IE49867B1 - O-substituted oxime derivatives of 7-((2-(2-aminothiazol-4-yl)-2-hydroxyimino-acetyl)-amino)-ceph-3-em-4-carboxylic acid - Google Patents

Description

This invention relates to new Ο-substituted oxime derivatives of 7-(amino-thiazolyl)-acetamido-ceph-3-em-A-carboxylic acid, processes for preparing them, and the pharmaceutical compositions containing them.

In one aspect the invention provides the new syn isomer 7-(amino-thiazolyl)-acetamido-ceph-3-em-A-carboxylic acid derivatives of the general fonnula: (wherein: a) B represents a radical R which is:i) a radical -C-R* in which X represents a sulphur or II X oxygen atom and R' represents: an alkyl or alkoxy radical having from 1 to 4 carbon atoms, - 2 or a phenyl radical R, or a radical -(CI^q-n^ in which n represents 0 or an integer from 1 to a and Rj and R^, which nay be the same or different, each represents a hydrogen atom or an alkyl radical having from 1 to a carbon atoms, or R£ and R^ together with the intervening nitrogen atom form a piperidino, morpholino or phthalimido group; ii) a radical -^11-002*' Ra in which A* represents a hydrogen atom, an alkali metal atom, an equivalent of an alkaline-earth metal atom or of a magnesium atom, an amnonium group, a; substituted ammonium group derived from an organic amino base or an easily-cleavable ester group, R,L represents a phenyl, hydroxyethyl or nitrile radical; iii) the Y-lactone of the formula —( > ; or iv) a radical -('^*l2^n'“R5 in wtlich 2·' represents an integer of from 1 to A and represents; an alkoxy radical containing from 1 to A carbon atoms or a radical Alk - S(O)ng- which Alk represents an alk radical containing from 1 to A carbon atoms and ns represents 0, 1 or 2, .Rn or a radical N in which Rg and R?, which i - 5 may be the same or different, each represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or Rg and Rr, together with the intervening nitrogen atom form a phthalimido or 1-pyridinio group, or, when n* is an integer other than 1, a cyano radical, or a radical - C - KH~ in wnich X' represents — „ 2 X’ a sulphur atom or, when n' is an integer other than 1, an oxygen atom, or a ’ι-nethyl- or 4-amino-l,3-thiazol-2-yl radical, or a 1,2,3,ώ-ίθϋΓ3ζο1-5-γ1 radical, or an azido radical, or an acyl radical having from 2 to 4 carbon atoms; b) B represents a radical R& which is a radical in which R^a represents a halogen atom, or a radical -S-Rar in wnich Rar represents a phenyl radical or a 5- or 6-membered aromatic heterocyclic radical containing from 1 to a heteroatoms selected from sulphur, nitrogen and oxygen, the phenyl and heterocyclic radicals being optionally substituted hy one or more radicals selected from amino, nitro and .and cyano radicals' alkyl radicals having from 1 to 4 carbon atoms; or c) B represents a radical R^ which is a radical R5)j which represents an imidazolyl, morpholinyl or N-alkyl piperazinyl radical, the N-alkyl radical containing from 1 to 4 carbon atoms; R^ represents a chloro or methoxy radical; or an alkyl, cycloalkyl or alkylthio radical having in each case from 1 to 5 carbon atoms; or a radical -CHg-S-Rj^ in which R^ represents an optionally-substituted heterocyclic radical containing nitrogen, an acyl radical having from 2 to a carbon atoms, the 2-oxo-C3H3-thiazo]in-4-yl-carbonyl radical or the 3~niethyl-l,2-oxazol-5-yl-carbonyl radical; or the acetoxymethyl or carbamoyloxymethyl radical; q H or a radical -KH-C-Alk; and A represents a hydrogen atom, or an alkali metal atom, an equivalent of an alkaline-earth metal atom or of a magnesium atom, an ammonium group, a substituted ammonium group derived from an organic amino base or an easily-cleavable ester group) and acid addition salts of the derivatives of general formula 1' formed with the mineral or organic acids.

The compounds of the invention are syn isomers by virtue of the position of the nitrogen-oxygen bond in tne oxime group relative to the adjacent carbonnitrogen double bond. All compounds having a similar oxime group which are depicted herein by formulae in which the nitrogen-oxygen bond is shown in the same relative: position are also syn isomers.

In the following description aud claims all references to general formulae by number are references to those formulae as first defined herein, and all substituents and symbols are as first defined herein, unless otherwise stated.

The invention therefore, extends to derivatives of the general formula: and the derivatives of general formula: x 4986 It is to be understood that the derivatives of general formula I' can exist either in the form indicated by the said fornulal’ or in the form depicted in the general formula: MK and all references to conpounds of the invention are to be construed accordingly.

When B represents the radical R this may be inter alia an acyl group containing from 1 to 5 carbon atoms such as an acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or tert-valeryl group, as well as a corresponding sulphur derivative such as the thioacetyl group. Radical R may also be a methoxycarbonyl, <ι σ σ vr « - 7 ethoxyearbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butoxycarbonyl, isobutyloxycarbonyl or tert-butoxycarbonyl group, or a corresponding sulphur derivative such as the methoxythiocarbonyl group.

Other possibilities for radical R include the carbamoyl, N-methyl-carbamoyl, N,N-dimethyl-carbamoyl, acinoacetyl, dimethylaminoacetyl, methylaminopropionyl, dimethylaminopropionyl, aminovaleryl, dimethylaninovileryl, N-piperidinocarbonyl, N-piperidino-acetyl, N-piperidino-propionyl, N-pnthalinido-carbonyl, N-phthalimido-acetyl, N-phthalimido-propionyl and benzoyl groups, and the acetylmethyl, acetylethyl, propionylmethyl, propionylethyl, methoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, methylthiomethyl, methylthio ethyl, ethylthiomethyl and ethylthioethyl groups and oxidised forms of the sulphur-containing radicals such as the methylsulphinylmethyl and methylsulphonylmethyl groups.

Radical R may also represent the aminomethyl, methylaminomethyl, dimet’;ylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, phthalimidomethyl, phthalinidoethyl, phthalimidopropyl, N-pyridinylmethyl, N-pyridinylethyl, N-pyridinylpropyl, thiocarbamoylmethyl carbamoylethyl, carbamoylpropyl, thiocarbamoylethyl, 4-amino-thiazol-2-yl-methyl, 4-methyl-thiazol-2-yl-rcethyl, 1,2,3»a-tetrazol-5-yl-methyl and 1,2,5,4--tetrazol-5-yl-ethyl groups. ίσου β - 8 When Β represents the radical (CHg^n'-^5a’ substituent R^a may be a halo group such as fluoro, chloro, bromo or iodo; a phenyl group; a 1,2,3-, 1.2.5- , 1,2,A- or 1,3,A-thiadiazolyl group; a 1H5 -tetrazolyl group; a 1,3-thiazolyl group; a 1,2,3-, 1,2,A- or 1,3,A-triazolyl group; a 1,2,3-, 1,2,a-, 1.2.5- or 1,3,A-oxadiazolyl group; a 2-, 3- or A— -pyridinyl group; a 2- or 3-furyl group; a 2- or 3-thienyl group; or a 2- or 3-pyrolyl group. The phenyl and heterocyclic radicals may be unsubstituted or substituted by one or more radicals selected from the amino, nitro, methyl, ethyl, propyl, isopropyl. butyl, sec-butyl, tert-butyl and nitrile radicals.

When 3 represents the radical (C^^n'-^b’ substituent R^ may be, for example, a N-alkyl-piperazin-1-vl radical, and especially the Α-methyl-, A-ethyl-, Α-propyl-, A-isopropyl-, ώ-butyl-, A-sec-butyl- and A-tert-butyl-piperazin-l-yl radicals.

R^ may be inter alia an alkyl group such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, sec-pentyl or tert-pentyl group or a cycloalkyl group such as a cyclopropyl, cyclobutyl or cyclopentyl radical. Rj may also be a methylthio, ethylthio, propylthio, isopropylthio, butylthio, iso25 butylthio or tert-butylthio group or an acetamido, propionylamido, butyrylamido, isobutyrylamido or valerylamido group. - 9 When R| represents the radical -CHg-S-R^, may be, for example a 1,2,3-, 1,2,5-, 1,2,4- or l,3,h-thiadiazolyl radical; a ΙΗ-tetrazolyl radical; a 1,3-thiazolyl radical; a 1,2,3-, 1,2,4- or 1,3,45 -triazolyl radical; or a 1,2,3-, 1,2,a-, 1,2,5- or 1,3,/L-oxadiazolyl radical, aud each of these heterocyclic radicals nay he unsubstituted or substituted by one or more radicals selected from alkyl groups such as the methyl, ethyl, propyl and isopropyl groups, alkoxy groups such as the methoxy, ethoxy, propyloxy and isopropyloxy groups, amino, hydroxycarbonylraethyl, dimetbylaminoethyl and di ethyl ainino ethyl radicals. Examples of substituted heterocyclic radicals include the 3-methyl-, 3-ethyl- and 3-propyl-l,2,4-thiadiazol15 -5-yl radicals, as well as the 3-methoxy-, 3-ethoxyand 3-propoxy-l,2,a-thiadiazol-5-yl radicals.

R^2 may also represent an acyl group such as the acetyl, propionyl and butyryl groups.

A preferred category of derivatives of general formula 1' are those in which R^g is ^e acetyl, 1-methyl-tetrazolyl, 2-methyl-l,3,4-thiadiazolyl; 3-methyl-l,2,4-thiadiazol-5-yl; 3-methoxy-l,2,4-thiadiazolyl; l,3,4-thiadiazol-5”yl; 2-amino-l, 3,/i-thiadiazol-5-yl; 3-hydroxycarbonylnethyl-l,2,4-thiadiazol25 -5-yl; 5-methoxy-l,2,4-thiadiazol-3-yl; 4-methyl-5-hydroxycarbonylmethyl-l,3-thiazol-2-yl or 1-dimethylaminoethyl-1,2,3,4-tetrazol-5-yl radical. 9 9 V I - 10 A may represent a hydrogen atom, in wnich case the compound of fornula 1' is an acid, it may represent a metal atom (or equivalent thereof) or a substituted or unsubstituted ammonium group, in wnich case the compound is a salt, or it may represent an ester group when the compound is obviously an ester. When A represents an equivalent of an alkaline-earth metal atom or of a magnesium atom it represents that proportion of the multivalent atom that corresponds to a single valence.

A may he, for exanple a sodium, potassium or lithium atom, an equivalent of calcium or magnesium , or an ammonium group. Examples of substituted ammonium groups include those derived from trimethylamine, diethylamine, triethylamine, methylamine, propylamine, Ν,Ν-dimethylethanolamine, tris(hydroxymethyl)- aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, N,N’-dibenzylethylenediamine, morpholine, benzylamine, procaine, lysine, arginine, histidine and N-methylglucanine.

By the term easily-cleavable ester group is meant an ester-forming group that may be removed to form the corresponding acid without modifying the remainder of the molecule other than by removing other similar removable groups. Examples of such groups include methoxymethyl, ethoxymethyl, isopropoxymethyl, a-methoxyethyl, a-ethoxyethyl, methylthiomethyl, ethylthiomethyl, isopropylthidmethyl.. pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, isobutyryloxymethyl, isovalerlyloxymethyl, propionyloxyethyl, isovaleryloxyethyl, 1-acetoxyethyl, 1-acetoxypropyl, 1-acetoxybutyl, 1-acetoxyhexyl and 1-acetoxyheptyl radicals.

The derivatives of general formula 1' may also be in the form of salts of organic or mineral acids since they contain at least one salifiable amino radical. Acids with which it is possible to salify the amino group(s) of the derivatives of general formula 1' are, inter alia, acetic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluene-sulphonic, hydrochloric, hydrobromic, hydroiodic, sulphuric and phosphoric acid.

These products of general formula I' in wnich B represents a radical R^, in other words the compounds of formula 1^, can also be in the form of internal salts, and the invention extends to such internal salts.

Preferred compounds of the invention are the compounds of general formula I wherein: i) R is the radical -GO-R* and R' represents an alkyl radical having from 1 to a carbon atoms, a phenyl radical or a radical -(in which n is 0 or 1; a phenyl radical or a hydroxyethyl radical, iii) R is the Ύ-lactone of formula _ or O iv) R is the radical -(CH2^n,_R5’ —' is 1 °r and R^ represents either a radical -NRgR?, a radical -C-NH-, a l,2,3,q.-tetrazol-5-yl radical or an acetyl II 2 s radical; and R^ represents an alkyl radical having from to 5 carbon atoms, an acetoxymethyl radical or a radical -CH2~S-R^2 in wnich R^ represents a 2-methyl-1,3,4--thiadiazolyl radical or a 1-methyl-tetrazolyl radical; and A represents a hydrogen atom, an alkali metal atom, an equivalent of an alkaline-earth metal atom or of a magnesium atom, ammonium or a substituted ammonium group.

Among these preferred compounds, a particularly preferred class of compounds are those wherein R represents an acetyl, benzoyl, phthalimidoacetyl, N,N-dinethylcarbamoyl, α-carboxyphenylmethyl, 2-oxo 3-tetrahydropyranyl, 1 ,a-dihydroxy-l-oxo-2-butyl, phthalimidomethyl, aminoethyl, tetrazol-5-yl-methyl. 2-arr.ino-2-thioxoethyl or 2-oxopropyl radical \ R^ represents a methyl, acetoxymethyl, 2-methyl-l,3,4-thiadiazol-5-yl-thiomethyl or 1-methyl-tetrazolyl-thiomethyl radical;and A represents a hydrogen or sodium atom.

Especially preferred compounds of general formula I are tnose wherein R represents an acetyl, benzoyl, phthalimidoacetyl, tetrazolyl-5-yl-methyl, aminoethyl - 13 or α-carboxy-phenylmethyl radical; represents an acetoxymethyl, 2-methyl-l,3,4-thiadiazol-5-yl-thiomethyl or l-methyl-tetrazol-5-yl-thiomethyl radical.

A preferred group of compounds of general formula 5 I are those wherein represents a hromine or iodine atom or a phenylthio, 2-pyridinylthio, 2-amino-1,3,4-thiadiazol-5-ylthio, 1-methyl-lH-tetrazol-5-ylthio, 2- amino-phenylthio, 5-nitro-2-pyridinylthio or 3-cyano-6-methyl-2-pyridinylthio group.

Specific preferred compounds are those described hereinafter in the Examples, and more especially: 3~ac etoxymethyl-7- C C 2-( 2-amino-thiazol-4-yl )-2-( 2-amino-ethoxyimino-acetyl3-amino3-ceph-3-em-a-carboxylic acid syn isomer, its salts with alkali metals, alkaline-earth metals, magnesium, ammonium and organic amino bases, and its esters formed with easily-cleavable ester groups; 3- acetoxymethyl-7-C C2-(2-bromoethoxyimino) -2-(2-aminothiazol-4-yl) -acetyl 3 -amino3 -ceph-3-em-4-carboxyl ic acid syn isomer, its salts with alkali metals, alkaline20 earth metals, magnesium, ammonium and organic amino bases and its esters formed with easily-cleavable ester groups; 3-acetoxymethyl-7_C C2-( 2-iodoethoxyimino)-2-(2-aminothiazol-a-yl)-acetyl 3-amino3-ceph-3-em-4-carboxylic acid syn isomer, its salts with alkali metals, alkalineearth metals, magnesium, ammonium and organic amino bases and its esters formed with easily-cleavable ester w %» w · -ingroups ; J-acetoxymethyl-7-CC2-(2-amino-thiazol-A-yl )-2-( carbamoy loxy imino ) -ac etyl}- amino ] -ceph-3-em-A-carboxylic acid syn isomer, its salts with alkali metals, alkaline-earth metals, magnesium, ammonium and organic amino bases and its esters formed with easily-cleavable ester groups.

This invention also provides a process for preparing the derivatives of general formula I’ wherein 1C A represents a hydrogen atom, in wnich process a compound of the general formula: (wherein represents a protecting group for the amino radical, and B' is the group B defined hereinbefore with the provisos that when B represents -CHR^CC^A1 , A' represents an easily-cleavable ester group when R^ represents a phenyl or cyano radical and A’ represents an alkali metal atom when R^ represents a hydroxyethyl radical and when B represents -(CH2)ni~NH2 the amino radical carries a protecting group and A^ represents an easily-cleavable ester group or a hydrogen atom the latter being replaced by an alkali metal atom when A' represents an alkali metal atom) is reacted with one or more of a hydrolysis agent, a hydrogenolysis agent and thiourea so as to remove the protecting group(s) and/or salifying group(s) and/or ester group(s) and form an acid of the general formula: NH COZH (who'ein B is the group B defined hereinbefore with the proviso that when B represents -CHR^COgA'jA' represents a hydrogen atom) which is optionally thereafter esterified and/or salified to form a compound of general fonnula 1' wnerein A, and where appropriate A', is other than hydrogen or an acid addition salt of general formula I’.

Thus, the invention provides processes in which compounds of the general formulae: (wherein A represents an easily-cleavable ester group or a hydrogen atom, and R'^ represents an alkyl radical having from 1 to a carbon atoms, an alkoxy radical having from 1 to a carbon atoms, a phenyl radical or a radical -(cH2)n-NR5 in wnich r,,2 3111(1 Rj’ which may be the same or different, each represent a hydrogen atom or an alkyl radical with the proviso that both R2 and R do not both represent hydrogen when n is zero, or R2 and Rj together with the intervening nitrogen atom represent a phthalimido, piperidino or morpholino group), (ΙΙΙ·4) (wherein R* represents a phenyl or a cyano radical and A' represents an easily-cleavahle ester group) (wherein A’^ represents an easily-cleavable ester group or an alkali metal atom and A1 represents an alkali metal atom), (wherein R'^ represents an alkoxy radical having from 1 to 4 carbon atoms, a radical Alk-S(O)ng-, or an acyl (Hip) An Ciii-jP (wherein Hal represents a halogen atom) 4U867 Ο (ΙΙΙΚ) (ΙΙΙ·Κ) (IIIL) - 21 (wherein Κ-^θ represents a group removable by acid hydrolysis or by hydrogenolysis or an alkyl radical having from 1 to n carbon atoms and R^q represents a hydrogen atom or an alkyl radical having from 1 to u carbon atoms, or R18 and R^g together with the intervening nitrogen atom form a phthalimido group) wherein R,„ is as defined above, ar are treated 'with one or more of hydrolysis agents, hydrogenolysis agent3 and thiourea to obtain respectively: the products of the general formula: the products of the general formula: the products of the general formula: the products of the general formula: of the general formula: (Ic) the products the general formula: (I'c) the products of (Ijj) the products of the general formula: I i«’ the products I I I '» of the general formula ^F these being compounds of general formula Ig in which R represents a hydrogen atom and Ra represents -(CH2^n,R5a’ R5a rePresentin8 a halogen atom, the products of the general formula: - 26 the products of the general formula: wherein substituents R^ may be the same or different, the products of the general formula I'b: these being compounds of general formula wherein A represents a hydrogen atom, and the products of the general formula: these being compounds of the general formula Ia wherein R^a represants -S-Rar and A represents a hydrogen atom.

As will be clear to those skilled in the art, in the general formulae IIIj and Ij given above and in general formula VIj given below, the positive charge on the nitrogen atom may be satisfied either by an external anion which is the residue of a mineral or organic acid, or internally.

The formed compounds of general formulae IA, I'A> Ιθ, Ic> I’c, 8- ID’ IF’ V TH’ IH’ TJ’ Ι'κ’ ί’ Z'b 3110 ZM thereafter be salifiec and/or esterified, if desired, using known techniques.

The protecting group R^ may be, for example, an alkyl radical having from 1 to 6 carbon atoms, and preferably is a tert5 butyl or tert-amyl radical. R^ may also represent an aliphatic acyl group, an aromatic or heterocyclic acyl group or a carbamoyl group. Examples of such acyl groups include alkanoyl groups such as the formyl, acetyl, propionyl, butynyl, isobutynyl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl radicals; alkoxycarbonyl, or cycloalkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, tert-pentoxycarbonyl and hexyloxycarbonyl radicals; the benzoyl, toluoyl, naphthoyl, phthaloyl, mesyl, phenylacetyl and phenyl15 propionyl radicals; and arylalkoxycarbonyl groups such as the benzyloxycarbonyl radical.

These acyl groups may be substituted - for example, by a chlorine, bromine, iodine or fluorine atom - and examples of substituted acyl groups are the chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroaeetyl and bromoacetyl radicals.

The substituent R^g may also represent a lower aralkyl group such as the benzyl, 4-methoxy-benzyl, phenylethyl, trityl, 3,4-dimethoxy-benzyl and benzhydryl radicals, a haloalkyl group such as the trichloroethyl radical, a chlorobenzoyl, para-nitrobenzoyl, para-tert-butyl-benzoyl, phenoxyacetyl, caprylyl, n-decanoyl or acryloyl radical, or a methyl- 29 <* 9 σ ν carbamoyl, phenylcarbamoyl or naphthylcarbamoyl group or a corresponding thiocarbamoyl group.

The possibilities for substituent R-^θ listed above do not constitute an exhaustive list, and it will be clear to those skilled in the art that other protecting groups, particularly those known from peptide chemistry, can also be used.

When the substituent A represents an easilycleavable ester group this may be one of the groups identified as such hereinbefore or any other ester group formed with an eaaly-removable radical. Preferred ester groups include alkyl radicals such as the butyl, isobutyl, tert-butyl, pentyl and hexyl radicals, acyloxy radicals such as the acetoxymethyl, propionyl15 oxymethyl, butyrylo^ymethyl, valeryloxymethyl, pivaloyloxymethyl, 2-acetoxyethyl, 2-propionyloxyethyl and 2-butyryloxyethyl radicals, or a 2-mesylethyl, 2-iodoethyl, 3,5,3-trichloroethyl, vinyl, allyl, ethynyl, propynyl, benzyl, n-methoxybenzyl, a-nitrobenzyl, phenylethyl, trityl, diphenylmethyl, 5 ,ZL-dimethoxy-henzyl, phenyl, a-chlorophenyl, tolyl or tert-butylphenyl radical.

Among the preferred protecting groups are the formyl, acetyl, ethoxycarbonyl, mesyl, trifluoroacetyl, chloroacetyl and trityl radicals.

The aim of the conversion of the compounds of - 30 formulae IIIA ΐη^° corresponding products of formulae to is to remove the protecting groups R^g in each case, as well as A when this is other than hydrogen and where appropriate radicals A’ (Illg), Αχ (HI'C) and Rlg (IIIL).

The removal of the protecting group R^g is conveniently carried out by hydrolysis, and this may be effected under acidic or basic conditions or hy using hydrazine.

Acid hydrolysis is preferably used to remove optionally-substituted alkoxycarbonyl and cycloalkoxycarbonyl groups such as the t^-pent oxy carbonyl or t_-butoxycarbonyl radicals, optionally-substituted aralkoxycarbonyl groups such as the benzyloxycarbonyl radical, or a trityl, tert-butyl or a-methoxy-benzyl group. In acid hydrolysis the acid is preferably hydrochloric, benzenesulphonic, para-toluenesulphonic, formic or trifiuoroacetic acid, although a variety of other mineral or organic acids nay be used. Formic and trifiuoroacetic acid are preferred.

Basic hydrolysis is preferably used to remove acyl groups such as the trifluoroacetyl radical. The base which is used is preferably a mineral base such as an alkali metal hydroxide, and especially sodium hydroxide or potassium hydroxide. It is, however, possible to use magnesium or barium hydroxide or an - 31 alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate. A variety of other bases may be used, including sodiun or potassium acetate.

The hydrolysis using hydrazine is preferably used to remove groups such as the phthaloyl radical.

The group R^g can also be removed using the zinc/ acetic acid system, particularly where the trichloroethyl radical is the protecting group. 3enzhydryl rand benzyloxycarbonyl groups are preferably removed by hydrogenolysis using hydrogen in the presence of a catalyst.

A chloroacetyl protecting group may be removed by the action of thiourea in a neutral or acidic medium, such as by the process described by NASAKI in JnCS, 90, a508, 1968.

As the man skilled in the art will appreciate it is possible to use various other means known in the literature to deprotect the amino radical.

Obviously the choice of protecting group R^g is effected by the nature of the substituent present on the oxyimino radical - substituent 3 and certain protecting groups should not be used with certain oxyimino substituents. Thus, wneu 3 represents an acetyl or other acyl radical, R^g ought not itself to represent an acyl radical since otherwise the removal of R16 would risk causing removal of B which clearly is not - 52 wanted. However, it is within the competence of one skilled in the art to select an appropriate protecting group that will be readily removable without causing unwanted cleavage of the molecule.

The removal of the radical A when this is other than hydrogen atom, as well as the removal of the radicals A', Ay and Ryg is effected under similar conditions to those described above for the removal of Ryg It is possible to use, inter alia, acid or basic hydrolysis.

Acid hydrolysis is preferably used to remove radicals such as substituted or unsubstituted alkyl or aralkyl radicals. Preferred acids include hydrochloric, formic, trifluoroacetic and p-toluenesulphonic acid.

Other radicals as substituents A, A’, Ay and Ryg may be removed using reagents and techniques well known to the skilled man.

Of course it is possible, particularly when Ryg I i and one or more of the other groups to be removed are of different types, that the compounds III must he : reacted with two or more of the specified agents to form the desired compound of general formula 11.

The conversion of compounds of general formula III to compounds of general formula I’ is preferably carried out under moderate conditions, - that is to say, at ambient temperature or with gentle heating.

[ The compounds of general formula Ι’θ may also be ί ! 1« j prepared by a process in which a compound of general formula Ιθ is reacted first with a base and then with an acid to yield the corresponding compound I'q. Tbe conditions under which this conversion is carried out are standard for the ring-opening of a α-lactone. The base, for example, may be dilute sodium or potassium hydroxide, sodium carbonate or calcium carbonate.

In the preparations described herein, it is possible that a fraction of the products obtained will be in the form of a ceph-2-em side-product rather than the desired ceph-3-em ( Δ5) product. In this case the Zig products may be converted into Δ^ products, and conversions of this type are known in the literature for products having a cephem nucleus. Briefly the conversion involves, the following steps: The product containing Δ2 compound is oxidised so as to obtain the corresponding sulphoxide, preferably using a peracid such as metachloroperbenzoic acid. The (±2 sulphoxide is converted to the sulphoxide in the presence of a hydroxylated solvent or water. Finally, the sulphoxide is reduced in the presence of an acid halide or phosphorus trichloride.

This type of conversion of the Δ2 products to Δ3 products has been described for example by KAISER and Colleagues in J.Org. 55. 2a 30 (1970), by SPRY and Colleagues in J.Org.AO, 2A11 (1975), in American Patent 5,705,897 and in German Patent 1,937,016.

An example of such a conversion is set out hereinafter in the Examples.

Where it is desired to salify the products of general formulae K - this can be carried out using conventional salification techniques.

The salification can, for example, be effected by reacting the acid of formula or a solvate thereof(for example the ethanolic solvate) or a hydrate thereof with a mineral base such as sodium or potassium hydroxide, sodium or potassium bicarbonate, or sodium or potassium carbonate. It is also possible to use the salts of mineral acids such as trisodium phosphate.

This results in the formation of the corresponding metal salt. It is also possible to employ metal salts of organic acids, and in particular the sodium salts of saturated or unsaturated, straight or branched chain aliphatic carboxylic acids having from 1 to 18, and preferably from 2 to 10, carbon atoms. The aliphatic radicals of these acids can be interrupted by one or more heteroatoms such as oxygen or sulphur, or be substituted by aryl radicals such as the phenyl, thienyl or furyl radical, by one or more hydroxy radicals, by one or more halogen atoms such as fluorine, chlorine or bromine (preferably chlorine), by one or more carboxylic or alkoxycarbonyl radicals, (preferably the methoxycarbonyl, ethoxycarbonyl or propyloxycarbonyl radical) or by one or more aryloxy radicals such as the phenoxy - 55 radical. Aromatic acids may also be employed provided they are sufficiently-soluble - for example, benzoic acid, preferably substituted by alkyl radicals, may be used.

Examples of such organic acids are: formic, acetic, acrylic, butyric, adipic, isobutyric, n-caproic, isocaproic. chloropropionic, crotonic, phenylacetic, 2-thienylacetic, 5~thienylacetic, A-ethylphenylacetic and glutaric acid, the monoethyl ester of adipic acid, hexanoic, heptanoic, decanoie, oleic, stearic, palmitic, 5~hydroxy-propionic, 5-raethoxypropionic -aethylthiobutyric, a-chlorobutyric, α-phenyl-butyric, -phenoxy-butyric, a-ethyl-benzoic and p-lso-propyl benzoic acid.

Preferably, however, sodium acetate, sodium 2-ethylhexanoate or sodium diethylacetate is used where it is desired to form a sodium salt.

Salification can also be effected by the action . of an organic amino base such as triethylamine, diethylamine, trimethylamine, propylamine, N,N-dimethyl-ethanolanine, tris(hydroxy methyl)-aminomethane, arginine, lysine, methylamine, ethanolamine, pyridine, picoline, dicyclohexylamine, procaine, histidine, N-aethyl-glucamine, morpholine or benzylamine.

Obviously, this results in the formation of the corresponding substituted ammonium salt.

This salification is preferably carried out in - 36 one or more solvents such as water, diethyl ether, methanol, ethanol or acetone.

The salts may be obtained in amorphous or crystalline form according to the reaction conditions employed. Crystalline salts are preferably prepared by reacting the free acid with one of the aliphatic carboxylic acid salts mentioned ahove, and preferably with sodium acetate.

Esterification of the products of formulae may also be carried out under standard conditions. In general work is carried out by reacting the acid with a derivative of formula: - R2q in which Z represents a hydroxy radical or a halogen atom such a fluorin'e, chlorine, bromine or iodine and R20 denotes the ester group to be introduced.

Various of the compounds of general formula III (and thus the compounds of general formulae III^ - Illjq) may be prepared by reacting a compound of the general fonnula: (II) - 57 with a compound capable of introducing the desired substituent B' on the oxime group.

The compounds of general formula IIIA may be prepared by a process in wnich a compound of general formula II is treated with a functional derivative of the acid HO-CX-R'j.

The functional derivative of the acid HO-CX-R'^ may be, for example, an acid halide such as the chloride or the bromide, a symmetric or mixed anhydride, a ketene or an acyl azide. The acylation may be carried out using a haloformate in the case where K'represents an alkoxy radical; for example a chloroformate may be used. An isocyanate may be used when R'^ represents a group -RR'^R^ in which one of R2 or Rj represents a hydrogen atom.

The acylation of the hydroxy function of the compound II is preferably carried out in an organic solvent and this may be a halogenated hydrocarbon such as methylene chloride, a cyclic ether such as dioxan or tetrahydrofuran, a nitrile such as acetonitrile, a nitro-substituted hydrocarbon such as nitromethane or an ester such as ethyl acetate. When an acyl halide is used, the reaction is preferably carried out in the presence of a base such as triethylamine, pyridine, propylene oxide, magnesium oxide, sodium carbonate or calcium carbonate.

The compounds of general formula III'A may be - 38 prepared by a process in which a compound of general fonnula II is reacted with a compound of general fonnula X=C=NH.

This reaction is preferably carried out under similar conditions to those described hereinbefore in relation to the preparation of the compounds III^.

The compounds of general formula Illg may be prepared by a process in which a compound of general fonnula II is reacted with a radical Y - CHR'^-CC^ A', in which Y represents a halogen atom, or a sulphate (i.e.SQ4H) cr sulptaate (i.e. crgaiic sulpbcnylcoy) ©ημρ.

The substituent Y may represent, for example, a chlorine, bromine or iodine atom or a sulphate (i.e. SO^H) or sulphonate (i.e. organic sulphonyloxy) group such as the mesylate (methanesulphonyloxy) or tosylate (p-toluenesulphonyloxy) radical.

The reaction may be carried out in the presence of a base which may be, for example, potassium tert-butylate or sodium hydride. It is also possible to operate in the presence of tertiary amines such as triethylamine or pyridine .

The reaction is preferably carried out in a solvent and preferred solvents include halogenated hydrocarbons such as methylene chloride, cyclic ethers such as tetrahydrofuran or dioxan, N,N-disubstituted amides such as dimethylformamide, or dimethyl sulphoxide.

Separation of the optical isomers created by the asymmetric carbon atom may be carried out, if desired, either before or after the etherification reaction.

The compounds of general formula IIIc may be - 39 prepared by a process in which a compound of general formula II is reacted with a compound of the general formula The preferred groups Y are as defined herein5 before in relation to the preparation of compounds IIIj, and the reaction is desirably carried out under the preferred reaction conditions for that preparation set out above.

The compounds of general formula ΙΙΙθ may be 1C treated with a base to convert them into compounds of the general formula ΙΙΙ’θ. The base is preferably an alkali-metal base sucn as sodium or potassium hydroxide (preferably as a dilute aqueous solution), sodium carbonate or sodium bicarbonate.

The compounds of general formula Illg may be prepared by a process in which a compound of general formula II is reacted with a compound of the general formula Y -(CHp)^,-R’,., and when R'^ represents an alkylthio radical the product may thereafter be oxidised to the corresponding sulphoxide or sulphone. Again Y is preferably one of the preferred groups defined in relation to the preparation of compounds Illg and IIIq, and desirably the reaction is carried out under the preferred conditions described above in relation to those preparations. - αθ· 10 The compounds of general formula IIIj. may be prepared by a process in wnicn a compound of general formula II is treated with a compound of the general formula Y -(CHj)^ “ ^et again the preferred groups Y and the preferred reaction conditions are as set out hereinbefore in relation to the preparation of compounds Illg.

The compounds of general formula Hip may be prepared by a process in which a compound of the general formula: (IV) is treated either with hydrogen sulphide or, when n' is an integer other than 1, by hydrolysis in the presence of a base to obtain the corresponding product of general formula Hip.

The conversion of the compounds of general formula IV into products Hip in wnich X' represents a sulphur atom and n' is an integer from 1 to 4 is carried out by the action of hydrogen sulphide, and this reaction is preferably carried out in the presence of a base, and most preferably a tertiary amine such as triethylamine. The reaction is also preferably carried - ul out in dimethylformamide aa solvent.

The conversion of the compounds of general formula IV into products Hip in which X' represents an oxygen atom and n' is an integer from 2 to 4, is carried out by careful hydrolysis in a basic medium. Preferably dilute sodium hydroxide is used to effect this hydrolysis.

The compounds of general formula Illg may be prepared by a process in which a compound of general formula Hip wherein X is a sulphur atom (which is preferably prepared as described hereinbefore) is treated with a compound of the general formula R'^-CO-CHj-IIal.

The substituent Hal preferably represents a chlorine or a bromine atom. The reaction of the compound Illp with the compound R'γ-C0-CHo-Hal may be carried out with or without catalysis. When no catalyst is employed the initial product is a thiazole halohydrate, which is converted into the free base by work-up using a base, and preferably an alkali-metal base, such as sodium bicarbonate.

The reaction can alternatively be catalysed with a base and preferably with an alkali metal base such as sodium bicarbonate.

The compounds of general formula III^ may be prepared by a process in which a compound of the general formula IV is treated with an azide. Preferably the azide employed is an alkali metal azide such as sodium or potassium azide. Sodium azide is particularly pre- λ.2 ferred. It is also possible to employ an azide of an organic amine such as tetramethyl guanidine azide or triethylamine azide. Ammonium azide prepared in situ hy the action of ammonium chloride on sodium azide may also be used.

The reaction is preferably carried out in dimethylformamide, but an alcohol such as ethanol can also be used.

The compounds of general formula IH’jj may be prepared by a process in wnich a compound of general formula II is treated with a compound of the general formula Hal-iCHg)^-Hal wherein the two Hal substituents may be the same or different. The Hal substituent in the product of general formula III'^ is preferably a bromine or iodine atom, but'it may also be a chlorine atom.

The compounds of general formula IIIj may he prepared by a process in which a compound of general formula III'^ (preferably prepared as described hereinbefore) is treated with pyridine. This reaction is preferably carried out in a solvent such as dimethylformamide.

The compounds of general formula Illg may he prepared by a process in which a compound of general formula III'H is treated with an azide.

The treatment with an azide is preferably carried out using the preferred reagents and conditions described hereinbefore in relation to the preparation of compounds IIIH.

The products of general formula Illg may be treated with a reducing agent to convert them into the corresponding products of general formula Ill'g.

The reducing agent wnich is used to convert the products IHg into the products IH’g is preferably hydrogen sulphide used in the presence of triethylamine, which is tantamount to using triethylammonium hydrosulphide formed in situ. This reaction is preferably carried out in a solvent such as dimethylformamide.

It is also possible to employ otner methods of gentle, specific reduction such as those wnich use alkaline hydrosulphides (and particularly sodium, potassium or ammoniun hydrosulphide) or stannous chloride.

The compounds of general formula III^ may be prepared by a process in which a compound of general formula III'^ is treated with an amine of the general formula NHR^gRyg.

When R^g is a removable group this is preferably a trityl radical, although it may be any of the protecting groups mentioned hereinbefore, subject of course to the consideration that the group must be removable without causing undesirable cleavage of the molecule.

The reaction with the amine NHRθί?is preferably carried in a solvent such as dimethylformamide. 98 67 - /Ul The compounds of general formula III'^ may be prepared by a process in which a compound of general formula III’jj is reacted with imidazole, morpholine or an N-alkyl piperazine.

The reaction with imidazole, morpholine or an N-alkyl piperazine is preferably carried out in the presence of an uptake agent which will neutralize and thus effectively remove formed hydrohalic acid. It is possible, for example, to use an organic base such as triethylamine. It is also possible to use a mineral base such as an alkali metal carbonate or bicarbonate, and the sodium salts are preferred.

It is also possible to employ the compound III'tj in the form of a salt ahd preferably as an amine salt such as the diethylamine salt.

The reaction can also be carried out in the presence of a quaternary ammonium salt such as methyl tricaprylammonium chloride.

The compounds of general formula III^ may be prepared by a process in which a compound of general formula Ill'y is reacted with a compound of the general formula R -SH. This reaction is preferably carried out ar in the presence of an uptake agent for formed hydrohalic acid, and preferred agents are as mentioned above.

Again the compound of general formula III’jj may be in the form of a salt such as the diethylamine salt.

The reaction can also be carried out in the presence of a quaternary ammonium salt such as methyl tricaprylammonium chloride.

It is also possible to use an alkali metal derivative of the compound of general formula Rar>-S-H such as the lithium derivative and to carry out the reaction in the presence of a catalyst such as an alkali metal halide, for example lithium iodide.

The compounds of general formula IV used as starting materials in some of the preparations described hereinbefore are, when n'is 2,3 or 4·, compounds of general formula Illg, and they may of course be prepared from compounds of general formula II by a process as described hereinbefore for the preparation of compounds IIIThe compounds of general formula IV where n' is 1 may be prepared from compounds of general formula II by an analogous process employing a compound of the general formula Y-Cf^-CN, and preferably chloroacetonitrile.

The starting materials of general formula II which ae employed in several of the preparations described hereinbefore may themselves be prepared by a process in which a compound of the general formula: - ΐι6 - (D) is treated with an aqueous mineral acid, and preferably with dilute hydrochloric acid.

The compounds of general formula D may in turn be preoared by a process in which a compound of the general formula: I cw, (C) or a functional derivative thereof, such as the symmetric anhydride, is reacted with a product of the general formula: to obtain the corresponding compound D.

(IX) - 4? The starting materials of general formula G may be prepared hy a process in which a compound of the general formula: (V) Ά>η is treated with 2-methoxypropene. The compounds of general formula V are known, being described, for example, in Belgian Patent No. 850,662.

This invention also provides, in another aspect, alternative processes for the preparation of the various compounds of general formula III, in which a compound of the general formula; (VI) (wherein B is the group B defined hereinbefore with the provisos that when B represents -CHR^COgA', R^ represents a phenyl or cyano radical and A' represents an easilycleavable ester group and when B represents -(0H2)n,-NH2 the amino radical carries a protecting group), or a functional derivative thereof, is reacted with a compound - 48 of general formula IX to obtain the corresponding compound of general formula III.

Thus, the invention provides processes in which compounds of the general formulae: -C -s' II ’ (VIA) (VI·,) /1 \O-C-NH.

II X I - zl9 - (VIC) (VID) (VIE) (VIP) I I Η (νιΗ) (VI ·Η) ΜΗ R/fo Α. Ν COaH Η (VIj) COXH Ν WL) (VI'L) -5 - β.,ατ (VIM) - 52 or their functional derivatives are reacted with a compound of general formula IX, to obtain, respectively, the compounds oi general formulae IIIA, III *A, Illg, IIIC, Illg, IIIE, IIIp, IIIG, IIIH, ΙΪΙ'Η. IIIj, IIIK> IIIL, III’L and IIIM.

In a preferred method of carrying out this process the compound of general formula IX is treated with a functional derivative of one of the products of formulae VIA to VIj.p set out above, and preferred functional derivatives include the halide, symmetric or mixed anhydride, amide and activated ester.

By way of example, the mixed anhydride may be that formed with isobutyl chloroformate. An example of an activated ester is the ester formed with 2,&15 -di.nitrophenol or 1-hydroxy-benzo-l-triazole. Preferred halides arc the chloride and the bromide.

It is also possible to employ the acid azide or acid amide.

The anhydride can be formed in situ by the action 20 of 1-di substituted-carbodiimides such as N,H-dicyclohexylcarbodiimide.

The acylation reaction is preferably carried out in an organic solvent such as methylene chloride. It is, however, possible to use other solvents such as tetrahydrofuran, chloroform or dimethylformamide.

When the compound of general formula VIA - VI^ is in the form of an acid halide or a mixed anhydride - S3 formed with isobutyl chloroformate, the reaction is preferably carried out in the presence of a base, and this may be an inorganic base such as sodium or potassium hydroxide, sodium or potassium carbonate or sodium or potassium bicarbonate, or an organic base such as sodium acetate, triethylamine, pyridine, morpholine or N-methyl-morpholine.

The reaction temperature is conveniently maintained at or below ambient temperature.

The invention is especially concerned with a process as described above in which substituent Rin the compound of general formula VIA - VI^ is a trityl, chloroacetyl, tert-pentoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl radical.

The products of general formula IIIq may of course be converted into compounds of general formula ΙΙΙ'θ by treatment with a base, as described above.

The various starting materials of general formula VI may be prepared directly or indirectly from compounds of general f ormula V.

The compounds of general formula VImay be prepared by a process in which a compound of general formula V is treated with a functional derivatives of the acid HO-CX-R’^, and this reaction is preferably carried out under the preferred conditions described above for the analogous reaction to prepare compounds IIIA. 5A The compounds of general formula VI *A may be prepared by a process in which a compound of general formula V is reacted with a compound of formula X=C=NH.

The conpounds of general formula VI g may be prepared by a process in which a compound of general formula V is reacted with a compound of the general formula Y-CHR'a-C02A'.

The compounds νΐθ may be prepared by reacting a compound of general formula V with a compound of the general formula _ o The compounds VI g may be prepared by reacting a compound of the general formula V with a compound of the general formula. Y-(CH2)ni-R'^· The compounds VIp may be prepared by reacting a compound of general formula V with a compound of the general formula Υ-(ΟΗ?)η?-ΟΝ.

The compounds VIp may be prepared by a process in which a compound of the general formula: (VII) is treated either with hydrogen sulphide or, wnen n' 'Xo-icHiv-' - 55 is an integer other than 1, by hydrolysis in the presence of a base, to obtain the corresponding product of formula VTy.

The compounds of general formula VI j, wherein X* represents a sulphur atom may be treated possibly with a compound of the general formula R'^-CO-C^-Hal to obtain a compound of general formula νΐθ.

The compounds of general formula VII may also be treated with an azide to obtain the corresponding compound of general formula VI^.

As in the preparation of the compounds of general formula VIA, the preferred conditions for the preparation of compounds VI^, , VIg, νΐθ, Vlg, VIg, VI^, VI,, and VI-, are as described above in relation to the analogous n compounds of general formulae III'^, Illg, IHq. TIIp, IIIE, Illy, IIIG and Illg.

The starting materials of general formula VII wherein n' is 2, 3 or 4 are compounds of general formula VIv and may he prepared by the process described hereinbefore. The compounds VII wherein n' is 1 may be prepared by an analogous process in which a compound of general formula V is reacted with a compound of the general formula Y-CHj-CN, and preferably chloroacetonitrile.

The compounds of general formula VI'g nay Be prepared as follows: a product of the general formula: ' - 56 - (wherein Rg represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms) - which are compound V and their alkyl esters - is treated with a compound of the general formula Hal-iCHj)^-Hal (wherein the substituents Hal nay be the same or different) to obtain a product of the general formula: which product of formula VIwhen Rg represents a hydrogen atom is a compound VIand when Rg represents an alkyl radical having from 1 to 4 carbon atoms, is treated first with a base and then with an acid to yeld a compound VI'y.

The compound of general formula: Hal-iCHg)*^-Hal, in wuich Hal preferably represents a bromine or iodine atom, is preferably reacted with the compound V* in the presence of a base to neutralize the hydrohalic acid formed. Suitable bases include mineral bases such as sodium or potassium carbonate or bicarbonate, and organic amine bases such as are known to the skilled man.

The saponification of the esters of general? formula VIR wherein Rg represents an alkyl radical having from 1 to 4 carbon atoms is carried out under typical known conditions for such reactions. It is possible, for example, firstly to react the ester with a base such as sodium hydroxide, potassium hydroxide or barium hydroxide, and then with an acid such as dilute hyrochloric acid, acetic acid or formic acid.

The compounds of general formula VIj- may be prepared by a process in wnich a compound of general formula VI'R is reacted with pyridine.

The compounds of general formula VI may be 15 prepared by a process in wnich a compound of general formula VI'R is reacted with an azide.

The compounds of general formula VI may be prepared by a process in wnich a compound of general formula VI'^ is reaoted with an amine of general formula NHR^gR^g.

The compounds of general formula VI'may be prepared by a process in which a compound VI'R is reacted with imidazole, morpholine or an N-alkyl piperazine.

The compounds of general formula VI^ may he prepared by a process in wnich a compound VI H is reacted with a compound of general formula Raj,-oH. - 58 The preparation of the compounds of general formulae VI j, VI^, VI^, VIand VI^ are preferably carried out under the preferred conditions described hereinbefore in relation to the preparation of the compounds IIIj, Illg, III^, III'^ H^M’ The derivatives of general formula 1' and their salts have snown very good antibiotic activity against Gram positive bacteria such as staphylococci and streptococci, and especially against the penicillin10 resistant staphylococci. In addition, their efficacy against the Gram negative bacteria, especially against the coliform bacteria, Klebsiella, Salmonella and Proteus, is particularly remarkable.

These antibiotic properties make the compounds of the invention suitable for use as medicaments in the treatment of diseases caused by sensitive microorganisms and especially in the treatment of staphylococcal infections such as staphylococcal septicaemia, malignant facial or skin staphylococcal infections, pyodermatitis, septic or suppurating sores, anthrax, phlegmons, erysipelas, acute primary or post-influenza staphylococcal infections, bronchopneumonia and pulmonary suppurations.

These products can also be used as medicaments in the treatment of colon bacillus infections and associated infections, in infections caused by Froteus, Klebsiella and Salmonella and in otner diseases caused by Gram negative bacteria. y B t» 7 - 59 The invention therefore also extends to the derivatives of general formula I', as well as their addition salts with the pharmaceutically-acceptable mineral or organic acids, for use as antibiotics in a method of treatment of the human or animal body by therapy.

Before using them in medicine however, it is preferred to form the compounds of the invention into pharmaceutical compositions, by association with pharmaceutically-acceptable vehicles.

Accordingly, in a further aspect, this invention provides pharmaceutical compositions containing as active ingredient one or more derivatives of general formula 1' and/or one or more addition salts thereof formed with pharmaceutically-acceptable mineral or organic acids, in association with a pharmaceutically-acceptable vehicle.

The compositions of the invention preferably contain those compounds mentioned hereinbefore as being preferred.

The description pharmaceutically-acceptable is used herein to exclude any possibility that the vehicle or the acid, considered of course in relation to the - 60 route by wnich the composition is to be administered, could be harmful to the patient to be treated. The choice of suitable vehicles or acids is believed to be within the competence of those accustomed to the preparation of pharmaceutical formulations.

The compositions of the invention may conveniently be administered hy a buccal, rectal, parenteral or intramuscular route, or locally by topical application to the skin or mucous membranes. In respect of these 1C routes the pharmaceutical vehicle is preferably: a) the ingestible excipient of a tablet or pill, such as a sugar-coated compressed tablet; the ingestible container of a capsule, and particularly a gelatin capsule; the ingestible pulverulent solid carrier of a powder or granules;‘or the ingestible liquid medium of a syrup, solution or suspension; b) the solid or liquid medium of a paste, cream, ointment or gel, or the liquified propellant gas of an aerosol; . c) a sterile injectable liquid solution or suspension medium; or d) a base material of a suppository.

Whilst the pharmaceutical vehicles just listed represent those most likely to be employed, they do not necessarily exhaust the possibilities and other pharmaceutical forms may dictate the use of different vehicles.

I By way of illustration it is pointed out that the vehicles employed will generally be composed of those excipients commonly employed in the formulation of pharmaceutical compositions. Such excipients may be solid or liquid as appropriate to the pharmaceutical form chosen, and may include a wide range of organic and inorganic solids, and aqueous and non-aqueous liquids; examples include talc, gun arabic, starch, lactose, magnesium stearate or fatty substances of animal or vegetable origin such as cocoa butter, paraffin derivatives or glycols. These excipients may be compounded with one or more wetting, dispersing or emulsifying agents and/or one or more preservatives.

These compositions of the invention may also be presented in the form of a powder intended for extemporaneous formulation into a solution by dissolution in an appropriate vehicle such as apyrogenetic sterile water.

The dose of the active ingredient to be administered may be varied according to the disease treated, the person concerned, the route of administration and the product under consideration. By way of illustration, a desirable dose in man is from 0.250 g to 4 g per day, for the compounds described in Examples 15, and a 5 administered orally, or from 0.500 g to 1 g when administered three times daily by intramuscular route. 4» 9 Ο l> < The derivatives of general formula 1' and their acid addition salts may also be used as disinfectants, especially for use on surgical instruments. Accordingly this invention al3O provides a method of disinfecting a locus, in which there is applied to the locus an effective disinfecting amount of a derivative of general formula I' or an acid addition salt thereof.

Certain of the intermediates described hereinbefore are themselves both new and part of this invention. Accordingly, this invention extends to these useful intermediates per se and in one such aspect this invention provides the compounds of the general formula: (A) wherein R^ represents: a radical -CX-R'^; a radical -CX-Nl^; a radical -CHR'^-CX^A'”; a radical a radial a radical -(CHgJ^CN; a radical -(ϋΗ^^,ΟΧ'-ΝΙ^; a radical -(0¾)^ _/ - 63 N-N a radical -(CH_) —< J n N-N l H a radical -(CH2)n,a radical (ΟΗ.,^,-Ν^; or a radical (CH2)n»~NR18R19 ’ with the proviso that R^ cannot represent a chloroacetyl radical when R^ ι «μ «salts -CX-CHj and R1 represents an acetoxymethyl radical.

In another such aspect the invention further provides the compounds of the general formula: (XII) and particularly the compounds of the formula: wherein R'^ represents a trityl or chloroacetyl radical, n\ represents 1 or 2; Hal’ represents a bromine or iodine atom and R* *1 represents a hydrogen atom, an acetoxy or carbamoyloxy radical or a 1-methyl-tetrazol-5-yl or 2-methyl-1,3,4-thiadiazol-5-yl radical.

Furthermore, certain other intermediates described hereinbefore are the subject of our co-pending Application No. 243/85 divided from the present Application, which describes and claims compounds of the general formula: (B) OR wherein R^ represents: a radical -CX-R’^ in which R'^ represents an alkyl having from 2 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a phenyl radical or a radical -((3^^-NR'^R^; a radical -CHR'-CC^A'; a radical a radical a radical -(CH^^-CN; a radical -(CH^.-CX'-NH^ a radical (C^^, w R · N_NH 7 a radical (CHO) , \ ., ··. ά n N-N © a radical (Q^) ,-N a radical -(CH2^n,-R5a in which R5a13 a hal°8en atoni> or a radical -S-R „ in which R „ represents a phenyl ar ar radical or a 5- or 6-membered aromatic heterocyclic 5 radical containing from 1 to 4 heteroatoms selected from sulphur, nitrogen and oxygen, the phenyl and heterocyclic radicals being optionally substituted by one or more radicals selected from amino, nitro and cyano radicals and alkyl radicals having from 1 to 4 10 carbon atoms; a radical RK which is a radical -(CH_) -R,-. in which b 2 n’ 5b R^b represents an imidazolyl, morpholinyl or N-alkyl piperazinyl radical, the N-alkyl radical containing from 1 to 4 carbon atoms; a radical -(CH-) ,-N-,: or 2 n 3 a radical “(CR2^n'~^R18R19' - 66 The following Examples and Formulations are given only by way of illustration, to show certain preferred aspects of the invention.

Example 1: The syn isomer of 3-acetoxymethyl-7-12-(25 -aminothiazol-,t-yl)-2-acetoxyimino-acetylamino3ceph-3-em-a-carboxylic acid.

At ambient temperature, a solution of 0.756 g of the syn isomer of di ethyl ammonium 3-acetoxymethyl-7-2-C2-tritylamino-thiazol-tt-yl]-2-hydroxyimino-acetylamino) -ceph-3-em-zi.-carboxylate, as prepared below in 1 ml of pyridine and 0.5 ml of acetic anhydride was agitated for 30 minutes. 3 ml of water were added, followed by 2N hydrochloric acid until the pH of the whole was 1.

The whole was then vacuum-filtered, and the solid thus obtained was washed with water and dried to give 0.75 g of crude acylated product. In a water bath, at zt5°C, a suspension of 0.520 g of the crude product thus obtained in 1 ml of aqueous formic acid (ΗΟί^’/^θ 2:1) was agitated for five minutes, after which 0.5 ml of water were added and the agitation in the water bath continued for 10 minutes at 4-5°C. After the subsequent addition of 5 ml of ethanol, the whole was concentrated under reduced pressure, and the concentrate taken up with diethyl ether. After evaporating to dryness under reduced pressure, washing and drying, 0.50/4· g of impure product (containing some deacylated derivative) were obtained. The impure product was dissolved in 1 ml of - 67 acetic anhydride and 2 drops of pyridine, from which the purified expected product (0.30 g) was precipitated with 10 ml of diethyl ether and then recovered. Hicroanalvsis: ^7^17%^¾ : 523.0 Calculated: C7' on.80 H% 3.75 14.70 S% 12.26 Pound : ua.6 3.8 la·.5 11.7 N.II.R. Spectrum 2.05 p.p.m. : OAc 6.75 p.p.m. : Hg of the thiazol.

Preparation of the syn isomer of di ethyl ammonium 3-n.cetoxyTr-ethyl-?-C2-( 2-tri-t?laniinothiazol-'i.-yO-2-hydroxyimino-acetylamino]-ceph-3-em-a-carboxylate.

Stage. A: The syn isomer of 2-(2-tritylaminothiazol-':-yl)-2^(. 1 -methyl-l-methoxy-ethoxyimino)acetic acid.

At ambient temperature, 12.9 g of the syn isomer of 2-hydroxyimino 2-(2-tritylaminothiazol-4-yl)acetic 3 acid in 120 cnr of methylene chloride and 12 cm of 2-methoxy propene were agitated for 2Q minutes. The whole was concentrated to dryness and after the 3 addition of 60 ctr of methylene chloride and 12 cm of methoxy propene, agitation was continued for 30 minutes. The whole was then concentrated to dryness under reduced pressure to obtain the expected product, which was used in the following stage without further purification.

Ot age_ 13: The syn isomer of diethyl ammonium 3-3cetoxymethyl~7~ C 2-( 2-trityla!T'.inothiazol-^--yl )-2-( 1-methyl-l-methoxy;2e£hox£imino)_ 3,C£tvlani_no_j£ceph-^-em-h-carboxvla_t£. - 68 One dissolves the amount of s.yn isomer of 2-(2-tritylaminothiazol-4-yl)-2-(1-methyl-l-methoxy-efchoxyimino)acetic acid obtained by following the procedure described in Stage A after starting with 47.25 g of 2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)x -acetic acid, in 230 cm of methylene chloride. 12.5 g of dicyclohexyl carbodiimide were added, and the whole was agitated for an hour at ambient temperature. The dicyclohexylurea thus formed was separated by vacuum10 filtration and rinsed with a little methylene chloride (9.82 g of dicyclohexylurea were formed). To the filtrate (and rinsings) were added a solution of 13.6 g of 7-aroino-cephnlosporanic acid in 70 cm^ of methylene x chloride and la cnr of triethylamine, and the whole was agitated for two hours at ambient temperature. After x washing in ampoule form with 350 cnr of N hydrochloric acid, decanting, washing with water, drying and concentrating to dryness, a residue was obtained, wnich was dissolved in 100 cm^ of ethyl acetate. Crystallisation was then initiated, and after 3θ minutes 5.5 g of starting product were recovered by vacuum-filtration.

The filtrate remaining was concentrated to dryness, and the formed residue agitated for 30 minutes with 200 cm^ of isopropyl ether. After vacuum-filtration and drying 37-35 g of crude product was obtained, wnicn was purified as follows. x The product was dissolved in 148 cm of ethyl - 69 10 acetate, and 5.5 cm^ of diethylamine were added. The product was then precipitated under intense agitation by adding 650 cm^ of diethyl ether, aud after vacuumfiltration, washing with diethyl ether and drying 26.55 g of the expected purified product were obtained. To obtain a second yield of product, the filtrate from the vacuum-filtration was concentrated to dryness and the residue formed taken up with 50 cm^ of ether. After drying 2.8 g of product identical to that of the first yield in T.L.C. were obtained. The combined products were used without any further treatment in the following stage.

N.M.R.' Soectrum (CDC1,) 60 MHz --CH5(a) j—CII5(a) OCH^(b) (a) =1.54- p.p.m. (b) =5.27 p.D.m. proton of the thiazol ring: 6.73 p.p.m.

St£ge C: The syn isomer of diethyl ammonium 5-acetoxy• me thyl-7-(2-( 2-tri.tyl aminot hiazol^^y l) ^2yhydro xyimino 20 -ac.etj’LarninoX^ejih^-em-'i-carboxxlate^. 7.6 g of the syn isomer of diethyl ammonium 3-acetoxy-methyl-7-(2-C2-tritylaninothiazol-a-ylj-2-Cl-methyl-l-methoxy-ethoxyiminoJ-acetylamino)-ceph-5-em-a-carboxylate, prepared in Stage 3 above, were dissolved in 50 5 3 cm of acetone and 10 cm' of 2N hydrochloric acid.

The whole was agitated for a.0 minutes at ambient teraperax ture, after which 20 cm' of water were added and the - 70 acetone was driven off at 30°C under reduced pressure. cm^ of ethyl acetate were added, and after decanting, re-extracting, washing with water, drying and vacuumfiltering, 1 cnr of diethylamine was added to the filtrate. After crushing and freezing the product formed was separated by vacuum-filtration aud washed with ether to give 6 g of pure product.

Analysis: O^gH /ιθθ7^ 6^2 Calculated : C;· 6U.5G !T’ 5.33 t·; 11.10 5?.' 8.A7 1C Found : 60.5 5.7 10.9 8.2 N.M.R. Spectrum (CDCl^) 60 MHz 6.63 p.p.n. : thiazol proton 7.33 p.p.m. : trityl proton Example 2: The syn isomer of 3~acetoxymethyl-7-C2-(215 -arinothiazol-'i -yl )-2-( phthalimidoacetoxyimino) acetylamino ]-ceph-3-em-A-carboxylic acid.

In a ml of methylene chloride were put into suspension under agitation 0.756 g of diethylaminium 3-acetoxymethyl-7~(2-(2-tritylamino-thiazol-a-yl)-220 -hydroxyimino-acetylaminoJ-ceph-3-em-A-carboxylate, syn isomer prepared in Example 1. 0.335 g of phthalimido acetyl chloride were added, and after 5 minutes at ambient temperature the product was precipitated hy the introduction of 10 ml of isopropyl ether, and then recovered by vacuum-filtration, pasting with water and drying. The crude product obtained was agitated for 20 minutes at 35-aO°C in 2 ml of aqueous formic acid - 71 (formic acid: water 2:1), and the product recovered again by adding 10 ml of water, vacuum-filtering, taking up with ether, vacuum-filtering again and then drying. The product thus recovered was further purified by dissolving it in ti ml of acetone, vacuumfiltering away the insoluble matter and then precipitating with 10 ml of ether. In this way 0.280 g of purified product were obtained.

Analysis : ^15^20^10^6^2 : 628.16 Calculated:.^ 13.77 3?' 10.20 Found : 12.5 10.4.

U.V. Spectrum (ethanol) Max. 217 - 218 nm 4 Inf. 230 nm Inf. 238 nm 4 Inf. 260 nm 4 Inf. 300 nm HCl Ν/^θ (ethanol) Max. 217-218 nm 4 Inf. 231 nm 4 Max. 239 nm Max. 258 nm pi Inf. 280 nm gl N.M.R . Spectrum DMSO 782 844 Λ53 242 107. 775 n29 352 286 230. 7-18 p.p.m. : thiazol. - 72 Example 3: The syn isomer of 5-acetoxymethyl-?-C2-(2- lninothin'/ol-'i-yl )-2-N ,N-( dimethyl-carbamoyloxyimino) ac.etyl 'imino 1 -ceph-3-em-u-ca rboxyl ic acid In il ml of methylene chloride were put into 5 suspension under agitation 0.756 g of di ethyl ammonium 3-acetoxymethyl-7-C2-(2-tritylamino-thiazol-4-yl)2-hydroxyimino-acetylaminoJ-ceph-3-em-a-carboxylate, syn isomer, prepared in Example 1. 0.2 ml of pyridine and 0.2 ml of dimethylcarbamoyl chloride were added, and after dissolving, the whole was washed with water and then with water acidified to pH 2.

The organic phase was dried, concentrated to dryness and crushed with ether, after which 0.6 g of crude product was recovered by vacuum filtration. This was agitated for 15 minutes at aO°C with 2 ml of aqueous formic acid (formic acid:water 2sl), then 5 ml of ethanol were added and the wnole was concentrated to dryness to give a residue which was taken up with ethyl acetate. 0.384 g of crude product were recovered and then purified by dissolving in an acetone .-methanol mixture (1:1), adding ether until light floculation occurs, vacuum-filtering away the insoluble matter and precipitating the product from the filtrate with ether. 2^ In this way 0.213 g of purified product were obtained. Analysis : ^βΗ-,θΟβΝθ^ : 511.52 - 73 - Calculated: Ν?.'· 16. Λ Pound : N% 15.2 I.R. Soectrum Nujol (Trade Mark) lactam 1770 cm C=0 172a cm'1 Amide 1667 cm Amide II 1532 cm U.V. Spectrum EtOH Max. 230 nm Ej = 357 ε 18 300 10 Inf. 251 nm Ej = 261 Max. 300 nm E} = 87 EtOH HCl N/10 Max. 256 nm eJ = 270 e 15 800 Inf. 280 nm Ξ1 = 218. 15 N.M.R. Spectrum DMSO 10.3 p.p.m. = thiazol. Examcle 'l: The syn isomer of 3-acetoxymethyl-7-(2-i -a’?inothinzol- /i-vl )-2-( nhthalimido- -methy loxy imino) acetylamino!-ceph-3-em-'i-carboxylic acid triflnoro20 acetate.

Stage _A: Dij2h£n2£lmethyl_3.3acetpxyraeXhxl,^7.x[2-.£2-trityX-_ amXn nthi a/nJ ^./1-^yX^ z/3 Rh^ha^l^mvl o^-me thyi oxyi mino ) ac e t y 1 aminoJ ^c eph-j5-em-'L^c^irboxy la At ambient temperature a mixture containing 0.085 g of diphenylmethyl 3_acetoxymethyl-7-(2-(2-tritylaminothiazol-'' -yl)-2-hydroxyimino-acetylamino]-ceph-3-em-a-carboxylate as prepared below, 0.12 g of bromoethyl phthalimide, 0.069 g of potassium carbonate and O./t ml - 74 4 96 67 of dimethylsulphoxide, was agitated briskly for 15 minutes. 10 ml of 0.1N hydrochloric acid were added to form a precipitate, which was vacuum-filtered, washed with water and dried to obtain 0.121 g of crude product. 5 This was dissolved in 1 ml of ethyl acetate and treated with active charcoal, and after eliminating the solvent the residue was crumbled with ether and vacuum-filtered to obtain 0.075 g of purified product. I.R, Spectrum CHClg NH 3/L08 cm'1 lactam phthalimide I ) ) ) 1782 cm-^ phthalimide II ? -1 ) 1730 cm ester ) amide 1665 cm C=C, C=N ) 1614 cm 1 aromatic 1599 cm-1 amide II ) ) 1511 cm 1 NH ) ) 1493 cm-l C-N-OR 1033 cm 1 N.N.R. Spectrum CDCl^ 7.03 p.p.m. aromatics(trityl- and diphenylmethyl) 7.8 p.p.m.:phthalimide 3.A p.p.m. : Ci^S - 75 Stage _B: The syn isomer of 3-acetoxymnthyl-7-C2-(^-arainothiazol-'i-yO-^-Cphthalimido-methytoxy imino) acetylamino]^. —c£ph.-^.-£m^^c arboxyli£ ac id_t r i f 1uproacet a t£.

To 0.32 g of the product obtained in Stage A were 5 added 3 til of trifiuoroacetic acid, ;nd the whole was agitated briskly for 10 minutes at ambient temperature, and then concentrated at 30°C under reduced pressure.

The residue was crumbled in 30 ml of isopropyl ether, vacuum-filtered and rinsed with isopropyl ether to obtain 0.21 g of the expected product.

Preparation: The syn isomer of diphenylmethyl 3-acetoxymethyl-7-(2-( 2-trityl aminothiazol-/· -yl)-2-hydroxy imino-acetylamino]-ceph-5-em-a.-carbox,ylate.

A) The syn isomer of diphenylmethyl 3-acetoxymethyl-7- - [ ,2-^2^ rity 1. amino £h i_ayol_-£-yl_^-^-£l£me_t hyl_-.l-me thoxy2pthoxyiminp2.ac.etylamino^-cenh^rpn-iL-carb^xyl ate.· a. 15 g of the product obtained in Stage B of the preparation of Exanple 1 were introduced into nO cm^ of methylene chloride and 55 era of 0.1M hyrochlonc acid. The whole was amitated for 10 minutes at ambient temperature, and after decanting tbe organic phase was 7 twice washed with 25 cnr of water, then dried, vacuumfiltered and rinsed with methylene chloride. Over ten minutes and under agitation, 15 cm^ of 8>'· diazodiphenyl methane in benzene were added; the whole was agitated for 15 minutes at ambient temperature after which the solvents were evaporated under reduced pressure at 30° - 76 to give a residue which was taken up and crumbled in · isopropyl ether. After again evaporating the solvent under reduced pressure and taking up with isopropyl ether, the solid was vacuum-filtered, rinsed and dried to obtain a.al g of expected product.

K.K.R. Spectrum (CDCl^) 60 MHz a = 1.53 p.p.m. b = 2.01 p.p.m. c = 3.26 p · p · Dl · d = 6.78 p.p.m. e = 7.33 p.p.m. B) The syn isomer of diphenylmethyl 3-acetoxymethyl- ^7^.[ 2-£2^t _2,i^y l_aminothia£ol_-A-yl_}_-2-hyd^roxvimino15 - a c.e tv l^amino ]_-c_e£h^3^em-a-c arboxyl at e;. 2.775 g of the product obtained above were placed z z in la cm of acetone and a.5 cm of N hyrochloric acid.

The whole was agitated for two hours at ambient tempera ture, after which the acetone was driven off under - 77 Ζ reduced pressure. 20 car of ethyl acetate were added, and after agitating and decanting, the organic phase was washed four times with 10 cm^ of slightly salted A water. The wash waters were extracred witn 5 cnr of 5 ethyl acetate, and the organic fractions were combined and dried, vacuum-filtered, rinsed with ethyl acetate and then evaporated under reduced pressure to drive off the solvent. The residue formed was taken up with ether and crystallised, and the drystals were crumbled, vacuum-filtered and rinsed with ether, to obtain, after drying, 1.88 g of desired product.

Rf = 0.5 (eluant = ether with 20% acetone).

N. M.R. Spectrum (CDCl^) 60 MHz 6.88 p.p.m. : proton of the thiazol cycle 7.33 p.p.m. : proton of the phenyl nuclei.

Example 5; The _svn isomer of sodium jj-acetoxymethyl-7-2-(2-aminothi azo l-/i -vl)-2-( nhthalimido-methyloxyamino) acetyl;?minol-cerh-3-em-/i.-carboxylate. 0.21 g of the product obtained in Example 4 was dissolved in O.a ml of methanol, and with agitation, O. 6 ml of a molar solution of sodium acetate in methanol were slowly added to the solution. 2 ml of ethanol were then slowly added, and the resultant precipitate was vacuum-filtered and rinsed with ethanol then ether to give 0.127 g of the desired product.

U.V. Spectrum HCl Ν/^θ (ethanol) ε 4ό,500 Max. 21? nm Inf. 237 nm ε 20,000 Max. 252 nm ε 16,300 Inf. 301 nm ε 7,400 Inf. 320 nm ε 5,850 N.M.R. Spectrum DMSO 8.05 p.p.m. aromatic 2 p.p.m. OAc I.R. Spectrum in nujol 0=0 1776 - 1764 - 1724 ca'1 10 Amide 1639 cm -1 0=0, 0=Ν ) ) ) 1659 cm 1 Aromatic 1611 cm 1 Amide II ) ) 1545 ca’1 00« ) ) 1525 cm-1 15 1511 cm Example 6: The syn isomer of 3~acetoxymethyl-7-(2-(2- -aminothiazol- -4-yl)· -2-(u-carboxybenzyloxy-imino)acetyl amino]cenh-3-em-4-carboxylic acid trifluoroacetate.

Stage A: The syn isomer of diethyl ammonium ’-acetoxymethyl-. 0 -7-C2-£2-tritylaminothiazol-4-yl)-2-(a-t-butoxyc.arbo^ny.lbenz^lo.xxininp2.ac.et.vi^Bi np]_ce^Dh-^-£m^'x^carbpjry^. l.a2ftx At ambient temperature, a mixture of 1.37 g of 3-acetoxynethyl-7-C2-(2-tritylaminothiazol-4-yl)-225 -hydroxyimino-acetylamino3-ceph-5-en-''--carboxy.lic acid, obtained in the course of Stage 0 of the previous preparation of Example 1, and 20 ml of methylene - 79 chloride was agitated. 20 ml of water were added, and 2.8 ml of triethylamine slowly added. A solution of .8 g of t-butyl α-bromophenylacetate in 5 ml of methylene chloride was introduced to the emulsion obtained, and the whole was agitated for 23 hours at ambient temperature before acidifying to oH 1 by the addition of 10 ml of 2N hydrochloric acid. After extracting with chloroform, washing the extracts with water, drying and distilling to dryness under reduced pressure at a maximum temperature of 3C°C, 6.1 g of brown oil were obtained. This was dissolved in 5 ml of ethyl acetate, and C.25 ml of diethylamine followed hy C ml of isopropyl ether were added to the solution. The solid htained was separated by vacuum-filtration to It give 1.11 g of impure product and the mother liquors gave a second portion of 0.1 g of product identical to the first. The two portions of impure product were purified by dissolving in 5 ml of ethyl acetate, filtering the solution and evaporating the solvent to 2C dryness to give a residue which was taken up with ether, recovered again by vacuum-filtration, rinsed with ether and dried at anbient temperature under reduced pressure. 0.96 g of the desired product were obtained, which were used in the following stage without further treatment. 2S I.R. Spectrum CHCl^ NH + associate : 3372 cm lactam 1781 cm AcO 1738 shoulder C ester II • 1729 cm_l II 0 amide : 1681 cm 1 COS \ 1602 cm-l 1526 cm 1 amide 11/ 1493 cm· 1 C=N=OR 1063 cm'^ U.V. Spectrum EtOH Inf. 230 nm 4 = 30a Inf. 260 nm 4 = 189 Inf. 303 nm 4 = 60 ε 9, 700 Max. /+/+7 nm „1 *1 = 8 Inf. 515 nm = 3 EtOH HCIΝΛο Max. 267 nm =•1' “1 = 160 ε 15 ,000 N.M.R. Spectrum 6.8 p.p.n. thiazol.

Stage, B: The syn isomer__o£ 3-acet£xymethyl-7-C2-(2^amino£hXa_zoX-a-xl}.-2-£a3carb£X2ben zy loxy ϊπΰηο} acetyl^ amino]£e£h^3^em-^-£arboxjr 1 ic_acid trifluoroacetat^e^ At ambient temperature 0.882 g of the product of Stage A above and 8.9 ml of trifluoroacetic acid were agitated together for 10 minutes. After dissolution the solution was concentrated under reduced pressure at a maximum temperature of 30°C to a volume of about 3 ml, which volume, after cooling, was taken up with 30 ml of isopropyl ether and agitated therein at ambient temperature fore 10 minutes. After vacuum-filtration, rinsing with isopropylether and drying under reduced pressure at 20-25°, 0.512 g of impure product were obtained. This was taken up with 2 ml of acetone containing 1/ water and agitated therein for 5 minutes at ambient temperature, before slowly diluting under agitation with 20 ml of diethyl ether. After 10 minutes the product was separated by vacuum-filtration, rinsed with diethyl ether and dried at ambient temperature under reduced pressure to give 0.443 g of purified product.

Example 7: The syn isomer of sodium 5~acetoxymethyl-7~ X^y^^yaminothiazolyZiyylJySy^a^carboxybenzyloxyi^no). acetylamino]ceph-3-em-4-carboxylate.

At ambient temperature, 0.4-21 g of the product of Example 6 were dissolved in 2.1 ml of a IM methanolic sodium acetate solution and 2.1 ml of methanol. The formed solution was treated with 40 mg of active charcoal and vacuum-filtered on silica, and the filtrate was concentrated under reduced pressure at a maximum temperature of 30°C to a volume of 1 ml. To this was added 10 ml of 100% ethanol, and the resultant precipitate was separated by vacuum-filtration, rinsed with ethanol then ether and dried under reduced pressure at ambient temperature to give 0.275 g of the desired product. - 82 Analysis : C23H19°9N5S2Na2 : 619·5 Calculated: C% 44.59 3.09 N% 11.3 S% 10.35 Pound : 44.8 5.5 11.5 10.2.

U.V. Spectrum EtOH/HCl n/jq Max. 260 nm eJ = 266 ε 16,500 Inf. 276 nm eJ = 222 ε 13,700 Inf. 395 nm = 8 I.R. Spectrum Nujol 1761 cm 1532 cm lactam Amide II C=N-0R 1027 cm Example 8: The syn isomer of 3-acetoxymethyl-7-C2-(2-aminothiazoI-a-yl)-2-(2-oxotetrahydrofuran-3-yloxyimino)acetylamino3ceph-3-em-a-carboxylic acid.

Stage A: Mixture of. the A £_and Aj isomers of the syn isomer_o£ diphpnylmethyl 3-acetoxymethyl-7-i2-(2-trityla.minethi^zo.l^a^yi.) ^.2^.( 2-pxotetrahydrpfuran^3^y 1.0 xyji imuio) jacet yl amino3 c^eph^-em-h-c arboxy 1 at e.

At ambient temperature, 1.7 g of diphenylmethyl 3-acetoxymethyl-7_C2-(2-tritylaminothiazol->i-yl)~2-hydroxyimino-acetylamino3ceph-3-em-4-carboxylate, obtained in the preparation of Example 4, was dissolved in 8.5 ml of dimethylformamide. Under agitation, 0.69 g of anhydrous potassium carbonate then 3.2 ml α-bromo- -butyrolactone were added, and the resultant suspension was agitated for 45 minutes at ambient temperature and under an inert atmosphere, after which 20 ml of water, - 83 12 ml of N hydrochloric acid and 50 ml of ethyl acetate were added. The organic phase was separated by decanting and washed with water containing sodium chloride until a neutral pH was achieved. After drying and evaporating the solvent to dryness under reduced pressure at a temperature lower than 35°, 6.6 g of a clear brown oil were obtained, which was taken up with 20 ml of isopropyl ether and agitated therein for 5 minutes at 40°C. The isopropyl ether phase was separated by decanting, and the operation described above was repeated to obtain a dry extract of about 2.5 g, which was treated in the same way with diethyl ether.

The residue was taken up with 20 ml of diethyl ether and agitated therein at ambient temperature for 15 minutes. The insoluble matter was then separated by vacuum-filtration, rinsed with diethyl ether and dried under reduced pressure to give 1.513 g of an amorphous yellow product, which was used in the following stage without further treatment.

I.R. Spectrum NH 3595 cm 1 β lactam ) _1 ) 1785 cm lactone ) OAc + ester 1744 cm 1 25 Amide 1691 cm 0 0 6 7 - θα - C=c C=N ) ) ) 1655 cm-1 Amide 11 1599 cm*1 Aromatic ) ) 1588 cm-1- ) ) 1515 cm-1· ) ) la95 cm1 N.M.R. Spectrum CDCl^ 6.80 p.p.m. thiazol Stage B: The syn isomer of diphenylmethyl l-oxo-J^ac.etpxymeXh2.1-7x>C2-£2-triXyXaminojthia£oX-a-^l2-2-£210 ^oxoXe_trah^drofuran-3-y1 oxy-imino) ac etyl anino 1 c eph~5~ ^em-a-cabbox2.1ate.

Under an inert atmosphere and under agitation, 1.525 g of a mixture of theZ^ andisomers obtained in the previous stage were dissolved in 8 ml of methylene chloride. The solution was cooled to 0° - +5°C with a hath of iced water, and at that temperature and over a period of 20 minutes 0.a20 g of metachloroperbenzoic acid in 8 ml of methylene chloride were added. The whole was agitated for one hour at the same temperature and concentrated under reduced pressure without heating to give a residue, which was taken up with 20 ml of ethyl acetate and washed therein with a solution of sodium bicarbonate and then with a solution of sodium chloride until neutrality was reached. The organic phase was then dried and distilled to dryness under reduced pressure at a temperature lower than 30°C to obtain a second residue, which was taken up with 10 ml - 85 of diethyl ether. The insoluble matter was separated by vacuum-filtration at ambient temperature and rinsed with diethyl ether to give 1.590 g of yellow product. I.R. Spectrum (CHCl^) NH 3386 cm C=0 lactone + 0 lactam : 1797 cm~l OAc ) _1 ) 1737 cm conjugated ester ) amide ) 1691 cm”l 10 C=C C=N ) aromatic ) 3 1634 - 1599 - 1587 - 1523 Amide II / ) S=0 possible ) , ) 1044 - 1035 - 1023 cm + oxime ether ) U.V. Spectrum (EtOH) Inf. 257 nm 4 = 02 196 Inf. 305 nm = - 53 e Of 5,000 (EtOH - HCI N/10) Miax. 265 nmEi = or 200 e —19,000 20 Inf. 300 nm = —85 e of 8,100 N.M.R. Spectrum (CDCl^) p.p.m. : OAc 6.73 and 6.77 p.p.m. : thiazol 7-3 p.p.m. aromatics. - 86 10 I ! i ί 25 Stage £: The syn isomer of diphenylmethyl 3_acetoxymethyl^7j-[2-jL2^tri^JLamino£hia£Oi-a~xlJ[-2-£2,xoxpte£rah2dro;^ fujran-^-xlo^xx-imi.no.j^c^txlaminolc.eEhxJ-em-a-c.arhoxylate,. 1.328 g of the product ohtained in the preceding stage were dissolved in 6.6 ml of dimethyl formamide.

The solution was cooled to -20°C, and under an inert atmosphere 0.6 ml of phosphorus trichloride were added over 30 seconds. The whole was agitated for 5 minutes at -20°C, and then 30 ml of ethyl acetate, 30 ml of a saturated solution of sodium bicarbonate and 15 g of ice were introduced. After extracting and decanting, the product was re-extracted with 20 ml of ethyl acetate and washed therein with a solution of sodium chloride until neutrality was reached. After drying and distilling to dryness under reduced pressure and at a temperature lower than a.0°C, a residue was obtained which was taken up with 10 ml of diethyl ether, recovered by vacuumfiltration, rinsed and then dried under reduced pressure and at ambient temperature to obtain 1.039 g of product, which was purified on silica by eluting with methylene chloride containing 10% ether. After distilling to dryness and taking up with ether, vacuum-filtering at ambient temperature and drying, 0.751 g of product were obtained.

N.M.R. Spectrum CDCl^ p.p.m. : OAc 6.8 p.p.m. : thiazol 43867 - 87 6.9 p.p.m. : COOCH 7.3 p.p.m. : aromatics.

Stage D: 3-acetoxymethyl-7-(2-(2-aminothiazol-4-yl)y2^( 2-oxo teXrahydrofur an-j5-yl oxy-imino ) ace ty lamino 35 ^ceph-X~£my4^c£rboxy lie. acid At 20°-25°G and for 10 minutes, 7.2 ml of trifluoroacetic acid and 0.720 g of diphenylmethyl 3-acetoxymethyl-7-(2-(2-tritylaminothiazol-4-yl)-2-(2-oxot et rahydro furan-3-yloxy-imino)ac ety1amino 3 c eph10 -3-em-a-carboxylate, 3yn isomer, obtained in the previous stage, were agitated together. The whole was concentrated under reduced pressure at a temperature lower than 30°C to a volume of about 2 ml, which was taken up, while cooling with a water and ice bath, with ml of isopropyl ether. After agitating for 10 minutes at ambient temperature and then vacuum-filtering, O.a.83 g of product were obtained. 0.480 g of the product were taken up with 0.5 ml of anisole and 4.8 ml of trifluoroacetic acid, and the whole was agitated for 5 minutes at ambient temperature and then concentrated to a volume of about 1 ml, which was taken up with 20 ml of isopropyl ether. After vacuum-filtering 0.472 g of product were obtained, and to 0.458 g of this were added 1.8 ml of formic acid containing 50% water. The whole was heated to 50°C for 10 minutes in an inert atmosphere, and whilst still hot was - 88 filtered to separate a light insoluble matter. The filtrate was then placed in a water hath not exceeding 3O°G and after cooling was concentrated to dryness under reduced pressure to give a residue which was taken up with 3 ml of water. After vacuum-filtering, rinsing with a very little water and then with ether, 0.283 g of product were obtained and used without further treatment in the following example.

Example 9: The syn isomer of sodium 3-acetoxymethyl-7-C2-(2-aminothiazol-/i-yl)-2-(2-oxotetrahydrofuran-3-yloxy-imino)acetylamino ] ceph-3-em-a-carboxylate . 0.283 g of 3_acetoxymethyl-7-(2-(2-aminothiazol-4-yl )-2-( 2-oxotetrahydrofuran-3-yloxy-imino)acetylaminoJ ceph-3-em-a-carboxylic acid obtained in Example 8 were dissolved in 1 ml of 1 M methanolic sodium acetate solution and 1 ml of methanol. The solution was treated with 30 g of active charcoal, filtered on silica and rinsed 3 times with methanol, and the filtrate obtained was concentrated under reduced pressure to a volume of 1 ml at a temperature not exceeding 30°G.

The 1 ml volume was diluted with 10 ml of ethanol at 100°, and after vacuum-filtering, rinsing with ethanol at 100° and then with ether, 0.165 g of product were obtained.

Analysis : CigH^gO^N^S^a : 54-7-5 Calculated: C% λΙ.68 3.51 12.79 S% 11.72 Na% 4.1 - 89 Found : C% '<5.8 11% 5.5 N% 11.8 S% 10.7 Na% 4.2 U.V. Spectrum Inf. 220 nm Max. 260 nm I.R. Spectrum EtOH/HCl N/10 E} = 255 E* = 302 e 16,500 Nujol 3 lactam ) ) 1765 cm-·1 λ lactone ) Amide 1673 cm-1 C=C G=N ) ) 1611 cm-l coo ) Amide II 1535 cm N.M.R. Spectrum DMSO 1.98 p.p.m. : OAc 6.78 p.p.m. : thiazol 4.33 p.p.m. : COOCH^ Example 10: The syn isomer of the disodfum salt of 3-8σ6Ϊοχγπΐ6ίΗγ1-7-[2-(2-Βΐηΐηο^Ϊ3ζο1-4-γΐ)-2-(1-θ3Γΐ)θχγ-5-hydroxypropoxy-imino)acetylamino3ceph-5-em-4-carboxylic acid. 0.257 g of sodium salt obtained in Example 9 were agitated with 2.7 ml of a 0.0865 M aqueous solution of sodium carbonate for 4 hours at ambient temperature. After leaving for a further 12 hours, the whole was distilled to dryness under reduced pressure at a maximum temperature of 30°C to give a residue which was taken up with 2 ml of methanol. The resulting solution was filtered to eliminate the brown insoluble matter and - 90 distilled to dryness to give a second residue, which was taken up with 2.5 ml of ethanol. After recovering the insoluble matter by filtration and rinsing with ethanol then ether, 0.226 g of the desired product were obtained.

Analysis : θΐ9®ΐ9θιο1ΐ82^2^5 : 587.5 Calculated: C% 38.8α 5.26 K% 11.92 S% 10.91 Na% 7.82 Pound: C% 59.8 H’S 3-7 N% 10.7 S% 10.1 Na% 7.6 U.V. Spectrum EtOH/HCl Ν/^θ E* = 198 = 22^ Inf. 22a nm Max. 262 nm e!5,000 IS Il.M.R. Spectrum D20 7.05 p.p.m. thiazol. I.R. Spectrum β lactam 1763 cm 1 amide 1667 -1 cm COO- 1575 cm”1- Example 11: The syn isomer of 3-acetoxymethyl-7_£2-(2· -acinothiazol-a-yl)-2-(2-oxotetrah,ydrofuran-5-yloxy -imino )acetylamino3 ceph-5~em-q-carboxylie acid.

Stage A: _ Di ethyl ann]2niyiii_32.a£.ei.03£7™e£.hi1-7r:t 2.“£2^tritj[laminot hi a.zol^a^y 1} 2-^.2χρ xo^e trahydro fur an-_J-xl· οχχ-_ 2.iaino j.ac etv 1 amino 3 c eph-3-em-_a-c arboxy late_j_ Under agitation and under an inert atmosphere, 1.367 g of 3-acetoxymetbyl-7-C2-(2-tritylaminothiazol-q-y1)-2-hydroxyimino-ac etylamino3 c eph-3-em-a-carboxy1ic acid, obtained aa an intermediate in Stage C of the preparation of Example 1, were dissolved in 20 ml of methylene chloride. 20 ml of water, 2.8 ml of triethylamine and then 1 ml of α-bromo -butyrolactone were added, and the whole was agitated for 17 hours at ambient temperature before adding another 1 ml of α-bromo -butyrolactone followed three hours later by l.A ml of triethylamine and, after a further 5 hours' agitation, by yet another 1.5 ml of α-bromo -butyrol10 actone and l.A ml of triethylamine. The agitation was then continued for 16 hours, after which 20 ml of 2N hydrochloric acid were added for acidification. The organic phase was decanted, washed with water until neutral, dried and distilled to dryness under reduced pressure to give a residue which was taken up with 10 ml of ethyl acetate. The insoluble matter was separated by vacuum-filtration and rinsed, after which the filtrate (and rinsings) was dried and distilled to dryness. The resultant residue was taken up in 10 ml of ethyl acetate, to which was slowly added 0.2 ml of diethylamine, and the diethylamine salt of the starting product was separated by vacuum-filtration at ambient temperature and rinsed with ethyl acetate then diethyl ether. The filtrate and rinsings were distilled to dryness and the formed residue was taken up with 2 ml of ethyl acetate, to which was then added 20 ml of isopropyl ether. Finally, the precipitate - 92 obtained was recovered by vacuum-filtration to give 0.500 g of the desired product.

U.V. Spectrum EtOH - HCI Ν/χ0 Max. 265 nm E* = 179 e 15,000 N.M.R. Spectrum (CDCl^) 6.76 p.p.m. thiazol Stage B: The syn _isom£r__o£ X~£C£toxym£thyX-2“J(2y(^-y yaminothiazpX-4-yl2.-^-X2-oxoXetrahydroXuran-3.-yloxy-_ iminjo)acetylamino)cejDh^2;em-4-£arbo3££lic_acid trifluoro10 acetate. 0.5 g of diethylamine salt obtained in Stage A were χ introduced into 5 cm' of trifluoroacetic acid, and the whole was agitated for 15 minutes at ambient temperature before distilling under reduced pressure to a volume of x 3 about 2 cm. 20 cm; of isopropyl ether were then added in one portion, and after agitating for 15 minutes at ambient temperature, separating the product χ by vacuum-filtration, rinsing 5 times witu 2 cnr of isopropyl ether and then drying under reduced pressure, the desired product was obtained.

Stage C: The syn isom£r_of _3-£C£to_x^me_thy^-7-^.2-^( 2-_ yaminoXhXazpX-4-ylX-2-£2^pxoXeXrahydrpfuran-X-yloxyXmXno^)acetylamXno.3ce£h^3-em-4-carboxylXc_ac>id.

The trifluoroacetate obtained above was placed in x a mixture consisting of 2 cm of a 1:1 methylene z chloride/methanol solution and 0.5 cm' of a IM ethanolic solution of pyridine, and pasted therein for 15 minutes - 93 at ambient temperature. Over a period of two minutes, X the whole was diluted with 8 cm of sulphuric ether containing 2% ethanol, and then agitated. The desired product was recovered by vacuum-filtering, ringsing with diethyl ether and drying under reduced pressure.

Example 12: The syn isomer of sodium 3-acetoxymethyl-7-(2-(2-aminothiazol-4-yl)-2-tetrazol-5-yl-methoxyimino)acetylamino 3 ceph-3-em-4-carboxylate.

Stage A: Thy syn £symyr_of y-£2ytyiyylaminothyayo.l-410 ^y1^-2-( t.et.razo.l^.S^yl.-meyhoxiimino^.aceyic. acid^. 2./t3 g of 2-(2-tritylaminothiazol-4-yl)-2-cyanomethoxyimino-acetic acid, the preparation of which is described below, were agitated in 12 ml of dimethylformamide. 1.5 g of sodium azide and 1.5 g of ammonium chloride were added and the whole was heated for 5 hours at 75°C and then left to cool at ambient temperature before adding 120 ml of distilled water, ml of ethyl acetate and 30 ml of formic acid. The precipitate thu3 formed was separated by vacuum-filtra20 tion, rinsed with water, ethyl acetate then dierhyl ether and dried to give 1.275 g of the desired product. 0.127 g of product were recovered from the filtrate. Analysis : θ26Η^1θ3Ν72 = 511.55 Calculated: C% 61.0 H% 4.1 N% 19.2 S% 6.3 Found : 61.1 4.6 17.8 5.8.

U.V. Spectrum (EtOH) (+ DMSO) Inf. 259 nm - 94 5 Inf. 265 nm e 11,000 Inf. 271 nm Inf. 294 nm ε 6,600 EtOH / HCI N_/in Inf. 27Ο nm Max. 275 nm ε 13,700 N.M.R. Spectrum DMSO 7.28 p.p.m. : trityl 6.88 p.p.m. : thiazol. I.R. Spectrum Aromatic NH C=N N=N co2^tage B: 1608 cm 1624 cm2 1580 cm-1- ( 1557 cm-1 ( -1 ( la.91 cm .

Th£ gyn isomer_o£ 3-acetoxymethyl-72.C£-£2^tpi£yl>aminotihiiapol.-4-y.lj.-2-£tptrapoJ_-5.-ylp pmpt hoxyhninp) a cetyl amino] pephp3-em-a -parbpxylatp.

To 1.024 g of 2-(2-tritylaminothiazol-a-yl)-2-(tetrazol-5-yl-methoxyimino)acetic acid prepared in the previous stage were added 0.656 mg of £-butyl 7-amino-3-acetoxymethyl-ceph-3-em-4-carboxylate and 2 ml of pyridine. After the addition of 0.5 g of dicyclohexylcarbodiimide in 5 ml of methylene chloride, the whole was agitated for an hour at ambient temperature, and then the dicyclohexylurea precipitate thus formed was eliminated hy vacuum-filtration. 25 ml of N hydrochloric - 95 acid were added to the filtrate, and after agitating for 5 minutes, the organic phase was separated hy decanting, washed with 25 ml of water and dried. The organic solvent was then distilled away under reduced pressure to give a residue, which was taken up with isopropyl ether and crumbled therein. The solid matter was recovered by vacuum-filtration and rinsed with isopropyl ether, and after drying 1.773 g of crude product were obtained. This was dissolved in 4 ml of ethyl acetate, treated with active charcoal and filtered on silica. Then, over 5 minutes and under agitation, 20 ml of isopropyl ether were added to the filtrate, and the whole agitated for a further 5 minutes. Finally, the solid was separated hy vacuum-filtration, 1$ rinsed with isopropyl ether and dried to give 1.412 g of a white product. M.p. = 158°C.

Analysis : θ^θΗ^Ο^^ Calculated: C% 58.5 H% a.8 N% 15.5 3% 7·θ Found : 58.5 5.0 14.7 7-8 U.V. Spectrum (EtOH - HCl Ν/^θ) Max. 267-268 nm ε = 19,^-00 Inf. 290 nm I.R. Spectrum (CHCl^) β lactam 1787 cm Esters 1758 cm-1 Amide ( 1686 cm £ 1675 cm-1 - 96 N.M.R. Spectrum (CDGl^) 7.2 p.p.m. : trityl 6.75 p.p.m.: thiazol 1.5 p.p.m. : .t-butyl 2.05 p.p.m.: acyl Stage C: The syn isomer of 3-acetoxymethyl-7-C2-£2-amino£ £hjja£oX-£-yl2^2-Lt±tra£Ol,-.5-£l£m£thoxyi.mino) acetylamino] £e£h^3£em-£-carboxylic_acid trifluoroacetate.^ At ambient temperature, 1.226 g of t^-butyl 3_ -acetoxymethyl-7-C2-(2-tritylaminothiazol-a.-yl)-2-(tetrazol-5-yl-methoxyiraino)acetylamino)ceph-3-em-/i-carboxylate find 12 ml of trifluoroacetic acid were agitated together for 30 minutes, after which the acid was partially evaporated under reduced pressure and a precipitate thrown down by the addition of 120 ml of isopropyl ether. The precipitate was separated by vacuum-filtration, rinsed with isopropyl ether and dried to give 1.061 g of a product containing some starting material, which had only partially reacted, as an impurity. However by repeating the whole operation twice, starting with trifluoroacetic acid, 0.879 g of 1he desired product were obtained.

Stage D: The syn isomer_o£ sodium 3-acetoxymethyl-7-C2-X.2saminot^hiazol-q.-yl)-2-(tetrazol-5-yl-methoxyimino_) £c£tyl£min£].cej)h-32;em-4-carboxyljite.

The trifluoroacetate obtained in the previous x stage was dissolved in 1.8 cm of methanol, and under - 97 49867 agitation and at ambient temperature, 2.8 cm? of a molar solution of methanolic sodium acetate were x slowly added, followed over 5 minutes by 18 cm of ethanol. The agitation was continued for 15 minutes whilst cooling in a bath of iced water, and the solid formed was separated by vacuum-filtration, rinsed with ethanol then diethyl ether and dried to give 0.447 g of the desired sodium salt in the form of crystals. Analysis : ^1^17^7^9^2 MW = 523.5 Calculated: C% 37-4 3-0 N% 23.1 S% 11.8 Found : 57.8 3-2 21.1 11.1 N.M.R. Spectrum (deuterochloroform) 6.73 p.p.m. : thiazol 7.25 p.p.m. : trityl The preparation of the syn isomer of 2-(2-tritylaminothiazol- 1) The syn isomgr o£ cyanomethyl 2-( 2-tritylaminorLthiiz^lz’LEyL^Z^^ianoffieLhx^xximino.^Kietate^ Under an inert atmosphere, 12.9 g of 2-(2-tritylaminothiazol-4-yl)-2-hydroxyimino-acetic acid, syn x isomer, 9.12 g of neutral potassium carbonate, 60 cm' of dry dimethyl formamide and 7·θ cm^ of chloroacetonitrile were mixed together, and agitated. The mixture then congealed, after which it was left for 65 hours in an enclosed atmosphere before being poured into a x x mixture of 750 cm of water, 150 cm of normal hydrox choric acid and 150 cm of ethyl acetate. After agita- 98 tion, the insoluble matter was separated by vacuumfiltration and rinsed with ethyl acetate and then with water. The phases of the filtrate were separated 7 hy decanting, and after washing with 100 cm of water 5 and re-extracting with 3 x 100 cm^ of ethyl acetate, the organic phase was dried. Insoluble matter was removed by vacuum-filtration, and after rinsing, the filtrate was concentrated to dryness to give a residue, which was chromatographed on a column of silica, eluting with ether. The ether was then driven off, and 8.69 g of the desired product were obtained in the form of oil. N.M.R. Spectrum : CDCl^ 60 MHz Thiazol proton : 6.8 p.p.m.

Trityl proton : 7.37 p.p.m. 2) The syn £somer_22( 2-trityl amin^t hi azol-a ^y _2cyanome_th£xyimino_2ac_et_i£ acid^_ 8.69 g of the product obtained in l) were placed in 52 cm^ of dioxan, and the whole was cooled in an ice 7 bath. Over twenty minutes, 17·1 cm of a normal solution of sodium hydroxide were added dropwise, after which the whole was left to reheat spontaneously. .5 cm* of 2N hydrochloric acid were then added, and the dioxan and almost all the water were driven off 7 before adding 20 cnr of water and 3θ cm of diethyl ether and agitating for 15 minutes. The crystals formed were separated hy vacuum-filtration, rinsed with water then diethyl ether and dried to give 4.32 g of the 43KB7 - 99 desired produce, melting at about 1SO°C with decomposition.

N.M.R. Spectrum : CDC1^ 60 MHz 4.7 p.p.m. : OC'H^CN 6.7 p.p.m. : thiazol proton 7.34 p.p.m.: trityl proton.

Example 13: The syn isomer of 3~acetoxymethyl-7-(2-(2-aainothiazol-4-yl)-2-benzoyloxyimino-acetylamino3 ceph-3-em-4-carboxylic acid.

Stage A: The yyn £s£m£r_°£ £iet£y£aainium_3_2a£e£oxy-me£h2l^7z(2-£2^trity£amnothiazpl.-4-2l£-c?-benzoylpxy.2. iminog-acetyl amino] ce£h^^em-4-carboxyl at .e.

To a solution of 0.683 g of the syn isomer of 3-acetoxymethyl-7-(2-(2-tritylaminothiazol-4-yl)-215 -hydroxyimino-acetylaminoJceph-3-em-4-carboxylic acid in 10 cm^ of methylene chloride, were added 0.2 cm^ of pyridine and 0.2 cm^ of benzoyl chloride. The whole was agitated for 10 minutes at ambient temperature and then washed in a separating funnel with water acidified to pH 1, and after drying, vacuum-filtering and concentrating to dryness 0.737 g of a crude product were obtained.

This was dissolved in 5 cm^ of ethyl acetate, and 0.1 cm^ of diethylamine were added to the solution. After 10 minutes the whole was vacuum-filtered to obtain 0.27 g of the desired diethylamine salt.

Stage B: _The syn _isomer of 3-^cetoxymethyl-7-(2-(2-aminothiazol-4-yl)-2-benzoyloxyimino-acetylamino3ceph- 100 z52.ei-i£a£boxzlic_a£id.

The 0.27 g of diethylamine salt were agitated for 10 minutes at 45°C with 2 cm^ of 50% aqueous formic acid, after which the whole was distilled to dryness and the residue obtained ground with diethyl ether. 0.155 g of crude product were separated and dissolved in 0.5 cm^ of methanol, from which a solid was x precipitated by introducing 5 cm of diethyl ether.

The solid was separated to give 0.1a g of desired product.

Analysis : θ22^19θ6^5^2 = 515-5 Calculated: N% 13.4 Found : 13.AExample 14: The syn isomer of 3-acetoxymethyl~7-£2-(215 -aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetylamino! ceph-3-em-a-carboxylic acid bis trifluoroacetate.

Stage A: Th£ syn £s£m£r_°£ £t£y£ 2-£2-tritylamino£hiaj5o£-^~2l£-2-£2;J;ri£y£amino£thoxyimino^acetate^.

Under an inert atmosphere 12.2 g of the syn isomer of ethyl 2-(2-tritylaminothiazol-a-yl)-2-(2-iodoethoxyX imino) acetate were introduced into 80 cm of anhydrous dimethyl formamide and 12.4 g of triethylamine. The whole was heated to 100°C for 5 hours after which 6.2 g of tritylamine were added. The temperature was maintained for a further 7 hours at 100°C, before being allowed to return to anbient temperature, at which stage 1600 cm^ of distilled water were introduced. - 101 3 The product was extracted with 6 x 250 cm of benzene and after washing with water then with a saturated solution of sodium bicarbonate then with a saturated solution of sodium chloride and drying, 23.5 g of a resin were obtained. This was chromatographed on silica, eluting with a benzene ether (95:5) mixture, and the principal was again chromatographed over silica, this time eluting with pure methylene chloride. 3·θ 6 of pure product were obtained.

N.M.R. Spectrum (CDCl^) Thiazol proton = 6.46 p.p.m.

C^-NH triplet centred on 2.4-5 p.p.m. ( J = 5 Hz) Stage _B: The syn isomer of 2-(2-tritylaminothiazol4-yl)-2-(2-trityIaminoethoxyimino) ,acetic_acid.

Whilst under nitrogen, 2 g ofthe ethyl ester prepared in Stage A were introduced into 10 cm of 3 dioxan and 66 cm' of absolute ethanol, and 3 cm of normal sodium hydroxide solution were added to the formed mixture. After leaving for 65 hours, the precipitate formed was separated by vacuum-filtration z and washed three times with 3.5 cm of dioxan ethanol (1:6.6) mixture. A first yield of 1.44.5 g of sodium salt was obtained. The above process, which is one of saponification, was repeated under identical conditions in respect of the mother liquors remaining, which gave a second yield of 0.4-40 g of sodium salt.

The 1.445 g of the first yield was poured into cm^ of water and 3θ cm^ of chloroform and, under * if OO f - 102 vigorous agitation, normal hydrochloric acid was added until pH 2 was obtained (about 1.9 cm^). The organic phase was decanted and washed until neutral with α x 10 cnr of water, each fraction of washing 3 water being subsequently re-extracted with 3 cm of chloroform. The total chloroformic phase was then dried and evaporated to dryness to give a white powder, χ which was pasted twice with 2 cm of dichloroethane 3 and then twice with 2 cm of isopropyl ether. After drying under reduced pressure until a constant weight, 1.202 g of product were obtained. M.p = 17&°C with decomposition.

The second yield of Ο./ιαΟ g of sodium salt was treated in the same way to give 0.325 g of desired product. M.p. = 176°C with decomposition.

Thus 1.527 g of product were obtained in total.

N.M.R. Spectrum (CDClj) 6.65 p.p.m. : proton in 5 of the thiazol 2.95 p.p.m. : CH2-N Stage C: The syn isomer diphenylmethyl 3-acetoxymethyl-7-(2-( 2-tritylaminothiazol-,i.-yl )-2-( 2-tritylaminoethoxyinino) acetylamino!ceph-3-em-a-carboxylate.

Under nitrogen, 0.286 g of the acid prepared in 3 Stage B were introduced into 2 cir of methylene chloride.

The suspension thus formed was agitated and to it were added dropwise O.a cm of a solution prepared extempor3 aneously by mixing 1.4 cnr of triethylamine and a - 103 χ quantity of methyl chloride sufficient to obtain 10 cnr of solution. The whole was cooled in a bath of acetone and dry ice to -20°G and left for 5 minutes to balance the formed solution, after which whilst under agitation O./ι cnr of a solution prepared extemporaneously by mixing 1.25 cm^ of pivaloyl chloride with a sufficient quantity of methylene chloride to 3 obtain 10 cnr of solution, were added dropwise. The bath was subsequently allowed to warm to -10°C, and was left at this temperature for 30 minutes before being allowed to warm further to 10°C in 10 minutes. 0.175 g of diphenylmethyl 7-amino-cephalosporanate were then immediately alcohol, and the whole was allowed to return to ambient temperature. After leaving for an hour and minutes, a further 17.6 mg of the dinhenylmethyl ester were added, and the whole was then agitated for 30 minutes at ambient temperature, placed for 15 hours in a refrigerator, allowed to return to ambient tempera ture and subsequently evaporated to dryness under reduced pressure. Finally, the residue was filtered on silica, eluting with a benzene ethyl acetate (8:2) mixture, to give 0.208 g of the desired product.

N.M.R. Spectrum (CDClj) 1.99 p.p.m. = O-C-CH, tl * 4-38 p.p.m. = N-O-CH2 t aa - 104 6.71 p.p.m. = proton in 5 of thiazol 6.88 p.p.m. = CO^OH _2 Stage D: The syn isomer of 3-acetoxymethyl-7-(2-(2-aminothiazp2-£L-il2-2-£22.amino£tho2cyiniin£)acetxlaraino]ce£h£ -3-^em-/i-carboxylic_acid bis. £rifluoroacetate.;. 186 mg of diphenylmethyl 3-acetoxymethyl-7-(2-(2-tritylaminothiazol-4-yl )-2-( 2-tritylaminoethoxy imino) acetylamino]ceph-3-em-4-carboxylate prepared in Stage C was introduced into 1.8 cm^ of pure trifiuoroacetic acid. The yellow solution thus obtained was agitated for 3 minutes at ambient temperature 3nd then, in an inert atmosphere and in an iced water hath, 18 cm of isopropyl ether were rapidly added. The whole was agitated for 10 minutes, after which the solid formed was separated by vacuum-filtration, rinsed with isopropyl ether then diethyl ether and dried to give 100 mg of a white powder. M.P. = about 210°C (decomposition).

N.M.R. Spectrum DMSO 2.03 p.p.m. = 0-C-CHj 3.17 p.p.m. = =N-O-CH2 6.85 p.p.m. = proton in 5 of thiazol.

The preparation of the syn isomer of ethyl 2-(2-tritylaminothiazol-/i.-yl)-2-(2-iodoethoxyimino) acetate used as starting material in Stage A. a) The syn isomer of ^thyl i - 105 371.)^.2^(2-b r£m£eth£xy imino.} acet ic_ac_id.

In an inert atmosphere, a mixture of A.9a g of ethyl 2-(2-tritylaminothiazol-/4.-yl)-2-hydroxyimino acetate hydrochloride syn isomer, was introduced into 10 cm of dimethyl fnrmami dp, and at ambient temperature and over 3 minutes, A.lA g of potassium carbonate were added. The wholeves agitated for 20 minutes at 20°C after which 8.65 cm^ of 1,2-dibromoethane were added. After agitation for a further 3θ hours the whole was poured into a medium containing 100 cm of distilled water and 20 cm7 of methylene chloride. The aqueous and organic phases were then separated by decanting, and after re-extracting with methylene chloride, washing with distilled water and re-extracting again, the combined organic phases were vacuum-filtered, with rinsing, and distilled to dryness. The crude product obtained was chomatographed on silica eluting with benzene containing 5% diethyl ether; and a first fraction was collected which was recrystallised in methanol after dissolution at 50-60°C and vacuum-filtering at 0° - +5°G 1.15 g of cream white product were obtained. M.p. = 117°C.

A homogenous fraction of 1.258 g was subsequently obtained.

N.M.R. Spectrum = p.p.m. (CDCl^) triplet = 3.55 J = 7 Hz CH2 Br triplet = A.51 J = 6 Hz N-O-CH^ - 106 10 ji single 6.55, thiazol proton cycle. b) The syn isomer of ethyl 2-(2-tritylaminothiazol-4pyl)p2p(2-ipd.opthoxyimin£)_ac.et.at.e_!L g of ethyl 2-(2-tritylaminothiazol-4-yl)-2-(2-bronoethoxyimino) acetate syn isomer prepared in a) were introduced into 60 cm^ of methylethylketone and 2.141 g of sodium iodide. The whole was taken to reflux for one hour and 10 minutes and then evaporated under reduced pressure to give a residue, which was taken up with 120 cm^ of methylene chloride. After washing five times with 40 cm of water, each washing z being re-extracted with 2 cnr of methylene chloride, the combined organic phases were dried and evaporated to dryness to give a resin, which was mixed with diethyl ether. After drying under reduced pressure, 6.22 g of product were obtained. M.p. = 110°C.

N.II.R. Spectrum = ( C DC 1 ^ ) CH2 I = triplet centred at 3·31 p.p.m. (J-7 Hz) Proton at 5 of thiazol : 6.53 p.p.m.

Example 15; The syn isomer of 3~acetoxymethyl-7-(2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino) acetylamino 3ceph-3-em-4-carboxylic acid. 220 mg of the bis trifluoroacetate prepared in χ Example 14 were introduced into a tube and 1.6 cm of a molar solution of sodium acetate in methanol were added. The whole was agitated until complete dissolution was obtained, and then the sides of the tube were - 107 rinsed with 0.66 cm^ of methanol before the addition 3 of 18.6 cm of absolute ethanol. Precipitation then occurred and at that time an equivalent mixture obtained in the same way but starting with 100 mg of bis trifluroacetate was added. After 1 hour 50 minutes, the combined mixtures were vacuum-filtered to separate the insoluble matter, which was washed with ethanol then with diethyl ether and dried until constant weight under reduced pressure to give 181 mg of a white powder melting at 270°C with decomposition.

Rf = 0.12 (ethyl acetate ethanol water - 60:25:15) The white powder was purified as follows: 120 mg of the powder were introduced into 1 cm^ of distilled water. After agitating for 5 minutes, pyridine was slowly added until a pH of 7.0 to 7-2 was obtained. After a further 15 minutes of agitation, the whole was vacuum-filtered, rinsed with 0.5 cm5 of water and aO cm^ of acetone were added to the filtrate, which was then agitated for 5 minutes, left to rest for minutes and vacuum-filtered to recover the product.

After washing three times with acetone and drying, 99.5 mg of a purified white powder were obtained.

U.V. Spectrum Max. 261 nm E^ = 3αβ Example 16: The syn isomer of 5-acetoxymethyl-7-C2-(2-aminothiazol-4-yl)~2-(2-amino-2-thioxo-ethoxyimino) acetylamino]ceph-3-em-A-carboxylic acid. ί - 108 0.502 g of sodium 3-acetoxymethyl-7-C2-(2-aminothiazol-4-yl)-2-cyanomethoxyimino-acetyl]ceph-3-em-q.-carboxylate, syn isomer, were placed in 2 cm^ of dimethylformamide and 0.14 cm^ of triethylamine. After total dissolution, some gaseous hydrogen sulphide was slowly introduced (bubble by bubble) over 15 minutes, and then the whole was left under agitation at ambient temperature for 30 minutes. 20 cm^ of isopropyl ether were subsequently added and after agitation the isopropyl ether phase was separated, leaving an oil remaining at the bottom of the container. 7 cm^ of ethanol were added to that oil, and after agitation an insoluble substance was formed, which was separated by vacuumfiltration, rinsed with ethanol and dried to isolate 0.388 g of crude product. This was purified by dissolving (0.309 g in 1.5 cm^ of water, adding 30 mg of charcoal, agitating and removing the charcoal by vacuum-filtration whilst rinsing with water. 5 drops of pure formic acid were added to the filtrate, and the precipitated product was rinsed with water and dried to obtain 0.195 g of p-. rified product.

N.M.R. Spectrum: (ΟΗ^^θ - log (a) single 2.02 p.p.m. (a) single 6.83 p.p.m. (b) tl 3.55 p.p.m. (e) tl 7.25 p.p.m. (c) If 4.75 p.p.m. (f) double centred on 9-73 p.p.m. (J=8Hz) U.V. Spectrum (in ethanol.ΝΛθ hydrochloric acid) max. 265 nm E* = 468 ε = 2/l.IOO The preparation of the syn isomer of sodium 3-acetoxymethyl-7-C2-(2-aminothiazol-&-yl)-2-cyanomethoxyimino-acetylamino3ceph-3rem-4-carbO3cylate used in Example 16 as starting material! A) The syn isomer_of t,“hutyl 3-acetoxymethyl-7-£2-(2-_ ;J;ri.^£amino£hia.Zo£-/k-il£-£-Cy.an£m,et22r£O3^£min,O-aC,etj5rl^ £min£]£ej>h^-em-4-carbox£late.

In an inert atmosphere 1.875 g of the syn isomer 15 of 2-(2-tritylaminothiazol-4-yl)-2-cyanomethyloscyimino-aoetic acid obtained as in the preparation of Example 12 were mixed with 1.312 g of .t-butyl 7-a®inocephlosporanate in 12 cm^ of dry methylene chloride. The whole was agitated, and a solution of 960 mg of dicyclohescyl carbodiimide in 12 cm^ of dry methylene 110 '-,. chloride added. After agitating and leaving at ambient temperature for one hour 45 minutes, 457 ng of formed dicyclohexylurea were separated by vacuumfiltration. The filtrate was then concentrated to dryness to give a residue, which was chromatorgraphed on silica while eluting with methylene chloride then diethyl ether. The resulting rich fractions were collected, and the diethyl ether therein was driven off, the residue being taken up with ether. Crystallisation was subsequently initiated, and the whole was left in the refrigerator whilst the product slowly crystallised. The crystals were separated by vacuumfiltration, rinsed with diethyl ether at 0°C by pasting and then dried to isolate 776 mg of desired product.

M.F. = 180°C with decomposition.

N.M.R. Spectrum : 60 MHz CDCl^ 4.9 p.p.m. : O-CH2- CN 6.8 p.p.m. : proton of the thiazol cycle 7.51 p.p.m. : proton of trityl.

B) The syn isomer_o£ ^-acetaxym£thy£-7-(2^(2-aniinot.hia£oX-4-yl}.-2-£yanomethyl.oxyimino-ac£tylamino.]£e£h3 -3^em-£-carboxylic_acid .trifluoroacetate^ 779 mg of the product obtained in A) were introduced into 4 cm^ of trifluoroacetic acid, and agitated until dissolution. 17 minutes after the 3 introduction the solution was poured into 40 cm of isopropyl ether, and after agitation the insoluble - Ill matter was separated by vacuum-filtration and dried to isolate 523 mg of tbe desired product, c) The syn isomerof sodium 3£ace£oxyiae£hy 1^7-(2-^2^ paminothi.apoi-^-yl^-^-cyano.mpthyXoicyiminp-pcptylaminp] ceph-3-em-4-carboxylate.

The 523 mg of trifluoroacetate obtained in B) x were dissolved in 2 cm of a normal methanlic solution of sodium acetate, and the formed solution X was diluted with 6.6 cm of ethanol and agitated for 10 10 minutes. The insoluble matter was separated by vacuum-filtration, rinsed with ethanol and dried to give 226 mg of the desired sodium salt. M.p. = about 200°C with decomposition.

N.M.R. Spectrum ; CDClj,60 MHZ 15 4.98 p.p.m. : 0-CH2- CN 6.86 p.p.m. : proton of the thiazol cycle.

Analysis ; C-^^H-^gO^NgS^a Calculated: C% 40.64 H% 3.01 Na% 4.57 Found : 40.2 3.3 4.5 Example 17: The syn isomer of 3-acetoxymethyl-7-[2-(225 -aminothiazol-4-yl)-2-( 2-amino-2-thioxo ethoxy imino) acetylamino3ceph-3-em-a-carboxylic acid.

Stage A: ^-^p.trityXaminothiapoi-p-yl^.-^-^pamino^p pthio,xo_-pthoxyimin£)_ape£ic. acpd^ 2.814 g of 2-(2-tritylaminothiazol-4-yl)-2-(cyano methoxyimino)acetic acid obtained in the preparation of Example 12 were introduced into 12 cm7 of a solution - 112 χ containing 1.6 cm of triethylamine diluted with 20 cm^ of dimethylformamide. At ambient temperature. gaseous hydrogen sulphide was introduced for 3° minutes, after which the mixture was corked and left χ for 2 hours 10 minutes under agitation. 100 cm of 3 water followed by 14.4 cm' of normal hydrochloric acid were then added, and the whole was agitated vigorously before removing the insoluble matter formed by vacuum-filtration and rinsing with water.

Methylene chloride was added to the filtrate, and the crystals formed were separated hy vacuum-filtration, rinsed and dried to isolate 2.i>7 g of the desired acid. M.P. = 180°C.

N. M.R. Spectrum - (CH^^SO 6.96 p.p.m. : trityl, 7.33 p.p.m. proton in 5 of thiazol.

Stage B: The syn isomer of 3-acetoxymethyl-7-C2-(2^t£i^XaminoXhXa£oX-a-xl}.-.2-£2-aminq^2^thioxo-ethoxy;2 mino^ace1:yXamino] ceph-3-em-4-carboxy 1 ic acidj. 1.01 g of the acid obtained in Stage A and O. 656 mg of 7-aminocephalosporanic acid were introduced into 2 cm^ of pyridine. After dissolution, 0.5 g of dicyclohexyl carbodiimide in 5 cm of methylene chloride were added, and the whole was agitated for one hour at ambient temperature. The formed precipitate was then removed by vacuum-filtration, rinsing with methylene chloride, and dried to isolate about 0.5 g of - 113 dicyclohexylurea. The filtrate was poured into 23 cm^ of normal hydrochloric acid. After agitating for 5 minutes, the organic phase was separated by decanting, z washed with 25 cm of water, dried and vacuum-filtered 5 . and the solvent was driven off from the filtrate to leave a residue, which was taken up and crumbled in isopropyl ether. The insoluble matter was then separated by vacuum-filtration and rinsed to obtain the desired product in impure form. This was dissolved z in A cm of ethyl acetate, and 0.18 g of active charcoal were added, which were subsequently removed by vacuum-filtration, rinsing with ethyl acetate. The z filtrate was agitated, and over 5 minutes 20 cnr of isopropyl ether were introduced before continuing the agitation for a further 5 minutes. The insoluble matter t was recovered by vacuum-filtration, rinsing with isopropyl ether, to obtain after drying the desired purified product.

Stage C: The syn isomer of 3-acetoxymethyl-7-(2-(220 xaminoXhXaz,0X-4-ylX-2-£2-amino^2xthioxo,-ethoxyimino) a>c_etylamXnjo)£ejoh^3^em-4-c.arb£xylXc_ac.id.

The product obtained in Stage B was introduced into 12 cm^ of trifluoroacetic acid, and the whole was agitated for 30 minutes at ambient temperature. The acid waa partially evaporated under reduced pressure and precipitation was initiated with 120 cm of isopropyl ether. The precipitate was crumbled and then «am - 114 recovered by vacuum-filtration, rinsing with isopropyl ether, to obtain after drying, a product identical to that of Example 16.

Example 18: The syn isomer of 3-acetoxymethyl-7-C2-(25 aminothia zol-4-y1)-2-(2-oxo-propoxyioino)ac etylamino] ceph-5-em-A-carboxylic acid trifluoroacetate.

Stage A: Thy syn isymyr_o£ £7ycytoxymythy£-7-£2y(2-_ ^trityXaminothiaz^oi-A-£l^-2-£2^oxo^roEpxyjjnino)acetylx £mino]ceph^3^em-4-carb£xylic_acid. 7.6 g of di ethyl ammonium 3~acetoxymethyl-7-C2-(2-tritylaninothiazol-4-yl)-2-hydroxyimino-acetylamino] ceph-3-em-4-carboxylic acid, syn isomer, prepared in X Example 1, was introduced into 114 cnr of methylene chloride and Ila cm^ of distilled water. Then at 20°C and under agitation, 14 cm^ of triethylamine were added. The whole was agitated for 5 minutes, after which 8.45 cm^ of bromoacetone were added at 20°-25°C. After agitation at 25°C for 5 hours, the whole was acidified . to pH 1-2 at 15°G with 6 cm^ of hydrochloric acid. The organic phase was separated by decanting, and product 5 was extracted from the aqueous phase with 250 cm methylene chloride. The organic phases were combined and washed with water, and after re-extracting the product from the washing waters, the total orgaic phase was dried and distilled to dryness to obtain 8.48 g of x a resin. This was dissolved in 8.5 cm of methylene chloride, and precipitation therefrom was then induced - 115 by the addition of 85 cm^ of diethyl ether. After agitation for 2 hours at ambient temperature, the precipitate was separated hy vacuum-filtration, rinsed three times with 10 cm^ of ether and dried to obtain 6.27 g of the desired product.

Purification by converting to the diethyl ammonium salt: The product obtained above was taken up in 62 cnr* of ethyl acetate, and pasted thereon at ambient temperature for 5 minutes. Insoluble matter was removed by vacuum-filtration, rinsing with ethyl acetate, and 7 the filtrate was concentrated to 50 cnr before the 7 introduction in one portion of 0.6 cnr of diethylamine. After agitation, the gum formed was rinsed three times with 5 cm^ of ethyl acetate. The filtrate was diluted with 130 cm^ of isopropyl ether, and the precipitate thus formed was agitated in the mother liquor for 15 minutes before being separated by vacuum-filtration, rinsing with isopropyl ether. After drying, 3.27 g of the desired salt were obtained. 3.25 g of this salt were dissolved in 25 cnr of distilled water and 98 cm^ of ethyl acetate, and 50 cm^ of a saturated aqueous solution of sodium chloride were added. One gum was decanted, it being recovered with the aqueous phase. After acidification to pH 1-2 with 2.5 cm^ of concentrated hydrochloric acid, inthe presence of 50 cm^ methylene chloride, product was extracted from the aqueous phase with methylene chloride 9 8 6 7 - 116 (50 cm^ twice). The organic phase was then washed with water, dried, vacuum-filtered with rinsing and distilled to obtain 1.79 g of a resinous product. This was dissolved in 4 cm^ of methylene chloride, and after dilution with 40 cm^ of diethyl ether, the insoluble matter was recovered by vacuum-filtration, rinsed with diethyl ether and dried to obtain 1.22 g of the desired product.

N.M.R. Spectrum - CDCl^ 2.03 p.p.m. O-C-CHj 2.13 p.p.m. 6.8 p.p.m. proton in 5 of thiazol.

Stag£ B: The syn £somer_o£ £-acetoxymethy£-7-£22( 2-_ 33Πΐϊηο£ήΪ3£θ1.-η-χ1^-2-£23θχθ3ρΓθ£θ.2^ΰηϊηο) acetylamino] £e£h^33em-4-£arboxylic_acid. trifluoroacetate.;. 1.22 g of the product obtained in Stage A were introduced into 12 cm^ of trifluoroacetic acid and agitated therein for 15 minutes at 20-22°C. The whole was reduced in vacuo to 6 cnr and then diluted with 60 cm^ of isopropyl ether, and the precipitate thus formed was agitated at ambient temperature for 15 minutes before being separated by vacuum-filtration, z rinsing five times with 5 cnr of isopropyl ether, to obtain, after drying under reduced pressure, 0.97 g of crude product. - 117 z This was purified by dissolving in 4 cnr of acetone containing 1% water and then adding 0.2 g of active charcoal, which, after agitating for 5 minutes at 20-22°C, was separated by filtration and rinsing five times with 1 cn' of acetone containing 1% water.

At 20°-22°C, 90 cm^ of diethyl ether were added to the filtrate, and after agitation at 20-22°C for one hour the insoluble matter was separated by vacuumfiltration, rinsing with diethyl ether and dried to obtain 0.57 g of the desired product.

Example 19? The syn isomer of sodium 3~acetoxymethyl~7~ -(2-(2-aminothiazol-4-yl)-2-(2-oxo-propoxyimino)acetylamino]ceph-3-em-4-carboxylate. 0.57 g of the trifluoroacetate obtained in Example 3 18 was dissolved in a mixture of 0.25 cm of distilled water, 2.3 cm^ of methanol and 2.3 cm^ of a normal methanlic solution of sodium acetate. The light insoluble matter obtained was removed by vacuum-filtration rinsing with 2.3 cm^ of methanol, and the filtrate was 3 concentrated to about 3 cm to obtain a coloured 3 solution, which was diluted with 20 cm of ethanol.

After agitating at 20-22°C for 10 minutes, the insoluble matter was separated by vacuum-filtration, rinsing three times with 3 cm^ of ethanol, and dried to obtain 0.38 g of the desired sodium salt.

By concentrating the mother liquors it was possible to obtain by vacuum-filtration a second portion <· - 118 of 0.12 g of sodium salt, which was pasted at 20°C for minutes in 0.6 cnr of methanol. After dilution with cm^ of ethanol and subsequently rinsing, 0.0? g of sodium salt were obtained.

The sodium salt thus obtained (0.45 g) was purified by dissolving at ambient temperature in 2 cm^ of distilled water, and slowly and under agitation at o 3 C adding 12 cm of acetone. The precipitated gums were removed hy vacuum-filtration, and the filtrate was brought to dryness to obtain a residue. The residue was treated as just-described, starting with 3 1.5 cm of distilled water and 10 cm of acetone, and the resulting residue was taken up with 5 cm of pure ethanol. The insoluble matter was then vacuum-filtered o 3 at 20 C, rinsing three times with 1 cm of ethanol, and dried under reduced pressure to obtain 0.26 g of the desired product.

N.M.R. Spectrum (CH^gSO 2 p.p.m. : O-^-CH^ ” 2.13 p.p.m. : Ci^-C-CHjj 6.78 p.p.m. : proton at 5 position of thiazol.

Example 20; The syn isomer of 5~methyl-7-C2-(2-aminothiazol-a-yl )-2-( 2-amino-ethoxyimino)acetylamino] ceph-3-em-4--carboxylic acid his trifluoroacetate. •β «cr vj w · - 119 Stage JU The syn isomer of diphenylmethyl 3-methyl-7_[ 2^(_2-_tri tylami nothiazol^/v^yl 2-_trit2lamino-_etho_2cy_2 _imino )acetylamino ]_ce_ph_;3j;e^-^-carboxy late. 0.923 g of the syn isomer of 2-(2-tritylamino5 thiazol-4-yl)-2-(2-tritylamino-ethoxyimino)acetic acid, prepared according to the method described in Stage B of Example 14, were introduced into and then dissolved 3 in 6.5 cm of methylene chloride and 1.3 cm of a solution of triethylamine, the triethylamine solution being prepared by mixing 1.4 cnr of triethylamine and a sufficient quantity of methylene chloride to obtain 10 cn3 of solution. After dissolution, the whole was cooled to -20°C, and 1.3 cm^ of a solution of pivaloyl chloride (prepared by mixing 1.25 cm^ of pivaloyl and a quantity of methylene chloride sufficient to obtain 10 cm^ of solution) were added. The temperature was then allowed to rise to -1O°C and maintained there fore 35 minutes, before being allowed to rise further to +10°C, at which point 0./1.90. g of benzhydryl 7-amino20 -desacetoxy-cephalosporanic acid were added. The whole was left to attain ambient temperature and was agitated for 1 hour 20 minutes, after which a further 77 mg of benzhydryl 7-amino-desacetoxy-cephalosporanic acid were added. After agitating for one hour and evaporating to dryness under reduced pressure, the residue was chromatographed on silica, eluting with a benzene ethyl acetate mixture (8:2), to obtain 0.504 g of the desired - 120 product.

N.M.R. Soectrum (CDC1,) 2.1 p.p.m. : methyl at 3 position 6.93 p.p.m·: proton of diphenylmethyl CH2 Stage B: The. syn isomer__o£ ^-mehh^l^^D-fZ-amini^ thi azo 1.-4-yl £-^-£2^aminp2e thpxyimino2.-a.cety 1amino 3 c eph-3-em-a-carb£xylic_acid bip trifluproapetape^ 357 mg of the product obtained in Stage A were x introduced into 3 cnr of trifluoroacetic acid, and 10 the solution formed was agitated for 2 hours 30 minutes and then placed in a hath of iced water before quickly adding under agitation uQ cm^ of a mixture (50:50) of isopropyl ether and petroleum ether (fraction 64-75°C). The whole was agitated for 10 minutes and the insoluble matter was then vacuum-filtered, rinsed with isopropyl ether then diethyl ether and dried until constant weight to obtain 200 mg of white powder. M.p. - about 25O°C with decomposition.

N.M.R. Spectrum (CH^)gSO 2.03 p.p.m. : methyl at 3 position 6.88 p.p.m. : proton at 5 position of thiazol.

Example 21: The syn isomer of 3-acetoxymethyl-7-C2-(2-nminothiazol-4-yl)-2-(2-bromoethoxyimino)acetylamino3 ceph-3-gm-a-carboxylic acid trifluoroacetate.

Stage A: The syn isomer of p-butyl 3~acetoxymethyl-7-C2^(2-t^ri.tylpmpnothipzo.l^4^yl)-2^(2-hromo.-pthp2grimin£)_ acetyl amino3 ceph^xam-a-carbpxylat e.. 121 1.185 g of the syn isomer of 2-(2-tritylaminothiazol-4-yl)-2-(2-bromo-ethoxyimino)acetic acid and 0.725 g of .t-butyl 7-amino-cephalosporanate were introduced into 20 cm^ of methylene chloride. The whole was cooled, and then under an inert atmosphere, 4.75 cm of 0.5M dicyclohexylcarbodiimide solution in methylene chloride were slowly introduced. After agitating at 0° - +5°C for one hour 30 minutes dicyclohexylurea crystallises out, which after agitating for a further one hour at 2O-25°G was separated by vacuum-filtration at 20°C, rinsing with methylene chloride. 0.293 g of dicyclohexylurea were obtained. The filtrate was brought to dryness under reduced pressure to obtain 2.09 g of impure product, which was purified by chromatography on silica, eluting with a mixture of benzene and sulphuric acid (1:1) to obtain 1.129 g of the desired product.

Stage B: The_sffi_is ome r of 3~acetoxymethyl-7-02-(2£m£n£thijiz£l24^y2 )-2^( 2-brom£-£thO2srimino) acetyl^ amino.3c.e£hy3xem-4-c.arb£xyli.c_ajcid. trifluoroaceta.te.j_ 1.301 g of product obtained from Stage A were introduced into 13 cm^ of trifluoroacetic acid, and the whole was agitated at ambient temperature for 10 minutes, with total dissolution occurring after one minute of agitation in an inert atmosphere. The formed solution was distilled under reduced pressure to drive off trifluoroacetic acid whilst in a water «»867 - 122 bath at a temperature lower than 35°C, the distillation 3 being continued until a residual volume of about 5 cm was obtained. Whilst cooling further with an ice bath and whilst under agitation, 42 cm^ of isopropyl ether were added, and a yellow precipitate was obtained, which after agitation at ambient temperature for a further 30 minutes was separated by vacuum-filtration, rinsed three times with 2.6 cm^ of isopropyl ether and dried under reduced pressure at ambient temperature to obtain 0.893 g of the desired product.

The preparation of the syn isomer of 2-(2-tritylaminothiazol-4-yl)-2-(2-bromo-ethoxyiiiiino) acetic acid used a3starting material in Stage A. a) The. syn isomer of ethy^ _2-(2-tr£t£laminothiazolj 15 2-br£mo-e,tho3cyimin£)_a£eXaXei Under argon, a mixture of 4.94 g of ethyl 2-(2-tritylamino-4-thiazolyl)-2-hydroxyiminoacetate hydrochloride, syn isomer, were introduced into 10 cm^ of dimethyl formamide, and at ambient temperature and over 3 minutes, 4.14 g of potassium carbonate were added. The whole was agitated for 20 minutes at 20°C before the addition of 8.65 cm^ of 1,2-dibromoethane, and after agitation for a further 3θ hours, the whole X was poured into a medium containing 100 cm' of distilled water and 20 cm^ of methylene chloride. The organic aqueous phases were separated by decanting before extracting product from the aqeuous phase with methylene - 123 chloride, washing the combined organic phases with distilled water and re-extracting product from the washings. The entire organic phase was then dried, vacuum-filtered and distilled to dryness to give a crude product, which was chromatographed on silica, eluting with benzene containing 5% diethyl ether.

A first fraction was collected, which was recrystallised from methanol after dissolving at 50-60°C and vacuumfiltering at 0° - +5°C. 1.16 g of cream white product were obtained, m.p. = 117°C, and subsequently a homogenous fraction of 1.258 g was obtained, b) The syn isomer of 2-(2-tritylaminothiazol-4-yl_)-2^(^-br£m£-£tyo2^i.mino)acetic_acid.

Under argon, 2.88 g of ethyl 2-(2-tritylamino15 thiazol-'i-yl)-2-(2-bromo-ethoxyimino) acetate, syn isomer, obtained from a), were introduced into 4.3 cm^ of dioxan. The whole was agitated at ambient temperature in an inert atmosphere until dissolution after which over 3 minutes and at 20-25°C were added 30«6 cm^ of 0.5M ethanolic solution of potassium in ethanol. After agitating at ambient temperature in an inert atmosphere for 24 hours, the potassium salt, which had crystallised out after 2 to 3 hours of reaction, was separated by vacuum-filtration at ambient temperature, rinsing with 1 cm^ of diethyl ether then three times with 2 cm of methylene chloride, to obtain 1.6g of the desired salt. This was taken up with a mixture of - 124 10 cm^ of distilled water, 10 cm^ of methylene chloride z and 1 cm of 2N hydrochloric acid, which was then agitated in an ampoule for several minutes before the addition of 10 cm^ of distilled water, 10 cm^ of methylene chloride and 1 cm^ of 2N hydrochloric acid.

The methylene chloride phase was washed to neutrality x with three times 20 cnr of distilled water, and the product was re-extracted from the washing waters with 10 cm^ of methylene chloride. The methylene chloride phases were then combined, dried, vacuum-filtered with rinsing and distilled to dryness to obtain l.n.65 g of resin. This was purified hy taking up with 15 cm^ of 1,2-dichloroethane and dissolving therein whilst heating to about 40°G. The temperature was then brought down to 20°C, when crystallisation started and the whole was agitated for 3 hours at 20°C. After vacuumx filtration, rinsing with 0.5 cnr of 1,2-dichloroethane and drying 1.185 g of a white product were obtained.

M.p. = 150°C. Rf. - 0.65 (acetone containing 5% water).

Analysis : Calculated: C% 58.21 4.13 N% 7.82 S% 5.98 Br% 14.89 Found : C%58.0 H% 4.2 N% 7.8 5.9 Bi# 15.2 N.M.R. Spectrum CDClj p.p.m. 3 .*»4 : (triplet) -CHg-Br J = 7.5 Hz 25 4.3 : (triplet) -N-O-CI^- J = 7 Hz 6.55 single : proton in 5-position of the thiazole - 125 Example 22: Sodium salt of 5-acetoxymethyl-7-C2-(2-aminothiazol-4-yl)-2-(2-bromoethoxyimino)-ac etyl-amino]-ceph-5-em-4.-carboxylic acid, syn isomer. 0.895 g of the trifluoroacetate obtained in 7 Example 21 and 3.5 cm of a molar methanolic solution of sodium acetate were mixed and agitated at ambient temperature under an inert atmosphere until dissolved, then filtered and rinsed first with 1 cnr , then twice 7 with 0.5 cm, of pure anhydrous methanol. 40 cm of absolute ethanol were added. Some cloudiness was observed and then the sodium salt precipitated. After agitation for 2 hours at ambient temperature, the salt formed was vacuum-filtered and rinsed three times with 7 7 cm of absolute ethanol then three times with 3 cm of diethyl ether. The salt was dried at ambient temperature under reduced pressure to obtain 0.545 g of product. Rf. = 0.6 acetone containing 10% water Ca]2^ = +'i5° - 1.5° (c = 1% in H20) . Analysis : Calculated: C% 35.80 H% 3.00 N% 12.28 S% 11.24 Br% la.01 Found : C% 36.0 H% 3.1 N% 11.9 S% 11.2 Br% 15.7 N.M.R. Spectrum (CD^^SO. (p.p.m.) 2.0 : -O-jj-CH^ 3.62 (triplet): -CHj-Br J = 6Hz 4.35 (triplet): =N-O-CH2- J = 6Hz -1266.75 : proton in 5-position of the thiazole.

Example 23: The syn isomer of 3-acetoxymethyl-7-(2-(2-aminothiazol-4-yl)-C2-(2-[2-aminophenylthio3-ethoxy-imino)-acetylamino]-ceph-3-em-a-carboxylic acid. stage A: The syn isoaier_o£ £-ac_etoxymethyl-7-£2-(£-_fcrityl-aminoXhia£oX-4-ylX-2-£2-C2-___ aminophenylthio]^ ^eXh£xy-imXn£)^a£eJ^XaminoX-£e£hy3;z.e.S~A-£arbox2lic_acid.

Successively 790 mg of 3-acetoxymethyl-7_C2-(2trityalminothiazol-z;-yl)-2-(2-'bromoethoxy-imino)-acetyl10 amino)-ceph-5-em-a-carboxylic acid, 8 ml of benzene and 0.28 ml of pure triethylamine were introduced into the reaction vessel. After total dissolution, 0.14 ml of 2-amino-thiophenol, 5 ml of distilled water and several mg of methyltricaprylammonium chloride were added. The mixture was agitated briskly for one night, then 2 ml of IM hydrochloric acid were added and the mixture was extracted with ethyl acetate, washed with water, dried and concentrated to dryness. The residue was taken up with diethyl ether, and vacuum-filtered to obtain 690 mg of 3-acetoxymethyl-7_C2-(2-tritylaminothiazol-a-yi)-2-(2-C2-aminophenyl-thio]-ethoxy-imino)-acetylamino]-ceph-5-em-4-carboxylic acid.

Stage B: The syn isomer_o£ £-acj5toxymethyly7-£2.2(2-_ yaminoXhia£oX-^-ylX-2-£2-C2-am£n£phenyX-£hio]_-ethoxy25 ^imino2.-ac£tylam_in£]2;ceph-^-£m2ayc£rboxyXi£ £cid^_ To the product obtained in Stage A 5.3 “I of 66% aqueous formic acid were added, and the mixture was 9 O w · - 127 heated to 55°C for 15 minutes, cooled, and vacuumfiltered. The solvents were driven off from the filtrate by distillation under reduced pressure, and the residue was taken up with ethanol then distilled to dryness under reduced pressure. The desired product was obtained and used without further purification in the following example.

The starting material for Stage A of this Example was prepared as follows. 26.85 g of the syn isomer of 2-(2-tritylaminothiazol-4-yl)-2-(2-bromoethoxy-imino)-acetic acid prepared in Example 1, 7·25 g of l-h;/droxy 1 H-benzo15 -triazol, 12 g of dicycloexylcarbodiimide and 350 ml of anhydrous methylene chloride were mixed and agitated for 23 hours at ambient temperature. The dicyclohexylurea thus formed was removed by vacuum-filtration, and the filtrate was washed with water, with a IM aqueous solution of sodium bicarbonate, then with water. The filtrate was dried, then concentrated to dryness under reduced pressure. The residue was taken up with 150 ml of ether and 25.4 g of crystals were obtained which were dissolved in 235 ml of anhydrous methylene chloride.

To the solution were added 10.56 g of 7-amino-cephalosporanic acid, 200 ml of anhydrous methylene chloride and 10.9 ml of triethylamine, and the mixture was agitated for 65 hours. 350 ml of water and 45 ml of «j σ u f - 128 2Ν hydrochloric acid were then added and the formed mixture was agitated to effect extraction. The organic phase was washed then dried and concentrated to dryness under reduced pressure. The residue was taken up with 75 ml of ethyl acetate and diluted with 520 ml of diethyl ether, then vacuum-filtered to obtain 24.75 g of the desired product.

Example 24: Sodium salt of 5-acetoxymethyl-7~(2-(2-aminothiazol-4-yl )-2-( 2-[2-aminophenyl-thio3-ethoxy10 -imino)-acetylamino3-ceph-5-em-carboxylic acid, syn isomer.

To the product obtained in Example 23 there were added 1.5 ml of a molar methanolic solution of sodium acetate and 1 ml of methanol. This was mixed, then diluted with 6 ml of ethanol. The precipitated product was vacuum-filtered off, washed with ethyl alcohol, then made into a paste with ether to yield 235 mg of the desired product.

Analysis : θ23Η23θ71,6®3Ν3 pM 614.65 Calculated: C% 44.9^· H% 3·77 N% 13.6? S% 15.65 Found : 4a.8 3·7 13·3 Ια.8 N.M.R. Spectrum (CD^gSO (p.p.m.) , -0ti.08 : =N-0-CH225 6.73 : proton in 5-position of thiazole. y 8 0 7 - 129 Example 25: The syn isomer of 3-aeetoxymethyl-7-C2-(2-aminothiazol-4-yl)-2-([2-amino-1.5.4-thiadiazol-5-yl)~ -thio-ethoxy-imino)-acetylamino)-ceph-3-em-a-carboxylic acid.

Stage A: ^-£ce,to,xym£thyl>-2,--C23>(2-tritylamin£thi£Z£l343 3yl^) 323(^233315031^3^43^18(118501.-5-213^10,136^33^2^ 3imin05-5c3t2lamw5l3ceph-5-.em3A3carb0xy.lic. acid^ a) 1.9 g of 2-amino-5-mercapto-l,3,4-thiadiazole were mixed with 15 ml of a molar solution of lithium methylate in methanol. After total dissolution, the solution was concentrated to.dryness under reduced pressure to obtain the lithium derivative of 2-amino-5-thiol-l,3,4-thiadiazole in the form of a resin which was used in that form. b) 7.91 g of the syn isomer of 3-acetoxymethyl-7-C2-(2-tritylaminothiazol-4-yl)-2-(2-bromoethoxy-imino)-acetylaminol-ceph-3-em-4-carboxylic acid prepared in Example 3 were introduced into 3θ ml of anhydrous dimethylformamide and 67θ mg of lithium iodide. After dissolution the lithium derivative obtained above was added with 15 ml of dimethylformamide. The mixture was agitated for 5 and a half hours at ambient temperature, then 450 ml of water and 1 ml of formic acid were added. Then the mixture was extracted with ethyl acetate, dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica eluting with a 70-20-10-1 ethyl acetate-methanol-water- 130 triethylamine mixture, to obtain 2.36 g of the desired product.

Stage B: 2-ac£tox2m£thy2-£-£22:(2-jiminothiazol24ry.l).22£ j-( ^^amino^l^j/vyt hi fid ia^o l-^-yl^thio 3yethoxy-imino)-_ 2,a£etyl.amino2-c.eE.h23se®-iL-£.a£Boxylic_ac_id. 8a3 mg of the tritylated product of Stage A were agitated for 15 minutes at 55°C with 6.4 ml of 66% aqueous formic acid. The mixture was concentrated to dryness under reduced pressure and the residue was taken up with 5 ml of ethanol and 50 ml of diethyl ether, then vacuum-filtered to obtain 606 mg of desired crude product.

Example 26; Sodium salt of 3~acetoxymethyl-7-(2-(2-aminothiazol-4-yl)-2-([2-amino-l,3.4-thiadiazol-5-yl15 -thio ] -ethoxy-imino) -ac etyl amino ] -ceph-3-em-a.-carboxyti.c acid, syn isomer.

The product obtained in Example 25 was mixed with 1.5 ml of molar sodium acetate in methanol and 0.5 ml of dimethylformamide. 5 ml of ethanol were added and the precipitate thus formed was vacuum-filtered off, taken up with 7 ml methanol and refluxed, then cooled and vacuum-filtered to remove impurities. The filtrate was concentrated to dryness under reduced pressure, and the residue was broken up in ethanol, vacuum-filtered and dried to obtain 146 mg of the desired product.

Analysis Cl9H19°7N8S4Na PM : 622.66 Calculated Found C% 36.65 H% 3.08 37.0 3.7 N% 17.99 S% 20.60 17.5 19.8 - 131 N.M.R. Spectrum (CD^^SO p.p.m. 1.99 -0-C-CH, II ~4.25 6.76 =N-0-CH2 : proton in 5~position of thiazole.

Example 27s 3-acetoxymethyl-7-(2-(2-aminothiazol-4-yl)-2-(2-[5-nitro-2-pyrid inyl-thio 3-ethoxy-imino)-ac ety1amino)-ceph-3-em-a-carboxylic acid, syn isomer.

Stage A: .2,-acetoxymethyl~Z-i2-(2_-£rityl£mi^n£thiyzol_^4xyl)x2-(2-£53nitroy2xpyridinyl£thio.]-eyboxy-imino)3 ^ac.etyl.amino]_-c.eoh^3^em-4-c_arb£xylj.c_a£iy.

Into a reaction vessel, 396 mg of 3-acetoxymethyl-7~(2-(2-tritylaminothiazol-4-yl)-2-(2-bromoethoxy-imino) -acetylamino]-ceph-3-em-4-carboxylic acid prepared in Example 3, 4 ml of benzene and 0.14 ml of trietfryalmine were successively introduced.

After dissolution 92 mg of 2-mercapto-5-nitro-pyridine, 5 ml of distilled water and several mg of methyltricaprylamnonium chloride were added, and the mixture was agitated for 72 hours at ambient temperature. Then 1 ml of N hydrochloric acid was added and the whole extracted with ethyl acetate. The organic phase was dried then concentrated to dryness under reduced pressure The residue was taken up with diethyl ether, and vacuumfiltered to obtain 416 mg of the tritylated productStage B: ^-ac£t£xym£thyl_-2-£2_^(£-ami_n£thiaz£l_24^7j-_2_-(2-_ ^[^-nihr^-^-pyridinyjL-thioj.-e.thoxy-imino^.-yce^tyl^minol^, £ceph-j5-£m-4-carboxylic. acid_. - 132 To the product obtained there were added 3-2 ml of 66% aqueous formic acid and the mixture was heated to 55°C for 15 minutes. The triphenylcarbinol thus formed was removed by vacuum-filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was taken up with ethanol and concentrated to dryness again to obtain the desired product.

Example 28: Sodium salt of 3~acetoxymethyl-7-(2-(210 -aminothiazol-a-yl)-2-(2-[5-nitro-g-pyridinyl-thio]-ethoxy-imino)-acetylamino]-ceph-3-em-a-carboxylic acid, syn isomer.

A little methanol was added to the product obtained in Exanple 27, followed by 2ml of a molar methanolic solution of sodium acetate. The traces of insoluble matter were removed by vacuum-filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was taken up with ethanol, and vacuum-filtered to obtain 153 mg of the desired sodium salt.

Analysis : C22H20°9N7S3Na6/t5.63 Calculated: C% 40.93 5.12 N% 15.19 S% 14.90 Found : 59.0 3.5 15.2 12.9 N.M.R. Spectrum (CD^j^SO p.p.m. 2.0 : -O-jji-CHj — 3·θδ — 4.3 — 4.4 : =N—0—CH2— 6.76 J proton in 5-position of thiazole. ( - 133 Example 29: The ayn isomer of 3-acetoxymethyl-7-C2-(2-aninothiazol-4-yl)-2-(-C3-cyano-6-methyl-2-pyridinyl-thio3-etyoxy-imino)-acetylamino3-ceph-3-em-4-carboxylic acid.

Stage A: a.ce.tp.x2me t hyi-2-C.2^,( 2-Xri.tylpnd.no thi a Z£ly4y ^y 1_) -2y( 2-£3x.cyano_6-methy 1.-2-pyridinyl-thio3,-ethoxypmino^apel^iamino^-ceph^-em-a-^arboxylic-acid. 791 mg of 3~acetoxymethyl-7_C2-(2-tritylaminothiazol-a-yl)-2-(2-bromoethoxy-imino)-acetylamino]-ceph10 3-em-/t-carboxylic acid prepared in Example 23 were mixed with 326 mg of 2-mercapto-3-cyano-6-methyl-pyridine, 10 ml of benzene, O.'t2 ml of triethylamine, 10 ml of water and several milligrams of methyltricaprylanmonium chloride. The mixture was agitated for 44 hours at ambient temperature, then acidified with 3 ml of N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and concentrated to dryness under reduced pressure. The residue was taken up with diethyl . ether, and vacuum-filtered to obtain 877 mg of a crude product.

Stage B: The syn isomer of 3-acetoxymethy£-7-[2£(2-_ _2aninoth_iazol-4-y l2.-2~i.22,(^-£ypn£-6-meXhyl yEypyridinyly ^thi£)-eXhpxy-imino ) pacetyl.aminoyc eph-^-pm-4pcarbojcy Ι,ΐρ acid..

To the product obtained in Stage A there was added 7 ml of 66% aqueous formic acid and the mixture was heated to 55°C for 15 minutes with agitation, then - 134 cooled and vacuum-filtered. The solvents were driven off from the filtrate hy distillation under reduced pressure, and the residue was taken up with ethanol and concentrated to dryness to obtain a crude product which was purified by forming the sodium salt and treating this with formic acid.

Analysis : * 617.69 C% 46.6? H% 3.75 N% 15.87 S% 15.57 Calculated Found 46.2 .8 .2 la.5 N.M.R. Spectrum (DMSO) p.p.m. 2.0 a.2 - a.5 - a.a : O-C-CH, I 1 =N-0-CHo 6.8 : proton in 5-position of thiazole.

Example 30: Sodium salt of 3-acetoxymethyl-7-(2-(2-aninothiazol-q-yl)-2-(2-(3-cyano-6-methyl-2-pyridinyl-thio3-ethoxy-imino)-acetylamino]-ceph-3-em-a-carboxylic acid, syn isomer.

To the product obtained in Example 29 there were added 5 ml of methanol then a ml of a methanolic solution of sodium acetate. The mixture was concentrated to dryness under reduced pressure, then the residue was broken up in ethanol and vacuum-filtered to obtain 505 mg of the desired eodium salt.

Example 311 The ayn isomer of 3-acetoxymethyl-7~(2-(2-aminothi a zol-α-y1)-2-(2-(1-methyl-t etrazol-5-y1-thio]-ethoxy-imino)-acetylamino]-ceph-3-em-a-carboxylic acid. 48867 - 135 Stage A: The. syn £somer_of 3-acetoxymethyl-7-(2-(2^.tr_i£yliaminoyhi.az.olL-/i.-yl£-£-£2^[X-me£hyl2it£trayo£-5.-yl^ amino ^th.io.]^eth£3^-i.mino) -a£®ty^-£e£h-3yem-4-£arboxylic_ acid. 432 mg of the diethylamine salt of 3-acetoxymethyl-7-£ 2-(2-tritylaminothiazol-4-yl)-2-(2-bromo ethoxy-imino)-acetylamino]-ceph-3-em-4-carboxylic acid, syn isomer were mixed with 64 mg of l-methyl-5-mercapto-l, 2,3,4-tetrazole and 2.2 ml of anhydrous dimethyl10 formamide. The mixture was heated for 1 hour 50 minutes in a water bath at 50°C with agitation, then maintained for 1 hour 3θ minutes at ambient temperature, and finally for 1 hour 10 minutes at 55°C. The mixture was cooled, diluted with 20 ml of water, agitated and the formed precipitate was vacuum-filtered to obtain 406 mg of a crude product.

Stage B: The. syn £somer of 3-acetoxymethyl-7~£2y(2-_ ^amino£hi.a£oX-£-yl£-2-^-£l;jne.thylrie£raz£ly5^yl.-th£o].-ethoxy-imino) ^acety1. amino-cephemy4-carboxylie. acixL 406 mg of the product obtained in Stage A were dissolved in 3.2 ml of 66% aqueous formic acid, and the solution was heated in a water bath at 55°C for 15 minutes. The triphenylcarbinol formed was removed by vacuum-filtration and the aqueous formic acid was driven off by distillation under reduced pressure. The residue was taken up with ethanol and again concentrated to dtyness. 3 ml of methanol were added to dissolve the - 136 10 residue and the solution was diluted with 3θ ml of diethyl ether, and the precipitate formed waa vacuumfiltered to obtain 201 mg of a crude produce which was dissolved in 1 ml of hot methanol and reprecipitated by adding 5 ml of ether. Vacuum-filtration yielded 171 mg of the desired product.

Analysis : ^19^21^7^9^3 Calculated: C% 39-10 H% 3-63 N% 21.6 S% 16.48 Found : 38*6 3-7 20.9 16 N.M.R. Spectrum (CD^^O p.p.m. 2.03 : -O-C-CH^ 4.35 (triplet): =N-O-CH2 (J 6 Hz) se : proton at 5-position of thiazole 3.91 (single) : =N-CH^ The diethylamine salt of 3-acetoxymethyl-7-£2-(2-tri tylaminothiazol-4-yl)-2-(2-bromoethoxy-imino)-ac etylamino]-ceph-3-em~'i-carboxylic acid, syn isomer, was prepared as-follows: 0.79 ol 3-acetoxymethyl-7-£2-(2-tritylamino-thiazol-4-yl)-2-(2-bromoethoxy-imino)-acetylamino]-ceph-3-em-4-carboxylic acid was added to 5 cur of ethyl acetate. On total dissolution, 0.12 cnr* of diethylamine were added, and the mixture was agitated, vacuum-filtered and rinsed with ethyl acetate to obtain the desired salt after drying. - 137 Example 52: The syn isomer of 3-acetoxymethyl-7~(2-(2-aninothiazol-4-yl)-2-(2-azido-ethoxy-imino)-acetylamino] -ceph-3-em-a-carboxylic acid.

Stage A: The syn isomer_of £-£2-tri£y£amino£hia£o£-4-_ 3yi)323(£-£zid£-£tho2^3imino.}-acetic_acid.

For one hour in a water bath at 5θ°θ, 24.8 g of sodium 2-(2-tritylamino-thiazol-4-yl)-2-(2-bromoethoxy-imino)-acetate were agitated with 125 ml of dimethylformamide and 7.5 g of tetramethylguanidine azidide.

After agitation for a further 45 minutes a clear brown solution was obtained, and this was cooled to ambient temperature. 500 ml of water and 50 ml of 2N hydro chloric acid were added, and the mixture was vacuumfiltered, made into a paste three times with water, then ground up in methylene chloride. The filtrate was decanted, washed with water then dried. After concentration to 50 ml under reduced pressure 250 ml of diethyl ether were gently added, and the mixture was vacuum-filtered to obtain 15.58 g of the acid.

The sodium salt of 2-(2-bromoethoxy-imino)-2-(2-tritylaminothiazol-4-yl)-acetic acid, syn isomer, was prepared as follows: g of sodium carbonate pellets were added to 280 cm^ of absolute ethanol. 28.2 g of ethyl 2-(225 -bromo-ethoxy-imino)-2-(2-tritylamino-thiazol-4-yl)-acetate, syn isomer (described in Example 21) were added, and the mixture was agitated for 65 hours at - 158 ambient temperature. The sodium salt separated, and this was vacuum-filtered, washed with ethanol and dried in vacuo to obtain 29.82 g of the desired product as a 12% solvate.

Stage B: The syn isomer_of 2-£C_et£xymet£y£-7-£2£(2-_ ^trityXaminothXa£oi-4-ylX-2^-£2^a£id>o-^eXh£xy-imino)^ ^ace^iamino£-£e£h^^em-4-carb£xylic_acid in_the_form £f_iXs_diethylamin£ salt 2.54 g of 7-amino-cephalosporanic acid, 25 ml of 10 anhydrous methylene chloride and 2.6 ml of triethylamine were agitated for 15 minutes at ambient temperature. 6.02 g of the 2-(2-tritylamino-thiazol-4-yl)-2-(2-azido-ethoxy-imino)-acetate of 1-hydroxy-lH-benzotriazole were added and the mixture was agitated for 45 hours at ambient temperature. 25 ml of water and 5 ml of N hydrochloric acid were added. The mixture was separated by decantation, and the organic phase was washed with water, dried and concentrated to dryness under reduced pressure. The residue was taken up with 50 ml of ethyl acetate, and after dissolution, 2.4 ml of diethylamine were added. The mixture was cooled to 0°C and vacuum-filtered to jaeld 5.9 g of the diethylamine salt.

The 2-(2-tritylamino-thiazol-4-yl)-2-(2-azido25 -ethoxy-imino)-acetate of 1-hydroxy-lH-benzotriazole used in Stage B was prepared in the following way: 9.84 g of 2-(2-tritylamino-thiazol-4-yl)-2-(2- 139 -azido-ethoxy-imino)-acetic acid was mixed with 2.93 g of 1-hydroxy-lH-benzotriazole, η.86 g of dicyclohexylcarbodiimide and 130 ml of anhydrous methylene chloride, and the mixture was agitated for 20 hours at ambient temperature. The dicyclohexylurea formed was removed hy vacuum-filtration, and the filtrate was washed with water to which had been added sodium bicarbonate, then with water alone. The washed filtrate was dried and concentrated to dryness under reduced pressure. The residue was taken up with ethyl acetate, cooled for half an hour at 0°C and suction-dried to obtain 7.31 g of the desired product. A further 1.5 g of product was recovered from the mother liquors.

Stagg £: The syn isomer_of £aminqth_ia zo lyil'Z1 }.T2-£22.ayidp2.e £ho>xy-imino ) yacety1.amin^n^ceph-^-^m^h-carboxylic, acicL.

For 15 minutes at 50°C 1.238 g of the product obtained in Stage B were agitated with 6 ml of 70% formic acid. The triphenylcarbinol formed was removed by vacuum-filtration and the filtrate was concentrated to dryness under reduced pressure. The residue was taken up with water, broken up, vacuum-filtered and dried to obtain 0.358 g of the acid.

Example 33: Sodium salt of 5-acetoxymethyl-7-C2-(225 -amino-thiazol-4-yl)-2-(2-azido-ethoxy-imino)-ac etylamino3-ceph-3-em-4-carboxylic acid, syn isomer. 0.385 g of the acid obtained in Example 32 was - luO 10 mixed with 1 ml of a methanolic molar solution of sodium acetate. To the clear solution thus obtained were slowly added 5 ml of ethanol. The mixture wqs vacuum-filtered and rinsed with ethanol, then with diethyl ether to obtain 0.215 6 of the sodium salt.

Analysis Calculated Found c17H17°7N8S2Na = 552.u9 C% 58.4 H% 3.2 N% 21.0 S% 12.0 38.3 3.2 20.4 N.M.R. Spectrum /(CD^^SO p.p.m. 1.98 = -O-C-CH, 12.1 II 4.18 (triplet) : “N-O-CHg- J=5 Hz 6.76 · proton at 5 of thiazole.

Example 54: The syn isomer of 3-acetoxymethyl-7-C2-(2-aciino-thiazol-u-yl)-2-(2-anino-ethoxy-imino)-acetylamino] -ceph-5-em-4-carboxylic acid.

Stage A: The syn isomer_of 3^-ac et oxyme thyl_-7-£22(2-_ ^trityXaminoXhia£oX-4-xl^-2-£2^amino<5thoxy^imino)_“acetxl a.minq]^ceph-3~a_m-4-c arboxy lie acid^ 0.752 g of 3-acetoxymethyl-7-C2-(2-tritylamino-thiazol-4-yl)-2-(2-azido-ethoxy-imino)-acetylamino]-ceph-3-em-4-carboxylic acid prepared in Example 32 were mi -red with 4 ml of dimethylformamide and 0.7 ml of anhydrous triethylamine. Hydrogen sulphide was bubbled into the mixture for 15 minutes, and 40 ml of water then 0.7 ml of acetic acid were added. After vacuum-filtration 0.707 g of a crude product were obtained. 141 Stage B: The syn isomer_of 5-_acet£X2Jne_thy£-7_£2£(£3aminothia5ol.-A-2l}.-2-£23amino3e5hox2-imino.)3ac.etyiamino]3cejph-5-®ffl343C3rho2cyXic, acicL· 1.054 g of the product obtained in Stage A were heated for 15 minutes at 50°C in 5 ml of 70% formic acid. The triphenyl carbinol formed was removed by vacuum-filtration and the filtrate was concentrated under reduced pressure. The dry residue was taken up with water and the insoluble matter eliminated. The filtrate was concentrated to dryness and taken up with ethanol, broken up and vacuum-filtered to obtain 0.125 g of the acid.

Example 55: Sodium salt of 5-acetoxymethyl-7-C2-(2-aminothiazol-4-yl)-2-(2-amino-ethoxy-imino)-acetylamino] -ceph-5-em-4-parboxylic acid, syn isomer.

The product obtained in Example 54 was dissolved in 0.2 ml of a molar solution of sodium bicarbonate. 0.4 ml of ethanol were carefully added, and the insoluble matter was removed by vacuum-filtration. The filtrate was concentrated to dryness under reduced pressure, and the residue was taken up with ethanol, crumbled and vacuum-filtered to obtain 0.047 g of the desired salt.

Example 56: The syn isomer of 5-C(1-methyl-1H-t etrazol-5-yl)-thiomethyl]~7~(2-(2-aminothiazol-A-yl)-2-(2-azido-ethoxy-imino)-acetylamino]-ceph-5-em-4-carboxylic acid. - 142 Stage A: The syn £somyr_of ^-^Q-meyh^l-LH-tetrazoly5y ^yl.)-thiomethyi3y7z[2-£2xtritylaminothiazpi-4-yl£-2-_ -(2-£zid£gethoocy-iminoj.-acetyl£niino]-ceph-^-eniy4-^carboxylic. acid.

For 15 minutes at ambient temperature 0.652 g of 7-amino-3-t(1-methyl^;etrazol-5-yl)-thio-methyl]-ceph-3-em-4-carboxlic acid were agitated with 6.5 ml of methylene chloride and 0.56 ml of triethylamine. 1.29 g of the a-(2-azido-ethoxy-imino)-2-(2-tritylamino10 -thiazol-4-yl)-acetate of 1-hydroxy-lH-benzotriazole prepared as described in Example 52, Stage B, were added, and the mixture was agitated for 20 hours at ambient temperature. 10 ml of water and 3 ml of 2N hydrochloric acid were added. The mixture was separated by decanting and the organic phase was washed with t water, dried and concnetrated to dryness under reduced pressure. The residue was taken up with 5 ml of ethyl acetate and 10 ml of diethyl ether were added. The mixture was agitated for half an hour at ambient temperature, and vacuum-filtered to obtain 1.416 g of a crude product.

Stage B: Thy syn isomer of 3-£(£-methylylH-tetrazol-5yy£> -thiomethyl.]-7j2[2-£2yaminothia£ol,-4-yl2-2-£2£ayidpy -ethoxy-imino)-acetylamino] -ceph-^-mnya^carboxylic. acid^.

For 15 minutes at 50°C 1.556 g of the product obtained in Stage A were agitated in 7 ol of formic acid. Tne triphenylcarbinol formed was removed by - U5 vacuum-filtration and the filtrate waa concentrated to dryness under reduced pressure. The residue was taken up with water, broken up and vacuum-filtered to obtain 0.77 g of a crude product which was dissolved in a mi ni mum amount of a 10% sodium bicarbonate solution. 0.07 6 of active charcoal were added, and the mixture was vacuum-filtered. To the filtrate formic acid was added to give a pH of 2. The purified acid was vacuumfiltered to obtain 0.171 g of the desired product.

Example 57? Sodium salt of 5-((l-methyl-lH-tetrazol-5-yl) -thiomethyl 1-7-(2-( 2-aminothiazol-'!-yl)-2-( 2-azido-ethoxy-imino)-acetylamihol-ceph-5-ein-A-carboxylic acid, syn isomer. 0.162 g of the purified acid obtained in Example 56 were dissolved in 0.5 ml of a molar solution of sodium bicarbonate. 1 ml of ethanol was added and the insoluble matter was vacuum-filtered off. The filtrate was concentrated to dryness under reduced pressure, and the residue was taken up with ethanol, broken up and vacuum-filtered to obtain 0.09 g of the sodium salt. Analysis : 5^12^5^3 : “ 588.58n Calculated: G% 5a.7 H% 2.9 N% 28.5 S% 16.5 Found : 5A.5 5·2 25.5 15.5 N.M.R. Spectrum ( CD)pSO p.p.m. .9 : 6.76 : proton in 5-position of thiazole, 9.55-9.A8 : -CONH- Izi4 Example 38: The syn isomer of 3-((1-methyl-lH-tetrazol-5-yl)-thiomethyl1-7-(2-(2-aminothiazol-ft—yl)-2-(2-amino-ethoxy-imino)-acetylaminol-ceph-3-em-4-carboxylic acid.

Stage A: J.-XiX-meXhyl-lH-t.et.razo.lxS^yll^.thiomethyll-Tx X.(2-£2xtrityl,aminoxthi£Zoly4^yX)x2x(^-amino.-etho2yyiminpX-jicetylamino!^ceph-^-^m-4-carboxylic. .acid^ 3.91 g of sodium 3-C(l-methyl-lH-tetrazol-4-yl)-thiomethyll-7-2-(2-tritylamino-thiazol-a-yl)-2-(210 -azido-ethoxy-imino)-acetylamino]-ceph-3-em-a-carboxylate were dissolved in 39 ml of dimethylformamide. 20 ml of water were slowly added, followed by 9.75 ml of triethylamine. Hydrogen sulphide was bubbled into the mixture. After 45 minutes, 3·9 ml of triethylamine were added and the bubbling in of hydrogen sulphide continued for a further 16 minutes. The mixture was poured into a solution of dilute hydrochloric acid at 10°C, and the whole was heated for 15 minutes at 30°C under agitation, . then cooled, and vacuum-filtered. The precipitate was washed until neutral and rinsed with diethyl ether to obtain 2 g of the desired product.

The sodium 3-((l-methyl lH-tetrazol-5-yl)-thiomethyll-7-(2-(2-tritylamino-thiazol-4-yl)-2-(2-azidoethoxy-imino)-acetylamino1-ceph-3-em-4-carboxylate used at the beginning of the Example wa3 prepared as follows: For one hour at ambient temperature 8.47 g of the syn isomer of 2-(2-tritylaminothiazol-4-yl)-2-(2-azido-ethoxy-imino)-acetic acid obtained in Example 32 were 0 0 0 7 I - 145 agitated with 50 ml of methylene chloride and 1.93 6 of dicyclohexylcarbodiimide. The dicyclohexylurea was removed by vacuum-filtration. The filtrate was added, over 20 minutes, to a mixture consisting of 3.07 g of 3-C(l-methyl-lH-tetrazol-5-yl)-thiomethyl3-7-amino-ceph-3-em-4-carhoxylic acid, >'-Q ml of anhydrous methylene chloride ana 5-9 ml of triethylamine. After agitation for a further hour the mixture was concentrated to dryness under reduced pressure. The residue was taken up with 50 ml of ethyl acetate at 20°C, acidified with 0.2 ml of acetic acid and vacuum-filtered. The filtrate was washed with N hydrochloric acid, then with water until neutral. The organic phase was dried and made up to a volume of 50 ml, then 1.7 ml of diethylamine were added. The salt of the starting acid crystallised, and was removed by vacuum-filtration. The filtrate was precipitated with 115 ml of isopropyl ether. The precipitate was vacuum-filtered to obtain 7.62 g of the diethylamine salt. 5.9 g of this salt was taken up and dissolved under agitation in a mixture of 60 ml of water, 60 ml of methlene chloride and 3.5 ml of 2N hydrochloric acid. The mixture was separated hy decanting and the organic phase was washed with water, dried and concentrated to dryness under reduced pressure.

The residue was taken up with 20 ml of isopropyl ether and vacuum-filtered to obtain 5.6 g of the free acid.

This latter was dissolved in a mixture of 9.5 ml of 48867 - 146 methanol and 6.7 ml of a IM methanol solution of sodium acetate. The sodium salt was precipitated with 27 ml of isopropanol containing 25% ethanol, then diluted with 270 ml of isonropanol to obtain 4.21 g of the desired product.

Stage B: The syn isomer of 5[0.-methyl-lH-tetrazo£-5-yl2“ ythiomethyl.].z7-C2-£2-amino;;thiazol-/i_2yl).z2.z( 2-aminoy £thp2£y^imino£-ac£txlamino]-caph-£-£my4-carboxylic acidL 2g of the product obtained in Stage A were heated to 40-45°C under agitation with 5 ml of formic acid. ml of water were added and the temperature maintained for 15 minutes. The mixture was then cooled and the triphenylcarbinol formed was vacuum-filtered off. The filtrate was concentrated to dryness under reduced pressure. The residue was taken up with 10 ml of ethanol, broken up, vacuum-filtered and rinsed with ethanol then with diethyl ether to obtain 1.36 g of a crude product which was taken up with 15 ml of 2N hydrochloric acid. The insoluble matter was vacuum20 filtered off and the filtrate was then brought to pH 4 by the addition of 3 ml of an aqueous IM solution of lithium acetate, then an aqueous solution of lithium hydroxide. The mixture was vacuum-filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was taken up with 30 ml of ethanol, broken up and vacuum-filtered to obtain 515 mg. of the desired product. 133 og of the product were - 147 recovered from the mother liquors. The two products were treated again in the same way as the crude product and 43Ο mg of a white product were isolated.

N.M.R. Spectrum (CD^^SO p.p.m. 6.86 : proton at 6-position of thiazole Example 59: Trifluoroacetate of 5~acetoxymethyl-7-(2-(2-aminothiazol-a-yl) -2-( 2-iodoethoxy-imino) -acetylamino] -ceph-3-em-4-carboxylic acid, syn isomer.

Stage A: Benzhydryl^^a^e^oxyme^hyl^T^r^-L^stri^yl.^ a>ni.no-thi£ZO.l343^}-2-£23iodo_e£h£X2-iimino)3ac.etyl.amino_].-ceph-5-em-A-carboxylate, syn isomer^ Under an inert atmosphere 1.28 g of the syn isomer of 2-(2-iodo-ethoxyimino)2-(2-tritylamino-thiazol -4-yl)-acetic acid solvated with 1,2-dichloroethane (being in fact 1.09 g of pure product) were mixed with 1.45 g of the benzhydryl ester of 7-amino-cephalosporanic acid in 22 cm^ of anhydrous methylene chloride. The mixture was cooled in an ice bath and, drop by drop, . 5 cm^ of a 0.5M solution (being 103 g/litre) of dicyclohexylcarbodiimide in methylene chloride were introduced. After agitation at 0° to +5°G for one hour thirty minutes, then for one hour at 26°C, the precipitated dicyclohexylurea was vacuum-filtered off, rinsing with methylene chloride. The filtrate and the washing waters were evaporated to dryness at a temperature lower than /±0°C under reduced pressure to obtain 2.98 g of a product which was chromatographed on silica eluting with a 92-8 methylene chloride-ethyl - 148 max. = 269 nm acetate mixture. 1.12 g of white product were obtained.

U.V. Spectrum (Ethanol/N hydrochloric acid) η /10 E£ = 209 I.R. Spectrum (chloroform) = β-lactam -1 r. .-1 1791 cm G=N-0R: 1042 cm-i·, C=C: 1638 cm'1 N.M.R. Spectrum (CDCl^) proton at 5-position of thiazole: 6.75 p.p.m.

Stage B: Tr^f luoroacetate_of X-^cetoxymethyl~2~X2-(2-_ -aminothiaxoi-4-xl2-2-£2-iodoeXhoxx-imino)j;a£e_tyXaminp2-ceph-3-em-4-carboxyl ic_a£id ♦_ sjpi_is omer. 960 mg of the product obtained in Stage A were introduced into 10 cm^ of pure trifluoroacetic acid.

The mixture was agitated for 3 minutes at ambient temperature, cooled for one minute in an ice bath and X then precipitated by the addition of 100 cnr of iced isopropyl ether. After agitation for 10 minutes at ambient temperature, the precipitate was vacuum-filtered rinsing it with isopropyl ether then with diethyl ether, and dried under reduced pressure to obtain 460 mg of the desired product, m.p.^ 2l4°C.

Analysis : C^^H^qN^O^SI, CF^COgH Calculated: N% 9-87 S% 9.04 Found : 9·7 9·2 U.V. Spectrum (Ethanol; N hydrochloric acid) 10 max. 262 nm = 290 N.M.R. Spectrum /(CDg)gSO/ proton at 5-position of thiazole : 6.83 p.p.m. - 149 The syn isomer of 2-(2-iodoethoxyimino)-2-( 2-tritylaminothiazol-4-yl)-acetic acid used at the beginning of Example 39 was prepared as follows: a) .Ethyl 2-^2.2iod£eJ;hox2imino2-2-.(.22trity_lainino_2 thiazol-4-yl)-acetate ,_sjn_i somer. g of Ethyl 2-(2-bromoethoxyimino)-2-(2-tritylaninothiazol-4-yl)-acetate, syn isomer (prepared as in Example l) were introduced into 60 cm^ of of methylethylketone and 2.141 g of sodium iodide. The mixture was refluxed for an hour and 10 minutes, and then was evaporated under reduced pressure. The residue was taken up with 120 cm^ of methylene chloride and washed five times in 40 cm^ of water. Each washing was re-extracted with 2 cm^ of methylene chloride and the organic phase was dried and evaporated to dryness. The resin obtained was added to diethyl ether, and dried under reduced pressure to obtain 6.22 g of product.

M.p. = 110°C. b) The syn isomer of 2-(2-iodoethoxyimino)-2-(220 £tri£yiamino£hiazpl.-£-yl2-.acetic_acid.

Under an inert atmosphere 6.7 g of the ethyl χ ester prepared in Stage a) were introduced into 5.5 cm of dioxan and 44 cm^ of absolute ethanol. Drop by drop, .5 cm^ of a 2N solution of sodium carbonate were added, then 7 cnr of absolute ethanol were added, and the mixture was agitated for one night at ambient temperature. The sodium salt thus formed was vacuum-filtered rinsing twice with 3 cm^ of a 4-1 ethanol-dioxan - 150 solution and then formed into a paste with diethyl ether. The product obtained was treated in a separating funnel with 100 cm^ of water and 100 cm^ of chloroform. The pH was adjusted to 2 with normal hydrochloric acid.

The organic phase was decanted, washed with a saturated solution of sodium chloride, dried and evaporated under reduced pressure. The resin thus obtained was dissolved at 40°C in 35 cm^ of dichloroethane. Crystallisation was initiated, and the solution was left at ambient temperature for 72 hours. The formed precipitate was vacuum-filtered, rinsed and dried.to obtain 5.4 g of a white product solvated with dichloroethane (being 4.61 g of pure product) m.p. = 161°C.

Analysis : θ26^22θ3^3^ = 583.35 Calculated: N% 6.16 S% 4·7θ Found : 5.9 4.8 U.V. Spectrum (Ethanol, N hydrochloric acid) i T° 278 nm E^ = 235 N.M.R. Spectrum (CDClj) proton at 5-position of thiazole : 6.58 p.p.m.

Example 40: N-C2-(2-C(2-carboxy-3~methyl-8-oxo-5-thia-1-azabicyclo[4.2.03oct-2-en-7~yl)-aminc3-l-i2-aminothiazol-4-yl3-2-oxo-ethyl)-iminoxy-ethyl3-pyridinium jodide trifluoroacetate double salt, syn isomer.

Stage A: Benzhydryl_3y,mpthy1-2-12-(2-Xritylj3minothiazo1χ -4^1 )-2-( 2-bromoethoxy-imino )-acety laminoi-c enh-5z.em-4-carboxylate, syn isomer. - 151 Under an inert atmosphere 536 mg of the syn isomer of 2-(2-bromoethoxyimino)-2-(2-tritylaminothiazol-a-yl)-acetic acid were introduced into 380 mg of the beniiydryl ester of 7~aniino-3-desacetoxycephalosporanic x acid and 6 cm of anhydrous methylene chloride. The mixture was cooled in an ice bath and after 5 minutes 230 mg of dicyclohexylcarbodiimide were added and rinsed χ with 2 cm' of methylene chloride. The mixture was kept for two hours at 0° to +5°C, then for one hour at ambient temperature, and vacuum-filtered washing the insoluble matter three times with methylene chloride (and collecting lll mg of product). The filtrate was brought to dryness and 1.02 g of resin were isolated.

Thi3 product was purified by fixing it on 100 g of silica and eluting with a 17~3 benzene-ethyl acetate mixture. 5u8 mg of resin were obtained. Rf = 0.27-0.28 with preceding eluant.

N.M.R. Spectrum proton at 5-position of thiazole: 6.75 p.p.m. -0Η2~Βγ - triplet centred on 3.58 p.p.m. J « 7 Hz.

Stage Β: N-£22(2-£(2-di£henylme£hyl£arbqnyloxy-2-metJiyTj82 yoxo^yt hi a-l_-az abycyc 1.0^4^2^0200 t2.2-en-2-yl2.-ami.no.] [2-trity1aminothiazol-α-yl]-2-oxo-ethyl)-iminooxy-ethyl]ypyrydinium iodide^, yyn ysoraer.

Under an inert atmosphere 500 mg of the product obtained in Stage A were introduced into 115 mg of x pyridine iodhydrate in 5 cm of pyridine. The mixture - 152 was heated at 50°C for 15 hours then evaporated under reduced pressure at a temperature lower than 40°C.

The residue was taken up with methanol and evaporated four times in succession to drive off residual pyridine, then dried under reduced pressure to obtain 620 mg of a crude product. This crude product was purified by chromatography on silica, eluting with a 85-15 chloroform-methanol mixture, to obtain 348 mg of a purer product in the form of resin.

N.M.R. Spectrum (CD^gSO proton at 5-position of thiazole : 6.81 p.p.m.

Stage £: N-523( 2-£(£-£arbox2-5-3e£hzl383pxo553thia-l.-_ ^azabicyclo [4.2.0] oct-2-en-7-yl) -amino! -1- [ 2-amino-. jthi.az.o5-a-2l2-2-o.xo-£thy5)3imino£X2]£thyll3P2ri.dinium iodide_tri£luoroacet;at£jlouble salt^ j?yn ^somer^ 300 mg of the product obtained in Stage B were added to 3 cm^ of pure trifluoroacetic acid. The solution was agitated for 3 minutes at ambient temperature and cooled for 20 seconds in an ice bath. A z precipitate was formed by adding 40 cnr of an iced 1-1 mixture of isopropyl ether and petroleum spirit B (boiling point between 65 and 75°C). The precipitate was vacuum-filtered, rinsed with isopropyl ether, then with diethyl ether and dried to obtain 152 mg of a powder, m.p. 222°C.

Rf = 0.05 (acetic acid-ethyl acetate-water 70-35-10) U.V. Spectrum (Ethanol; N hydrochloric acid) - 153 max. = 260 nm = 355 I.R. Spectrum β-lactam 1768 cm 0=N-0R 1038 cm'1 N.M.R. Spectrum /(C )2S0/ proton at 5-position of thiazole = 6.76 p.p.m.

Example /tl; Trifluoroacetate of 3-acetoxymethyl-7-f2-(2-aminothiazo1-4-yl)-2-(2-dimethyIaminoethoxy-imino)-acetylamino3-ceph-3-em-4-carboxylic acid, syn isomer.

Stage A: Hydriodic of_2-(2-dime£hylaminoethoxyimino2-2-££-£r£tyljjminothiazol£A-y£)-ace£i£ £ci,dj_ syn i.s£m£rj_ x At ambient temperature 120 cm of a 9:1 mixture of chloroform and dimethylamine and 10 mg of the syn isomer of 2-(2-iodoethoxyimino)-2-(2-tritylaminothiazol15 -4-yl)-acetic acid Were agitated for about 3 hours.

The mixture was evaporated to dryness without the temperature exceeding 40°C and the residue was taken up with 100 cm^ of isopropyl ether, ground, agitated for minutes at ambient temperature, vacuum-filtered and x rinsed. The residue was taken up with 50 cm of acetone, refluxed for 5 minutes then vacuum-filtered at ambient temperature, dried and the solvents removed by evaporation under reduced pressure. 9*35 g of product were obtained which were taken up with 46 cm^ of water, agitated, then vacuum-filtered x and rinsed. The residue was taken up with 80 cnr of acetone, agitated, vacuum-filtered and dried under 48867 - 154 reduced pressure to give the desired product.

M.p. = 208-210° C (decomposition). N.M.R. Spectrum (D20 + CgD,-N) : p.p.m. Triplet centred on 4.55 (J = 5 Hz) : =N-0-CH2 5 single at 6.98 : proton at 5-position of thiazole single at 7-33 : -C(Ph)3 U.V. Spectrum (Ethanol, N hydrochloric acid) 1 10 inf1. 270 nm e| = 271 max. 275 nm E* = 280 ε = 14,000 10 inf1. 284 nm eT = 260 Stage B: Benzhydryl_32;ac.etoxyme£hyl£7r.C2-(22tityl£minjothiayoi-zi-yl^-^-^^dimethyl.aminoe.thpjcy^imino^-a.^tyl^ amino l-ceph-^-^nr^c arboxy2a2ejl _is£.m£r_l g of the acid prepared in Stage A was dissolved in a mixture of 15 cm^ of chloroform and 1.5 cm* of methanol and 3O'i mg of triethylamine hydrochloride were added. The mixture was heated for 5 minutes at 60°C then evaporated to dryness. The residue was taken up in 15 cm* of- chloroform, and brought to 0° to +5°C by χ means of an ice bath. Drop hy drop, 2 cm of a solution of pivaloyl chloride (prepared by making 1.25 g of pivaloyl chloride up to 10 cm* with chloroform) were added. The mixture was left to return to ambient temperature.

At the end of two hours, 1.1 g of benzhydryl 7-amino-cephalosporanate were added.

At the end of one hour thirty minutes the mixture 3 0 0 7 - 155 was evaporated to dryness and chromatographed on silica eluting with chloroform containing 5% methanol, to obtain 4-30 mg of the desired product.

Stage C: TrifXuoroacetate_of X-£C£t£xymethyl-2-_(2y(2-_ £mXn£thiazol^4yyl )y2^( 2-dimethyl £ndn£eXh£xy-imino)y -acetylamino]-ceph£3-em-4-carboxylic_acid,_7syn isomer.

A mixture of 100 mg of the product obtained in z Stage B in 1 cnr of trifluoroacetic acid was agitated for 3 minutes at ambient temperature. A precipitate was formed by adding ether, which was taken up with 0.2 cm^ of methanol. Again a precipitate was formed with 2 cm^ of ether. This was formed into a paste with chloroform then vacuum-filtered and rinsed with chloroform, then with ether, to obtain 40 mg of the desired product. M.p. = 25O°C.

N.M.R. Spectrum (CD,)nS0 (p.p.m.) single at 6.8 : proton at 5-position of thiazole U.V. Spectrum Ethanol max. 25a nm E* = 305 ε = 15,600 infl. 254 nm E* = 247 ε = 12,650 inf1. 296 nm eJ = 103 e = 5,300 Ethanol; N hydrochloric acid . 10 max. 260 nm 4 = 2?9 ε = 14,300 infl. 276 nm E^ = 245.

Example 42: Trifluoroacetate of 5-acetoxymethyl-7-[2-(2-aminothiazoI-4-yl)-2-(2-pyridylethoxy-imino)-acetylamino!-ceph-3-sm-4-carboxylic acid, _syn isomer (in the form of internal pyridinium salt). - 156 10 Stage A: Syn isomer of 2-(2-tritylamino-thiazol-4-yl)-2-(£-j2yridyX-ethO2g^iminpX-ai,etic_acid £in the £prm_ of_internal. jjyridiniumjsalt)^ g of the syn isomer of 2-(2-iodo-ethoxy-imino)2-(2-tritylaminothiazol-4-yl)-acetic acid solvated with dichloroethane,(corresponding to 4.27 g pure compound and obtained as described in Example 39) were heated to 60°C for 24 hours in 3θ cm^ of pyridine then left for 56 hours at ambient temperature. The precipitate thus formed was vacuum-filtered, rinsed with pyridine then with ether and dried to obtain 1.66 g of product, m.p. = 250°C (decomposition).

N.M.R. Spectrum (CD^GOCD^, DgO = 1-1) 6.8 p.p.m. : of thiazole 7.5 to 8 p.p.m. : pyridyl proton 4.58 to 5.08 p.p.m. : = N-O-CHg-GHp U.V. Spectrum (EtOH-HCl N/10) Max. 260 nm E^ = 324 I.R. Spectrum (nujol) co2 θ 1639 cm 1 C = C 1583 cm 1 C = N 1523 cm I Stage B: Benzhydryl_3~a£et.o3cymethyl^7-C2-£2-triXyl-_ amino_thiazol^/i27i)^2^(2-£yriXyXe_thOxyimino2-ac£tyl_L amino]-ceph-3-em-4-carboxylate iodide,_syn_isomer. 540 mg of the product obtained in Stage A were agitated for 20 minutes at ambient temperature with - 157 210 mg of pyridine hydriodide, 420 mg of dicyclohexylcarbodiimide, 350 mg of benzhydryl 7-amino-3-acetoxyx methyl-ceph-3-em-4-carboxylate and 5 cm of anhydrous dimethylformamide. The dicyclohexylurea precipitate formed is vacuum-filtered and rinsed with dimethylformamide, and the filtrate was poured into 60 cm^ of diethyl ether, where it formed a gum. The whole was agitated for 5 minutes at ambient temperature, decanted and the supernatent liquid was removed. The gum was taken up and ground in 60 cm^ of diethyl ether. The precipitate formed was vacuum-filtered to obtain 754 mg of a crude product. This was purified by agitation for x minutes with 1.6 g of magnesium silicate in 7.5 cm of dichloroethane. The insoluble matter was vacuum15 filtered off and washed with 0.5 cm^ of 1,2-dichloroethane, then the filtrate was evaporated to dryness to obtain 368 mg of the desired product.

Stage C: Tri.f5uoroacetate_of 5-a.cetoxymethy2 3aminothia£ol.-£-2l2-2-5.23P2ri.d2lethoxy3imino5-ace.tvl3 amino]-ceph-3-em-4-c£rboxyli£ The 368 mg of product obtained in Stage B were x agitated for 3 minutes at ambient temperature in 3 cm of pure trifluoroacetic acid. The insoluble matter was rapidly vacuum-filtered off. A precipitate was formed in the filtrate by adding 40 cm^ of diethyl ether and agitating for 5 minutes. The precipitate was vacuumfiltered and rinsed with diethyl ether to form - 158 χ a hygroscopic product which was taken up with 0.35 cm X of methanol and precipitated with 4 cm of diethyl ether. The reformed precipitate was vacuum-filtered and rinsed with diethyl ether to obtain 1^0 mg of the desired product. M.p. = 205°C (decomposition).

N.M.R. Spectrum (DMSO) 2.06 p.p.m. : OAc 6.86 p.p.m. : Hg thiazole 8.9-9.1 p.p.m. : H2 and Ηθ ) 8.55 to 8.78 p.p.m. : H^ 8.03 to 8.26 p.p.m. : H^ and Hg ) U.V. Spectrum (EtOH, HCI N/10) Max. 260 nm E^ 318 I.R. Spectrum (nujol) β lactam : 1777 cm-1· OAc : 17a0 cm 1 co2 “ : 1633 cm 1 C=N0-R : 1057 cm-1- Example 4^: Trifluoroacetate of 5-acetoxymethyl-7-C2-(2-aminothiazol-a-yl)-2-(2-imidazol-l-yl-ethoxy-imino)-acetylamino]-ceph-3-gm-4-carboxylic acid, syn isomer.

Stage A: The syn isomer_o£ 2-£2_-trity]_amino_th£a£o£-4-yl)_-2^(£-i>midyz£l^l^yli-£tho2cy^imino_2-acetic_ac.id £in £he fprm_of. £n£ernal_imidazplj.uni_sal£). g of the syn isomer of 2-(2-tritylaminothiazol-4-yl)-2-(2-iodoethoxyimino)-acetic acid, solvated with 1,2-di chloroethane (corresponding to 2.56 g pure compound) - 159 10 were agitated for 3 hours at ambient temperature with 4.2 g ofimidazole and 10 cm^ of dimethylacetamide. A further 10 cm^ of dimethylacetamide were added and the agitation continued for 40 hours at ambient temperature. The mixture was poured into 200 cm^ of isopropyl ether, agitated for 30 minutes, left to separate and then the supernatent liquid was removed. The gum thus obtained was taken up by grinding in 200 cm^ of isopropyl ether, and again in 300 cm^ of diethyl ether, then agitated for 30 minutes, vacuum-filtered, rinsed with diethyl ether, taken up with 30 cm^ of acetone, agitated for one hour, vacuum-filtered, rinsed with acetone then with diethyl ether and dried to obtain 1.2 g of the desired product. M.p. = 280°C (decomposition).

N.M.R. Spectrum (DMSO) /1.35 p.p.m. N-O-CH2-CH2 —“ N^ 6.8 p.p.m. of thiazole 7.82 p.p.m. a/η N _ U.V. Spectrum (EtOH, HCl N/10) Max. 277 nm E* = 259 I.R. Spectrum (nujol) CO2 1614 cm aromatic 1^92 cm heterocyclel527 cm 4#8β7 - 160 Stage Β: Benzhy2ryl_3£a£e£o2cyme£hyl2:72[2-£22.trityl.2_ £miinothiaz£l£.4£yi)^,22>(^-i1m2d£zo.l£l2yi-£thpxy£imino2 £a£e£yiamino2-e“_A-£arbox2la.te. 780 mg of the product obtained in State A were 5 agitated vigorously in a bath of iced water with 315 mg of pyridine hydriodide, 630 mg of dicyclohexylcarbodiimide, 600 mg of benzhydryl 7-amino-3-acetoxymethyl-cephz -3-em-/!-carboxylate and 6 cm of anhydrous dimethylformamide. Dicyclohexylurea precipitated. The mixture was taken to ambient temperature and the agitation was continued for 20 minutes. The insoluble matter was removed by vacuum-filtration and rinsed with dimethylz formamide. The filtrate was treated with 120 cm of diethyl ether to form a precipitate, then agitated for minutes and left to separate. The supernatent liquid was removed and the gum obtained was taken up and z triturated in 100 cur of diethyl ether. This mixture was agitated for 10 minutes at ambient temperature, Vacuum-filtered, rinsed with diethyl ether and dried to obtain 1.3 g of a product which was chromatographed on silica, eluting with a 8-1-0.5 mixture of ethyl acetateethanol-water to obtain 332 mg of the desired product.

H. M.R. Spectrum (GDCl^) p.p.m. : OAc 6.75 p.p.m. : H,. syn thiazole I. R. Spectrum (CHGl^) β lactam : 1788 cm-^ ester and OAc: 1759 cm 9 σ ** - 161 heterocycles : 1525 cm Stage G: Trifluor£a£etate_o£ ^-£C£t£xym£thyi-2-£2y(2-_ -aminothi.azpj1-4-yl2-2-£2j;imida£oi-l.-ylyeth£xy-imin£)^ acetylamino]-ceph-3-em-4-carboxylic ac£d_j_ syn i.s£m£r_. 230 mg of the product obtained in Stage B were agitated for 3 minutes at ambient temperature with 2 cm^ of pure trifluoroacetic acid. The formed solution was poured into a 1-1 mixture of isopropyl ether-diethyl ether and agitated for 20 minutes at ambient temperature.

The formed precipitate was rinsed with diethyl ether, then taken up in 0.4 cm^ of methanol and again precipitated with 4 cm^ of diethyl ether, agitated for 10 minutes at ambient temperature, vacuum-filtered, rinsed with diethyl ether and dried to obtain 140 mg of the desired product. M.p. = 2O5°C (decomposition).

N.M.R. Spectrum (DMSO) 2.03 p.p.m. : OAC 6.8 p.p.m. : syn thiazole 7.66 and 7-71 p.p.m. : H^ and ) imidazole 8.95 p.p.m. : Hg U.V. Spectrum (EtOH, NCI N/10) Max. 260 nm eJ = 271.

Example 44: Trifluoroacetate of 3-acetoxymethyl-7-C2-(2-aminothiazol-4-yl)-2-(ethoxycarbonyloxy-imino)-acetyl25 amino]-ceph-3-em-4-carboxylic acid, syn isomer.

Stage A: Di£thy_lamine_s£l£ of_3£a£eto3cymethyl£72C2-£2£ -trity£aminothiazol-4-yl)-2-(ethoxycarbonyloxy-imino)-acetylamino]-ceph-3-em-4-carboxylic_acid,_s2n_isomer. - 162 Under agitation and in an inert atmosphere 1.67 g of the syn isomer of 3-acetoxymethyl-7-C2-(2-tritylaminothiazol-4-yl)-2-hydroxyimino-acetylamino]-ceph-33 -em-4-carboxylie acid were dissolved in 25 cm of 5 methylene chloride and 0.37 cm^ of pyridine. The solution was cooled in an ice bath, and then over five minutes 2.7 cm^ of a molar solution of ethyl ehloroformate in methylene chloride were added. After 10 minutes and still at 0° to +5°G, 20 cm^ of water and 2.7 cm^ of N hydrochloric acid were added. This mixture was agitated, then separated. The organic phase was washed with water until neutral and then dried. The solvent was distilled off under reduced 3 pressure and the residue was taken up with 10 cm of ethyl acetate, then 0.23 cm^ of diethylamine were added.

The diethylamine salt was precipitated by adding 10 cur of isopropyl ether. The salt was vacuum-filtered and rinsed with a 1-1 mixture of isopropyl ether-ethyl acetate, then with isopropyl ether, to obtain 1.50 g of a product which was dissolved in 5 cnr of methylene chloride and 10 cm^ of ethyl acetate. The solution was concentrated under reduced pressure to obtain a final 3 volume of about 6 cur and then diluted with 5 cm' of isopropyl ether, vacuum-filtered and rinsed as previously to obtain 1.47 g of the desired product. N.M.R. Spectrum (CDCl^) 2.03 p.p.m. : OAc - 163 6.95 p.p.m. : of thiazole 7.66 p.p.m. : trityl 4.13 - 4.25 - 4.36 - 4.48 p.p.m. : CH-, of CC^Et I.R. Spectrum (CHCl^) β lactam 1781 cm-1- OAc 17^0 cm-1 amide 1694 cm1 co2 1634 cm1 Stage B: Triflu£roac_etate_o_f i-yc£t£xymethyl_-2“X.2z(Z~ z.a2i not hi. a zol.-4-yl 2_-2-£eth£xy carb ony loxy ^imino^.-ac£ty I2 amino J -cyp^-^-ym^-cyrboxy 1ic_acid,_syn_iyomer. 1.43 g of the product obtained in Stage A were agitated for 20 minutes at ambient temperature with x x .7 cm' of trifluoroacetic acid. 57 cm' of isopropyl ether were rapidly added and the mixture was agitated for a further 15 minutes, then vacuum-filtered and rinsed with isopropyl ether to obtain 1.04 g of a crude x product which was dissolved in 4 cm of acetone con. taining 1% water. To the solution was added 12 cm^ of diethyl ether to precipitate 0.69 g of the desired product. A further 0.11 g of identical product were recovered from the mother liquors.

Example 45: Sodium salt of 5-acetoxymethyl-7-[2-(2-aminothi3zol-4-yl)-2-(ethoxycarbonyloxy-imino)25 -acetylamino]-ceph-3~em-4-carboxylic acid, syn isomer. 0.8 g of the product obtained in Example 4/1 were dissolved in a. cm^ of a IM methanolic solution of sodium acetate and 2 cm^ of methanol. The solution was treated SEaa ·» a o q f - 164 x with active charcoal and diluted with 20 cnr of anhydrous ethanol then concentrated to a final volume of 10 cm^ by distilling under reduced pressure at 30°C maximum. The precipitate obtained was vacuum-filtered, rinsed with ethanol and then with ether to obtain /+20 mg of product. 580 mg of product prepared in this way were taken up with 5.8 cm3 of methanol and while agitating 1.2 cnr of ethanol were slowly added. The precipitate was vacuum-filtered off and the filtrate was diluted with 10 cm^ of ethanol then concentrated by distilling under reduced pressure at 30°C maximum to a final volume of 5 cm\ This was vacuum-filtered and rinsed with ether to obtain 460 mg of product which was treated again in the same manner to obtain 420 mg of the desired product.

N.M.R. Spectrum (DMSO) 1.13 - 1.25 - 1-36 p.p.m. ) ) COpEt 4.03- 4.16 - 4.28 - 4.4 p.p.m. ) 1.98 p.p.m. : OAc 7.03 p.p.m. : of thiazole U.V. Spectrum (EtOH/HCl N/10) Max. 259 nm E^ = 324 ε 17,550 Infl. 278 nm E* = 252 I.R. Spectrum (nujol) β lactam : 1763 cm OAc : 1726 cm COp : 1609 cm C=N-0 : 1038 cm-1 & κ» · - 165 Example 46: 3-acetoxyiuethyl-7-C2-(2-aminothiazol-4-yl)-2-(2-morpholino-ethoxy-imino)-acetylamino3-ceph-3-em-a-carboxylic acid, syn isomer in the form of internal salt.

Stage A: 2-X2^tritylaminothia£oX-4-ylX-2-X2ymor£holinoethoxy-imino)-acetic acid,_syq isomer _in_Je_form of int_ernal_S£l.t. g of the syn isomer of 2-(2-tritylaminothiazol-4-yl)-2-(2-iodoethoxy-imino)-acetic acid solvated with 1,2-dichloroethane (corresponding to 1.71 g of pure compound) were dissolved in 7 cm^ of morpholine. The solution was agitated for one hour at ambient temperature then concentrated in a current of nitrogen, and taken up with 30 cm^ of ethyl acetate, agitated for twenty minutee at ambient temperature and vacuum-filtered, rinsing with ethyl acetate. The product was agitated z for fifteen minutes in 15 cm of 1,3-dimethoxypropane then vacuum-filtered and rinsed with the same solvent. The 3 product was then taken up with 15 cnr of ether, agitated for 15 minutes, vacuum-filtered and rinsed with diethyl ether to obtain 2.3 g of product, m.p. = 180°C (decomposition), which was used for the following stage in that form. 100 mg of the product was purified by recrystal25 lisation from 0.5 cm^ of ethanol to obtain 46 mg of recrystallised product, m.p. : 182-184°C (decomposition). N.M.R. Spectrum (CDC1,) 166 7.33 p.p.m. : trityl 6.75 p.p.m. : H<- syn thiazole U.V. Spectrum (EtOH, HCl N/1O) Max. 276 nm E* = 172 I.R. Spectrum (GHC1) CO2 and aromatics 1606 - 1529 and 1495 cm ^;-NH 3399 cm Stage B: Benzhydryl^ ^.-^cetoxymethyl. 2-(2^( 2-tri tyl; arajLnothi£Z£l-4£yi)£2£(2-morplwXino£e£h£xy-imino]2: -ac etylamino 3 ^c eph-^-cmy^ yc arboxyla£e_hydriodide, isomer^ lg of the product obtained in Stage A, 0.38 g of pyridine hydriodide, 0.63 g of dicyclohexylcarbodiimide and 0.60 g of benzhydryl 5-acetoxymethyl-7-amino-ceph-3~em-4-carboxylate were dissolved in 5 cm of anhydrous dimethylformamide. The solution was agitated for 30 minutes at ambient temperature. The dicyclohexylurea thus formed was removed hy vacuum-filtration; 100 cm* of diethyl ether were added to the filtrate, and the mixture was agitated for ten minutes, vacuum20 filtered, rinsed with diethyl ether and chromatographed on silica eluting with a 7-1 ethyl acetate-ethanol mixture to obtain 0.524 g of product. M.p. : 167°θ (decomposition).

N.M.R. Spectrum (CDCl^) 2.03 p.p.m. : OAc 3.72 p.p.m. : CHjO 6.75 p.p.m. : H,. syn thiazole 4^0 υ - 167 U.V. Spectrum (EtOH, HCl N/10) Max. 268 nm eJ = 165 6=15,900 l. R. Spectrum (CHCl^) β lactam 1791 cm ester and OAc 1740 cm amide 1678 cm 1 Stage C: 2-Xc£t_oxymethyl-^2^( 2-amino thi£Z£l£/(-_2yX)£.2_2 -(2-morpholinoethoxy-imino)-acetylamino l^ceph-^-ern^p; -carboxylic acid_j_ syn iswner^ in the_form of_internal £alt.i 0.42 g of the product obtained in Stage B were agitated for two minutes at ambient temperature with απ'* of trifluoroacetic acid. The insoluble matter was vacuum-filtered off and rinsed with trifluoroacetic χ acid. The filtrate,was collected in 3θ cnr of diethyl ether and agitated for 15 minutes at ambient temperature.

The precipitate formed was vacuum-filtered, rinsed with ether and dissolved in 0.5 cm^ of methanol. Then it 3 was again precipitated with 5 cm of diethyl ether.

After agitation for 5 minutes, the precipitate is vacuum-filtered off to obtain 208 mg of product, m. p. = 212-214°C (decomposition), which was salified in various ways, and in particular by trifluoroacetic acid.

N.M.R. Spectrum (DMSO) 2.05 p.p.m. : OAc 3.17 to 4.66 p.p.m. : Ci^-N and CHgO 6.85 p.p.m. : H,- syn thiazole - 168 U.V. Spectrum (EtOH, HCI N/10) Max. 260 nm 253 I.R. Spectrum (CHClj) -1 lactam CO “ 1797 cm 1634 cm amide 1667 cm Example 47: 5-acetoxymethyl-7-C2-(2-aminothiazol-4-yl)· -2-(2-[a-me thy1-pipera zin-1-yl3-ethoxy-imino)-acety 1 -1 amino3- Srage A; 2-£2^trityiaminoXhi.az,oi-4-yl2-2-£2-[x.-meXhylj; 2pij>£r£zinzlzyi)ze£H£xZ“imin.2).zacetic. a.cidj_ £n_the_ form_of irrternal_s_al£. x 2.22 g of N-methyl-piperazine in 15 cnr of dioxan and 3.325 g of the syn isomer of 2-(2-tritylaminothiazol« -4-yl)-2-(2-iodoethoxy-imiuoJ-acetic acid solvated with dichloroethane, (corresponding to 2.84 g pure compound and prepared as in Example 39) were agitated vigorously for 16 hours at ambient temperature. The N-methyl piperazine hydriodide thus formed was vacuum-filtered off and the filtrate was concentrated under reduced pressure to a volume of about 5 cm^, then 200 cm^ of isopropyl ether were added and the mixture was agitated for 30 minutes. The mixture was vacuum-filtered and χ the product was taken up with 10 cnr of dimethoxypropane, agitated for thirty minutes, vacuum-filtered, taken up with 24 cm^ of water, agitated for ten minutes, then again vacuum-filtered. The insoluble matter was - 169 agitated for two hours in 100 cm^ of 1-1 isopropyl ether-diethyl ether mixture, then vacuum-filtered off and recrystallised from ethanol at 100° to obtain 1.4-7 g of product. M.p. : 220°C (decomposition).

N.M.R. Spectrum (CDClj) 2.52 p.p.m. : -NCHg 3.0 p.p.m. : CHpN 6.7 p.p.m. : of thiazole U.V. Spectrum (EtOH/HCl N/10) Max. 277 nm E* = 257 e 14,300 I.R. Spectrum (nujol) C02~ 1602 cm-1 heterocycle 1529 cm absence of COpH Stage B: Benzhydr2l_53a£e£oxyTneth2l373.£2“.iL23tri_tylaminothiaz£l343y5)323(2-543methyi-£i£erazin3l-2ll3e£h£xy-i®in£)3a£etyl/amino l^ceph-^-em^a^carboxylatejsyn isomer. 560 mg of product obtained in Stage A was heated to 60°C for ten minutes with 14-0 mg of triethylamine hydrochloride in 5 cm^ of chloroform and 5 cm^ of methanol. The solvents were evaporated off under reduced pressure, and the residue was taken up with 20 cm^ of methylene chloride then cooled to -20°C. Over ten minutes 1 cm^ of a 12.5% solution of pivaloyl chloride in methylene dichloride was added and the whole agitated for an hour at ambient temperature. The - 170 solution was cooled to -10°C and, in one go, 350 mg of benzhydryl 7-amino-3-acetoxymethyl-ceph-3-en-4carboxylate were added. The mixture was agitated for three hours, then concentrated to dryness under reduced pressure at a maximum of 30°C. The residue was taken up with 50 cm^ of an 8-2 benzene-ethyl acetate mixture, and the insoluble matter was eliminated. The solution was evaporated to dryness under reduced pressure, and the residue taken up with 25 cm^ of 1,2-dichloroethane. 1.5 g of activated magnesium silicate were added and the mixture was agitated for 30 minutes, then vacuum-filtered and rinsed with 1,2-dichloroethane. The filtrate was evaporated under reduced pressure at 30°C maximum to obtain 870 mg of white resin.

N.M.R. Spectrum (CDCl^) 2.02 - 2.03 p.p.m. : OAc 6.87 p.p.m. : Hg of thiazole 2.45 p.p.m. : N-CH3 U.V. Spectrum (EtOH, HCl N/10) Max. 267-268 nm : 14,700.

Stage C: 2-acetoxywethyl-2-[2-(2-aminothiazol;4;yl)2-£ 2^ [ 4-methyI3 pipe razing l^y1 ] 3 ethoxy- imino ) 3 ac e tyl amino.] ceph-3-em-4-carboxylic acid, syn isomer, in the form of internal_salt £trifluoroacetate) 524 mg of the product obtained in Stage B were dissolved in 3 cm^ of pure trifluoroacetic acid and the solution agitated for one minute at ambient temperature. - 171 A precipitate was formed, by adding 30 cm^ of isopropyl ether and the whole was agitated for a further 5 minutes, then vacuum-filtered to obtain 320 mg of a hygroscopic product. This was dissolved in 1 cm^ of methanol and χ caused to precipitate by adding 10 cm of diethyl ether. The mixture was agitated for 5 minutes, vacuum-filtered, rinsed with diethyl ether, made into a paste with chloroform then with ether to yield 220 mg of a salified product (trifluoroacetate) M.p. = 245°C.

N.M.R. Snectrum (DMSO) 2.03 p.p.m. : OAc 2.75 to 5.67 p.p.m. : CHjN 6.78 p.p.m. : of thiazole U.V. Spectrum (EtOH, HCI N/10) Max. 262 nm : 14,200 I.R. Snectrum (nu.iol) -1 β lactam 1773 cm A OAc 1726 cm-1 co20 1627 cm1 -1 C = NO- 1035 cm Α Example 48: -7-[2-(2-amin Bis trifluoroacetate salt of 3-acetoxymethyl- othiazol-4—yl)-2-(2-aminoethoxy-imino-acetyl- -amino]-ceph-5-em-4-carboxylic acid, syn isomer Stage A: 2-£2-tritylaminoethoxyimino);22(2-tritylaminothiazol-4-yl)-acetic acid, ayn isomer A mixture of 75 g of tritylamine, 50 g of ethyl »»ββ - 172 and 100 cm* of dimethyl sulphoxide was placed under argon, and the suspension was agitated for 82 hours at 60°C.

It was then cooled to ambient temperature and caused to precipitate with 10 volumes of water. The precipitate was vacuum-filtered, washed with water, and then put into solution in one litre of chloroform and washed with water, then with a saturated solution of sodium chloride. The solution was dried and evaporated under reduced pressure at a temperature lower than 4O°C. The crude product was taken up with a mixture of 320 cm* of dioxan, 2 litres of absolute ethanol and 200 cm* of 2N sodium carbonate, and agitated for 24 hours at ambient temperature, then evaporated to dryness under reduced pressure at a temperature lower than or equal to 4O°C.

This product was pasted 5 times with 60 cnr of a 1-7 dioxan-methanol mixture. The product was taken up with a mixture of a litre of chloroform and a litre of water.

Under agitation normal hydrochloric acid was added to adjust the pH to 2. The organic phase was separated, washed with water and then with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure at a temperature lower than 4O°C. The product thus obtained was suspended in 3θθ cm* of 1,2-dichloro ethane and heated for 15 minutes at 5θ°θ· Then it was vacuum-filtered after returning to ambient temperature under light vacuum, and rinsed with dichloroethane then with isopropyl ether and finally with diethyl ether.

After being dried to constant weight 40 g of powder were obtained. M.p. = 176°C. 4300 1 - 175 N.M.R. Snectrum (CDCl^) 6.68 p.p.m. : proton at 5 of thiazole 2.95 p.p.m. : CH^-N Stage B: 2-(2^tlitylaminoethojfy;imino)-2-^2^tritylamino5 thiazol-4-yl)-acetate of hydroxy-benzotriazole, syn isomer_ 6.97 g of the acid obtained in Stage A were mixed with 1.54 g of hydroxy 1-benzotriazole in 35 cm of methylene chloride, and agitated in an ice bath. Drop by drop a solution of 2.44 g of dicyclohexylcarbodiimide in 35 cm^ of methylene chloride was added. After being left to return to ambient temperature, the mixture was agitated for three hours thirty minutes. The dicyclohexylurea formed was vacuum-filtered off and rinsed with methylene chloride.

The filtrate wan washed with sodium bicarbonate, then with water, then finally with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The resin thus obtained was taken up with 5θ cm' of isopropyl ether and agitated vigourously for one hour at ambient temperature. The precipitate thus obtained was vacuum-filtered, rinsed with isosrooyl ether and dried to constant weight to obtain 8.046 g of product.

M. p. = 15O-152°C (decomposition).

N. M.R. Spectrum (CDCl^) 6.68 p.p.m. : proton at 5 of thiazole 2.56 p.p.m. : -CHp-N 174 Stage C: Diphenylmethyl_3;acetoxymethyl;7;(2-(2;trityl-_ aminoethoxy-imino );2;(2-tritylamino-thiazol-4-yl)-acetyl; amino]-ceph-3-em-4-carboxylate, syn isomer 11*55 g of the activated ester product prepared in Stage B were mixed with the equivalent of 7*65 g of the diphenylmethyl ester of 7-amino cephalosporanic acid in 75 x cm7 of methylene chloride. The mixture was agitated for 18 hours at ambient temperature, evaporated under reduced pressure and chromatographed on silica and under pressure, eluting with an 85-15 benzene-ethyl acetate mixture to obtain 9.1 g of the desired product.

Stage D: Bis trifluoroacetate_salt of_5zacetoxymethyl;7; ; (2-(2;aminothiazol-4-yl2-2-£2; aminoethoxy; imino}-acetyl; amino]-ceph-3-em-4-carboxylic acid, syn isomer Diphenylmethyl 3~acetoxymethyl-7-(2-(2-tritylaminothiazo 1-4-yl)-2-(2-tritylamino ethoxy-imino)-acetylamino]ceph-3-em-4-carboxylate prepared in Stage C were introduced x into 1.8 cm of pure trifiuoroacetic acid. The yellow solution thus obtained was agitated for 3 minutes at ambient temperature, then under an inert atmosphere in a x bath of iced water when 18 cm of isopropyl ether were rapidly added. The mixture was agitated for 10 minutes, vacuum-filtered, rinsed with isopropyl ether then with diethyl ether and dried to obtain 100 mg of a white powder.

M.p. = about 210°C (decomposition).

Formulation 1: Injectable Preparation An injectable composition was prepared from the - 175 following: The syn isomer of 3~acetoxymethyl-7~(2- ( 2- am i no th i azo 1- 4- y 1) - 2- ( 2- amino e thoxy- imino) acetylamino]-ceph-3-em-4-carboxylic acid ......... 5θθ og Aqueous sterile excipient q.s............... 5 cm^ Formulation 2: Injectable Preparation An injectable composition was prepared from the following: The syn isomer of 3-acetoxymethyl-7_C210 -(2-aminothiazol-4-yl)-2-acetoxyimino-acetylamino J-ceph-3-em-4-carboxylic acid ............... 5θθ og χ Aqueous sterile excipient q.s............... 5 cm Formulation 5: Gelatin cansules Gelatin capsules were prepared as follows: The syn isomer of 5-acetoxymethyl-7-(2-(2-aminothiazol-4-yl)-2-(2-amino ethoxy-imino)-acetylamino]-ceph-3-em-4-carboxylic acid ......... 250 mg Excipient q.s. for a geltain capsule ........ 400 mg Formulation 4: Injectable Preparation 20 An injectable composition was prepared from the following: Sodium salt of 3-acetoxymethyl~7jj2- (2-aminothiazol-4-yl)-2-(2-bromoethoxy-imino)-acetylamino]-ceph-5-em-4-carboxylic - 176 acid, syn isomer .............................. 5θθ ®β Sterile aqueous excipient q.s............ 5 cm^ Formulation 5' Injectable Preparation An injectable composition was prepared from the following: The syn isomer of 3-C(l-inethyl-l,2,3,4tetrazol-5-yl)-thiomethyl]-7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxy-imino)-acetylamino]-ceph-3-em-4-carboxylic acid ........................ 5°θ mg Sterile aqueous excipient q.s............. 5 cm Formulation 6: Injectable Preparation An injectable composition was prepared from the following: Trifluoroacetate of 3~acetoxymethyl-715 -C2-(2-aminothiazol-4-yl)-2-(2-iodoethoxyimino)-acetylamino]-ceph-3-em-4-carboxylic acid, syn isomer ............................... 5θθ mg Sterile aqueous excipient q.s............. 5 cm Formulation 7‘ Gelatin capsules 20 Gelatin capsules were prepared aa follows: The syn isomer of 3-[(1-methyl-l,2,3,4tetrazo1-5- yl)“thiomethyl]-7~[2-(2-aminothiazo1-4-yl)-2-(2-aminoethoxy-imino)-acetyl25 amino]-ceph-3-em-4-carboxylic acid.............. 250 mg Excipient q.s. for a gelatin capsule....... 400 mg - 177 Formulation 8: Injectable Preparation An injectable composition was prepared from the following: The syn isomer of 3-acetoxymethyl-7~ -[2-(2-aminothiazol-4-yl)-2-(2-imidazol-lyl-ethoxy-imino) -acetylamino ]-ceph-3-em-4carboxylic acid ................................... 5θθ ng χ Sterile aqueous excipient q.s................ 5 cm Formulation 9: Injectable Preparation 10 An injectable composition was prepared from the following: Sodium salt of 3~acetoxymethyl-7-[2-(2-aminothiazo1-4-yl)-2-(2-ethoxycarbonyloxyimino)-acetylamino]-ceph-3-em-4-carboxylic acid, syn isomer .................................. 5θθ ®g Sterile aqueous excipient q.s. ............... 5 cnr Formulation 10: Gelatin capsules Gelatin capsules were prepared as follows: Sodium salt of 3-acetoxymethyl-7-C220 -(2-aminothi azol-4-yl)-2-(2-ethoxyc arbonyloxyimino)-acetylamino]-ceph-3-em-4-carboxylic acid, syn isomer.................................. 250 mg Excipient q.s. for a gelatin capsule......... 400 mg • 49867 - 178 The following Pharmacological Studies and the results obtained thereby are now set out, though only by way of illustration, to show the relative activities of various compounds of the invention in relation to a number of strains of bacteria. An amount of the compound to be tested was introduced into each tube, so that the amount introduced increases from tube to tube in the series. Then each tube was inoculated with a bacterial strain. After twenty-four or forty-eight hours’ incuba10 tion in the oven at 37°C, inhibition of growth was assessed by transillumination, and by observing the inhibition in each tube relative to the amount of compound present the minimum inhibiting concentrations (M.I.C.) was determined for the bacterial strain. The results obtained are set out in the following tables in terms of M.I.C. expressed in mg/cm^ for a number of bacterial strains. n » ο οι - 179 PRODUCT OF EXAMPLE 22 STRAINS M.I.C· 24H in ug/ml 48H Penicillin- Staphylococcus aureus ATCC 6 538 sensitive O.S 1 „ . , · ,,- , , Penicillin- Staphylococcus aureus UC 1 123 resistant 1 1 Staphylococcus aureus βκρ.ϊί®54 146........ 1 1 Streptococcus pyogenes A 561.............. <0.02 <0.02 Streptococcus faecalis 5 432.............. ‘2 10 Streptococcus faecalis 59 F 74............ 10 >40 Bacillus subtil'is ATCC 6 633.............. 0.2 1 Escherichia Coli sensitive toTetracyclinc ATCC 9 h 3 7................................ 1 1 Escherichia Coli resistant to Tetracycline ATCC 11 303·.·........................ 0.2 0 .2 Escherichia Coli Exo. TC_-Bc.............. 26 6 0.5 0.5 Escherichia Coli resistant to Gentamycin Tobramycin R 55 12 3 D.................... 0.5 0.5 Klebsiella pneumoniae Exp. 52 145 ......... 0.2 0.5 Klebsiella pneumoniae 2 536 resistant to Gent: amye in .......... 2 2 Proteus mirabilis (indol-) A 235.......... 0.2 0.2 Salmonella tvphimurium 420 ............... i 2 Enterobacter cloacae 681.................. 5 10 Providencia Du 48 ........................ 5 5 Serratiaresistant to Gentaraycin 2 532...... 5 5 180 PRODUCT OF EXAMPLE 24 STRAINS M.I.C., in ug/ml 24H 48H Staphyloccccus auieus ATCC 6 538 sensitive 1 1 Staphylococcus aureus UC 1 12 8 penicillyiresistant 1 1 Staphvlococcus aureus exo.N’ 54 146 ....... 1 1 Streptococcus pyogenes A 561.............. 40. 02 ^0,02 Streptococcus faecalis 5 432............. 2 20 Streptococcus faecelis 99 F 74 .......... 10 10 Bacillus subtiiis ATCC 6 633............. 0.5 0.5 Escherichia Coli sensitive toTetracycline ATCC 9 637 .............................. 2 2 Escherichia ..Coli resistant to Tetracycline ATCC 11 30 3'............................. 1 1 Escherichia Coli Exp. TO^^Bg............. 2 3 Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D................... 1 2 Klebsiella pneumoniae Exp. 52 145 ........ 1 1 Klebsiella pneumoniae 2 5 36 resistant to Gentamycin.................................. 10 10 Proteus mirabilis (indol-, A 235 ........ 1 1 Salmonella typniraurium 420 .............. 2 · 3 Providencia Du 4 8........................ 20 20 Serratia resistant to Gentamycin 2 532..... 10 10 - 181 PRODUCT OF EXAMPLS26 ί 1 STRAINS M.I.C. in ug/ml 24H 48H ____ , Penicillin- Staphylococcus aureus ATCC 6 5 38 sensitive 2 2 Staph'/lococcus auicux UC I 12 8 Penicillinresistant 2 2 S t λ phy 1 po rrri! s av. mu ς ρχρ. n 0 5 4 146... . . . ., 2 2 S t* r nphori'mi s cyocj pups A 5 5 1 ............. «0.02 «0.02 Streptococcus faocalis 5 4*12 ............. 3 >40 Strcatococrus ^accal is 99 F 74............ 10 >40 Ρ.··ΐ r i 1 1 us su i i i s 6 6 ? Λ.............. 1 Escherichia Coli sensitive toTetracycline ATCC 9 S37................................ 2 2 Escherichia Coli resistant to Tetracycline ATCC 11 303............................... 1 2 r^rhorirhia Cn' i Γχη.ΤΠ. _B ................ 2 2 Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D.................... 1 2 Xlnh^i n] ) q Dn^iinnn ian Fkd. 5 145........., 1 1 Klebsiella pneumoniae 2 5 36 resistant to Gentnnyc in .... ..................... 5 5 P ro h nu s nir ah i 1 i <·» findol — 1 A 7 25.. ........ 0.5 0.5 1 non «1 In h yph i mu r hint 470 2 2 PrnviHpncia On 4 P _ ........................ 40 40 Sorratia TwHqfnnt fn Gcntnmycin 2 522.'. .... 10 10 182 PRODUCT OF . EXAMPLE 28 STRAINS M.I.C. in- ug/ml 24K 48H . . . , Penicillin- Staphylococcus aureus ATCC 6 5 38 sensitive 0.5 1 Staphvlococcus aureus UC 1 128 Penicillin• . resistant 1 Staohyloi'oecus aureus exp.ne54 146 ....... 1 1 Streptococcus Dyocenes A 561 ............. 40.02 <0.02 Bacillus subtilis ATCC 6 633 ............. 1 2 Escherichia Coli sensitive to Tetracycline ATCC 9 637 ............................... 3 3 Escherichia Coli resistant to Tetracycline ATCC 11 303............................... 1 1 2 2 Escherichia· Coli Exp. TO^gSg.............. Escherichia Coli resistant to Gentamycin Tobramvcine R 55 123 D ................... 2 2 KlphiiAila Dnpp’nnnitip P/d. 5? 145 ........ 1 1 Klebsiella pneumoniae 2 536 resistant to Gent- nmyn in .................................. 10 10 ----------------————— Pxotcus mirabilis (indol—) A 23S.......... 1 1 Salmonella typhimurium 420................ 2 2 ?.nf probaetpf cl oacap fift 1 ~ . ......... . . . . . . 20 40 Providencia Du 4fi ........................ 10 20 Serratia resistant to Gentamycin -2 532...... 5 5 - 183 PRODUCT OF EXAMPLE 30 • STRAINS M.I.C. 24H in ug/nl 48H Staphylococcus aureus ATCC 6 5 38 2 2 Staphylococcus aureus UC' 1 128 Pen^11^'c J resistant 2 2 Staphylococcus aureus exp.n°54 146 ....... 2 2 Streptococcus pyogenes A 561.............. 0,05 0.05 Bacillus subtilis ATCC 6 633 .............. 1 1 Escherichia Coli sensitive to Tetracycline ATCC 9 537............................... 5 5 Escherichia Coli resistant to Tetracycline ATCC 11 303.............................. 2 2 Escherichia Coli Exo. TO_.B,.............. 26 6 3 3 Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D.................... 3 3 Klebsiella pneumoniae Exp. 52 145 ......... 1 1 Klebsiella pneumoniae 2 536 resistant toGflntamyc in.................................... 20 20 Proteus mirabilis (indol-) A 235 ......... 2 2 Salmonella typhimurium 420..........·...... 3 5 Providencia DU <18 ........................ 20 20 Serratia resistant to Gentamycin.’ 2 532...... 5 10 - 184 ί » 8 by PRODUCT OF EXAJMPLE 31 STRAINS M.I.C. in Ug/ml 24H 48H Staphvlococcus aureus ATCC 6 5 33 Peni?^linc - sensitive 2 2 Staphylococcus aureus UC 1 128 Penicillinresistant 2 2 Si* a ph v 1 ococf.u s an ron s p. n° S 4 146-. . . . . •2 2 Streotococcus oyogenes A S61 ............. 40.02 40.02 StrcDtococcus faecalis 5 432 .............. 3 40 3 ac illus subtiiis ATC C ό 6 33.............. •2 3 Escherichia Coli sensitive toTetracycline ATCC J 637 ............................... 3 3 Escherichia- Coli resistant to Tetracycline ATCC 11 303 .............................. 3 3 Escherichia Coli Exp. TO_,B............... 2 2 Zb b Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D.................... 2 2 Klebsiella pneumoniae Exp. 52 145......... O.S 0.5 Klebsiella pneumoniae 2 535 resistant to Gent run ye in .....'.............. 10 10 Proteus mirabi1 is (indoi —) A 235.......... 1 1 Salmonella typhimurinm Λ20 ............... 2 2 Providencia Du 4S ........................ 20 20 'Serratia resistant to Gentamycin. 2.532...... 3 5 - 185 PRODUCT OP EXAMPLE 33 STRAINS MaleCs 24H in ug/ml 48H Penicillin- Staphylococcus aureus ATCC 6 538 sensitive 2 2 Stao'nylococcus aureus UC 1 128 Penicjllin- . 2 2 Staphylococcus aureus o: 2 2 Streptococcus pyogenes A 561.............. 0. 05 0.05 Streptococcus faecalis 5 432 ............. 3 40 Bacillus subtilis ATCC 6 633.......'....... 2 2 Escherichia Coli .sensitive toTetracycline ATCC 9 fi17 ............................... 1 2 Escherichia Coli resistant to Tetracycline ATCC 11 303 .............................. 0.5 0.5 Escherichia Coli Exp- TOjgB^.............. 1 1 Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D............'........ 1 1 Klebsiella pneumoniae Exp. 52 145......... ' 0. 1 0.5 Klebsiella pneumoniae 2 536 resistant to Gentamycin .................................. 2 3 Proteus mirabilis (indol-) A 235....-...... 0.2 0 .2 Salmonella tvphimurium 420................ 1 1 Provideneia Du' 48 ......................... 5 5 Serratia resistant to Gentamycin 2 532 ...... 2 3 - 186 PRODUC.T OF EXAMPLE 37 STRAINS M.I.C. 24H In pg/ml 48H Staphylococcus aureus ATCC 6 538 1 1 Staphylococcus aureus UC 1 12 3 1 1 Staphylococcus aureus exp. n®54 146....... 1 1 . Streptococcus pyogenes A 56.1.............. O'.OS 0.05 Bacillus· subtilis ATCC 6 633 ............. 1 2 Escherichia Coli sensitive toTetracycline ATCC 9 637 ............................... ' 2 2 Escherichia Coli resistant to Tetracycline ATCC 11 101 .............................. 0.5 0 .5 Escherichia Coli Exp. TO^^Bg.............. 1 1 Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D.................... 2 2 Klebsiella pneumoniae Exp. 52 145......... 0.05 ' 0 .05 Klebsiella pneumoniae 2 536 resistant to Genh amyc in .................................. 3 3 Proteus mirabilis (indol-) A 235.......... 0.5 0 .5 Seilmonella typhimurium 420................ 3 3 Enterobacter cloacae 681 ..........·’...... ' 10 20 Providencia Du 48 ........................ 10 10 Serratia resistant to Gentamycin. 2 532...... 2 3 - 187 PRODUCT . OF EXAMPLE 38 STRAINS M.I.C. 24H in ug/ml 4 8H Penicillin- Staphylococcus aureus ATCC 6 538sensitive 2 3 . , ' , ,_o Penicillin- Staphylccoccus aureus UC 1 128 resiBtant 3 5 Staphylococcus aureus exp. n°54 146 ...... 3 5 Streptococcus pyogenes A 561 ............. 40 .02 40 .02 SL^eetccoccus faecalis 5 432 .............. 2 40 Streptococcus faecalis 99 F 74............ 40 >4 0 Bacillus subtilis /YTCC 6 6 33.............. .1 2 Escherichia Ccli sensitive to Tetracycline ATCC 9 637 ............................... 0 .5 0. 5 Escherichia .Ccli resistant to Tetracycline ATCC 11 303 .............................. 0.1 0- I Escherichia Coli Exp. TC^gBg.............. 0. 2 o. 5 Escherichia Coli resistant to Gentaraycin Tobramycin R 55 123 D ................... 0. 2 0. 2 Klebsiella oneuinoniae Exp. 52 145 ......... 0.05 0-05 Klebsiella pneumoniae 2 536 resistant to Gentamycin .................................. 2 2 Proteus numbi.lxs (indol+) A 2 32........... 1 2 Proteus mirabilis (indol-) A 235.......... 0. 2 1 Salmonella typhimurium 420 ............... 0. 2 . 0.5 Enterobacter cloacae 681.................. 2 3 Providencia Du 4 8......................... 2 3 Serratia resistant to Gentamycin. 2 5 32.....: 1 1 - 188 PRODUCT OF EXAMPLE 39 STRAINS M.I.C. 2.4 H in Ug/ml 48H , „ Penicillin- Staphylococcus aureus aTCC C 5 38sensjtive 1 1 Staphylococcus aureus UC 1 12 8 penicill»resistant 1 2· Staphylococcus aureus cxp.n® 54 1a6 ...... 1 1 Streptococcus pyogenes Λ 561 ............. <0.02 <0.02 Streptococcus faecalis 5 432 .............. 2 10 Bacillus subtiiis ATCC 6 633.............. 1 5 Escherichia Coli sensitive toTetracycline ATCC 9 637 ............................... 3 5 Escherichia Coli resistant to Tetracycline ATCC 11 30 3 .............................. 0.5 0.5 t Escherichia Coli Exp. TO2636..........'· · · · 2 2 Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D.................... 2 2 Klebsiella pneumoniae Exp. 52 145 ........ 0. 2 0.2 Klebsiella pneumoniae 2 536 resistant to Gentamycin .................................. 5 5 Proteus mirabilis (incol-) A 235 ........ 0. 5 0.5 Salmonella typhimurium 420 ............... 1 1 Providencia Du 48 ........................ 10 10 Serratia resistant ta Gentamycin. 2 532...... 10 10 9867 - 189 PRODUCT OF EXAMPLE W STRAINS M.I.C. in pg/ml 24H · • 48H Streptococcus pyogenes A. 561........... 0.C5 0 .1 Escherichia Coli sensitive to Tetracycline ATCC 9 637 ........................... 2 3 Escherichia Coli resistant to Tetracycline ATCC 11 30 3 .....................’...... 1 1 Escher icl’.ia Coli Exp. TO^gBg........... 2 2 Escherichia Coli resistant to Gentamycin' Tobramycin R 55 123 D................. 3 3 Klebsiella pneumoniae Exp. 52 145...... • 1 1 Klebsiella pneumoniae 2 536 resistant to Gentamycin ................................ 5 10 Proteus mirabilis (indol-) A 235 ....... 1 .1 Salmonella typhirourium 420 ............ 3 5 Provider.cia Du 43 ..................... 5 5 Serratia resistant to Gentamycin 2 532... 20 20 9867 - 190 PRODUCT OF EXAMPLE 41 STRAINS M.I.C. 24H in ug/ml 48H . . , _ ,„ Penicillin- Staphylococcus aureus ATCC 6 538 sensitive ' . 10 10 Staphylococcus aureus UC 1 12 3 5 10 Staphylococcus aureus exp. ne 54 i4G...... 10 10 Streptococcus pyogenes Λ 561 ............. 0 .02 0.02 Bacillus subtilis /ATCC 6 633.............. 2 2 Escherichia Coli amsitive toTetracycline ATCC 9 617 ............................... • 1 1 Escherichia Coli resistant to Tetracycline ATCC 11 30 3............................... 0 .05 0. 1 Escherichia Coli Exp. TO2636.............. 0 .5 0 J Escherichia Coli resistant to Gentaraycin Tobramycin R 55 12 3 D.................... 0.5 0.5 Klebsiella pneumoniae Exp. 5 2 145......... 0 .2 0.2 Klebsiella pneumoniae 2 536 resistant to Gen· t-amycin .................................. 2 2 Proteus mirabilis (indol-) A 235 ......... 0 .2 0 2’ Proteus mirabilis (indol+) A 232 ......... 5 5 Salmonella typhimurium 420................. 0.5 1 Enterobacter cloacae 681 ..........'....... 20 20 · Providencia Ou 48 ...........,.'....'....... 3 3 Serratia reeistant to. Gentamycin 2 532......1 2 - 191 PRODUCT OF EXAMPLE 1 STRAINS H.I.C. in pg/ml • 24H 48H _ . . , Penicillin- Staphylococcus aureus ATCC 6 5 38 ncnsitive 0. 5 1 Penicillin- Staphylococcus aureus UC 1 128 resistant 1 1 Staphylococcus aureus exp.· n°54 146 ......... 1 1 ---------------------------------------------Ί Streptococcus pyogenes Λ 561 ............... 0.1 0.1 Streptococcus faecal is 5 4 32 .............. 5 10 Streptococcus faecalis 99 F 74 ............. 10 20 Bacillus subtilis ATCC 6 633 ............... 1 2 Escherichia Coli sensitive toTetracycline ATCC 9 637 ................................. 0. 1 0.1 Escherichia Coli resistant to Tetracycline ATCC 11 303 ................’................ 0. 1 0.1 Escherichia Coli Exp. TO2gDg................ 0.1 o.l Escherichia Coli resistant to Gsntamycin Tobramycin R 55 123 D ..................... 0.5 0.5 Klebsiella pneumoniae Exp. 52 145 .......... 0.05 0 .1 Klebsiella pneumoniae 2 536 resistant to Gantamycin ...................................... 0.5 2 Proton:. n.1 γ,.Ιι 1 1 1 s {liub.l-) A 235 ........... 0. 1 0 · 1 Salmonella typhimurlum 420 ................. 0.2 0 .2 Enterobacter cloacae 681 ................... 20 20 Providencia Du 48 .......................... 5 10 Serratia resistant to Gentamycin 2 532 ....... *10 20 • 49867 - 192 PRODUCT OF EXAMPLE 2 STRAINS ' . M.I.C. inpg/ml 24H 48H Staphylococcus aureus ATCC 6 538 0.5 0.5 Staphylococcus aureus UC 1 128 resistint” 1 1 Staphylococcus aureus exp: n* 54 146 ........ 0.5 1 Streptococcus pyogenes A 561 ............... 0.05 0.05 Streptococcus faecalis 5 432 ............... 5 5 Streptococcus faecalis 99 F 74 ............. 10 20 Bacillus subtilis ATCC 6 633 ............... 1 1 Escherichia Coli sensitive to Tetracycline ATCC 9 637.................................. 0.2 0.2 [Escherichia Coli resistant to Totracycline ATCC 11 303 ................................ 1 0.1 0.1 Escherichia Coli Exp. TOjgBg................ 0.05 0 .95 Escherichia Coli resistant to Gfentamycin Tobramycin R 55 12 3 D..................... 0.5 0 .5 Klebsiella pnotuuoniae Exp. 52 145 .......... 0.05 0 .05 Klebsiella pneumoniae 2 536 resistant to Ghntamy cin ...................................... 0.5 0 .5 Proteus mirabilis (indol**) A 235 ........... 0* 1 0..1 Salmonella typhimurium 420 ...........·...... o.i 0 .2 Enterobacter cloacae 681 ................... 20 20 Provjdencla Du 48 .......................... 2 5 * • - 193 PRODUCT OF EXAMPLE 3 STRAINS M.I.C. in ug/ml 24H 48H Penicillin- Staphylococcus aureus .ATCC 6 5 38 sensitive 1 2 _ Penicillin- Staphylococcus aureus UC 1-128 resistant 2 2 Staphylococcus aureus exp. N°5 4 146 ........ 2 2 Streptococcus pyogenes A 561 ............... 0,2 0.2 Bacillus subtilis ATCC 6 6 33 ............... 2 3 Escherichia Coli sensitive toTetracycline ATCC 9 637 ................................. 0. 5 0.5 Escherichia Coli resistant to Tetracycline ATCC 11 303 ................................ 0. 2 0.2 Escherichia Coli Exp. TO2gBg ............... 0. 1 0.1 Escherichia Coli resistant to Cfentamycin Tobramycin R 55 12 3 D ..................... 0. 5 1 Klebsiella pneumoniae Exp. 52 145 .......... 0. 1 0.2 Klebsiella pneumoniae 2 536 reeistant to. Gcnta- mycin ...................................... 1 1 Proteus mirabilis (indol-) A 235 ........... 0.2 0.2 Salmonella typhimurium 420 ................. 0.5 0.5 Enterobacter cloacae 681 ................... 20 40 Provideneia Du 48 .......................... 3 5 Serratia reeistant to Cbntamycin 2 532 ....... 3 5 - 194 PRODUCT OF EXAAPLE 5 STRAINS M.I.C. in. pg/ml 24H 48Π Staphylococcus aureus ATCC 6 538 sensitive11” 2 3 „ , . Penicillin- Staphy)ococcus aureus UC 1 128 resistant 5 5 Staphylococcus aureus exp. N*54 146 ......... 2 3 Streptococcus pyogenes A 56 1 ................ 0.5 0.5 Bacillus subtilis ZiTCC 6 633 ................. 10 10 Escherichia Coli sensitive to Tetracycline ATCC 0.5 0. 5 Escherichia Coli resistant to Tetracycline ATCC 11 303 ................................. 0. 1 0.1 • Escherichia Coli Exp. TOjgBg··............... 0. 5 0.5 Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D ...................... 2 2 1 Klebsiella pneumoniae Exp. 52 145 ........... 0.2 0.2 Klebsiella* pneumoniae 2 536 resistant toChntaraycin ......................................... 2 2 Proteus mirabilis (indol-) A 235 ............ 0,2 0.2 Salmonella typhimurium 420 .................. 0.5 0.5 - 195 PRODUCT OF EXAMPLE 7 STRAINS M.I.C. laug/ml 24H 4 8H Staphylococcus aureus ATCC 6 538 sensitive” ‘ 5 20 Staphylococcus aureus UC 1 128 . reeistent™ 10 10 Staphylococcus aureuc exp. n*54 146 ........ 10 10 Streptococcus pyogenes A 561 ............... 0.5 1 Bacillus subtiiis ATCC 6 633 ............... 5 20 Escherichia Coli sensitive to Tetracycline ATCC 2 637 ................................. 1 1 1 Escherichia Coli resistant toTetracycline ATCC 11 303 ................................ 0.5 1 Escherichia Coli Exp.TOjgBg................. 1 1 I Escherichia Coli resistant to OBntamycin Tobramycin R 55 123 D ..................... 1 __2„j Klebsiella pneumoniae Exp. 52 145 .......... 0. 5 i 1 ί Klebsiella pneumoniae 2 536 resistant to Gentatnycin ..................................... 2 2 Proteus mirabilis (indol-) A 235 ........... 0. 1 0.1 Proteus vulgaris (indol+) A 232 ............ 1 2 Salmonella typhimurium 420 ................. 1 1 Providencia Du 48 .......................... 20 20 Serratia resistant to Qsntamycin 2 532........ 10 10 Ί 0 U V I - 196 PRODUCT OF EXAAPLE 9 STRAINS. M.I.C. in yg/n»i 2 ό (I 4811 Staphylococcus aureus ATCC 6 538 t’cnicillinr J sensitive . 2 2 . , , i-,β Penicillin- Gtaphylococcus aureus UC 1 128 resistant 3 3 Staphylococcus aureus exp. N” 54 146........ 3 3 Streptococcus pyogenes A 561 .............. 0. 2 0.2 Bacillus subtilis ATCC 6 633 .............. 1 2 Escherichia Coli sensitive to Tetracycline ATCC 9 637 ................................ 0.5 0.5 Escherichia Coli resistant to Tetracycline ATCC 11 303 ............................... 0.1 0 . 1 Escherichia Coli Exp. TO2 6B.6...............1 1 1 Escherichia Coli resistant to Cfentamycin Tobramycin R 55 123 D..................... 0.5 0.5 Klebsiella pneumoniae Exp. 52 145 ......... 0. 1 0.1 Klebsiella pneumoniae 2 536 resistant to Ofentamyc in .................................... 1 1 Proteus mirabilis (indol-) A 235 .......... 0. 1 0. 1 Proteus vulgaris (indol+) A 2 32 ......'..... 1 1 Salmonella typhimurium 420 ................ 0.5 1 Enterobacter cloacae 68 1 .................. 20 >40 Prpvidencia Du 48 ......................... 3 3 serratia resistant to Cfentamycin 2 532....... 3 5 - 197 prodlPt of exanple 10 STRAIKC M.I.C. in' Ug/ml 24H 4 8H Staphylococcus aureus ATCC 6 538 Peni^illinsennxtive 10 20 Staphylococcus aureus UC I 128 Penxcxllxn- r J resistant 20 20 Staphylococcus aureus exp. n°54 146 ......... 10 20 Streptococcus pyogenes A 561 ................ 1 3 Bacillus subtilis ATCC 6 633 ................ 10 20 Escherichia Coli sensitive to Tetracycline ATCC 9 637 ................................... 0.5 0, i 1 Escherichia Coli resistant to Tetracycline ATCC 11 303 ................................. 0.5 1 1 0.5 ί Escherichia Coli Exp. TC^gBg ................ 0.5 0.5 i Escherichia Coli resistant to Gentamycin Tobramycin P. 55 12 3 D ...................... 1 1 Klebsiella pneumoniae Exp. 52 145 . . ......... 0.5 0.5 Klebsiella pneumoniae 2 5 36 resistant to Cfentam yc in ....................................... 1 1 Proteus mirabilis (indol-) A 235 ............ 0.1 0. 1 Proteus vulgaris (indol+) A 232 ............. 0.2 0.2 Salmonella typhimurium 420 .................. 0.5 1 Enterobacter cloacae 681 .................... 20 40 Providencia Du 48 ..'.............*............. 2 3 Serratia resistant to Gsntamycin 2 532......... • 10 10 9 Ο V < - 198 PRODUCT OF EXAMPLE STRAINS . M. I.C. ia yg/ml 24H 48H Penicillin- Staphylococcus aureus ATCC 6 538 sensitive 1020 Penicillin- Staphylococcus aureus UC 1 128 resistant 10 10 Staphylococcus aureus exp. n°54 146 ......... 10 10 Streptococcus pyogenes A 561 ............... 0. 1 0.1 . Streptococcus faecalis 5 432 ............... 20 >40 Bacillus subtilis ATCC 6 633 ............... 10 10 Escherichia Coli sensit ive toTetracycline ATCC 9 637 ................................. 0.2 0.2 Escherichia Coli resistant to Tetracycline ATCC 11 303 ................................ 0.05 0.05 Escherichia Coli Exp. TO2(,Bg ............... 0. 2 0.2 Escherichia Coli resistant to Cbntamycin Tobramycin R 55 12 3 D...................... 0. 5 0.5 Klebsiella pneumoniae Exp. 52 145 .......... 0.1 0.1 Klebsiella pneumoniae 2 536 resistant to Gentamyc in ...................................... 0.2 0.2 Proteus mirabilis (indol-) A 235 .....·..... 0.02 0.02 Proteus vulgaris (indol+) A 232 ............ 1 1 Salmonella typhimurium 420 .................. 0.5 0.5 Enterobacter cloacae 681 ................... 40 40 10 - Serratia resistant to Gentamycin 2 532 ....... 2 - - 201 PRODUCT OF EXAM’LE l5 STRAINS M.I.C. in Pg/n»l 24H 48H Staphylococcus aureus ATCC 6 538 p®nicillin-- censAUjrfi 5 5 Staphylococcus aureus UC 1 128 Penicillin- _____________ ______________rfiaisApji__ 10 10 Staphylococcus aureus exp. ne54 146 ........ 5 10 Streptococcus pvogenes A 561 ............... 0.02 < 0.02 Streptococcus faecalis 5.432 ............... 10 >40 Bacillus subtilis ATCC 6 633 ............... 1 2 Escherichia Coli sensitive to Tetracycline ATCC 9 637 ................................. 0 . 1 0.3 |Escher i'cliia Coli resistant to Tetracycline (ATCC 11 303 ................................ 0,05 i 1 0.05' Escherichia Coli Exp. TO_,Br................ 2 0 o 0. 1 0.1 » Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D ..................... 0. 1 0.1 Klebsiella pneumoniae Exp. 52 145 .......... 0.05 0.05 Klebsiella pneumoniae 2 536 resistant to Gbntamycin ...................................... 0.2 0.2 Proteus mirabilis (indol-) A 235 ........... 0.1 0.2 Proteus vulgaris (indol+) A 232 ............ 1 2 Salmonella typhimurium 420 ................. 0.1 0. 1 Enterobacter cloacae 681 ..............'..... 2 2 Provideneia Du 48 .......................... 1 1 Serratia resistant toCfentamycin 2 532 ........ 0.5 1 - 202 PRODUCT OF EXAMPLE 16 STRAINS M.I.C. in ug/ml 24H 48H „ v , n co Penicillin- Staphylococcus aureus ATCC 6 538 oensitive 1 1 , Pcnicillin- Staphylococcus aureus UC 1 128 resistant 1 2 Staphylococcus aureus exp. n°54 146 ........ 2 2 Streptococcus pyogenes A 561 ............... 0.05 o o Streptococcus faecalis 5 432 ............... 5 40 Streptococcus faecalis 99 F 74 ............. 20 > 40 ! Bacillus subtilis ATCC 6 633 ............... 2 1 1 3 Escherichia Coli sensitive toTetracycline ATCC 9 637 ................................. 0 5 1 1 Escherichia Coli resistant to Tetracycline ATCC 11 303 ................................ 0.05 0.05: Escherichia Coli Exp. Ti^gDg................ 0. 5 0.5 ; Escherichia Coli resistant toQentamycin Tobramycin R 55 123 D...................... 0.2 1 0.2 Klebsiella pneumoniae Exp. 52 145 . .......... 0.2 0.2 Klebsiella pneumoniae 2 536 resistant to Cbntamycin...................................... 1 1 Proteus mirabilis (indol-) A 235 ........... 0.1 0.1 Salmonella typhimurlum 420 ...........:..... 0.5 0^5 Providencia Du 48 .......................... 10 10 Serratia resistant toGbntamycin 2 532 ....... * 2 2 - 203 — PRODUCT OF EXAMPLE t? STRAINS M. I.C. in ug/ml 24H 48H „ . , , _ ,a Penicillin- Staphylococcus aureus ATCC 6 538 sens£tive . 1 1 Penicillin- Staphylococcus aureus UC 1 128 resistant 2 2 Staphylococcus aureus exp. n°54 145 ........ 2 2 Streptococcus pyogenes Λ 551 ............... 0. 1 0.1 Streptococcus faecalis 5 432 ............... 10 40 I Bacillus eubtilis ATCC 6 633 ............... 3 J 1 Escherichia Coli sensitive to Tetracycline i/\TCC 9 637 ................................ 0.5 ! 1 0.5 1 'Escherichia Coli resistant to Tetracycline iATCC 1 1 30 3 ......................'·.......... 0.05 1 0.05 > · iEscherichia Coli Exp. ΤΟ2(-Οθ................ 0.2 0.2 : 1 Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D ..................... 0.5 0.5 ' » [Klebsiella pneumoniae Exp. 52 145 .......... 0.05 0.05’ Klebsiella pneumoniae 2 536 resistant tocentamycin ..................................... 0.5 1 i : Proteus mirabilis (indol-) A 235 ........... 0.1 0.1 1 Salmonella typhimurium 420 ....... 0.1 0.1 Enterobacter cloacae 681 ................... 10 20 Providencia Du 48 .......................... 3 5 Serratia resistant to Gentamycin 2 532 ....... 5 10 MUUUV 1 . vr -,.STRAINS .M.I.C. in Η/«η1 24 II ι 48 II Staphylococcus Quroue ATCC 6 53θ Penicillin-sensitive ··············« > Staphylococcus euroU3 UC 1 128 1 1 1 1 1 10 t t io , Penic lllin^rss its 1 ’ Staphylococcus aurous oxp.n® 54 146 ! 1 t 5 1 I 5 ! Straptococcus pyoffanoa A 561... 1 « · I X ^0.02t ζ°·°< Streptococcus 1‘c.ocalis 5 432..., 1 . · i > 20 1 40 : Ducillut subtiiis ATCC 6 633......

Eschoriehia Coli sensitive to Totracyclins ATCC 9 637«··«· Escherichia Coli resistant to Totracyclino ATCC 11 303····< 0.2 0.2 Escborichia Coli Exp. TC^ 3^, 0.2 0.5 Eschoriehia Coli resistant to Con tamycin , Tobramycin Π 55 123 D 0.5 0.5 Klobaiolla pnoucnoniaa Exp. 52 145· I I t 1 1 t t 1 : Klobaiolla pnounonino 2 536 t 1 , resistant to Gontaiuycln , ............ t 1 1 t s 1 , ί Protouo mirabilis (indol-) A 235,. 1 1 t t 1 1 » •1 . ;| Salmonella typhimurium 420····,,·. 1 t t 0.5 » • 1 Entorobaotor cloacao 681.

Providoncia DU 48, Serratia resistant to Gentamycin 2532 1 1 . > ' »- STRAINS - »·' M.I.C., in 24 H 1 8 Λ&Λί , 48 H . 1 . t Staphylococcus aureus ATCC 6 538 t 1 1 : 1 > 2 8 t 3 , Staphylococcus auroua UC 1 128 i 8 8 8 1 > 3 « 3 Staphylococcus aureus oxn. n°54 146. 1 8 8 8 2 1 1 3 ' Streptococcus pyogenes A 561······· 8 8 8 0.05 1 t 0.05 Streptococcus faecalis 5 432e....o. 1 1 8 > 10 I >,° j ’ Bacillus subtilis ATCC 6 633.·.·» 8 8 1 1 J Eschovichia Coll sensitive to Totraeycllrio ATCC 9 637»·«····** 8 1 8 1 1 / 1 ' Escherichia Coli -resistant to J To traoyoliiio ATCC 11 303 8 8 8 1 0.C5 0.05 ; ί Eochorlohla Coll ExpaTOggB^,··, . t 8 t 0.2 0,2 ; 1 Eooheriohia Coli resistant -to ( Gontomycin, Tobramycin B 55 1233» 8 1 1 1 0.2 0.2 ;( Eloboiolla pnnumoniao Exp, 52 145 1 8 1 0.2 0.2( Eloboiolla pr.ounoniao 2 536 > resistant toGentamycin.«.···,···.».« 1 8 t 1 1 ' ' Proteus mirabilis (indol») Λ 235·· 8 8 8 0.1 0.1 J Salmonella typhimurium 420···*···, 8 8 8 1 1 ' ' Entorobaotor cloacae 681,·.········ 8 t • 2020 ' ' Providonoia'Du 48.,.,,,,,,,,,,,,,, 8 8 1 10 10 ; Serratia resistant to Gontaoycin 2 532............................. 8 8 8 1 1 *» ο σ ν < PKODVCT OF EXAMPLE / STRAINS 1 1 1* 1 I M.I.C. in - 24 ii ι t /*c/wi 48 H \ Stnphylocoocuo r.urouo ATCC 6 538 1 I < J 1 1 ι i 1 ' Staphylococcus aureus UC 1 125 t 1 t ! Penic illin-resistant ·····. ········ > ι ι t 1 Stcphylocoocun aursus οχρ·η°54ΐ46 t t J t 1 » 1 1 Stroytococcun pyeconos A 561··»·· 1 1 > 1 0.05 « > 0.05 ’ Stroptcooccua iuocalia 5 432..... 1 s I t 5 « t 5 ;| Bacillus subtilis ATCC 6 653····· 1 1 t 2 ι 2 ! Eoclioi'icliia Coli sensitive to , Teti’ftcycliBO ATCC 9 637.......... I 1 β • I t 0.5 » > 1| Escherichia Coli resistant to Totracyclino ATCC 11 303........ I 1 1 J t t 0.05 » 1 0.05 Eochorichia Coli Exp. T0qz34,,,, 1 «co o 1 1 ι 1 0.2 ι t 0.2 Eac’ioriohia Coli resistant to Gontanycin, . Tobx’auycin: Π 55 123 D··.· ι t ( » 1 0.2 » 1 0.2 KlubsisXln pnounonlao Exp. 52 145· 1 1 t 1 0.05 » t 0.05 : , Kloboioiia pnoumoniao 2 536 resistanttoGontaciycin ·.,*·«······ » 1 1 0,5 j 1 0-5 Ii PxOvOua uiira'oiXis (indol-JA 2J5·· 1 1 0.05 « 1 0.05 ,1 Salmonella typhimurium 420··.···· t I 0.2 ’ 0.2r Entorobaotor cloacae 631·.········ 1 I »5 : 20 ’ Prftvldnngjp. J>_i 43.....············ 1 1 5 J 5 ; ' Sorratia resistant to Gentamycin 2 532............................. t I 1 2 t 2 < PRODUCT OF -EXAMPLE 56 1 · ' STRAINS, ‘ M.I.C-. in A/r/ml 1 24 11 1 ι 48 II , Staphylococcus aurouo ATCC 6 538 I I i ’ 5 ' ι 5 ι Penicillin-sensitive*··· t Staphylococcus aurouo UC 1 120 1 1 , Penicillin-resistant·· · · I 5 t l 10 1 Staphyloooocus ourous oxp.n® 5^ 146.

Streptoooccuo pyocenoa Λ 56V 0.05 0.05 Baoilluo subtilis ATCC 6 633, E3chcrichia Coli sensitive to Tetraoyollno ATCC 9 637...............s.

Eochorichia Coll resistant to Totrncyclino ATCC li 303·*·< 0.2 0.5 Eachorichia Coli Exit, TO^^B1 2o o Escherichia. Coli resistant- toGcntamyoin Tobramycin R 55 123 B,,, Klabaiolia pneumoniae Exp· 52 145·· 0.5 Klebeiolla pneumoniao 2 536 resistant to Gentamycin ······, ( Protouo mirabilis (indol—) Λ 235··· I i 1 < I 1 I , 1 Salmonella typhimurium 420··.······ ι ι 1 1 1 2 I , Providcnoia. Du 40.·..·············· t 1 4o t t 4o I t ( Sorrntia resistant.to Gontamycin 2 532, t 1 2 t 1 2 1

Claims (5)

1. ° 1,3,4-oxadiazolyl radical, and each of these heterocyclic radicals being either unsubstituted or substituted by one or more radicals selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyloxy and isopropyloxy, amino, hydroxycarbonylmethyl, dimethylaminoethyl and 15 diethylaminoethyl radicals. 6. A compound as claimed in any of Claims 1 to 4, wherein R^ represents the radical -CH 2 -S-Rl 2 in which K 12 is an acetyl, propionyl or butyryl group. 7. A compound as claimed in any of Claims 1 to 4, 20 wherein Rj represents the radical -CH 2 ~S-R^ 2 in which R^ 2 is the acetyl, 1-methy1-tetrazolyl, 2-methy1-1,3,4-thiadiazolyl; 3-methy1-1,2,4-thiadiazol-5-yl; 3-methoxy-1,2,4thiadiazolyl; l,3,4-thiadiazol-5-yl; 2-amino-l,3»4,-thiadiazol- 5~yl; 3~hydroxycarbonylmethy1-1,2,4-thiadiazol-5~ 25 yl; 5-methoxy-l,2,4-thiadiazol-3-yl; 4-methyl-5-hydroxy- 215 carbonylmethyl-l,5-thiazol-2-yl or 1-dimethylaminoethyll,2,5,4-tetrazol~5-yl radical. 8. A compound as claimed in Claim 2, wherein: i) R is the radical -CO-R' and R' represents an 5 alkyl radical having from 1 to 4 carbon atoms, a phenyl radical or a radical i n n is 0 or 1; or ii) R is the radical -CH-COOH and R^ represents a phenyl radical or a hydroxyethyl radical, or iii) R is the γ lactone of formula —» or iv) R is the radical n' is° 1 or 2 and R^ represents either a radical -NRgR^, a radical -C-NHp, a l,2,5,a-tetrazol-5-yl radical or an acetyl S radical; and R-]_ represents an alkyl radical having from 1 to 5 carbon atoms, an acetoxymethyl radical or a radical -CH2~S-R^2 i Q which R^ represents a 2-methy1-1,5«4-thiadiazolyl radical or a 1-methyl-tetrazolyl radical; and A represents a hydrogen atom, an alkali metal atom, an equivalent of an alkaline-earth metal atom or of a magnesium atom, ammonium or a substituted ammonium group. 9. A compound as claimed in Claim 8, wherein R represents an acetyl, benzoyl, phthalimidoacetyl, Ν,Ν-dimethylcarbamoyl, α-carboxyphenylmethyl, 2-oxo-5-tetrahydropyranyl, 1,4-dihydroxy-l-oxo-2-butyl, phthalimidomethyl, aminoethyl, tetrazol-5~yl~methyl, 2-amino-2-thioxoethyl ι' ΐ! - 214 or 2-oxopropyl radical; R^ represents a methyl, acetoxymethyl, 2-methyl-l,3,4-thiadiazol~5-yl-thiomethyl or 1methyl-tetrazolyl-thiomethyl radical; and A represents a hydrogen or sodium atom. 5 10. A compound as claimed in Claim 9, wherein R represents an acetyl, benzoyl, phthalimidoacetyl, tetrazol5-yl-methyl, aminoethyl or α-carboxy-phenylmethyl radical; R^ represents an acetoxymethyl, 2-methyl-l,3,4-thiadiazol5-yl-thiomethyl or l-methyl-tetrazol-5-yl-thiomethyl 10 radical. 11. A compound as claimed in Claim 3» wherein R^ a represents a bromine or iodine atom or a phenylthio, 2pyridinylthio, 2-amino-l,3»4-thiadiazol-5”ylthio, 1-methyllH-tetrazol-5-ylthio, 2-amino-phenyIthio, 5~aitro-215 pyridinylthio or 5**cyano-6-methyl-2-pyridinylthio group. 12. 3-Acetoxymethyl-7-[[2-(2-amino-thiazol-4-yl)-2-(2aminoethoxyimino-acetyl]-amino]-ceph-3-em-4-carboxylic acid syn isomer, its salts with alkali metals, alkalineearth metals, magnesium, ammonium and organic amino bases, 20 and its esters formed with easily-cleavable ester groups. 13· 3~Acetoxymethyl-7-C[2-(2-bromoethoxyimino]-2-(2amino-thi azo1-4-yl)-acetyl]-amino]-ceph-3-em-4-c arboxylie acid syn isomer, its salts with alkali metals, alkalineearth metals, magnesium, ammnniua and organic amino 25 bases and its esters formed with easily-cleavable ester groups. 14. 3~Acetoxymethyl-7-C[2-(2-iodoethoxyimino)-2-(249867 - 215 ami nn—thia2ol—4—yl)—acetyl]—aminol—ceph-5—em—4—carboxylic acid syn isomer, its salt? with alkali metals, alkaline-earth metals, magnesium, ammonium and organic amino bases and its esters formed with easily-cleavable ester groups. 5 15. 3-Acetoxymethyl-7-[[2-(2-amino-thiazol-4-yl)-2( carbamoyloxyimino)-acetyl ]-atnino]+ceph-3-em-4-carboxylic acid syn isomer, its salts with alkali metals, alkalineearth metals, magnesium, ammonium and. organic amino bases and its esters formed with easily-cleavable ester groups. 10 16. A process for preparing the derivatives of general formula 1' wherein A represents a hydrogen atom, in which process a compound of one of the general formulae: S 1 < ITI A> (wherein represents a protecting group for the amino radical 15 A represents an easily-cleavable ester group ’ or a hydrogen atom, and R 1 represents an alkyl radical having from 1 to 4 carbon atoms, an alkoxy radical having from 1 to 4 carbon atoms, a phenyl radical or a radical -(CH 2 ) n -NR 2 R 5 in which R 2 and R^ which may be the same 20 or different, each represent a hydrogen atom or an alkyl radical with the proviso that both R2 and Rj do not both represent hydrogen when n is zero, or R n 2 and Rj together with the intervening nitrogen atom represent a phthalimido, - 216 - (ΙΙΙ· 4 ) (ΙΧΙ Β ) - 217 (wherein A'^ represents an easily-cleavable ester group or an alkali metal atom and. Α χ represents an alkali metal atom),

1. The new ayn isomer 7-(amino-thiazolyl)-acetamidoceph-3-em-4-carboxylic acid derivatives of the general formula: (wherein: a) B represents a radical R which is:i) a radical -C-R' x represents a sulphur or X oxygen atom and R' represents: an alkyl or alkoxy radical having from 1 to

2. Derivatives of the general formula: HH, wherein R, Rj and A are as defined in claim 1.

3. Derivatives of the general formula: (I) wherein R , R, and A are as defined in claim 1. 3 I - 212 Derivatives of the general formula: 5. A compound as claimed in any of the preceding 5 claims, wherein R^ represents the radical -CH 2 -S- «12 in which R^ 2 is a 1,2,3 - » 1*2,5·”, 1*2,4- or 1,3,4-thiadiazolyl radical; a ΙΗ-tetrazolyl radical; a 1,3-thiazolyl radical, a 1,2,3“ or 1,2,4-triazolyl radical; or a 1,2,3-, 1*2,4-, 1,2,5- or

4. -4 i' ' N-N a radical -(CHg): ,-·ο *»B67 - 246 a radical ( CH 2^n’”^3* Or a radical (CH 2 ) n ,-»R ia R 19 , with the proviso that R 16 cannot represent a chloroacetyl radical when R^ represents -CX-CHj and R^ represents an acetoxymethyl radical. ll?. The compounds of the general formula: Ri (XII) 118. The compounds of the general formula: CONH \ -N (XII') CHg-R’j. wherein R' ia represents a trityl or chloroacetyl radical, n*£ represents 1 or 2; Hal' represents a bromine or \ COgA (GH 2^n'.-Hal' 48807 - 247 iodine atom and R'^ represents a hydrogen atom, an acetoxy or carbamoyloxy radical or a 1-methy1-tetrazol-S-yl or 2-methyl-l,3,4-thiadiazol-6-yl radical. 5 119. The compounds of general formula Dated this 8th day of August 1979, (signed) 4»»° - 238 - (vi K ) NHk.z J C0 x H N (VI L ) (vr L ) NHR, Λ COj,H N, '0 On' ^ar (vi M ) - 239 or a functional derivative of a compound of one of these general formulae is reacted with a compound of general formula IX, to obtain, respectively, the compounds of general formulae III A , HI' Hlg, IIIq, Hip* IHg» 5 III F , III G , IIIjp IH'fp IHj, III K , III L , III' L and III M . 81. A process as claimed in Claim 80, in which the functional derivative is an acyl halide, symmetric or mixed anhydride, amide or activated ester. 82. A process as claimed in Claim 80 or Claim 81, in . 10 which the reaction is carried out in an organic solvent. 83. A process as claimed in Claim 81, in which, when the compound of general formula IX is reacted with an acyl halide or a mixed anhydride formed with isobutyl chloroformate, the reaction is carried out in the presence of a I 15 base. 84. A process as claimed in Claim 83, in which the base is sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, sodium acetate, triethylaminei pyridine, morpholine or N-methyl-morpholine. 20 85. A process as claimed in any of Claims 80 to 84, in which substituent R^g is a trityl, chloroacetyl, tertpentyloxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl radical. 86. A process as claimed in any of Claims 80 to 85, in 25 which the formed compound of general formula ΙΙΙθ is * treated with a base to form a corresponding compound of general formula III'q. - 240 87. A process as claimed in any of Claims 80 to 85, in which the compound of general formula VI^ is prepared by treating a compound of general formula V with a functional derivative of the acid HO-CX-R·^. 5 88. A process as claimed in any of Claims 80 to 85, in which the compound of general formula VIis prepared by reacting a compound of general formula V with a compound of formula X=C=NH. 89· A process as claimed in any of Claims 80 to 85, in 10 which the compound of general formula VIg is prepared by reacting a compound of general formula V with a compound of the general formula Y-CHR’^-COgA''’. 90. A process as claimed in any of Claims 80 to 86, in which the compound VI^, is prepared by reacting a compound 15 of general formula V with a compound of the general formula 91. A process as claimed in any of Claims 80 to 85, in which the compound VIg is prepared hy reacting a compound of the general formula V with a compound of the general 20 formula Y-(CH 2 )-R' 92. A process as claimed in any of Claims 80 to 85, in which the compound VIp is prepared by reacting a compound of general formula V with a compound of the general formula Y-(CH 2 )n2-CN . 25 93· A process aa claimed in any of Claims 80 to 85, in which the compound VIp is prepared by a process in which - 241 a compound of the general formula: zSv co x K (»1» is treated either with hydrogen sulphide or, when n' is an integer other than 1, by hydrolysis in the presence of a base, to obtain the corresponding product of formula VI^. 5 94. A process as claimed in any of Claims 80 to 85, in which the compound of general formula VIq is prepared by treating the compound of general formula VIp wherein X 1 represents a sulphur atom with a compound of the general formula R'^-CO-C^-Hal. 10 95* A process as claimed in any of Claims 80 to 85, in which the compound of general formula VI^ is prepared by treating the compound of general formula VII with an azide. 96. A process as claimed in Claim 95 on Claim 95, in which the compound of general formula VII wherein n’ is 15 2, 3 or 4 is prepared by a process as defined in Claim 92 in relation to compounds VI^.. 97· A process as claimed in Claim 93 or Claim 95, in which the compound VII wherein n* is 1 is prepared by reacting a compound of general formula V with a compound < 20 of the general formula Y-CHg-CN. 98. A process as claimed in any of Claims 80 to 85, in which the compound of general formula VI' H is prepared by • 49867 - 242 reacting a compound of the general formula: H (V) (wherein R g represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms) with a compound of the general formula Hal-(CHg)—Hal (wherein the substituents Hal may be the same or different) to obtain a product of the general formula: co, R St which product of formula VIjp when R e represents an alkyl radical having from 1 to 4 carbon atoms, is treated first with a base and then with an acid. 99. A process as claimed in Claim 98, in which Hal represents a bromine or iodine atom. 100. A process as claimed in Claim 98 or Claim 99, in which the compound of general formula Hal-(CHg) n «-Hal is reacted with the compound V* in the presence of a base to neutralize the hydrohalic acid formed. 101. A process as claimed in any of Claims 98 to 100, in which the ester of general formula VIg wherein R e - 245 represents an alkyl radical having from 1 to 4 carbon atoms is reacted firstly with sodium hydroxide, potassium hydroxide or barium hydroxide, and then with dilute hydrochloric acid, acetic acid or formic acid. 5 102. A process as claimed in any of Claims 80 to 85, in which the compound of general formula VIj is prepared by reacting a compound of general formula VI'g with pyridine. 103. A process as claimed in any of Claims 80 to 85, in which the compound of general formula VIg is prepared by 10 reacting a compound of general formula VI'g with an azide. 104. A process as claimed in any of Claims 80 to 85, in which the compound of general formula VI^ is prepared by reacting a compound of general formula Vl*g with an amine of general formula NHR^gR^g. 15 IO5. A process as claimed in any of Claims 80 to 85, in which the compound of general formula VI' is prepared by reacting a compound of general formula VI'g with imidazole, morpholine or an N-alkyl piperazine. 106. A process as claimed in any of Claims 80 to 85, in 20 which the compound of general formula VI^ is prepared by reacting a compound of general formula VI' g with a compound of general formula R ar ,-SH. * IO?. A process as claimed in any of Claims 102 to 106, in which the compound VI* g is prepared by the process · 25 defined in any of Claims 98 to 101. 108. A process for the preparation of a derivative of general formula 1' or a salt thereof as defined in Claim 1 substantially as described herein with reference to any - 244 one of the Examples. 109. A derivative of general formula i'or a salt thereof as defined in Claim 1 whenever prepared by a process as claimed in any of Claims 16 to 79 and 108. 5 110. A derivative of general formula 1' as-defined in Claim 1 or an addition salt thereof formed with a pharmaceutically-acceptable mineral or organic acid for use in a method of treatment of the human or animal body by antibiotic therapy. 111. A derivative of general formula I' as claimed in any of 10 Claims 2, 3 and 4 or an addition salt thereof formed uith a pharmaceutically-acceptable mineral or organic acid for use in a method of treatment of the human or animal body by antibiotic therapy. 112. A compound of general formula I* as defined in any of Claims 5 to 15 for use in a method of treatment of the human or animal 15 body by antibiotic therapy. 113- Pharmaceutical compositions containing as active ingredient one or more derivatives of general formula I· and/or one or more addition salts thereof formed with pharmaceutically-acceptable mineral or organic acids, 20 in association with a pharmaceutically-acceptable vehicle. 114. A composition as claimed in Claim 113, in which the active ingredient is or includes one or more compounds as claimed in any of Claims 2 to 15. 115. A method of disinfecting a locus excluding on human 25 beings, in which there is applied to the locus an effective disinfecting amount of a compound as claimed in Claim 1. 116. The compounds of the general formula: (A) wherein R^ represents· a radical —CX-R'^; a radical -CX-NH 2 ; a radical -CHR’ 4 -C0 2 A ‘ ; a radical a radical -(CH 2 ) n ,-R' a radical -(CH 2 ) n2 CN; a radical -(CH 2 ) n ,CX'-NH 2 ; a radical -(CH 2 ) q i Η * 10 a radical “( CI ^ n Μ—M 4-2. A process as claimed in Claim 16, in which the com15 pound of general formula IHp is prepared by treating a compound of the general formula: either with hydrogen sulphide or, when n’ is an integer other than 1, by hydrolysis in the presence of a base to obtain the corresponding product of general formula Hip. 20 4-5. A process as claimed in Claim 42, in which the reaction of the compound of general formula IV with hydrogen sulphide is carried out in the presence of a tertiary amine. - 230 44. A process as claimed in Claim 42 or Claim 43, in which the reaction is carried out in dimethylformamide as solvent. 45· A process as claimed in Claim 42, in which the hydrolysis of the compound of general formula IV in which X' represents an oxygen atom and n' is an integer from 2 to 4 is carried out using a dilute sodium hydroxide solution. 46. A process as claimed in Claim 16, in which tbe compound of general formula ΙΙΙθ is prepared by reacting a compound of general formula Hip wherein X is a sulphur atom with a compound of the general formula R'^-CO-CHg-Hal. 47. A process as claimed in Claim 46, in which the compound of general formula IIIp is prepared by a process as defined in any of Claims 42 to 44. 48. A process as claimed in Claim 46 or Claim 47, in which Hal represents a chlorine or a bromine atom. 49. A process as claimed in Claim 16, in which the compound of general formula IIIjj is prepared by treating a compound of the general formula IV with an azide. 50. A process as claimed in Claim 49» in which the azide is sodium azide. 51. A process as claimed in Claim 49 or Claim 5θ* in which the reaction with the azide is carried out in dimethylformamide. 52. A process as claimed in Claim 16, in which the compound of general formula III‘g is prepared by treating a compound of general formula II with a compound of the - 231 9867 general formula Hal--Hal wherein the two Hal substituents may be the same or different. 53. A process as claimed in Claim 52., in which Hal represents a bromine or iodine atom. 54. A process as claimed in Claim 16, in which the compound of general formula IIIj is prepared by treating a compound of general formula III'g with pyridine. 55- A process as claimed in Claim 54, in which the reaction is carried out in dimethylformamide as solvent. 56. A process as claimed in Claim 16, in which the compound of general formula III^ is prepared by treating a compound of general formula HI’jj with an azide. 57. A process as claimed in Claim 5θ, in which the azide is sodium azides 58. A process as claimed in Claim 56 or Claim 57, in which the product of general formula Illg is reduced to form the corresponding product of general formula IH'g. 59. A process as claimed in Claim 58, in which the reduction is effected using hydrogen sulphide in the presence of triethylamine. 60. A process as claimed in Claim 59» which is carried out in dimethylformamide. 61. A process as claimed in Claim 16, in which the compound of general formula 111^ is prepared by treating a compound of general formula IH'g with an amine of the general formula NHR^gR^g. 62. A process as claimed in Claim 61, in which “is is - 232 -r a trityl radical. 63. A process as claimed in Claim 61 or Claim 62, in which the reaction with the amine is carried in dimethylfo rmamide. 64. A process as claimed in Claim 16, in which the compound of general formula ΠΙ'^ is prepared by a compound of general formula 111¾ with imidazole, morpholine or an N-alkyl piperazine. 65· A process as claimed in Claim 64, in which the reaction is carried out in the presence of triethylamine, or an alkali metal carbonate or bicarbonate. 66. A process as claimed in Claim 64 or Claim 65, in which the compound 111¾ is used in the form of a salt. 67. A process as claimed in Claim 66, in which the I diethylamine salt of the compound 111¾ is used. 68. A process as claimed in Claim 64, in which the reaction is carried out in the presence of a quaternary ammonium salt. 69. A process as claimed in Claim 16, in which the compound of general formula 11¾ is prepared by reacting a compound of general formula 111¾ with a compound of the general formula R ar ~SH. 70. A process as claimed in Claim 69, in which the reaction is carried out in the presence of triethylamine, or an alkali metal carbonate or bicarbonate. 71. A process as claimed in Claim 69 or Claim 70, in which the diethylamine salt of the compound of general formula 111¾ is used. - 233 72. A process as claimed in Claim 69, in which the reaction is carried out in the presence of a quaternary ammonium salt. 73. A process as claimed in Claim 69, in which an 5 alkali metal derivative of the compound of general formula R -S-H is used and the reaction is carried out in the < ar presence of an alkali metal halide. 74. A process as claimed in any of Claims 54- to 73, in which the compound III'jj is prepared hy a process as 10 defined in Claim 52 or Claim 55· 75. A process as claimed in any of Claims 42 to 45 and 49 to 51, in which the compound of general formula IV wherein n' is 2, 3 or 4 is prepared by a process as defined in any of Claims 39 to 41 for the preparation of compounds 15 m E . 76. A process as claimed in any of Claims 42 to 45 and 49 to 51, in which the compound of general formula IV wherein n' is 1 is prepared by reacting a compound of general formula II with a compound of the general formula 20 Y-CH 2 -CN. 77. A process as claimed in any of Claims 21 to 41, and 52 and 53, in which the starting material of general » formula II is prepared by treating a compound of the general formula: 4a«b7 with an aqueous mineral acid. 78. A process as claimed in Claim 77, in which the compound of general formula D is prepared hy reacting a compound of the general formula: (C) or a functional derivative thereof, with a product of the general formula: 79. A process as claimed in Claim 7θ> ia which the compound of general formula C is prepared by a process in which a compound of the general formula: (IX) - 235 - is treated with 2-methoxypropene. 80. A process for the preparation of the compounds of general formula III^, III’ A , IHg» ΙΙΙθ, IHjj, i 11 ?» III G , III H , III’ H , IIIj, III K , III L , III* L or IIIj,, in 5 which a compound of one of the general formulae: (VI.) (VI’ A ) (VIJ - 236 - (Ϊΐ ο ) (VI„> Μ (νι Ε ) o-CcHx\,-C-MHj. χ' (VXp) - 257 498B7 Nl CO t H (vi G ) (vi H ) (VIj) 4-1. A process as claimed in Claim 59 or Claim 40, in which the reaction conditions are as defined in Claim 29 or Claim 50· 4»«t>7 - 222 a product of the general formula: a product of the general formula: - 223 a product of the general formula: (I G ) (Ig) (I' H ) - 22a. a product of the general formula: a product of the general formula: (Ι χ ) (ι· κ ) or different - 225 - or a product of the general formula: CM I 43Sb7 - 226 17. A process as claimed in Claim 16, in which a formed compound of general formula 1^, is reacted first with a base and then with an acid to yield the corresponding compound I'g. 18. A process as claimed in Claim 16 or Claim 17, in which the formed 5 acid of general formula I A , I' A , Ι θ , I c> I* c , Ιθ, l £ , l p , Ig, I H , I‘ H · Ij> *K· 1 'ie I L* I 'b 0Γ thereafter salified and/or esterified to form a salt or an ester of general formula Γ in which A is as defined in claim 1 except that it does not represent a hydrogen atom. Ιθ. A process as claimed in Claim 18, in which sali10 fication is carried out in one or more of water, diethylether, methanol, ethanol and acetone. 20. A process as claimed in Claim 18, in which esteri fication is carried out hy reacting the acid with a derivative of the general formula: 15 Z “ ®20 in which Z represents a hydroxy radical or a halogen atom and R2Q denotes the ester group to be introduced. 21. A process as claimed in Claim 16, in which the compound of general formula III^ is prepared by treating 20 a compound of general formula II with a functional derivative of the acid HO-CX-R’^. 22. A process as claimed in Claim 21, in which the functional derivative of the acid HO-CX-R'^ is an acyl halide, a symmetric or mixed anhydride, a ketene or an 25 acyl azide, or a haloformate when R'^ represents an alkoxy radical, or an isocyanate when R'^ represents a group Ί — - 227 -NR'^R'^ and one of R 2 or R^ represents a hydrogen atom. 23. A process as claimed in Claim 21 or Claim 22, in which the acylation is carried out in a solvent, the solvent being a halogenated hydrocarbon, a cyclic ether, a 5 nitrile, a nitro-substituted hydrocarbon or an ester. 24. A process as claimed in Claim 22, in which the functional derivative is an acyl halide and the reaction is carried out in the presence of triethylamine, pyridine, propylene oxide, magnesium oxide, sodium carbonate or 10 calcium carbonate. 25· A process as claimed in Claim 16, in which the compound of general formula III’ A is prepared by reacting a compound of general formula II with a compound of general formula X = C = NH. 15 26. A process as claimed in Claim 25, carried out in a solvent as defined in Claim 23. 27. A process as claimed in Claim 16, in which the compound of general formula Illg is prepared by reacting a compound of general formula II with a compound of the 20 general formula Ϊ - CHR'^-C0 2 A 1 *' in which Y represents a halogen atom, or an SO^H or organic sulphonyloxy group. 28. A process as claimed in Claim 27, in which Y represents a chlorine, bromine or iodine atom or an S0 4 H, methanesulphonyloxy . or p-toluenesulphonyloxy radical. 25 29. A process as claimed in Claim 27 or Claim 28, in which the reaction is carried out in the presence of potassium tert-butoxide, sodium hydride or a tertiary amine. - 228 50. A process as claimed in any of Claims 27 to 29» in which the reaction is carried out in a solvent, the solvent being a halogenated hydrocarbon, a cyclic ether, an Ν,Ν-disubstituted amide or dimethyl sulphoxide. 51. A process as claimed in Claim 16 or Claim 17, in which the compound of general formula III C is prepared by reacting a compound of general formula II with a compound of the general formula: -v· 52. A process as claimed in Claim 51, in which Y is as defined in Claim 28. 55· A process as claimed in Claim 51 or Claim 52, which is carried out under the conditions defined in Claim 29 or Claim 3θ· 34. A process as claimed in any of Claims 51 to 55, in which the formed product of general formula ΙΙΙθ is treated with a base to form the corresponding compound of general fonnula III'q. 55· A. process as claimed in Claim 16, in which the compound of general formula IIIp is prepared by reacting a compound of general formula II with a compound of the general formula Υ 56. A process as claimed in Claim 55, in which, when R’^ represents an alkylthio radical, the product of general formula III D is thereafter oxidised to the corresponding sulphoxide or sulphone of general formula Hip· 57· A process as claimed in Claim 35 or Claim 36, in - 229 4-9867 which Y is as defined in Claim 28. 58. A process as claimed in any of Claims 55 to 57» in which the reaction is carried out under the conditions defined in Claim 29 or Claim 5θ· 5 59. A process as claimed in Claim 16, in which the compound of general formula Illg is prepared by treating a compound of general formula II as defined herein with a compound of the general formula Y -(CH?) n? - CN. 40. A process as claimed in Claim 59, in which Y is as 10 defined in Claim 28. 4 carbon atoms, a radical Alk-S(O) ng -, or having from 2 to 4 carbon atoms), having from 1 to an acyl radical (III E ) *)» (Illy) <σσ υ (ΙΙΙ Ο ) (ΙΧΙ Η ) (wherein Hal represents a halogen atom) radical) (III'h) NH fs,, A - 219 - (I«l? - 220 (wherein R^g represents a group removable by acid hydrolysis or by hydrogenolysis or an alkyl radical having from 1 to 4 carbon atoms and R^ represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, 5 or R 18 and R^ together with the intervening nitrogen atom form a phthalimido group) (III'!,) (11¾) is treated with one or more of hydrolysis agents, hydro· genolysis agents and thiourea to obtain respectively: a product of the general formula: a product of the general formula: (Ιβ) (i c ) 4-9867 -211 10 or the acetoxymethyl or carbamoyloxymethyl radical; θ II or a radical -HH-C-Alk; and A represents a hydrogen atom, or an alkali metal atom, an equivalent of an alkaline-earth metal atom or of a magnesium atom, an ammonium group, a substituted ammonium group derived from an organic amino base or an easily-cleavable ester group) and acid addition salts of the derivatives of general formula I’ formed with mineral or organic acids. 4 carbon atoms; or a phenyl radical or a radical -(CH^^-N.^ in which n B, represents 0 or an integer from 1 to 4 and R 2 and Rj, which may he the same or different, each represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or R2 and R^ together with the intervening nitrogen atom form a piperidino, morpholino or phthalimido group; i I I 498 67 - 209 ii) a radical -CH-CO^' in which A’ represents a hydrogen atom, an alkali metal atom, an equivalent of an alkaline-earth metal atom or of a magnesium atom, an ammonium group, a substituted ammonium group derived from an organic amino base or an easily-cleavable ester group, and R^ represents a phenyl, hydroxyethyl or nitrile radical; iii) the γ-lactone of the formula ; or iv) a radical -(CH 2 ) n< -R^ in which n* represents an integer of from 1 to 4 and R^ represents: an alkoxy radical containing from 1 to 4 carbon atoms or a radical Alk - S(0)_ - in which Alk represents an ns alkyl radical contairiing from 1 to 4 carbon atoms and ns represents 0, 1 or 2, Λ or a radical —N in which Rg and R?, which may be the same or different, each represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or Rg and R? together with the intervening nitrogen atom form a phthalimido or 1-pyridinio group, or, when η/ is an integer other than 1, a cyano radical, or a radical - C - NH O in which X' represents ~ II 2 X' a sulphur atom or, when n’ is an integer other than 1, - 210 an oxygen atom, or a 4-methyl- or 4-amino-l,3-thiazol-2-yl radical, or a 1,2,3,4-tetrazol-5~yl radical, 5 or an azido radical, or an acyl radical having from 2 to 4 carbon atoms; b) B represents a radical R , which is a radical -(CH 2 ) n ,-R5 a in which R^ a represents a halogen atom, or 10 a radical ~S~ R ar in which R ar represents a phenyl radical or a 5 or 6-membered aromatic heterocyclic radical containing from 1 to 4 heteroatoms selected from sulphur, nitrogen and oxygen, the phenyl and heterocyclic radicals being optionally substituted by one or more radicals selI 15 ected from amino, nitro and cyano radicals and alkyl radicals having from 1 to 4 carbon atoms; or c) B represents a radical R& which is a radical -(CH 2 ) n ,-R^ in which R^ represents an imidazolyl, morpholinyl or N-alkyl piperazinyl radical, the N-alkyl 20 radical containing from 1 to 4 carbon atoms; R^ represents a chloro or methoxy radical; or an alkyl, cycloalkyl or alkylthio radical having in each case from 1 to 5 carbon atoms; or a radical -CH 2 -S-R^ 2 in which R^ 2 represents 25 an optionally-substituted heterocyclic radical containing nitrogen, an acyl radical having from 2 to 4 carbon atoms, the 2-oxo-t3Hl-thiazolin-4-yl-carbonyl radical or the 5 - niethyl-l,2-oxazol-5-yl“carbonyl radical;

5. Dartmouth Road, DUBLIN 6 Having regard to the provisions of Section 14 of the Patents Act, 1964, attention is directed to claims 15 and 16 of our Patent No. 45015, and to the claims