHCO 3 (1:1:1), gave 165 mg (54%) of a white substance after reverse phase chromatography (0-20% acetonitrile in water).

NMR (DMSO-d 6 ): 3.56 (d, J = 18 Hz) 1 H (1/2 CH 2 S); 4.41 (s) 2 H (CH 2 ); 4.89, 5.17 (d of d, J = 12 Hz) 2 H (CH 2 OCO); 5.05 (d, J = 6 Hz) 1 H (C 6 ); 5.64 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.77 (d, J = 8 Hz) 1 H (Ar); 6.84 (s) 1 H (thiazole); 7.12 (S) 1 H (OH); 7.29 (d, J = 8 Hz) 1 H (Ar); 7.34 (s) 1 H (Ar); 7.50 (s) 1 H (OH) 9.75 (d, J = 8 Hz) 1 H (NH). IR (KBr): 1762, 1672, 1608. UV (H 2 O): A max 218 nm (e = 17,900), y max 261 (e = 14,350). Exact mass calculated for<C>22<H>21N6<O>10S2Na (M + H): 616.0614. Found: 616.0658.

Example 43

[ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[[ 3, 4- bis( acetyloxy) benzoyl]-thio] methyl]- 7-[[[( 2- amino- 2- oxoethoxy) imino](2-amino-4-thiazolyl)- acetyl] amino]- 8- oxo- 5- thia- 1- azabicyclo[ 4. 2. 0] oct-2- ene- 2- carboxylic acid- monosodium salt 1, 1- dimethyl ethyl ester

By following the procedures and conditions described in Example 18, 243 mg (0.434 mmol) of (6R-trans)-3-[[[3,4-bis-(acetyloxy)benzoyl]thio]methyl]-7-amino-8- oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester monohydrochloride and 158 mg (0.400 mmol) S-(2-benzothiazolyl)-

Z-aminothio-4-thiazolyl-glyoxylate-O-(carbamoylmethyl)oxime i

8 ml DMF and 16 ml CH 2 Cl 2 gave 180 mg of a white substance after chromatography (0-50% methanol in methylene chloride).

NMR (CDCl 3 ): 1.57 (s) 9 H (t-Bu); 2.31 (s) 6 H (2 OAc); 3.39, 3.63 (d of d, J = 18 Hz) 2 H (CH 2 S) 3.98, 4.36 (d of d, J = 15 Hz) 2 H (CH 2 SCO); 5.07 (d, J = 6 Hz) 1 H (C 6 ); 5.60 (br) 2 H (NH 2 ); 5.95 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.85 (s) 1 H (thiazole); 7.30 (d, J = 8 Hz) 1 H (Ar); 7.80 (d, J = 2 Hz) 1 H (Ar); 7.88 (d of d, J = 2 Hz, J = 8 Hz) 1 H (Ar); 8.32 (br) 1 H (NH). IR (KBr): 1778, 1710, 1672. UV (EtOH): X max 240 nm (e = 20,750), A max 278 nm (e = 17,300). MS: m/z 749 (M+H).

Example 44

[ 6R- E6 alpha, 7 beta( Z)]]- 7-[[[ 2- amino-[( 2- araino- 2- oxoethoxy3iminoJ- 4- thiazolyl] acetyl3amino3- 3-[[( 3, 4- dihydroxybenzoyl) thio]- methyl 3- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2-ene- 2- carboxylic acid monosodium salt

By following the procedures and conditions described in Example 20, 305 mg (0.408 mmol) of [6R-[6 alpha, 7 beta(Z)]]-3-[[[3,4-bis(acetyloxy)benzoyl]thio]methyl ]-7-[[[(2-amino-2-oxoethoxy)imino](2-amino-4-thiazolyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylic acid 1,1-dimethylethyl ester (Example 43) in 6 mL CH 2 Cl 2 and 600 µl anisole, treated with 13 mL TFA, followed by stirring the residue with EtOAc, MeOH and saturated NaHCO 3 (1:1:1 ), gave 200 mg of a white substance after reverse phase chromatography (0-20% acetonitrile in water).

NMR (DMS0-d6): 3.09, 3.51 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.03, 4.18 (d of d, J = 12 Hz) 2 H (CH 2 SCO) 4.41 (s) 2 H (OCH 2 ); 5.00 (d, J = 6 Hz) 1 H (C 6 ); 5.59 (d of d, J = 6 Hz, J = 10 Hz) 1 H (C 7 ); 6.79 (d, J = 8 Hz) 1 H (Ar); 6.83 (s) 1 H (thiazole); 7.09 (s) 1 H (OH); 7.30 (ra) 6 H (2 Ar, 2 NH 2 ) 7.48 (s) 1 H (OH); 9.73 (d, J = 10 Hz) 1 H (NH). IR (KBr): 1760, 1672, 1592, 1162, 1088. UV (H2O): A max 230 nm (e = 16,850), A max 282 nm (e = 12,900). HRMS calcd for<C>22<H>i9N609S3Na: 631.0375. Found: 631.0352.

Example 45

[ 6R-[ 6 alpha, 7 beta( Z)]]- 3-[[[ 3, 4- bis( acetyloxy) benzoyl]-oxy] methyl]- 7-[[( 2- amino- 4- thiazolyl)[ [ 2-( 1, 1- dimethylethoxy)-2- oxoethoxy] imino] acetyl] amino]- 8- oxo- 5- thia- 1- azabicyclo-[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester

By following the procedures and conditions described in Example 18, 1.20 g (2.37 mmol) of (6R-trans)-7-amino-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl] -8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester monohydrochloride in 46 ml CH2Cl2 and 1.0 g (222 mmol) 2-[[[ 1-(2-amino-4-thiazolyl)-2-(benzothiazol-2-yl-thio)-2-oxoethyl]-imino]oxy]acetic acid 1,1-dimethylethyl ester in 46 ml DMF and 23 ml CH 2 Cl 2 gave after 4 hours stirring 920 mg of a white substance after silica gel chromatography (8:2 CH 2 Cl 2 /EtOAc).

NMR (CDCl 3 ): 1.42 (s) 9 H (t-bu); 1.55 (s) 9 H (t-but); 2.31 (s) 6 H (2 OAc); 3.41, 3.62 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.73, 4.77 (d of d, J = 17 Hz) 2 H (CH 2 OCOAr); 5.06, 5.39 (d of d, J = 16 Hz) 2 H (OCH 2 CO); 5.09 (d, J = 7 Hz) 1 H (C 6 ); 5.97 (d of d, J = 7 Hz, J = 10 Hz) 1 H (Cl) ; 7.03 (s) 1 H (thiazole); 7.29 (d, J = 8 Hz) (e.c.) 1 H (Ar); 7.85 (d, J = 2 Hz) 1 H (Ar); 7.95 (d of d, J = 2 Hz, J = 8 Hz) 1 H (Ar); 8.63 (d, J = 10 Hz) 1 H (NH). IR (KBr): 3400, 1780, 1722, 1682. UV (EtOH): A max 236 nm (e = 27,500). MS: M/T 790 (M + H).

Example 46

[ 6R-[ 6 alpha, 7 beta( Z)]- 7-[[( 2- amino- 4- thiazolyl)[( carboxy-methoxy) imino] acetyl] amino]- 3-[[ 3, 4- dihydroxybenzoy1) oxy]-methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid disodium salt

By following the procedures and conditions described in Example 20, 920 mg (1.16 mmol) [6R-[6 alpha, 7 beta(Z)]]-3-

[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-7-[[(2-amino-4-thiazolyl)[[2-(1,1-dimethylethoxy-2-oxoethoxy]imino]acetyl] -amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester in 24 ml CH 2 Cl 2 and 2.3 ml anisole, treated with 24 ml TFA, followed by stirring the residue with EtOAc, MeOH and saturated NaHCO 3 , gave 385 mg (62%) of a white solid after reverse phase chromatography (0-30% acetonitrile in water).

NMR (D 2 O): 3.28, 3.56 (d of d, J = 18 Hz) 2 H (CH 2 S), 4.42 (s) 2 H (CH 2 CO 2 Na), 4.67, 4.96 (d of d, J = 15 Hz) 2 H (CH2O), 5.07 (d, J = 6 Hz) 1 H (C 6), 5.68 (d, J = 6 Hz) 1 H (C 7), 6 .71 (d, J = 8 Hz) 1 H (Ar) 6.87 (s) 1 H (thiazole) 7.30 (m) 2 H (Ar). IR (KBr): 1755, 1650, 1602. UV (H20): A max 203 nm (e = 17,600), A max 231 nm (e = 15,400), A max 260 nm (e = 9,800), A max 302 nm (e = 8,080).

Example 47

( 6R- trans )- 7-[[( 2- amino- 4- thiazolyl)[[ 1-( aminocarbonyl)- 1-methylethoxy] imino] acetyl] amino]- 3-[[[ 3, 4- bis( acetyloxy )-benzoyl] oxy] methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2-ene- 2- carboxylic acid 1, 1- dimethyl ethyl ester

A solution of 542 mg (1.01 mmol) of (6R-trans)-7-amino-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester monohydrochloride in 25 ml CH 2 Cl 2 was washed with 2 x 25 ml saturated NaHC 2 /saline (1:4). The organic solution was dried over MgSO 4 and filtered. To this solution was added a solution of 411 mg (1.00 mmol) of 2-2-amino-α-[(2-amino-1,1-dimethyl-2-oxoethoxy)imino]-4-thiazoleacetic acid, 136 mg (1.00 mmol) of N-hydroxybenzotriazole (NHBT) and 211 mg (1.00 mmol) of dicyclohexylcarbodiimide (DCC) in 25 mL of dry DMF. The solution was then stirred for 24 hours to give 320 mg (42%) after silica gel chromatography.

NMR (CDCl 3 ): 1.50 (s) 6 H (2 CH 3 ); 1.54 (s) 9 H (t-bu); 3.42, 3.61 (d of d, J = 18 Hz); 5.06 (m) 2 H (1/2 CH 2 O, C 6 ); 5.32 (d, J = 13 Hz) 1 H (1/2 CH 2 O); 5.90 (d of d, J = 5 Hz, J = 9 Hz) 1 H (C 7 ); 6.40 (br s) 2 H (NH 2 ); 6.75 (s) 1 H (thiazole); 7.28 (d, J = 8 Hz) 1 H (Ar); 7.83 (d, J = 2 Hz) 1 H (Ar); 7.93 (d of d, J = 2 Hz, J = 8 Hz). IR (KBr): 1780, 1722, 1680, 1532. UV (EtOH): A max 236 nm (e = 29,050). MS: ra/z 761 (M+H).

Example 48

( 6R- trans )- 7-[[( 2- amino- 4- thiazolyl)[[ 1-( aminocarbonyl)- 1-methylethoxy] iraino] acetyl] amino]- 3-[[( 3, 4- dihydroxybenzoyl)- oxy] methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2-carboxylic acid monosodium salt

By following the procedures and conditions described in Example 20, 320 mg (0.421 mmol) of (6R-trans)-7-[[(2-amino-4-thiazolyl)[[1-(aminocarbonyl)-1-methylethoxy]iraino] acetyl]-amino]-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2- carboxylic acid 1,1-dimethylethyl ester in 5 ml CH 2 Cl 2 and 500 u-l anisole, treated with 5 ml TFA, stirred for 3 h and treatment of the residue with EtOAc, MeOH and saturated NaHCO 3 gave 123 mg (45%) of a white solid after reverse phase chromatography (0-30% acetonitrile in water).

NMR (D 2 O): 1.60 (s) 6 H (2 CH 3 ) 3.53, 3.78 (d of d, J = 18 Hz) 2 H (CH 2 S); 4.93, 5.17 (d of d, J = 13 Hz) 2 H (CH 2 O); 5.28 (d, J = 4 Hz) 1 H (C 6 ); 5.90 (d, J = 4 Hz) 1 H (C 7 ); 688 (d, J = 8 Hz) 1 H (Ar); 7.12 (s) 1 H (thiazole); 7.50 (s) 1 H (Ar); 7.55 (d, J = 8 Hz) 1 H (Ar). IR (KBr): 1762, 1672, 1605. UV (H 2 O): A max 218 nm (e = 22,300). Exact mass calculated for C24<H>23Ng<0>^2S2N2: 643.0947. Found: 643.0893.

The following example illustrates pharmaceutical preparations containing the cephalosporin derivatives provided by the present invention:

Example A

Preparation of dry ampoules for intramuscular administration 1 g freeze-dried [6R-(6a, 7(3) ( Z) ] ]-3-[ [ ( 3, 4-dihydroxybenzoyl)oxy]methyl]-7-[[[2-amino -4-thiazolyl][(2-amino-2-oxoethoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid monosodium salt is prepared in the usual way and supplied in an ampoule. The sterile water ampoule contains 10% propylene glycol. Just before administration, the freeze-dried material is treated with 2.5 ml of 2% aqueous lidocaine hydrochloride solution.

Claims (15)

1. Acyl derivatives of the formula characterized in that X is -0C0-, -SCO-, -NHCO- or -OCONH-, % is an acyl group; R 2 is hydrogen or lower alkoxy; and R3 is wherein R 4 , R 4 < and R 4 .1 are independently hydrogen or -COR 2 o O' wherein R 200 is straight chain or branched lower alkyl, A and B are halogen, a, b, x, y and z are independently 0 (after which a hydrogen atom is present in the ring position) or 1, except that at least two of x, y and z are always 1, and m is 0 or an integer from 1-8, as well as readily hydrolyzable esters and pharmaceutically acceptable salts of these compounds, and hydrates of compounds of formula I or of their esters or salts. 2. Compound according to claim 1, characterized by atmerO or 1, and wherein R 4 , R 4 ! and R411 is independently hydrogen or -COCH3. A and B are chlorine, R is hydrogen, X is -OCO- or -SCO- or -NHCO- or -OCONH-. 3. Compound according to claim 1 or 2, characterized by ata) the acyl group R^ is an aliphatic group with the formula wherein R 5 is selected from the group consisting of lower alkyl, lower cycloalkyl, lower alkoxy, lower alkenyl, C 3 -C 7 -cycloalkenyl or cyclohexadienyl; or lower alkyl or lower alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, lower alkylthio or cyanomethylthio groups, orb) the acyl group R^ is a carbocyclic aromatic group selected from the groups consisting of wherein n is 0, 1, 2 or 3; Rg, R7 and Rq are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or aminomethyl; and R90 is selected from the group consisting of amino, acylamino, hydroxy, a carboxyl salt, protected carboxy, azido and a sulfosalt, or c) the acyl group R 1 is a heteroaromatic group selected from the group consisting of wherein n is 0, 1, 2 or 3; Rgg is selected from the group consisting of amino, acylamino, hydroxy, a carboxyl salt, protected carboxy, azido and a sulfosalt; and R^ oi is a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 nitrogen, oxygen and/or sulfur atoms, or d) the acyl group R1 is a [[(4-substituted-2,3-dioxo-1- piperazinyl)carbonyl]amino]arylacetyl group of formula wherein R-xii is lower alkyl, hydroxy-lower alkyl, a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms, or an aromatic group of the formula wherein Rg, R7 and R8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or aminomethyl, and R120 is lower alkyl or substituted alkyl (in which the lower alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups) or) the acyl group is an (acylamino)arylacetyl group of the formula wherein R 1 is lower alkyl, hydroxy-lower alkyl or an aromatic group of the formula wherein Rg, R7 and Rg are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, aminomethyl or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms, and <R>140 is (where Rg, R7 and Rg are as previously defined and n is 0, 1, 2 or 3), hydrogen, lower alkyl, substituted lower alkyl, amino, lower alkylamino, di-lower alkylamino, (cyano-lower alkyl)amino, hydrazine, lower alkyl -hydrazine, aryl-hydrazine or acyl-hydrazine, or f) the acyl group R 1 is a (substituted acylimino)arylacetyl group of the formula wherein R] _] _i is lower alkyl, hydroxy-lower alkyl or an aromatic group of the formula wherein Rg, R7 and Rg are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, aminomethyl or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 nitrogen, oxygen and/or sulfur atoms, and R140 is (wherein Rg, R7 and Rg are as defined above, and n is 0, 1, 2 or 3), hydrogen, lower alkyl, substituted lower alkyl, amino, lower alkylamino, di-lower alkylamino, (cyano-lower alkyl)amino, hydrazine, lower alkylhydrazine, arylhydrazine or acylhydrazine, and R22 and <R>23 are independently selected from the group consisting of hydrogen and lower alkyl, or R22 and R23 are combined with the carbon atom to which they are attached to form a C3 -C7" carbocyclic ring, g) the acyl group R^ is a [[[3-substituted-2-oxo-1-imidazole-idinyl]carbonyl]amino]arylacetyl group of the formula wherein R 1 is lower alkyl, hydroxy-lower alkyl or a aromatic group with the formula wherein Rg, R7 and Rg are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, aminomethyl or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 nitrogen, oxygen and/or sulfur atoms, and R;l5 is hydrogen, lower alkylsulfonyl, arylmethyleneamino (ie -N =C HR1 11 wherein Rm is as defined above), -COR]_g (wherein R^ g is hydrogen, lower alkyl or halogen-substituted alkyl), aromatic group (as defined by Rm above), lower alkyl or substituted alkyl (wherein the lower alkyl group is substituted by one or more halogen-, cyano, nitro, amino and/or mercapto groups), h) the acyl group R]_ has the formula wherein Rioi is a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms, wherein the heterocyclic ring is substituted with halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, C]_-C4 -alkyl or C]_-C4 -alkoxy and R130 is hydrogen, lower alkyl, C3 -C7 -c <y> chloroalkyl, carboxy-C3 -C7 -cycloalkyl or substituted lower alkyl [in which lower alkyl is substituted by one or more halogen-, cyano-, nitro-, amino-, mercapto-, lower alkylthio-, aromatic group (as defined by Rm ), carboxy-, (including salts thereof), carbamoyl-, lower alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxy-lower alkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl, di-lower methoxyphosphinyl substituents]. 4. Compound according to claim 3, h, characterized in that the acyl group Rioi is the formula wherein R 2 o is hydrogen or an amino protecting group, preferably hydrogen or triphenylmethyl, and R 130 is hydrogen, lower alkyl or a group of the formula wherein R 22 and R 23 are selected from the group consisting of hydrogen and lower alkyl or taken together with the carbon atom to which they are attached to form a C 3 -C 7 carbocyclic ring, and P is hydroxy or NHR 19 , where R 9 is hydrogen or lower alkyl, amino, lower alkylamino, arylamino or acylamino. 5. Compound according to claim 1, characterized in that it is [6R-[6 alpha, 7 beta(Z)]]-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-7-[ [[2-amino-4-thiazolyl][(2-amino-2-oxoethoxy)imino]acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylic acid, as well as salts of this compound and hydrates of this compound and salts. 6. Compound according to claim 1, characterized in that it is [6R-[6 alpha, 7 beta(Z)]]-3-[[(3,4-dihydroxybenzoyl)oxy]methyl]-7-[[[2- amino-4-thiazolyl][(2-amino-2-oxoethoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, so as well as salts of this compound and hydrates of this compound and salts. 7. Compounds according to claim 7, characterized in that they can be [6R-[6 alpha, 7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl ] amino] -3 - [ [(3,4-dihydroxybenzoyl]oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, [6R-[6 alpha, 7 beta(Z)]]-7-[[[(2-amino-4-thiazolyl)[1-carboxy-1-methylethoxy]imino]acetyl]amino]-3-[[( 3,4-dihydroxybenzoyl)oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, [6R-[6 alpha, 7 beta(S <*> )]]-7-[[a-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]- 3-[[[(3,4-dihydroxy)benzoyl]oxy]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid, [6R-[6 alpha, 7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino) acetyl ]amino]-3-[[[(3,4-bis(acetyloxy) benzoyl)]oxy]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, [6R-[6 alpha, 7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino) acetyl] amino] -3- [ [[(2,3-dihydroxyphenyl)carbonyl] -oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (6R-trans)-3-[[[3,4-bis(acetyloxy )benzoyl]oxy]methyl]-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, [6R-[6 alpha, 7 beta(Z)]]-3-[[[3,4,5-tris(acetyloxy)benzoyl]oxy]methyl]-7-[[(2-amino-4-thiazolyl) (methoxyimino)acetyl ]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid, [6R-[6 alpha, 7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino) acetyl ] amino] -3- [ [2-(3,4-dihydroxyphenyl)acetoxy ]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, [6R-[6 alpha, 7 beta(Z)]]-3-[[[3,4-bis(acetyloxy)benzoyl]-oxy]methyl]-7-[[(2-amino-4-thiazolyl)[ (1-carboxy-1-methylethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, [6R-[6 alpha, 7 beta(S <*> )]]-3-[[[3,4-bis(acetyloxy)benzoyl]-oxy]methyl]-7-[[a-[[(4- ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (6R-cis)-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1 -azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid, (6R-cis)-3-[[3,4-dihydroxybenzoyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2. 0]oct-2-ene-2-carboxylic acid, [6R-[6 alpha, 7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino ) acetyl] amino] -3- [ [[(3,4-bis(acetyloxy) -2,5-dichlorobenzoyl]oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, [6R-[6 alpha, 7 beta(Z)]]-3-[[[[[3,4-bis(acetyloxy)phenyl]-amino]carbonyl]oxy]methyl]-7-[[(2-amino -4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, [6R-E6 alpha, 7 beta(Z)]]-3-[[[[[3,4-bis(acetyloxy)phenyl]-amino]carbonyl]oxy]methyl]-7-[[[[2-amino -[2-amino-2-oxoethoxy]imino]-4-thiazolyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, [6R-[6 alpha, 7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino )acetyl]amino]-3-[[(3,4-dihydroxybenzoyl)thio]methyl ]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, E6R-[6 alpha, 7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino) acetyl] amino] -3- [ [[(3,4-bis(acetyloxy)benzoyl )]thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, [6R-E6 alpha, 7 beta(Z)]]-3-[[(3,4-bis(acetyloxy)benzoyl)]-amino]methyl]-7-[[(2-amino-4-thiazolyl)( methoxyimino)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, [6R-[6 alpha, 7 beta(Z)]]-3-[[[(3,4-dihydroxy)benzoyl]-amino]methyl]-7-[[(2-amino-4-thiazolyl)(methoxyimino )acetyl]-amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, and salts of these compounds and hydrates of these compounds and salts. 8. Compounds according to claim 1, characterized in that they are selected from the group consisting of [6R-[6 alpha, 7 beta(Z)]]-7-[[[2-amino-[(2-amino-2-oxoethoxy )imino]-4-thiazolyl]acetyl]amino]-3-[[(3,4-dihydroxybenzoyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene -2-carboxylic acid, [6R-[6 alpha, 7 beta(Z)]]-7-[[(2-amino-4-thiazolyl)[(carboxy-methoxy)imino]acetyl]amino]-3-[[3,4-dihydroxybenzoyl )oxy]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (6R-trans)-7-[[(2-amino-4-thiazolyl)[[1-(aminocarbonyl)-1-methylethoxy]imino]acetyl]amino]-3-[[(3,4-dihydroxybenzoyl)- oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts of these compounds and hydrates of these compounds and salts. 9. Connections, characterized by the formula wherein R is hydrogen or a carboxylic acid protecting group; R 2 is hydrogen or lower alkoxy; R3 is in which R4 , R4 1 and R41! is independently hydrogen or -COR2 0O' in which R200 is straight chain or branched lower alkyl, A and B are halogen, a, b, x, y and z are independently 0 (after which a hydrogen atom is present in the ring position) or 1, except that at least two of x, y and z are always 1, and m is 0 or an integer from 1-8, and salts of these compounds. 10. Compound according to claim 9, characterized in that it is selected from the group consisting of (6R-trans)-7-amino-3-[[[3,4-bis(acetyloxy)benzoyl]oxy]methyl]-8-oxo -5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester, (6R-trans)-7-amino-3-[[[3,4-bis( acetyloxy)benzoyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester and acid addition salts thereof. 11. Compounds set forth in claims 1-23 as pharmaceutically active substances. 12. Process for preparing the compounds according to claims 1-11, characterized by (a) reacting a compound with the formula wherein X and R3 are as above, and the carboxy group and/or amino group may be present in protected form, with an acid of formula R^OOH, wherein R^ is as above, or with a reactive functional derivative thereof, or (b) in the preparation of a carboxylic acid of formula I to convert an ester of the formula wherein R-p R2 and R3 are as above, and R is a carboxylic acid protecting group, to the carboxylic acid of formula I, or (c) in the preparation of a compound of formula I in which R] _ contains an amino substituent, or an ester or salt thereof, cleaving the amino protecting group in the substituent R^ q to a compound of the formula wherein R 2 and R 3 are as above, and R 3 q is an acyl group containing a protected amino group, or of an ester or salt thereof, or (d) in the preparation of a compound of formula I, wherein X is -OCO- or -SCO-, reacting a compound with the formula wherein R-L is as above, and Y is a leaving group, or an ester or salt thereof, with a salt of the carboxylic acid R3 COQH, wherein R3 is as above and Q is 0 or S, or (e) in the preparation of a compound of formula I, in which X is -OCO- or -OCONH-, reacting a compound of the formula wherein R] _ and R 2 are as above, or an ester or salt thereof, with a compound of formula R 3 COZ, R 3 NHCOZ or R 3 NCO, wherein R 3 is as above, and Z is an acyl activating group, or (f) in the preparation of a compound of formula I, in which X is -NHCO-, reacting a compound of the formula wherein Ri and R 2 are as above, and A is the anion of an acid, or an ester or salt thereof, with an acid of formula R 3 -COOH, wherein R 3 is as above, or (g) in the preparation of a readily hydrolysable ester of a compound of formula I, subjecting a carboxylic acid of formula I to a corresponding esterification, or (h) in the preparation of salts or hydrates of formula I, or hydrates of said salts, to convert a compound of formula I into a salt or hydrate or into a hydrate of said salt. 13. Pharmaceutical preparation. characterized in that it contains an end product according to one of claims 1-11. 14. Pharmaceutical preparation for the treatment and prevention of infectious diseases containing an end product according to claims 1-11. 15. The use of the end products according to claims 1-11 in the manufacture of drugs for the treatment and prevention of infectious diseases.