PT96108A - PROCESS FOR THE PREPARATION OF BETA-LACTAMIC COMPOUNDS - Google Patents

Description

The present invention relates to novel compounds containing Bocsctama 5 in a process for their preparation and their use. The present invention particularly relates to a novel class of phsalosporins. These compounds have anti-bacterial properties and are consequently useful in the treatment of infections caused by a wide range of bacteria in arthropods, particularly in mammals including humans'

Cephalosporin-like compounds are well known as antibiotic antibiotics. They generally encompass the 7Î ± -acrylamino-3-carboxylic acids and the various nontoxic derivatives thereof, for example salts thereof. esters, amides, hydrates, etc. The structure of the invention may contain various substituents at the position of these substituents may influence the biological activities of the compounds. Applications in the United Kingdom Patent Nos. 1399-86 and 393,388 (both filed by Glaxo) disclose generally a broad range of substituted cephalosporins.

Other compounds of the cephalosporin type are disclosed in the applications of German patent No. 224452 and 22233753 in the applications of French patent No. 2191883 and No. 2244443 in U.S. patent application 47472 and in the application U.S. Patent Nos. 3,912,589. These compounds contain a 7β side chain with the structures

Het CONH- ϊ

, Wherein H 1 is phenyl, furyl or thienyl *

The present inventors have now discovered a particular class of the cephalosporins which have high levels of antibacterial and antibacterial activities. furthermore offer resistance to in vivo degradation caused by this invention with respect to a compound of the formula (I) or a salt thereof.

J r2hn

R H

d

Does it represent hydrogen? R 2 represents an acyl group of the formula: wherein R 1 represents an acyl group of the formula:

N

Represents thiasolyl optionally substituted with an amino or substituted amino group optionally in protected form and

A4 is hydrogen or an organic residue, or a carboxyl or an aryl group; protecting group of cardiol which can be readily removed; X represents S "SO3 B0", O or CHos s. R 1 represents a group (5)

Wherein R 1, R 2, R 3, R 4 and R 5 are independently selected from the group consisting of: hydrogen or alkyl having 1 to 6 carbon atoms and R '' 'and R' '' '' '' '' '' '' '' '' ''

R 4 represents hydrogen, alkyl of 1 to 6 carbon atoms or alkenyl of 2 to 4 carbon atoms.

Since the B-lachrymic antibiotic compounds according to the present invention are intended to be used as therapeutic agents in pharmaceutical compositions, it is clear that the preferred compounds of formula (I) are pharmaceutically acceptable, that is, they are formula C1a) or pharmaceutically acceptable salts thereof or in vivo hydrolysable esters thereof? 1

R

R 2 and R 1 and X have the meanings given above for formula (I) and the group CO 2 ' represents an unsubstituted or substituted carbamoyl group,

I R " represents hauntingly Hydrogen »

In the compounds of formula (I) in which R3 represents formamide, the formamido group may have cis or trans configurations with respect to the hydrogen atoms of the moiety -MH-CHG. In general,

It should be noted that the compounds according to the present invention wherein H "represents a group of the formula Ca) may be used as sin and anti isomers or mixtures thereof. Both isomers are encompassed by the Smothite of the present invention.

Lys compounds according to the present invention comprise wherein FT " represents a group of the formula Ca) preferably have the Z configuration. the OA4 group is sin relative to the amide bond) or. were enriched with respect to these isotopes. The thiazolyl system A 1. is preferably a thiazol-4-yl system, i.e.

Suitable meanings of the acyl group R * " of the formula a > g 2-aminothiazol-4-yl] -5-sminothio] -4-yl, 2- (2-chloroacetic acid) thiazole-4-yl] -2-trityl-thiadiazol-4-yl]; THE_,

O

Preferred meanings of the group are hydrogen, methyl, triphenylphystyl, Cl-thiyl, ethyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclooctyl, carbonyldiethyl phenyl, carboxypropyl, t-butyldimethylsilyl, butoxycarbonylmethyl

and CH 3, wherein R 1 is a number from 1 to 3, X is light or fluoro; 2 within the acyl group H of the formula < a >; hydrogen, methyl, triaryl * is preferably hydrogen or methyl,

When referred to in the present invention as the variable Α =, the expression "organic residue" encompasses all organic residues associated with the thiololyloximinoacetamido substituent at the 7-position of a cephalosporin with anti-bacterial activity. Suitable meanings are, inter alia, 6-carbon atoms, alkylene of 2 to 6 carbon atoms and alkynyl of 1 to 6 carbon atoms, all of which are optionally substituted, cycloalkyl of 3 to 8 carbon atoms, aryl and heterocyclyl, are optional alkyl, alkyl or alkynyl substituents; ; carboxy, C 1 -C 6 -alkoxycarbonyl, hydroxy, C 1 -C 6 -alkoxy, cyano, hydrogen, amino, substituted amino, aryl, heterocyclyl and cycloalkyl of 3 to 8 carbon atoms *

The compounds of the formula < I) wherein R3 represents a carboxy-profective group which can be readily removed is not a pharmaceutically acceptable in vivo hydrolysable ester; or which are in the form of pharmaceutically acceptable salts are essentially useful as intermediates for the preparation of the compounds of formula (Ia) or a pharmaceutically acceptable salt thereof or an in vivo acceptable hydrolyzable ester thereof

Carbamyl protecting groups suitable for the group include groups which form carboxylic acid ester derivatives including in vivo hydrolysable esters. the derivative can be easily removed in vivo.

Suitable ester-forming carbohydrate protecting groups are those which may be removed under conventional conditions. These groups include, in the case of benzyl, benzenesulfonyl, benzenesulfonyl, benzoylmethyl, o-nitrobenzyl, 4-pyrimidylmethyl, 2,2,2-trifluoroethyl, 2,2,2-tribroinoethyl, 3-methylthio, diphenylmethyl-5-trifluoromethylamines, adamantyl, 2-benzyl, 5-methylphenyl, 4-methylthiophenyls, tetrahydrofuran- tetrahydro-pyran-2-yl, pentachlorophenyl, acetonyl, β-talosnossulfonylethyl, a silyl, stannyl or phosphorous containing group, a < 3-oxo-3-oxazolidine-3-one. wherein Ν 'is aryl or heiercyclyl or an in vivo hydrolysable ester as defined by "

A carboxy group may be obtained by regenerating any of the aforementioned esters by customary methods suited to the particular group, for example acid catalysed hydrolysis or a base, by catalyzed hydrolysis. i

>

or by hydrogenolysis under conditions that the residue of the molecule is not substantially absent. Examples of such esterizable ester groups are those which dissociate within the human body to give the parent acid or to the appropriate ester salts thereof, including those of partial formulas (i). (iii) 5 (iii) and (iv)

R a (i) -co2ch-o.co.r

(iii) (iv) R4 represents hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms,

Rw represents alkyl of 1 to 6 carbon atoms; alkoxy having 1 to 6 carbon atoms, benzyl, benzyl, cycloalkyl, C 1 to C 3 to 7 carbon atoms, (C 1 to C 7 alkyl), C 3-7 alkyloxy 1 to 6 carbon atoms) or C1-6 alkyl having 1 to 6 carbon atoms) amino (C1-4 alkyl), or R3 and R4 together form an optionally substituted (C1 -C6) alkyl group substituted coo? Cycloalkyl of 3 to 7 carbon atoms, (alkyl of 1 to 6 carbon atoms) (cycloalkyl of 3 to 7 carbon atoms), 1-aminoalkyl of 1 to 6 carbon atoms) or - C 1 -C 6 -alkylamino) C 1 -C 6 -alkyl, or R 2 and R 3 together form a 1? 2-phenylene group optionally substituted with 1 or 2 methyl groups R 1 represents alkyls of 1 to 6 carbon atoms optionally substituted with a methyl group or ethyl group, and R 2 and R 2 are independently alkyl of 1 to 6 carbon atoms of carbon, r · fr represents alkyl of 1 to 10 carbon atoms,

W s represents hydrogen or phenyl optionally substituted with up to three halogen substituted, halogen, C 1-6 -alkyl or alkoxy groups having from 1 to 6 carbon atoms

Examples of suitable ester groups are, for example, in the presence of acyloxyalkyl groups such as < RTI ID = 0.0 >

Acetoxyethyl, β-acetoxyethyl, β-pivaloyloxyethyl, β-Ccyclobexylcarbonyloxylprop-1-yl, β-aminostilibarbiphenyl, alkoxycarbonyloxyalkyl groups such as Î ± -toxycarboxyloxymethyl and Î ± -ethoxycarbonyloxystyl; dialkylaminoalkyl groups, especially N-dialkylamino groups such as dimethylaminomethyl, dimethylaminoethyl diethylaminomethyl or diethylaminoethyl lactone groups such as phthalidyl and dimethoxyphthalides and esters linked to a second antibiotic monkey or to a R-lactamase inhibitor.

Another suitably acceptable in vivo, hydrolysable in vivo hydrolysable ester group is that of the formula.

In which R 1 'represents hydrogen, C 1 -C 6 -alkyl or phenyl, it is understood that the salts thereof are also encompassed by the scope of the present invention, including the hydrolyzable esters in vivo, of any carboxy groups optionally present with the optional substituents on compounds of the formulas Cl) or (Ia) '

Most suitable pharmaceutically acceptable salts of the carboxy group in the compound of formula (I) include metal salts, for example aluminum salts, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or ammonium salts for example t

those with such lower alkylamines such as hydroxyethylcellamines, hydroxyquinolines such as 2-hydroxyethylamine, bis- (ω-hydroxyethylaminocarbonyl-β-hydroxyphecillamine, cycloalkylamines such as dicyclohexylamine, or with procaine β-dibenzylamine, dibenzylenediamines, N-methylmorpholine, N-ethylpiperidine, benzyl-R-methylethylamine, dehydroabieyl amine, N-diisobenzoyl amine, ethylene diamine or bases of the pyridine type such as pyridine, 5-quinoline or quinoline, or other amines used in forming salts with known penicillins and alkaloids. Other useful salts are those of lithium and silver. The salts of the compounds of the formula (Cl) may be prepared by exchanging salts according to conventional methods.

In the compounds of the formulas I > or < Is > the group X may represent sulfur or an oxidized sulfur atom (i.e., a sulfoxide CSO) or a sulfone group CSO ". In cases where X represents a sulfoxide group, it may be present in the form of the α and B isomers. both of which are within the scope of the present invention. X is preferably sulfur. Suitable amino acid residues are methyl esters of 2-methylbut-2-amino-2-SBS-1 ? but-2-enoyl] hexahydro-2-phenylethyl] -2-methyl-but-2-enoyl]

It should also be noted that the group may be present in two isomeric forms which are geometric isomers depending on the arrangement of the double bonded groups. Both cis and trans isomers are encompassed by the scope of the present invention.

Certain compounds of the present invention include an amino group which may be protected as appropriate amino protecting groups, which are known to those skilled in the art, which can be removed under standard conditions without disruption of the remainder of the molecule. Examples of the groups Alkaline amine protectors with t &amp; 6-carbon atoms * benzoyl, benzyl optionally substituted on the phenyl ring with 1 or 2 substituents selected from alkyl of 1 to 4 carbon atoms, fluorophenyl, halogen or nitro, C 1 -C 4 -alkylcarbonyl, benzyloxycarbonyl or trichloroethoxycarbonyl or chloroacetyl. Also included within the scope of the present invention are the acid addition salts with all amino groups or substituted amino groups present as optional substituents on compounds of the formulas Cl) or Preferred acid addition salts are the hydrochlorides. The term &quot; aryl &quot; refers to, in the context of the present invention, both phenyl and naphthyl, both of which are optionally substituted with one or two substituents. maximum of five, most preferred, maximum of three, groups selected from halogen, mercapt, alkyl of 1 to 6 carbon atoms carbon, phenyl, alkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms), mercapto < alkyl of 1 to 6 carbon atoms), haloalkyl of 6 carbon atoms), hydroxy, amino, nitro, carboxy, (C1-6 alkyl) carbonyloxy, alkoxycarbonyl, formyl or (C1-6 alkyl) ) carbonyl,

The terms "heterocyclyl" and "hateraciclic" In the safener of the present invention, simple and condensed aromatic and non-aromatic rings containing up to four halo atoms in each ring are selected from oxygen, nitrogen and sulfur, and the rings may be substituted or unsubstituted. for example, a maximum of three groups selected from halogeno, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloCalkyl of 1 to 6 carbon atoms), hydroxy, carboxy, salts of carboxy, carboxy esters such as the &lt; akoxy &lt; / RTI &gt; groups having 1 to 6 carbonylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, aryl and oxo. Each heterocyclic ring suitably contains 4 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and necessarily includes only one hydroxyalkyl ring. The compounds of the present invention contain one g The heterocyclic group may be present in two or more tautomeric forms depending on the nature of the heterocyclic group. All such tetrameric forms are encompassed by the scope of the present invention.

The terms "alkyls" or "lower alkoxy" are referred to in the context of the present invention as straight chain alkyl or branched alkyl groups containing 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, the preferred alkyl group is methyl, the term &quot; halogen &quot; refers to fluorine, chlorine, bromine and iodine in the context of the present invention.

Some of the compounds according to the present invention may be crystallized or recrystallized from solvents such as organic solvents. In these cases solvates may be formed. The present invention includes solvates thereof

quaternary ammonium stearic acids, also hydrates, as well as co-formulates containing varying amounts of water which may be obtained by processes such as lyophilization.

While the antibiotic compounds according to the present invention are intended to be used in pharmaceutical compositions, it is clear that each of them will be prepared in a pure form, for example pure at least 66%, more suitably pure at least at least 75%? preferably at least 85% and in particular at least 93% pure (the percentages are percentages by weight). Impure preparations may be used for the preparation of the purest forms used in These less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably between 16% to 59% of a compound of the formula (I) or a salt thereof,

From what has been said, it will readily be understood that a preferred subclass of compounds, or pharmaceutically acceptable salts thereof, or their pharmaceutically acceptable in vivo, hydrolysable esters according to the present invention may be represented by the formula CI1>

Η H

(II): wherein: and m has the abovementioned meanings and

. represents hydrogen or alkyl of 6 carbon atoms.

THE

Compounds of the formula &lt; RTI ID = 0.0 &gt; (1) &lt; / RTI &gt; and R3 represents 3-ethylhexyl-2-enoyls-2-methylprop-2-enoyl. but-2-snoi-

And 2,4-dichloro-2-ethyl-2-enoyl 5-hydroxy-

R 2 is hydrogen or methyl. R 2 represents hydrogen or CO 2 R 5 represents a pharmaceutically acceptable salt or a hydrocollotically acceptable in vivo ester of this acid.

In confarmidation the specific compounds of formula (Ia) according to the present invention included in the preferred subclass of the compounds of formula (I) include the following compounds and their pharmaceutically acceptable salts are pharmaceutically acceptable in vivo hydrolysable esters of C6RS7R7- 4-yl) -2- (2-methoxyiminoacetamido) -3 '- [3-methylbut-2-enoyloxymethyl) ceph-3 (6R, 7R) -7- [2- (2-aminoethylsol-4-yl) -2- [2-hydroxy-iminoacetamido] -3- &lt; / RTI &gt; 3-ene-3-carboxylic acid tert-butyl ester; 2-Cyano-4-yl) -2- (Z) -Mioxyiminosine-3-carboxylic acid (E5E3) heKa 4-Carboxy-2-hydroxy-3-hydroxy-3-methyl-3-oxazepin-3-yl] (2-aminothiazole-2-carboxylic acid) -7- (2-amino-2-oxo- 4-yl] -2- (Z) -hydroxyiminoacetamide-3-carboxylic acid 3-amide <6R, 7R) -L2- (2-aminoethyl) -4-yl} -2-cyclopentyloxyphenylacetylidene-3 - [( (2-aminothiazal-4-yl) -benzoic acid (2-methylpyrrolidin-2-yl) -6- The present invention also relates to the preparation of a compound of the formula (II): wherein R1, R2, R3, R4, R4, R4 and R4 are each independently hydrogen, C1-4-alkyl, to a process for the preparation of a compound of the formula (I), by treating a compound of formula (I) or a salt thereof

H

CO R 2 3

H (III): â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ 5A and X are as defined above, any reactive groups present are optionally protected in which the amino group is optionally substituted with a group permitting acylation to take place, with an N-acylated derivative of an acid of the formula CIv ), R 2 OH (IV) & the same meaning as in formula (I) and that all the present reactive groups are optionally protected, it is subsequently necessary or desirable to proceed one or more steps between the following (i) all protecting groups. )

iii) converting the X group to a different X group (i) to the reaction product in a salt. Suitable compounds of the formula (l) are esters and esters, for example an ester in which R &quot; represents diphenylmethyl "

The acids of formula (I) may be prepared by methods known to those skilled in the art or by methods analogous to such processes. Suitable processes are those described by SKemplcq in U.S. patent applications ηθ 2 1Θ7 3Θ7 B5 n 1 1 536 281 s n 91 Suitable groups which enable the acylation which are optionally present on the amino group of the starting compound of the formula &lt; 11) or N-alkyl groups are suitable. N-stannyl and N-phosphorus-i- for example trialkylsilyl groups such as trimethylsilyl, trialkylthio groups, such as tri-n-butyltin-3,11,12- groups of the formula â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒwherein R4 'represents an alkyl, 1 same meaning as R "&quot; or represents halogen or in which R 1 a 2 a ... H 2 = form the ring 5 being a suitable phosphorus group - P i OC 4 -L ·) 0 5 (çh 2) 2 <h2> 3

P 0

P 0

A group which may be introduced into the alkyl group of the compound of the formula (III) is α-trimethylsilyl. The silylation reaction can advantageously be carried out in the presence of the reaction with a silylating agent - which does not require the concomitant addition of bases. Are suitable sialing agents? for example ^

Np-C-trimethylsilyl) -actamamide

NsO-bis- <trimethylsilyl-1-acetamide; N 5 0; - b i s < ΐ r i ms t i 1 s i 1 i 1 &gt; 5-methyl-β-triisopropylsilyl-5-methyl-N-methyl-5-trifluoroacetinate 5 M tr tris (trimethoerythyl) urea, s

A preferred blowing agent is N, O-bis (trimethylsilyl) acetamide The reaction of the invention may also be carried out in an inert, anhydrous organic solvent such as dichloromethane at ambient temperature or at a temperature for example, from about 30Â ° to about 50Â ° C, preferably from about 50Â ° to 60Â ° C. The process described above may optionally also be carried out in the presence of a small amount, for example, of a diester halide for example a trialkyl halide of 1 to 6 carbon atoms), especially triethylsilyl chloride

A preferred reactive W-acyl derivative of (IV) is described in the process described above. The choice of the reactive derivative will of course be influenced by the chemical nature of the substituents of the formula

Suitable N-acylating derivatives include an acid halide, preferably chlorides or acid bromides. Acylation with an acid halide may be effected in the presence of an acid binding agent, for example a tertiary amine (such as pyridine or dimethylaniline) ? (e.g., calcium carbonate or sodium bicarbonate) or a hydrogen atom which forms a bond with the hydrogen halide released in the course of the acylation reaction, the oxirane is of the formula: alkyl of 1 to 6 carbon atoms) such as ethylene oxide or propylene oxide. The acylation reaction using an acid halide may be carried out at a temperature ranging from -5 ° C to 0 ° C and preferably from -20 ° C to 120 ° C in an aqueous or non-aqueous medium, such as acetone, tetrahydrofuran, ethyl acetate, dimethylacetamide, dimethylsulfamide, acristrinine, dichloromethane, or the like, or mixtures of these compounds. Alternatively, the reaction may be effected in an unstable emulsion of a non-water soluble solvent. especially an aliphatic ester or ketone, such as methyl isobutyl isone or butyl acetate, the acid halide can be prepared by the reactions of the acid (IV) or a salt or a reactive derivative thereof with a halogenating agent (for example chlorination or brominol "such as pentacyretradecylphosphate, thionyl chloride, oxalyl chloride or phosgene, the N-acylating derivative of the formula (IV) may be a symmetrical or mixed anhydride. Suitable anhydrides are the anhydrides with, for example, monoesters of carbonic acid, trimethylacetic acid, thioacetic acid, diethylenetetraacetic acid, benzoic acid; (such as phosphorothiophosphoric and phosphinic acid) or aromatic or aliphatic sulfonic acids (such as n-tolusnossulfonic or methanesulfonic acids). When a symmetrical or mixed anhydride is used. -? 0: -. The reaction may be carried out in the presence of a weak base such as pyridine or 2α-lutidine as catalyst. Alternatives are the Ng-acylators of the alternative acid; acid esters or acid esters such as esters with 2-mercaptopyridine, cyanomethanol, p-nitrophenol, 254-dinitrophenols, and halophenols, including pentachlorophenol, monomethylphenol, N-hydroxysuccinimides, or hydroxymethylene or 8-hydroxyquinoline ? or aids such as ξ-acylsaccharins, N-acylthiozolidin-2-yl or th-acylphalimies, or an alkylimino imino ester prepared by reacting CIv) with an oxime =

Other (IV) reactive acid N-acyl derivatives include reactive intermediates obtained by the in situ reaction with a condensing agent such as a carbodiimide for example-diethyl-dipropyl or diisocpropylcarbodiimide. . Methyl dicyclohexylcarbodiimide or Methyl-N '- (5-methylamino) propylcarbodiimide is a suitable carbanyl compound, for example M, N'-carbonyldiimidazoles or NJ '-carbonylditriazole salt', for example, N-benzyl-5-phenyl-isoxazoline-3-sulfanate or h-t-butyl-6-methylisoxazolyl perchlorate. or an N-alkanoylamino-2-alkynyl-1,2-dihydrazinoline 5 such as a 4-ethoxycarbonyl-2-ethoxy-2-dihydroquinoline. Other condensing agents are the acids of Le In an exemplary embodiment of the invention, The condensation reaction is preferably carried out in an organic reaction medium, for example in methylene chloride, dimethylformamide, acetonitrile, ethanol, benzene, potassium carbonate, potassium carbonate, dioxane or tetrahydrofuran =

A further method for the preparation of the N-acylating acid derivative of the formula (IV) is the treatment of the acid of formula (IV) with a solution or suspension previously prepared by the addition of a carbonyl halide, or a phosphoryl halide, such as phosphorus oxychloride, to a hydrogenated hydrocarbon solvent. preferably dichloromethane, a lower acyl tertiary amide, preferably N, 4-dimethylformamide. The N-acylating acid derivative of the formula (IV) thus prepared may be housed in the reaction with a compound of the formula (III). The acylation reaction may be conveniently carried out at -40 ° C to -10 ° C, preferably in the presence of an acid binding agent such as pyridine. A catalyst such as 4-dimethylaminopyridine may also optionally be added. The preferred solvent for the above acylation reaction is dichloromethane.

In a preferred reaction, a compound of formula (III) is treated; wherein the amine group located at the 7th step is protected with an N-acylated derivative of the olefinic acid of formula (IV) in the form of a methanesulfonic anhydride in the presence of pyridine. The mixed anhydride is suitably prepared in situ by reaction of the acid or an ester thereof, optionally in the form of the salt, with methanesulfonyl chloride =

The optional conversion of CO-R '&quot; in a CU-.R '&quot; different s. of an X in a different X to the optional preparation of a salt can be carried out by methods well known to those skilled in the art of the pharmaceutically acceptable salts and penicillins.

For example, when the group X represents B, SO or BLU, the λ group can be converted into a different X group by oxidation or reduction methods well known to those skilled in the art and the penicillins as described for example in the application European Patent No. 114,752. For example, the sulphoxides Cem which X represents SO) may be prepared from the corresponding sulphide (wherein X represents

S) by oxidation with a suitable oxidizing agent, for example an organic ingredient such as m-chloroperbenzoic acid,

In the process described above as well as in the process described below? the removal of protecting groups may be necessary. Deprotection may be effected by any of the convenient methods known to those skilled in the art in order to minimize the occurrence of undesired side effects. Separation of by-products may be accomplished by conventional methods.

For example, a protest group can be removed from the compound. trityl in the fw or A * fraction of the acyl side chain of h &quot; under acidic conditions using aqueous hydrochloric acid in thermal acid. under the same reaction conditions as a carboxyl protecting group in acidic and labile Rw '

In a further process according to the present invention, compounds of the formula (I) can be prepared by reacting a compound of the formula: ?

in which R 1, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2 and R 2 are as defined above or an acyl group which may be converted therein and wherein all the selective groups are optionally protected with a olefinic acylating acid of the formula (VI) or a derivative thereof

··.! ί J | - | wherein R 'has the meaning given above for formula (I) and the subsequent carrying out, if desired, of one or more subsequent steps

v V i) converting the group into groups, ii &gt; removal of all protecting groups, conversion of the group Cu2 H &quot; (iv) converting the X group to a different X group, (v) converting the reaction product into a leaving group. The group R 3 in which R 1 and R 2 are as defined in formula (I) are in particular diphenylmethyl = 2 and the group F 1 in compounds of formula (IV) is in particular acetylactyl. The reaction of a compound of formula (iv) with a carboxylic acid of formula (VI) may be effected under Mitsunobu conditions by treatment of a mixture of the compound of formula alcohol of the formula (V) to that of the olsfinic acid of the formula (VI) in an aprotic solvent having a phosphine derivative, which may suitably be triphenylphosphine, an asadicarboxylate ester, which may suitably be diethyl asadicarboxylate.

Ξ5 adsquad more than I? tetrahydrofuran and trifluoroacetic acid at a temperature in the range of 5Â ° C to 67Â ° C; of the temperature at the temperature of the reactor.

When 'in a compound of the formula &lt; V &gt; no rsprsssnta

V V V R "&quot;? the conversion of R 7 to H may be carried out in the presence of a compound of the formula &lt; 111 / containing an amine group at the 7-position of the cephalosporin nucleotide = commonly used in the fs-flactams technique &gt; Suitable reaction conditions include treatment with phosphorus pentacyride and N-methylmorpholine. The reaction product is preferably isolated at the beginning as a hydrochloride salt. The reaction product is initially isolated as a hydrochloride salt, for example at &lt; RTI ID = 0.0 &gt; which allows to eliminate all starting compounds5 isomers or phosphorus-containing compounds. The free base can then be isolated by treatment with a hase =

The compounds of the formula &lt; V &gt; and the salts thereof which are intermediates for the compounds of the present invention as defined above may be prepared by the optional acylation of the functional group as a compound of the formula (VII):

(VII)

wherein R 1, R 2, R 3 and R 4 are as hereinbefore defined, with an acylsondar derivative of an acid of formula (III): f

R / OH where R.-6 &quot; has the meaning defined hereinbefore, and the subsequent embodiment is if desired, of one or more subsequent steps x &gt; conversion of the C0oR group &quot; in a group UO2 K &quot;different; ii) removal of all protecting groups present; iii &gt; converting the X group to a different X group, iv) converting the product into a salt.

be at home

For example, a compound of the formula &lt; v &gt; R 2 represents diphenylmethyl and may be prepared by reacting a compound of the formula &lt; RTI ID = 0.0 &gt; (1) &lt; / RTI &gt; 3 followed by the preparation of carboxylic acid and treatment with diphenylmethane

The compounds of the formula (VII) are known compounds or can be prepared from known compounds by methods known to those skilled in the art of the β-lactams. A suitable starting compound for the preparation of the compounds of the formula CV1I) wherein X represents a (7-ACA) which is readily deacetylated in the 3-position to give the corresponding compound of formula (VII): Compounds of the formula: ) (VIII) are known compounds or may be prepared from known starting compounds by standard methodology.

As to the compounds of the formula CHI) the present inventories are thought to be novel compounds being as such objects. present invention.

The compounds of formula (II)

can be prepared from known compounds such as the corresponding N-substituted acetamide derivatives by 7-phenylacetamido and 3-em-4-carborylates and carboalkyl derivatives such as esters thereof. The compounds of formula &lt; III &gt; can be prepared from compounds of the formula (X) known from commercially available

H

CU- {Z. R13 co (X) 2 Λν .-

Halogen, especially chlorine or bromines

represents an acyl group, in particular an acyl group which provides a compound 5 which can be readily removed as will be recognized by those skilled in the art, for example phenylmethyl, a protecting group of DNA which can be easily removed as such will be recognized by those skilled in the art, for example an ester, especially diphenylmethyl, ester.

Compounds of the formula &lt; Xϊ) can be prepared by reacting the compounds of the formula &lt; 50 with the acid R'uH &lt; vl) in the presence of a tertiary ammonium salt of the formula R, that R &quot; represents alkyl or aryl and Y represents the anion of the salt, especially iodide, in the presence of sulfite, under the conditions of aqueous solvent-phase transfer).

(XI) Six-membered ring rearrangement can be performed by oxidation-reduction sequence * for example oxidation with a perbinic acid followed by reduction of the resulting sulfoxide (XIϊ)?

. Ο &quot; '

(XII), and R 3 is hydrogen, for example in order to obtain an acetamide derivative of formula (III). a compound of formula (XIII) ???

(XIII) The compound of the formula &lt; III &gt; may be obtained from the compound of the formula CXIII) by removal of the protecting groups R12CD and R1 ''% for example by Dslft cleavage in the case of these groups; resinsctivaments5 PhCH3 CO to CH2 =. A typical overall scheme for the reaction is given below, which yields compounds of the formula (Cl) from a compound of the formula &lt; X) wherein CF representa represents phenylmethyl &lt; RTI ID = 0.0 &gt; represents diphenylmethyl and R represents the unsaturated side chain *

R5 R6 I I 3®

Although specific examples of substituent groups for the various compounds of the formula (I) are given (for example, Râ,,), hydrogen (Râ,,) â, "thiol-4-ylidene containing an amino or protected aminosulfonyl or a pharmaceutically acceptable salt thereof. acid addition salt, hydrogen or triphenylphosphine)) will it be readily understood by those skilled in the art that the synthetic synthetic route is applicable to all of the aforementioned possible reactions. I}

PhCH, CONH

PhCH2 CONHCH3 CH2 CH2 COOHCH2

N _ θ 'y ^ ch2ocor C02CHPh2

X

XI

PhCH, CONH

PhCH2CONH

CH2OCOR C02CHPh2

CH2OCOR C02CHPh2

XII

III h2n s JXfX ch2ocor C02CHPh2

XIII

PhCH2CONH Ο 'Ύ &quot; CH2OCOR co2h (R1OH)

• N

CHOOCOR OCPh3 C02CHPh2 N.

1 H-NMR

PhCH2 CONHCH2 or -CH2OCORCOOR'N ·

CONH, SΊί TT Nv À N

H, N

CH2OCOR

III co2h o y ^ ch2ocor co2r1

H N

CONH cr N J-ϊΓ

Y2 CH2 CH2 COOR2

Ph 3 CNH N

CONH S, N

N o oCPh3

COoR ch2ocor

I 1 (R OH)

It will be appreciated that in the processes according to the invention, the compositions may function as intermediates in the sequences of the syntheses. The subsequent isomerisation steps are carried out by methods well known in the art of nephalosporins. will enable the preparation of the compositions according to the present invention. The present invention also makes it possible to prepare a pharmaceutical composition containing a compound of the formula (Ia) P or a pharmaceutically acceptable salt thereof or a hydraldehyde ester thereof. The compositions according to the present invention include those in forms suitable for administration by the oral or topical route or to be administered for the treatment of infections of mammalian origin in the mammals. including humans =

The antibiotic compounds according to the present invention may be formulated so that they can be administered by any convenient route in human or veterinary medicine, by analogy with other antibiotics. The composition may be formulated so that it can be administered by any route, for example The compositions may be in the form of tablets, capsules, feet, granules, drags, creams or liquid preparations, such as orally-administrable suspensions or solutions or sterile suspensions or sterile solutions which may be administered via the psenteric route.

The topical formulations of the invention may be present in the form of, for example, ointments, creams or lotions, ophthalmic ointments, or ophthalmic drops. Aerosol impregnated dressings? and may contain suitable conventional additives such as preservatives? solvents which facilitate the penetration of the medicament and emulents into ointments and creams.

The formulations may also contain conventional compatible supports? such as cream bases or eyanol ointment or oleyl alcohol for lotions. These carriers may be present in percentages of from 1% to about 98% of the filler furnishes. will constitute about 8% of the formula =

Viable tablets and capsules may be in the form of unit doses and may be required to contain conventional syrups, such as binding agents, for example syrup, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone? fillers? for example lactose? sugar, cornstarch? calcium phosphate? sorbitol or glycine, tablet lubricants? for example magnesium stearate? baby powder? polyethylene glycol or silica, disintegrating agents? for example potato starch? or malicious agents? such as sodium lauryl sulfate. The tablets may be coated according to hem methods known in standard pharmaceutical practice. Liquid orally administrable preparations may be in the form of? for example? aqueous or oily suspensions? solutions? emulsions? syrups or elixirs? which may be in a solid form to be reconstituted with water or other suitable carrier prior to use: These liquid preparations may contain conventional additives; such as suspending agents? for example sorbitol? methylcellulose? glucose syrup gelatine? hydroxyethylcellulose? carboxymethylcellulose? aluminum stearate gel or hyaluronicated food fats? emulsifying agents? for example

. Γ lecithin, sorbitan monocyclic or acacia. non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerol, prooylene glycol or alcohol preservatives, for example methyl or propyl hydroxibenzoyl or sorbic acid. if desired9 conventional coloring agents or flavorings'

The suppositories should contain conventional suppository bases; for example cscsu butter or other glyceride *

When intended for administration by the parsimeric route, the unit dosage forms are prepared from the compound and a sterile vehicle, preferably water. The compound can be suspended or dissolved in the vehicle; depending on its characteristics and the concentration used. To prepare solutions the compound may be dissolved in water for preparation of injections and sterilized by filtration before being introduced into a suitable vial or ampules and sealed therefrom. at

Agents such as local anesthetics, preservatives and buffers may be advantageously dissolved in the vehicle. For the purpose of improving its stability, the composition may be frozen after it has been introduced into the bottle and the water may be removed under vacuum, the vial containing the dehydrated lyophilized powder is then sealed, and a vial containing water for injection to allow reconstitution of the liquid prior to its use. The suspensions which are administrable parenterally are prepared in a substantially substantially similar manner, unless otherwise provided that the compound is suspended in the vehicle after dissolution and sterilization can not be carried out by filtration. The compound may be sterilized by ethylene oxide prior to suspension in the sterile vehicle. Advantageously

composition of the surfactant or wetting agents in order to facilitate uniform distribution of the compound

The compositions may contain percentages by weight of active compound of not less than preferably not less than 10-00%? varying those percentages depending on the method of administration. In cases where the compositions are comprised of dosage units, each unit will preferably contain an amount of active ingredient comprised between 5 μg / mg SM. Dosages used in the treatment of adult humans will be in the range of from 1 to 3 mg / dis, for example 15Mq / day. these amounts varying according to the route and the frequency of administration. This dosage corresponds to values ranging from 0.5 to 5 kg / day.

A suitable dosage will be between 5 and 50 mg / kg &gt; / day = No toxic effects were observed after administration of dosages comprised between the above values of a compound of formula (I) or a salt or an ester thereof The compound of formula (Ia) may be the only therapeutic agent present in the compositions according to the present invention or may be in combination with other antibiotics or with an is lactamase inhibitor »

The compositions may also advantageously contain a compound of the formula (XIV) or a pharmaceutically acceptable salt or ester thereof

ch2-a Η (Yh ') in. A is hydroxyl, substituted hydrosyl, thiol, substituted thiol, smino, substituted by man- or dihydrocarbyl, or mono- or dis- solminent, a optionally substituted triazolyl group, or a chloroform group optionally substituted as described in European Patent Application No. WO 053 893,

Another advantageous composition contains an antibiotic compound according to the present invention and a pharmaceutical carrier or pharmaceutically acceptable salts together with a B-lactamase inhibitor of the formula (XV) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof acceptable.

(V) wherein B represents hydrogen, halogen or a group of the formula.

Τ Η where R 'and R "bId are identical or different and represent $ each? hydrogen, alkanyl having 1 to 6 heteroatoms of cardanylcarbonyl or carbamoyl or a pharmaceutically acceptable salt thereof.

Other suitable cytoprotective inhibitors include the Î ± -lipidene penem of formula (XIV).

OJ

II

-W

N-co2h or a salt thereof or a pharmaceutically acceptable in vivo lyophilisable ester thereof wherein R 'and R " are identical or different; each hydrogen or a hydrocarbon having 1 to 10 carbon atoms; carbon atoms or a heterocyclic group having 1 to 1 carbon atoms which are functionally substituted with a functional group and R 2 'is hydrogen or a group of the formula R 1' or -SR 5 '', wherein R 1 'represents a hydrocarbyl or heterocyclic group with substituted or unsubstituted carbon atoms; as described in European Patent Application No. 81301083, 9 (published under No. 0 041 768). Another embodiment contains a compound (Ia) or a pharmaceutically acceptable salt or a hydrolysable ester thereof in vivo together with a compound of the formula (VIII) or a pharmaceutically acceptable in vivo hydrolysable salt or ester thereof

wherein B represents hydrogen or chlorine.

Other suitable Î ± -chromopenicillanic acid inhibitors include their pharmaceutically acceptable salts and hydrolysable in vivo esters thereof and 6β-iodophenyl-cyclic acid and their pharmaceutically acceptable salts and in vivo hydrolysable esters thereof. in European Patent Applications Nos. 41 768 and Nos. 154 154 (both filed by Bsecham Group)

The compositions according to the present invention which contain a β-lactamase inhibitor amount of a β-lactamase inhibitor are formulated in a conventional manner using techniques and procedures known to those skilled in the art. The present invention allows to prepare a compound of formula The present invention also provides a compound of the formula (Ia) or a pharmaceutically acceptable salt or a pharmaceutically acceptable in vivo hydrolysable ester thereof useful in the treatment of The present invention also relates to a method for the treatment of human-to-human infections with animals characterized in that an effective therapeutically effective amount of an antibiotic compound according to the present invention is administered. formula C1a) or a pharmaceutically acceptable in vivo hydrolysable ester thereof vel.

In addition, the present invention further relates to the use of a compound of formula (Ia) or a salt or an in vivo hydrolysable ester thereof which is acceptable in the manufacture of a medicament for the treatment of infections of bacterial origin.

Antibiotic compounds according to the present invention are active against a broad spectrum of organisms, including Gram-negative organisms and Gran-positives.

Subsequent Examples illustrate the preparation of compounds according to the present invention. The data concerning &amp; biological activity in vitro are presented as a geometric mean MIC (minimum inhibitory concentration) values of 9æg / ml for a compound of the invention when compared to the known compound FK 482. 4® 4®

S & BgBlaJL

(4R t / F: -7-1) 2- &lt; 2-Aminot-4-yl] -4-methyl-2-oxazolidinyl] 2-ene-2-enoyl] amino] carbonyl] -4-carbaldehyde (a) (R, 7 R) -3- Diphenylmethyl-3-amino-4-carboxylate To a stirred solution of 3-methylthiobut-2-enoic acid (0.5 g) in dichloromethane tetrahydrofuran (3 ml) was slowly and successively added triphenylphosphine (in g) is (R) -3-hydroxy-7-phenylacetamidoceph-3-em-4-carboxamide diphosphonic acid (2S-g) and azodicarboxylate were dissolved in dichloromethane and the color of the reaction mixture changed from brown initial to dark green After 2 minutes the mixture was diluted with toluene (300 ml) and evaporated under reduced pressure until a reduced volume was obtained. Further toluene was added and the disodium hydrazodicarboxylate was crystallized, : This was collected by filtration and the filtrate was washed with a small amount of saturated solution of the title hydrogen sulfonate then? with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a quaternary ammonia. This gum was chromatographed on silica gel using ethyl acetate / hexane as the eluent. The fractions contained the desired product (TLC analysis = Thin Layer Chromatography) were combined and evaporated to a reduced volume, whereupon the compound crystallized. The compound was filtered, washed with a small amount of ether and dried under vacuum. giving the title compound as a white powder (KBr disc)? between outross 697? 1225; 17175 1779 s 328® cnf1. m / z (bAH → isobutyrate with Fast Atoms »Mn a») or 619 =

The product of Example 1 (a) is prepared as described in Example 1 (a) and (b) in the same manner as in Example 1 (a) and (b). (A) (g) was dissolved in aqueous sulfuric acid (200 ml) and cooled under stirring under a nitrogen atmosphere to -20 DEG C. N-Methyl- ml) and a solution of phosphorus trifluoride (0.8 g) in dichloromethane (7.5 ml). The mixture was stirred at -20 DEG C. for one hour and a half. 2 = 5 ml) and stirring was continued for a further half an hour, followed by water (15 ml). After one and a half hours the mixture reached room temperature, ethyl acetate (25 ml) was added and the mixture was partitioned more The precipitate was collected, washed with ether with a small amount of acetone and dried under vacuum for a few moments. The infra-red spectrum revealed that this product was the hydrochloride of the title compound. The mother liquors were treated with a small amount of hydrochloric acid 511 and further evaporated with additional ethyl acetate to give a new dose of crystals. These crystals were collected, washed with ether The combined crystals were then suspended in water (25 ml), the suspension was chromatographed using tetrahydrofuran / toluene / (ethyl acetate) 1 = 1 = 1 as eluent, and the pH was brought to 6 by careful addition of a solution of NaOH. When no crystals were suspended, the fractions were separated and the resulting non-aqueous phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solution was filtered s? evaporated to give a gum which partially crystallized in the course of storage at 2-3 ° C overnight. The solid solidified in the course of trituration with a small amount of ether. Was filtered off with a small ether amount and drying in vacuo to give the title compound (28 g) as a colorless crystalline solid, (KBr disk): 697 (M + H) +, 224: 1654, i 1726, 1765 and 3414 cm -1. m / z IRB, HM + '; ) s 5Θ1.

Hc &gt; &lt; &amp; R '/ R) -7 &quot; 12-yl) -Methoxy-2-methyl-2-trifluoromethyl-4-methoxy-2-methyl- -4-carboxamide &lt; / RTI &gt; JrfiimilitMlp. To a solution of dihydrochloride; 2- (Z) -methoxyimino-2- (2-fluorenyl) methylaminothiazol-4-yl; acetic acid &lt; 0.024 g) in non-aqueous DHF &lt; 4 ml), cooled and stirred under a charging atmosphere at -40 DEG C. was added diisopropylethylamine (0.26 g) to methanesulfonyl chloride <12 g). The mixture was then added the product of I (h) <0.124 g) and diisopropylamine (13 g) and the title compound the mixture was stirred at -30øC to -10øC for one hour. Toluene (15 ml) was added tetrahydrofuran (1 ml) ethyl acetate &lt; The fractions were separated and the solvent-containing fraction was washed with water (<50 ml) then with saturated brine. This fraction was dried over anhydrous sodium sulfate, filtered and evaporated to give the product as a gum C6-6 g. This gum was purified by silica gel column chromatography using ethyl acetate / hexane-2: 3 as eluent to afford V, - -.

The product is only in the form of a gum (5 p2 g) in combination with pure mono- = nufflii, (KBr disc): 7θθ? 1138 = 1.223 = 1522 = 1684 = 1718, 1787 = 33 and 33 ?! cm-1 =

(5-aminothasal-4-yl) -2 (Z) -methoxyiminoaceten-dp-3β- (3-methoxyphenyl) 2-enoyloxymethyl). and (b) D = 4-phosphate buffer (2-step deprotection).

To the product according to Example Kc) (32 mg) was added tetramethyuramine (533 ml), water (533 ml) and 98% formic acid (3 ml). The mixture was stirred at room temperature for one hour at which time most of the starting compound had been converted to a new more polar compound (according to CCFS 70% ethyl acetate in hexane). The solvents and acid were coevaporated with toluene and tetrabrofuran, optionally to dryness. Trifluoroacetic acid (3 ml) was added at ice-bath temperature for 1 minute. Toluene was evaporated to dryness, The residue was dissolved in toluene / tetrahydrofuran / (ethyl acetate), and water was added and the mixture titrated to give pH 7, with dilute sodium hydroxide solution. The fractions were separated, the aqueous fraction was acidified to obtain pH 2P 3 in the presence of a portion of chloroform. The fractions were separated and the aqueous fraction extracted with toluene / tetrahydrofuran / (room acetate). water to the non-aqueous fraction and titrated to pH 7.0 with dilute sodium hydroxide solution. The aqueous phase was separated and evaporated to near dryness by addition of i-propanol and then again evaporated with several &lt; RTI ID = 0.0 &gt; The solid residue was triturated with acetone / ether, filtered off and washed with a small portion of acetone and dried under vacuum ,; giving the title compound (72 mg), m.p. (KBr disk), 1145, 1529, 1611, 1680, 1763, = H, cU; ..... 336Θ and 3412 cm *¹.

Su (D-O): Î'1.7 (3H, d, d = 8 Hz), 2.09 (3H, d, J = 9.9

(3H, s), 4.72 and 4.92 &lt; 2H, ABq, J = 12.5Hz), 5.35 (1H, (1H, d, J = 5Hz), 5.73-5.44 (1H, t), 5.8 (1H, d, d = 4Hz) ) and 7.0 (1H, s).

(2R) -7-C2- (2-aminothiazol-4-yl) -C2) -hydroxy) -iminoacetamido] -benzyl] -benzyl} -benzoyloxymethyl} -amide -4-carbo; (6R, 7S) -5- (3-Hept-1-yl-2-ene-1-ylmethoxy) -7- [2- (5-1- 1-yl) -piperazin-1-yl) -benzoyl) -piperazine-4-carboxylic acid tert-butyl ester A solution of 2 - [(Z) -triphenyl-2-methoxyimino] -2- (triphenylphenyl) -4-thiazole-4-ylacetic acid sodium salt (®, 52%) in non-aqueous M, N-dimethylformamide cooled and stirred under a nitrogen atmosphere at -35 ° C was added methanesulfonyl chloride (0.18 g). After half an hour at -35 ° C, was added <6R , 7R) -7-Amino-3- (3-methyl-butyn-2-ylamino) ethyl)

(0.36 g, prepared in the manner described in Example Hb)) and pyridine (6 mg). The temperature

The solvent was removed by evaporation in vacuo and the residue was partitioned between talcum / tetrahydrofuran / ethyl acetate (water) and evaporated to dryness. The aqueous phase was washed with a small portion of the toluene and combined with the solvent phase. The combined phases were washed successively with water. saturated brine, dried over anhydrous sodium sulfate, and evaporated to give a C g g gum (9 g). This gum was subjected to silica gel column chromatography using 3: 7 ethyl acetate / hexane as eluent to remove trace The fractions containing the desired compound were combined and evaporated under reduced pressure to give a gum, yielding the title compound (0.65 g) (KBr disk), 699 1218 (2-aminothiazol-4-yl) -2- (2-methoxyphenyl) -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ) -hydroxy-imino- (3-oxoethyl) -2-ene-5-ene-4-carboxylic acid

To the product of Example 2 (s) (656 mg) was added (9% thermal acid / (1% water &lt; 4 ml) with stirring. After 4 minutes', concentrated hydrochloric acid The insoluble fraction was collected by filtration and the filtrate was washed with a small portion of the filtered heat of 100%. The residue was evaporated to give The residue was treated with ether (1 ml) and water (1 ml). The insoluble fraction was collected by filtration (filtrate) and the filtrate was dried (Na2 SO4) and evaporated to dryness neutralized &quot; The solid fraction crystallized in both steps. It was collected, washed first with a few drops of water and then with toluene and dried (Na 2 SO 4) The title compound was obtained in vacuo affording the title compound as a crop (155 mg), 20% yield (30 mg), NaOH Bv CKBr): 1076, 1144, 1226, 1528, 1637 = 1773 and 3321 gi / ) s 482,%: 1 H -DMSO): 1.39 (3H, t, J = 6 Hz), 2.1 (3H, d, J = 0.7 Hz) (2H, ABq, &lt; 3 = 13 Hz), 5.16 (1H, d, J = 5 Hz) ), 5.71-5.72 (1H, m), 5.31 (1H, dd, J = 5.9 and 9 Hz, with D2 O drop for d, J = 5 Hz), 6.66 ( 1H, s), 7.15 &lt; 5, exchange) and 9.4B (1H, d, J = B Hz, exchange) 0 -717) -7-1,2- (1,2-Aminothio-ol-4-inoacetamido [3,2-c] [1,4] diazepin-4-yl) Sodium 3-yl) -benzenesulfonamide; &quot; He κ a-2,4-dienoylmethoxyethylphenylmethionec-4-em-4-carboxylate To a solution of mild trifluoroacetic acid (g) trifhnylphosphine (1.45 g) in non-aqueous tetrahydrofuran (30 ml), stirred under an atmosphere of nitrogen, added (6R57R) -3-Hydroxy-2-methyl-7-phenylsulfanyl-3-smr-4-diphenylmethylcarbamoylphthalate <2, q). After dissolution was completed, distilled asicarboxylic acid 1.0 ml). A vigorous SKothermal reaction occurred, turning the initial color reddish brown to dark green. After a few minutes, most of the solvents were under reduced pressure, toluene (50 ml) was added and the residue was evaporated again until a total volume of about 30 ml of the extract was obtained. The insoluble fraction was filtered off, washed with a small portion of toluene and the filtrate evaporated to a gum 5 which was chromatographed on a silica gel column, using fractions containing the desired compound (TLC analysis) were combined and evaporated to a gum which was crystallized and triturated with ether / hexane. This product was collected by filtration, washed with a small portion of the same solvent and dried under vacuum to give the title compound (0.65 g), mp 697, 1133, 1655, 1717, 1737, 1785 and 3297

(KBr disk), 699, XWQ, 1133, 1185, 1218, 1239, 1615, 1640, 1717, 178 Î », 332Â ° C and 34C2 cm-1, m / z (BAR ,, MNa +) s 513, 3 (b) (6R, 7R) -7 &quot; -imino-3 &gt; The product of Example 3 (a) (0.5 g) was dissolved in non-aqueous dichloromethane (250 ml) and the product of Example 3 (a) (0.5 g) was dissolved in dichloromethane and the cooled solution was stirred under an atmosphere of nitrogen at -20 ° C. To this solution was added N-methylmortaline (20 ml) and phosphate buffer (0.022 g) in dichloromethane (5.5 ml). The reaction mixture was stirred at -20 ° C for half an hour, methanol was added. (0.5 ml) was stirred for 0.5 h at which time the reaction mixture reached approximately room temperature. Water (2 ml) was added and vigorous stirring was continued for half an hour. (5.0 ml) and evaporated under reduced pressure. The addition of toluene / tetrahydrofuran / ethyl acetate) and some water were titrated to the solution until the pH was reached by cautious addition of solid potassium carbonate. The fractions were separated and the organic fraction was washed with saturated brine, dried and evaporated to give a gum. The TLC of this gum showed that it consisted substantially of a product. However, it had a strong odor of phenylacetic acid5 and was thus taken up in toluene / tetrahydrofuran / ethyl acetate) and washed with 5% aqueous sodium hydrogencarbonate solution, then saturated brine, dried over sodium sulfate anhydrous filtered and evaporated to give a gum. This gum was used as such to prepare the ethyl ester 3Cc> 3. In the course of another experiment to prepare this smino compound. the initial hydrochloride crystallized, confront ICb)) allowing to obtain a purer specimen of the free amine. This product was used in the preparation of the hydroxime (Example 4). 3 &gt; (6R) -7- [2- (Z) -1-Ethoxy-2- (5-triphenylmethylaminothiazole-4-carboxylic acid (4-methylphenyl) 1-methyl-isothiazol-

A solution of 2-hydroxy-2-hydroxyethyl 2-triphenylphosphinothiol-4-yl) acetic acid hydrochloride (N, 3.beta.) In N, N-dimethylformamide ) was treated with N, N-diisopropylsilylamine (0.39 g) was stirred under a nitrogen atmosphere and cooled to -40 ° C. Methanesulfonyl chlorate (1.07 g) was added and the mixture was stirred at -0 ° C For 1 hour. The compound of the amino of Example 3Cb> The mixture was stirred and allowed to warm slowly for one hour until it reached room temperature. Toluene / dimethylformamide (1 g) was added, The organic fraction was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to yield a solution of the title compound as a white solid. gum which was subjected to silica gel column chromatography? using ethyl acetate / hexane as eluent. The fractions containing the desired compound (TLC analysis) were combined and evaporated to give the title product as a gum (22 g). max. (film) s 7®®s i®®5? (17β, 7β) -7β- (β-aminothiol-4-yl) -5- (β- (4-methoxyphenyl) methoxyiminoacetamido] -3- (E) -hexahydro-2,4-dienoyloxymethyl] -3-methyl-4-carboxyamide The product of Example 6 (c) in dichloroethane (3.times.3 ml) was treated with trifluoroacetic acid (1 ml) at a temperature comprised between 2 and 3 ° C for half an hour. Thereafter it was diluted with tetrahydrofuran and evaporated to give the gum and evaporated several times with The residue was treated with water (a few ml) which was removed. The remaining residue was taken up in toluene / ethyl acetate (1: 1) and water b neutralized until pH 7S was reached with a solution of The aqueous solution was washed with toluene and evaporated to dryness under vacuum. The remaining water was evaporated.

The residue was diluted with a small portion of acetone and precipitated with ether, filtered off, washed with ether to give the crude product as a white solid (62 mg) . This product was chromatographed on silica gel using water / ethanol / ethyl acetate (7:23:17) as eluent. The fractions containing the desired product (second CCF) were combined, evaporated, again evaporated with acetone and precipitated with EtOAc. dried over sodium sulfate, filtered, washed with ether and dried under vacuum to give the title product as a white solid (25 mg, Nujol): 722 == B 2, 1 2, 1142 , 119 °, 1215, IMS, 1645 == 1765 and 33® (very broad) cm â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ , 3.45 (3H, s), 4.75 and 4.95 (2H, q, J = 12.5 Hz), 5.19 (1H, d, J = . J = 4.5 Hz), 5.99 (s, 2H), 6.26-6.29 (m, 2H), 6.99 (s, 1H), 7.26-7 , 37 (1H, m),

(1) -2- (L) -hydroxy-imine-4-carboxylic acid-3-oxime 13cgf -3-hydroxy-4-yl) -2- (Z) -triphenylphenoxy-4-methoxyquinazolin-4-yl] -amide. 4. The composition of claim 1, of diphenylamine To a solution of 2- [ (0.7 g) of N-dimethylformamide (2 ml) was added dropwise, while stirring at reflux temperature for 2 hours. at -35 ° C under a nitrogen atmosphere was added methanesulfonyl chloride (0.13 g). The mixture was kept at that temperature for half an hour. The amino nucleus, the compound of Example 3c (b), was added. , 5 g) dissolved in a small amount of non-aqueous tetrahydrofuran and pyridine (3 ml) was added dropwise over a period of 4 minutes. The temperature was allowed to reach almost room temperature. Toluene / tetrahydrofuran / ethyl acetate , the mixture was separated, the organic fraction was washed with water and saturated brine and dried over anhydrous sodium sulfate. It was then evaporated to reduced volume and chromatographed on a silica gel column using The fractions containing the desired compound (second TLC) were The combined extracts were evaporated to give the title compound (δ, 65 g), δ 15 g of a less pure product, 1132, 1184, 1218, 1239 cm -1 (KBr disk), 677, 6415, 1715, 1791 and 3389 caT1 52

4-Amino-2-hydroxy-2-oxazolidinecarboxylic acid (2-aminohex-4-yl) -2- The product of Example 4 <a) <6, g> was stirred with a mixture of 98% ferric acid (6 ml) and 1N aqueous hydrochloric acid (6 ml, 6 ml) at ambient temperature for one hour. Concentrated hydrochloric acid (1 ml) was added the stirring was continued for an additional hour. The insoluble fraction was removed by filtration, washed with a small amount of 9% formic acid and the filtrate was evaporated to volume.

Several portions of toluene and / or tetrahydrofuran were added and the resulting mixture was evaporated to give a white solid. This residue was partitioned between water and toluene, the pH adjusted to 3.3 by the cautious addition of solid potassium carbonate. After stirring for one hour, the product was filtered, washed with a small amount of ether and with water, and dried under vacuum to give the title compound (165 mg) (KBr disk): i.e., 1137, 1243, 1641, 1636,: ΐ ΐ v. Λ,.

(D6 -DMSO) Î'= 83 (3H, d, d = 4, 5 Hz), 3.53 and 3.64 (2H, ABq, J = 18 Hz); 4.75 and 5.07 (2H, ABq, J = 13Hz), 5.16 (1H, d, d = 5

Hc &lt; / RTI &gt; 5,81 ΐ 1H =, dd, u-5, 8 H, collapsed to d, J = 5 H with 0, 0), 5.88 Î'H, d, J = 15 Hz), 6.28 -6.31 &lt; 2H, m), 6.67 (1H, s), 7.20-7.39 (1H), and 9.51 (1H, d, u = 8, Hc exchange with Ό, -β).

J .; ν. \ '. Acid (&gt; 7R) - / - L2- (S-aminothiazole-4-yl) -2 - (R) -hydroxyiminoacetyl-3-but-2-yloxy imet i 1 &gt; cgfT3-gm-4. a &gt; &lt; 6R, / k) -5-im-2-yne. 1 sx ima ti 1) - - - - - - - - - - - - - - - - - - - - - - - - - -

A solution of triphenylphosphine (1.45 g) in tetrahydrofuran (3 ml) and argon was stirred under reflux for 2 hours. But-2-picenoic acid (? Diphenylmethyl (25 g) and diethyl acydicarboxylate (25 g) in dichloromethane (5 ml) was added dropwise. After vigorous stirring for 1 minute, a similar volume of toluene was added and the mixture was washed with ice and saturated sodium hydrogencarbonate solution with water and saturated brine A The organic solution was dried over anhydrous sodium sulfate, filtered and evaporated to give a gum. Toluene was added and the reaction mixture was cooled to 23 DEG C. at that temperature until the following day. The precipitate Crystalline dimethyl acodicarboxylate was removed by filtration and washed with toluene- the filtrate was partially evaporated and the residue was chromatographed on a silica gel column using ethyl acetate / hexane as the oil. Partial purification The fractions containing the desired product (TLC analysis) were combined The residue was dissolved in ether and allowed to crystallize at 2-3 ° C. It was collected by filtration, washed with ether and dried under vacuum to give the title compound. epigraph <= 35 g) containing a small amount of the cef-2-isomers. A new, double-scale reaction of the above gave 1.5 g of the title compound.

&quot; The compound was recrystallized from dichloromethane / stanol by partial evaporation of dichloromethane and subsequent chilling at 2 ° -3 ° C. There was thus obtained a substance which was free from cis-2- in = nu_ <disc dsKBr) g 697, 1073, 1251 = 1522, 1651, Î »max. (b) 5-Bromo-3-ethyl-4-carboxylate: (b) 5-Bromo-3-oxo-3-oxo-3- The product of example 5 (a) &lt; / RTI &gt; C1375 g) in non-aqueous dichloromethane (25 ml) was cooled and stirred under a nitrogen atmosphere at -20 DEG C. to this product was added N-methylmorphine (57 ml) and then a solution of pentachloride of <5e43 g) in dichloromethane <16 ml). The reaction mixture was stirred at -20 ° C for half an hour. Methanol (6 ml) was added and the reaction mixture was heated for half an hour until it reached room temperature. Water (<25 ml) was then added, vigorous stirring was continued for half an hour. Ethyl acetate (50 ml) was added and the mixture was evaporated under reduced pressure until its volume was reduced to half. This procedure was repeated then ether was added. A heavy oil was removed. The flask and contents were rapidly cooled, the oil crystallized during this time. It was collected by filtration and washed with a small portion of hydrochloric acid in. then with ether & dried for some time in the air. Suspended in a toluene mixture &lt; 1000 ml)? tetrahydrofuran (200 ml) and water (300 ml) and solid potassium carbonate was added to give pH 6.5. At

The fractions were separated and the argon fraction was washed with water and saturated brine, dried over sodium sulfate and evaporated to give a gamma which crystallized. This gum was dissolved in dichloromethane and ethanol was added in order to slightly turbidate the solution. It was allowed to settle and cooled to 2-3 ° C. After one hour the crystals were collected by filtration, washed with a quantity of ftexane and dried under vacuum to give the title compound (Θ, 46 g) = 1-flor Ethers also contained the compound &lt; CCF) 3. nb, KBr Cdisk) s 697 = 7Θ6 = 742 = 1077 = 1225 = 124Â °, max 1739 = 17265 1766 = 2235 and 3416 cm -1. &lt; = &gt; diphenylmethyl ester To a solution of 2- (Z) -triphenylmethoxy) -benzoic acid methyl ester A solution of 2-benzyloxyphenylmethyl-2-methyl- -2-C2-trifluoromethylaminothiadiazol-4-yl lacetate (Θ.7 g) in N = N-dimethyl-formamide, n-aq., Stirred under an atmosphere of nitrogen at -350C of &lt; 513 g) =

After half an hour the product of Example 5Cb) was added, followed by pyridine (8 mg). The mixture was stirred at -25 ° C for 45 h. water = toluene, tetrahydrofuran and ethyl acetate were added thereto, further stirred and separated. The organic fraction was washed with dilute hydrochloric acid sodium hydroxide solution and saturated brine; dried over anhydrous sodium sulfate, filtered and evaporated to give a gum. This gum was subjected to silica gel column chromatography using ethyl acetate / hexane as sols. Fractions counting the cleared compound (TLC analysis) were combined and collected to give the title compound (0.63 g) and 0.12 g of a crude product. (Brs disc) 699, 751, 1248, 171 °, 1791, 2239 and 3384 cm m / z (BAR5 rjNa ') s 1138 = 5β) (R) -hydroxy-4-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (2-hydroxyethyl) The product of Example 5 (c) (0 = 63 g) was wetted with tetrahydrofuran, dissolved in 98% to 1% thermal acid (5 ml) containing 1M hydrochloric acid (5 ml). After one hour, C 3 concentrated hydrochloric acid (1 ml) was added and stirred for more than half an hour. The crystalline precipitate was collected by filtration and washed with a small amount of 9% ferric acid. The filtrate was diluted with toluene and tetrahydrofuran and evaporated under reduced pressure to dryness. The residue was partitioned between ether and water and the pH adjusted to 3.3. The mixture was cooled on ice, filtered off, washed with a small amount of water. then ether, dried under vacuum to give the title product (0.25 g) contaminated with some less polar impurities. The mixture was subjected to silica gel column chromatography using water / ethanol / ethyl acetate) = 3: 7 as the eluant to give the title product &lt; 25 mg) as a white solid after evaporation of the solvents and water. s 330Θ 57

(DMSO-d 6, 300 MHz): δ 4.32 (3H, s); (2H, ABq, J = 12.5 Hz), 5.517 (1H, d, J = 18 Hz), 5.57 (1H, d, J = and 8 Hz, collapses to d, d = 5 Hz with C) )H =): δ: 66.76 (S); 4 ' CIH, d. J = 8Hz and exchanged with (C6R7R) 7-C2- (2-aminothiazol-4-yl) -2- 3-yl) -3,3- (2-methylprop-2-enooyloxymethyl) -5,5-em-4-carbaphthyl] acetamide. .......................... of diphenylmethyl) (i) To a stirred solution of 2-n-propyl-2-p-2-enoic acid (methacrylic acid) (0.9 ml) in tetrahydrofuran at gentle reflux temperature (65 ml) under nitrogen was added successively (6R57R) -3-hydroxymethyl-7-phenylacetoxy-5-oxo-3-methyl-4-methylphenylcarbamate <5514 g. After 2 minutes, the mixture was cooled and diluted with toluene (5 ml), and the solvent was evaporated to dryness. The residue was purified by chromatography on silica gel eluting with dichloromethane (25 ml). The mixture was washed with dilute sodium hydrogen carbonate solution and then with water and dried over anhydrous sodium sulfate. The solution was collected by filtration and washed with a small amount of toluene, the filtrate was partially evaporated. The solution was submitted (ethyl acetate) hexanes / 2: 3 as the solvent. The fractions which contained the title compound in the purest form were combined and evaporated in ether, cooled to 2-3 ° C and kept at that temperature overnight. The crystalline product was collected by filtration, washed with cold ether and dried under vacuum to afford the title compound (4). The compound was crystallisable by dissolution in dichloromethane (minimum quantity), addition of ethanol (1 ml) and partial evaporation of the dichloromethane to give the title compound as a white solid. There was obtained a new amount of 4 g &gt; from less pure fractions of the mother liquors by chromatography and crystallization. (iii) To a solution of methacrylic acid (0.7 ml) in non-aqueous pyridine <2 ml> cooled and stirred under a nitrogen atmosphere Methanesulfonyl chloride (7 ml) was added. After half an hour at 0 ° C. lt; RTI ID = 0.0 &gt; (6R, 7R) -3-Aminoethyl) -7-phenylacetamidoceph-3-em-4-carboxylate (5 g). a small excess of sulfuric acid 235M = the product was extracted into ethyl acetate which was washed with water, dilute sodium hydrogencarbonate solution, and saturated brine, dried over sodium sulfate and evaporated to volume The residue was chromatographed on a silica gel column using ethyl acetate / hexane 2: 3 as eluent. The extracts containing the desired product were combined and evaporated and recrystallised from ethanol as described in The title compound was prepared as a white powder (KBr disc), 696 * 1145 * 1224 * 1648 * 1717 * 1781 and 3,777 cm -1 (mbar). 5-yl) propyl-2-oxazolidin-2-carboxylic acid (2-chlorophenyl) tila 4-yl) -2- (Z) -triphenylmethyl] amino] acetic acid (3-chloro-4-methyl-4-methanesulfonate). of diphenylmethyl is prepared as a solution of 2-CZ → triisopropylimidazo [2- (2-trifluoromethylphenyl) thiazol-4-yl] acetate (0.87 g) in N, N-dimethyl formamide Cl ml = cooled to 35 ° C and stirred under a stirring atmosphere was added methanesulfonyl chloride (533 g) =

After half an hour at a temperature below -3 ° C? the amine compound from Example 6 (â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (â € ƒâ € ƒâ € ƒ (θ 559 g) and n-aqueous pyridine was added and the mixture stirred for 45 minutes, allowing the temperature to rise to about room temperature. A mixture of toluene, tetrahydrofuran and ethyl acetate were stirred and the fractions were separated. The solvent-containing fraction was washed with dilute hydrochloric acid with a dilute solution of sodium hydrogen carbonate, water and brine saturated and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was evaporated to volume, and then chromatographed on silica gel using 35% ethyl acetate The fractions containing the desired compound (TLC analysis) were combined and evaporated to give a gum <9 g) =

Obtains a small amount (about 1 g) of the starting amino compound by washing the column with ethyl acetate, in vacuo. (KBr disc) s 699 = 757, 787, 115®, 1491, 1688, 17203 1791 and 3386 cm -1. (CHâ,ƒ) â,,Nâ,,N +)

X 6 6) Acid <6B, .7R> 7-C2- (2-Aminothiazol-4-yl) -2- (Z) -hydroxy- N α -acylated amine. 2-methylprop-2-enooyloxymethyl) ceph-3-yl] carbamate as a white solid. (g) was dissolved in 98-1 Θθ% thermal cycling (5 ml) under stirring. 1M hydrochloric acid (3 x 30 ml) was added and the product of Example 1 (c) The reaction mixture was cooled to -78Â ° C and the solution was stirred for 0.5 h. The reaction mixture was cooled to -78Â ° C, and the solution was stirred for 30 minutes. The solvent was removed by filtration. The precipitate was evaporated to dryness. The residue was triturated with ether, dried over sodium sulfate and evaporated to dryness. filtered, washed with ether and dried under vacuum. The solid hydrochloride was moistened with tetrahydrofuran (2-3 ml). toluene &lt; 2 & ml) and water (20 ml) were titrated to pH 3-1 by the cautious addition of solid potassium carbonate. The crystalline precipitate was collected by filtration, washed with toluene / tetrahydrofuran and water vacuum drying? giving the title acid &lt; 13 mg &gt; = New acid crops (totaling 15Φ mg) will be obtained by evaporation of the molasses-

Dissolved from the first crop (5 mg) in water (3 ml) and tetrahydrofuran (1 ml) were titrated to pH 6 by addition of sodium hydroxide The solution was evaporated to dryness and ether evaporated and evaporated to give a solid which was then triturated with ether, filtered off, washed with ether and dried under vacuum overnight. giving the title salt (38 mg)

Free acid nums (Wiijol): 116: 1634, 167Â °, 1712, 1775 and 3303 m / z (FAB, MH +, 468,

Salt of the naked sages. (Nujol): 1160, 1535, 1610, 1710, 1765, 3265 (M + H) +, 4 CDA-DMSO): 1388 (3H, s), 3.52 and 3 , &Lt; 2H, ABq, J = 1B Hz), 4.77 and 5.10 C2 H, ABq, d = 13 Hz), 5.16 (1H, d, 3-5 Hz), 5.71 (1H, s ), 5.11 (1H, dd, J = 5 and 8 Hz, glidose to d, J = 5 Hz cam DJ3), 6.05 (1H, s), 6.65 (1H, s), 7.15 , exchange with D2 O), 9.48 (2H, d, J = 8 Hz, exchange with D2 O) and 11.31 (s, 1H). D-O), 6 (&gt; 1.6R 5.7R) &quot; 7- (C2-Amino-thiazol-4-yl) -2- (Z) -hydroxyiminoacetamid Q1 -3- 2-ene-2-ene-1-yl] imidazol-4-carboxylate, 2,2-dimethylpropanoylmethyl ester, i.e., pivaloyloxymethyl ester)

The last harvests of the acidic free of Example 6Cd &gt; (15 ml) in water (25 ml) and tetrahydrofuran (10 ml) were titrated to give 6H with a solution of the sodium hydroxide θ. The mixture was evaporated under reduced pressure until its volume was about of 1 ml, was added N, N-dimethylformamide (1 ml) and the evaporation was continued under high vacuum until the volume was reduced to about 5 ml.

N, N-dimethylformamide (1 ml) was added and the residue was re-evaporated to a volume of 5 ml, followed by addition of 5 ml of 5 ml of this mixture, and a solution of 2- (Prepared from the bromomethyl compound (65 mg) and sodium iodide <1®®) in acetone (5 ml) by stirring at 2-3 ° C for 1 minute, filtration, evaporation and further filtration after addition of toluene (3 ml)) The mixture was stirred at ambient temperature under a nitrogen atmosphere for 45 minutes and protected from light. Tetrahydrofuran was added, toluene and water, stirred and the mixture was separated The solvent fraction was washed with water, a dilute sodium hydrocarbon solution and saturated brine, dried over sodium sulfate and evaporated to give a gum which was evaporated under high vacuum after the addition of several portions of toluene s, then made into foam with u This residue was triturated with a small amount of ether, filtered, washed with further portions of ether and dried under vacuum overnight. The title compound was obtained as a tan solid ( 6 mg). , (film) s 75®, 986, 116®, 95% * 168® * 1725 * ma ;; 1,755, 179® and 33®® cm &quot; *

CDCl3: 1.23 (9H, s), 1.94 (3H, s), 3.43 and 3.6 (Î', ABq5 J = 11 Hz), 4.91 and 5.26 (2H, ABq (1H, s), 5.86 and 5.97 (2H, ABq, 4-5.5 Hz, 1H), 6.85 (d, J = (1H, s), 7.33 (1H, s), 1.45 (1H, br s, exchange with D2 O), 63

Hidroelorefcc? in. 7-yl) -aminoethyl] -4-yl) -2- (Z) -hydrofuran-3-yl] -acetic acid 3-3- (2-methylglycine (6R, 7R) -3-Amino-3-oxazolidin-1-yl] (R, S) -1-acetyl-2-enoyl-oxo-imidazo [3,7-phenylacetamido] propyl] -S-benzenesulphonyl ester,

Of this! see-ss &lt; 2-methyl-prop-3-eno-1-oxime-8-yl) -phenylacetamidoacetic acid-4-carboxylate (Example A) (a) 98-1®% &lt; 45 &gt; 5H hydrochloric acid &lt; 1 ml) ε water &lt; 5 ml) was added. and the reaction was monitored for the disappearance of the starting compound by TLC. Toluene was added and the reaction mixture was evaporated almost to dryness. New portions of toluene and tetrahydrofuran were added and the reaction mixture was again evaporated. The procedure was repeated with toluene and ethyl acetate. The residue was treated with toluene &lt; 1000 ml): tetrahydrofuran &lt; i &gt; n! &gt; ? ethyl acetate &lt; 3 ml) and water (2 ml) and titrated to pH 8 by the addition of solid potassium hydrogencarbonate. The fractions were separated and the aqueous fraction was washed with a small portion of (ethyl acetate) toluene, then dichloromethane (2 ml), tetrahydrofuran (2 g) acetate, 1-bromoethyl &lt; 1 &gt; ml). The pH was maintained between 5.5 and 7.0 by addition, in small portions, of the solid potassium hydrogen carbonate. New (? 34 ml and 1.1 ml) portions of 1-bromoethyl acetate were added after 1.5 to 3.5 hours. After 4.5 hours, the mixture was diluted with ethyl acetate &lt; 500 ml) and dichloromethane was added. evaporated under high pressure. A small portion of toluene was added, the fractions were separated in fraction. The solvent was washed with water and then with brine and dried over anhydrous sodium sulfate. This fraction was filtered. The fractions containing the desired product were combined and evaporated to give a foam (1.33 g) in tetrahydrofuran (1: 1) to give the title compound as a white foam (KBr disc): 698, 943, 1073, 1375, 1528, 1664, 1719, 1776, 1786 and 3289 cm-1: m / z (BAR5 MNaN): 523 (CDCl3) s), 2.38 (1H, d, J = 6 Hz), 1.94 (3H, s), 2.38 and δ = 1.1: ; 2H, ABq, d 19 Hz), 3.6 (s, 3, br: 12K, ABq, J = 16Hz), 4.80-5.25 (3H, m), 5.62 < 1H, br s), 5.80-5.90 (1H, m), 6.62 (1H, d, d = 12 Hz, exchange with D₂O), 6.11 (1H, s), 6.99 and 7 , 8 &lt; 1H total, 2 xq, J = 5.5 Hz) and 7.20-7.4 &lt; 5H, m), 7 (b &gt; (6R 7R) -3- &lt; 2-n- prop-5-ennoyloxymethyl) -1-12- &lt; 2-yl) -2-hydroxy-2-trifluoromethyl-benzoic acid, 4-methoxy- (a) &lt; tb &gt; &lt; RTI ID = 0.0 &gt; 1 &lt; / RTI &gt; , 3 g &gt; in N-aqueous dichloromethane (15 ml) at -28 ° C was added N-phlegly-morpholine (0.61 ml) and a solution of phosphorus pentachloride (0.66 g, 16.5 ml of a solution of 4- In dichloromethane)

After half an hour at a temperature below -20 ° C, methanol (7 ml) was added and after a further half hour in which the temperature rose to -9 ° C, water &lt; 4 ml). agitated

vigorously for one hour. Ethyl acetate (5 ml) was added and the major parts of the dichloromethane were evaporated under reduced pressure. Evaporation of the diethyl ether is typically complete. Saturated ammonium chloride solution (15 ml), ethyl acetate (2 ml), tetrahydrofuran (1 ml) and toluene (1 ml) were added, the resulting mixture was stirred vigorously and neutralized until pH 6.5 is obtained. by the careful addition of solid potassium hydrogen carbonate. The fractions were separated, the aqueous fraction was washed with ethyl acetate. the combined solvent fractions were washed with water and saturated brine and then dried over anhydrous sodium sulfate and filtered. The solution had, in TLC (silica gel, (ethyl acetate) / hexanes Is 1), a major polar zone and a less intense less polar zone. The solution was evaporated to give an oil which was immediately precipitated from non-aqueous tetrahydrofuran (3 ml) and used in the next step. To a solution of sodium 2- (2-triphenylmethylaminothiazol-4-yl) acetate &lt; 1.5 g &lt; in non-aqueous N, N-dimethylformamide (15: 1) at -35 ° C under a nitrogen atmosphere was added methanesulfonyl chloride (0.5 g)

After half an hour at a temperature below -30 ° C, pyridine (175 mg) and the tetranhydrofuran solution of the 7-amine compound prepared in the first step were added. The mixture was allowed to gradually warm for one hour, until its temperature almost reaches room temperature. Toluene, tetranhydrofuran, ethyl acetate and water were added and the resulting mixture was stirred and separated. The aqueous phase was again extracted with toluene / ethyl acetate, the solvent fractions were combined, washed with aqueous hydrochloric acid 1M potassium hydrogen carbonate solution, water with saturated brine and dried over anhydrous sodium sulfate. The solution was filtered, the filtrate was evaporated to volume (about 5 ml) reduced under reduced pressure and subjected to silica gel column chromatography using as an eluent an (ethyl acetate) / hexane gradient ranging from The fractions containing the desired product were combined and evaporated to give the title compound as a foam (4 g) = num 4 (KBr disc) = 7 °, 72 °, 1153 , 121 °, 1447, 1491, 15233, 1679, 1776, 1791, 3556 and 338 ° cm⠻¹. ffi / o. (BAR5nNa &quot; &gt; s®6® =

 € ƒâ € ƒâ € ƒ1.5-1.6 <3H, m>, 1.95 C3H, s> 2.1,1 and 2.11 C3H total, 2 x s>, 3.22 and 3.49 (2H, ABq , J = 19 Hz), 4.7® 5.3 ° (3B, m, inc, ABq, J = 14 Hz), 5.62 (1H, brs), Î'-O, , inc. s for 6,12), 6.41 &lt; 1H, s), 6.73 (1H, br s), 7.00 (d, J = 5 Hz) and 7.15-7.5® <3> H, <n) = 7 (c) __ (ÓR, 78) -7-12- (2-aminothiazol-4-1.1) -2- - &lt; Z-3-en-4-carboxylate, from (1-benzyloxyphenyl) -2- (4-methoxy- (S) -1-acetoxyethyl ester (i.e., methyl ester)

To the title compound of Example 7 &lt; f &gt; (1.38 g) was added 9Β-10 ácido thermal acid (14 ml) and 5% aqueous hydrochloric acid (75 ml). The mixture was stirred at room temperature for one hour. The crystalline precipitate however formed was removed by filtration and washed with a small portion of 9% heat acid. The filtrate was evaporated to ca. dried under reduced pressure and then, after addition of two successive portions of toluene-tetrahydrofuran, evaporated to dryness to give a white solid. This solid was triturated with ether, filtered off, washed with ether and evaporated to dryness.

dried under vacuum to give the title compound as a colorless solid (CDâ,,Oâ,, 65 g) as a white solid (KBr): 946.1 (br s, 107: 11), 4.04 (br. 1676, 1718, 176Â °, 1786 and 311Â ° cm-1. m / z (BAR, ΜΗ +> 554 = o M CDa-DM80) 3 1 = 46 and 1.47 C3H total, 2 xd, d-5.5 Hz>, 1.89 &lt; 3H, s), &lt; / RTI &gt; 2.03 and 2, â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ x ABq, J = 13 Hz), 5.22 and 5.24 total HU, 2 x d, 3-5 = 5 Hz), 5.72 (1H, s), 5.86-5.90 (1H, m), , 6.82 to 6.83 (total 1H, 2 xs), 6.9® to 6.99 total HU, 2 κq, 3-5.5 Hz), 9.73 HU , d = 3, 8 Hz, exchanges with 0.01, 12.3, 1H, broad s, exchange with D2 O) =

......

(6R, 7R) -7- (2-Aminothiazol-4-yl) -2- (hydroxy) -6- (2-methoxyimino) 5-effl-4-carboxylate of 2,2-dimethylpropansyloxymethyl SC (a) (ii):. -pyrrolidin-1-yl] -piperazine-1-carboxylic acid (2-dimethylpropanoyl) methyl ester The title compound of Example 6Ca) (2.3 g) was deprotected as described in Example 7Ca (b). and then again esterified with dichloromethane (20 ml), tetrabutylammonium iodide (1.5 g) and bromomethyl 2,2-dimethylpropsnoate (ml). Was the mixture allowed to stir for a further 3 hours? a fresh portion of the bromo compound (<3 ml) was added and the mixture was kept under stirring overnight. Ethyl acetate was added and the dichloromethane was evaporated under reduced pressure. A small amount of tetraene was added, the fractions were separated, the solvent was washed with water and saturated brine and dried over anhydrous sodium sulfate. It was filtered, evaporated to a reduced volume and subjected to column chromatography using ethyl acetate / hexanes and dichloromethane. The fractions containing the desired product were combined and evaporated to give the title compound as a foam (50 ml). S,. (CDCl3): 1 H a * 22 C9 H * s) * 1 * 94 <3H * s> * 3 * a5 s 3 * 54 <2H * ABq * 3-19 Hz) * 3 * S * S 1 H-NMR (CDCl3): Î'(CDCl3): Î'(CDCl3, 300 MHz) m)

Hz * exchange with l> 0> 1 H-NMR (DMSO-d 6): δ (DMSO-d 6) δ (DMSO-d 6) 2,2-dimethylacetoxyphenylmethyl. (through spin-off

DMSO to give the 7-amino compound) To a solution of the title compound of Example 8 (a) (41 g) in dichloromethane (5 ml) cooled to -25 DEG C. and kept under stirring at that temperature. A solution of phosphorous pentachloride (4 g, dichloromethane (1 ml) and N-methylmorpholine (1 ml) was added. After half an hour, methanol (2 x 5 ml) was added after another half hour water (14 ml). The mixture was stirred vigorously for half an hour, then ethyl acetate (20 ml) was added and the dichloromethane was evaporated. 69

saturated solution of ammonium chloride (5 ml) and toluene (5 ml) was adjusted to pH 6.5 by the cautious addition of solid potassium hydrogen carbonate. The mixture was separated, washed with water, saturated brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure until the volume reduced to about 5 ml. Thereafter, tetrahydrofuran was added and the solution was evaporated to a volume of 2-3 ml. volume of solution was directly used in the next step (see below). To a solution of sodium 2- (2-trifluoromethylphenyl) -2- (2-fluorenyl) methylamino] -4-yl) acetate (5 ml) at -45 ° C under a nitrogen atmosphere was added methanesulfonyl chloride (5516 g). After half an hour at a temperature below -30 ° C was added solution obtained in the first step, immediately to asguir, pyridine &lt; 54 mg). The reaction mixture was allowed to warm to room temperature, and toluene (3 ml), ethyl acetate (20 ml) and water (40 ml) were added. The mixture was stirred, The solvent fraction was washed with dilute sulfuric acid (1: 1) then with saturated sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered and evaporated to volume before chromatography on a silica gel column using ethyl acetate / hexane (1: 2 as eluent) to give the product as a foam after evaporation of the solvents. The title compound (KBr disk), 780, 978, 1154, 1290 = 1447 = 1522, 1685, 1719, 1755, 2973, 3325 cm-1 was obtained. m / z (FAB, HNa +); 1088 = 7 10

CDCl3) δ 1.23 (9H, s), 1.95 (3H, s), 3.21 and 3.49 (2H, ABq, J = 1; Hz), 4.87 and 5.23 (2H, ABq, Î'= 14 Hz), Î'= 5 (1H, d, J = 5 Hz), 5.63 (1H, s), 3.88 s 5.96 C2H, ABq, Î'= 5.5 Hz), 6.05 (1H, br s, collapsed for d, Î'= 5 Hz, with Dâ, †), 6.12 (1H, s), 6.46 (1H, s ), 6.78 (1H, brs) and 7.20-7.4 (3 H, brs). 4-yl) -2- (2-methoxyphenyl) -2-methylimidazo [1,2-a] pyrimidine; (26 ml) was dissolved in ferric acid (98 ml) (3 ml = 5M aqueous hydrochloric acid, 14 ml) and the mixture was stirred in an ice bath which was not The insoluble precipitate which formed was removed by filtration and washed with a small amount of 9% thermal acid. Several portions of toluene and tetrahydrofuran were added to the filtrate to washings which were evaporated This was repeated with tetrabrofuran alone. The gummy residue was triturated with ether, the solid hydrochloride was collected by filtration, washed with ether and dried under high vacuum to give the title compound (â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ 1 g) = nu. (DMSO-d 6 -DMSO): 1.15 (9H, s), 1.88 (3H, s), 1.88 (3H, s) (3H, s), 3.61 and 3.74 (2H, ABq, J = 1Hz), 4.78 and 5.64 (2H, ABq, J = 3Hz), 5.24 (1H, d, = 5 Hz), 5.73 (5H, s), 5.21 (2H, ABq, J = 6 Hz), (obscure quartet 7CH>, 6.05 (1H, s), 6.81 (1H, , s) and 9.72 (1H, d, J = 8 Hz, exchange with 0, - 0) =

Example 6 (a) &lt; / RTI &gt; via? 16R, 7R) -5- (2-n-propyl) -pent-2-enyl] imino] -7- (3,5-difluorobenzyl) (5 g) in dichloromethane (3 ml.) in dichloromethane (5 ml) was added dropwise to a solution of (R) -3-chlorophenyl-7-phenylacetonitrile in dichloromethane ) at room temperature, water (15 ml) was added tetrabutylammonium iodide (2 g, methacrylic acid Cl ml) and sodium metabisulfite (0.02 g) .The mixture was stirred and neutralized to pH 7, was treated with 5% aqueous sodium hydroxide and then maintained at a pH comprised between 7 and 7 by the occasional addition of 1M sodium hydroxide solution. After 4 hours, the fractions were separated, the solvent fraction was diluted with an equal volume of toluene, then washed with water, a solution of sodium metabisulfite, a solution of sodium hydrogen carbonate and saturated brine, then dried over anhydrous sodium sulfate Finally, the solution was filtered and evaporated under reduced pressure to give a gum (6 g). This gum essentially consists of the β-isomer. Example 6 (a) &gt; was again dissolved in dichloromethane (1 ml) and cooled in an ice bath to a temperature of 2 to 3 ° C. 55% 4-Chloraper-2-oxyacetic acid (4 g) was added after one and half hours, the mixture was washed with water, sodium hydrogen carbonate solution, sodium metabisulfite solution, water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated to near dryness 2-propanol

and evaporated steadily to give a SiO 2. This was dissolved in 2-propanol (30 ml) and kept under refrigeration overnight. The crystalline mass was triturated, filtered off and washed with 2-propanol and then ether and dried under vacuum to give the title compound &lt; 4.5 g &gt; =

Munia another one-day experience * 5ubinetsu-sss for cjut.ro3 !, SC1H &quot; (1.0 g) was added to a substitution reaction. The oxidizing agent of the second step was added in portions (control by TLC to avoid over-oxidation) to give the title compound &lt; 8.7 g &gt; = nu .... iw (KBr disc) s 696 * 1 © 345 11503 165®, 1717, 1785 :: ϊ w. . and 3205 cm &quot; ' (2H, ABq, d = 19 Hz), 3.59 and 3 (2H, d, J = 9 Hz) , 66 (2H, ABq, 3 = 16 Ha), 4.43 (1H, d, J = 5 Hz, 5 Hz), 4 = 79 and 5 = 39 &lt; 2H = ABq, 1H), 6.10 (1H, dd, J = 5 and 1 Hz), 6.73 (1H, d, J = 10 Hz) (8 g, 7 g) was dissolved in N, N-dimethylformamide (7 ml) and the title compound (0.8 g) , stirred and cooled to -25 to -30Â ° C under an atmosphere of anhydrous nitrogen. Phosphorous trichloride (&lt; 2 = 4 ml) was added rapidly, &lt; / RTI &gt; The product was collected by filtration, washed with a large amount of water, dried over sodium sulfate, filtered, and evaporated to dryness.

dichloromethane, washed another vial with water, dried over sodium sulfate, filtered, and evaporated to form a gum. This gum was dissolved with a small amount of toluene and subjected to silica gel column chromatography using (ethyl acetate) hexanes The fractions containing the pure compound C according to CCF) were combined and evaporated. The less pure fractions were combined and the plates were chromatographed. Again the fractions containing the required compound were combined again and the combined fractions were evaporated and added to the above product obtained starting from trituration with a small amount of ether, using ethyl acetate / hexane as eluent. filtration and drying * &amp; a total of 5.6 g of the title compound was prepared. The title compound was prepared according to the procedure described in Example 1 (a) to give 2- (Z) -methy iminoacetam-

(1.) sodium salt (a) &lt; tb &gt; m * 7R) &quot; 3 &quot; 2-heptyl-prop-2-ylmethoxyimino) -7- [2- 2-trifluoromethyl-2-trifluoromethyl- Z) .- (R) -1-Hexahydroacetamido-3-cephem-3-em-4-carboxylic acid diphenylmethyl ester

A solution of 2-CZ) -methoxyimino-2-C-triisopropylsuinothiazole-4-carboxylic acid hydrochloride (5.5 g) in non-aqueous M5M-dimethylformamide (7 ml) was cooled to -35 DEG C. To this solution was added diisopropylethylamine (35 ml) and methylsulfonyl chloride (δ 50 ml) and the resulting mixture was stirred for 1/2 hour with the thisamine compound from Example 6 (b) (6.5 g) and aqueous pyridine (6.68 g) were added and the resulting mixture was allowed to warm to room temperature until it was brought to room temperature. Add toluene ( 6 ml of tetrahydrofuran (4 ml) and water (2 ml) was stirred and the mixture was separated. The aqueous section was further extracted with a small amount of alcohol, the solvent fractions were combined Washed several times with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give This gum was subjected to silica gel column chromatography using ethyl acetate / hexane as eluents. The fractions containing the desired compound (according to TLC) were combined and evaporated to give gum <gt; g) = nu "(KBr disk &gt; = 76®, 754 = 1®375 U49, 122®, 1522, ϊΪ52λΛ. 1684, 1719, 1788, 2926, 333 and 3395 cηΓ1. tn / z <BAR> Hfe '); 9.12 (3H, s), 3.4, and 3.58 (2H, ABa, J = 19).

Hz), 4.86 (3H, s), 4.09 and 5.17 &lt; 2H, ABq, ϋ -14 Hz), 5.66 (1H, d, 4 ~ 3 Hz), 5.66 (1H , 5.97 (1H, dd, J = 5 and 9 Hz), 6.63 (1H, s), 6.74, 6.79, 6.95 (s,  € ƒâ € ƒâ € ƒ20-7.56 (about 25H, m &gt; = 10Cb): νmax 6 (R) -12 &quot;2-affinothiazal-4-yl; -2- (Z) -methoxyimino-acetamido] -8- (2-methylprop-2-enoxyimethyl) ceph-5-em-4-carboxylic acid sodium salt

To the product of Example 1Ca) was added tetrahydro-1-methane (2 ml). After a quarter of an hour, Thermochemical acid (98-10% C5 ml) was added, the mixture cooled in a bath of Λ -

The reaction mixture was cooled to -78 ° C. After a further half-hour, the mixture was treated with concentrated hydrochloric acid (50 ml). then stirred for three quarters of an hour. The volatiles were removed in vacuo and the residue triturated with ether. It was found that it was only partially deprotected, so it was dissolved in thermal acid (3 ml) at room temperature. then treated successively with 1% aqueous hydrochloric acid (0.4 ml) and conc. hydrochloric acid <1 mls. After three quarters of an hour the reaction mixture was evaporated under reduced pressure with a mixture of toluene and tetrahydrofuran to give a gum which was triturated with ether. The insoluble fraction was collected by filtration, washed with ether and dried under vacuum. This fraction was treated with tetrahydrofuran (1 ml) and water (3 ml) and the pH of the reaction mixture was adjusted to 3.3 by cautious addition of potassium carbonate. The aqueous phase was decanted and the gum was stirred with 1 ml of water for one hour. The crystalline free acid was removed by filtration, washed with a small amount of water and dried under vacuum to give the title product (1 g), mp. , 16S, 1630, 1775, 1714, 1783, 2939 and 337 cm-1. The product was suspended in a small volume of water and gradually titrated to pH 6.5 by the addition of a very dilute solution of sodium hydroxide. The undissolved fraction was removed by filtration and the filtrate was evaporated to dryness after the successive addition of 1-propanol, tetrahydrofuran and acetone as co-solvents, the residue was triturated with acetone / ether, filtered off and dried under vacuum to give

(Nujol) s 103B, 1164, 1536, 1614, 1711, 1768 and 337 cm⠻¹ in the title compound. (2H, s), 1.35 (3H, s), 3.24 and 3.51 &lt; 2B, ABq, J = 17Hz), 3.35 (H, OCH3), 3.83 OH, s (1H, d, J = 5Hz), 5.53 (1H, t, J = 5 and 8Hz) , colspsa at 0 · 5 to 5 · 5 (1H, d, J = 5 Hz), 5.67 (1H, s), 6.02 &lt; 1H, s), 6.74 (1H, s),  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ7.44 Si at 9.54 (1H = d, J = 8 Hz, exchanges with D2 O), 6KMLoL._i

(Z) -2-Methylbut-2 (Z) -hydroxy-aminoacetamido-3-C (Z) -2-methyl-2- 3-carboxylic acid-3-carboxamide; (a) C6 H10 N3 O3: (Z) 2-Fluorobut-2-enoyl-oxymethyl-1,3- 3,7-fsn-11-acetamidazo [3,1-c] [1,4] diazepin-4-carboxylate

A mixture of BC1H and Cys Example 9 (a) &gt; (5 g), dichloromisomethane (30 ml), water (15 ml), acidic (Z) -2-methylbut-2-ethylic acid, C2.5 g> and tetrabutylammonium iodide (1.7 g) was stirred until titrated to pH 7.0 by the addition of 1% aqueous sodium hydroxide solution. The sodium hydroxide solution was also used to maintain the solution neutral A small amount of chloroform was also added to replace the lost dichloromethane by evaporation. The resultant residue was stirred overnight. The fractions were separated, the solvent fraction was diluted with toluene (50 ml. ) and washed successively with a solution of sodium metabisulfite, a solution of sodium hydrogencarbonate, water with saturated brine, and dried over anhydrous sodium sulfate. The solution was collected by filtration and evaporated under reduced pressure to give gum*

This gum was redissolved in dichloromethane (100 ml) and the resulting 55% 3-chloroperbenzoic acid solution was added &lt; 4 g &gt; The mixture was stirred for 2 hours in an ice bath. A success rate of sodium metabisulfite solution was added and the resulting mixture was separated. The solvent fraction was washed with a solution of hydrogen carbonate dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The product was evaporated to dryness, and the filtrate was evaporated to dryness. , and the product was collected by filtration, washed with 2-propanol, then ether and dried in vacuo to give the product under heading &lt; 3.9 g &gt; =

A small amount of the product was recrystallized from dichloromethane-propanol (KBr): 697 * 1034 * 1221 * 1249, s 1382, = 1532 * 1648. 1718, 1784, 3031 and 3289 cm-1. m / z (BAR * MNa +): 635 * SH (CDCl3) δ: 79 (3H, s), 3.15 and 3.81 (2H, ABq, J = 19Hz), 3.6® and 3.67 , ABq, J = 16Hz), 4.44 (1H, d, J = 5Hz), 4.78 and 5.38 (2H, ABq, J = 14Hz), 6.75- 6.85 (1H, d, e), 6.93 (1H, s) and 7.20-7.50 (15H, ). 1 (R, 7 R) -3-yl] Z) -2-Mer-1-naphth-2-sulphonyl] methyl] (3.66 g) was dissolved in non-aqueous N, N-dimethylformamide under a nitrogen atmosphere and cooled. with stirring, to -22Â ° C.). After 8 minutes at -20Â ° C (external temperature), the mixture was poured into the solid which was collected by filtration, washed with large amounts of water and dried under vacuum, the title compound (3.4 g) was obtained.

A small sample was recrystallised from tetrahydrofuran / ethanol = numAv (KBr disc) s 698, 733, 1259, 1528, 1647, 1705, 1785, 3333 and 3295 cm -1; (3H, s), 3.34 and 3.52 (2H), ABq, J = 19Hz (CDCl3): 1.73 (3H, d, ), 3.61 and 3.69 (2H, ABq, J = 6Hz), 4.84 and 5.11 (2H, ABq, J = 14Hz), 4.95 (1H, d, , 6.92 (1H, d, J = 9Hz), 6.75-6.85 (1H, m), 6.92 (1H, s) 20-7.5® Π.5Η, m) (IKc) C 6 H, 7 R) -H-amino-6- The product of Example 1 (b) C3.3 which was dissolved in dichlorophenethan (4 ml) was dissolved in dichloromethane (50 ml). Was cooled to -20 ° C and stirred at that temperature with nitrogen. N-methylmorpholine (34 ml) and a solution of pentachloro-phosphorous (1.5 g) in dichloromethane (34 ml). The internal temperature rose from -25Â ° C to -12Â ° C and then rechecked rapidly to -2Â ° C. The mixture was stirred for half an hour. Methanol C12 mg) and after another half hour, water &lt; 50 ml). During this time, the temperature was allowed to rise to near ambient temperature. The ethyl acetate (5 ml) was added to dichloromethane and the major part of the ethyl acetate was evaporated under reduced pressure. Aqueous hydrochloric acid (2 ml) and ether (5 ml), the aqueous ether was decanted from the heavy oil, extracted with water, tetrahydrofuran and toluene and titrated to pH 65 by addition of a diluted solution of sodium hydroxide. The solvent fraction was dried over anhydrous sodium sulfate, filtered, and evaporated to volume, reduced, and subjected to silica gel column chromatography using ethyl acetate / hexane as a white solid. The fractions containing the desired product (CCCF) were combined and evaporated to an oil which was dissolved in ether (5 ml) and kept under refrigeration at -10 DEG C. until crystallized overnight. This period was collected by filtration, washed with a small portion of ether and dried under vacuum to give the title compound (7.2 g) as a white solid (0.8 g). 122Â °, 1252, 1371, 1630, 1647, 1712, 1779, 1795, 2918, 3345, 3397, CaT1. (FAB, MWa &quot;) 5α-

1 H-NMR (CDCl3): Î'13.7 (3H, d, J = 7Hz) overlap at Î "SS (3H, s), 3.44Â ° s 3.57 (2H, ABq, J = 1.9Hz), 4.78 , J = 5Hz), 4.84 and 5.10 (2H, ABq, J = 14Hz), 4.95 (1H, d, J = 5Hz) 6.95 (1H, s), 7.75-7.75 (about 1 H, m, includes interchangeable proton), and (S) 7B). (Z) -diphenylphiethoxymethoxy-imidazo [3,4-a] pyrimidin-4-yl] -2- (2-methoxyphenyl) 2-trifluoromethylaminothiazol-4-yl) acetate (75 g) in N-N-dimethylformamide was added a solution of 2-amino-2- Cl® ιη 1 &gt; cooled to -37 ° C and stirred under a hydrogen atmosphere was added methanesulfonyl chloride (8.0 g, 8 ml). The mixture was stirred for 0.5 h at -35 DEG-45 DEG C. product of the

Example SCc) (θ, 5 g) and pyridine (85 mg) were added and the resulting mixture was allowed to warm to room temperature for 45 minutes. Toluene (1 ml), tetrahydrofuran (5 ml) The solvent mixture was washed successively with aqueous hydrochloric acid (ca. 5%) with a solution of sodium hydrogen carbonate and ethyl acetate (5 ml) and water (25 ml). with brine and dried over anhydrous sodium sulfate. The solution was filtered and evaporated until its volume was reduced. Chromatography was performed on silica gel column only, using ethyl acetate / hexane 2% as eluent. After evaporation of the solvents, the title compound was isolated as a foam, 89 g of the title compound (KBr): νmax, Î »53, 1206, 144/54, 169, 3 179 °, 3357 s 3378 Cf./F (z, MNa +) s 1154. 1.8 ABq,

(CDCl3): 1.79 (3H, d, J = 7Hz), &lt; 3H, s), 3.22 and 3.48 &lt; 2H, ABq, J = 19Hz), 4,86 and 5,16 &lt; 2H, J = 14 Hz), 5.05 (5H, d5 J-5 Hz), 6.11 Π.Η, dd, ν5 s 9 Hz, 5 Hz with D-D), 6.42 (1H, s), 6.75 &lt; 1H, s, exchange with Z-), 6.75-6.90 (1H, m), 6.96 (1H, s) and 7.7-7.6 (35H, m). (6R, 7R) -7- [2- (2-aminothiazol-4-yl) amino] imino] acetic acid. The product from Example 11 (d) was dissolved in dry dichloromethane at 9 DEG C. The product of Example 11 (d) was dissolved in dichloromethane (7 ml) was added aqueous hydrochloric acid (0.7 ml) and the mixture was stirred for half an hour. Concentrated hydrochloric acid (1 ml) was added, and the resulting mixture was stirred for one hour. The precipitate which formed was then removed by filtration and washed with a small amount of formic acid at 90%. The filtrate was mixed with the cake, almost evaporated to dryness, and further evaporated after addition of toluene and tetrahydrofuran, the residue was triturated with ether and collected by filtration. The ether-wetted product was added to water and titrated to pH 3.5 by the addition of dilute aqueous sodium hydroxide solution free of the title compound was collected by filtration, washed with water and suspended sm water, fractionated with a small amount of toluene is titrated to pH 6.5 by addition of a dilute aqueous sodium hydroxide solution. The mixture was filtered through a silica filter, aqueous sodium hydroxide solution was diluted with i-propanol and evaporated to dryness under reduced pressure. The residue was triturated with ether to evaporate to dryness after addition of tetrahydrofuran. filtered, washed with ether and dried under vacuum to give the title compound sodium salt (175 mg) = nu, s (KBr disc): 735 * 1264, 1395 * 1528, 1675, m. - 1764 and 3324 cm-3 (Nujol) s 15375 1613, 1767 and 3295 cm-1 A. m / z (BAR? MhTib 5®4 * (DA-DHSO) at 1.76 (6H, 5>), 3.23 and 2.49 (2H, ABq, J = 7 Hz), 4.8 # and 5.55 (2H, ABq, u = 12 Hs &gt; (1H, d, J = 8Hz), 1.61 (1H, d, J = 8Hz) (6R, 7R) -C2 -heterocyclic &lt; 2-aminothiazol-4-yl-2- (7) -hydroxy-9- (2-hydroxy-2-enoyl) amino] -3- [ (B) (R, 5) -? - acetic acid

Ag product of Example 1) &lt;#, 97 g &gt; was added 1 ml of a 1.0M aqueous hydrochloric acid solution in 98-1% (1 ml) thermal acid in the resulting solution (1M hydrochloric acid, 9 ml). After 3 minutes, concentrated aqueous hydrochloric acid (1 ml). After a further hour and half hour at room temperature, the insoluble fraction was removed by filtration and washed with a small amount of 9% formic acid. The filtrate was evaporated to dryness in vacuo and methanol dissolved in formic acid (4 ml) was added hydrochloric acid (&lt;# 15 ml), and the mixture was kept under stirring for 1 hour.

filtration and washed with a small amount of 90% thermal acid and the filtrate was evaporated to dryness in vacuo. The residue was triturated with ether, filtered off, washed with ether and dried to give the title compound as a white solid. of a colorless solid C,, 25 æg. (KBr) δ 734, 1073, 1259, 1380, 1527, 1429, 16775, 1788, 1785 and 315 (very broad) on &quot; 1. m / z &lt; RTI ID = 0.0 &gt; R, to &quot;) s 568. δΗ (DA-DSSS0) g 1 = 46 (3H, d, 5 Hz), 1.79 (3H, s), 2.03 and 2.06 (3H, 2s), 3.60 and 3.73 (2H, ABq, d = 18 Hz), 4.76-4 , 78 and 4.96 &lt; 2H, ABq with a duplicate peak pair, J = 13 Hz &gt;, 5.23 and 5.24 (1H, 2d, O = 5.5 Hz), 5.80-5 = (1H, m), 6.81 (1H, d, J = 9 Hz), 6.81 (6H, m) ) and 12.20 (1H, br s). * * &lt; and &gt; The compound of formula (I) is prepared by reacting the compound of formula (I) with the compound of formula (I): ## STR1 ## in which R 1 is as defined in formula (I). 1 act of CRBJ.-1-acetoxyethylene Intermediate 2h ... §CMc

The product of Example 1 (a) (3 g) was dissolved in 98-1% aqueous (5 ml) and treated with aqueous hydrochloric acid in &lt; 5 ml &gt; After 2 hours CCCF after 1.5 hours, the compound was evaporated to no more than 1/4 of the initial volume, and talcum and tetrahydrofuran were added thereto. The mixture was then evaporated to dryness (the residue consisting of an oil being a suspended solid). This residue was treated with ethyl acetate, toluene, tetrahydrofuran and saturated sodium hydrogen carbonate in order to obtain pH 8 = The fraction in

The solvent was discarded in the aqueous fractions and dichloromethane (2 ml), chloroform (1 ml), tetrabutylammonium iodide (Θ, 75 g), α-bromomethyl acetate (2 ml) and solid calcium carbonate (5 g). The mixture was stirred vigorously for 2 hours and then a further portion (1 ml) of i-bromoethyl acetate was added and the reaction was continued The insoluble fraction was removed by filtration, washed with water, chloroform and a large amount of ethyl acetate, the filtrate was partially evaporated to remove the solvents. clarified solvents. Toluene, tetrahydrofuran and ethyl acetate were added and the resulting mixture was partitioned. The solvent was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated, giving rise to a gum, that gum being subjected to column chromatography (ethyl acetate) / hexane as eluent. The title product was obtained as a foam (0.9 g) after combining and evaporating the fractions which were crystallized from silica gel using ethyl acetate / hexane. (CDCl3) δ (CDCl3) δ (CDCl3): δ (CDCl3) δ (CDCl3): Î'(CDClâ,ƒ) (3H, s), 3.83 (3H, s), 2.82 (3H, s) , 3.61 and 3.69 (2H, ABq, J = 17Hz), 4.8Â ± 5.2.2 (3H, m), 5.80 (1H, m), 6.80-6.95 (1H, m), 6.99 and 7.09 (1H, 2 x q, J = 5.5 Hz) and 7.20-7.40 (5H, m). (4-methoxyphenyl) -6-methoxy-4-methoxy-4-methyl-4-methyl-4H-indol-

To a solution of the product of Example 1 (g) (Θ, 9 g) was added n-aqueous dichloromethane (1 g) in dichloromethane. mg) cooled to a temperature below -20 ° C & stirred at that temperature under a nitrogen atmosphere 5 M-methylmorpholine (42 ml) was added to a solution of phosphorus palladium fluoride (â¼46 g) in dichlorosethane. The solution was stirred at a temperature below -2Â ° C. (5 ml) After half an hour, at which time the temperature rose to -8 ° C, water (25 ml) was added and stirred vigorously for half an hour = Ethyl acetate was added and the dichloromethane evaporated under reduced pressure. Ethyl acetate (50 ml) and saturated ammonium chloride (1.0 ml) were added and the mixture was neutralized at 120Â ° C with solid potassium hydrogencarbonate to give pH 5.5. The fractions were separated , the solvent fraction was washed with saturated brine and dried over anhydrous sodium sulfate, the filtrate was evaporated to a reduced volume. Tetrahydrofuran (ca. 2 ml) was added and evaporated to give a residue of 2-3 ml which was used in the next step (see below). TLC showed the absence of starting compound in the presence of a new, more polar zana. To a solution of 2- (Z) -trienylmethoxyimino-2- ( (Ι, Θ 4 g), n-aqueous dimethylformamide (5 ml), cooled to -4Â ° C and stirred at that temperature under an atmosphere of (Θ, 37 g). After half an hour at this temperature was added pyridine (12 mg) and the solution of tetrahydrofuran was prepared in the manner described above. The reaction mixture was allowed to warm to room temperature until almost room temperature. Toluene, tetrahydrofuran and water were added and stirred, the resulting mixture. The solvent fraction was washed with dilute hydrochloric acid (about β.5%), diluted sodium hydrogencarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solution was evaporated to a volume of water. reduced and chromatographed on a silica gel column using 35% haftian acetate as eluent. The title compound was obtained as a foam from the appropriate fractions after evaporation of the solvents. ηυφέΐί (KBr disk) s 70®, 1072, 1251, 1523, 169®, 17®7 ;; 1 H-NMR (CDCl 3): δ 1.65-1.60 (3H, m), 1.81 (3H, d, J = 9 Hz) , 1.433 (3H, s), 2.86 and 2.69 <3H, 2 xs), 3.22 and 3.48 (2H, ABq, J = 19 Hz), 4.89, 4.93 and 5.22 (2H, ABq a pair of duplicate peaks, J = 14 Hz), 5.04 and 5.05 (1 H, 2 x d, J = 4.5 Hz), 6.0-6.15 (1H, m) 1H), 6.72 (s, 1H, s, exchange with D0), 6.80-6.95 (m, 1H), 7.03 and 7.13 (d, 5.5 Hz) and 7.2~-7540 (3x, m). 2-Amino-4-2- (Z) -methoxyiminoacetyl) methyl] aminobutyl] amino] -1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Z) -2- (2-methylbut-2-yl) phenyl) ethyl] -7- [2- (2-triisophenylaminoethyl) thiazol-4-yl] &lt; RTI ID = 0.0 &gt; 2- (Z) -methoxy-iso-ηα-2 '- &lt; / RTI &gt; trifentanyl 4-yl) acetic acid (Θ.47 g) in N-dimethylformamide (9 ml) cooled to -3 DEG C. under a nitrogen atmosphere is stirred at that temperature. added N-silyldiisopropylamine (0.5 ml) and methanesulfonyl chloride &lt; B &gt; &gt; After half an hour at -35 ° C the amine product from Epsilon (8.8 g) ) and pyridine (8æmol) were added, and the temperature gradually allowed to rise for one hour to reach room temperature. Toluene (1 ml), tetrahydrofuran (5 ml), ethyl acetate (5 ml) and water (25 ml) were added, the resulting mixture was stirred, and the aqueous fraction was washed with toluene and the fractions in the solvent were combined successively washed with aqueous hydrochloric acid (ca. 055), dilute sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The fractions containing the desired product (w / w) were combined and evaporated under reduced pressure to give the title compound as a foam (+) as eluent. , g). (KBr), 7.07, 125.5, 1522, 1665, 1708, 1787, 2935, 3292 and 339Â ° cm-1. m / z (FAB, MNa)

(3H, d, J = 7Hz), 1.80 (3H, s), 3.46 and 3.57 &lt; 2H, ABq, J = 19Hz), 4.08 (3H (s), 4.89 and 5.13 (2H, ABq, u = 14 Hz), 5.05 (1H, d, J = 5Hz), 5.96 (1H, dd, J = 5 and 8Hz), 6.75 (1H, s), 6.80-6.90 (br, m), 6.95 (1H, s), 7.01 (1H, s) and 7.20-7.50 (25H, m) b) 7R) -7- [2- (2-Aza-thiazol-4-yl) -5- (Z) -methyl] imidazo [1,2-a]

My love sodium salt The product of Example 12Ca &gt; (,, 58 g) was dissolved in 98-10%% thermal &lt; 5 ml). The resulting solution was added 1M aqueous hydrochloric acid (Θ.5 ml), vigorously stirring to dissolve the precipitated gum was again collected. After half an hour, concentrated hydrochloric acid (0.1 ml) was added and the resulting mixture was stirred for 45 minutes. The insoluble fraction was removed by filtration and washed with a small amount of The filtrate was evaporated to dryness after the addition of toluene and tetrahydrofuran as co-solvents. The residue was again evaporated with the addition of tetrahydrofuran, triturated with ether, and the hydrochloride was removed by filtration, washed with ether was dried under vacuum to give 3 g. This product was suspended in water containing a small amount of toluene and titrated to pH 3.5 by the addition of a very dilute hydroxide solution The fraction undissolved was r filtered, washed with a small amount of water and with toluene, giving the free acid under a weakly colored solid <about 0.1 g; The suspension was again suspended in water and the suspension was titrated to pH 55 with very dilute aqueous sodium hydroxide. A small amount of the insoluble fraction was removed by filtration and the filtrate was evaporated to near dryness after addition of i-propanol as co-solvent. The residue was again evaporated after the addition of the tetrahydrofuran and then acetone, triturated with acetone / ether, filtered off, washed with ether and dried under vacuum to give the title product (175 mg) s 735, 1339, 1262, 1389, 1529, 1760, 1764, 2939 and 3295 cm-1 (m, 2H), 1.59 (s, , 3.24 (3H, s), 4.86 (5H, ABq, J = 12 Hz), 5.02 (2H, 1H), 5.59 (dd, J = 5 Hz, 8 Hz, d, J = 9 Hz, 1H), 5.60 (d, (s), exchange with (i) o): 9.55 (1H, d, J = 8 Hz); »

Ex. 6 ^ CH3 Geometric Mean of MICs ORGANISM N2 of FM 82 and p.tir.pe. 3 ......... Ex. 6 S.aureua Axaena 10 0.23 0.23 S.auraa Axa 10 0.3B 0.27 S.elevidermia Axaena 4 0.13 0.1S S.epidralgia Axa 9 0.04 0.13 S.aaprophyticua 5 0.11 0.25 H .influenzae Axaena 8 0.30 0.11 H. iniluenrae Axes 7 0.23 o.oa H.influemae IR 1 0.50 1.00 E.catarrhalia Axaena £ 0.09 0.13 S.catarrhaia Axrea 12 0.22 0.84 E. coli (Rl 5 '0.11 0.04 E. coli tR + 1 S 0.13 '0.07 E.coli tCt] 5 9.19 0.14 KPneiLnoniae CFZaena 4 0.07 0.11 KPneumonlae CFZrea 4 0.21 0.25 S.marceaeens CTXaena 3 16.00 1.00 S.narceaeena CTXrea 3> 32 32.00 E.cloacae CTXaena 2 8.00 0.50 E.cloacae CTXrea 1 &gt; 32 16.00 E.aerogenea 3 12.70 0.79 P.vulgaria 3 0.40 0.20 H.iaorganii 3 12.70 O ** o P.rettgeri 3 0.03 0.20 P.mirallia Axaena 3 0.10 0.03 P.mirabilia Axrea 5 0.11 0.06 C.recentii s o.7 «0.14 C.koaeri 4 o.oe and 0.04 P.druglnoaa 3> 32 ---- 1 &gt; 32

Claims (2)

A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. (I) R 'represents hydrogen,: methoxy or formamido R5 represents an acyl group of the formula (a)> (a) wherein W represents an optionally substituted iissolyl with an optionally substituted amino or amino group optionally protected in the form of a hydrogen atom or an organic residue T CO ^ R '- &quot; â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ- represents a carbonyl protecting group which may be easily removed; X represents S, SO, SD ', or CH', s R &quot; &quot; R3 is hydrogen or C1-4 alkyl; Wherein R 1 and R 2 are each independently hydrogen or C 1-6 alkyl; and R5 together represent an alkyne bond, and F '' represents hydrogen, alkyl of 1 to 6 carbocyclic or alkynyl of 2 to 4 carbon atoms characterized in that it is treated with a compound of the formulas &lt; ϊ11) or (v) 5 '· _ " _ s. in which R 2, H 'and X have the meanings given above, and wherein all reactant groups are optionally protected, in which in formula (1), the amino group is optionally substituted with a group which allows the occurrence of the acylation and wherein in the formula &quot; V &quot; is a radical, with the indicated meaning for the formula CIK or an acyl group which may be converted into 2, with a N-acylation derivative of an acid of formula (IV) in the case of formula (ϊΙΙ)? or the formula &lt; VI)? in the case of the formula Cv &gt; (VI) in which R 2 and R 3 have the meanings given for formula (I) and in which all the reactive groups are optionally protected if necessary or desired. one or more of the following steps g i &gt; conversion of the group into a group ii) removal of all the protest groups, iii) conversion of the group CO 2 R 3 to a group which is different from or a group of the group X in a different X group. v) converting the reaction product into a salt. 94 A process according to claim 1, characterized in that the compound of the formula (Cl) has the formula (CIA), R1 is H (IA) in which R &quot;, R &quot; 'are H and X are the above indicated meanings for &amp; formula (i) in claim 1, the COOH group represents CO 2 R 3, wherein CO 2, R 5 represents carboxy or a carboxylate anion; or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof. The process according to claim 1 or 2, wherein R 1 is hydrogen. The composition according to any one of claims 1 to 2, characterized in that the group R &quot; represents a rump of the formula &lt; ® &gt; in a Z-configuration. A process according to any one of the preceding claims, characterized in that the stereoisomer A? The method according to claim 5 or 6, characterized by A- being 2-aminothiazal-4-yl 7. A compound according to any one of the preceding claims, characterized in that A 1 is selected from hydrogen, triphenylmethyl, ethylpropylmethyl, cyclopropylmethyl, cyclopropylmethyl, cyclopropylmethyl and cyclopropylmethyl. cycloheptyl-3-cyclohexyl- phenylglycine carboxylic acid; carboxyrapyl " t-butoxycarbonylsilyl) and? m is n = 3 and X represents chlorine or fluorine BD according to any one of the preceding claims characterized in that X represents sulfur. The process according to any one of the preceding claims, characterized in that R is selected from 3-ethylhexyl-2-enoyl; 2-methylprop-2-enoyl] but-2-enoyl] hexeno-254-disynyl and 2-methylbut-2-enoyl. A process according to any one of the preceding claims, which is prepared by preparing a compound selected from &lt; RTI ID = 0.0 &gt; 7R-7- (2-aminothiazol-4-yl) -2- (N, N-methoxyiminoaccat- (3-methyl-but-2-enoxyloxymethyl) -4-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrolysable ester thereof ((RS) (2-Aminothioisol-4-yl) -β-CZ-hydroxy-iminoacetamido-3-methyl-but-2-snoxyoxymethyl) -cis-4-carboxylic acid or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester thereof, Cèè 7 7-R g-R g-R₂-R g-R₂-R g-R₂-R g- (EsE) -hsxa-2S4-thienyloxymethyl] -3-sm-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a hydroxysuccinimide ester thereof ((R, 7 R) -7- [2- [2- (4-aminothiazol-4-yl) -2- (2,1-hydroxyiminoacetamide- Or a pharmaceutically acceptable salt thereof or a hydrolysable salt thereof in vivo, (6R, 7R) -hexahydro-3-methyl- (2-aminoethylamino) -2 (Z) -hydroxyiminoacetamido) -3-methyl-but-2-ylamino] -3-methyl-4- carboxylic acid or a pharmaceutically acceptable salt thereof or an ester thereof which is hydrolysable in vivo, (R37R &gt; -2- (2-aminoindol-4-yl) -2- (Z) -hydroxy) iminoacetyl) -3- ( 2-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrolysable ester thereof in the presence of a pharmaceutically acceptable salt thereof. (Z) -2-methylbut-2 (6R, 7R) -7- [2- (2-aminoethyl) -4-yl) -2-hydroxy- 1-carboxylic acid or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. (6R, 7R) -7-L2 -C2 -aminothiazol-4-yl) -2- (2-methyl-1H-benzoimidazol-3-yl) -but-2-enoyl] (2-aminothiazol-4-yl) -2-CZ> -methoxyimino-benzoic acid> 3- (E3E) -hexahydro-4-disenoyl] pyrazole-4-carboxylic acid (6R, 7R) -7- [2- (2-aminothiazole-11- } -Hydroxyiminoacetamide 3-methyl-2-methylpyridin-2-ylamino) -3,3-dihydro-4-carboxylate 5 (R) 4-yl) -2 (Z) -hydroxyiminoacetamido] -3- (2-methylpropyl) -2-bromoimidazo [4,5-b] in 2-di-methyl-propanesiloxymethyl-4-carboxy lactone (2R) -7-L-2- (2-Aminoethyl) -1H-indol-2-yl) -hydroxy-3- (2-methyl- 2-naphthyloxyimino-1-cephem-4-carboxylate (CRsS) -1-acetyl] 6R " 7R) -7-C2- [2-amino-2-oxo-4-yl) -2- (1) -hydroxy-2-hydroxyacetamido] -3- (2-methylprop-2-ylmethyl) Dimethylpropanoyloxymethyl] -3-em-4-carboxylate (2R, 7R) -7-E2- (C2-Aminothiazol-4-yl) -2- (Z) -ethylamino] acetamido] -3-3- (β-ethylpropyl) -2- (2-aminothiazol-4-yl) -2- (7-hydroxyiminoacetamido) -3-C (Z) -S- (6 R, 7 R) -7-C2- (2-Aminothiol-4-yl) -2- (2-Aminoethyl) -2- (2-aminothiazol-4-yl) (2S) -7-iminoacetamide 33-C (Z) -2-methyl-butyl-S-enooyloxymethyl] -phenyl} -9- (CR5 S) -l-acetoxymethyl = 2-aminoethylsol-4-yl) -2- (Σ) -Methoxy-aminoacetamide 3-3- (Z) -2-methylbut-2-enoyl) dimethyl] -3- 4-carboxylate A process for the preparation of a pharmaceutical composition containing a weight percentage of at least 50% of a compound of the formula (Ia) according to claim 2, characterized in that a compound of the formula (Î ±) or a salt thereof or a hydroxyl ester thereof acceptable in vivo with a pharmaceutically acceptable carrier * # ΪΓ W 9S -% '' - ιΛ &quot; Λ A method for the use of a compound of the formula (la) according to claim 2 or a pharmaceutically acceptable salt or hydrolyzable ester thereof for the preparation of a medicament for the treatment of infections caused by bacteria of the method for the treatment of infections caused by bacteria in humans or animals characterized in that a therapeutically effective amount of an antibiotic compound of the formula (Ia) according to claim 1 or a salt or an in vivo hydrolysable ester thereof pharmaceutical acceptable to humans or animals = Lisbon * December 6, 1W0 Official Agent of Industrial Property RUA VtCTOR CORDON, 10-A 3. »1200 LISBOA