Cephalosporins, process for their preparation and pharmaceutical compositions containing them

This invention relates to novel β-lactam containing compounds, in particular to a novel group of cephalosporin derivatives, their preparation and their use. These compounds have antibacterial properties and are therefore of use in the treatment of bacterial infections in humans and animals caused by a wide range of organisms.

7β-[2-(2-amino-4-thiazolyl)-2-oxyiminoacetamido] cephalosporin derivatives have been reported, of which a particular subgroup are those comprising at the 3-position a substituent -CH ₂ S-Het in which 'Het' is an optionally substituted heterocyclic group. EP-A-0 248 645 (Tanabe Seiyaku) discloses inter alia a class of such compounds in which 'Het' is a pyridinium ring (bonded through carbon), optionally substituted on the pyridinium nitrogen by acylamino and exemplified by an N-acetyl derivative.

In addition, EP-A-153 709 (Meiji Seika Kaisha) discloses generically another class of such compounds wherein 'Het' is a bicyclic heterocyclic system comprising a pyridinium ring (bonded through carbon) which may be substituted on the pyridinium nitrogen by an amino group, optionally substituted by alkyl. No exemplification thereof is however provided.

European Patent Application No. 90309493.6 (Beecham Group pic) discloses generically a class of cephalosporin derivatives having a 3-(optionally substituted N-amino pyridinium thiomethyl)substituent, in combination with a 7-[ (2-amino-4-thiazolyl)-2-(optionally substituted)- oxyimino)acetamido]substituent.

It has now been found that certain novel compounds within this generic class have particularly useful antibacterial activity.

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

wherein:

Y ¹ is sulphur, -SO-, or -S0 ₂ -;

R is hydrogen or an amino protecting group;

BX is hydrogen, optionally substituted ~ -i2 alkyl, or optionally substituted C~-- _j cycloalkyl;

CO2R is carboxy or a carboxylate anion, or the group R^ is a readily removable carboxy protecting group;

Y^ is a group of the formula:

wherein :

R ⁴ and R ⁵ which may be the same or different is each selected from hydrogen, optionally substituted C*-__g alkyl, optionally substituted C- _j __g alkenyl, optionally substituted C ₁ _g alkynyl, or R^ and R^ together form an optionally substituted ^_ - alkylidene group;

X is an inorganic or organic anion; and n is 0 or 1, with the proviso that when: (I) CO2R is carboxylate, n is 0, and

(11) CO2R ~ is carboxy or the group R ~\ is a readily removable carboxy protecting group, then n is 1 and the anion X is present in the appropriate stoichiometric proportion to balance the positive charge on the pyridinium group.

It will be appreciated that the compounds of formula (I) are quaternary salts and the positive charge on the pyridinium group must always be balanced by a counter anion. The counter anion may be present on a negatively charged group within the molecule, such as the carboxylate anion CO2R (when n is 0) , or the counter anion may be present as an external anion X (when n is 1) .

It will be further appreciated that one or more chiral centres may be present in the compound of formula (I) , for example in the oxime etherifying group. The invention includes within its scope the individual R and S forms at each chiral centre as well as mixtures thereof.

Suitable C ₁ _ ₁ 2 alkyl groups include straight and branched chain alkyl groups containing 1 to 12 carbon atoms. Preferred alkyl groups contain 1 to 6 carbon atoms, such as methyl or ethyl. Suitable C-_η cycloalkyl groups include cyclopentyl.

When used herein the term 'aryl' includes phenyl and naphthyl each optionally substituted with up to five, preferably up to three groups.

When used herein the terms 'heterocyclyl' and 'heterocyclic' suitably include unless otherwise defined aromatic and non-aromatic, single and fused, rings suitably containing up to four heteroatoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three groups. Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.

Some examples of optional substituents in groups for instance alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkylidene, aryl or heterocyclyl, mentioned hereinbefore as being optionally substituted, include, unless otherwise defined, up to three groups (which may be the same or different) chosen from:

(i) halogen, cyano, azido, nitro, phthalimido, formyl, carboxy, carboxylate salts, sulphonyl, sulphonate salts, or oxo;

(ii) amino, hydrazino, guanidino, carbamoyl, or sulphonamido, in each of which groups a nitrogen may be further optionally substituted by one or two groups (which may be the same or different) selected from the groups listed in subparagraphs (iv) , (v) and (vi) ;

(iii) hydroxy, oxyimino, or mercapto, in each of which groups hydrogen may be replaced by one of the groups listed in subparagraphs (iv) , (v) and (vi) ;

(iv) a group R wherein R ^p denotes aryl, or heterocyclyl;

(v) a group R~- wherein R^ denotes ^~ ι- _ζ alkyl,

C3_ ₇ cycloalkyl, C2_ alkenyl, C5_3 cycloalkenyl, or C2_galkynylcarbonyl, each of which groups R^ may be further optionally substituted by up to three groups (which may be the same or different) chosen from the groups listed in subparagraphs (i) , (ii) , (iii) , (iv) and (vi) ; and

(vi) a group RPCO-, RPOCO-, R^CO-, R^OCO-, RPSO-, RPS0 ₂ ~, R ^q SO-, or R ^q S0 ₂ - wherein R ^p and R ^q are as defined in subparagraphs (iv) and (v) respectively.

When used herein, the term 'halogen' refers to fluorine, chlorine, bromine and iodine.

Preferably a substituent which may be present on those groups R~- defined hereinabove as being optionally substituted is selected from carboxyl, esterified carboxy, hydroxy, alkoxy, cyano, carbamoyl, N-substituted carbamoyl, aryloxy, aralkoxy, mercapto, alkylthio, arylthio, amino, substituted amino, halogen, nitro, azido, formyl, acyl, acyloxy, phthalimido, acylamino, alkoxycarbonylamino, aralkoxy-carbonylamino, aryl and heterocyclyl.

Preferably a substituent for an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkylidene, or alkynyl group is selected from halogen, cyano, azido, nitro, carboxy, (C-^.g)alkoxycarbonyl, carbamoyl, mono- or di-(C-^ )alkylcarbamoyl, sulphono, sulphamoyl, mono- and di-(C- _j __g)alkylsulphamoyl, amino, mono- and di-(C ₁ _g)alkylamino, acylamino, (C ₁ _ )alkoxycarbonyl amino, aryl, heterocyclyl, hydroxy, (C-^ )alkoxy, acyloxy, oxo, arylcarbonyl, heterocyclylcarbonyl, ( ^~ ι- -)alkylthio, (C^.gjalkanesulphinyl, and (C- _ -)alkanesulphonyl.

Preferably a substituent for an aryl group is selected from halogen, (C- _j ^ )alkyl, phenyl, (C-^ )alkoxy, hydroxy(C- _j^ .g)alkyl, mercapto(C- _j ^g)alkyl, halo(C-^.g)alkyl, mercapto, hydroxy, amino, mono- or di-(C^g)alkylamino, nitro, carboxy, (C^g)alkoxycarbonyl,

(C^. )alkoxycarbonyl(C-^g)alkyl, (C*^_g)-alkylcarbonyloxy, formyl, and (C^_ -)alkylcarbonyl.

Preferably a substituent for a heterocyclyl group is selected from halogen, (C*^_g)alkyl, (C- _j ^g)alkoxy, halo(C- _j __g)alkyl, hydroxy, amino, mono- and di- (C* _] __g)alkylamino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, (C- _j __g)alkoxycarbonyl, aryloxycarbonyl, (C*^_g)alkoxycarbonyl(C* _] __g)alkyl, aryl, and oxo groups.

Suitable amino protecting groups Rr are those well known in the art which may be removed under conventional conditions without disruption of the remainder of the molecule. A comprehensive discussion of the ways in which amino groups may be protected and methods for cleaving the resulting protected derivatives is given in, for example, 'Protective Groups in Organic Synthesis' by T. W. Greene ^•* - ^* (Wiley-Interscience, New York, 1981) . Particularly suitable protecting groups include, for example, amides and carbamates.

Examples of such amino protecting groups include (C ₁ _g)alkanoyl; benzoyl; benzyl optionally substituted in the phenyl ring by one or two substituents selected from (C1-4)alkyl, (C*-^)alkoxy, trifluoromethyl, halogen, or nitro; (C _1-4 )alkoxycarbonyl; benzyloxycarbonyl or trityl substituted as for benzyl above; allyloxycarbonyl, trichloroethoxycarbonyl or chloroacetyl.

In one preferred aspect the ^" C ₁ _ ₁₂ alkyl group for R ² is methyl, substituted by aryl and optionally further substituted by carboxy. Suitably the aryl group is 3,4- dihydroxyphenyl.

₉

Specific examples of the group R^ include methyl, 1-carboxy-l-methylethyl, cyclopentyl, hydrogen, ethyl and carbox (3,4-dihydroxyphenyl)methyl.

Specific examples of the groups R^ and R ^J include hydrogen, methyl, ethyl, 4-carboxybutan-l-yl, methoxycarbonylethyl, cyclopropylmethyl, isopropylidene, propyl, isopropyl, butyl, hexyl, cyclopentyl, prop-2-en-l-yl, and 2-hydroxyethyl.

Included within the scope of readily removable carboxy protecting groups for R ^J are, for example, ester groups including pharmaceutically acceptable in vivo hydrolysable ester groups.

Compounds of the invention may exist in two or more tautomeric forms, e.g. those having the partial structures below:

Compounds of the present invention may exist as either syn or anti isomers, or may exist as mixtures of syn and anti isomers containing at least 75% of one such isomer, or preferably at least 90% of one such isomer.

When used herein, the terms syn and anti refer to the

₉ configuration of the group OR with respect to the carboxamido group, the syn-configuration (sometimes called the Z-configuration) being denoted thus:

and the anti configuration (sometimes called the E-configuration) being denoted thus:

CONH

R^HN N

/

R ² 0

Preferred compounds of the present invention are the syn-isomers of the formula (II) :

(II)

~ ~ ~ ~ 9 wherein R , R , R , X, Y , Y and n are as hereinbefore defined.

It will be appreciated that also included within the scope of the invention are salts and carboxy-protected derivatives, including in vivo hydrolysable esters, of any carboxy groups that may be present as optional substitutents in compounds of formula (I) . Also included within the scope of the invention are acid addition salts of any amino or substituted amino groups that may be present as optional substituents in compounds of formula (I) .

, ₉ It will be appreciated that, in the group Y , the pyridinium ring may be bonded to sulphur by a carbon which is α-, β- or γ-, preferably α- or γ-, more preferably γ-, to the pyridinium nitrogen.

Since the β-lactam antibiotic compounds of the present invention are intended for use in pharmaceutical compositions, it will be readily appreciated that preferred compounds within formula (I) are pharmaceutically acceptable, i.e. are compounds of formula (la) or pharmaceutically acceptable salts or pharmaceutically acceptable in vivo hydrolysable esters thereof:

(la)

wherein R _?, Y1 , Y ~ and n are as hereinbefore defined, the group C0 ₂ R is carboxy or a carboxylate anion and Z is a

pharmaceutically acceptable inorganic or organic anion present in the appropriate stoichiometric proportion to balance the positive charge on the pyridinium ring of the

₉ group Y .

Suitable values of Z include chloride, bromide, iodide, phosphate (i.e. 1/3 P0 ³ -) , and sulphate (i.e. ^~ *. S0 ₄ ² -) , when the anion is an inorganic anion; and acetate, hydrogen maleate, methyl sulphonate,dihydrogen citrate, and hydrogen fu arate when the anion is an organic anion.

Non-pharmaceutically acceptable salts of the compound of formula (I) wherein R ~ ^J is hydrogen are pri •marily of use as intermediates in the preparation of a compound of formula (I) wherein R ^J is hydrogen or a pharmaceutically acceptable salt thereof.

Salts within compounds of formula (I) may be prepared by salt exchange in conventional manner.

Similarly, carboxy-protected derivatives of formula (I) , i.e. those compounds of formula (I) wherein R ^J is a readily removable carboxy protecting group, may be used as intermediates in the preparation of a compound of the* formula (I) wherein R ^J is hydrogen, or a pharmaceutically acceptable salt thereof. Included within the scope of readily removable carboxy protecting groups for R ³ are ester groups including pharmaceutically acceptable in vivo hydrolysable ester groups.

From the foregoing, it will be appreciated that within the compounds of the formula (la) there exist a sub-group of compounds of the formula (lb) :

(lb)

wherein R 9, Y1, and ^" -9 ^■ are defined wi.th respect to formula

(la) ;

which compounds of formula (lb) may also be described as betaines, a betaine being defined as an uncharged species having isolated non-adjacent cationic and anionic sites, and not possessing a hydrogen atom bonded to the cationic site.

There also exists within the compounds of formula (la) a second sub-group, the compounds of the formula (Ic) :

C0 ₂ H

OR

(ic)

wherein R , Y , Y , and Z are defined with respect to formula (la) .

Since the β-lactam antibiotic compounds of the present invention are intended for use in pharmaceutical compositions, it will be further understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis) . Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will readily be understood that the substantially pure form is preferred as for the β-lactam antibiotic compounds. Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.

When some of the compounds of this invention are allowed to crystallise, or are recrystallised, from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.

Suitable readily removable carboxyl protecting groups for

^•* } the group -CO2R include groups forming ester derivatives of the carboxylic acid, including in vivo hydrolysable esters. The derivative is preferably one which may readily be cleaved.

Suitable ester-forming carboxyl-protecting groups are those which may be removed under conventional conditions. Such groups for R ^J include benzyl, p_-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl,

2,2,2-trichloroethyl, 2,2,2-tribromoethyl, t-butyl, t-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, acetonyl, p-toluenesulphonylethyl,methoxymethyl, a silyl, stannyl or phosphorus- containing group, an oxime radical of formula -N=CHR° where R° is aryl or heterocyclic, or an _in vivo hydrolysable ester radical such as defined below.

A carboxyl group may be regenerated from any of the above . esters by usual methods appropriate to the particular R ^J group, for example, acid- and base- catalysed hydrolysis, or by enzymically-catalysed hydrolysis, or by hydrogenolysis under conditions wherein the remainder of the molecule is substantially unaffected.

Examples of suitable pharmaceutically acceptable in. vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt. Suitable ester groups of this type include those of part formula (i) , (ii) , (iii) and (iv) :

C0 ₂ CH ₂ -OR ^J - (iii)

(iv)

wherein R ^a is hydrogen, (C-_g alkyl), (C3_ ₇ ) cycloalkyl, methyl, or phenyl; R ^b is (C^g) alkyl, (C ₁ _g) alkoxy, phenyl, benzyl, (C3_ ₇ ) cycloalkyl, (C^_g) alkyl (C3_ ₇ ) cycloalkyl, 1-amino C^_ -) alkyl, or 1- (C ₁ _g) alkylamino (C-^. ) alkyl; or R ^a and Rr together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; R ^c is (Ci _g) alkylene optionally substituted with a methyl or ethyl group and R^ and R ^e independently are (C^_ -) alkyl; R ^f represents (C* _j __g)alkyl; R^ is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C- _j __g) alkyl, or (C-^. ) alkoxy; and Y is oxygen or NH.

Examples of suitable pharmaceutically acceptable in vivo hydrolysable ester groups include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl,

1- (cyclohexylcarbonyloxy)prop-l-yl, and

(1-aminoethyl)-carbonyloxymethyl; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and α-ethoxycarbonyloxyethyl; dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; lactone groups such as phthalidyl and dimethoxyphthalidyl; and esters linked to a second β-lactam antibiotic or to a β-lactamase inhibitor.

A further suitable pharmaceutically acceptable in vivo hydrolysable ester group is that of the formula:

Q wherein R ^J is hydrogen, C^g alkyl or phenyl.

Suitable pharmaceutically acceptable salts of the carboxy group of the compound of formula (I) include metal salts, for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium; and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)- amine, cycloalkylamines_such as dicyclohexylamine, or with procaine, dibenzylamine, N,N-dibenzylethylene- diamine, 1-ephenamine, N-methylmorpholine, N-ethylpiperidine, N-benzyl-β- phenethylamine, dehydroabietylamine, N,N'-bisdehydro-abietylamine, ethylenediamine or

N-methylglucosamine; or basic amino acids such as lysine, arginine, or bases of the pyridine type such as pyridine, collidine or quinoline; or other amines which have been used to form salts with known penicillins and cephalosporins. Other useful salts include the lithium salt and silver salt.

Specific classes of compounds within compounds of formulae (I) , (la) , (lb) , Ic) and (II) as hereinbefore defined are those compounds in which Y ¹ is sulphur.

Suitable compounds of formula (I) include:

[6R,7R]-7-[2- (2-Amin -4-thiazolyl)-2-(Z)-(cyclopentyl- oxyimino)acetamido]-3-[1-(methylamino)pyridinium- 4-thiomethyl]ceph-3-em-4-carboxylate;

[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2- (Z)-(hydroxyimino) acetamido]-3-[1-(methylamino)pyridinium-4-thiomethyl]ceph- 3-em-4-carboxylate;

[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino) acetamido]-3-[1-(4-carboxybutan-l-yl)aminopyridinium-4- thiomethyl]ceph-3-em-4-carboxylate;

[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(ethoxyimino) acetamido]-3-[1-(methyla ino)pyridinium-4-thiomethyl]- ceph-3-em-4-carboxylate;

[6R,7R]-3-[1-[ (2S)-2-Amino-2-(methoxycarbonyl)ethyl- amino]pyridinium- -thiomethyl]-7-[2-(2-amino-4- thiazolyl)-2-(Z)-(methoxyimino)acetamido]ceph-3-em-4- carboxylate;

[6R,7R]-7-[2- (2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino) acetamido]-3-[1-(cyclopropylmethylamino)pyridinium-4- thiomethyl]ceph-3-em-4-carboxylate;

16R,7R] -1-[2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)- acetamido]-3-[1-(isopropylidineamino)pyridinium-4- thiomethyl]ceph-3-em-4-carboxylate;

[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino) acetamido]-3-[1- (propylamino)pyridinium-4-thiomethyl]- ceph-3-em-4-carboxylate;

[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxy¬ imino)acetamido]-3-[1-(cyclopentylamino)pyridinium-4- thiomethyl]ceph-3-em-4-carboxylate;

[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxy¬ imino)acetamido]-3-[1-(prop-2-en-l-yl)aminopyridinium- 4-thiomethyl]ceph-3-em-4-carboxylate;

[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxy¬ imino)acetamido]-3-[l-butylaminopyridinium-4-thio- methyl]ceph-3-em-4-carboxylate;

[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z) (methoxyimino) acetamido]-3-[1-(hexylamino)pyridinium-4-thiomethyl]- ceph-3-em-4-carboxylate;

[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino) acetamido]-3-[1-(1-isopropyl)aminopyridinium-4-thio- methyl]ceph-3-em-4-carboxylate;

[6R,7R]-7-[2- (2-Amino-4-thiazolyl)-2-(Z)- (methoxyimino) acetamido]-2-[1-[ (2-hydroxyethyl)amino]pyridinium-4- thiomethyl]ceph-3-em-4-carboxylate;

[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2- (Z)-[ [R,S]- carboxy(3,4-dihydroxyphenyl)methyloxyimino]acetamido]- 3-[1- (methylamino)pyridinium-4-thiomethyl]ceph-3-em-4- carboxylate;

[6R,7R]-7-[2-(2-Amino-4-thiazolyl) -2-(Z)-[ (S)- carboxy(3,4-dihydroxypheny1)methyloxyimino]acetamido]- 3-[1-(methylamino)ρyridinium-4-thiomethyl]ceph-3-em- 4-carboxylate;

[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-[ (R)- carboxy(3,4-dihydroxyphenyl)methyloxyimino]acetamido]- 3-[1- (methylamino)pyridinium-4-thiomethyl]ceph-3-em-4- carboxylate;

[6R,7R]-3-[l-Aminoρyridinium-4-thiomethyl]-

7-[2 (2-amino-4-thiazolyl)-2-(Z)-[ (R,S)-carboxy(3,4-

dihydroxyphenyl)methyloxyimino]acetamido]ceph-3-em-4- carboxylate;

[6R,7R]-3-[1-Aminopyridiniu -4-thiomethyl]- 7-[2-(2-amino-4-thiazolyl)-2-(Z)-[ (S)-carboxy-

(3,4-dihydroxyphenyl)methyloxyimino]acetamido]ceph-3- em-4-carboxylate; and

[6R,7R]-3-[l-Aminopyridinium-4-thiomethyl]-7- [2-(2-amino-4-thiazolyl)-2-(Z)-[ (R)-carboxy(3,4- dihydroxyphenyl)methyloxyimino]acetamido]ceph-3- em-4-carboxylate;

or a salt, preferably a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester thereof.

The antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, according to techniques and procedures per se known in the art with reference to other antibiotics, and the invention therefore includes within its scope a pharmaceutical composition comprising an antibiotic compound according to the present invention such as, for example a pharmaceutically acceptable compound of formula (I) or a salt or in vivo hydrolysable ester thereof above together with a pharmaceutically acceptable carrier or excipient. The compositions may be formulated for administration by any suitable route, such as oral or parenteral, or by topical application. Normally administration will be via a parenteral route. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional

excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl- cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils) , for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p_-hydroxybenzoate or sorbic acid; and, if desired conventional flavouring or colouring agents. Suppositories will contain conventional suppository base, eg cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99.5% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 100 mg to 12 g per day for an average adult patient (body weight 70 kg) , for instance 1500 mg per day, depending on the route and frequency of administration. Such dosages correspond to approximately 1.5 to 170 mg/kg per day. Suitably the dosage is from 1 to 6g per day.

The daily dosage is suitably given by administering a compound of the invention several times in a 24-hour period. Typically, 250 mg is administered 4 times a day although, in practice, the dosage and frequency of administration which will be most suitable for an individual patient will vary with the age, weight and response of the patients, and there will be occasions when the physician will choose a higher or lower dosage and a different frequency of administration.

Such dosage regimens are within the scope of this invention.

No toxicological effects are indicated when a pharmaceutically acceptable compound of the invention of formula (I) or a salt or in. vivo hydrolysable ester thereof is administered in the above mentioned dosage range.

The antibiotic compounds according to the present invention may be the sole therapeutic agent in the compositions of the invention or a combination with other antibiotics and/or β-lactamase inhibitors may be employed.

Advantageously the compositions also comprise a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof:

H

(III)

wherein A is hydrox 1; substituted hydroxyl; thiol; a-group of formula S0 ₂ R ¹⁰ wherein R ¹⁰ is C--__g alkyl; substituted thiol; amino; mono- or di-(hydrocarbyl)substituted amino; mono- or di-acylamino; an optionally substituted triazolyl group; or an optionally substituted tetrazolyl group as described in EP-A-0 053 893 (to Beecham Group pic) .

A further advantageous composition comprises a pharmaceutically acceptable antibiotic compound of the formula (I) or a salt or an jLn vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier or excipient together with a β-lactamase inhibitor of formula (IV) or a pharmaceutically acceptable salt or jLn vivo hydrolysable ester thereof:

CO H

( IV)

wherein B is hydrogen, halogen or a group of formula:

in which R 1 ^~ ~1 and R1 -9" are the same or different and each is hydrogen, C-^_g alkoxycarbonyl, or carboxy or a pharmaceutically acceptable salt thereof.

Further suitable β-lactamase inhibitors include 6-alkylidene penems as described in EP-A-0 041 768 and EP-A-0 154 132 (to Beecham Group pic) .

Further suitable β-lactamase inhibitors include

6β-bromopenicillanic acid and salts and in vivo hydrolysable esters thereof and 6β-iodopenicillanic acid and salts and in vivo hydrolysable esters thereof.

Such compositions of this invention comprising a β-lactamase inhibitor are formulated in conventional manner.

The present invention also includes a method of treating bacterial infections in humans and animals which comprises the administration of a therapeutically effective amount of

a pharmaceutically acceptable antibiotic compound of the present invention of the formula (I) or a salt or in vivo hydrolysable ester thereof.

In a further aspect, the present invention also provides for the use of a compound of the formula (I) for the manaufacture of a medicament.

The pharmaceutically acceptable antibiotic compounds of the present invention of formula (I) or salts or in vivo hydrolysable esters thereof are active against a broad range of Gram-positive and Gram-negative bacteria, and may be used to treat a wide range of bacterial infections including those in immunocompromised patients.

Amongst many other uses, the pharmaceutically acceptable compounds of the invention of formula (la) or salts or in vivo hydrolysable esters thereof are of value in the treatment of respiratory tract and urinary tract infections in humans and may also be used to treat mastitis in cattle.

A particular advantage of the antibacterially active compounds of this invention is their stability to β-lactamase enzymes and they are therefore effective against β-lactamase producing organisms.

The present invention further provides a process for the preparation of a compound of formula (I) (as hereinbefore defined) which process comprises treating a compound of formula (V) :

(V)

1 "3 1 wherein R , R , R , and Y are as hereinbefore defined, and RRιι ~~ ^~~ -- ii.ss aa lleeaavving group; and wherein any reactive groups may be protected;

with a thiopyridone compound of the formula (VI)

N (VI)

R

wherein the nucleus:

hereinafter referred to as the ring Q is such that it is converted to the nucleus of the group Y^ (as hereinbefore defined) in situ during the course of the reaction, and

R - and R ⁵ are as hereinbefore defined;

13 , -3 with the proviso that, when R ^~ "- is an acyloxy group, -CO2R must be in the free acid form or a salt thereof; and thereafter if necessary carrying out one or more of the following steps:

i) converting each or any one of the groups R , R , R ⁴ and R ⁵ into a different group R , R , R - and R , ^•

ii) removing any protecting groups; or

iii) converting the product into a salt.

At the end of the process described hereinabove and in other processes for the preparation of the compound of formula (I) described hereinbelow it may be necessary to remove protecting groups. Deprotection may be carried out by any convenient method known in the art that does not cause unwanted side reactions to occur to any appreciable extent.

Suitable leavi .ng groups Rι ^{~ ~} -\ include halogen such as chlorine, bromine or iodine or an acyloxy group such as, for example, the acetoxy group. Preferred groups for R—' are chloro and iodo.

This reaction is desirably conducted in a solvent. For example, use can be made of water, or of organic solvents inert to the starting compounds, such as dimethylformamide, dimethylacetamide, dioxane, acetone, dichloromethane, 1,2- dichloroethane, acetonitrile, dimethylsulfoxide or te ..ahydrofuran, or mixtures thereof. The reaction temperature and time depend, among other factors, upon the starting compounds and solvent to be employed but generally the reaction is carried out at a selected temperature within the range of 0 to 100°C for a selected time of a few minutes

to several days.

Compounds of formula (V) wherein R ¹ is acyloxy may be prepared by analogy with procedures described in Bucourt R., et al. Tetrahedron, 1978, 34./ 2233.

Preferred compounds of the formula (V) include salts and esters in which R ³ is as hereinbefore defined and in

^• 3 particular in which R ^J is diphenylmethyl, p-methoxybenzyl or trimethylsilyl.

Compounds of formula (VI) may be prepared by treatment of the corresponding thiopyranone with a hydrazine derivative of the formula (VII) :

H ₂ NNR ⁴ R ⁵ (VII)

wherei .n R^ Δ and R~ *-> ae as herei•nbefore defined, by analogy with the process described by Ibrahim El-Sayad El-Kholy et aJL., J. Het. Chem., 1974, 11, 487.

Alternatively, compounds of formula (VI) may be obtained from the corresponding pyridone by treatment with for instance Lawesson's reagent or phosphorus pentasulphide according to conventional procedures. Suitable pyridones may be prepared according to the methodology of Freeman et al. J. Amer. Chem. Soc, 1947, J59_, 858.

Included within the compounds of formula (VI) are sub-groups of compounds of the formulae (Via) and (VIb) .

(via) (Vlb)

wherein R and R are as hereinbefore defined.

The compounds of formula (I) may also suitably be prepared by reacting a compound of formula (VIII) or a salt thereof:

H

(VIII)

wherein X, Y ¹ , Y and n are as hereinbefore defined, R ^x is hydrogen or a readily removable carboxyl blocking group and the 7β-amino group is optionally substituted with a group which permits acylation to take place; and any reactive groups may be protected;

with an N-acylating derivative of an acid of formula (IX) :

9 , c , wherein R is as hereinbefore defined and Y is a group of formula:

or a group which is convertible thereto, and R 1 is as hereinbefore defined; and wherein any reactive groups may be protected; and thereafter, if necessary, carrying out one or more of the following steps:

(i) removing any protecting group, including an ammo-protecting group R 1 ;

(ii) converting the group R ^x into a group R ³ ;

(iϋ) converting the product to a .salt;

(iv) converting a group which is convertible to Y into Y ⁵ , or

(v) converting each or any one of the groups R - or R ⁵ into a different group R ⁴ or R .

Suitable groups which permit acylation to take place and which are optionally present on the amino group of the starting material of the formula (VIII) include silyl, stannyl and phosphorus groups, for example trialkylsilyl

groups such as trimethylsilyl, trialkyltin groups such as tri-n-butyltin, phosphorus groups of formula wherein R ^x - is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy or dialkylamino group, Rι ^~ is the same as R ¹ ' or is halogen or R ¹⁶ and R ¹ together form a ring; suitable such phosphorus groups being

-P(OC ₂ H ₅ ) ₂ . -P(C ₂ H ₅ ) ₂ ,

0 (CH ₂ ) ₂ 0 (CH ₂ ) ₃

— p .0 P 0

A group which may optionally be introduced in situ prior to acylation onto the amino group in the compound of formula (VIII) is trimethylsilyl.

An appropriate reactive N-acylating derivative of the acid (IX) is employed in the above process.

Suitable N-acylating derivatives include an acid halide, preferably the acid chloride or bromide. Acylation with an acid halide may be effected in the presence of an acid binding agent, for example a tertiary amine (such as pyridine or dimethylaniline) , molecular sieves, or an inorganic base (such as calcium carbonate or sodium bicarbonate) or a silylated derivate of acetamide [such as trimethylsilylacetamide or N,0-bis(trimethylsilylacetamide) ] or an oxirane, which binds hydrogen halide liberated in the acylation reaction. The oxirane is preferably a (Cτ_g)- 1,2-alkylene oxide, such as ethylene oxide or propylene oxide. The acylation reaction using an acid halide may be carried out at a temperature in the range -50°C to +50°C, preferably -20°C to +20°c, in aqueous or non-aqueous media such as water, acetone, tetrahydrofuran, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile,

dichloromethane, 1,2-dichloroethane, or mixtures thereof. Alternatively, the reaction may be carried out in an unstable emulsion of water-immiscible solvent, especially an aliphatic ester or ketone, such as methyl isobutyl ketone or butyl acetate. Preferred solvents include tetrahydrofuran, and anhydrous chlorinated hydrocarbons, especially dichloromethane.

The acid halide may be prepared by reacting the acid (IX) or a salt or suitable derivative thereof with a halogenating * (eg chlorinating, or brominating) agent such as phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, oxalyl chloride, or phosgene.

Suitable derivatives of the acid (IX) which may be employed in the above process include labile esters such as silyl esters. Suitable silyl esters include, for example, tri (C ₁ _g)alkyl silyl esters, especially the trimethylsilyl ester.

Alternatively, the N-acylating derivative of the acid (IX) may be a symmetrical or mixed anhydride. Suitable mixed anhydrides are alkoxyformic anhydrides, or anhydrides with, for example, carbonic acid monoesters, trimethyl acetic acid, thioacetic acid, diphenylacetic acid,, benzoic acid, phosphorus acids (such as phosphoric, phosphorous, and phosphinic acids) or aromatic or aliphatic sulphonic acids (such as p_-toluenesulphonic acid or methanesulphonic acid) . When a symmetrical anhydride is employed, the reaction may be carried out in the presence of 2,6-lutidine as catalyst.

When a mixed anhydride is employed the N-acylating derivative is preferably prepared in the presence of an organic base such as triethylamine and/or N,N-diisopropylethylamine in a suitable solvent such as DMF or dichloromethane at between -50°C and room temperature.

Alternatively, the N-acylating derivative may be prepared from an alkali metal salt of the acid of formula (IX) , such as the sodium salt, in a suitable solvent such as DMF at between -50°C and room temperature. The N-acylating derivative of the acid of formula (IX) so derived may then be reacted with a compound of formula (VIII) . The acylation reaction may conveniently be carried out at -50°C to +50°C in a suitable solvent such as water, acetonitrile, DMF or dichloromethane at a temperature of not more than 0°C. The reaction may be carried out in the presence of a suitable • base such as triethylamine or sodium hydrogen carbonate.

Alternative N-acylating derivatives of acid (IX) are the acid azide, or activated esters such as esters with cyanomethanol, p-nitrophenol, 2,4-dinitrophenol, thiophenol, halophenols, including pentachlorophenol, monomethoxyphenol, N-hydroxy succinimide, N-hydroxybenzotriazole, or 8-hydroxyquinoline; or amides such as N-acylsaccharins, N-acylthiazolidin- 2- ;hione or N-acylphthalimides; or an alkylidene iminoester prepared by reaction of the acid (IX) with an oxime.

Other N-acylating derivatives of the acid of formula (IX) are thioesters of formula (X)

(X)

wherein R 1 and R9 are as hereinbefore defined an represents a 5- or 6-membered heterocyclic ring, which may contain, in addition to the nitrogen atom, one or two further heteroatoms, selected from oxygen, nitrogen and sulphur and which may be substituted or fused to a benzene

ring which may itself be substituted.

Preferred acylating agents derived from the acid of formula (IX) are the thio-esters (Xa) or (Xb) :

(Xa)

(Xb)

wherein R 1 and R 9 are as hereinbefore defined.

Compounds of the formula (Xa) and (Xb) may be prepared by treatment of the acid (IX) with 2,2'-dipyridyl-disulphide or 2,2'-dibenzothiazolyldisulphide respectively, in the presence of triphenylphosphine, analogously to the routes described in EP-A-0 037 380 (to Biochemie GmbH) . Conveniently, in compounds of the formula (Xa) and (Xb) , R ¹ may be hydrogen.

Other suitable N-acylating derivatives of the acid (IX) include the reactive intermediates formed by reaction in situ with a condensing agent such as a carbodiimide, for example, N,N'-diethyl-, di-n-propyl- or

diisopropylcarbodiimide, N,N'-di-cyclohexyl- carbodiimide, or N-ethyl-N'-[3-(dimethylamino)propyl]- carbodiimide; a suitable carbonyl compound, for example,

N,N'-carbonyldiimidazole or N,N'-carbonyldi- triazole; an isoxazolinium salt, for example, N-ethyl-

5-phenylisoxazolinium-3-sulphonate or N-t-butyl-5- methylisoxazolinium perchlorate; or an N-alkoxycarbonyl 2-alkoxy-l,2-dihydroquinoline, such as N-ethoxycarbonyl 2-ethoxy-l,2-dihydroquinoline. Other condensing agents include Lewis acids (for example BB^.CgHg); or a phosphoric acid condensing agent such as diethylphosphorylcyanide. The condensation reaction is preferably carried out in an organic reaction medium, for example, methylene chloride, dimethylformamide, acetonitrile, alcohol, benzene, dioxan or tetrahydrofuran.

A further method of forming the N-acylating derivative of the acid (IX) is to treat the acid of formula (IX) with a solution or suspension preformed by addition of a carbonyl halide, preferably oxalyl chloride, or a phosphoryl halide such as phosphorus oxychloride, to a halogenated hydrocarbon solvent, preferably dichloromethane, containing a lower acyl tertiary amide, preferably N,N-dimethylformamide. The N-acylating derivative of the acid (IX) so derived may then be caused to react with a compound of formula (VIII) . The acylation reaction may conveniently be carrisd out at -40° to +30°C, if desired in the presence of an acid binding agent such as pyridine, trimethylsilylacetamide or N,(}-bis (trimethylsilyl acetamide) . A catalyst such as 4-dimethylaminopyridine may optionally also be added. A preferred solvent for the above acylation reaction is dichloromethane.

A preferred am o protecting group R 1 m the intermediate of formula (IX) is trityl, which R group may be suitably removed from the product of formula (I) by treatment with formic acid or trlfluoracetic acid.

Compounds of formula (IX) may be prepared by routes analogous to those disclosed in GB 2 025 398A and by Takasugi et al., J.Antibiotics [1983] 36., 846 et seq and modifications thereto described in EP-A-0 210 815 (Beecham Group pic) .

The compounds of formula (VIII) herein which are, inter alia, intermediates for the compounds of formula (I) as hereinbefore defined may be prepared by reacting a compound of formula (XI) or acid addition salt thereof:

(XI)

wherein R ~\, R1 ~\, and Y1 are as hereinbefore defined, and the 7β-amino group is optionally protected with an amino protecting group; with a compound of the formula (VI) as hereinbefore defined;

with the proviso that when Rι ^{J ~} i .s an acyloxy group, the group C0 ₂ R° must be in the free acid form or a salt thereof;

and thereafter if necessary carrying out one or more of the following steps:

i) converting each or any of the groups R ⁴ and R^ into a different group R ⁴ and R ⁵ ;

ii) removing any protecting group; or

iii) converting the group R ³ into a group R ^x .

Compounds of formula (V) , as hereinbefore defined, may be prepared by reacting a compound of formula (XI) as hereinbefore defined or a derivative thereof in which the 7β-amino group is substituted with a group which permits acylation to take place; and any reactive groups may be protected; with an N-acylating derivative of an acid of formula (IX), as _, hereinbefore defined and thereafter, if necessary,carrying out one or more of the following steps:

(i) removing any protecting group,

(ii) replacing a group R 1 ^-4 -- ~ ^* '\ by another group R1- ^L ~ ^" ~ ^> ; or

(iii) converting a group which is convertible to Y^ into Y .

Compounds of formula (XI) are well known and readily available.

Compounds of the formula (I) in which Y is sulphur, -SO-, or -S0 ₂ - may be inter-converted by methods known in the art.

The compounds of formulae (la) , (lb) , and (Ic) may be prepared by similar processes to those described hereinabove as suitable for the preparation of a compound of the formula (I) , except that each process for the preparation of the compound of formulae (la) , (lb) or (Ic) further comprises, if necessary, the step of converting the product into a pharmaceutically acceptable salt or pharmaceutically acceptable in. vivo hydrolysable ester.

Conversion of betaines of formula (lb) into salts of formula (Ic) and vice versa may readily be carried out by conventional methods. For example salts of the formula (Ic) may be prepared from betaines of formula (lb) by treatment with a dilute mineral acid such as hydrochloric acid.

Quaternary salts within formula (Ic) may also be prepared by salt exchange in a conventional manner, for example by means of an ion-exchange resin.

The antibiotic compounds of the present invention are active against a wide range of Gram-negative and Gram-positive organisms including E.coli such as, for example ESS, JT4, JT425 and NCTC 10418; Pseudomonas Spp. such as Ps.aeruginosa for example 10662 and Dalgleish; Serratia marcescens US32; Klebsiella aerogenes A; Enterobacter cloacae Nl; P.mirabilis such as, for example C977 and 889; P.morganii; P.rettgeri; B.subtilis; Staph. aureus such as, for example Oxford and Russell; N.catarrhalis 1502.

The following Examples illustrate the preparation of the compounds of the present invention.

1-(Methylamino)-4-thiopyridone

N-Methylhydrazine (1.6ml; 0.03mol) in dichloromethane (20ml) was treated with di-t-butyl dicarbonate (6.6g; 0.03mol) in 5 dichloromethane (25ml) dropwise, and stirred for 90 minutes. The mixture was decanted from the sticky residue and evaporated to minimum volume twice from dichloromethane and once from dichloromethane/toluene to give t-Butyl 1-methylhydrazinecarboxylate (4g, 97%); δH (CDCI3) 1.47 (9H, 0 s) , and 3.03 (3H, s) .

t-Butyl 1-methylhydrazinecarboxylate (0.5g; 3.4mmol) and 4-thioρyrone (0.34g; 3mmol) in ethanol (20ml) were refluxed. for 24 hours. The solution was evaporated to dryness and 5 the product purified by chromatography on silica gel eluting with mixtures of hexane and ethyl acetate to give 1-[N- (t-Butyloxycarbonyl)-N-methylamino]-4-thiopyridone (0.55g, 76%); δH (CDCI3) 1.47 (9H, s) , 3.37 (3H, s) , 7.19 and 7.32 (4H, ABq, J 7Hz) ; λ _maχ (EtOH) 356nm (E 29050 dm ³ 0 mol- ¹ cm- ¹ ) (Found: M ⁺ , 240.0945, C ₁₁ H- _L gN ₂ 0 ₂ S requires M, 240.0932) .

1-[N-(t-Butyloxycarbonyl)-N-methylamino]-4-thiopyridone (lg, 4.16mmol) in dichloromethane (40ml) was treated with 5 trifluoroacetic acid (5ml) and stirred for 2 ^~ ά hours. On completion of the reaction the mixture was evaporated to dryness and the residue dissolved in ethyl acetate. The product was extracted into water maintained at pH 6.8 with sodium bicarbonate. The water was evaporated to low volume

30 and then the product absorbed onto silica gel by evaporation.

The product was then purified by chromatography on silica gel eluting with mixtures of ethanol in dichloromethane to give the title compound (0.4g, 67%) v _maχ (KBr) 1685, 1605,

351523 and 1108 cm- ¹ ; δH (CDCI3) 2.95 (3H, d, J 6Hz) , 5.46 (1H, q, J 6Hz), and 7.34 (4H, s) ; M ⁺ 140.

1-T (3S)-3-(t-Butyloxycarbonylamino)-2-oxoazetidin-l-vπ- 4-thiopyridone.

(3S)-l-Amino-3-(t-butyloxycarbonylamino)-2-oxoazetidine (O.lg, 0.5mmol) and 4-thiopyranone (0.056g, 0.5mmol) were dissolved in pyridine (5ml) and heated for 4h at ⁴ ^°C then 18h at 35°C. The volatiles were removed under reduced pressure and the residue chromatographed on silica gel 60, eluting with dichloromethane then ethyl acetate, to yield the title compound (0.036g, 25%) ;v _maχ (CH ₂ C1 ₂ ) 1805, 1710 and 1615cm- ¹ ;δ _H (CDCI3) 1.46 (9H,s), 4.00 (IH, t, J 5Hz) , 4.12-4.19 (lH,m), 4.43-4.58 (lH,m) , 5.40 (IH, d, J 7Hz) , and 7.40 (4H,s).

1-TN-(t-Butyloxycarbonyl)-N-(cyclopropylmethyl)aminol-4- thiopyridone.

1-(t-Butyloxycarbonylamino)-4-pyridone (0.23g, l.Ommol) in N,N-dimethylformamide (5ml) was treated successively with potassium carbonate (0.14g, l.Ommol) and cyclopropylmethyl bromide (O.lg, l.Ommol). The reaction mixture was stirred for 3h and evaporated under reduced pressure. Purification on silica gel 60 eluting with ethanol, dichloromethane (1:19) gave 1-[N-(t-Butyloxycarbonyl)- N-(cyclopropylmethyl)amino]-4-pyridone (0.22g, 76%); V,,,----. (KBr) 1708, 1649, 1629, and 1583 cm- ¹ ; δ _H (CDCI3) 0.18 (2H, q, J 5Hz),0.59(2H,m) , 0.88-1.04 (lH,m) 1.45 (9H,s), 3.54 (2H,d, J 7Hz), 6.40 (2H,d, J 6Hz) , and 7.30 (2H,d, J 6Hz) ; M ⁺ 264.

The latter intermediate product (0.22g O.δmmol) in toluene (5ml) was treated with Lawesson's reagent (0.17g, 0.4mmol) and heated at 80°C for lh. The mixture was allowed to cool and chromatographed on silica gel 60 eluting with ethanol, dichloromethane mixtures to give the title compound (0.079g, 35%); δ _H (CDCI3) 0.19 (2H,q, J 5.5Hz) , 0.60 (2H,q, J 5.5Hz),

0. 88 (lH, t, J 5.5Hz) , 1.29 ^' (9H, s) , 3. 62 (2H, d, J 7Hz) , and 7 .2-7 . 8 (4H, m) ; M ⁺ 280 .

1-TN-(t-Butyloxycarbonyi -N-(prop-2-en-l-yl)amino]-4- thiopyridone.

(i) 1- (t-Butyloxycarbonylamino)-4-pyridone (0.21g, l.Ommol) in 1,2-dimethoxyethane (10ml) was treated successively with 50% sodium hydride dispersion in oil (0.048g, l.Ommol) and cyclopropyl bromide (1.0ml, 12.5mmol) . After being stirred for 48h, the mixture was evaporated under reduced pressure. Purification on silica gel 60 eluting with ethanol, dichloromethane (1:9) gave 1-[N-(t-Butyloxy¬ carbonyl)-N-(prop-2-en-l-yl)amino]-4-pyridone (0.042g, 17%); δ _H (CDC1 ₃ ) 1.37 (9H,s), 4.24 (2H,d, J 9Hz) , 5.0-5.9 (3H,m) , 6.35 (2H,m), and 7.26 (2H,m); M ⁺ 250.

The latter intermediate product from Example 9(a) (0.199g, 0.48π--:-ol) in toluene (5ml) with Lawesson's reagent (0.194g, 0.48mmol) was heated at 80°C for 2h, then allowed to cool and chromatographed in silica gel 60 eluting with ethanol, dichloromethane (1:50) to give the title compound (0.089g, 70%); v _maχ (KBr) 11, and 1615 cm- ¹ ; δ _R (CDCI3) 1.46 (9H,s), 4.26 (2H,d, J 7Hz) , 5.10-5.40 (2H,m) , 5.62-5.77 (lH,m), 7.03 (2H,d, J 6Hz) , and 7.39 (2H,d, J 6Hz) ; M ⁺ 266.

1- (Propylamino)-4-thiopyridone

1- (t-Butyloxycarbonylamino)-4-pyridone (O.lg, 0.047mmol) in N,N dimethylformamide (2ml) was treated successively with potassium carbonate (0.064g, 0.047mmol) and iodopropane (O.Oδlg, 0.047mmol) . The reaction mixture was stirred at room temperature for 3h and evaporated under reduced pressure. Purification on silica gel 60 eluting with ethanol, dichloromethane (1:9) gave 1-[N-

(t-Butyloxycarbonyl)-N-propylamino]-4-pyridone, (0.098g, 82%); δ _H (CDC1 ₃ ) 0.98 (3H,t J 7Hz) , 1.45 (9H,s), 1.53-1.68 (2H,m) 3.62 (2H,t, J 7.5Hz), 6.35 (2H,d, J 8Hz) , and 7.21 (2H,d, J 8Hz) ; M ⁺ 252.

The latter intermediate product (0.098g, 0.39mmol) in toluene (10ml) was treated with Lawesson's reagent (0.15g, 0.37mmol) and heated at 80°C for 0.5h. The mixture was allowed to cool and chromatographed on silica gel 60 eluting with ethanol, dichloromethane mixtures to give

1-[N-(t-Butyloxycarbonyl)-N-propylamino]-4-thiopyridone (0.05g, 48%); δ _H (CDCl ₃ ) 0.96 (3H,t, J 7Hz) , 1.45 (9H,s), 1.5-1.65 (2H,m), 3.64 (2H,t, J 7Hz) , 7.03 (2H,d, J 7Hz) , and 7.40 (2H,d, J 7Hz); M ⁺ 268.

The latter intermediate product (0.2g, 0.75mmol) was dissolved in trifluoroacetic acid (3ml) , the reaction mixture was stirred for 10 minutes, toluene (10ml) was added and the mixture was evaporated under reduced pressure. A further two (10ml) volumes of toluene were added and evaporated under reduced pressure. Water (10ml) was added and the pH adjusted to 7.2 using aqueous sodium hydrogen carbonate. The product was extracted into dichloromethane and dried over magnesium sulphate, filtered and evaporated under reduced pressure. Purification on silica gel 60 eluting with ethanol, dichloromethane (1:9) gave the title compound (0.074g, 59%); δ _H (CDCI3) 1.0 (3H,t, J 7Hz) , 1.5-1.6 (2H,m), 3.09 (2H,t, J 7Hz) , and 7.29-7.38 (4H,m) ; M ⁺ 168.

1-fN-(t-Butyloxycarbonyl)-N-(cyclopentyl)amino]-4-thio- pyridone

1-(t-Butyloxycarbonylamino)-4-pyridone (0.2g, 0.94mmol) in N,N dimethylformamide (4ml) was treated successively with

potassium carbonate (0.128g, 0.94mmol) and

1-iodocyclopentane (0.184g, 0.94mmol). The reaction mixture was stirred at room temperature for 3h and evaporated under reduced pressure. Purification on silica gel 60 eluting 5 with ethanol, dichloromethane (1:9) gave

1-[N-(t-Butyloxycarbonyl)-N-(cyclopentyl)amino]-4-pyridon e (0.109g, 41%) δ _H (CDC1 ₃ ), 1.45 (9H,s), 1.5-2.07 (8H,m) , 4.5-4.62 (lH,m), 6.4 (2H,d, J 8Hz) and 7.2 (2H,d, J 8Hz) ; M ⁺ 278. 0

The latter intermediate product (0.104g, 0.37mmol) in toluene (10ml) was treated with Lawesson's reagent (0.15g, 0.37mmol) and heated at 80°C for 0.5h under Argon. The mixture was allowed to cool and chromatographed on silica 5 gel 60 eluting with ethanol, dichloromethane mixtures to give the title compound (0.042g, 37%); δ _H (CDCI3) inter alia 1.45 (9H,s), 1.5-2.25 (8H,m) , 4.5-4.65 (lH,m) , 7.25 and 7.6 (4H, 2 s) ; M ⁺ 294.

0 1-TN-Butyl-N- (t-butyloxycarbonyl)amino]-4-thiopyridone

1-(t-Butyloxycarbonylamino)-4-pyridone (O.lg, 0.47mmol) in N,N dimethylformamide (2ml) was treated successively with potassium carbonate (0.66g, 0.47mmol) and 1-bromobutane 5 (0.065g, 0.47mmol) . This mixture was stirred for 4h and then evaporated under reduced pressure. Purification on silica gel 60 eluting with ethanol, dichloromethane (1:9) gave 1-[N-Butyl-N-(t-butyloxycarbonyl)amino]-4-pyridone (0.088g, 70%); δ _R (CDCI3) 0.96 (3H,t, J 7Hz) , 1.3-1.64

30 (4H,m), 1.45 (9H,s) 3.66 (2H,t, J 7Hz) , 6.32 (2H,d,J 7Hz) , 7.21 (2H,d, J 7Hz); M ⁺ 266.

The latter intermediate product (0.088g, 0.33mmol) in toluene (10ml) was treated with Lawesson's reagent (0.13g, 350.32mmol) and heated at 80°C for 0.5h. The mixture was allowed to cool and chromatographed on silica gel 60 eluting with ethanol, dichloromethane (1:9) to give the title

compound (0.053g, 57%); δ _H ^" (CDCl ₃ ) 0.95 (3H,t, J 7Hz) 1.25-1.63 (4H,m), 1.45 (9H, s) , 3.67 (2H, t, J 7.5Hz), 7.02 (2H, d,J 7.5Hz), and 7.40 (2H,d, J 7.5Hz); M ⁺ 282.

1-TN-(t-Butyloxycarbonyl)-N-hexylamino]-4-thiopyridone

1- (t-Butyloxycarbonyl amino)-4-pyridone (0.2g, 0.94mmol) in N, N dimethylformamide (4ml) was treated successively with potassium carbonate (0.132g, 0.95mmol) and 1-bromohexane (0.203g, 1.22mmol) . The mixture was stirred for 18h and then evaporated under reduced pressure. Purification on silica gel 60 eluting with ethanol, dichloromethane (1:9) gave 1-[N-(t-Butyloxycarbonyl)-N-hexylamino]-4-pyridone, δ _H (CDC1 ₃ ) 0.89 (3H,t, J 6Hz), 1.21-1.76 (17H, m) , 3.65 (2H,t, J 7.5Hz), 6.35 (2H,d, J 8Hz) , and 7.21 (2H,d, J 8Hz) ; M ⁺ 294.

The latter intermediate product (0.28g, 0.95mmol) in toluene (10ml) was treated with Lawesson's reagent (0.38g, 0.94mmol) and heated at 80°C for 35 minutes. The mixture was allowed to cool and chromatographed on silica gel 60 eluting with ethanol, dichloromethane (1:9) to give the title compound

(0.179g, 66%); δ _R (CDCI3) 0.89 (3H,t,J 6Hz) , 1.23-1.70

(8H,m), 1.45 (9H,s), 3.67 (2H, t,J 7.5Hz), 7.02 (2H, d,J 7Hz), and 7.4 (2H, d,J 7Hz) M ⁺ 310.

1-TN-(t-Butyloxycarbonyl)-N-(1-isopropyl)aminol-4- thiopyridone

1-(t-Butyloxycarbonyl amino)-4-pyridone (0.2g, 0.94mmol) in

N,N dimethylformamide (4ml) was treated successively with potassium carbonate (0.132g, 0.95mmol) and 2-bromopropane

(0.152g, 1.22mmol) . The mixture was stirred for 24h and then evaporated under reduced pressure. Purification on silica gel 60 eluting with ethanol, dichloromethane (1:9)

gave 1-[N-(t-Butyloxycarbonyl)-N- (1-isopropyl) amino]-4-pyridone, (0.116g, 49%); δ _R (CDCI3) 1.21 (6H,d, J 7Hz), 1.44 (9H,s), 4.61 (lH,t, J 7Hz) , 6.33 (2H,d, J 8Hz) and 7.15 (2H,d, J 8Hz) ; M ⁺ 252. 5 The latter intermediate product (0.116g, 0.46mmol) in toluene (10ml) was treated with Lawesson's reagent (0.124g, 0.31mmol) and heated at 80°C for 35 minutes. The mixture was allowed to cool and chromatographed on silica gel 60 10 eluting with ethanol, dichloromethane (1:9) to give the title compound (0.05g, 41%); δ _H (CDCI3) 1.22 (6H, d, J 7Hz), 1.45 (9H,s), 4.65 (lH,t, J 7Hz) , 6.96 (2H, d, J 7Hz) , and 7.38 (2H, d, J 7Hz) M ⁺ 268.

151-TN-(t-Butyloxycarbonyl)-N-(2-hydroxyethyl)amino]-4- thiopyridone

2-Hydroxyethylhydrazine (0.228g, 3.0mmol) in dichloromethane (10ml) was treated with di-t-butyldicarbonate(0.65g,

203.0mmol). The reaction mixture was stirred for 0.75h and then evaporated under reduced pressure. Purification on silica gel 60 eluting with ethanol, dichloromethane (1:9) gave N- (t-Butyloxycarbonyl)-N-(2-hydroxyethyl)hydrazine, (0.413g, 78%); 5 _R (CDCI3) 1.48 (9H,s), 3.58 (2H,t, J 4.5Hz)

253.83 (2H, t, J 4.5Hz), and 3.3-4.0 (IH, brs) .

N- (t-Butyloxycarbonyl)-N-(2-hydroxyethyl)hydrazine (0.413g, 2.37mmol) in ethanol (10ml) was treated with 4-thiopyranone (0.16g 1.43mmol) . The mixture was stirred at 60°C for 18h,

30 then allowed to cool and evaporated under reduced pressure. Purification on silica gel 60 eluting with ethanol, dichloromethane (1:9) gave the title compound (0.351g, 91%); δ _H (CDCI3), 1.47 (9H,s), 3.30-3.95 (5H,m) , and 7.32 (4H,d, J 5Hz) ; M ⁺ 270.

35

1-(2-0xopiperidin-l-yl)-4-thiopyridone

l-Amino-2-oxopiperidine (0.228g, 2mmol) and 4-thiopyranone (0.23g, 2mmol) in ethanol (25ml) were heated at reflux for 53.5h. The volatiles were removed under reduced pressure and the residue purified on silica gel 60, eluting with dichloromethane then ethyl acetate, to give the title compound (0.264g, 68%); v _maχ (CH ₂ C1 ₂ ) 1690, 1610 and 1115cm- ¹ ; δ _R (CDCI3) 1.80-2.30 (4H, m) , 2.59 (2H, t, J 7Hz) , 103.8 (2H, t, J 7Hz), and 7.15-7.40 (4H, m) ; (Found: M ⁺ , 208.0669. C ₁₀ H ₁₂ N ₂ OS requires M, 208.0670).

2-[ (Z)-[SI-(3,4-Diacetoxyphenyl) (diphenylmethyloxycarbonyl) methyloxyimino]-2-(2-tritylamino-4-thiazolyl)acetic acid and 152-[ (Z)-fRI-(3,4-Diacetoxyphenyl) (diphenyl¬ methyloxycarbonyl)methyloxyimino]-2- (2-tritylamino-4- thiazolyl)acetic acid

Diphenylmethyl [RS]-2-(3,4-diacetoxyphenyl)-2- 20 (phthalimidooxy) acetate (3.8g, 6.56mmol) was dissolved in dichloromethane (100ml) , treated with trifluoroacetic acid (10ml) and stirred for 2h. The mixture was diluted with toluene (50ml) and evaporated to dryness under reduced pressure. The residue was triturated under hexane (2x200ml) 25 and then dissolved in acetone (30ml) . The resulting solution was treated with R-(+)-α-methylbenzylamine (0.84ml, 6.53mmol) and, after 30 minutes the solid was collected by filtration and washed with acetone, to give the R- (+)-α-methylbenzylamine salt of 30 [S]-2- (3,4-diacetoxyphenyl) -2-(phthalimidooxy) acetic acid (1.05g, 60%); [α] _D ²¹ + 189° (c 0.05 in EtOH) ; δ _jj (CDCI3) 1.48 (3H, d, J 6Hz), 2.19 (3H, s) , 2.23 (3H, s) , 4.25 (IH, q, J 6Hz) , 5.76 (IH, s), 7.00-7.50 (8H, m) , and 7.60-7.70 (4H,

s) .

The filtrate from above was evaporated under reduced pressure and partitioned between dilute hydrochloric acid and ethyl acetate. The ethyl acetate layer was dried (MgS0 ₄ ) and evaporated to dryness under reduced pressure. The residue was dissolved in acetone (15ml) and treated with S-(-)-α-methylbenzylamine (0.69ml, 5.3mmol). After 30 minutes the solid was collected by filtration and washed with acetone to give the S-(-)-α-methylbenzyl amine salt of [R]-2- (3,4-diacetoxyρhenyl)-2-(phthalimidooxy) acetic acid (1.07g, 67%); [α] _D ²¹ -184° (c 0.04 in EtOH) ; δ _R (CDCI3) 1.50 (3H, d, J 6 Hz), 2.21 (3H, s) , 2.24 (3H, s) , 4.28 (IH, q, J 6 Hz), 5.78 (IH, s) , 7.05-7.50 (8H, m) , and 7.70 (4H, s) .

R- (- )-α-Methylbenzylamine salt of [S]-2-(3,4-diacetoxy- phenyl)-2-(phthalimidooxy)acetic acid (1.31g, 2.45mmol) was partitioned between dilute hydrochloric acid and ethyl acetate. The ethyl acetate later was dried and treated with an excess of diphenyldiazomethane. The solution was evaporated under reduced pressure and the residue purified by chromatography on silic gel 60, eluting with mixtures of hexane and ethyl acetate, to give Diphenylmethyl [S]-2- (3,4-diacetoxyphenyl)-2-(phthalimidooxy)acetate, (1.4g, 98%); δ _R (CDCI3) , 2.21 (6H, s) , 6.00 (IH, s) , 6.87 (IH, s), 7.00-7.60 (13H, m) , and 7.65-7.75 (4H, m) .

Diphenylmethyl

[S]-2- (3,4-diacetoxyphenyl)-2-(phthalimidooxy)acetate (1.36g, 2.35mmol) was dissolved in dichloromethane (25ml) and cooled to -60°C. This solution was treated with methylhydrazine (0.125ml, 2.35mmol) and the temperature allowed to rise slowly to +5°C. The mixture was then stirred at ambient temperature for lh. The solid was

removed by filtration and the filtrate evaporated to dryness under reduced pressure. The residue was dissolved in methanol (40ml) and treated with 2-(2-tritylamino-4- thiazolyDglyoxylic acid (0.95g, 2.3mmol) . After 2h, the reaction mixture was evaporated to dryness under reduced pressure. Chromatography on silica gel 60, eluting with mixtures of dichloromethane and ethanol gave 2-[ (Z)-[S]-(3,4-Diacetoxyphenyl) (diphenylmethyl- oxycarbonyl)methyloxyimino]-2-(2-tritylamino-4-thiazolyl) acetic acid, (1.15g, 58%); δ _R (CDCI3) 2.27 (3H, s) , 2.29 (3H, s), 6.00 (IH, s) , 6.76 (IH, s) , 6.85 (IH, s) , and 6.90-7.40 (29H, m) .

2-[ (Z)-[R]~(Diacetoxyphenyl) (diphenyl ethyloxycarbonyl) methyloxyimino]-2-(2-tritylamino-4-thiazolyl)acetic acid was similarly prepared from the [S]-(-)-α-methylbenzylamine salt of [R] -2-(3,4-diacetoxyphenyl)-2-(phthalimidooxy)acetic acid (1.20g, 2.28mmol), (0.91g, 47%), δ _R (CDCI3) , 2.27 (3H, s), 2.29 (3H, s), 6.01 (IH, s) , 6.79 (IH, s) , 6.85 (IH, s) , and 6.90-7.40 (29H, m) .

EXAMPLE 1

T6R.7R1-7- Ϊ2-(2-Amino-4-thiazolyl)-2-(Z)-(cvclopentyl- oxyimino)acetamidol-3-TI-(methylamino)pyridinium-4- thiomethyl]ceph-3-em-4-carboxylate.

2-(2-Amino-4-thiazolyl)-2-(Z)-(cyclopentyloxyimino) acetic acid (2.57g, lOmmol) was dissolved in N,N dimethylformamide (20ml) with N,N-diisopropylethylamine (1.74ml, lOmmol) and cooled to -30°C. The mixture was treated with methanesulphonyl chloride (0.78ml, lOmmol) and allowed to warm to 0°C for 10 minutes and recooled to -30°C. 4-Methoxybenzyl [6R,7R]-7-amino-3-(chloromethyl) ceph-3-em-4-carboxylate hydrochloride (4.05g, lOmmol) was dissolved in N,N dimethylformamide with N,N diisopropylethylamine (3.50ml, 20mmol) and added to the cooled solution of activated acid. The mixture was allowed to warm to room temperature and stirred for 2h. The mixture was partitioned between ethyl acetate (250ml) and water. The aqueous layer was back extracted with a further portion of ethyl acetate and then these two organic phases were sequentially washed with water (200ml x 2) , dilute citric acid (100ml x 2) , water, dilute sodium hydrogen bicarbonate and brine. The organic phases where then combined, dried over MgS0 ₄ and evaporated to give 4-Methoxybenzyl [6R,7R]-7-[2- (2-amino-4-thiazolyl)-

2-(Z)- (cyclopentyloximmo)acetamido]-3-(chloromethyl)ceph-3- em-4-carboxylate, (4.2g 69%); V _maχ (KBr) 1785, 1723, 1675, 1612 and 1513cm_l. ^~ ^ _(CDCl3 ) 1.5-2.0 (8H,m), 3.50 and 3.70 (2H, ABq J 18Hz) , 3.82 (3H,s), 4.40 and 4.60 (2H, ABq, J 12Hz), 4.98 (lH,m), 5.05 (lH,d, J 5Hz) 5.23 and 5.27 (2H, ABq, J 12Hz) , 5.96 (lH,dd, J 9 and 5Hz) 6.1-6.4 (2H,broad), 6.91 and 7.35 (4H, 2d, J 8Hz) , 7.07 (lH,s), and 7.39 (lH,d, J 9Hz) ; m/z (FAB, thioglycerol) MH ⁺ 606.

This compound (0.15g, 0.25mmol) was dissolved in acetonitrile (5ml) and treated with sodium iodide (0.045g, 0.3mmol) and then after 10 minutes with

1- (methylamino)-4-thioρyridone (0.04g, 0.29mmol) . A gum 5 precipitated gradually from the solution so a further volume of acetonitrile (5ml) was added. After 70 minutes the mixture was evaporated to dryness and the product purified by chromatography on silica eluting with methanol, dichloromethane mixtures. Fractions containing product were 10 combined and evaporated to give 4-Methoxybenzyl

[6R,7R]-7-[2-(2-amino-4-thiazolyl)-2-(Z)-(cyclopentyloxy- imino)acetamido]-3-[1-(methylamino)pyridinium-4-thio methyl]ceph-3-em-4-carboxylate iodide, (0.13g, 62%); δ _R

(CDC13 + CD30D) 1.5 ^~ 2.0 (8H,m) , 3.07 (3H,s), 3.83 ^(3H ' ^S >' 154.22 and 4.50 (2H, ABq, J 11Hz) , 4.8-4.9 (lH,m)5.11 (IH, d,

J 5Hz) , 5.20 and 5.30 (2H, ABq, J 12Hz) , 5.90 (lH,d,J 5Hz) ,

6.82 (1H,S), 6.9 (2H,ABq, J 8Hz) , 7.75 and 8.65 (4H, 2d, J

7Hz) .

20 This compound was dissolved in dichloromethane (10ml) with trifluoroacetic acid (0.36ml). The mixture was stirred until the reaction was complete at 50 minutes. The mixture was evaporated twice from dichloromethane and then the residue was titurated with ether. The product was dissolved

25 in water at pH8 and then purified by chromatography on HP20SS. Fractions containing product were combined, evaporated to low volume and freeze dried to give the title compound (O.Ollg 12%); v _maχ (KBr) 1762, 1670, 1617, and 1533 cm- ¹ ; δ _H (D ₂ 0) 1.5-2.1 (8H,m), 3.00 (3H,s), 3.45 and 3.70

30 (2H, ABq, J 18Hz) 4.10 and 4.41 (2H, ABq, J 13Hz) , 4.7

(lH,m), 5.14 (lH,d, J 5Hz) , 5.72 (lH,d, J 5Hz) , 6.94 (lH,s), 7.79 (2H,d, J 7Hz), and 8.50 (2H,d, J 7Hz) ; m/z (F.A.B., thioglycerol/acetic acid) MH ⁺ 590.

EXAMPLE 2

r6R,7R1-7- 2-(2-Amino-4-thiazolyl)-2-(Z)-(hvdroxy- imino)acetamido]-3-TI-(methylamino)pyridinium-4-thio 5 methyl]ceph-3-em-4-carboxylate

2- (2-Tritylamino-4-thiazolyl)-2-(Z)-(trityloxyimino) acetic acid (0.067g, O.lmmol) was dissolved in dichloromethane (6.7ml) and treated with N,N diisopropylethylamine 0 (0.017ml), O.lmmol) and methanesulphonyl chloride (0.008ml, O.lmmol). After _, 10 minutes at room temperature infra red showed only partial activation so further amounts of N,N diisopropylethylamine (0.0174ml) and methane-sulphonyl chloride (0.0077ml) were added. After a further 10 minutes 5 infra red showed reaction was complete. 4-Methoxybenzyl [6R,7R]-7-amino-3-(chloromethyl)ceph-3-em-4-carboxylate hydrochloride (O.Oδlg, 0.2mmol) was dissolved in dichloromethane (5ml) containing N,N diisopropylethylamine (0.07ml, 0.4mmol), added to the activated acid solution and 0 stirred for 1.5h. The solution was diluted with ethyl acetate and then washed with water, dilute citric acid, water, and brine. The solution was dried over MgS0 ₄ and evaporated. The product was purified by chromatography on silica gel eluting with hexane, ethyl acetate mixtures to 5 give 4-Methoxybenzyl [6R,7R]-3-(chloromethyl)-7-

[2- (2-tritylamino-4-thiazolyl)-2-(Z)- (trityloxyimino) acetamido]ceph-3-em-4-carboxylate, (0.055g, 55%); δ _R (CDCI3) 3.22 and 3.56 (2H,ABq, J 18Hz) , 3.78 (3H,s), 4.35 and 4.53 (2H,ABq, J 12Hz), 5.00 (lH,d, J 5Hz) , 5.22 (2H,s),

30 6.00(lH,dd, J 9 and 5Hz) , 6.40 (lH,s), 6.87 (2H,d, J 8Hz) , and 7.0-7.6 (32H,m) .

The latter compound (0.055g, 0.054mmol) was dissolved in acetonitrile (3ml) and treated with sodium iodide (O.Olg, 350.06mmol) and then 1-(methylamino)-4-thiopyridone (0.008g, 0.06mmol). After stirring for 1.5h the solution was added

dropwise to ether (40ml) . The product was filtered off and washed with ether, then water, and dried in vacuo to give 4-Methoxybenzyl [6R,7R]-3-[1-(methylamino)pyridinium-4- thio ethyl] -1-[2-(2-tritylamino-4-thiazolyl)-2-(Z)- (trityloxyimino)acetamido]ceph-3-em-4-carboxylate iodide, (0.046g, 68%); δ _R (CDC1 ₃ ) 3.04 (3H,d, J 6Hz) , 3.34 and 3.57 (2H,ABq, J 18Hz), 3.82 (3H,s) , 4.20 and 4.44 (2H,ABq, J 13Hz), 5.07 (lH,d, J 5Hz) , 5.22 and 5.30 (2H,ABq, J 11.5Hz), 6.04 (lH,dd, J 9 and 5Hz) , 6.43 (lH,s), 6.72 (lH,s,exch), 6.91 and 7.38 (4H,2d, J 8.5Hz), 7.06 (lH,d, J 9Hz,exch), 7.2-7.38 (30H ,m) _, , 7.61 (2H,d, J 7Hz) , 8.65 (lH,q, J 6Hz) , and 8.75 (2H,d, J 7Hz) ; m/z (F.A.B., 3 nitrobenzylalcohol/sodium acetate) M ⁺ 1126.

This compound (0.044g, 0.035mmol) was deprotected by treatment with in trifluoroacetic acid (1ml) with, as per example 1, to give the title compound (0.009g, 50%); V _maχ (KBr) , 1764, 1660 (sh) , 1617 and 1528 cm- ¹ ; δ _R (D ₂ 0) 3.00 (3H,s), 3.43 and 3.71 (2H,ABq, J 17.5Hz), 4.11 and 4.41 (2H,ABq, J 13.5Hz), 5.15 (lH,d, J 5Hz) , 5.77 (lH,d, J 5Hz) , 6.92 (lH,s), 7.78(2H,d, J 7Hz) , and 8.50 (2H,d, J 7Hz) ; m/z (F.A.B., thioglycerol) MH ⁺ 522.

EXAMPLE 3

f6R,7R]-7-f2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxy¬ imino)acetamido]-3-fl-(4-carboxybutan-l-yl)aminopyridinium- 4-thiomethyl1ceph-3-em-4-carboxylate sodium salt

4-Methoxybenzyl [6R,7R]-3-(chloromethyl)-7-[2-(Z)-

(methoxyimino)-2-(2-tritylamino-4-thiazolyl)acetamido]cep h- 3-em-4-carboxylate (O.lg, 0.13mmol) was reacted with

1-(2-oxopiperidin-l-yl)-4-thiopyridone (0.0244g, 0.13mmol) and sodium iodide (0.127g, O.lmmol) in acetonitrile (5ml). The mixture was stirred for 2.5h, filtered through celite and evaporated to dryness under reduced pressure. The 5 product was obtained after chromatography on silica gel 60, eluting with dichloromethane, ethyl acetate and finally mixtures of methanol in dichloromethane, as a yellow foam to give 4-Methoxybenzyl [6R,7R] -1-[2-(Z)-(methoxyimino)-2-(2- tritylamino-4-thiazolyl)acetamido]-3-[1-(2-oxopiperidin-l- 10 yl)pyridinium-4-thiomethyl]ceph-3-em-4-carboxylate iodide,. (0.078g, 56%); V _maχ (CH ₂ C1 ₂ ) 1780, 1680, and 1610cm- ¹ ; δ _R (CDC1 ₃ ) 1.80-2.20 (4H, m) , 2.35-2.75 (2H, m) , 2.90-3.30 (2H, m) , 3.50-4.20 (8H, m) , 4.30-4.65 (2H, m) , 4.90-5.30 (3H, m) , 6.43 (IH, s), 6.70-7.40 (19H,m) , 7.80-8.10 (2H, ) , and 158.70-9.15 (2H, m) ; m/z (F.A.B., thioglycerol) MH ⁺ 966.

This compound (0.078g, 0.07mmol) was deprotected with trifluoroacetic acid (0.0488g, 4.3mmol) in dichloromethane (5ml) at room temperature as described in Example 1 (c) , to

20 give the title compound (0.0079g, 17%); v _maχ (KBr) 1762, 1664 and 1617cm- ¹ ; δ _R [D ₂ 0 + (CD ₃ ) ₂ C0] 1.39-1.66 (4H, m) , 2.08-2.19 (2H, m) , 3.25 (2H, t, J 7 Hz), 3.40 and 3.67 (2H, ABq, J 18 Hz) , 3.92 (3H, s) , 4.11 and 4.36 (2H, ABq, J 14 Hz), 5.12 (IH, d, J 5 Hz), 5.71 (IH, d, J 5 Hz), 6.93 (IH,

25 s) , 7.76 (2H, d, J 7 Hz), 8.48 (2H, d, J 7Hz) ; m/z (F.A.B., thioglycerol) MH ⁺ 644.

EXAMPLE 4

30 f6R,7R]-7- \2- (2-Amino-4-thiazolyl)-2-(Z)-(ethoxyimino)- acetamido]-3-[1-(methylamino) yridinium-4-thiomethyll- ceph-3-em-4-carboxylate

4-Methoxybenzyl [6R,7R]-7-amino-3-(chloromethyl)

ceph-3-em-4-carboxylate hydrochloride (0.405g, lmmol) was partitioned between ethyl acetate (50ml) and saturated, aqueous sodium hydrogen carbonate (25ml) .The phases were separated and the organic phase washed with water, saturated brine, dried (MgS0 ₄ ) and evaporated to dryness under reduced pressure. The residue was redissolved in acetonitrile (10ml) and treated with 1-[N-(t-butyloxycarbonyl)- N-methylamino]-4-thiopyridone (0.24g, lmmol) and sodium iodide (0.15g, lmmol). After lh the volatiles were removed under reduced pressure and the residue chromatographed on silica gel 60, eluting with dichloromethane, ethyl acetate then mixtures of methanol in dichloromethane, to give 4-Methoxybenzyl [6R,7R]-7-amino-3-[1- (N-t-butyloxycarbonyl-N-methylamino)pyridinium-4-thiomethyl] ceph-3-em-4-carboxylate iodide, (0.617g, 90%); _maχ (KBr) 1772, 1718 and 1614cm- ¹ ; δ _R (CDCI3) 1.54 (9H, s) , 1.72 (2H, brs, exch) , 3.49 and 3.87 (2H, m) , 3.69 (3H, s) , 3.81 (3H, s) , 4.46 and 4.53 (2H, ABq, J 13 Hz), 4.79 (IH, d, J 5 Hz), 5.01 (IH, d, J 5Hz), 5.20 and 5.29 (2H, ABq, J 12 Hz), 6.88 (2H, d, J 9 Hz), 7.37 (2H, d, J 9Hz) , 8.11 (2H, d, J 7 Hz), and 8.61 (2H, d, J 7 Hz); m/z (F.A.B., 3-nitrobenzyl alcohol) M ⁺ 573.

2- (Z)- (Ethoxyimino)-2-(2-tritylamino-4-thiazolyl)acetic acid (0.431g, 0.94mmol) was dissolved in dry

N,N-dimethylformamide (5ml) under argon and the solution cooled to -40°C. N,N-Diisoρropylethylamine (0.122g, 0.94mmol) then methanesulphonyl chloride (O.lOδg, 0.94mmol) were added and the mixture stirred at -20°C for 0.5h. The mixture was cooled to -40°C and treated with a solution of 4-methoxybenzyl [6R,7R]-7- amino-3-[1-[N-(t-butyloxycarbonyl)-N-methylamino]- pyridinium-4-thiomethyl]ceph-3-em-4-carboxylate iodide (0.6g, 0.86mmol) and pyridine (0.074g, 0.94mmol) in dry dichloromethane (10ml) . The resulting mixture was allowed to regain room temperature then stirred for lh before being

diluted with dichloromethane (50ml) . This mixture was washed with water (5x) , saturated brine, dried (MgSO^) and evaporated to dryness under reduced pressure. Chromatography on silica gel 60, eluting with 5 dichloromethane, ethyl acetate then mixtures of methanol in dichloromethane, gave 4-Methoxybenzyl [6R,7R]-3-[1-[N-(t-butyloxycarbonyl)-N-methylamino] pyridinium-4-thiomethyl]-7-[2-(Z)-(ethoxyimino)-2- (2-tritylamino-4-thiazolyl)acetamido]ceph-3-em-4-carboxylate 0 iodide, (0.526g, 54%); V _maχ (CH ₂ C1 ₂ ) 1785, 1725 br, 1670 and 1615cm- ¹ ; δ _R (CDCI3) 1.34 (3H, t, J 7 Hz), 1.52 (9H, s), 3.55 and 3.87 (2H, ABq, J 19Hz) , 3.69 (3H, s) , 3.81 (3H, s), 4.36 (2H, q, J 7 Hz), 4.52 and 4.58 (2H, ABq, J 13 Hz), 5.12 (IH, d, J 5 Hz), 5.23 and 5.27 (2H, ABq, J 12 Hz), 5.98

15 (IH, dd, J 5 and 9 Hz), 6.72 (IH, s) , 6.81 (IH, d, J 9 Hz, exch.), 6.88 (2H, d, J 9 Hz) , 6.99 (IH, brs, exch.), 7.21-7.40 (17H, m) , 8.09 (2H, d, J 7 Hz), and 8.56 (2H, d, J 7 Hz); m/z (F.A.B., thioglycerol) M ⁺ 1012.

20 This compound (0.52g, 0.46mmol) was then deprotected as in Example 1 as to give the title compound (O.Oδlg, 32%); ^v _maχ (KBr) 1762, 1670, and 1618cm- ¹ ; δ _R [D ₂ 0 + (CD3) ₂ C0] 1.27 (3H, t, J 7 Hz), 3.02 (3H, s) , 3.45 and 3.71 (2H, ABq, J 18 Hz), 4.13 and 4.42 (2H, ABq, J 14 Hz), 4.23 (2H, q, J 7 Hz),

255.16 (IH, d, J 5 Hz), 5.77 (IH, d, J 5 Hz), 6.94 (IH, s) , 7.81 (2H, d, J 7 Hz), and 8.53 (2H, d, J 7 Hz); m/z (F.A.B., thioglycerol) MH ⁺ 550.

EXAMPLE 5 30 r 6R. 7R1 -3- f 1- f (2S) -2-Amino-2- (methoxycarbonyl) ethyl- amino] pyridinium-4-thiomethyl] -7- [2- (2-amino-4-thia- zolyl) -2- (Z) - (methoxyimino) acetamido] ceph-3-em-4-carboxylate

35 1- [ (3S) -3- (t-Butyloxycarbonylamino) -2-oxoazetidin-l-yl] -4-

thiopyridone (0.075g, 0.26mmol) was dissolved in a mixture of tetrahydrofuran (2ml) , N,N-dimethylformamide (2ml) and acetone (2ml) with warming and the solution treated with a solution of 4-methoxybenzyl [6R,7R]-3-(chloromethyl)-7- [2-(Z)-(methoxyimino)-2-(2-tritylamino-4-thiazolyl) acetamido]ceph-3-em-4-carboxylate (0.207g, 0.26mmol) and sodium iodide (0.039g, 0.26mmol) in acetone (5ml) . After 1.5h, the volatiles were removed under reduced pressure and diethyl ether (50ml) added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried in air. The dried solid was redissolved in dry dichloromethane and the title compound obtained by chromatography on silica gel 60, eluting with dichloromethane, ethyl acetate then mixtures of methanol in dichloromethane to give 4-Methoxybenzyl

[6R,7R]-3-[1-[ (2S)-2-(t-butyloxycarbonylamino)-2- (methoxycarbonyl)ethylamino]pyridinium-4-thiomethyl]-7- [2-(Z)-(methoxyimino)-2-(2-tritylamino-4-thiazolyl) acetamido]ceph-3-em-4-carboxylate iodide, (0.0514g, 16%); v _maχ (CH ₂ C1 ₂ ) 1775, 1690 br, and I ^β lOcm- ^ g^ ( _CDCl3 ) _{1> 4} (9H, s), 3.45-3.87 (10H, m) , 4.07 (3H, s) , 4.42-4.49 (IH, m) , 4.27 and 4.49 (2H, ABq, J 13Hz) , 5.09 (IH, d, J 5 Hz), 5.23 and 5.27 (2H, ABq, J 12 Hz), 5.60 (IH, d, J 8 Hz, exch.), 5.94 (IH, dd, J 5 and 8 Hz), 6.81 (IH, s) , 6.81 (IH, d, J 8 Hz, exch.), 6.90 (2H, d, J 8 Hz), 7.00 (IH, s) , 7.21-7.40 (17H, ) , 7.69 (2H, d, J 7Hz) , δ.7δ (IH, brm, exch.), and δ.90 (2H, d, J 7Hz) ; m/z (F.A.B., thioglycerol) MH ⁺ 1086.

This intermediate (0.05g, 0.04mmol) was deprotected as in Example 1 (c) to give the title compound (0.012δg, 49%); ^v max ( ^KBr > ^{1758 br} ' 1669, and 1617cm- ¹ ; δ _R [D ₂ 0 + (CD ₃ ) ₂ C0] 3.39-3.64 (5H, ) , 3.69 (3H, s) , 3.94 (3H, s) , 5.14 (IH, d, J 5 Hz), 5.74 (IH, d, J 5 Hz), 6.96 (IH, s) , 7.8.) (2H, d, J 6 Hz), and 8.52 (2H, d, J 6 Hz); m/z (F.A.B., thioglycerol), MH ⁺ 623.

EXAMPLE 6

r6R,7R1-7-T2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxy¬ imino)acetamido]-3-[1-(cyclopropylmethylamino)pyri- 5 dinium-4-thiomethyl]ceph-3-em-4-carboxylate

4-Methoxybenzyl [6R,7R]-3-(chloromethyl)-7-[2-(Z)- (methoxyimino)-2-(2-tritylamino-4-thiazolyl)acetamido] ceph-3-em-4-carboxylate (0.10g, 0.12mmol) in dichloromethane

10 (5ml) was treated with 1-[N-(t-butyloxycarbonyl)-N-(cyclo * propylmethyl)amino]-4-thiopyridone(0.07g, 0.25mmol) and sodium iodide (0.0i.g, 0.13mmol), the mixture was stirred for 3h, then evaporated under reduced pressure. Purification on silica gel 60 eluting with ethanol, dichloromethane mixtures

15 gave 4-Methoxybenzyl [6R,7R]-3-[1-[N-(t-butyloxy carbonyl-N-(cyclopropylmethyl) amino]pyridinium-4-thiomethyl]-7-[2-(Z)- (methoxyimino)- 2-(2-tritylamino-4-thiazolyl)acetamido]ceph-3-em-4- carboxylate iodide, (0.098g, 68%); V _maχ (KBr) 1782, 1726,

20 1677, and 1613cm- ¹ ; δ _R (CDCI3) 0.21 (2H, q, J 5 Hz), 0.62 (2H, q, J 7.5 Hz), 0.83-1.15 (IH, m) , 1.52 (9H, s) , 3.57 (IH, d, J 19 Hz), 3.75-3.97 (6H, m) , 4.07 (3H, s) , 4.56 and 4.65 (2H, ABq, J 12 Hz), 5.09 (IH, d, J 5 Hz), 5.19 and 5.25 (2H, ABq, J 12 Hz), 5.95 (IH, 2d, J 9 and J 5 Hz), 6.71 (IH,

25 s), 6.89 (2H, d) , 6.90-7.50 (17H, m) , 8.21 (2H, d, J 7 Hz), and 8.55 (2H, d, J 7 Hz); m/z (F.A.B., 3-nitrobenzylalcohol) M ⁺ 1038.

This intermediate product (0.09g, 0.077mmol) was treated 30 with tr- ^~ luoroacetic acid (1.0ml, 13mmol) . The reaction mixture was stirred for 10 minutes then diluted with toluene (2ml) and evaporated under reduced pressure. Purification on Diaion HP20SS resii eluting with acetone, water mixtures gave the title compound (0.026g, 58%); v _maχ (KBr) 1765, 351670, and 1619cm- ¹ ;δ _R (D ₂ 0) 0.37 (2H, m) , 0.44 (2H, m) ,

0.77-0.98 (IH, m) , 3.10 (2H, d, J 7 Hz), 3.42 and 3.70 (2H, ABq, J 17.5 Hz), 3 3)4 (3H, s) , 4.11 and 4.40 (2H, ABq, J 14

Hz) , 5.13 (IH, d, J 5 Hz), 5.72 (IH, d, J 5 Hz), 6.97 (IH, s) , 7.78 (2H, d) , and 8.50 (2H, d, J 7 Hz); m/z (F.A.B., thioglycerol) MH ⁺ 576.

5 EXAMPLE 7

[6R,7R]-7-[2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino) acetamido]-3-[1-(isopropylidineamino)pyridinium-4- thiomethyl]ceph-3-em-4-carboxylate

10

This intermediate product (0.02g, 0.038mmol) in acetone, (0.5ml), and water (0.5ml) was stirred for 24h, evaporated under reduced pressure to remove acetone and then freeze dried to give the title compound (0.019g, δδ%) ; v _maχ (KBr)

151769, 1670, and 1612cm- ¹ ; δ _R (D ₂ 0) 1.93 (3H, s) , 2.31 (3H, s) , 3.45 and 3.73 (2H, ABq, J 17.5 Hz), 3.96 (3H, s) , 4.13 and 4.43 (2H, ABq, J 13.5 Hz), 5.16 (IH, d, J 5 Hz), 5.75 (IH, d, J 5 Hz), 7.00 (IH, s) , 7.66 (2H, d, J 7 Hz), and δ.26 (2H, d, J 7 Hz); m/z (F.A.B., thioglycerol) MH ⁺ 562.

20

EXAMPLE δ

r6R,7R]-7- \2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino) acetamido]-3-[1-(propylamino)pyridinium-4-thiomethyl] 25 ceph-3-em-4-carboxylate

4-Methoxybenzyl [6R,7R]-3-(chloromethyl)-7-[2-(Z)- (methoxyimino)-2-(2-tritylamino-4-thiazolyl)acetamido]ceph-3 -em-4-carboxylate (0.34g, 0.43mmol) in acetonitrile (15ml) 30 was treated with 1-(propylamino)-4-thiopyridone (0.074g, 0.044mmol) and sodium iodide (0.064g, 0.43mmol). The mixture was stirred for 35minutes, filtered and then evaporated under reduced pressure. Purification on silica gel 60 eluting with ethanol, dichloromethane mixtures gave

4-Methoxybenzyl [6R,7R]-7-[2- (Z)-(methoxyimino) -2- (2-tritylamino-4- thiazolyl)acetamido]-3-[1-(propylamino) pyridinium-4-thiomethyl]ceph-3-em-4-carboxylate iodide, (0.38g, 97%); δ _R (CDCI3) 1.02 (3H, t, J 7 Hz), 1.66-1.75 (2H, m) , 3.25 (2H, q, J 7 Hz), 3.52 and 3.82 (2H, ABq, J 18 Hz), 3.80 (3H, s) , 4.08 (3H, s) , 4.29 and 4.53 (2H, ABq, J 13 Hz), 5.09 (IH, d, J 5 Hz), 5.23 (2H, ABq, J 12 Hz), 5.94 (IH, 2d, J 5 Hz and 9 Hz), 6.71 (IH, s) , 6.80 (IH, d, J 9 Hz), 7.02 (IH, s) , 6.90 and 7.35 (4H, 2d, J 8 Hz), 7.25-7.40 (15H, m) , 7.72 (2H, d, J 7 Hz), 8.32-6.38 (IH, m) , and 8.80 (2H, d, J 7 Hz);, m/z (F.A.B., thioglycerol) MH ⁺ 926.

The previous intermediate product (0.38g, 0.41mmol) was dissolved in dichloromethane (20ml) , treated with trifluoroacetic acid and stirred at room temperature for 0.5h. Dilution with toluene (5ml), evaporation under reduced pressure and purification on Diaion HP20SS resin gave the title compound (0.078g, 34%); V _maχ (KBr) 1768, 1671, and 1617cm- ¹ ; δ _R (D ₂ 0) 0.9 (3H, t, J 7 Hz), 1.5 (2H, q, J 7 Hz), 3.2 (2H, t, J 7 Hz), 3.42 and 3.71 (2H, ABq, J 17.5 Hz), 3.96 (3H, s) , 4.1 and 4.4 (2H, ABq, J 14 Hz), 5.13 (IH, d, J 5 Hz), 5.72 (IH, d, J 5 Hz), 7.0 (IH, s) , 7.78 (2H, d, J 7 Hz), and 8.48 (2H, d, J 7 Hz); m/z (F.A.B., thioglycerol) MH ⁺ 564.

EXAMPLE 9

f 6R. 7R] -7- \2- (2-Amino-4-thiazolyl) -2- (Z) - (methoxy-imino) acetamido] -3- TI- (cvclopentylamino) pyridinium-4-thiomethyl1 ceph-3-em-4-carboxylate

4-Methoxybenzyl [ 6R, 7R] -3- (chloromethyl) -7- [2- (Z) - (methoxyimino) -2- (2-tritylamino-4-thiazolyl) acetamido] ceph- 3-em-4-carboxylate (O . lg, 0.126mmol) in acetonitrile (5ml) was treated with 1- [N- (t-butyloxycarbonyl) -N- (cyclopentyl)

amino]-4-thiopyridone (0.038g, 0.126mmol) and sodium iodide (O.Olβg, 0.126mmol) . The mixture was stirred for 0.5h., filtered and then evaporated under reduced pressure. Purification on silica gel 60 eluting with ethanol, 5 dichloromethane (1:9) gave 4-Methoxybenzyl

[6R,7R]-3-[1-[N-(t-butyloxycarbonyl)-N- (cyclopentyl) amino]pyridinium-4-thiomethyl]-7-[2-(Z)-(methoxyimino)-2-(2- tritylamino-4-thiazolyl)acetamido]ceph-3-em-4-carboxylate iodide, (0.126g, 95%); v _maχ (CH ₂ C1 ₂ ) 1760, 1720, and 101605cm- ¹ ; δ _R (CDCI3) 1.52 (9H, s) , 1.58-1.80 (2H, m) , 1.62 (4H, s) , 2.05-2.20 (2H, m) , 3.57 and 3.95 (2H, ABq, J 19 Hz), 3.81 (3H, s), 4.07 (3H, s) , 4.05-4.72 (IH, m) , 5.08 (IH, d, J 5 Hz), 5.13-5.30 (2H, m) , 5.96 (IH, 2d, J 5 and 9 Hz), 6.72 (IH, s) , 6.90 and 7.36 (4H, 2d, J 9 Hz) , 7.01 (IH, 15 s) , 7.24-7.36 (17H, m) , and 8.31 (2H, d, J 8 Hz); m/z (F.A.B., thioglycerol) MH ⁺ 1052.

This latter intermediate product (0.12g, 0.114mmol) was treated with trifluoroacetic acid (1ml) and stirred for 2

20 minutes, toluene (5ml) was added and the mixture evaporated under reduced pressure. Purification on Diaion HP20SS resin gave the title compound (0.013g, 19%); V _maχ (KBr) 1761, 1726, 1675, and 1613cm- ¹ ; δ _R (D ₂ 0) 1.35-1.86 (8H, m) , 3.42 and 3.71 (2H, ABq, J 17.5 Hz), 3.94 (3H, s) , 4.11 and 4.40

25 (2H, ABq, J 14 Hz), 4.70-4.98 (IH, m) , 5.15 (IH, d, J 5 Hz), 5.73 (IH, d, J 5 Hz), 6.97 (IH, s) , 7.78 (2H, d, J 7 Hz), and 8.4δ (2H, d, J 7 Hz); m/z (F.A.B., thioglycerol) MH ⁺ 590.

30 EXAMPLE 10

18 r 6R, 7R] -7- [2- (2-Amino-4-thiazolyl) -2- (Z) - (methoxy iminoacetamido] -3- [1- (prop-2-en-l-yl) aminopyridinium- 4-thiomethyl] ceph-3-em-4-carboxylate 35

4-Methoxybenzyl [6R, 7R] -3- (chloromethyl) -7- [2- (Z) -

(methoxyimino)-2-(2-tritylamino-4-thiazolyl)acetamido] ceph-3-em-4-carboxylate (0.12g, 0.15mmol) in acetonitrile (5ml) was treated with 1-[N-(t-butyloxy carbonyl)-N- (prop-2-en-l-yl) amino]thiopyridone (0.045g, 50.17mmol) and sodium iodide (0.022g, 0.148mmol). The mixture was stirred for 0.5h. and then evaporated under reduced pressure. Purification on silica gel 60 eluting with ethanol, dichloromethane mixtures (1:19) gave 4-Methoxybenzyl [6R,7R]-3-[1-[N- 0 (t-butyloxycarbonyl)-N-(prop-2-en-l-yl) amino]-7-[2- (Z)- (methoxyimino)-2- (2-tritylamino-4- thiazolyl) acetamido]ceph-3-em-4-carboxylate, (0.13g, 84%); δ _R (CDC1 ₃ ) 1.53 and 1.62 (9H, 2s), 3.55 and 3.90 (2H, ABq, J 18 Hz), 3.81 (3H, s) , 4.07 (3H, s) , 4.40-4.68 (2H, m) , 5.00-

155.48 (4H, m) , 5.32-6.00 (2H, m) , 6.70-6.80 (2H, m) , 6.87

(2H, d, J 8 Hz), 7.20 (IH, s) , 7.25-7.43 (17H, m) , 8.14 (2H, d, J 7 Hz), and 8.49 (2H, d, J 7 Hz); m/z (F.A.B., thioglycerol) M ⁺ 1024.

20 The latter intermediate product (0.13g, 0.127mmol) was treated with trifluoroacetic acid (2ml) . The reaction mixture was stirred for 3 minutes, toluene (5ml) was added and then the mixture evaporated under reduced pressure. Purification on Diaion HP20SS resin gave the title compound

25 (0.046g, 65%); V _maχ (KBr) 1764, 1670, and 1617cm- ¹ ; δ _R (D ₂ 0) 3.44 and 3.72 (2H, ABq, J 17.5 Hz), 3.87 (2H, d) , 3.96 (3H, s), 4.12 and 4.41 (2H, ABq, J 14 Hz), 5.00-5.29 (3H, m) , 5.76 (IH, d, J 5 Hz), 5.80-6.00 (IH, m) , 6.99 (IH, s) , 7.78 (2H, d, J 7 Hz), and 8.46 (2H, d, J 7 Hz); m/z (F.A.B.,

30 thioglycerol) MH ⁺ 562.

EXAMPLE 11

f6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxy¬ imino)acetamido]-3-[l-butylaminopyridinium-4-thio- 5 methyl]ceph-3-em-4-carboxylate

4-Methoxybenzyl [6R,7R]-3-(chloromethyl)-7-[2-(Z)-

(methoxyimino)-2-(2-tritylamino-4-thiazolyl)acetamido]cep h- 3-em-4-carboxylate (O.lg, 0.126mmol) in acetonitrile (10ml) 10 was treated with

1-[N-butyl-N-(t-butyloxycarbonyl)amino]-4-thioρyridone

(0.04g, 0.14mmol) and sodium iodide (0.018g, 0.12mmol). The mixture was stirred for 0.5h and then evaporated under reduced pressure. Purification on silica gel 60 eluting 15 with ethanol, dichloromethane (1:9) gave 4-Methoxybenzyl

[6R,7R]-3-[1-([N-butyl-N-(t-butyloxycarbonyl) amino]pyridinium-4-thiomethyl]-7-[2-(Z)-(methoxyimino)-2-

(tritylamino-4-thiazolyl)acetamido]ceph-3-em-4-carboxylat e iodide, (O.llg, 84%); δ _R (CDCI3) 0.91-1.10 (3H, m) , 201.23-1.67 (4H, m) , 1.45 and 1.50 (9H, 2s), 3.55 and 3.92

(2H, ABq, J 19 Hz), 3.81 (3H, s) , 3.99 (2H, t J 7.5 Hz), 4.07 (3H, s) , 4.56 and 4.64 (2H, ABq, J 12.5 Hz), 5.09 (IH, d, J 5 Hz), 5.23 (2H, d, J 2.5 Hz), 5.96 (IH, q, J 5 Hz),

6.72 (IH, s) , 6.75 (IH, d, J 9 Hz), 6.89 (2H, d, J 9 Hz), 257.02 (IH, s) , 7.24-7.43 (17H, m) , 8.22 and 8.45 (4H, 2d, J 7 Hz), m/z (F.A.B., thioglycerol) M ⁺ 1040.

The latter intermediate product (0.105g, O.lmmol) was treated with trifluoroacetic acid (2ml) . The reaction

30 mixture was stirred for 3 minutes, toluene (5ml) was added and the mixture evaporated under reduced pressure. Purification on Diaion HP20SS resin gave the title compound (0.017g, 29%); V _maχ (KBr), 1761, 1670 and 1618cm- ¹ ; δ _R (D ₂ 0) 0.84 (3H, t, J 7 Hz), 1.21-1.53 (4H, m) , 3.24 (2H, t, J 7

35 Hz), 3.41 and 3.70 (2H, ABq, J 18 Hz), 3.93 (3H, s) , 4.09 and 4.39 (2H, ABq, J 14 Hz), 5.23 (IH, d, J 5 Hz), 5.72 (IH,

d, J 5 Hz), 6.95 (IH, s) , 7.76 (2H, d, J 7 Hz), and 8.47 (2H, d, J 7 Hz); m/z (F.A.B., thioglycerol) MH ⁺ 578.

EXAMPLE 12 5

T6R.7R]-7-[2- (2-Amino-4-thiazolyl)-2- (Z) (methoxyimino)- acetamido]-3-[1-(hexylamino)pyridinium-4-thiomethyl]- ceρh-3-em-4-carboxylate

104-Methoxybenzyl [6R,7R]-3-(chloromethyl)-7-[2-(Z)-

(methoxyimino)-2-.(2-tritylamino-4-thiazolyl)acetamido]ce ρh-3 -em-4-carboxylate (O.lg, 0.126mmol) in acetonitrile (10ml) was treated with 1-[N-(t-butyloxycarbonyl)-N- heχylamino]-4-thioρyridone (0.05g, 0.16mmol) and sodium

15 iodide (O.lg, 0.12mmol) . The mixture was stirred for 35 minutes and evaporated to a small volume. This was then added to diethyl ether (30ml) while stirring vigorously. The precipitate was filtered off and dried in vacuo to give 4-Methoxybenzyl

20 [6R,7R]-3-[1-[N-(t-butyloxycarbonyl)-N-hexylamino]pyridinium -4-thiomethyl]-7-[2- (Z)-(methoxyimino)-2-(2-tritylamino-4-th iazolyl)acetamido]ceph-3-em-4-carboxylate iodide, (0.09g, 90%) V _maχ (CH ₂ C1 ₂ ) 1780, 1720, and 1605; δ _R (CDCI3) 0.83-0.96 (3H, m) , 1.25-1.74 (17H, m) , 3.56 and 3.83 (2H,

25 ABq, J 19 Hz), 3.81 (3H, s) , 3.98 (2H, t, J 7 Hz), 4.0δ (3H, s) , 4.55 and 4.64 (2H, ABq, J 12 Hz), 5.10 (IH, d, J 5 Hz), 5.23 (2H, d, J 1.5 Hz), 5.96 (IH, 2d, J 5 and 9 Hz), 6.73 (IH, br.s), 6.90 (IH, br.s), 6.89 (2H, d, J 8 Hz), 7.23-7.40 (17H, m) , 8.18 (2H, d, J 7 Hz), and 8.41 (2H, d, J 7 Hz);

30 m/z (F.A.B., thioglycerol) MH ⁺ 1068.

The latter intermediate product (0.90g, 0.84mmol) was treated with trifluoroacetic acid (2ml) . The reaction mixture was stirred for 10 minutes, toluene (10ml) was then 35 added and the mixture evaporated under reduced pressure.

Purification on Diaion HP20SS resin gave the title compound (0.023g, 45%); V _maχ (KBr) 1764, 1674, and 1619cm- ¹ ; δ _R (D ₂ 0) 0.80 (3H, t, J 7 Hz), 1.16-1.57 (δH, m) , 3.25 (2H, t, J 7 Hz), 3.41 and 3.69 (2H, ABq, J 16Hz) , 3.93 (3H, s) , 4.12 and 54.40 (2H, ABq, J 14Hz) , 5.12 (IH, d, J 5 Hz), 5.71 (IH, d, J 5 Hz), 6.94 (IH, s) , 7.79 (2H, d, J 7 Hz), and δ.49 (2H, d, J 7 Hz); m/z (F.A.B., thioglycerol) MH ⁺ 606.

EXAMPLE 13 0

[6R,7R]-7- \2- (2-Amino-4-thiazolyl)-2-(Z)-(methoxy¬ imino)acetamido]-3-[1-(1-isopropyl)aminopyridinium-4- thiomethyl]ceph-3-em-4-carboxylate

54-Methoxybenzyl [6R,7R]-3-(chloromethyl)-7-[2-(Z)-

(methoxyimino)-2-(2-tritylamino-4-thiazolyl)acetamido]cep h- 3-em-4-carboxylate (0.14g, 0.176mmol) in acetonitrile (10ml) was treated with 1-[N- (t-butyloxycarbonyl)-N- (1-isopropyl)amino]-4-thiopyrido 0 ne (0.05g, 0.186mmol) and sodium iodide (0.026g, 0.17mmol). The mixture was stirred for 35minutes, filtered and evaporated to a smaller volume under reduced pressure. This was then added dropwise to a stirred solution of diethylether (40ml) and the precipitate was filtered off to 5 give 4-Methoxybenzyl [6R,7R]-3-[1-[N-(t-butyloxycar¬ bonyl)-N-isopropylamino]pyridinium-4-thiomethyl]-7-[2-(Z)- (methoxyimino)-2-(2-tritylamino-4-thiazolyl)acetamido] ceph-3-em-4-carboxylate iodide, δ _R (CDCI3) interalia 1.32 (6H, d, J 7 Hz), 1.51 (9H, S) , 3.59 and 3.87 (2H, ABq, J 19 0 Hz), 3.80 (3H, s), 3.75-3.86 (IH, m) , 4.06 (3H, s) ,

4.5δ-4.82 (3H, ) , 5.08 (IH, d, J 5 Hz), 5.21 (2H, d, J 3 Hz), 5.95 (IH, 2d, J 5 and 9 Hz), 6.69 (IH, s) , 6.68 (2H, d, J 8 Hz), 7.20-7.45 (19H, m) , and 8.30 (2H, d, J 7 Hz).

5 The latter intermediate product was treated with trifluoroacetic acid (2ml) . The reaction mixture was stirred for 10 minutes, toluene (2ml) was added and the

mixture was slowly filtered through Celite into a stirred solution of diethylether (40ml) . The precipitated product was filtered and dried in vacuo to give the title compound

(0.078g, 79%); V _maχ (KBr) 1782, 1675, and 1623cm- ¹ ; δ _R (D ₂ 0) 51.08 (6H, d, J 6 Hz), 3.45 and 3.74 (2H, ABq, J 18 Hz), 3.54

(IH, t, J 6 Hz), 4.01 (3H, s) , 4.30-4.50 (3H, m) , 5.16 (IH, d, J 5 Hz), 5.73 (IH, d, J 5 Hz), 7.09 (IH, s) , 7.79 (2H, d, J 7 Hz), and 8.47 (2H, d, J 7 Hz), m/z (F.A.B., thioglycerol) MH ⁺ 564. 0

EXAMPLE 14

r6R,7R1-7-[2- (2-Amino-4-thiazolyl)-2- (Z)- (methoxy¬ imino)acetamido]-2-[1-[ (2-hydroxyethyl)amino]- 5 pyridinium-4-thiomethyl]ceph-3-em-4-carboxylate

4-Methoxybenzyl [6R,7R]-3-(chloromethyl)-7-[2- (Z)- (methoxyimino)-2- (2-tritylamino-4-thiazolyl) cetamido]ceph- 3-em-4-carboxylate (0.14g, 0.176mmol) in acetonitrile (10ml) 0 was treated with

1-[N-(t-butyloxycarbonyl)-N-(2-hydroxyethyl)amino]- 4-thiopyridone (0.05g, 0.185mmol) and sodium iodide (0.026g, 0.17mmol) . The mixture was stirred for 35 minutes, filtered and evaporated to a smaller volume under reduced pressure. 5 The solution was added dropwise to diethyl ether (40ml) , and the precipitate filtered off to give 4-Methoxybenzyl [6R,7R]-3-[1-[N- (t-butyloxycarbonyl)- (2-hydroxyethyl)amino]pyridinium-4-thiomethyl]-7-[2-(Z)-(me thoxyimino)-2- (2-tritylamino-4-thiazolyl)acetamido]ceph-3-em 0 -4-carboxylate iodide, (0.156g, 86%); δ _R (CDCI3) 1.45-1.60 (9H, m) , 3.55-3.65 (1H-, m) , 3.75-3.95 (7H, m) , 4.08 (3H, s) , 4.41 and 4.51 (2H, ABq, J 12 Hz), 5.15 (IH, d, J 5 Hz), 5.20 and 5.28 (2H, ABq, J 12 Hz), 5.93 (IH, q, J 5 Hz), 6.74 (IH, s) , 6.89 and 7.36 (4H, 2d J 8 Hz), 7.25-7.35 (15H, m) , 7.80 5 and 8.52 (4H, 2d, J 7 Hz); m/z (F.A.B., thioglycerol) M ⁺ 1026.

The latter intermediate product (0.151g, 1.47mmol) was treated with trifluoroacetic acid (2ml) . The reaction mixture was stirred for 10 minutes, toluene (10ml) was added and the mixture evaporated under reduced pressure. Purification on Diaion HP20SS resin gave the title compound (0.022g, 27%); v _maχ (KBr) 1771, 1670, and 1619cm- ¹ ; δ _R (D ₂ 0) 3.35-3.50 (3H, m) , 3.60-3.78 (3H, m) , 3.95 (3H, s) , 4.12 and 4.41 (2H, ABq, J 14 Hz), 5.12 (IH, d, J 5 Hz), 5.72 (IH, d, J 5 Hz), 7.00 (IH, s) , 7.78 and 8.53 (4H, 2d, J 7 Hz); m/z (F.A.B.,. thioglycerol) MH ⁺ 566.

EXAMPLE 15

Sodium [6R,7R]-7-[2- (2-amino-4-thiazolyl)-2-(Z)- \ \R,SI- carboxy(3,4-dihvdroxyphenyl)methyloxyimino]- acetamido]-3-TI-(methylamino)pyridinium-4-thiomethyl]- ceph-3-em-4-carboxylate

2-[(Z)-[R,S] (3,4-Diacetoxyphenyl) (diphenylmethyloxy- carbonyl)methyloxyimino]-2- (2-tritylamino-4-thiazolyl)acetic acid (0.8g, 0.95mmol) was dissolved in dichloromethane (16ml) and treated with N,N-diisopropylethylamine (0.25ml, 1.43mmol). Methanesulphonyl chloride (0.11ml, 1.40mmol) was added dropwise to the stirred solution. After lh, the mixture was treated dropwise with a solution of 4-methoxybenzyl [6R,7R]-7-amino-3-(chloromethyl) ceph-3-em-4-carboxylate hydrochloride (0.δ5g, 2.lmmol) and N,N-diisopropylethylamine (0.72ml, 4.2mmol) in dichloromethane (20ml) . The mixture was stirred for 1.5h and evaporated to dryness. The residue was partitioned between ethyl acetate and water and the organic phase washed with dilute citric acid and brine, then dried and evaporated under reduced pressure. The residue was. purified on silica gel 60, eluting with hexane, ethyl acetate mixtures, to give 4-Methoxybenzyl [6R,7R] 3-(chloromethyl)-7-[2-(Z)-[R,S]-

(3,4-diacetoxyphenyl) (diphenylmethyloxycarbonyl) methyloxyimino]-2-(2-tritylamino-4-thiazolyl)acetamido] ceph-3-em-4-carboxylate, (0.65g, 72%); δ _R (CDC1 ₃ + D ₂ 0) 2.23, 2.26, 2.29 and 2.30 (each 3H, 4s), 3.15 and 3.33 (2H, 5 ABq, J 16 Hz), 3.33 and 3.47 (2H, ABq, J 18 Hz), 3.81 (6H, s), 4.00 and 4.55 (2H, ABq, J 12 Hz), 4.00 and 4.62 (2H, ABq, J 12 Hz), 4.90 (IH, d, J 5 Hz) , 4.97 (IH, d, J 5 Hz), 5.20 and 5.26 (each 2H, 2 ABq, J 12 Hz), 5.8-5.9 (2H, m) , 6.01 (IH, s), 6.10 (IH, s) , 6.76 (2H, s) , 6.8-7.4 (approx 10 66H, m), 8.16 (IH, brs) , and 8.24 (IH, brs) ; m/z (F.A.B., 3-nitrobenzyl alcohol, sodium acetate) MNa ⁺ 1218.

The latter intermediate product (0.2g, 0.17mmol) was dissolved in acetonitrile (10ml) and treated with sodium

15 iodide (0.025g, 0.17mmol) . After 5 minutes

1- (methylamino)-4-thiopyridone (0.025g, O.lδmmol) was added and the mixture stirred for 3 h. The mixture was added dropwise to stirred diethyl ether (70ml) . The solid was collected by filtration, washed with dry ether and water and

20 dried at reduced pressure over KOH overnight to give 4-Methoxybenzyl [6R,7R]-7-[2-(Z) [ [R,S]-(3,4-dia- cetoxyphenyl) (diphenylmethyloxycarbonyl)methyloxy¬ imino]-2- (2-tritylamino-4-thiazolyl)acetamido]-3-[1- (methylamino)pyridinium-4-thiomethyl]ceph-3-em-4-

25 carboxylate iodide, (0.15g, 65%); V _maχ (KBr) 1775, 1724, 1684, 1617, and 1513cm- ¹ ; δ _R (CDCI3 + D ₂ 0) 2.21, 2.26, 2.29 and 2.31 (each 3H, 4s), 3.00 and 3.02 (each 3H, 2s), 3.16 and 3.25 (2H, ABq, J 16Hz) , 3.25 (2H, s) , 3.81 (6H, s) , 4.22 and 4.38 (2H, ABq, J 13 Hz), 4.25 and 4.38 (2H, ABq, J 13

30 Hz), 4.93 (IH, d, J 5 Hz), 5.00 (IH, d, J 5 Hz), 5.16 and 5.27 (2H, ABq, J 12 Hz), 5.18 and 5.2δ (2H, ABq, J 12 Hz), 5.76 (IH, d, J 5 Hz), 5.δl (IH, d, J 5 Hz), 6.01 (IH, s) , 6.10 (IH, s) , 6.76 (2H, s) , 6.8-7.4 (66H, m) , 7.52 (2H, d, J 8 Hz), 7.57 (2H, d, J 8 Hz), and 8.72 (4H, d, J 8 Hz); m/z

35 (F.A.B., thioglycerol) MH ⁺ 1300.

The latter intermediate product (0.15g, 0.105mmol) was dissolved in dichloromethane (10ml) and treated with trifluoroacetic acid (0.5ml, 6.5mmol) . The mixture was stirred for lh. and evaporated to dryness under reduced 5 pressure. The residue was triturated with diethyl ether (3 x 20ml) and then dissolved in water with dilute aqueous sodium hydrogen carbonate to pH 7. The product was purified on Diaion HP20SS resin, eluting with water and mixtures of water and tetrahydrofuran. Fractions containing the product

10 were combined and freeze dried to give Sodium [6R,7R]-7-[2- (2-amino-4-thiazolyl)-2-(Z)- [[R,S]-carboxy(3,4-diacetoxyphenyl)methyloxyimino]- acetamido]-3-[1-(methylamino)pyridinium-4-thiomethyl]- ceph-3-em-4-carboxylate, (0.03g, 36%); V _maχ (KBr) 1764,

151670, 1617, 1529, and 1501cm- ¹ ; δ _R (D ₂ 0) 2.29 (6H, s) , 2.31 (6H, s), 2.99 (6H, s) , 3.24 and 3.51 (2H, ABq, J 19 Hz), 3.24 and 3.53 (2H, ABq, J 19 Hz), 4.14 and 4.35 (2H, ABq, J 14 Hz), 4.14 and 4.37 (2H, ABq, J 14 Hz), 5.02 (IH, d, J 5 Hz), 5.03 (IH, d, J 5 Hz), 5.54 (2H, s) , 5.64 (IH, d, J 5

20 Hz), 5.68 (IH, d, J 5 Hz), 6.98 (2H, s) , 7.2-7.5 (6H, m) , 7.79 (4H, d, J 7 Hz), and 8.48 (4H, broad); m/z (F.A.B., thioglycerol) M (H-Na) ⁺ 772.

The latter intermediate product (0.023g, 0.03mmol) was 25 dissolved in water (5ml) and methanol (5ml) and treated with dilute sodium hydroxide to pH 9.4. After 5 minutes the mixture was neutralised with 0.1M hydrochloric acid and the solvent removed under reduced pressure. The product was purified on Diaion HP20SS resin, eluting with mixtures of 30 water and tetrahydrofuran. Fractions containing product were combined and freeze dried to give the title compound (0.016g, 75%); V _maχ (KBr) 1762, 1660, 1617, and 1527cm- ¹ ; δ _R (D ₂ 0) 3.00 (6H, s) , 3.12 and 3.46 (2H, ABq, J 18 Hz), 3.15 and 3.46 (2H, ABq, J 18 Hz), 4.13 and 4.30 (2H, ABq, J 14 35 Hz), 4.13 and 4.36 (2H, ABq, J 14 Hz), 4.97 (IH, d, J 5 Hz), 4.99 (IH, d, J 5 Hz), 5.37 (2H, s) , 5.58 (IH, d, J 5 Hz), 5.61 (IH, d, J 5 Hz), 6.75-6.92 (4H, m) , 6.96 (4H, s) , 7.79

(4H, d, J 7 Hz), and 8.47 (4H, d, J 7Hz) ; m/z (F.A.B., thioglycerol) M(H-Na) ⁺ 688.

EXAMPLE 16

Sodium [6R,7R]-7-[2-(2-amino-4-thiazolyl)-2-(Z)-. (S)-carboxy

(3,4-dihydroxyphenyl)methyloxyimino]- acetamido]-3-[1-(methylamino)pyridinium-4-thiomethyl]- ceph-3-em-4-carboxylate

The title compound is prepared from

2-[ (Z)-(S)- (3,4-diacetoxyphenyl) (diphenylmethyloxycarbonyl) methyloxyimino]-2- (2-tritylamino-4-thiazolyl)acetic acid using the method described in Example 15.

EXAMPLE 17

Sodium T6R,7R]-7-r2- (2-amino-4-thiazolyl)-2-(Z)- [ (R)-carboxy (3,4-dihydroxyphenyl)methyloxyimino]acetamido]-3-[1-(methyl amino) yridinium-4-thiomethylceph-3-em-4-carboxylate

The title compound is prepared from

2- (Z)-[ (R)- (3,4-diacetoxyphenyl) (diphenylmethyl-oxycarbonyl) methyloxyimino]-2- (2-tritylamino-4-thiazolyl)acetic acid using the method described in Example 15.

EXAMPLE 18

Sodium f6R,7R]-3- \l-aminopyridinium-4-thiomethyl]-7- [2-(2-amino-4-thiazolyl)-2-(Z)-[ (R,S)-carboxy

(3,4-di-hydroxyphenyl)methyloxyimino]acetamido]ceph-3- em-4-carboxylate

The title compound is prepared as described in Example 15 except that l-amino-4-thiopyridone replaces 1

ethylamino)-4-thiopyridone.

EXAMPLE 19

Sodium T6R,7R]-3-ri-aminopyridinium-4-thiomethyl]-7- ^~ 2-(2-amino-4-thiazolyl)-2-(Z)-f (S)-carboxy (3,4-di-hvdroxyphenyl)methyloxyimino]acetamido]ceph-3- em-4-carboxylate

The title compound is prepared from

2-[ (Z)-[ (S)-(3,4-diacetoxyphenyl)

(diphenylmethyloxycarbonyl)methyloxyimino]-2-(2-tritylami no-

4-thiazolyl)acetic acid and l-amino-4-thiopyridone using the method described in Example 15.

EXAMPLE 20

Sodium [6R,7R]-3-[l-aminopyridinium-4-thiomethyl]- -7- \2-(2-amino-4-thiazolyl)-2-(Z)-f (R)-carboxy (3,4-di- hydroxyphenyl)methyloxyimino]acetamido]ceph-3-em-4- carboxylate

The title compound is prepared from 2-(Z)-[ (R)-(3,4- diacetoxyphenyl) (diphenylmethyl-oxycarbonyl)methyloxy imino]-2-(2-tritylamino-4-thiazolyl)acetic acid and l-amino-4-thiopyridone using the method described in Example 15.