LT4193B - Cephalosporin antibiotics - Google Patents

Abstract

This invention is intended for new cephalosporin antibiotics, namely for new (7R)-7-(acylamine)-3-(arylthio)-3-cephem-4-carboxiacides and for their pharmacologically relevant salts, for pro-medicine and their use, and also for pharmaceutical compositions, which include these compounds. The new compounds are distinguished by an antibiotic effect against a wide spectre of organisms, including organisms resistant to beta-lactamine antibiotics. Production methods of these compounds are described.

Description

This application is in part a continuation of U.S. Application Ser. No. 08/369798, filed May 1995 January 6, which is in part a continuation of U.S. Application Ser. No. 08/222262, filed April 1994 April 1; complete both of these applications are appended to this application as references, including all drawings.

The present invention relates to cephalosporin antibiotics. More particularly, the present invention includes novel (7R) -7- (acylamino) -3- (arylthio) -3-cephem-4-carboxylic acids and their pharmacologically acceptable salts, and their prodrugs, processes for their preparation and use. These compounds exhibit antibiotic activity against a wide range of organisms, including organisms that are resistant to β-lactam antibiotics.

Numerous antibiotics for clinical use have emerged in the last three decades. One class of antibiotics that has grown tremendously is cephalosporins (see below). Since 1965 more than 70 such antibiotics have been used in the clinical treatment of bacterial infections in mammals. Cephalosporimi's biological activity is determined by their inhibition of bacterial peptidoglycan biosynthesis, and these compounds are particularly effective in treating a variety of bacterial infections. Cephalosporins having antibacterial activity are described in U.S. Patent No. 3,992,377 and U.S. Patent No. 4,267,639.

H

Ns

-N

R ¹

CO, H (I)

Unfortunately, the widespread and disordered use of these antibiotics has led to a very rapid increase in the number of bacterial strains resistant to these compounds. More importantly, this resistance occurred among clinically relevant microorganisms and threatened to limit the use of the currently available cephalosporin antibiotics. Particularly resistant strains were Salmonella, S. pneitmoniae, Enterobacteriae, and Pseudomonas, which can reverse most of the gains made in reducing mortality and pathologies resulting from bacterial infections.

Bacterial resistance to cephalosporins occurs by three different pathways: (a) formation of β-lactamases that can inactivate the cephalosporin β-lactam ring; (b) reduction in bacterial uptake of cephalosporin due to changes in bacterial cell wall composition; and c) poor binding to penicillin binding proteins (PBPs). The latter pathway is of particular importance because the binding of β-lactams to the PDB is the most important factor that inhibits bacterial cell wall biosynthesis. Some gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus ("MRSA") and enterococci, are highly resistant to β-lactam antibiotics. MRSA resistance results from the presence of abnormal PBP (PBP2a), which is insensitive, or has poor binding to β-lactam antibiotics. The activity of β-lactam antibiotics against PBP2a-containing organisms was shown to correlate well with the ability of the antibiotic to bind to PBP2a. Currently, the glycopeptides vancomycin and teicoplanin are used to treat MRSA bacteremia. Quinolone antibacterial agents and some carbapenems, such as imipenem, have been reported to be active against several strains of MRSA, but their use is limited due to the emerging resistance of MRSA strains.

Experimental compounds that could be useful as anti-MRSA or anti-enterococcal bactericides include glycylcyclines (see, e.g., P.-E. Sum et al., J. Med. Chem., 37 (1994)), FK. -037 (see, e.g., H. Ohki et al., J. Antibiotics, 46, 359-361 (1993)), RP-59500 (see, e.g., SK Spangler et al., Antimicro. Agents Chemother., 36, 856-9 (1992)), evernomycin complex (see, e.g., WE Sanders et al., Antimicro. Agents Chemother., 6, 232-8 (1974)), 2- (biaryl) carbapenems (see, e.g. e.g., U.S. Patent No. 5,025,006), 3- (benzothiazolylthio) cephem (see, e.g., RJ Ternansky et al., J. Med. Chem., 36, 1971 (1993) and U.S. Patent No. 5077287), and arbecacin. (S. Kondo et al., J. Antibiotics, 46, 531 (1993)).

This invention includes compounds and compositions for treating mammalian infections caused by bacteria resistant to β-lactam antibiotics.

In one aspect, the present invention relates to a (7R) -7 (acylamino) -3 (arylthio) -3-cephem-4-carboxylic acid cephalosporin antibiotic having anti-β-lactam antibiotic activity against the body. Examples of such classes of compounds having this activity are described below and data demonstrating the in vitro and in vivo efficacy of such compounds are provided. Such compounds have a minimum inhibitory concentration (MIC) of less than 50%, preferably less than 10%, and preferably less than 1% of the MIC of cefotaxime for β-lactam-resistant organisms such as those listed in Table 1, with preference for β-lactam-resistant staphylococci or for enterococcal organisms. Other suitable compounds protect or reduce mortality in mice infected with β-lactam resistant organisms over vancomycin or cefotaxin.

One embodiment of the invention includes cephalosporin compounds having the structural formula II:

CO _? R ²

Π in which

R ¹ is -NHC (O) Z R ³ or -NR ⁴ R ⁵ where Z is -CH 2 (X) m -, -C (NOR ⁶ ) -, CH (OR ⁷ ) -, -C (CHCO ² R ⁸ ) - or -CH (NR ⁹ R ¹⁰ ) -, X is O or S, and m is 0 or 1;

S or R ¹ is -NHC (O) Z S

R is hydrogen, alkyl, alkenyl, aryl, heterocycle, aralkyl, heteroaralkyl or trialkylsilyl;

R ³ may be cyano, alkyl, aryl, heterocycle and heteroaralkyl;

R ⁴ ' ⁷ may be independently hydrogen, alkyl, aryl and acyl;

o

R may be selected from the group consisting of hydrogen, alkyl and aryl;

R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, alkyl, acyl and heterocyclylcarbonyl; n is 0 or 1; and

Y is selected from the group consisting of aryl and heterotricyclic; and their pharmaceutically acceptable salts and prodrugs.

However, when n is 0 and R ¹ is selected from the group consisting of phenylacetamide, phenylthioacetamide, phenyloxyacetamide, Da-aminophenylacetamide, thienylacetamide and D-mandeloylamide, Y is not phenyl substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxyl or halogen. , except 2-bromine and 2-iodine. In addition, when n is 1, Y is not phenyl, when R ³ is 4- (2-amino) thiazolyl, and Ring is -C (NOCH ₂ CO ₂ H) -.

Preferred compounds include those wherein R is phenyl, R 'is hydrogen, n is 0, and Y is 2-iodo- or 2-bromo-substituted phenyl. Another suitable embodiment is that wherein R ³ , R ² and n are as defined above and Y is dibenzfuranyl. Another suitable compound is that wherein Y is 2-biphenyl.

In other embodiments, the compounds described above have the following substituents on the phenyl group: ortho-cyano, thienyl (or substituted thienyl), hydroxymethyl, trifluoromethyl, methylthio, substituted furanyl, nitro, and formyl. In other preferred embodiments, the compounds described above have rings such as those disclosed in compounds 5457.

In yet another embodiment, the present invention includes compositions comprising an amount of a compound of Formula II that is effective in treating bacterial infections in mammals caused by bacteria resistant to β-lactam antibiotics.

Another embodiment of the present invention comprises the use of said compounds for the treatment of mammalian infections caused by bacteria resistant to β-lactam antibiotics, by administering to such mammal a therapeutically effective amount of a compound of formula II.

In another aspect, the present invention provides compounds of the formula:

in which

R ¹ is -NHC (O) Z R ³ or -NR ⁴ R ⁵ where Z is -CH ₂ (X) _m -, -C (NOR ⁶ ) -,

-CH (OR ⁷ ) -, -C (CHCO ₂ R ⁸ ) - or -CH (NR ⁹ R ¹⁰ ) -, X is O or S and m is 0 or 1;

s or R ¹ is -NHC (O)

R ² is hydrogen, alkyl, alkenyl, aryl, heterocycle, aralkyl, heteroaralkyl or trialkylsilyl;

R ³ may be cyano, alkyl, aryl, heterocycle and heteroaralkyl;

R ⁴ ' ⁷ may be independently hydrogen, alkyl, aryl and acyl;

R ⁸ may be selected from the group consisting of hydrogen, alkyl and aryl;

R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, alkyl, acyl and heterocyclylcarbonyl;

R ¹¹ is H or halo;

R ¹² is W NR ¹⁵ r '_; wherein W = S, NH or CH ₂ , and R ¹³ -R ¹⁶ are H, alkyl, cycloalkyl, acyl, hydroxyl, amino, amidino or phosphoryl, and may be taken together to form a 5- or 6-membered ring;

or R ¹² is SR ¹⁷ , wherein R ¹⁷ is alkyl, cycloalkyl, or a 5- or 6-membered heterocyclic ring having 0-4 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms, which may be substituted such as alkyl, hydroxyl, alkoxyl, amino, hydroxymethyl, aminomethyl or mono- or dialkylaminomethyl;

and p is 0, 1 or 2;

and their pharmacologically acceptable salts and prodrugs.

Suitable compounds are those wherein R ¹¹ is hydrogen, R ¹² is n ⁺ r ¹³ r ¹⁴ u

<> W NR ¹⁵ R \ y = s, NH or CH ₂ , p is 0, 1 or 2, and R ¹³ -R ¹⁶ are H or lower alkyl. Particularly suitable compounds are those wherein R ¹¹ is hydrogen, R ¹² is n ⁺ r ¹³ r ¹⁴

W NR ¹⁵ R, w = S or NH, p is 1 and R ¹³ -R ¹⁶ are hydrogen.

In yet another embodiment, the present invention provides compositions comprising an effective amount of a compound of Formula III for treating bacterial infections in mammals caused by bacteria resistant to β-lactam antibiotics.

Another embodiment of the present invention is the use of such compounds for the treatment of bacterial infections in mammals caused by bacteria resistant to β-lactam antibiotics, by administering to a mammal suffering from such an infection a therapeutically effective amount of a compound of formula III.

In yet another aspect, the present invention includes compounds of the formulas:

AB co ₂ r ²

IV

V i

R ¹⁸

in which

R ¹ is -NHC (O) Z R ³ or -NR ⁴ R ⁵ , -CH (OR ⁷ ) -, -C (CHCO ₂ R ⁸ ) - or -CH (NR ⁹ R ¹⁰ ) -, wherein Z is -CH ₂ (X) _m -, -C (NOR ⁶ ) X is O or S, and m is 0 or 1;

or R ¹ is -NHC (O) / S.

R is hydrogen, alkyl, alkenyl, aryl, heterocycle, aralkyl, heteroaralkyl or trialkylsilyl;

R ³ may be cyano, alkyl, aryl, heterocycle and heteroaralkyl;

R ⁴ ' ⁷ may be independently hydrogen, alkyl, aryl and acyl; R ⁸ may be selected from the group consisting of hydrogen, alkyl and aryl;

R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, alkyl, acyl and heterocyclylcarbonyl;

R ¹⁸ is phenyl optionally substituted, heteroaryl, or cyano;

V = C or N;

AC is CR ¹⁹ , N or S, wherein R ¹⁹ is hydrogen, alkyl, hydroxyl, amino, cyano, hydroxymethyl or mono- or dialkylaminomethyl;

DG is CR ¹⁹ or N, wherein R ¹⁹ is hydrogen, alkyl, hydroxy, amino, cyano, hydroxymethyl or mono- or dialkylaminomethyl, and their pharmacologically acceptable salts and prodrugs.

Specific comparisons of groups A-C and D-G are limited to examples of heterocyclic groups known in the art. Specific examples of such heterocyclic groups include:

Preferred compounds include those compounds wherein the AC, V and DG groups are pyrazole, thiadiazole and pyridine and R ¹⁸ is phenyl which may be substituted, pyridyl, pyrazolyl or cyano.

In yet another embodiment, the present invention provides compositions comprising an effective amount of a compound of Formula IV for treating bacterial infections in mammals caused by bacteria resistant to β-lactam antibiotics.

Another embodiment of the invention is the use of such compounds for the treatment of bacterial infections in mammals caused by bacteria resistant to β-lactam antibiotics by administering to a mammal suffering from such an infection a therapeutically effective amount of a compound of formula IV.

Other features and advantages of the invention will be apparent from the following description of the preferred embodiments and from the definition.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

I. Definitions

As used herein, the term "alkyl" means a branched or unbranched hydrocarbon chain having from one to six, preferably one to four, carbon atoms such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, secondary butyl, isobutyl, tert-butyl, and 2-methylpentyl. These groups may be substituted with one or more functional groups which are usually attached to such chains, e.g., hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, cyano, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, alkoxycarbonyl. , alkyl, alkenyl, nitro, amino, alkoxy, amido and optionally substituted isothiourea, amidine, guanidine, and the like, to form alkyl groups such as trifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, 4-cyanobutyl, 2-guanidinoethyl, 3-N, N'-dimethylisothiouronium propyl and the like.

The term "alkenyl" means an alkyl group as defined above containing at least one double bond, such as allyl, 3-hydroxy-2-buten-1-yl, 1-methyl-2-propen-1-yl and the like.

The term "aryl" means a chain of carbon atoms having at least one aromatic ring, preferably having from about 6 to about 14 carbon atoms, such as, for example, phenyl, naphthyl, indenyl, etc., and which may be substituted with one or more functional groups usually attached to such chains, such as, for example, hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, cyano, cyanamido, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido and the like to form aryl groups such as biphenyl, iodobiphenyl, methoxybiphenyl, anthryl, bromophenyl, iodophenyl, chlorophenyl, hydroxyphenyl, methoxyphenyl, formylphenyl, acetylphenyl, acetylphenyl, acetylphenyl, acetylphenyl, acetylphenyl, acetylphenyl thiazolylphenyl, oxazolylphenyl, imidazolylphenyl, imidazolylmethylphenyl las, cyanophenyl, pyridylphenyl, pyrrolylphenyl, pyrazolylphenyl, triazolylphenyl, tetrazolylphenyl and the like.

The term "heterocycle" refers to a chain of carbon atoms and at least one non-carbon atom which together form one or more aromatic or non-aromatic rings, preferably having about 6 to 14 atoms such as, for example, furyl, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzfuranyl, dibenzthienyl. Rings such as substituents may have one or more functional groups normally attached to such rings, such as, for example, hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, cyano, cyanamido, alkylthio, heterocycle, aryl. , heteroaryl, carboxyl, oxo, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido and the like, to form rings such as 2-aminothiazol-4-yl, 2,3-dioxopiperazinyl, 4-alkylpiperazinyl, 2- iodine-3-dibenzylfuranyl and 3-hydroxy-4-dibenzthienyl and the like.

The term "heteroaromatic" or "heteroaryl" (HetAr) means an aromatic heterocycle as defined above.

The term "heterotricyclic" refers to an aromatic heterocyclic substituent as defined above, which has three aromatic rings.

The term "heterocyclylcarbonyl" means a -C (O) Het group wherein Het is a heterocycle as defined above.

The term "alkoxyl" means an -OR group wherein R is as defined above, e.g., methoxy, ethoxy, η-propoxy, iso-propoxy, η-butoxy, sec-butoxy, isobutoxy- tert-butoxy, trifluoromethoxy-3-hydroxyhexyloxy-2-carboxypropyloxy,

2-fluoroethoxy, carboxymethoxy, cyanobutyloxy and the like.

The term "alkylthio" refers to -SR wherein R is alkyl as defined above such as methoxy, ethylthio, η-propylthio, iso-propylthio, η-butylthio, sec-butylthio, isobutylthio, tert-butylthio, trifluoromethylthio, 3-hydroxyhexylthio, 2-carboxypropylthio, 2-fluoroethylthio, carboxymethylthio, cyanobutylthio, and the like.

The term "acyl" means -C (O) R where R is alkyl as defined above, for example formyl, acetyl, propionyl or butyryl.

The term "aryloxy" means -OAr groups wherein Ar is an aryl group as defined above.

The term "aralkyl" means -RAr, wherein R is alkyl as defined above and Ar is aryl as defined above.

The term "heteroaralkyl" refers to -RHetAr where R is alkyl and HetAr is heteroaryl as defined above.

The term "trialkylsilyl" refers to the group RR'R "Si where R, R 'and R" are alkyl as defined above.

The term "trialkylammonium" refers to [RR'R "N-] ⁺ , wherein R, R 'and R" are alkyl as defined above.

The term "amino" refers to a group NRR 'wherein R and R' may independently be alkyl, aryl or acyl, or hydrogen as defined above.

The term "amido" means a -C (O) NR'R "group in which R and R 'independently of one another may be alkyl, aryl or acyl or hydrogen as defined above.

The term "cyanamide" refers to the group -NH-C ^ N.

The term “β-lactam resistant bacterium” refers to a bacterium against which the minimum inhibitory concentration (MIC) of β-lactam antibiotics is greater than 32 mg / ml.

The term "prodrug" refers to an agent that is converted into a parent drug in vivo.

In some cases, the use of a prodrug may be easier than the parent drug. For example, the prodrug may be bioavailable by the oral route and the parent drug is bioavailable, or the prodrug may improve solubility and be suitable for intravenous administration.

II. Compounds of the Invention

The present invention provides compounds, methods, and compositions that are effective in treating bacterial infections, particularly infections caused by bacteria that have become resistant to conventional β-lactam antibiotics. More importantly, the present invention provides compounds, methods and compositions that are effective in treating bacterial infections, particularly infections caused by bacteria that have become resistant to conventional cephalosporin antibiotics.

A. Preferred embodiments of the compounds of formula II

Preferred embodiments include those compounds wherein Y is aryl, more particularly phenyl, which may be substituted with acyl, alkyl, hydroxyl, halogen, carbonyl, thioalkyl, amido, alkoxyl, trialkylammonium, cyanoalkylamido, imidazolyl, thiazolyl, oxazolyl, imidazolyl, imidazolyl, oxazolylmethyl, imidazole, imidazoliomethyl, thienyl, thienylmethyl, furyl, furylmethyl, pyridine, cyano, pyridyl, pyrrolyl, pyrazolyl, triazolyl and tetrazolyl. More preferred substituents in the phenyl group are those wherein n is 0 and the substituent is in the 2 position of the phenyl ring with respect to the attachment of the sulfur atom linking the Y group to the cephem ring.

Another preferred substituent Y is when Y is phenyl substituted phenyl and biphenyl is formed. Even more preferred is biphenyl which may be substituted such as acyl, alkyl, hydroxyl, halogen, trialkylammonium, imidazolyl, thiazolyl, oxazolyl, imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, imidazole, imidazoliomethyl, thienyl, thienyl, thienyl, thienyl, Preferred substituents are halogens, especially bromine, chlorine and iodine. Preferably the substituents are in the 2 position of the biphenyl ring with respect to the attachment of the biphenyl group to the cephalosporin residue. Particularly suitable substituted biphenyls are 2-iodo-4-biphenyl, 2-bromo-4-biphenyl and 2-chloro-4-biphenyl. Also preferred are 4-substituted 2-biphenyls, such as 4-iodo-2-biphenyl, 4-bromo-2-biphenyl and 4-chloro-2-biphenyl.

Yet another suitable substituent Y is when Y is heteroaryl, especially dibenzfuranyl or dibenzthienyl, which may be substituted such as acyl, alkyl, hydroxyl, halogen, trialkylammonium, imidazolyl, thiazolyl, oxazolyl, imidazolylmethyl, thiazolylmethyl, imidazolylmethyl, imidazolylmethyl, , thienyl, thienylmethyl, furyl, furylmethyl or pyridine. Particularly suitable are dibenzfuranyl and dibenzthienyl.

With respect to R ³ , particularly preferred embodiments are those wherein R ^J is cyano, alkyl, aryl, heterocycle or heteroaralkyl. Other suitable options are ¹² EN 4193 B, those wherein R ³ is hydroxyphenyl, preferably 4-hydroxyphenyl, heterocycle and heteroaralkyl. Preferred heterocyclic substituents are thienyl, furyl and thiazolyl, especially 2-thienyl, 2-furyl, and heterocycles which may be substituted such as 2-aminothiazol-4-yl.

Particularly suitable compounds containing a combination of the substituents described above are as follows:

(7R) -7 - [(Phenylacetyl) amino] -3- (4-biphenylmethylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Phenylacetyl) amino] -3- (m-iodophenylthio) - 3-cephem-4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino] -3- (p-chlorophenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino] - 3- (o-Bromophenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Phenylacetyl) amino] -3- (p-bromophenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino] -3- (o-iodophenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino] -3- (dibenzofuranyl-3-thio) -3-cephem -4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino] -3- (4-biphenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino] -3- ( 2-Biphenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Phenylacetyl) amino] -3- (3-biphenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [( phenylacetyl) amino] -3- (2-bromo-4-biphenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino] -3- (2-fluoro-4-biphenylthio) - 3-Cephem-4-carboxylic acid, (7R) -7 - [(Phenylacetyl) amino] -3- (4-bromo-2-biphenylthio) -3-cephem-4-carboxylic acid tis, (7R) -7 - [(Phenylacetyl) amino] -3- (o-chlorophenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Phenylacetyl) amino] -3- (2,5-dichlorophenylthio) ) -3-cephem-4-carboxylic acid, (7R) -7 - [(cyanoacetyl) amino] -3- (o-iodophenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino ] -3- (3,4-Dichlorophenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Phenylacetyl) amino] -3- (o-carbomethoxyphenylthio) -3-cephem-4-carboxylic acid, ( 7R) -7 - [(2-Thienylacetyl) amino] -3- (o-bromophenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Phenylacetyl) amino] -3- (dibenzofuranyl-1-) thio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Z) - (2-aminothiazol-4-yl) -2- (syn-hydroxyimino) acetamide] -3- (o-iodophenylthio) - 3cephem-4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino] -3- (2- (4-cyanophenyl) phenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino] -3- (2,3-dichlorophenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(2-thienylacetyl) amino] -3- (o-iodophenylthio) -3-cephem-4- carboxyir £ Shtis.

(7R) -7 - [(2-Thienylacetyl) amino] -3- (2,5-dichlorophenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Phenylacetyl) amino] -3- (2 - (2-Furyl) phenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Phenylacetyl) amino] -3- (2,4-dichlorophenylthio) -3-cephem-4-carboxylic acid, (7R) ) -7 - [(p-methoxyphenylacetyl) amino] -3- (o-iodophenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(p-chlorophenoxyacetyl) amino] -3- (o-iodophenylthio) ) -3-cephem-4-carboxylic acid, (7R) -7 - [(p-chlorophenoxyacetyl) amino] -3- (2,5-dichlorophenylthio) -3-cephem-4-carboxylic acid, (7R) -7- [ (p-methoxyphenylacetyl) amino] -3- (2,5-dichlorophenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino] -3- (2-bromo-5-fluorophenylthio) -3-cephem-4-carboxylic acid.

With respect to Z, preferred embodiments include compounds wherein Z is methylene, substituted oximinomethylene (-C (NOR) -), substituted oxymethylene (-CH (OR) -), substituted (carboxymethylene) methylene (-C (CHCO ₂ R)). -) and aminomethylene (-CH (NRR ') -). Preferred Z = oxyiminomethylene, oxymethylene and (carboxymethylene) methylene substituents are hydrogen, alkyl, aryl and heterocycle. Such groups include, for example, hydrogen, 2-fluoroethyl, cyclopropylmethyl, cyclopentyl, allyl and dichloralyl. Preferred substituents Z = aminomethylene are alkyl, aryl, heterocycle and acyl.

In another embodiment, the present invention encompasses intermediates that are particularly useful in the preparation of the bactericides of the invention. In general, such intermediates include embodiments of the invention wherein R ¹ is -NRR ', wherein R and R' are hydrogen and acyl. Examples of such groups include t-butyloxycarbonyl and benzyloxycarbonyl.

Finally, R ² may be selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heterocycle, aralkyl, heteroaralkyl, alkoxy, or trialkylsilyl. In general, only compounds in which R ² is hydrogen are biologically active. However, the present invention also contemplates other R substituents that are readily hydrolyzed under biological conditions, that is, those groups which can be readily cleaved when administered to a mammal by ingestion or digestion (see, e.g., U.S. Patent No. 527686, Al. to Tsushina et al., which is given as a literature reference). The present invention also contemplates those R substituents which effectively protect the carboxy group from adverse reactions during the synthesis of the compounds of the present invention. Many such protecting groups are well known to those skilled in the art (see, for example, Green ans Wuts, Protective Groups in Organic Synthesis (Wiley 1991), which is incorporated herein by reference).

Examples of such groups include allyl, t-amyl, benzhydryl, t-butyl, t-butyldimethylsilyl, benzyl, 2-chloralyl, 3,3-dimethylallyl, 2,4-dimethoxybenzyl, 4,4'-dimethoxybenzyl, 4-methoxybenzyl. , 4-methoxytrityl, methoxymethyl, 4-nitrobenzyl,

2-nitrobenzyl, phenacyl, 2,2,2-trichloroethyl, trimethylsilyl, 2- (trimethylsilyl) ethyl and trityl, as well as their salts such as trifluoroacetate, hydrochloride, hydrobromide and sulfate.

B. Preferred embodiments of the compounds of formula III

In another aspect, the present invention provides compounds of the formula:

in which

R ¹ is -NHC (O) Z R ³ or -NR ⁴ R ⁵ where Z is -CH 2 (X) m -, -C (NOR ⁶ ) -, -CH (OR ⁷ ) -, -C (CHCO ² R ⁸ ). - or -CH (NR ⁹ R ¹⁰ ) -, X is O or S and m is 0 or 1;

or R ¹ is -NHC {Oy $;

R is hydrogen, alkyl, alkenyl, aryl, heterocycle, aralkyl, heteroaralkyl or trialkylsilyl;

R ³ may be cyano, alkyl, aryl, heterocycle and heteroaralkyl;

R ⁴ ' ⁷ may be independently hydrogen, alkyl, aryl and acyl;

D

R may be selected from the group consisting of hydrogen, alkyl and aryl;

R ⁹ and R 7 '' are independently selected from the group consisting of hydrogen, alkyl, acyl and heterocyclylcarbonyl; p = 1 or 2;

R ¹¹ is H or halo;

rRr ¹³ r ¹⁴

^{R 2} is NR ¹⁵ S V R 'wherein W = S, NH or CH _2, and R ^cr R ^l6 is H, alkyl, cycloalkyl, acyl, hydroxy, amino, amidino, or phosphoryl and taken together may form a 5- or a 6 membered ring;

or R ¹² is SR ¹⁷ , wherein R ¹⁷ is alkyl, cycloalkyl, or a 5- or 6-membered heterocyclic ring having 0-4 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms, which may be substituted such as alkyl, hydroxyl, alkoxyl, amino, hydroxymethyl, aminomethyl or mono- or dialkylaminomethyl;

and their pharmacologically acceptable salts and prodrugs.

Suitable compounds include those wherein R ¹ 'is hydrogen, R ¹² is NR ¹³ R ¹⁴

W is NR ¹ R ¹ , w = S, NH or CH ₂ , p is 0, 1 or 2, and R ¹³ -R ¹⁶ are H or lower alkyl. Particularly suitable are compounds wherein R ¹¹ is hydrogen, R ¹² is nr ^{13 and} R ¹⁴ <> W NR R _; w = S or NH, p is 1 and R ^{, J-} R ^11f are hydrogen.

Particularly suitable compounds having a combination of the above substituents are as follows:

Inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (2-isothiouronomethylphenylthio) -3-cephem-4-carboxylic acid;

(7R) -7 - [((4-Isothiouronomethylphenyl) acetyl) amino] -3- (2-isothiouronomethylphenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt;

Inner salt of (7R) -7 - [((4-hydroxyphenyl) acetyl) amino] -3- (2-isothiouronomethylphenylthio) -3-cephem-4-carboxylic acid;

(7R) -7 - [(Phenylacetyl) amino] -3- (2- (2-isothiouronio) ethylphenylthio) -3-cephem-4-carboxylic acid inner salt;

(7R) -7 - [((2-Aminomethylphenyl) acetyl) amino] -3- (2-isothiouronomethylphenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt;

Inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (2-tetramethylisothiouronomethylphenylthio) -3-cephem-4-carboxylic acid;

(7R) -7 - [(Phenylacetyl) amino] -3- (2-N, N'-diethylisothiouroniomethylphenylthio) -3-cephem-4-carboxylic acid inner salt;

Inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (2-N-methylisothiouriomethylphenylthio) -3-cephem-4-carboxylic acid;

(7R) -7 - [(Phenylacetyl) amino] -3- (2-N-cyclopropylisothiouronomethylphenylthio) -3-cephem-4-carboxylic acid inner salt;

Inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (3-isothiouronomethylphenylthio) -3-cephem-4-carboxylic acid;

(7R) -7 - [((2-Guanidinoethylthio) acetyl) amino] -3- (2-isothiouronomethylphenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt;

(7R) -7 - [(Z) -2- (Aminothiazol-4-yl) -2- (hydroxyimino) acetamide] -3- (2-isothiouronomethylphenylthio) -3-cephem-4-carboxylic acid inner salt;

Inner salt of (7R) -7 - [(Z) -2- (phenyl) -2- (hydroxyimino) acetamide] -3- (2-isothiouronomethylphenylthio) -3-cephem-4-carboxylic acid;

Internal salt of (7R) -7 - [(methylthioacetyl) amino] -3- (2-isothiouronomethylphenylthio) -3-cephem-4-carboxylic acid.

C. Preferred Embodiments of Compounds of Formulas IV and V In yet another aspect, the present invention includes compounds of formula:

CO, R ²

A-B, C

V

I

RIS

R ¹

1

CC> R ²

G

R ^1S

IV which

R ¹ is -NHC (O) Z R ³ or -NR ⁴ R ⁵ where Z is -CH ₂ (X) _m -, - C (NOR ⁶ ) -, -CH (OR ⁷ ) -, -C (-CH 2 - R ⁸ ) - or -CH (NR ^y R ¹ ) -, X is O or S, and m is 0 or 1;

or R ¹ is -NHC (O)>'S.

R ² is hydrogen, alkyl, alkenyl, aryl, heterocycle, aralkyl, heteroaralkyl or trialkylsilyl;

R ³ may be cyano, alkyl, aryl, heterocycle and heteroaralkyl;

R ⁴ ' ⁷ may be independently hydrogen, alkyl, aryl and acyl;

R ⁸ may be selected from the group consisting of hydrogen, alkyl and aryl;

R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, alkyl, acyl and heterocyclylcarbonyl;

R ¹⁸ is phenyl optionally substituted, heteroaryl, or cyano;

V = C or N;

AC is CR ¹⁹ , N or S, wherein R ¹⁹ is hydrogen, alkyl, hydroxyl, amino, cyano, hydroxymethyl or mono- or dialkylaminomethyl;

DG is CR ¹⁹ or N, wherein R ¹⁹ is hydrogen, alkyl, hydroxy, amino, cyano, hydroxymethyl or mono- or dialkylaminomethyl, and their pharmacologically acceptable salts and prodrugs.

The specific juxtaposition of groups A-C and D-G is limited to examples of heterothermal cyclic groups known in the art.

More preferred compounds are those wherein AC, V and DG are pyrazole, thiadiazole and pyridine and R ¹⁸ is phenyl optionally substituted, pyridyl, pyrazolyl or cyano.

Particularly suitable compounds having a combination of the above substituents are as follows:

(7R) -7 - [(Phenylacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(4-chlorophenylacetyl) amino] -3- (2-Phenylpyridin-3-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Phenylacetyl) amino] -3- (1N-phenyltetrazol-5-ylthio) -3-cephem-4-carboxylic acid , (7R) -7 - [(Phenylacetyl) amino] -3- (2-oxazol-5-ylphenylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Phenylacetyl) amino] -3- ( 1N-phenyl-1,2,3-triazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(cyanoacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) - 3-Cephem-4-carboxylic acid, (7R) -7 - [(Phenylacetyl) amino] -3- (2-amino-4-phenylthiazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(cyanoacetyl) amino] -3- (2-phenylpyridin-3-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino] -3- (4-phenyl-1), 2,3-Thiadiazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Z) -2- (Aminothiazol-4-yl) -2- (cyclopentyloxyimino) acetamide] -3- (1N-Phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Z) -2- (Aminothiazol-4-yl) -2- (fluoroethyloxyimino) acetamide] -3- ( N-sterile pyrazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (cyclopentyloxyimino) acetamide] -3- (2-phenylpyridin-3-ylthio) ) -3-cephem-4-carboxylic acid, (7R) -7 - [((2-aminomethylphenyl) acetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) ) -7 - [(Z) -2- (2-Amino-5-chlorothiazol-4-yl) -2- (2-fluoroethyloxyimino) acetamido] -3- (1-N-phenylpyrazol-5-ylthio) -3-cephem -4-Carboxylic acid, (7R) -7 - [(phenylacetyl) amino] -3- (2-cyanopyridin-3-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino] -3- (2- (pyrazol-1-yl) pyridin-3-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2 - (3-Pentyloxyimino) acetamide] -3- (1N-phenylpyrazole-5-thio) -3-cephem-4-carboxylic acid, (7R) -7 - [(phenyl) acetyl) amino] -3- (1N- (pyridine) 2-yl) pyrazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(methylthioacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4- carboxylic acid, (7R) -7 - [(cyclopropylacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Z) -2- (2-Amino) Thiazol-4-yl) -2- (cyclopropylmethyloxyimino) acetamide] -3- (1-N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Hexanoyl) amino] -3- (1N-Phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(4-Pyridylthioacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid , (7R) -7 - [(2-Furylacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Phenyloxyacetyl) amino] -3 - (1N-Phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(Phenylacetyl) amino] -3- (1N- (3-nitrophenyl) pyrazol-5-ylthio) -3 -cephem-4-carboxylic acid, (7R) -7 - [(phenylacetyl) amino] -3- (1N- (4-methoxyphenyl) pyrazol-5-ylthio) -3-cephem-4-carboxylic acid, (7R) -7 - [(2-Dithiolanylcarbonyl) amino] -3- (1N- (3-nitrophenyl) pyrazol-5-ylthio) -3-cephem-4-carboxylic acid.

D. Synthesis of Compounds of Formula II

The compounds of the present invention can be readily prepared according to the following schemes. However, it is to be understood that other routes of preparation of the compounds of the present invention are possible, and those described below are merely exemplary and do not limit the scope of the invention. In addition, it will continue to be accepted that a variety of commonly accepted group blocking and unblocking strategies can be used (see, for example, Green and Wuts). It is known to those skilled in the art that the choice of a particular protecting group (e.g., for carboxy blocking) depends on the stability of the blocked residue with respect to the reaction conditions that follow.

In general, the cephalosporins of the present invention may be synthesized using well known techniques and readily available materials (see, e.g., March; Larock, Comprehensive Organic Transformations (VCH Publishers, 1989); and GI Georg, The Organic Chemistry of β-Lactams, (VCH 1992) which are given as references). As shown in Scheme 1 below, cephem triflate 1 is treated with the desired thiolate nucleophile 'S (CH2) _n Y using standard procedures such as those described by Farina et al., J. Org. Chem., 54, 4962 (1989) and Baker et al. U.S. Pat. 4870168 (both of which are incorporated herein by reference), gives 3-thiodar 2. Deprotection according to techniques known to those skilled in the art yields the biologically active 4-carboxycephem 3.

the compound is readily prepared from commercial starting materials, e.g., by treatment with (7R) -7 - [(phenylacetyl) amino] -3-hydroxy-3-cephem-4-carboxylic acid (Otsuka Chemical Co., Ltd., Otsuka, Japan), triflate anhydride (Aldrich, Milv / aukee, WI) using known techniques (see, e.g., Farina; and Baker et al., U.S. Patent No. 4870168). Other 3-hydroxy-3-cephems may be obtained by ozonolysis of 3-ethoxymethylenephephem according to known procedures (see, e.g., Farina).

~ S (CH ₂ ) _n Y ₀ ^{Z /} OTf co ₂ r ²

o ^z > - ^N ^ s / (cą) _n Y co ₂ r ² v

₀ /> - Ν ^ Λ _S X ^CH 2) _n Y co ₂ h 3

Similarly, a thiolate nucleophile having the desired substituent Y and - (CHty) 1 - bridge may be prepared using known techniques and commercial starting materials. For example, if Y = substituted aromatic ring, on-0, the desired thiolate nucleophile can be obtained by well-known procedures by introducing nucleophilic or electrophilic substituents into a commercial thiol aromatic ring (e.g., thiophenol derived from Aldrich) or into aromatic thiols, obtained by known methodologies (see March). When n # 0, the β-lactam 3-thio-3-cephem derivative can be exposed to LG-CPtyY, where LG is a corresponding leaving group such as a halogen such as iodine (see, e.g., J. Antibiot. pp. 498-506 (May 1991, given as a source of literature).

The substituent R ¹ can be any of the groups described above, and is either commercially available (e.g., Aldrich, Milwaukee, WI) or may be obtained using known techniques and known materials (see, e.g., March; Larock ). Such groups may be introduced by replacing groups in the starting materials according to a number of known methodologies (see, e.g., Barrett, JCS Perkin I, 1629 (1979) or Chauvette, J. Org. Chem., 36, 1259 (1971), both of which are incorporated by reference). as in the literature) such as transaminating an existing substituent to the desired substituent or hydrolytic cleavage of the existing substituent and then acting on the appropriate reactive form of the desired substituent such as acyl chloride. Again, appropriate reagents and procedures are well known to those skilled in the art.

The carboxyl R groups may be protecting groups which are prone to reductive cleavage, such as benzyl, p- and o-nitrobenzyl, 2,2,2-trichloroethyl, allyl, cinnamyl, benzhydryl, 2-chloralyl and the like. Alternatively, R ² may be a protecting group prone to acid degradation such as t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, p- (trimethylsilyl) ) ethyl, benzyl, 4 (or 2) -methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, benhydryl or 3,3-dimethylalyl. Preferred protecting groups are p-methoxybenzyl, p-nitrobenzyl, allyl and benzhydryl. Such groups may be attached to the parent Cephalosporin starting material by an unblocked carboxy group using known reagents and known techniques, e.g. such as those described by Green and Wuts.

An alternative synthesis route for the desired cephem 3 is described below for treatment of the required amino-blocked cephem 4 (P - protecting group) with the deprotected intermediate 5 which is then treated with the appropriate acylation reagent (s) and deprotected to give the desired product 3. Also shown and another alternative route in which the carboxyl is first deprotected to form intermediate 6 followed by removal of the protecting group and coupling of the desired acyl

ąN, s - (cą) _n Y co ₂ r ²

PHN «ψ

zS.

R ¹

'/

-N

S / (CH ₂ ) _n Y co ₂ h co ₂ h

Suitable amino protecting groups include trityl, formyl, phenoxyacetyl, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, urethane type protecting groups (such as t-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-chloroalyl), trimethylsilyl) ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, (C4-C6) cycloalkanyloxycarbonyl or 9-fluorenylmethoxycarbonyl (FMOC)). Particularly suitable protecting groups are trityl, allyloxycarbonyl, benzyloxycarbonyl, phenoxyacetyl and t-butoxycarbonyl. These groups can be added and removed using standard procedures (see Green and Wuts). The choice of the amino protecting groups to be used depends on the stability of the blocked β-lactam under further reaction conditions.

In cases where Y is biphenyl or substituted biphenyl, the biphenyl moiety may be introduced by carbon-carbon copulation of 3- (halophenylthio) cephem (or 3- (trifluorosulfonyloxy) phenylthiophem) with the correspondingly substituted phenyltrialkylstanan in the presence of palladium catalyst, or triheterocyclylphosphine, such as tris (dibenzylideneacetone) dipaladium (0) -tris (2-furyl) phosphine, to give the desired substituted (biphenylthio) cephem 9 as shown below.

E. Synthesis of Compounds of Formula III

Compounds of general formula III are prepared in a similar manner to compounds of formula II. In most cases, the parent step is the coupling of the hydroxymethyl-substituted benzentiolate with cephem triflate 1. This provides the major intermediate which, upon conversion of the hydroxyl group to the corresponding leaving group, allows the desired R ¹² to be obtained by treatment with the appropriate nucleophile.

F. Synthesis of Compounds of Formulas IV and V

Compounds of general formulas IV and V are prepared in a similar manner to compounds of general formula II by combining heteroaromatic thiolate with cephem triflate 1. The required heteroaromatic thiols are prepared by a variety of methods known in the art as described in the Examples.

III. Pharmaceutical application and preparations

According to the present invention, a therapeutically or pharmaceutically effective amount of a cephalosporin, in particular a compound of formula II, is administered to a mammal suffering from an infection caused by bacteria resistant to β-lactam antibiotics, particularly 5. bacterial resistant bacteria; this amount must be effective, at least in part, in relieving the infection. Of particular interest are infections caused by strains resistant to β-lactams that have similarities to strains such as 5. aureus ATCC 29213, 5. aureus ATCC 25913, 5. aureus ATCC 31432, S. aureus col (Meth ^R ) (lac) '), 5. aureus 76 (Meth ^R ) (lac ⁺ ), S. aureus ColBA (Meth ^s ) (lac', strains of E. faecium ATCC 35667 or E. faecalis ATCC 29212, β-lactam resistant activity.

Compositions containing the compound (s) of the present invention may be for prophylaxis and / or treatment. For therapeutic use, the compositions are administered to a patient already suffering from an infection as described above; the amount administered should be sufficient to cure the infection or at least partially relieve the symptoms of the infection. The amount that can accomplish this is called a "therapeutically effective amount or dose." The amounts effective for such use will depend on the severity and course of the infection, previous treatment, the patient's health status and response to the medication, and the judgment of the attending therapist. For prophylactic use, the compositions comprising the compounds of the present invention are administered to a patient susceptible to or at risk of an infection. This amount is called the "prophylactically effective amount or dose". For these uses, the exact amounts also depend on the patient's state of health, weight, and similar factors.

If the patient's condition has already improved, a maintenance dose may be given. Thereafter, the dose or frequency of administration, or the dose and frequency depending on the symptoms, may be reduced to maintain an improvement. Once symptoms have been alleviated to the desired level, treatment may be discontinued. However, patients may require alternating long-term treatment if their symptoms return.

In general, an effective effective amount of a compound of the present invention is 0.1 to 1000 milligrams (mg) / day per recipient, preferably 1 to 100 mg / day. It is best to take the desired dose as one, two, three, four or more sub-doses at appropriate intervals throughout the day. Such sub-doses may be administered in unit dosage forms, for example containing 5 to 1000 mg, preferably 10 to 100 mg, of the active ingredient in unit dosage form. Preferably, the compounds of the present invention are administered in an amount of 2.0 mg / kg to 250 mg / kg of patient body weight 1-4 times daily.

Although the active ingredient of the present invention may be used alone, it is preferable to use it as part of a pharmaceutical composition. The compositions of the present invention comprise a therapeutically or pharmaceutically effective dose of at least one compound or inhibitor of the present invention together with one or more pharmaceutically or therapeutically acceptable carriers. Solid carriers include, for example, starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, as well as other therapeutic ingredients, if necessary. Liquid carriers may include, for example, sterile water, polyethylene glycols, nonionic surfactants, and edible oils, such as corn, peanut, and sesame oils. Additionally, various additives commonly used in the art may be included, such as: flavoring agents, coloring agents, preservatives and antioxidants such as vitamin E, ascorbic acid, BHT and BHA. Various other possibilities have been described, e.g., Gilman et al. (eds) (1990) Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press; and Remington’s supra. Methods of administration, such as oral, intravenous, intraperitoneal or intramuscular, etc. are also discussed herein. Pharmaceutically acceptable carriers may be water, saline, buffers and other compounds described, e.g., MERK INDEX, Merck & Co., Rahway, NJ. In general, the most suitable routes of administration are intravenous and intraperitoneal.

These pharmacological agents can take many forms. Such forms are, for example, solid, semi-solid and liquid dosage forms such as tablets, pills, powders, liquid solutions or suspensions, liposomes, solutions for injection and infusion. Preferred forms depend on the intended route of administration and therapeutic application. In general, it is preferable to use a pharmaceutically acceptable salt of the compound to facilitate the preparation of the composition. Preferred salts are sodium, potassium, arginine, glycine, alanine, threonine. It is best to make them in water mixed with a suitable surfactant such as hydroxypropylcellulose.

Depending on the condition to be treated, such agents may be formulated and administered systemically or locally. Formulation and administration methodologies can be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, PA (1990). Suitable routes of administration may include oral, rectal, transdermal, vaginal, transmucosal or gastric administration; parenteral route of administration, including intramuscular, subcutaneous, intramedullary, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injection, to name but a few.

The injectable agents of the present invention should be in the form of aqueous solutions, preferably in physiologically acceptable buffers such as Hanks's solution, Ringer's solution or saline. Formulations for transmucosal administration should use substances which penetrate the appropriate barrier. Such penetrating materials are generally known to those skilled in the art.

In the case of soft capsules, the active compound may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, a stabilizer can be added.

IV. Biological activity

In vitro antibacterial tests

The compounds of the present invention were tested for activity against several strains of β-lactam resistant bacteria by determining the minimum inhibitory concentration (MIC, Mg / ml) of each compound for each strain. The MIC (minimum concentration of antibiotic that inhibits the growth of the test organism) was determined by the agar dilution method.

To determine the MIC of bacterial isobates, test compounds are plated in double dilution series on Liquid Müller-Hinton agar. Once the agar has solidified, a number of bacterial strains are inoculated with dots on the agar surface using a replication device. Incubate overnight and determine the MIC breakpoint, i.e. the lowest concentration of drug that completely inhibits growth, whether in a single colony or in weak plaque. The methodology used in these studies was standardized by the National Committee for Clinical Laboratory Standards (NCCLS), which is named in the NCCLS publication Methods for Dilution Antimicrobal Susceptibility Tesis (1991).

Samples of antimicrobial agents were prepared in phosphate buffer (PBS), pH 7.2. Where appropriate, Tween 20 or DMSO was used as a solubility enhancer. Intensive mixing, ultrasound and gentle warming techniques were used to dissolve the test agent. Generally, the concentration of the stock solution was 10 times the maximum concentration of the test drug. A stock solution concentration of 1.28 mg / ml was used and the maximum working concentration was 128 mg / ml. A series of double dilutions of <0,25 Mg / ml is made. Each drug concentration is measured twice. Double dilutions are made in sterile 50 ml tubes and the final volume is 5 ml. Addition of 45 ml of molten agar gives a 10-fold dilution. Then place two 25 ml dishes in 15x150 mm square Petri dishes with partitions and allow to harden.

The control plate containing the reference drug (cefotaxime, vancomycin or imipenem) was used as a positive growth control. Stock solutions of standard antibiotics were prepared and frozen at -80 ° C. The prepared control plates are sealed and refrigerated for up to a week before use. but imipenem control plates were made just before use. All test plates were used within 24 hours of production.

Satisfactory results are obtained when the inoculum contains approximately 10 ⁴ colony forming units (cfu) ± 0.5 log. Starting the experiment with pure test cultures isolates on agar plates, several of the isolated colonies are transferred to a feeding broth tube and allowed to grow for 4-6 hours at 35-36 ° C until the log phase is reached. Broth culture drips into PBS until

Q * achieves a 0.5 McFarland turbidity standard of 10 cfu / ml. This solution is again diluted 10 times in PBS to give an inoculum working concentration of 10 ⁷ cfu / ml. If 1 μl of working inoculum is applied to the agar surface, about 10 ⁴ cfu per spot is obtained.

Dispensable sterile 1 μΐ loops are used for inoculation of test plates by placing each isobath in an appropriate cell on an agar plate. Another method of inoculation was the use of a replication patch (a device with 48 steel pins allowing inoculation of a large number of isobats at a time). After drying, the plates are incubated at 35-36 ° C for 16-20 hours. The minimum inhibitory concentration (MIC) of the antimicrobial agent is determined by evaluating the end points.

These results are shown in Table 1. It is noted that the novel agents of the present invention exhibit increased activity against 5. aureus Col and enterococci (E. faecium and E. faccalis). S. aureus Col strain is a producer of high levels of PBP2a, whereas 5. aureus Col 8A, its isogenic partner, does not contain PBP2a. Some compounds, such as 6 ((7R) -7 - [(phenylacetyl) amino] -3- (o-iodophenylthio) -3-cephem-4-carboxylic acid) and 9 ((7R) -7 [(phenylacetyl) amino) ] -3- (2-biphenylthio) -3-cephem-4-carboxylic acid) exhibits broad activity against both 5. aureus Col and S. aureus Col 8A and against enterococci. S. aureus Col 8A strain was highly sensitive to all agents tested, including control cefotaxime. Thus, the compounds of the present invention are effective against PBP2a producing bacteria. Compound 12, although not having activity against 5. aureus Col, shows potential activity against enterococci. Some other compounds of the present invention, such as 22 ((7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (hydroxyimino) acetamide] -3- (o-iodophenylthio) -3cefem- carboxylic acid) are effective against E. coli as well as against gram positive organisms.

Table I, Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 1 2 3 4 5 6th S. aureus ATCC 29213 2 0.03 0.03 0.03 0.125 0.03 <0.015 5. aureus ATCC 25923 <1 <0.015 <0.015 <0.015 <0.06 <0.015 <0.015 S.epidermidis ATCC 31432 2 <0.015 <0.015 <0.015 <0.06 <0.015 <0.015 S. aureus Col (Meht ^R ) (lac ') > 32 16th 2 2 1-2 2 1 S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 32 16th 16th 4 16th 1 5. aureus Col8A (Meth ^s ) (lac ') 2 0.03 0.03 0.015 <0.06 0.03 <0.015 S. haemolyticus (Meth ^R ) > 32 > 32 16th 16th 16th 16th 4 E. faecium ATCC 35667 > 32 8th 2 4 2 4 0.5 E. faecalis ATCC 29212 > 32 2 2 2 4 2 0.5 E. coli ATCC 25922 <1 > 32 > 32 > 32 > 32 > 32 > 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 :> 32> 32 > 32 X. maltophilia ATCC 13637 > 32 > 32 > 32 > 32 > 32> 32> 32

table (continued). Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 7th 8th 9-10 11th 12th S. aureus ATCC 29213 2 <0.06 <0.125 0.25 0.125 0.125 <0.06 S. aureus ATCC 25923 <1 <0.06 <0.125 0.125 <0.06 <0.015 <0.06 S.epidermidis ATCC 31432 2 <0.06 <0.015 0.125 <0.06 0.03 <0.06 5. aureus Col (Meht ^R ) (lac ') > 32 4 4 4 8 1 > 32 S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 16th > 32 8 32 4 > 32 S. aureus Col8A (Meth ^s ) (lac ') 2 0.06 <0.125 0.25 0.125 0.06 <0.06 S. haemolyticus {Meth ^R j > 32 - - 0.125 - 4-8 - E. faecium ATCC 35667 > 32 - - 2 4 ... E. faecalis ATCC 29212 > 32 1 4 4 2 2 4 E. coli ATCC 25922 <1 > 32 > 32 > 32> 32 > 32 > 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32> 32> 32 > 32 X. maltophilia ATCC 13637 > 32 > 32 > 32 > 32> 32> 32> 32

table (continued). Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 13 14 15 16 17 18

S. aureus ATCC 29213 2 0.06 0.25 0.06 0.5 0.25 <0.25 S. aureus ATCC 25923 <1 <0.015 0.06 0.03 ... - - S.epidermidis ATCC 31432 2 0.03 0.06 0.03 <0.5 <0.25 <0.25 S. aureus Col (Meht ^R ) (lac ') > 32 4 4 - <0.5 2 4 S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 16th 4 8th 4 4 16th 5. aureus Col8A (Meth ^s ) (lac ') 2 0.06 0.25 0.06 <0.5 <0.25 <0.25 5. haemolyticus (Meth ^R ) > 32 16th 8th 16th 16th 8th 32 E. faecium ATCC 35667 > 32 4 1 2 4 1 4 E. faecalis ATCC 29212 > 32 2 2 2 - - - E. coli ATCC 25922 <1 > 32 > 32 > 32 > 16 > 64 > 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 - - - X. maltophilia ATCC 13637 > 32 > 32 > 32 > 32 ... - ...

Table 7 (cont'd) · Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 19th 20th 21st 22nd 23rd 24th 5. aureus ATCC 29213 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 5. aureus ATCC 25923 <1 ... ... - ... ... ... S.epidermidis ATCC 31432 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 5. aureus Col (Meht ^R ) (lac ') > 32 4 0.5 1 2 2 1 5th aureus 76 (Meth ^R ) (lac ⁺ ) > 32 16th 4 4 4 8th 4 S. aureus Col8A (Meth ^s ) (lac ') 2 <0.25 <0.25 <0.25 0.5 <0.25 <0.25 5. haemolyticus (Meth ^R ) > 32 32 8th 32 4 16th 8th E. faecium ATCC 35667 > 32 2 2 4 2 2 2 E. faecalis ATCC 29212 > 32 - ... - - - - E. coli ATCC 25922 <1 > 32 > 32 > 32 4 > 32 > 32 P. aeruginosa ATCC 27853 8-16 ... ... - ... ... ... X. maltophilia ATCC 13637 > 32 ... ... ... - ... -

table (continued). Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 25th 26th 27th 28th 29th 30th S. aureus ATCC 29213 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 5. aureus ATCC 25923 <1 ... ... ... ... ... ... S.epidermidis ATCC 31432 2 <0.06 <0.25 <0.25 <0.25 <0.25 <0.25 S. aureus Col (Meht ^R ) (lac ') > 32 1 0.5 1 1 1 0.5 5th aureus 76 (Meth ^R ) (lac ⁺ ) > 32 4 4 4 4 4 2 S. aureus Col8A (Meth ^s ) (lac ') 2 0.125 <0.25 <0.25 <0.25 <0.25 <0.25 5. haemolyticus (Meth ^R ) > 32 16th 8th 16th 8th 16th 4 E. faecium ATCC 35667 > 32 2 2 1 2 1 1 E. faecalis ATCC 29212 > 32 - - - - - ... E. coli ATCC 25922 <1 > 32 > 32 > 32 > 32 > 32 > 32 P. aeruginosa ATCC 27853 8-16 - - ... ... ... - X. maltophilia ATCC 13637 > 32 ... ... ... ... ... -

table (continued). Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 31st 32 33 34 35 36 S. aureus ATCC 29213 2 <0.25 <0.25 <0.25 - - ... 5. aureus ATCC 25923 <1 - - - <0.25 <0.25 <0.25 S.epidermidis ATCC 31432 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 S. aureus Col (Meht ^R ) (lac ') > 32 1 1 1 2 0.5 2 S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 4 4 4 8 2 8th S. aureus Col8A (Meth ^s ) (lac ') 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 S. haemolyticus (Meth ^R ) > 32 8th 16th 16 8 8th 16th E. faecium NYCC 35667 > 32 4 2 1 2 1 4 E. faecalis ATCC 29212 > 32 - - 2 1 2 E. coli ATCC 25922 <1 > 32 > 32 > 32> 32 > 32 > 32 P. aeruginosa ATCC 27853 8-16 - - > 32 > 32 > 32 X. maltophilia ATCC 13637 > 32 - - ... ...

table (continued). 7- (acylamido) -3- ^(arylthio>) CEFEM Antibacterial

The organism Cefotax. 37 38 39 40 41 42

5. aureus ATCC 29213 2 ... ... ... ... ... ... 5. aureus ATCC 25923 <1 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 S.epidermidis ATCC 31432 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 S. aureus Col (Meht ^R ) (lac ') > 32 2 4 0.5 4 1 4 S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 8th 16th 4 16th 4 8th 5. aureus Col8A (Meth ^s ) (lac ') 2 <0.25 <0.25 <0.25 <0.25 <0.25 0.5 5. haemolyticus (Meth ^R ) > 32 16th 32 8th 32 16th 16th E. faecium ATCC 35667 > 32 2 4 2 4 2 2 E. faecalis ATCC 29212 > 32 2 2 2 .4 4 2 E. coli ATCC 25922 <1 > 32 > 32 > 32 > 32 > 32 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32> 32 > 32 > 32 X. maltophilia ATCC 13637 > 32 - - - - ... ...

table (continued). Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 43 44 45 46th 47 48 S. aureus ATCC 29213 2 - ___ ___ --- ___ - 5. aureus ATCC 25923 <1 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 S.epidermidis ATCC 31432 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 5. aureus Col (Meht ^R ) (lac ') > 32 4 2 4 1 1 4 5th aureus 76 (Meth ^R ) (lac ⁺ ) > 32 8th 4-8 16th 8th 8th 16th 5. aureus Col8A (Meth ^s ) (lac ') 2 <0.25 <0.25 0.5 <0.25 <0.25 0.5 S. haemolyticus (Meth ^R ) > 32 16th 8th 32 16th 16th 16th E. faecium ATCC 35667 > 32 4 4 4 2 2 4 E. faecalis ATCC 29212 > 32 4 4 4 2 4 4

E. coli ATCC 25922 <1 > 32 > 32 > 32 LT 4193 B > 32> 32> 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 > 32 > 32 > 32 X. maltophilia ATCC 13637 > 32 - - - - - -

table (continued). Antimicrobial properties of 7-f Acylamido) -3- (arylthio) cephem

The organism Cefotax. 49 50 51 52 53 54 S. aureus ATCC 29213 2 - - 0.5 0.5 1 <0.25 S. aureus ATCC 25923 <1 <0.25 <0.25 <0.25 <0.25 ... - S.epidermidis ATCC 31432 2 <0.25 <0.25 <0.25 <0.25 - <0.25 5. aureus Col (Meht ^R ) (lac ') > 32 4 2 4 4 4 1 S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 16th 8th 8th 16th 8th 8th S. aureus Col8A (Meth ^s ) (lac ') 2 0.5 <0.25 <0.25 0.5 1 <0.25 S. haemolyticus fMeth ^R ) > 32 32 8th 32 16th 8th 16th E. faecium ATCC 35667 > 32 4 4 4 2 8th 4 E. faecalis ATCC 29212 > 32 4 4 4 4 8th ... E. coli ATCC 25922 <1 > 32 8th > 32 > 32 1 > 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 > 32 8th > 32 X. maltophilia ATCC 13637 > 32 - - - - - ...

table (continued). Antimicrobial properties of 7- (Acylamido) -3-furylthio) cephem

The organism Cefotax. 55 56 57 5. aureus ATCC 29213 2 ... ... ... 5. aureus ATCC 25923 <1 <0.25 <0.25 <0.25 S.epidermidis ATCC 31432 2 <0.25 <0.25 <0.25 5. aureus Col (Meht ^R ) (lac ') > 32 4 1 0.5 5th aureus 76 (Meth ^R ) (lac ⁺ ) > 32 16th 4 2 5. aureus Col8A (Meth ^s ) (lac ') 2 <0.25 <0.25 <0.25 5. haemolyticus (Meth ^R ) > 32 16th 16th 4 E. faecium ATCC 35667 > 32 8th 4 1 E. faecalis ATCC 29212 > 32 16th 2 2 E. coli ATCC 25922 <1 > 32 > 32 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 32 X. maltophilia ATCC 13637 > 32 ... - -

table. Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 58 59 60 61 62 63

5. aureus ATCC 29213 2 —- --- --- - 5. aureus ATCC 25923 <1 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 S.epidermidis ATCC 31432 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 S. aureus Col (Meht ^R ) (lac ') > 32 <0.25 2 0.5 4 4 4 5th aureus 76 (Meth ^R ) (lac ⁺ ) > 32 4 8th 4 16th 16th 16th 5. aureus Col8A (Meth ^s ) (lac ') 2 <0.25 <0.25 <0.25 0.5 <0.25 <0.25

5. haemolyticus (Meth ^R ) > 32 4 16th 4-8 > 32 32 32 E. faecium ATCC 35667 > 32 0.5 4 1 4 4 1 E. faecalis ATCC 29212 > 32 1 4 1 4 2 1 E. coli ATCC 25922 <1 32 > 32 > 32 > 32 > 32 8th P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 > 32 > 32 > 32

table. Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 64 65 66 67 68 69 S. aureus ATCC 29213 2 <0.25 <0.25 --- <0.25 <0.25 <0.25 5. aureus ATCC 25923 <1 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 S.epidermidis ATCC 31432 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 5. aureus Col (Meht ^R ) (lac ') > 32 0.5 8th 2 4 8th 4 S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 4 32 8th 16th 16th 16th S. aureus Col8A (Meth ^s ) (lac ') 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 S. haemolyticus (Meth ^R ) > 32 8th 32 8th 16th 32 32 E. faecium ATCC 35667 > 32 0.5 2 1 2 4 2 E. faecalis ATCC 29212 > 32 1 1 4 2 4 2 E. coli ATCC 25922 <1 > 32 > 32 > 32 > 32 > 32 > 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 > 32 > 32 > 32

table. Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 70 71 72 73 74 75

5. aureus ATCC 29213 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 5. aureus ATCC 25923 <1 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 S.epidermidis ATCC 31432 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 S. aureus Col (Meht ^R ) (lac ') > 32 4 16th 4 4 16th 8th S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 16th > 32 32 32 > 32 > 32 S. aureus Col8A (Meth ^s ) (lac ') 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 5. haemolyticus (Meth ^R ) > 32 32 > 32 32 32 > 32 > 32 E. faecium ATCC 35667 > 32 2 2 2 1 2 2 E. faecalis ATCC 29212 > 32 0.5 1 1 0.5 1 1 E. coli ATCC 25922 <1 > 32 > 32 > 32 > 32 > 32 > 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 > 32 > 32 > 32

table. Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 76 77 78 79 80

5. aureus ATCC 29213 2 <0.25 <0.25 0.25 0.06 <0.06 5. aureus ATCC 25923 <1 <0.25 <0.25 --- ... S.epidermidis ATCC 31432 2 <0.25 <0.25 - - - 5. aureus Col (Meht ^R ) (lac ') > 32 2 8th 4 4 2 S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 8th 32 16th 8th 8th S. aureus Col8A (Meth ^s ) (lac ') 2 <0.25 <0.25 0.25 0.06 <0.06

5. haemolyticus (Meth ^R ) > 32 32 > 32 > 32 32 8th E. faecium ATCC 35667 > 32 2 2 4 2 2 E. faecalis ATCC 29212 > 32 1 1 4 1 1 E. coli ATCC 25922 <1 > 32 > 32 > 32 > 32 16th P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 > 32 > 32

Table, Antimicrobial Properties of 7- (Acylamido) -3-Farrylthio) Cephem

The organism Cefotax. 81 82 83 84 85 86 S. aureus ATCC 29213 2 --- - - ... <0.25 1 5. aureus ATCC 25923 <1 <0.25 <0.25 <0.25 <0.25 <0.25 - S.epidermidis ATCC 31432 2 <0.25 <0.25 <0.25 <0.25 <0.25 ___ 5. aureus Col (Meht ^R ) (lac ') > 32 2 4 4 2 4 8th S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 4 16th 16th 8th 16th 16th S. aureus Col8A (Meth ^R ) (lac ') 2 <0.25 <0.25 <0.25 <0.25 <0.25 1 5. haemolyticus (Meth ^R ) > 32 16th 32 32 8th 16th 16th E. faecium ATCC 35667 > 32 1 4 2 1 2 2 E. faecalis ATCC 29212 > 32 2 1 1 1 4 4 E. coli ATCC 25922 <1 > 32 > 32 > 32 > 32 > 32 2 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 > 32 > 32 32

table. Antimicrobial properties of 7-f Acylamido) -3-farylthio) cephemn

The organism Cefotax. 87 88 89 90 91 92

5. aureus ATCC 29213 2 ... ... 0.5 1 ___ <0.25 5. aureus ATCC 25923 <1 <0.25 <0.25 <0.25 0.5 <0.25 <0.25 S.epidermidis ATCC 31432 2 <0.25 <0.25 <0.25 <0.25 <0.25 <0.25 5. aureus Col (Meht ^R ) (lac ') > 32 1 4 2 8th 4 2 5th aureus 76 (Meth ^R ) (lac ⁺ ) > 32 4 16th 4 16th 16th 16th 5. aureus Col8A (Meth ^s ) (lac ') 2 <0.25 <0.25 0.5 1 <0.25 <0.25 5. haemolyticus (Meth ^R ) > 32 16th 16th 8th 32 > 32 8th E. faecium ATCC 35667 > 32 1-2 2 4 16th 2 16th E. faecalis ATCC 29212 > 32 2 4 2 32 1 16th E. coli ATCC 25922 <1 > 32 > 32 2 4 > 32 > 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 8th 16th > 32 > 32

table. Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem Organism Cefotax. 93 94 95 96 97 98

S. aureus ATCC 29213 2 <0.25 - 0.25 0.06 0.5 5. aureus ATCC 25923 <1 <0.25 <0.25 <0.25 ___ - - S.epidermidis ATCC 31432 2 <0.25 <0.25 <0.25 ... - - S. aureus Col (Meht ^R ) (lac ') > 32 2 4 4 8th 2 2 S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 8th 16th 8th 16th 4 8th S. aureus Col8A (Meth ^s ) (lac ') 2 <0.25 <0.25 <0.25 0.5 0.125 ...

5. haemolyticus (Meth ^R ) > 32 8th > 32 16th 16th 8th 8th E. faecium ATCC 35667 > 32 0.5 2 4 4 1 4 E. faecalis ATCC 29212 > 32 <0.25 1 4 1 0.5 1 E. coli ATCC 25922 <1 > 32 > 32 > 32 > 32 > 32 8th P. aeruginosa ATCC 27853 8-16 > 32 > 32 8th 16th > 32 16th

table. Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 99 100 101 102 103 104 5. aureus ATCC 29213 2 0.125 <0.06 0.25 0.125 0.25 0.5 S. aureus ATCC 25923 <1 - ... ... ... ... ... S.epidermidis ATCC 31432 2 - ... ... - - ... 5. aureus Col (Meht ^R ) (lac ') > 32 4 4 4 4 2 2 5th aureus 76 (Meth ^R ) (lac ⁺ ) > 32 16th 8th 8th 16th 8th 4 5. aureus Col8A (Meth ^s ) (lac ') 2 - ... 0.25 0.125 0.25 0.5 S. haemolyticus (Meth ^R ) > 32 16th 16th 16th 32 4 4 E. faecium ATCC 35667 > 32 1 4 2 4 2 4 E. faecalis ATCC 29212 > 32 1 1 1 2 1 2 E. coli ATCC 25922 <1 > 32 > 32 > 32 32 > 32 8th P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 > 32 > 32 16th

table. Antimicrobial properties of 7- (Acylamide ^, ) -3-farrylthio) cephem

The organism Cefotax. 105 106 107 108 109 110 S. aureus ATCC 29213 2 0.25 0.25 0.25 0.5 0.125 0.25 S. aureus ATCC 25923 <1 - - --- - - S.epidermidis ATCC 31432 2 ... ... ... ... ... ___ 5. aureus Col (Meht ^R ) (lac ') > 32 4 1 4 4 4 2 S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 16th 8th 16th 8th 16th 8th S. aureus Col8A (Meth ^s ) (lac) 2 0.25 0.125 0.25 0.5 0.125 0.25 S. haemolyticus (Meth ^R ) > 32 32 32 32 16th 32 > 16 E. faecium ATCC 35667 > 32 2 4 8th 16th 4 2 E. faecalis ATCC 29212 > 32 1 4 8th 16th 4 2 E. coli ATCC 25922 <1 > 32 > 32 > 32 4 > 32 > 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 16th > 32 > 32

table. Antimicrobial properties of 7-phacylamido) -3- (arylthio) cephem

The organism

Cefotax. 111 112 113 114 115 116

S. aureus ATCC 29213 2 0.5 <0.06 0.125 0.25 0.25 0.25 5. aureus ATCC 25923 <1 ... ... ___ ... --- --- S.epidermidis ATCC 31432 2 - ... - - ... ... S. aureus Col (Meht ^R ) (lac ') > 32 8th 4 4 4 4 4 S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 16th 16th 16th 16th 8th 16th S. aureus Col8A (Meth ^s ) (lac ') 2 0.25 <0.06 0.125 0.125 0.25 0.125

5. haemolyticus (Meth ^R ) > 32 32 32 > 32 LT 4193 B 32 32 16 E. faecium ATCC 35667 > 32 4 4 4 2 8th 2 E. faecalis ATCC 29212 > 32 4 4 1 1 4 2 E. coli ATCC 25922 <1 > 32 > 32 > 32 > 32 > 32 > 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 > 32 > 32 > 32

table. Antimicrobial properties of 7-phacylamido) -3-farylthio) cephem

The organism Cefotax. 117 118 119 120 121 122 S. aureus ATCC 29213 2 0.25 0.25 0.125 0.25. 0.5 0.25 S. aureus ATCC 25923 <1 - ... ... - - ___ S.epidermidis ATCC 31432 2 - - - - - - S. aureus Col (Meht ^R ) (lac ') > 32 8th 4 2 8th 4 4 S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 16th 8th 8th 16th 8th 8th S. aureus Col8A (Meth ^s ) (lac ') 2 0.125 0.125 0.06 0.25 0.5 0.25 S. haemolyticus (Meth ^R ) > 32 32 32 16th 32 16th 16th E. faecium ATCC 35667 > 32 1 4 1 8th 2 4 E. faecalis ATCC 29212 > 32 2 4 1 4 0.5-1 4 E. coli ATCC 25922 <1 > 32 > 32 > 32 > 32 > 32 > 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 > 32 > 32 > 32

table. Antimicrobial properties of 7-phacylamid ') - 3-farlylthio) cephem

The organism Cefotax. 123 124 125 126 127 128 5. aureus ATCC 29213 2 0.06 0.25 0.5 0.125 <0.06 <0.06 S. aureus ATCC 25923 <1 - - ___ ___ ___ - S.epidermidis ATCC 31432 2 - - - ... ... ... S. aureus Col (Meht ^R ) (lac ') > 32 4 4 4 8th 4 8th 5th aureus 76 (Meth ^R ) (lac ⁺ ) > 32 8th 16th 8th 16th 8th 16th 5. aureus Col8A (Meth ^s ) (lac ') 2 <0.06 0.25 0.5 0.125 <0.06 <0.06 S. haemolyticus (Meth ^R ) > 32 16th 16th 8th - - ... E. faecium ATCC 35667 > 32 4 1 2 2 1 2 E. faecalis ATCC 29212 > 32 2 1 0.25 1 1 2 E. coli ATCC 25922 <1 > 32 > 32 > 32 > 32 > 32 > 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 > 32 > 32 > 32

table. Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 129 130 131 132 133 134 S. aureus ATCC 29213 2 <0.06 0.125 <0.06 0.125 0.125 0.125 5. aureus ATCC 25923 <1 ... - ... ... - S.epidermidis ATCC 31432 2 ... - - ... ... ... S. aureus Col (Meht ^R ) (lac ') > 32 8th 2 1 8th 2-4 2 S. aureus 76 (Meth ^R ) (lac ⁺ ) > 32 8th 4 4 32 8th 8th S. aureus Col8A (Meth ^s ) (lac ') 2 <0.06 0.25 <0.06 0.25 0.125 0.125

S. haemolyticus (Meth ^R ) > 32 16th 4 32 > 32 16th 16th E. faecium ATCC 35667 > 32 - 0.5 1 4 1 1 E. faecalis ATCC 29212 > 32 0.25 0.25 0.5 4 1 0.5 E. coli ATCC 25922 <1 2 > 32 > 32 > 32 > 32 > 32 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 > 32 > 32 > 32

table. Antimicrobial properties of 7- (Acylamido) -3- (arylthio) cephem

The organism Cefotax. 135 136 137 S. aureus ATCC 29213 2 0.125 0.125 0.125 _: 5. aureus ATCC 25923 <1 ... ... ... S.epidermidis ATCC 31432 2 ... ... - 5. aureus Col (Meht ^R ) (lac ') > 32 8th 2 2 5th aureus 76 (Meth ^R ) (lac ⁺ ) > 32 16th 4 4 5. aureus Col8A (Meth ^s ) (lac ') 2 <0.06 - 0.06 5. haemolyticus (Meth ^R ) > 32 32 4 16th E. faecium ATCC 35667 > 32 2-4 1 0.25 E. faecalis ATCC 29212 > 32 2-4 0.5 0.5 E. coli ATCC 25922 <1 > 32 > 32 4 P. aeruginosa ATCC 27853 8-16 > 32 > 32 > 32 Under investigation The title

compound

Cefotaxime (7R) -3-acetoxymethyl-7 - [(Z) -2- (aminothiazol-4-yl) -2- (methoxyimino) acetamide] -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino ] -3- (p-Fluorophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (m-iodophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (p-chlorophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (o-bromophenylthio) -3-cephem-4- carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (p-bromophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (o-iodophenylthio) - 3-Cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (dibenzofuranyl-3-thio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] - 3- (4-Biphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2-biphenylthio) -3-cephem-4-carboxylic acid (7R) -7- [ (phenylacetyl) amino] -3- (3-biphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2-bromo-4-biphenylthio) -3-cephem-4 -carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (4-biphenylmethylthio) -3-cef em-4-Carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2-fluoro-4-biphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] - 3- (4-Bromo-2-biphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (o-chlorophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2,5-dichlorophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(cyanoacetyl) amino] -3- (o-iodophenylthio) -3- cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (3,4-dichlorophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (o-Carbomethoxyphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(2-thienylacetyl) amino] -3- (o-bromophenylthio) -3-cephem-4-carboxylic acid (7R) -7- [ (phenylacetyl) amino] -3- (dibenzofuranyl-1-thio) -3-cephem-4-carboxylic acid (7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (hydroxyimino) acetamide ] -3- (o-iodophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2- (4-cyanophenyl) phenylthio) -3-cephem-4-carboxylic acid (7R) ) -7 - [(phenylacetyl) amino] -3- (2,3-dichlorophenylthio) -3-cephem-4-carboxylic acid this (7R) -7 - [(2-thienylacetyl) amino] -3- (o-iodophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(2-thienylacetyl) amino] -3- (2 , 5-Dichlorophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(Phenylacetyl) amino] -3- (2- (2-furyl) phenylthio) -3-ceferno-4-carboxylic acid (7R) - 7 - [(Phenylacetyl) amino] -3- (2,4-dichlorophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(p-methoxyphenylacetyl) amino] -3- (o-iodophenylthio) -3 -cephem-4-carboxylic acid (7R) -7 - [(p-chlorophenoxyacetyl) amino] -3- (o-iodophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(p-chlorophenoxyacetyl) amino] -3- (2,5-Dichlorophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(p-methoxyphenylacetyl) amino] -3- (2,5-dichlorophenylthio) -3-cephem-4-carboxylic acid (7R) - 7 - [(Phenylacetyl) amino] -3- (2-bromo-5-fluorophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(cyanoacetyl) amino] -3- (2-biphenylthio) -3 -cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2,5-dichlorophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3 - (2-Vinylphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2- (2-thienyl) phenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2-hydroxymethylphenylthio) -3-cephem-4- carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2,4-dibromophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (4-trifluoromethylphenylthio) ) -3-Cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2-cyanophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (hydroxyimino) acetamide] -3- (2-biphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2- (2- (4-Methoxyphenylmethyl) thien-5-yl) phenylthio-3-cephem carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2-methylthiophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2- (2- (N-methylimidazoliomethyl) thien-5-yl) phenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2-tert-Butylphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2-isopropyloxyphenylthio) -3-cephem-4-carboxylic acid (7R) -7- [ (phenylacetyl) amino] -3- (2- (3- (N-methylimidazoliomethyl)) furan-2-yl) phenylthio) '3 cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (4-cyano-2-nitrophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2-formylphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2,4-dicyanophenylthio) -3- cephem-4-carboxylic acid (7R) -7 - [(cyanoacetyl) amino] -3- (2-cyanophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(Z) -2- (aminothiazole-4) -yl) 2- (cyclopentyloxyimino) acetamide] -3- (2-cyanophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (1-naphthalenylthio) -3-cephem -4-Carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2,3-dihydro-2,2-dimethylbenzofuran-7-yl) -3-cephem-4-carboxylic acid (7R) -7 - [( phenylacetyl) amino] -3- (5,6,7,8-tetrahydronaphthalen-1-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (1-bromonaphthalene-2- thio) -3-cephem-4'-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (4-isothiuronomethyl-2-iodophenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (4- (2-imidazolin-2-ylthiomethyl) -2-iodophenylthio) -3-c efe

4-Carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (4- (N-amidino) isothiuronomethyl-2-iodophenylthio) -3-cephem-4-carboxylic acid inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (4- (N-morpholinoethyl) isothiuronomethyl-2-iodophenylthio) cephem-4-carboxylic acid inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (4-tetramethylisothiuronomethyl-2-iodophenylthio) -3-cefe

4-Carboxylic acid inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (4-isothiuronomethylphenylthio) -3-cephem-4-carboxylic acid inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (2-Isothiuronomethylphenylthio) -3-cephem-4-carboxylic acid inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (4- (1,2,3-triazol-5-ylthiomethyl) phenylthio) -3 -cephem-4-carboxylic acid (7R) -7 - [(cyanoacetyl) amino] -3- (4-isothiuronomethyl-2-iodophenylthio) -3-cephem-4-carboxylic acid inner salt of (7R) -7 - [(phenylacetyl) amino] -3 - (2- (1,2,4-Triazol-5-ylthiomethyl) phenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2- (2-imidazoline-4-) is-2-yl) thiomethyl) phenylthio) -3-cephe

4-Carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2-tetramethylisothiuronomethylphenylthio) -3-cephem-4-carboxylic acid inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (2- ( pyridin-4-yl) thiomethyl) phenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (1N-methyltetrazol-5-yl) thiomethyl) phenylthio) -3-cephem-4 carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2- (2-imidazolin-2-yl) thiomethylphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3 - (2- (N-Methylpyridin-4-ynyl) thiomethyl) phenylthio) -3-cephem carboxylic acid inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (2-N, N'-diethylisothiouronomethylphenylthio) - Internal salt of 3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2- (pyrimidin-2-yl) thiomethylphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2-N-methylisothiouroniomethylphenylthio) -3-cephem-4-carboxylic acid inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (2- (2-methyl-1,3,4-thiadiazole) -5-yl) thiomethyl) phenylthio) -3cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2 -N-Acetylamidomethylphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(Phenylacetyl) amino] -3- (2-N-cyclopropylisothiuronomethyl-phenylthio) -3-cephem-4-carboxylic acid inner salt (7R) -7 - [( phenylacetyl) amino] -3- (3-isothiuronomethylphenylthio) -3-cephem-4-carboxylic acid inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (2-phenylpyridin-3-ylthio) -3-cephem-4 -carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2-phenyl-N-methylpyridin-3-thio) -3-cephem-4-carboxylate (7R) -7 - [(phenylacetyl) amino] -3 - (2-Phenyl-N-benzylpyridin-3-thio) -3-cephem-4-carboxylate (7R) -7 - [(4-chlorophenylacetyl) amino] -3- (2-phenylpyridin-3-ylthio) -3-cephem -4-Carboxylic acid (7R) -7 - [(cyanoacetyl) amino] -3- (2-phenylpyridin-3-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(Z) -2- (Aminothiazole) 4-yl) -2- (cyclopentyloxyimino) acetamide] -3- (2-phenylpyridin-3-thio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (1N-phenylpyrazole) 5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(cyanoacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (cyclopentyloxyimino) acetamide] -3- (1-N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(Z) -2- (Aminothiazol-4-yl) -2- (2-fluoroethyloxyimino) acetamide] -3- (1-N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (1N-phenyl-1,2,3-triazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (2 -amino-4-phenylthiazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (4-phenyl-1,2,3-thiadiazol-5-ylthio) - 3-Cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (1N-phenyltetrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] - 3- (2-Oxazol-5-ylphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [((2-aminomethylphenyl) acetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3 -acephem-4-carboxylic acid (7R) -7 - [((4-isothiuronomethylphenyl) acetyl) amino] -3- (2-isothiuronomethylphenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt (7R) -7 - [(Z) -2 -amino-5-chlorothiazol-4-yl) -2- (2-fluoroethyloxyimino) acetamide] -3- (1H) enylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(4-hydroxyphenylacetyl) amino] -3- (2-isothiuronomethylphenylthio) -3-cephem-4-carboxylic acid inner salt of (7R) -7- [(Phenylacetyl) amino] -3- (2- (2-isothiuronio) ethylphenylthio) -3-cephem-4-carboxylic acid inner salt of (7R) -7 - [((2-aminomethylphenyl) acetyl) amino] -3- (2- isothiuronomethylphenyl-5-ylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt of (7R) -7 - [(phenyl) acetyl) amino] -3- (2-cyanopyridin-3-ylthio) -3-cephem-4-carboxylic acid ( 7R) -7 - [(Phenylacetyl) amino] -3- (2- (pyrazol-1-yl) pyridin-3-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(Z) - (2- aminothiazol-4-yl) -2- (3-pentyloxyimino) acetamide] -3- (1-N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3 - (1N- (Pyridin-2-yl) pyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(methylthioacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3- cephem-4-carboxylic acid (7R) -7 - [(cyclopropylacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(Z) -2- (2 -aminothiazole-4- yl) -2- (cyclopropylmethyloxyimino) acetamide] -3- (1-pyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(hexanoyl) amino] -3- (1N-phenylpyrazole-5- thio) -3-cephem-4-carboxylic acid (7R) -7 - [(4-pyridylthioacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [( furylacetyl) amino] -3- (1N-phenylpyrazole-5-thio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenyloxyacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3 -cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (1N- (3-nitrophenyl) pyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino ] -3- (1N- (4-Methoxyphenyl) pyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(2-dithiolanylcarbonyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(2-thienylacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (1N- (3-methoxyphenyl) pyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(2-methyl-1,3,4-thiadiazol-5-ylthio) acetyl ) amino] -3- (1N-phenylpyrazol-5-ylthio) cephem-4-carboxylic acid (7R) -7 - [(Phenylthioacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(2-amino-1,3,4) -thiadiazol-5-ylthio) acetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) cephem-4-carboxylic acid (7R) -7 - [(2- (2-furyl) -2- (hydroxyimino) acetamide ] -3- (1N-Phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(cyanomethylthioacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid ( 7R) -7 - [(phenylthioacetyl) amino] -3- (1N- (4-fluorophenyl) pyrazol-5-ylthio) -3-cephem-4-carboxylic acid (7R) -7 - [((4-aminomethylphenyl) acetyl) amino ] -3- (2-Isothiuronomethylphenylthio) -3-cephe

Trifluoroacetic acid 4-carboxylic acid salt of (7R) -7 - [((N, N'-diisopropylisothiuronium) acetyl) amino] -3- (2-isothiuronomethylphenylthio)

3-Cephem-4-carboxylic acid trifluoroacetic acid salt of (7R) -7 - [(methylthioacetyl) amino] -3- (2- (N-amidino) isothiuronomethylphenylthio) -3-cephe

4-Carboxylic acid inner salt of (7R) -7 - [(methylthioacetyl) amino] -3- (2-isothiuronomethylphenylthio) -3-cephem-4-carboxylic acid inner salt of (7R) -7 - [(phenylacetyl) amino] -3- (2 -guanidiniomethylphenylthio) -3-cephem-4-carboxylic acid inner salt of (7R) -7 - [(Z) -2- (aminothiazol-4-yl) -2- (hydroxyimino) acetamide] -3- (2-isothiuronomethylphenylthio) -3- inner salt of cephem-4-carboxylic acid (7R) -7 - [(Z) -2- (phenyl) -2- (hydroxyimino) acetamide] -3- (1N- (phenyl) pyrazol-5-ylthio) cephem-4- carboxylic acid inner salt of (7R) -7 - [((Z) -2-chlorovinyl) thioacetyl) amino] -3- (1N-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid inner salt of (7R) -7- [ (phenylacetyl) amino] -3- (2- (pyrazol-1-yl) phenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(methylthioacetyl) amino] -3- (2- (N-amino) ) isothiuronomethylphenylthio) -3-cephemcarboxylic acid inner salt of (7R) -7 - [(3-iodoprop-1-ylthioacetyl) amino] -3- (2-isothiuronomethylphenylthio) -3-cephem-4-carboxylic acid inner salt

135 (7R) -7 - [(Methylthioacetyl) amino] -3- (2-guanidiniomethylphenylthio) -3-cephem-4-carboxylic acid inner salt

Inner salt of 136 (7R) -7 - [(Z) -2- (phenyl) -2- (hydroxyimino) acetamide] -3- (2-isothiuronomethylphenylthio) cephem-4-carboxylic acid

137 (7R) -7 - [(2-Guanidinoethylthioacetyl) amino] -3- (2-isothiuronomethylphenylthio) -3-cephemcarboxylic acid trifluoroacetic acid salt

Antibacterial tests in vivo

Compounds that showed the highest activity in vitro compared to reference antibiotics were further investigated using a murine model for lethal bacterial peritonitis.

Groups of 5 Swiss-Webster female mice (Simonsen, Gilroy, CA) were injected intraperitoneally (IP) with ten-fold increments of bacterial inoculum. This allowed the calculation of the median lethal dose (LD50) and LDioo. For preliminary evaluation of the new antibiotic, mice were treated with IP LDioo bacterial titer. Groups of 10 mice were dosed subcutaneously with two doses of the test drug and an antibiotic of known efficacy in mice and humans (ie, positive control) at equal doses administered by bacterial treatment and after 2 hours. The mice were observed for 72 hours. Mice that survived 72 hours are considered long-term survival mice. The total drug dose (mg / kg) that prevented death in 50% of the group of mice is called the median protective dose (PD50). PD ₅₀ for several pathogens are similarly determined. The quantitative endpoints for the new drugs are then compared to the points obtained for the reference antibiotics.

Six ten-fold dilutions of inoculum samples suspended in 0.5 ml of sterilized 7% hog gastric mucin (Sigma) are administered IP to each mouse in a group of 5 mice. A control group of 5 mice received mucin alone. Mice were observed for 72 hours. Those mice that survived 72 hours are considered long-term survival mice. The median lethal dose (LD50) and 100% lethal dose (LDioo) were determined using the probittest.

In antibiotic efficacy studies, mice are treated with bacterial titers that give the test strain LDioo · Each mouse of the group of 10 mice is treated subcutaneously (SC) with two equal doses of the test antibiotic administered subcutaneously at 2 hours; another group is similarly treated with a reference antibiotic whose efficacy in mice and humans is known. Doses of drugs may be in the range of 0.01-512 mg / kg. If the drug is poorly soluble, Tween 20 or propylene glycol is used to increase the solubility of the drug. The animals are observed for 72 hours. The probit method calculates a 50% protective dose (PD50) · The PD50 is the same as the 50% effective dose (ED50) and 50% therapeutic dose (CD50).

Blood samples from hearts of all dead and half surviving mice were cultured on brain-heart infusion agar. Animals receiving a protective dose of study drug survive for 72 hours, although they appear to be moderately to severely ill throughout the observation period. Infected, placebo-treated control mice and mice receiving ineffective, i.e. lower dose of the study drug indicates a very high mortality rate. Most such mice die within 6-48 hours. Those mice that survived 72 hours are considered long-term survival mice.

(The compound numbers correspond to those in the MIC tables; data are available for methicillin-susceptible S. aureus strain ATCC 13709).

Mortality

Compound: Dose: Vancomycin 6th 17th 81 87 16 mg / kg 0/10 0/10 0/10 2/10 0/10 8 mg / kg 0/10 1/10 0/10 5/10 0/10 4 mg / kg 2/10 5/10 5/10 10/10 3/10 2 mg / kg 8/10 8/10 8/10 8/10 4/10 ED ₅₀ (mg / kg) 2.81 3.65 3.41 8.46 1.89 Processing strain MIC (µg / ml) 1 <0.5 0.125 0.125 0.06

Mortality

Compound: Vancomycin Cefotaxime ; 6th 41 88 Dose: 40 mg / kg 0/10 20 mg / kg 4/10 10 mg / kg 2/10 3/10 1/10 0/10 0/10 5 mg / kg 5/10 5/10 1/10 0/10 0/10 2.5 mg / kg 5/10 8/10 4/10 0/10 0/10 1.25 mg / kg 6/10 4/10 6/10 1/10 0.625 mg / kg 8/10 9/10 8/10 2/10 0.3125 mg / kg

ED ₅₀ (mg / kg) 2.79

95% confidence interval 0.79-4.80 Ref. strain MIC (µg / ml) 1

7.47

2.91-12.04

1.57

0.83-2.31

0.03

1.13

0.81-1.45

0.06

0.31

0.12-0.74

0.25

Mortality

Compound: 89 97 101 103 104 Dose: 40 mg / kg 20 mg / kg 10 mg / kg 8/10 0/10 0/10 9/10 5 mg / kg 8/10 0/10 0/10 5/10 8/10 2.5 mg / kg 9/10 2/10 0/10 7/10 8/10 1.25 mg / kg 9/10 3/10 2/10 7/10 10/10 0.625 mg / kg 9/10 5/10 5/10 7/10 6/10 0.3125 mg / kg 8/10 ED ₅₀ (mg / kg) > 10 0.74 0.65 2.67 > 10 95% confidence interval 0.39-1.08 0.36-0.94 1.13-4.21 - Processing strain MIC (µg / ml) 0.5 0.062 0.125 0.125 0.5

Mortality

Compound: 102 106 115 108 110 Dose: 40 mg / kg 20 mg / kg 10 mg / kg 0/10 10/10 0/10 5 mg / kg 0/10 4/10 10/10 6/10 2.5 mg / kg 5/10 1/10 7/10 9/10 8/10 1.25 mg / kg 7/10 2/10 9/10 8/10 7/10 0.625 mg / kg 8/10 6/10 8/10 9/10 8/10 0.3125 mg / kg 10/10 9/10 0.1562 mg / kg 9/10 ED ₅₀ (mg / kg) 1.75 0.72 3.04 > 10 3.45 95% confidence interval 1.12-2.38 0.44-1.00 1.73-4.34 - 1.13-4.21 Processing strain MIC (µg / ml) 0.125 0.125 0.25 0.5 0.25

Compound:

Mortality

107 118 119 122 125

Dose:

mg / kg 20 mg / kg

10 mg / kg 0/10 2/10 0/10 7/10 5 mg / kg 0/10 4/10 8/10 0/10 4/9 2.5 mg / kg 5/10 8/10 7/10 0/10 7/10 1.25 mg / kg 6/10 6/10 10/10 6/10 10/10 0.625 mg / kg 8/10 8/10 9/10 8/10 9/10 0.3125 mg / kg 10/10 0.1562 mg / kg ED ₃₀ (mg / kg) 1.58 3.38 > 5 1.13 > 10 95% confidence interval 0.99-2.17 1.10-5.66 - 0.81-1.45 - Processing strain MIC (µg / ml) 0.125 0.06 0.25 0.125 -

Mortality

Compound: 127 130 131 137 Dose: 40 mg / kg 20 mg / kg 10 mg / kg 6/10 0/10 5 mg / kg 1/10 6/10 0/10 2.5 mg / kg 2/10 9/10 4/10 1.25 mg / kg 4/10 7/10 7/10 0.625 mg / kg 5/10 10/10 9/10 6/10 0.3125 mg / kg 6/10 5/10 0.1562 mg / kg 7/10 0.0781 mg / kg 9/10 0.0391 mg / kg 8/10 ED ₅₀ (mg / kg) 0.59 > 10 1.73 0.75 95% confidence interval 0.11-1.07 - 1.18-2.27 0-1.75 Processing strain MIC (µg / ml) - 0.125 0.06 0.06

EXAMPLES

The invention will be illustrated in more detail by the following specific examples, which in no way limit the scope thereof.

Example 7 Benzhydryl of (7R) -7 - [(phenylacetyl) amino] -3- (4-biphenylthio) -3-cephem-4-carboxylic acid

To a stirred solution of (7R) -7 - [(phenylacetyl) amino] -3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylic acid benzhydryl ester (760 mg, 1.2 mmol) in dry DMF (12 mL) at -60 ° C under nitrogen was added. DMF (3 mL) of a solution of 4-phenylbenzentiolate sodium (320 mg, 1.56 mmol) in sodium hexamethyldisilazide (1.2 mL of a 1 M solution in THF, 1.2 mmol) was added. After 25 minutes the reaction was quenched by the addition of 10% aqueous ammonium chloride solution (1 mL) and water (120 mL). The resulting milk solution was extracted with dichloromethane (3x50 mL) and 10% EtOAc / hexane (3x50 mL). The organic extracts were dried over sodium sulfate and filtered, and the solvent was removed by rotary evaporation. The crude product is purified by chromatography on silica gel (chromatotron, 4 mm plate, 5% EtOAc / hexane followed by 0.25%

MeOH / dichloromethane) to give 450 mg (56%) of the title compound. 1 H NMR (CDCl ₃ ) δ 3.17 (d, 1H, J = 18), 3.31 (d, 1H, J = 17), 3.63 (d, 1H, J = 16), 3.69 (d, 1H, J = 16), 5.01 (d, 1H, J = 4), 5.79 (dd, 1H, J = 4.9), 6.06 (d, 1H, J = 9). , 7.00 (s, 1H), 7.2-7.7 (m, 25H).

Example 7 Benzhydryl of (7R) -7 - [(phenylacetyl) amino] -3- (4-bromophenylthio) -3-cephem-4-carboxylic acid

To a well-stirred suspension of (7R) -7 - [(phenylacetyl) amino] -3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylic acid benzhydryl ester (190 mg, 0.30 mmol) in dry THF (20 mL) at -78 ° C under nitrogen atmosphere a suspension of sodium 4-bromobenzenethiolate prepared from 4-phenylbenzthiol (62 mg, 0.33 mmol) and sodium hexamethyldisilazide (0.30 mL of a 1M solution in THF, 0.30 mmol) was added in THF (5 mL). After 1 or. the reaction is quenched by the addition of 5% aqueous ammonium chloride solution (3 mL). The resulting mixture was extracted with dichloromethane (3x25 mL) and the extracts were washed with water and brine. The organic phase was dried over sodium sulfate and filtered, and the solvent was evaporated on a rotary evaporator. The crude product was purified by silica gel chromatography (chromatotron, 2 mm plate, 0.25% MeOH / dichloromethane) to give 85 mg (42%) of the title compound. 1 H NMR (CDCl ₃ ) δ 3.10 (d, 1H, J = 18), 3.28 (d, 1H, J = 17), 3.63 (d, 1H, J = 16), 3.69 (d, 1H, J = 16), 5.00 (d, 1H, J = 4), 5.81 (dd, 1H, J = 4.9), 6.07 (d, 1H, J = 9). , 6.98 (s, 1H), 7.2-7.5 (m, 20H).

Following the procedures described in Examples 1 and 2, the compounds of the present invention are listed below in Examples 3-14.

Example (7R ') - 7 - [(' Phenylacetyl) amino] -3- (4-fododenylthio) -3-cephem-4-carboxylic acid benzhydryl ester

This compound was prepared according to a procedure similar to that described in Example 1 except that sodium 4-phenylthiolate was used.

Example 7 Benzhydryl of (7R) -7-phenylphenylacetaminamine-3 - ('2-bromo-4- (phenylphenylthio)) - 3-cephem-4-carboxylic acid

This compound was prepared according to a procedure similar to that described in Example 1 except that sodium 2-bromo-4- (phenyl) phenylthiolate was used.

Example 7 Benzhydryl of (7R) -7 - [(phenylacetyl) amino] -3- (2-phenyl-4-bromophenylthio) -3-cephem-4-carboxylic acid

This compound was prepared according to a procedure similar to that described in Example 1 except that sodium 2-phenyl-4-bromophenylthiolate was used.

Example 7 Benzhydryl of (7R) -7 - [(Yenylacetyl) amino] -3- (3-iodophenylthio ') - 3-cephem-4-carboxylic acid

This compound was prepared according to a procedure similar to that described in Example 1 except that sodium 3-iodophenylthiolate was used.

Example 7 Benzhydryl of (7R) -7 - [('phenylacetyl) amino] -3- (' 2,4-dichlorophenylthio) -3-cephem-4-carboxylic acid

This compound was prepared according to a procedure similar to that described in Example 1 except that 2,4-dichlorophenylthiolate sodium was used.

example (7R) -7-phenylphenylacetyl) aminol-3- (4-f2-imidazolyl) phenylthio) -3-cephem-4-carboxylic acid benzhydryl ester

This compound was prepared according to a procedure similar to that described in Example 1 except that sodium 4- (2-imidazolyl) phenylthiolate was used.

Example 7 Benzhydryl of ('7R) -7- [phenylacetyl) amino] -3- (clibenzofuran-3-ylthio) -3-cephem-4-carboxylic acid

This compound was prepared according to a procedure similar to that described in Example 1 except that dibenzofuran-3-thiolate sodium was used.

Example 7 Benzhydryl of ('7R) -7- [(' phenylacetyl) amino] -3-dibenzofuran-2-ylthio) -3-cephem-4-carboxylic acid

This compound was prepared according to a procedure similar to that described in Example 1 except that dibenzofuran-2-thiolate sodium was used.

Example 7 'Benzhydryl ester of' 7 R '-7-l (phenylacetyl) aminol-3 - (' dibenzofuran-1-ylthio-3-cephem-4-carboxylic acid)

This compound was prepared according to a procedure similar to that described in Example 1 except that dibenzofuran-l-thiolate sodium was used.

Example (7Rj-7 - [(Phenylacetyl) aminol-3-dibenzofuran-4-ylthio) -3-cephem-4-carboxylic acid benzhydryl ester

This compound was prepared according to a procedure similar to that described in Example 1 except that dibenzofuran-4-thiolate sodium was used.

Example 7 Benzhydryl of ('7R) -7- [(phenylacetyl) amino] -3- [6- (hydroxymethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid

This compound was prepared according to a procedure similar to that described in Example 1 except that sodium 6- (hydroxymethyl) dibenzofuran-3-thiolate was used.

Example 7 Benzhydryl of (7R) -7 - [(phenylacetyl) amino] -3- [7- (hydroxymethyl) dibenzofuran-3-ylthio] -3-cephene-4-carboxylic acid

This compound was prepared according to a procedure similar to that described in Example 1 except that sodium 7- (hydroxymethyl) dibenzofuran-3-thiolate was used.

Example 7 (7R) -7- [(Phenylacetyl) amino] -3- (2-biphenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

To a stirred solution of (7R) -7 - [(phenylacetyl) amino] -3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylic acid 4-methoxybenzyl ester (700 mg, 1.2 mmol) in dry DMF (12 mL) at -60 ° C under nitrogen to the atmosphere was added DMF (3 mL) of a solution of 2-phenylbenzentiolate sodium (320 mg, 1.56 mmol) and hexamethyldisilazide sodium (1.2 mL of 1 M in THF, 1.2 mmol). After 25 minutes the reaction was quenched by the addition of 10% aqueous ammonium chloride solution (1 mL) and water (120 mL). The resulting milk solution was extracted with dichloromethane (3x50 mL) and 10% EtOAc / hexane (3x50 mL). The organic extracts were dried over sodium sulfate and filtered, and the solvent was removed by rotary evaporation. The crude product was purified by silica gel chromatography (chromatotron, 4 mm plate, 5% EtOAc / hexane followed by 0.25% MeOH / dichloromethane) to give 450 mg (56%) of the title compound.

According to the procedure described in Example 15, the compounds of the present invention listed below in Examples 16-32 are obtained.

Example 7 (7R) -7- (Phenylacetyl) amino-3- [2- (4-cyanophenyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that sodium 2- (4-cyanophenyl) phenylthiolate was used.

Example 7 4-Methoxybenzyl ester of (7R) -7 - [(phenylacetyl) amino] -3- [2,3-dichlorophenylthio] -3-cephem-4-carboxylic acid

This compound was prepared according to a procedure similar to that described in Example 15 except that 2,3-dichlorophenylthiolate sodium was used.

Example 7 (4R) -7- [(Phenylacetyl) amino] -3- [2,5-dichlorophenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that 2,5-dichlorophenylthiolate sodium was used.

Example 7 (7R) -7- [Phenylacetyl ') amino] -3- (2-bromo-5-fluorophenylthio) -3-cephem-4-carboxylic acid, 4-methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that sodium 2-bromo-5-fluorophenylthiolate was used.

Example (7R) -7-f (phenylacetyl ') amino1-3- ^{(2-bromfeniltio')} - 3-CEFEM-4-carboxylic ester 4metoksibenzilo

This compound was prepared according to a procedure similar to that described in Example 15 except that sodium 2-bromophenylthiolate was used.

Example 7 (4R) -7 - [(Phenylacetyl) amino] -3- (4-chlorophenylthio ') - 3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that sodium 4-chlorophenylthiolate was used.

Example 7b) -7 - [(Phenylacetyl) aminol-3- [4- (ethoxycarbonyl) phenylthiol-3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that sodium 4- (ethoxycarbonyl) phenylthiolate was used.

Example 7b) -7-N- (Phenylacetyl) aminol-3- [2- (ethoxycarbonyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that sodium 2- (ethoxycarbonyl) phenylthiolate was used.

Example 7 4-Methoxybenzyl ester of (7R) -7- [(phenylacetyl) amino] -3- [2-iodophenylthio] -3-cephem-4-carboxylic acid

This compound was prepared according to a procedure similar to that described in Example 15 except that sodium 2-iodophenylthiolate was used.

Example 7 (7R) -7 - [(Phenylacetyl) amino] -3- [2-chlorophenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that sodium 2-chlorophenylthiolate was used.

Example 7 (7R) -7 - [(Phenylacetyl) amino] -3- [4-bromo-3-trifluoromethoxy) phenylthio-3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that sodium 4-bromo-3- (trifluoromethoxy) phenylthiolate was used.

Example 7 (R) -7 - [(Phenylacetyl) amino] -3 - [[4- (2-imidazolyl) methyl] phenylthiol-3-cephem-4-carboxylic acid

4-Methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that potassium 4 - [(2-imidazolyl) methyl] phenylthiolate was used.

Example (7R) -7 - ^{[(phenylacetyl,)} amino1-3 - [[4-fl-methyl-2-imidazolyl) metil1feniltioĮ-3-CEFEM 4karboksirūgšties-4-methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that potassium 4 - [(1-methyl-2-imidazolyl) methyl] phenylthiolate was used.

Example 7 (7R) -7 - [(Phenylacetyl) amino] -3- [2-fluoro-4-f2-phenyl ') phenylthio-3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that potassium 2-fluoro-4- (phenyl) phenylthiolate was used.

Example 7b ') - 7- [Phenylacetyl] amino] -3- [3- (' 2-thienyl) phenylthio-3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that sodium 3- (2-thienyl) phenylthiolate was used.

Example 7 (4R) -7 - [(Phenylacetyl) amino] -3- [3,4-dichlorophenylthiol-3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that sodium 3,4-dichlorophenylthiolate was used.

Example 7 (7R) -7 - [(2-Thienylacetyl) amino] -3- [5-bromo-4- (1-methyl-2-imidazolyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared according to a procedure similar to that described in Example 15 except that (7R) -7 - [(2-thienylacetyl) amino] -3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylic acid 4-methoxybenzyl ester and 5-bromo sodium were used. -4- (1-Methyl-2-imidazolyl) phenylthiolate.

Example 7 Benzhydryl of (7R) -7-amino-3- (2-bromophenylthio-3-cephem-4-carboxylic acid

To the benzhydryl ester of (7R) -7- (phenylacetyl) amino-3- (2-bromophenylthio) -3-cephem-4-carboxylic acid (812 mg, 1.21 mmol) and pyridine (195 µL, 2.42 mmol) solution of dichloromethane (5 mL) at 0 ° C was added slowly a solution of phosphorus pentachloride (403 mg, 1.94 mmol) in dichloromethane (9 mL). After 15 minutes Isobutyl alcohol (1.1 mL, 12.1 mmol) was added immediately at 0 ° C. The mixture was diluted with dichloromethane (20 mL) and washed with 5% aqueous sodium bicarbonate solution (20 mL). The organic layer was dried over sodium sulfate and the solvent was removed by rotary evaporation. The residue was chromatographed on silica gel (33 to 50% acetate / hexane) to give 300 mg (45%) of the title compound.

Example 7 7R-7-Amino-3- (2-iodophenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

To (7R) -7- (Phenylacetyl) amino-3- (2-iodophenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (850 mg, 1.21 mmol) and pyridine (195 μϊ, 2.42 mmol) a solution of dichloromethane (5 mL) at 0 ° C was added slowly a solution of phosphorus pentachloride (403 mg, 1.94 mmol) in dichloromethane (9 mL). After 15 minutes Isobutyl alcohol (1.1 mL, 12.1 mmol) was added immediately at 0 ° C. The mixture was diluted with dichloromethane (20 mL) and washed with 5% aqueous sodium bicarbonate solution (20 mL). The organic layer was dried over sodium sulfate and the solvent was removed by rotary evaporation. The residue is chromatographed on silica gel (33 to 50% acetate / hexane) to give 300 mg (50%) of the title compound.

The procedures described in Examples 33 and 34 provide the compounds of the present invention listed below in Examples 35-50.

Example 7 Benzhydryl of (7R) -7-amino-3- (4-biphenylthio) -3-cephem-4-carboxylic acid

The procedure described in Example 33 is used except that the benzhydryl ester of (7R) -7 [(phenylacetyl) amino] -3- (4-biphenylthio) -3-cephem-4-carboxylic acid is used.

Example (7R) -7-amino-3- [4- (2-imidazolyl ^s) feniltiol CEFEM-3-carboxylic acid-4-benzhydryl ester

The procedure described in Example 33 is followed except that the benzhydryl ester of (7R) -7 [(phenylacetyl) amino] -3- [4- (2-imidazolyl) phenylthio] -3-cephem-4-carboxylic acid is used.

Example 7 Benzhydryl of (7R) -7-amino-3- [3-bromo-4- (phenyl) phenylthio-thio-3-cephem-4-carboxylic acid

The procedure described in Example 33 is used except that the (7R) -7 [(phenylacetyl) amino] -3- [3-bromo-4- (phenyl) phenylthio] -3-cephem-4-carboxylic acid benzhydryl ester is taken.

Example 7 Benzhydryl of (7R) -7-amino-3 - [(2-trifluoromethoxyphenylthio-3-cephem-4-carboxylic acid)

The procedure described in Example 33 is used, except that the (7R) -7 [(phenylacetyl) amino] -3 - [(2-trifluoromethoxy) phenylthio] -3-cephem-4-carboxylic acid benzhydryl ester is taken.

Example 7 Benzhydryl of (7R) -7-amino-3- (dibenzofuran-2-ylthio) -3-cephem-4-carboxylic acid

The procedure described in Example 33 is used except that the benzhydryl ester of (7R) -7 [(phenylacetyl) amino] -3- (dibenzofuran-2-ylthio) -3-cephem-4-carboxylic acid is used.

Example (7R) -7-amino-3- [4- ^(2-thienyl) feniltio1-3-CEFEM-4-carboxylic acid benzhydryl ester

The procedure described in Example 33 is used except that the benzhydryl ester of (7R) -7 [(phenylacetyl) amino] -3- [4- (2-thienyl) phenylthio] -3-cephem-4-carboxylic acid is used.

Example 7 (7R) -7-Amino-3- (6-chloromethyl) dibenzofuran-2-ylthio-3-cephem-4-carboxylic acid 4-methoxybenzyl ester

The procedure described in Example 33 is used except that the (7R) -7 [(phenylacetyl) amino] -3- [6- (hydroxymethyl) dibenzofuran-2-ylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester is taken, in the presence of a second equivalent of phosphorus pentachloride and pyridine.

Example 7 '(7R) -7-Amino-3- (1H-chloromethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

The procedure described in Example 33 is used except that the (7R) -7 [(phenylacetyl) amino] -3- [7- (hydroxymethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester is taken, in the presence of a second equivalent of phosphorus pentachloride and pyridine.

Example 7b) 4-Amino-3- (2,5-dichlorophenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

The procedure described in Example 33 is used except that the (7R) -7 [(phenylacetyl) amino] -3- (2,5-dichlorophenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester is taken.

Example 7 4-Methoxybenzyl ester of (7R) -7-amino-3- [4- (2-oxazolylmethyl) phenylthio] -3-cephem-4-carboxylic acid

The procedure described in Example 33 is used except that (7R) -7 [(phenylacetyl) amino] -3- [4- (2-oxazolylmethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester is taken.

example (4R-7-amino-3- [4- (1-imidazolylmethylphenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

The procedure described in Example 33 is used except that (7R) -7 [(phenylacetyl) amino] -3- [4- (1-imidazolylmethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester is taken.

Example 7 7R-7-Amino-3- [4- (1-imidazolylmethyl ') phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

The procedure described in Example 33 is used except that (7R) -7 [(phenylacetyl) amino] -3- [4- (1-imidazolylmethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester is taken.

Example 7 (7R ') - 7-Amino-3- [2-bromo-4-methoxycarbonyl) phenylthio-3-cephem-4-carboxylic acid 4-methoxybenzyl ester

The procedure described in Example 33 is used except that (7R) -7 [(phenylacetyl) amino] -3- [2-bromo-4- (ethoxycarbonyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester is taken.

Example 7 7R -7-Amino-3- [4- (2-thiazolyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

The procedure described in Example 33 is used except that (7R) -7 [(phenylacetyl) amino] -3- [4- (2-thiazolyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester is taken.

Example f7Rj-7-Amino-3- [4- (cyanamidoylphenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

The procedure described in Example 33 is used except that the (7R) -7 [(phenylacetyl) amino] -3- [4- (cyanamido) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester is taken.

Example 7 7R-7-Amino-3- [4 - ('2-furyl) phenylthiol-3-cephem-4-carboxylic acid 4-methoxybenzyl ester

The procedure described in Example 33 is used except that the (7R) -7 [(phenylacetyl) amino] -3- [4- (2-furyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester is taken.

Example 7b] 7 - [[2- (2-Amino-4-thiazolyl) -2- (5z-methoxyimino) acetylamino] -3- (4-bromophenylthio) -3-cephem-4-carboxylic acid benzhydryl ester

To a solution of 2- (2-amino-4-thiazolyl) -2- (1 ', 7-methoxyimino)] acetic acid (40 mg, 0.20 mmol) and 1-hydroxybenzotriazole (27 mg, 0.20 mmol) in DMF (2 mL) dicyclohexylcarbodiimide (45 mg, 0.22 mmol) was added. After stirring for 15 min, a solution of (7R) -7-amino-3- (2-bromophenylthio) -3-cephem-4-carboxylic acid benzhydryl ester (110 mg, 0.20 mmol) in DMF (1.5 mL) was added. The mixture was stirred at room temperature overnight, then partitioned between 20% hexane / EtOAc (20 mL) and water (50 mL). The organic layer was dried over sodium sulfate and the solvent was removed by rotary evaporation. The title product is chromatographed on silica gel (30% EtOAc / hexane) to give 74 mg (50%) of the title compound.

Using essentially the same procedure as described in Example 51, the compounds of Example 5282 were prepared.

Example 7 Benzyl-7 - [[2- (2-amino-4-thiazolyl) -2- (5-tri-methoxyimino) acetylamino] -3- (biphenylthio) -3-cephem-4-carboxylic acid benzhydryl ester

Use the same procedure as in Example 51, except that the reagents are 2- (2-amino-4-thiazolyl) -2- (5H-methoxyimino) acetic acid and (7R) -7-amino-3- (biphenylthio) -3-cephem-4-carboxylic acid benzhydryl ester.

Example 7S (7R) -7 - [[2- (2-Amino-4-thiazolyl) -2- (5m-hydroxyimino) acetyl] -amino-3- (biphenylthio) -3-cephem4-carboxylic acid benzhydryl ester

Use the same procedure as in Example 51 except that the reagents are 2- (2-amino-4-thiazolyl) -2- (1 H -hydroxyimino) acetic acid and (7 R) -7-amino-3- (biphenylthio) -3-cephem -4-Carboxylic acid benzhydryl ester.

Example (7R) -7 - [[2-f2-Amino-4-tiazoIil) -2-F5M-hidroksiiminojacetil] -amino] -3- ^{(2-jodfeniltio)} -3cefem-4-carboxylic acid 4-methoxybenzyl ester

Use the same procedure as in Example 51 except that the reagents are 2- (2-amino-4-thiazolyl) -2- (5'-hydroxyimino) acetic acid and (7R) -7-amino-3- (2-iodophenylthio) - 3-Cephem-4-carboxylic acid 4-methoxybenzyl ester.

EXAMPLE f7Rj-7-R 2? -2-Amino-4-thiazolyl] -2-oxo-7-hydroxyimino-acetyl-1-amino} -3- [4- (ethoxycarbonyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

Using the same procedure as in Example 51, only the reagents are 2- (2-amino-4-thiazolyl) -2- (5z'-hydroxyimino) acetic acid and (7R) -7-amino-3- [4- (ethoxycarbonyl) phenylthio ] -3cephem-4-carboxylic acid 4-methoxybenzyl ester.

Example 7 (7R) -7 - [[2- (2-amino-4-thiazolyl) -2 - [[[5'-tert-butoxy) carbonyl-methoxyiminolacetylamino] -3- [4-f2-thienyl) phenylthiol -3-Cephem-4-carboxylic acid 4-methoxybenzyl ester

Use the same procedure as in Example 51 except that the reagents are 2- (2-amino-4-thiazolyl) -2- [5z> 2- (tert-butoxy) carbonylmethoxyimino] acetic acid and (7R) -7-amino-3- [4 - (2-Thienyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

Example 7 (7R) -7 - [[2- (2-Amino-4-thiazolyl] -2 - [[5 '- (tert-butoxycarbonylmethoxyimino] acetylamino) -3- [4-f2-furyl) phenylthio] -3- cephem-4-carboxylic acid 4-methoxybenzyl ester

Use the same procedure as in Example 51 except that the reagents are 2- (2-amino-4-thiazolyl) -2- [5z / z- (tert-butoxy) carbonylmethoxyimino] acetic acid and (7R) -7-amino-3- [4 - (2-Furyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

Example (7Rj-7-l [2-f2-amino-4-thiazolyl) -2 - ('5ZZZ-2-fluoroethoxyimino) acetylamino] -3- (' 2-iodophenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

Using the same procedure as in Example 51, only the reagents are 2- (2-amino-4-thiazolyl) -2- (5z (-2-fluoroethoxyimino) acetic acid) and (7R) -7-amino-3- (2-iodophenylthio) - 3-Cephem-4-carboxylic acid 4-methoxybenzyl ester.

Example 7 Benzhydryl of (7 R '- [? - 2-thienylacetyl) amino] -3- [6- (chloromethyl) dibenzofuran-3-ylthio-3-cephem-4-carboxylic acid

Following the same procedure as in Example 51, only the reagents are 2-thienylacetyl chloride-pyridine and (7R) -7-amino-3- [6- (chloromethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid benzhydryl ester.

Example (7R ') - [(2-Thienylacetyljamino-3- [6-chloromethyl] dibenzofuran-1-ylthio] -3-cephem-4-carboxylic acid benzhydryl ester

Using the same procedure as in Example 51, only the reagents are 2-thienylacetyl chloride-pyridine and (7R) -7-amino-3- [6- (chloromethyl) dibenzofuran-1-ylthio] -3-cephem-4-carboxylic acid benzhydryl ester.

example (7Rj- [trans-2-amino-4-thiazolyl) acetylamino] -3- (2-bromophenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

Using the same procedure as in Example 51, only the reagents are (2-amino-4-thiazolyl) acetic acid and (7R) -7-amino-3- (2-bromophenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

Example (7R ') - [[(2-Amino-4-thiazolyl) acetylaminol-3-f2-iodophenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

Using the same procedure as in Example 51, only the reagents are (2-amino-4-thiazolyl) acetic acid and (7R) -7-amino-3- (2-iodophenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

Example 7 7R - [(2-Furylacetyl) aminol-3- [4- (2-oxazolylmethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

Using the same procedure as in Example 51, only the reagents are 2-furylacetic acid and (7R) -7-amino-3- [4- (2-oxazolylmethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

Example 63a Benzhydryl ester of (7R) - [(2-furylacetyl) amino] -3- [4- (2-imidazolylmethyl) phenylthio] -3-cephem-4-carboxylic acid

Using the same procedure as in Example 51, only the reagents are 2-furylacetic acid and (7R) -7-amino-3- [4- (2-imidazolylmethyl) phenylthio] -3-cephem-4-carboxylic acid benzhydryl ester.

Example f7Rj- [f4-bromfenilacetiljamino] -3-I ^/ 3-dibenzofuran-3-iltioj CEFEM-4-carboxylic acid benzhydryl ester

Using the same procedure as in Example 51, only the reagents are 4-bromophenylacetyl chloride and (7R) -7-amino-3- (dibenzofuran-3-ylthio) -3-cephem-4-carboxylic acid benzhydryl ester.

Example (7R ') - [(' 2-Iodophenylacetyljamino-3- (2-bromophenylthio) -3-cephem-4-carboxylic acid benzhydryl ester)

Using the same procedure as in Example 51, only the reagents are 2-iodophenylacetyl chloride and (7R) -7-amino-3- (2-bromophenylthio) -3-cephem-4-carboxylic acid benzhydryl ester.

example (7Rj- [f (2-iodophenylthio) acetylamino] -3- (f2-iodophenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

The same procedure as in Example 51 is used except that the reagents are 2 (iodophenylthio) acetic acid and (7R) -7-amino-3- (2-iodophenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

example (7R) - [f (2-iodophenylthio ') acetylamino] -3- (' biphenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

Using the same procedure as in Example 51, only the reagents are 2 (iodophenylthio) acetic acid and (7R) -7-amino-3- (biphenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

Example 7 (R) - [((Trifluoromethylthio) acetylamino) -3- [4- (2-oxazolyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

Using the same procedure as in Example 51, the reagents are (trifluoromethylthio) acetic acid and (7R) -7-amino-3- [4- (2-oxazolyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

Example 7 (7R ') -? - (Trifluoromethylthio) acetylamino-3- [2-bromo-4- (' ethoxycarbonyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

Following the same procedure as in Example 51, only the reagents are (trifluoromethylthio) acetic acid and (7R) -7-amino-3- [2-bromo-4- (ethoxycarbonyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

example (7R) -7 - [[2-f2-furyl) -2- (sz'z-methoxyimino ') acetylamino-3-f2-bromophenylthio) -3-cephem-4-carboxylic acid benzhydryl ester

Using the same procedure as in Example 51, only the reagents are 2- (2-furyl) -2 (5N-methoxyimino) acetic acid and (7R) -7-amino-3- (2-bromophenylthio) -3-cephem- Benzhydryl ester of 4carboxylic acid.

Example (7R ') - 7 - [[2- (2-Furyl) -2- (5zz-methoxyimino') acetylamino] -3- (dibenzofuran-2-ylthio ') -3-cephem-4-carboxylic acid benzhydryl ester

Use the same procedure as in Example 51 except that the reagents are 2- (2-furyl) -2 (rin-methoxyiminoacetic acid and (7R) -7-amino-3- (dibenzofuran-2-ylthio) -3-cephem-4-carboxylic acid benzhydryl ester.

Example 7 (7R) -7 - [[2- (2-Furyl) -2- (transmethoxyimino) acetyl] amino] -3- [4- (1-methyl-2-imidazolyl) phenylthio-13-cephem-4-carboxylic acid benzhydryl ester

Using the same procedure as in Example 51, only the reagents are 2- (2-furyl) -2 (5zn-methoxyimino) acetic acid and (7R) -7-amino-3- [4- (1-methyl-2-imidazolyl). ] phenylthio] -3cephem-4-carboxylic acid benzhydryl ester.

Example 7 Benzhydryl of (7R) -7 - [[2- (2-furyl) -2- (methoxyimino) acetylamino] -3- [6- (hydroxymethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid

Using the same procedure as in Example 51, only the reagents are 2- (2-furyl) -2 (rin-methoxyiminoacetic acid) and (7R) -7-amino-3- [6- (hydroxymethyl) dibenzofuran-3-ylthio] -cephem- Benzhydryl ester of 4-carboxylic acid.

Example 7b) 7 - [('D-Phenylglycyl) aminol-3 - (' dibenzofuran-1-ylthio ') - 3-cephem-4-carboxylic acid benzhydryl ester

This compound was prepared by reaction of D-phenylglycyl chloride hydrochloride with benzhydryl ester of (7R) -7-amino-3- (dibenzofuran-1-ylthio) -3-cephem-4-carboxylic acid in tetrahydrofuran and aqueous sodium bicarbonate.

Example 7 Benzhydryl of (7R) -7- [(D-phenylglycyl) amino] -3- (dibenzofuran-2-ylthio) -3-cephem-4-carboxylic acid

This compound was prepared by reaction of D-phenylglycyl chloride hydrochloride with benzhydryl ester of (7R) -7-amino-3- (dibenzofuran-2-ylthio) -3-cephem-4-carboxylic acid in the presence of tetrahydrofuran and aqueous sodium bicarbonate.

Example 7 Benzhydryl of (7R) -7- [(D-phenylglycyl) amino] -3- (dibenzofuran-3-ylthio) -3-cephem-4-carboxylic acid

This compound was prepared by reacting D-phenylglycyl chloride hydrochloride and benzhydryl ester of (7R) -7-amino-3- (dibenzofuran-3-ylthio) -3-cephem-4-carboxylic acid in tetrahydrofuran and aqueous sodium bicarbonate.

Example 7 7R) -f (D- (2-Formyloxy) phenylacetyl) amino-3- [4- (2-furyl) phenylthiol-3-cephem-4-carboxylic acid 4-methoxybenzyl ester

Following the same procedure as in Example 51, only the reagents are D- (2-formyloxy) phenylacetic acid and (7R) -7-amino-3- [4- (2-furyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

Example 7 (7R) -7 - [(Cyanoacetyl) amino] -3- [3- (imidazolylmethyl) phenylthiol-3-cephem-4-carboxylic acid 4-methoxybenzyl ester

Using the same procedure as in Example 51, only the reagents are cyanoacetic acid and (7R) -7-amino-3- [3- (imidazolylmethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

Example 7 (R) -7- (Cyanoacetyl) aminol-3- [3-dibenzothien-1-ylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

Using the same procedure as in Example 51, only the reagents are cyanoacetic acid and (7R) -7-amino-3- [3-dibenzothien-1-ylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

Example 7 (7R) -7-N- (Cyanoacetyl) aminol-3- [4- (trifluoromethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

Using the same procedure as in Example 51, only the reagents are cyanoacetic acid and (7R) -7-amino-3- [4- (trifluoromethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester.

example (7R) -7 - [(α- [D-4-ethyl-2,3-dioxo-1-piperazinecarboxamido-1-a-phenylacetyl) amino] -3- [2-iodo-4-cyanamido) phenylthio-3-cephem-4- carboxylic acid 4-methoxybenzyl ester

This compound was prepared by reaction of α- [D-4-ethyl-2,3-dioxo-1-piperazinecarboxamido-α-phenylacetyl chloride and (7R) -7-amino-3- [2-iodo-4- (cyanamido) phenylthio] -3 -acephem-4-carboxylic acid 4-methoxybenzyl ester in the presence of tetrahydrofuran and aqueous sodium bicarbonate.

Example 7 (7R) -7 - [(a- [D-4-Ethyl-2,3-dioxo-1-piperazinecarboxamidol-q-phenylacetyl) amino] -3- [dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid 4-Methoxybenzyl ester

This compound was prepared by reaction of α- [D-4-ethyl-2,3-dioxo-1-piperazinecarboxamido-α-phenylacetyl chloride and (7R) -7-amino-3- [dibenzofuran-3-ylthio] -3-cephem-4- carboxylic acid 4-methoxybenzyl ester in tetrahydrofuran and aqueous sodium bicarbonate solution.

Example 7 Benzhydryl of (7R) -7- [phenylacetyl) aminol-3- [6- (chloromethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid

This compound was prepared by reacting the benzhydryl ester of (7R) -7 - [(phenylacetyl) amino] -3- [6- (hydroxymethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid with 1.1 equivalents of thionyl chloride and of pyridine in methylene chloride at 0 ° C.

By essentially the same procedure as described in Example 83, the compounds of Examples 84-88 below are obtained.

Example 7 '(7R) -7-Phenylacetyl) amino] -3- [7- (chloromethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared by reacting the (7R) -7 - [(phenylacetyl) amino] -3- [7- (hydroxymethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester with 1.1 equivalent of thionyl chloride and pyridine methylene chloride at 0 ° C.

Example 7b) -7 - [('2-Furylacetyl) aminol-3- [7- (chloromethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared by reacting (7R) -7 - [(2-furylacetyl) amino] -3- [7- (hydroxymethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester with 1.1 of thionyl chloride equivalent and pyridine methylene chloride at 0 ° C.

example (7R) -7- [2- (2-thienylacetyl) -2-trans-methoxyimino) acetyljamino-3- [4- [4'-chloromethyl] phenyl] phenyl] thio-3-cephem-4-carboxylic acid 4-methoxybenzyl ester

This compound was prepared by reacting the (7R) -7 - [(2-thienylacetyl) amino] -3- [4- [4 '(hydroxymethyl) phenyl] phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester with 1, 1 equivalent of thionyl chloride and pyridine in methylene chloride at 0 ° C.

example

C7R) -7- [2- (2-amino-4-thiazolyl) -2- (2-fluoroethoxyimino) acetyl] amino] -3- [4 - [(chloromethyl ') phenylthio] -3-cephem-4-carboxylic acid 4-Methoxybenzyl ester

This compound was prepared by reacting (7R) -7 - [[2- (2-amino-4-thiazolyl) -2- (trans) -2-fluoroethoxyimino) acetyl] amino] -3- [4- (hydroxymethyl) phenylthio ] -3-cephem-4-carboxylic acid for 4-methoxy63 benzyl ester with 1.1 equivalent of thionyl chloride and pyridine in methylene chloride at 0 ° C.

Example (7RJ-7 - [(α-β-D-4-ethyl-2,3-dioxo-1-piperazinecarboxamide-α-phenylacetyl) amino] -3- [4-chloromethyl) phenylthio-3-cephem-4-carboxylic acid 4-methoxybenzyl ester This compound was prepared by reacting 7 - [(α- [D-4-ethyl-2,3-dioxo-1-piperazinecarboxamide] -α-phenylacetyl) amino] -3- [4- (hydroxymethyl) phenylthio] -3- of 4-methoxybenzyl ester of cephem-4-carboxylic acid with 1.1 equivalent of thionyl chloride and pyridine in methylene chloride at 0 ° C.

Example 7 (7R) -7 - [(Phenylacetyl ') amino] -3- [6-pyridin-1-iomethyl) dibenzofuran-3-ylthiol-3-cephem-4-carboxylic acid benzhydryl ester hydrochloride This compound was prepared by reacting (7R) -7 - Benzhydryl ester of [(phenylacetyl) amino] -3- [6- (chloromethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid with 4 equivalents of pyridine acetonitrile. The desired material is obtained by precipitation with diethyl ether.

Example 7 (R) -7-Methylphenylacetyl) amino] -3- [6- (N-methylimidazol-1-ylmethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid benzhydryl ester hydrochloride This compound was prepared by reacting (7R) -7- [(Phenylacetyl) amino] -3- [6- (chloromethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid benzhydryl ester with 4 equivalents of 1-methylimidazole acetonitrile. The desired material is obtained by precipitation with diethyl ether.

Example (7R) -7 - [(Phenylacetyl) amino] -3- [7-pyridine-1-iomethyl] dibenzofuran-3-ylthio-3-cephem-4-carboxylic acid benzhydryl ester hydrochloride This compound was prepared by reacting (7R) -7 - [( phenylacetyl) amino] -3- [7- (chloromethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid benzhydryl ester with 4 equivalents of pyridine acetonitrile. The desired material is obtained by precipitation with diethyl ether.

Example 7 (7R) -7 - [(2-Furylacetyl) amino] -3- [7- (N-methylimidazol-1-iomethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester hydrochloride

This compound was prepared by reacting (7R) -7 - [(2-furylacetyl) amino] -3- [7 (chloromethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester with 4 equivalents of 1- methylimidazole acetonitrile. The desired material is obtained by precipitation with diethyl ether.

Example 7 (7R) -7- [2- (2-Furylacetyl) amino] -3- [6- (pyridin-1-iomethyl) dibenzofuran-2-ylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester hydrochloride

This compound was prepared by reacting the (7R) -7 - [(2-furylacetyl) amino] -G- [6- (chloromethyl) dibenzofuran-2-ylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester with 4 equivalents of pyridine acetonitrile. The desired material is obtained by precipitation with diethyl ether.

Example 7 (7R) -7 - [[2- (2-thienyl) thienyl] -2- (5m-methoxyiminoacetyljaminol-3- [4- (N-pyridin-lyomethyl) phenyl] thio-3-cephem-4-carboxylic acid 4-methoxybenzyl ester hydrochloride

This compound was prepared by reacting (7R) -7 - [[2- (2-thienylacetyl) -2- (sm-methoxyimino) acetyl] amino] -3- [4- (chloromethylmethyl) phenylthio] -3-cephem-4- of the carboxylic acid 4-methoxybenzyl ester with 4 equivalents of pyridine acetonitrile. The desired material is obtained by precipitation with diethyl ether.

example

C7R) -7- [2- ('2-amino-4-thiazolyl') -2- (5'm-2-fluoroethoxyimino) acetylamino] -3- [4- (N-methylimidazole-1-iomethyl) phenylthio] -3-cephem -4-Carboxylic acid 4-methoxybenzyl ester hydrochloride

This compound was prepared by reacting (7R) -7 - [[2- (2-amino-4-thiazolyl) -2- (sm-2-fluoroethoxyimino) acetyl] amino] -3- [4- (chloromethylmethyl) phenylthio] - Of 3-cephem-4-carboxylic acid to 4-methoxybenzyl ester with 4 equivalents of 1-methylimidazole acetonitrile. The desired material is obtained by precipitation with diethyl ether.

example (7R) -7 - [[2- (2-amino-4-thiazolyl) -2- (5m- (tert-butoxy) carbonylmethoxyimino ') acetylaminol-314-N-methylimidazol-1-iomethyl) phenylthio] -3-cephem -4-Carboxylic acid 4-methoxybenzyl ester hydrochloride

This compound was prepared by reacting (7R) -7 - [[2- (2-amino-4-thiazolyl) -2 - ([tert- (tert-butoxy) carbonylmethoxyimino) acetyl] amino] -3- [4- (chloromethylmethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester with 4 equivalents of 1-methylimidazole acetonitrile. The desired material is obtained by precipitation with diethyl ether.

Example 7 (7R) -7 - [(α-β-D-4-ethyl-2,3-dioxo-1-piperazinecarboxamide] -α-phenylacetyl) amino] -3- [4- (pyridin-1-iomethyl) phenylthio] -3-cephem -4-Carboxylic acid 4-methoxybenzyl ester hydrochloride

This compound was prepared by reaction of 7 - [(α- [D-4-ethyl-2,3-dioxo-1-piperazinecarboxamide] -α-phenylacetyl) amino] -3- [4- (chloromethyl) phenylthio] -3-cephem. Of 4-carboxylic acid to 4-methoxybenzyl ester with 4 equivalents of pyridine acetonitrile. The desired material is obtained by precipitation with diethyl ether.

Example 7 (7R ') - 7- [(2,4-Dibromophenylacetyl) amino] -3- [4' - ( ^, pyridin-1-iomethyl) biphenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester hydrochloride

This compound was prepared by reacting (7R) -7 - [(2,4-dibromophenylacetyl) amino] -3- [4 '(chloromethyl) biphenylylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester with 4 equivalents of pyridine acetonitrile. The desired material is obtained by precipitation with diethyl ether.

Example 7R) -7 - [[('2,4-Dichlorophenylthio') acetyl] amino] -3- [2-bromo-4- (N-methylimidazol-thiomethyl) phenylthio] -3-cephem-4-carboxylic acid 4- methoxybenzyl ester hydrochloride

This compound was prepared by reacting the (7R) -7 - [[(2,4-dichlorophenylthio) acetyl] amino] -3- [2-bromo-4- (chloromethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester with 4 equivalents of 1-methylimidazole acetonitrile. The desired material is obtained by precipitation with diethyl ether.

Example 100 (7R) -7- [[2,4-Dichlorophenylthio) acetylamino] -3- [2-bromo-4- (pyridin-1-iomethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester hydrochloride

This compound was prepared by reacting (7R) -7 - [[(2,4-dichlorophenylthio) acetyl] amino] -3- [2-bromo-4- (chloromethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester with 4 equivalents of pyridine acetonitrile. The desired material is obtained by precipitation with diethyl ether.

Example 101 (7R) -7- [(Phenylacetyl) amino] -3- (4-biphenylthio) -3-cephem-4-carboxylic acid (7R) -7 - [(phenylacetyl) amino] -3- (4-biphenylthio) -3 Benzhydryl ester of -cefem-4-carboxylic acid (450 mg, 0.670 mmol) and anisole (0.4 mL) in dichloromethane (3 mL) were treated with trifluoroacetic acid (4 mL) at 0 ° C. After 1 hour, the volatiles were removed by rotary evaporator. The residue was chromatographed on a silica gel column (dichloromethane followed by 10% AcOH / dichloromethane) to give 232 mg (69%) of the title compound. 'H. NMR (dg-acetone) δ 3.37 (d, 1H, J = 18), 3.63 (d, 1H, J = 18), 3.84 (d, 1H, J = 16), 3.92 ( d, 1H, J = 16), 5.25 (d, 1H, J = 5), 5.93 (dd, 1H, J = 5.9), 7.2-7.8 (m, 14H), 8.15 (d, 1H, J = 9); IR (KBr) 1513.1619, 1713.1784, 3377 cm @ ^-1 .

Example 102 f7R) -7 - [(Phenylacetyl) amino] -3- (4-bromophenylthio) -3-cephem-4-carboxylic acid

To a solution of (7R) -7 - [(phenylacetyl) amino] -3- (4-bromophenylthio) -3-cephem-4-carboxylic acid benzhydryl ester (80 mg, 0.12 mmol) in phenol (230 mg) at 45 ° C trifluoroacetic acid (9 μΐ) was added. After 1.5 hours, the volatiles were removed by rotary evaporation and the residue was triturated with isopropanol / hexane. The resulting white solid was washed with ether and dried in vacuo. 48 mg (79%) of the title compound are obtained. 1 H NMR (d ₆ -acetone) δ 3.67 (d, 1H, J = 16), 3.75 (d, 1H, J = 16), 3.64 (d, 1H, J = 18), 3 , 67 (d, 1H, J = 18), 5.25 (d, 1H, J = 5), 5.92 (d, 1H, J = 5), 7.2-7.7 (m, 9H). ; IR (KBr) 1347, 1386, 1606, 1756, 3276 cm ^-1 .

Example 103 (7R) -7- [[2- (2-Amino-4-thiazolyl) -2- (5m-methoxyimino) acetyl] amino] -3- (4-bromophenylthio-3-cephem-4-carboxylic acid)

To the benzhydryl ester of (7R) -7 - [[2- (2-amino-4-thiazolyl) -2- (5-methoxyimino) acetyl] amino] -3- (4-bromophenylthio) -3-cephem-4-carboxylic acid (71 mg, 0.096 mmol) and anisole (0.2 mL) were added trifluoroacetic acid at 0 ° C. After 1 hour, the volatiles were removed by rotary evaporator. The crude product was chromatographed by reverse phase chromatography using Cis adsorbent (acetonitrile / water 3: 2) to afford 11.6 mg (21%) of the title compound.

Using essentially the same procedures as described in Examples 101-103, the materials of Examples 104-141 can be similarly obtained.

Example 104 (7R) -7- [[2- (2-Amino-4-thiazolyl) acetyl] amino] -3- (2-bromophenylthio) -3-cephem-4-carboxylic acid

Example 105 (7 R ') - 7 - ([2- ^{(2-amino-4-thiazolyl)} acetyl ") aminol-3- (2-iodfeniltio) -3-CEFEM-4-carboxylic acid

Example 106 (7R) -7- [[2- [2-Amino-4-thiazolyl]) - 2- (5m-hydroxyimino ') acetyl) amino] -3- [4- (ethoxycarbonyl) phenylthio] -3-cephem-4-carboxylic acid

Example 107 (7R) -7- [2- (2-Amino-4-thiazolyl) -2- (sm-methoxyimino) acetyl) amino] -3- (2-iodophenylthio) -3-cephem-4-carboxylic acid

Example 108 (7R) -7 - [[2- (2-Amino-4-thiazolyl) -2-fluoroethoxyimino) acetyl ') amino] -3- (2-iodophenylthio') - 3-cephem-4-carboxylic acid

Example 109 (R) -7 - [[2- (2-Amino-4-thiazolyl) -2- (5m-carboxymethoxyimino ') acetyl) amino] -3- [4- (2-thienyl) phenylthio] -3-cis-fem-4-carboxylic acid

Example 110 ('7R) -7- [fa -? - 4-Ethyl-2,3-dioxo-1-piperazinecarboxamidol-α- (hydroxyphenyl) acetyl) amino] -3- [2-iodo-4- (cyanamido) phenylthio] - 3-Cephem-4-carboxylic acid

Example 111 ('7R) -7 - [(' α- [D-4-Ethyl-2,3-dioxo-1-piperazinecarboxamide] -q-hydroxyphenyl) acetyl) amino-13- [dibenzofuran-3-ylthio] -3- cephem-4-carboxylic acid

Example 112 (7R) -7 - [(2-Iodophenylthioacetyl) amino] -3- (2-iodophenylthio) -3-cephem-4-carboxylic acid

Example 113 (7R) -7 - [(2-Iodophenylthioacetyl) amino] -3- ('biphenylthio) -3-cephem-4-carboxylic acid

Example 114 (7R) -7- (Cyanoacetyl) amino] -3- [3-imidazolylmethyl) phenylthio-3-cephem-4-carboxylic acid

115 Pavy zdys ^(, 7R) -7-f ( 'cianacetil) aminoĮ-3- (l-dibenzotien ~ ylthio) -3-CEFEM-4-carboxylic acid

Example 116 (7R) -7 - [(Cyanoacetyl) amino] -3- [4- (trifluoromethyl) phenylthio] -3-cephem-4-carboxylic acid

Example 117 (7R) -7- [(2-Thienylacetyl) amino] -3- [6- (chloromethyl) dibenzofuran-3-ylthio] -3-ceferno-4-carboxylic acid

Example 118 (7R) -7- (2-Thienylacetyl) amino] -3- [dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid

Example 119 (7R) -7 - [(2-Furylacetyl) amino] -3- [4- (2-oxazolylmethyl) phenylthiol-3-cephem-4-carboxylic acid

Example 120 (7R ~) -7- [f2-Furylacetyl ') aminol-3- [4- (1-imidazolylmethyl) phenylthio] -3-cephem-4-carboxylic acid

Example 121 (7R) -7 - [[(trifluoromethyl) thioacetyl] amino] -3- [4- (2-oxazolylmethyl) phenylthio] -3-cephem-4-carboxylic acid

Example 122 (7R) -7- [(Trifluoromethyl) thioacetylamino] -3- [2-bromo-4- (ethoxycarbonyl) phenylthio] -3-cephem-4-carboxylic acid

Example 123 (7R) -7- [D - (2-Formyloxy) phenylacetyl) amino] -3- [4- (2-furyl) phenylthio] -3-cephem-4-carboxylic acid

Example 124 (7R) -7- [(Phenylacetyl) amino] -3- (dibenzofuran-1-ylthio) -3-cephem-4-carboxylic acid

Example 125 (7R) -7- [(Phenylacetyl) amino] -3-dibenzofuran-3-ylthio) -3-cephem-4-carboxylic acid

Example 126 (7R) -7-Methylphenylacetyl) amino-3- (6-hydroxymethyl-dibenzofuran-3-ylthio) -3-cephem-4-carboxylic acid

Example 127 (7R) -7 - [(Phenylacetyl) amino] -3- (7-hydroxymethyl-dibenzofuran-3-ylthio) -3-cephem-4-carboxylic acid

Example 128 (7R) -7-FFD-phenylglycyl) amino] -3- ^{(dibenzofuran-l-ylthio>)} -3-CEFEM-4-carboxylic acid

Example 129 (7R) -7 - [('D-Phenylglycylaminol-3- (dibenzofuran-2-ylthio) -3-cephem-4-carboxylic acid)

Example 130 (7R) -7- [2- (2-FurB-2- (Syn-methoxyimino) acetyl) amino] -3- (dibenzofuran-1-ylthio) -3-cephem-4-carboxylic acid

Example 131 (7R) -7- [2- (2-Furyl) -2- (syn-methoxyimino) acetyl) amino] -3-dibenzofuran-2-ylthio) -3-cephem-4-carboxylic acid

Example 132 ( '7R) -7 - [(2- (2-amino-4-thiazolyl) -2- (5m-methoxyimino) acetyl) amino1-3- ^{(6hidroksimetildibenzofuran-2-ylthio,)} -3-4-CEFEM -carboxylic acid

Example 133 (7R) -7 - [(2 - ('2-Amino-4-thiazolyl) acetyl') amino-3- (6-hydroxymethyl-dibenzofuran-3-ylthio ') - 3-cephem-4-carboxylic acid

Example 134 (7R) -7 - [(2- (2-furyl) -2- (methoxyimino) acetyl) amino] -3- ^{(7-hidroksimetildibenzofuran-3iltio)} -3-CEFEM-4-carboxylic acid

Example 135 (7R) -7- (2- (2-Furyl) -2- (methoxyimino) acetyl) amino] -3- (7-hydroxymethyl-dibenzofuran-ylthio) -3-cephem-4-carboxylic acid

Example 136 Internal salt of (7R) -7-phenylphenylacetyl] amino] -3- [6-pyridiniomethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid

Example 137 Internal salt of (7R) -7 - [(phenylacetyl) amino] -3- [6- (N-methylimidazol-1-ylmethyl) dibenzofuran-3-ylthio] -3cephem-4-carboxylic acid

Example 138 Internal salt of ( ⁽ 7R) -7- [(2-thienylacetyl) amino] -3- [6- (N-methylimidazol-1-ylmethyl) dibenzofuran-3-ylthio] -3cephem-4-carboxylic acid

Example 139 Internal salt of (7R) -7 - [(2-thienylacetyl) amino] -3- [6- (pyridinomethyl) dibenzofuran-3-ylthio] -3-cephem-4-carboxylic acid

Example 140 Internal salt of (7R) -7- [(2-thienylacetyl) amino] -3- (6- (pyridinomethyl) dibenzofuran-2-ylthio] -3-cephem-4-carboxylic acid

Example 141 (7R) -7- [2- (2-Amino-4-thiazolyl) -2- (s-n-hydroxyimino) acetylamino] -3- (2-iodophenylthio) -3-cephem-4-carboxylic acid

Example 142 Sodium salt of (7R) -7 - [(phenylacetyl) amino] -3- [4 - [(3-hydroxymethyl) phenylphenylthio] -3-cephem-4-carboxylic acid (Pd coupling)

To a stirred mixture of (7R) -7 - [(phenylacetyl) amino] -3- (4-iodophenylthio) -3-cephem-4-carboxylic acid (25.0 mg, 0.045 mmol), 3-hydroxymethyl-1-trimethylstanyl-benzene (16, A solution of 3 mg, 0.060 mmol), tri (2-furyl) phosphine (1.1 mg), sodium bicarbonate (4.2 mg, 0.045 mmol) and 2,6-di-t-butyl-4-methylphenol (2 mg) in N Trimethyl (dibenzylideneacetone) dipaladium (O) (4.5 mg, 0.0049 mmol) was added to -methylpyrrolidinone (0.3 mL). The mixture was heated at 65 ° C for 2 hours and then quenched by the addition of 1% aqueous sodium bicarbonate solution (10 mL). The resulting solution was chromatographed on chromium using reverse phase chromatography (Cis adsorbent, 30% acetonitrile / water) to give 9.2 mg (37%) of the title compound. ¹ H NMR (d-acetone) δ 3.35 (d, 1H, J = 16), 3.38 (d, 1H, J = 16), 3.64 (d, 1H, J = 18), 3, 67 (d, 1H, J = 18), 5.23 (d, 1H, J = 5), 5.83 (dd, 1H, J = 5.9), 7.2-7.8 (m, 13H ), 8.15 (d, 1H, J = 9); IR (KBr) 1387, 1610, 1654, 1762, 3264 cm ^-1 .

According to the procedure detailed in Example 142 above, the compounds of the present invention described in Examples 143-156 can be obtained.

Example 143 Sodium salt of (7R) -7 - [(thienylacetyl) amino] -3- [4- (2-imidazolyl) phenylthio] -3-cephem-4-carboxylic acid

Example 144 Sodium salt of (7R) -7- 1- (2,4-dichlorophenylthio) acetylamino-3- [4- (1-methylimidazol-4-yl) phenylthio] -3-cephem-4-carboxylic acid

Example 145 Sodium salt of (7R) -7 - [(2,4-difluorophenylthio) acetylaminol-3- [4- (1-methylimidazol-4-yl) phenyl] thio-3-cephem-4-carboxylic acid

Example 146

Example 146 f7R) -7- [E2- (2-Furyl) -2- (sm-methoxyimino) acetylamino] -3- [4 - [(T-methylimidazol-4yl) 1-phenylthio] -3-cephem-4-carboxylic acid sodium salt

Example 147 (7R) -7- [α-trans-4-Ethyl-2,3-dioxo-1-piperazinecarboxamido-phenyl-thiacetylamino] -3- (4-methyl-imidazol-4-yl) -phenyl-thio-3-cephem-4-carboxylic acid sodium salt

Example 148 Sodium (7R) -7- [D - [(2-formyloxy) phenylacetyl] arruno] -3- [4 - [(T-methylimidazol-4-yl) 1-phenylthio] -3-cephem-4-carboxylic acid

Example 149 ('7R) -7- [2- (' 2-Amino-4-thiazolyl) -2- ('5m-methoxyimino) acetyl) amino] -3- [4 - [(T-methylimidazol4-yl)] phenylthio] Sodium salt of -3-cephem-4-carboxylic acid

Example 150 (7R ') - 7- (2- (2-Amino-4-thiazolyl) -2- (5m-cyclopentoxyimino) acetyl) amino] -3- [4- [methylmethylimidazol-4-yl) phenylthio] -3-cephem-4 -Sodium salt of a carboxylic acid

Example 151 f7R ") - 7- [f2 - ( '2-amino-4-thiazolyl) ^{-2-F5M-ciklobutoksiimino>)} acetyl) amino] -3- [4- [flmetilimidazol-4-yl) -3- Įfeniltiol cephem-4-carboxylic acid sodium

Example 152 Sodium salt of (7R) -7- [(D - (2-formyloxy) phenylacetylacetyl) amino] -3- [4- (2-furyl) phenylthio] -3-cephem-4-carboxylic acid

Example 153 f7R) -7 - [('4-Chlorophenylacetyl) aminol-3- [2-f2-furyl) phenylthio] -3-cephem-4-carboxylic acid, sodium salt Example 154 f7R) -7 - [[f4-methoxyphenylthio) acetylamine ] -3- [4- (Trifluoromethoxy) -2-phenyl]) phenylthio] -3-cephem-4-carboxylic acid sodium salt

Example 155 ('7R') - 7 - [(2-Thienylacetyl) amino] -3- [2- [3,4-dicyanophenyl) phenylthio] -3-cephem-4-carboxylic acid sodium salt

Example 156 Sodium salt of (7R) -7 - [(phenylacetyl) amino] -3- [2- (2-furyl) phenylthio] -3-cephem-4-carboxylic acid

Example 157 Benzhydryl ester of (7R) -7- [(phenylacetyl) amino] -3- (2-hydroxymethylphenylthio-3-cephem-4-carboxylic acid)

A solution of sodium 2-hydroxymethylbenzentiolate was prepared by adding a solution of sodium bis (trimethylsilyl) amide (1.0 M in THF, 1.86 mL, 1.86 mmol) to a solution of 2-mercaptobenzyl alcohol (276 mg, 1.96 mmol) in DMF ( 8 ml). After 10 minutes, the resulting yellow-orange solution was concentrated on a rotary evaporator to remove THF. This solution was added dropwise to a stirred solution of (7R) -7 - [(phenylacetyl) amino] -3- (trifluoromethanesulfonyloxy) -3-cephem-4-carboxylic acid benzhydryl ester (1.00 g, 1.58 mmol) in dry DMF (15 mL) - At 45 ° C under argon. After 20 min. At -45 ° C, the mixture was quenched with saturated ammonium chloride solution and poured into stirring water (200 mL). After 10 minutes. the resulting white precipitate is filtered off and dried. 0.93 g (95%) of the title compound is obtained. 1 H NMR (CDCl ₃ ) δ 3.03 (d, 1H, J = 18), 3.09 (d, 1H, J = 18), 3.62 (d, 1H, J = 16), 3.66 (d, 1H, J = 16), 4.72 (d, 1H, J = 14), 4.76 (d, 1H, J = 16), 4.97 (d, 1H, J = 4), δ , 75 (dd, 1H, J = 4.9), 6.05 (d, 1H, J = 9), 6.98 (s, 1H), 7.2-7.6 (m, 19H).

Example 158 Benzhydryl ester of (7R) -7 - ((phenylacetyl) aminol-3- (2-bromomethylphenylthio) -3-cephem-4-carboxylic acid

To a stirred solution of triphenylphosphine (90.5 mg, 0.34 mmol) in THF (5 mL) was added carbon tetrabromide (80 mg, 0.24 mmol) at room temperature and under argon. After 20 minutes a solution of (7R) -7 - [(phenylacetyl) amino] -3- (2-hydroxymethylphenylthio) -3-cephem-4-carboxylic acid benzhydryl ester (124 mg, 0.20 mmol) in THF (3 mL) was added to this cloudy white mixture. After stirring overnight at room temperature, the mixture was concentrated by rotary evaporation and the residue was subjected to silica gel chromatography (5 g, 2% methanol / dichloromethane) to give 66 mg (48%) of the title compound. Ή NMR (CDCl ₃ ) δ 3.15 (d, 1H, J = 18), 3.23 (d, 1Η, J = 18),

3.60 (d, 1H, J = 16), 3.64 (d, 1H, J = 16), 4.61 (s, 2H), 5.00 (d, 1H, J = 4), 5, 78 (dd, 1H, J = 4.9), 6.17 (d, 1H, J = 9), 6.99 (s, 1H), 7.2-7.6 (m, 19H).

Example 159 Hydrobromide of (7R) -7 - [(phenylacetyl) amino] -3- (2-isothiuronomethylphenylthio) -3-cephem-4-carboxylic acid benzhydryl ester

To a stirred solution of (7R) -7 - [(phenylacetyl) amino] -3- (2-bromomethylphenylthio) -3-cephem-4-carboxylic acid benzhydryl ester (66 mg, 0.096 mmol) in acetonitrile (1 mL) was added thiourea (6, 0 mg, 0.079 mmol). After 1.5 or. the mixture was concentrated to a yellow oil and subjected to flash chromatography on silica gel (10% methanol / dichloromethane). 30 mg (50%) of the title compound are obtained. ³ H NMR (CDCl ₃ / CD ₃ OD) δ 2.80 (d, 1H, J = 18), 3.31 (d, 1H, J = 18), 3.63 (s, 2H), 4.46 (s, 2H), 5.05 (d, 1H, J = 4), 5.57 (d, 1H, J = 4), 6.91 (s, 1H), 7.1-7.5 (m , 19H).

Example 160 Trifluoroacetic acid salt of (7R) -7 - [(phenylacetyl) amino] -3- (2-isothiuronomethylphenylthio) -3-cephem-4-carboxylic acid

To a stirred solution of (7R) -7 - [(phenylacetyl) amino] -3- (2-isothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid benzhydryl ester hydrobromide (30 mg) in dichloromethane (0.5 mL) was added at 0 ° C. solution of anisole (0.2 mL) in trifluoroacetic acid (0.4 mL). After 1 hour at 0 ° C, the mixture was concentrated on a rotary evaporator and the residue was triturated with ether, filtered and dried. 11.8 mg of the title compound are obtained. Td NMR (CDCl ₃ / CD ₃ OD) δ 3.12 (d, 1H, J = 18), 3.21 (d, 1H, J = 18), 3.58 (d, 1H, J = 16), 3.62 (d, 1H, J = 16)), 4.60 (d, 1H, J = 12), 4.71 (d, 1H, J = 12), 5.01 (d, 1H, J = 4), 5.58 (d, 1H, J = 4), 6.89 (d, 1H, J = 10), 7.2-7.5 (m, 7H), 7.58 (d, 1H, J = 10).

Example 161 4-Methoxybenzyl ester of (7R) -7 - [(phenylacetyl) amino] -3- (2-hydroxymethylphenylthio) -3-cephem-4-carboxylic acid

To a mixture of sodium methoxide (969 mg, 17.9 mmol) in dry THF (50 mL) at 0 ° C was added a solution of 2-mercaptobenzyl alcohol (2.51 g, 17.9 mmol) in dry THF (25 mL). The resulting yellow solution was stirred at 0 ° C for 30 min and then the solvent was evaporated in vacuo. To the resultant thiolate salt is added (7R) - [(phenylacetyl) amino] -3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylic acid 4-methoxybenzyl ester (10.0 g, 17.0 mmol) and the solid mixture is cooled to - 40 ° C. Dry DMF (100 mL) was added to the mixture via a funnel at -45 ° C and a yellow solution was obtained by stirring the mixture at -45 ° C. After 30 minutes of the mixture over 30 mi.

it is allowed to rise to -10 ° C and the mixture is poured into ice water (1 L). After stirring for 15 min, the mixture is filtered, the precipitate is thoroughly washed with water and air dried. Rinse with ether to give the title compound (6.90 g, 71%) as an off-white solid. 1 H NMR (CDCl 3) δ 2.43 (m.s, 1H), 3.06 (d, 1H, J = 18), 3.15 (d, 1H, J = 18), 3.60 (d, 1H, J = 16), 3.63 (d, 1H, J = 16)), 3.81 (s, 3H), 4.75 (d, 1H, J = 14), 4.78 (d, 1H) , J = 14), 4.93 (d, 1H, J = 4), 5.24 (s, 2H), 5.70 (dd, 1H, J = 4.9), 6.32 (d, 1H) , J = 9), 6.88 (d, 2H, J = 10), 7.2-7.6 (m, 11H).

Example 162 4-Methoxybenzyl ester of (7R) -7 - [(phenylacetyl) amino] -3- (2-bromomethylphenylthio) -3-cephem-4-carboxylic acid

This compound is prepared according to the procedure described in Example 158, except using the (7R) - [(phenylacetyl) amino] -3- (2-hydroxymethylphenylthio) -3-cephem-carboxylic acid 4-methoxybenzyl ester.

Example 163 4-Methoxybenzyl ester of (7R) -7-amino-3- (2-bromomethylphenylthio) -3-cephem-4-carboxylic acid

To a stirred mixture of (7R) -7 - [(phenylacetyl) amino] -3- (2-bromomethylphenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (1.24 g, 1.98 mmol) and pyridine (0.320 mL) , A solution of 3.96 mmol) in dichloromethane (7 mL) at -10 ° C was added slowly a solution of phosphorus pentac chloride in dichloromethane (7.32 mL, 3.17 mmol). After 2.5 or. At -10 ° C, the mixture was cooled to -40 ° C and isobutanol (1.82 mL, 19.8 mmol) was added. The mixture was allowed to warm to -10 ° C and stirred for 1 hour. and is distributed between water and dichloromethane. The organic phase is washed with 10% aqueous HCl and saturated aqueous sodium bicarbonate, dried (sodium sulfate) and concentrated by rotary evaporation. The resulting off-white solid was triturated with ether and dried. 504 mg (48%) of the title compound are obtained. 1 H NMR (CD ₃ OD) δ, 3.26 (d, 1H, J = 18), 3.42 (d, 1H, J = 18), 3.58 (s, 3H), 4.71 (d) , 1H, J = 8), 4.77 (d, 1H, J = 8), 4.82 (s, 2H), 5.01 (d, 1H, J = 4), 5.28 (d, 1H) , J = 4), 6.86 (d, 2H, J = 10), 7.33 (d, 2H, J = 10), 7.3-7.6 (m, 4H).

Example 164 4-Methoxybenzyl ester of (7R) -7H-bromomethylphenylacetyl) amino-3- (2-bromomethylphenylthio) -3-cephem-4-carboxylic acid

To a stirred suspension of (7R) -7-amino-3- (2-bromomethylphenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (200 mg, 0.374 mmol) and 4-bromomethylphenylacetic acid (103 mg, 0.449 mmol) in THF (2) mL) at -40 ° C was added phosphorus oxychloride (41.7 μΐ, 0.449 mmol) followed by diisopropylethylamine (0.26 mL, 1.50 mmol). The mixture was stirred overnight at -10 ° C. Water is added and the mixture is extracted with dichloromethane. The organic phase is washed with saturated aqueous sodium bicarbonate, 1M phosphoric acid and brine, dried (sodium sulfate), filtered and concentrated by rotary evaporation. The crude product is purified by column chromatography over silica gel (0.5% methanol / dichloromethane) to give 168 mg (61%) of the desired product. Ή NMR (CDCl ₃ ) δ 3.15 (d, 1H, J = 18), 3.27 (d, 1H, J = 18), 3.61 (s, 2H), 3.82 (s, 3H) , 4.46 (s, 2H), 4.65 (d, 1H, J = 8), 4.68 (d, 1H, J = 8), 4.95 (d, 1H, J = 4), δ , 26 (s, 2H), 5.74 (dd, 1H, J = 4.9), 6.20 (d, 1H, J = 9), 6.86 (d, 2H, J = 10), 7 , 2-7.5 (m, 10H).

Example 165 (7R) -7 - [(4-Isothiuronomethylphenylacetyl) amino] -3- (2-isothiuronomethylphenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester dibromide

To a stirred solution of (7R) -7 - [(4-bromomethylphenylacetyl) amino] -3- (2-bromomethylphenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (168 mg, 0.229 mmol) in acetonitrile (5 mL) was added thiourea ( 34.9 mg, 0.458 mmol). After stirring at room temperature overnight, the solvent was removed by rotary evaporation to give 203 mg (100%) of the title compound as a yellowish fine powder. NMR (CD3OD) δ 4.01 (d, 1H, J = 18), 4.31 (s, 2H), 4.36 (d, 1H, J = 18), 4.54 (s, 3H), δ , 25 (s, 2H), 5.40 (d, 1H, J = 10), 5.43 (d, 1H, J = 10), 5.95 (d, 1H, J = 12), 5.99 (d, 1H, J = 12), 6.02 (d, 1H, J = 4), 6.50 (dd, 1H, J = 4.9), 7.65 (d, 2H, J = 10). , 8.0-8.2 (m, 10H), 8.39 (d, 1H, J = 9), 9.97 (m, 8H).

Example 166 Trifluoroacetic acid salt of (7R) -7- [(4-isothiuronomethylphenylacetyl) amino] -3- (2-isothiuronomethylphenylthio) -3-cephem-4-carboxylic acid

To a stirred mixture of (7R) -7 - [(4-isothiuronomethylphenylacetyl) amino] -3- (2-isothiuronomethylphenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester dibromide (203 mg, 0.229 mmol) and anisole (0.1) ml) suspension of dichloromethane (1 ml) at 0 ° C was added trifluoroacetic acid (1 ml). The suspension is transformed into a solution and the reaction mixture is stirred for 30 min. The solvent is then removed by rotary evaporation. The residue was dissolved in water (150 mL using ultrasound), washed with diethyl ether and filtered. The filtrate is lyophilized to give 205 mg of the title compound. NMR (D ₂ O) δ 3.20 (d, 1H, J = 18), 3.38 (d, 1H, J = 18), 3.61 (s, 2H), 4.40 (s, 2H) , 4.61 (d, 1H, J = 8), 4.64 (d, 1H, J = 8), 5.15 (d, 1H, J = 4), 5.59 (d, 1H, J = 4), 7.2-7.6 (m, 8H).

Example 167 Benzhydryl ester of (7R) -7 - [(phenylacetyl) aminol-3- (2-phenylpyrid-3-ylthio) -3-cephem-4-carboxylic acid

A mixture of 2-bromo-3-hydroxypyridine (2.20 g, 12.6 mmol), phenylboronic acid (2.00 g, 16.3 mmol) and palladium (tetrakis) triphenylphosphine (250 mg) in toluene (30 mL) in ethanol (15 mL) and 5% aqueous sodium hydroxide (15 mL) were degassed with a stream of nitrogen and stirred vigorously at 100 ° C overnight. The mixture was diluted with water (50 mL) and ethyl acetate (100 mL), and the organic layer was dried over sodium sulfate and concentrated. A yellow solid is obtained. This material was suspended in water (100 mL), several mL of IN HCl was added and the resulting solution was extracted with ethyl acetate. The aqueous layer was neutralized with saturated aqueous sodium bicarbonate and re-extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated to an oiled solid which was triturated with 2: 1 hexane / ethyl acetate. 0.98 g of 3-hydroxy-2-phenylpyridine is obtained.

To a stirred solution of 3-hydroxy-2-phenylpyridine (425 mg, 2.48 mmol) in DMF (8 mL) was added sodium bis (trimethylsilyl) amide DMF (2M, 1.36 mL, 2.72 mmol) at room temperature. After a few minutes, a solution of N, N-dimethylthiocarbamoyl chloride (338 mg, 2.72 mmol) in DMF (2 mL) was added to the mixture. After stirring overnight, the mixture is partitioned between water and ethyl acetate, the organic phase is concentrated and chromatographed on silica gel by express chromatography. 536 mg of 3-N, N-dimethylthiocarbamoyl-2-phenylpyridine are obtained. ^{1 H} NMR (CDCl ₃ ) δ 3.23 (s, 3H), 3.40 (s, 3H), 7.3-7.7 (m, 7H), 8.60 (d, 1H, J = 6). . This material is heated in a melted ampoule at 250-255 ° C for 1.5 hours. The product was dissolved in ethanol (10 mL), 10% aqueous potassium hydroxide (4 mL) was added and the resulting mixture was heated under a nitrogen atmosphere at 95-100 ° C for 2 h. The mixture was partitioned between ethyl acetate and aqueous acetic acid solution, the organic phase concentrated and the residue chromatographed on silica gel, eluting with 6: 1 hexane / ethyl acetate. 337 mg of 3-mercapto-2-phenylpyridine are obtained. NMR (CDCl 3) δ 3.47 (s, 1H), 7.11 (m, 1H), 7.45 (m, 3H), 7.64 (m, 3H), 8.47 (d, 1H, J = 5).

To a stirred solution of 3-mercapto-2-phenylpyridine (65 mg, 0.35 mmol) in DMF (1 mL) at 0 ° C was added sodium bis (tetramethylsilyl) amide THF (0.175 mL 2M solution, 0.35 mmol). The resulting solution was poured through a funnel into a stirred solution of (7R) -7 [(phenylacetyl) amino] -3- (trifluoromethanesulfonyloxy) -3-cephem-4-carboxylic acid benzhydryl ester (233 mg, 0.368 mmol) in DMF (5 mL) at -40 ° C. At C. After 30 minutes at -40 ° C, the reaction is quenched by the addition of 10% aqueous ammonium chloride solution and the mixture is partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and concentrated by rotary evaporation. The crude product is purified by chromatography on silica gel (5% methanol / dichloromethane) to give 165 mg of the title compound. Ή NMR (CDCl ₃ ) δ 3.02 (d, 1H, J = 18), 3.23 (d, 1H, J = 18), 3.61 (d, 1H, J = 16), 3.64 ( d, 1H, J = 16), 4.81 (d, 1H, J = 4), 5.79 (dd, 1H, J = 4.9), 6.20 (d, 1H, J = 9), 7.01 (s, 1H), 7.2-7.6 (m, 21H), 7.67 (d, 1H, J = 10), 8.61 (d, 1H, J = 5).

Example 168 Trifluoroacetic acid salt of (7R) -7 - ((phenylacetyl) aminol-3- (2-phenylpyrid-3-ylthio) -3-cephem-4-carboxylic acid

To a stirred solution of (7R) -7 - [(phenylacetyl) amino] -3- (2-phenylpyrid-3-ylthio) -3-cephem-4-carboxylic acid benzhydryl ester (32 mg) and anisole (0.1 mL) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) at 0 ° C. After 0.5 or. At 0 ° C, the mixture is concentrated on a rotary evaporator. The primary product is triturated with ether, filtered and dried. 20.1 mg of the title compound is obtained, which is an off-white solid. ¹ H NMR (CD ₃ OD) δ 3.22 (d, 1H, J = 18), 3.49 (d, 1H, J = 18), 3.55 (d, 1H, J = 16), 3, 60 (d, 1H, J = 16), 5.03 (d, 1H, J = 5), 5.71 (d, 1H, J = 5), 7.27 (m, 5H), 7.55 ( m, 3H), 7.60 (m, 3H), 8.08 (d, 1H, J = 10), 8.59 (d, 1H, J = 5).

Example 169 4-Methoxybenzyl ester of (7R) -7 - [(phenylacetyl) amino] -3- (2-cyanopyrid-3-ylthio) -3-cephem-4-carboxylic acid

To a solution of 3-hydroxypicolininamide (2.00 g, 14.5 mmol) in phosphorus oxychloride (10 mL) was added phosphorus pentachloride (6.00 g, 28.8 mmol) at room temperature. The mixture was refluxed for 90 min and the solvent was distilled off. The residue is poured into water, the aqueous solution is neutralized by the addition of sodium bicarbonate and extracted with ethyl acetate. The organic phase is filtered through silica gel, the filtrate is concentrated, and the residue is subjected to flash chromatography on silica gel. 300 mg of 3-chloro-2-cyanopyridine are obtained. ¹ H NMR (CDCl ₃ ) δ 7.50 (dd, 1H, J = 4.8, 8.4), 7.89 (dd, 1H, J = 1.6, 8.4), 8.63 ( dd, 1H, J = 1.6, 4.8).

To a stirred solution of 4-methoxy-α-toluene thiol (268 mg, 1.74 mmol) in DMF (1 mL) at 0 ° C was added a solution of sodium bis (trimethylsilyl) amide in THF (1.3 mL, 1M, 1.3 mmol). . The resulting solution was poured through a funnel into a solution of 2-cyano-3-chloropyridine (200 mg, 1.45 mmol) in DMF (1 mL) at 0 ° C. After stirring for 2 hours. At 0 ° C, the mixture was poured into water and extracted with ethyl acetate, and the organic extracts were concentrated. The crude product is purified by column chromatography over silica gel to give 2-cyano-3- (4-methoxybenzylthio) pyridine in quantitative yield. Ή NMR (CDCl ₃ ) δ 3.80 (s, 3H), 4.20 (s, 2H), 6.83 (d, 2H, J = 10), 7.22 (d, 2H,

J = 10), 7.34 (dd, 1H, J = 5, 8), 7.66 (d, 1H, J = 8), 8.50 (d, 1H, J = 5). To a solution of this compound (245 mg, 0.96 mmol) and anisole (0.52 mL, 4.8 mmol) in trifluoroacetic acid (1.5 mL) at 0 ° C was added trifluoromethanesulfonic acid (0.25 mL, 2.8 mmol) ). The mixture was allowed to warm to room temperature and then stirred for 1 h, filtered through a pad of silica gel, washing with 1: 1 dichloromethane / ethyl acetate. After concentration of the filtrate, the product is purified by silica gel chromatography to give 158 mg (90%) of the title compound. 1 H NMR (CDCl ₃ ) δ 3.15 (d, 1H, J = 18), 3.60 (d, 1H, J = 18), 3.63 (d, 1H, J = 16), 3.68 (d, 1H, J = 16), 3.80 (s, 3H), 5.04 (d, 1H, J = 4), 5.15 (d, 1H, J = 12), 5.27 (d) , 1H, J = 12), 5.90 (dd, 1H, J = 4, 9), 6.00 (d, 1H, J = 9), 6.81 (d, 2H, J = 10), 7 , 2-7.5 (m, 8H), 7.70 (d, 1H, J = 8), 8.55 (d, 1H, J = 5).

Example 170 (YR, N -ffenylacetaminamine-S-tJ-cyanopyrid-S-ylthio-C-cephemA-carboxylic acid

To a stirred mixture of (7R) -7 - [(phenylacetyl) amino] -3- (2-cyanopyrid-3-ylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (158 mg, 0.277 mmol) and anisole (0, Trifluoroacetic acid (1 mL) was added at 0 ° C to a solution of 4 mL) in dichloromethane (1 mL). After 1 or.

At 0 ° C, the solvent is evaporated off on a rotary evaporator and the residue is triturated with ether, filtered and dried. 104 mg (83%) of the title compound are obtained. Ή NMR (CDC1 ₃₎ δ

3.15 (d, 1H, J = 18), 3.54 (d, 1H, J = 18), 3.65 (d, 1H, J = 16), 3.69 (d, 1H, J = 16) ), 3.80 (d,

1H, J = 4), 5.89 (dd, 1H, J = 4, 9), 6.18 (d, 1H, J = 9), 7.2-7.5 (m, 5H), 7, 53 (dd, 1H, J = 5.8), 7.90 (d, 1H, J = 8), 8.66 (d, 1H, J = 5).

Example 171 4-Methoxybenzyl ester of (7R) -7 - [(phenylacetyl) amino] -3- (1-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid

To a stirred solution of 1-phenylpyrazole (1.44 g, 10.0 mmol) in THF (7 mL) at -30 ° C was added a solution of n-butyllithium in hexane (1.6M, 6.88 mL, 11.0 mmol). After 30 min at -30 ° C, sulfur (352 mg, 11.0 mmol) was added and the mixture was allowed to warm to 0 ° C and stirred for 7 h. Saturated ammonium chloride solution and 10% aqueous HCl are added and the mixture is extracted with ethyl acetate. The organic layer was extracted with 5% aqueous potassium carbonate solution, the aqueous phase was acidified with 10% aqueous HCl, and extracted with ethyl acetate. The organic phase is dried (sodium sulfate), filtered and concentrated. 1.03 g of 5-mercapto-1-phenylpyrazole are obtained. 4-1 NMR (CDCl ₃ ) δ 3.42 (s, 1H), 6.50 (d, 2H), 7.4-7.6 (m, 5H), 7.67 (d, 2H).

To a stirred solution of 5-mercapto-1-phenylpyrazole (396 mg, 2.25 mmol) in THF (3 mL) at 0 was added sodium bis (trimethylsilyl) amide solution in THF (2M, 1.02 mL, 2.04 mmol). . After 5 minutes The solvent was evaporated in vacuo and the residue dissolved in DMF (3 mL) and the resulting solution was added via syringe to the stirred (7R) -7 - [(phenylacetyl) amino] -3- (trifluoromethanesulfonyloxy) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (1.20 g, 2.04 mmol) in DMF (10 mL) at -50 ° C. After 10 minutes. Saturated aqueous ammonium chloride solution is added at -50 ° C, the mixture is poured into water at 0 ° C and stirred for 1 hour. After precipitation, the product is filtered off and recrystallized from isopropanol. 856 mg (68%) of the title compound are obtained. 4l NMR (CDCl ₃ ) δ 2.93 (d, 1H, J = 18), 2.99 (d, 1H, J = 18), 3.59 (d, 1H, J = 16), 3.63 ( d, 1H, J = 16), 3.81 (s, 3H), 4.63 (d, 1H, J = 4), 5.18 (d, 1H, J = 12), 5.22 (d, 1H, J = 12), 5.66 (dd, 1H, J = 4, 9), 5.95 (d, 1H, J = 9), 6.70 (d, 1H, J = 2), 6, 90 (d, 2H, J = 10), 7.2-7.5 (m, 12H), 7.76 (d, 1H, J = 2).

Example 172 (17R) -7 - [(Phenylacetyljaminol-3-fl-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid

To a stirred mixture of (7R) -7 - [(phenylacetyl) amino] -3- (1-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (80 mg, 0.12 mmol) and anisole ( A solution of 0.02 ml) in dichloromethane (2 ml) was added at 0 ° C with trifluoroacetic acid (0.5 ml). After 2 or. At 0 ° C, the solvent is evaporated off on a rotary evaporator and the residue is chromatographed on silica gel (3% acetic acid / ethyl acetate). 49 mg (83%) of the title compound are obtained. NMR (d ₃ -acetone) δ 3.21 (s, 2H) 3, 3.60 (d, 1H, J = 16), 3.65 (d, 1H, J = 16), 4.69 (d, 1H , J = 4), 5.71 (dd, 1H, J = 4, 9), 6.83 (d, 1H, J = 2), 7.2-7.6 (m, 10H), 7.80 (d, 1H, J = 2), 8.05 (d, 1H, J = 9).

Example 173 (7R) -7-Amino-3-fl-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester hydrochloride

To a stirred mixture of (7R) -7 - [(phenylacetyl) amino] -3- (1-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (1.60 g, 2.61 mmol) and To a solution of pyridine (0.53 mL, 6.5 mmol) in dry dichloromethane (10 mL) at 0 ° C was added a solution of phosphorus pentachloride (1.09 g, 5.2 mmol) in dichloromethane (12 mL). After 2.5 or. Isobutanol (2.4 mL, 26 mmol) was added at 0 ° C and the mixture was stirred for 1.5 h. Water is added, the layers are separated, and the organic phase is washed with 5% aqueous sodium bicarbonate and 5% aqueous HCl, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The resulting yellow oil was triturated with ether, filtered and dried to give 1.25 g (90%) of the title compound. Ή NMR (CDCl ₃ / CD ₃ OD) δ 2.74 (d, 1H, J = 18), 3.17 (d, 1H, J = 18), 4.65 (d, 1H, J = 4), 4.84 (d, 1H, J = 4), 6.65 (d, 1H, J = 2), 6.75 (d, 2H, J = 9), 7.20 (d, 2H, J = 9) ), 7.2-7.4 (m, 5H), 7.64 (d, 1H, J = 2).

Example 174 4-Methoxybenzyl ester of (7R) -7 - [(cyanoacetyl) aminol-3- (1-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid

To a stirred mixture of (7R) -7-amino-3- (1-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester hydrochloride (110 mg, 0.222 mol) and cyanoacetic acid (36 mg, 0.42 mmol) ) in dry THF (4 mL) at -30 ° C was added diisopropylethylamine (0.19 mL, 1.11 mmol) followed by phosphorus oxychloride (39.5 μΐ, 0.42 mmol). After 1 or. The mixture is partitioned between water and ethyl acetate at -20 ° C. The organic phase is washed with 5% aqueous sodium bicarbonate and 5% aqueous HCl, dried over sodium sulfate and concentrated. The crude product is purified by chromatography on silica gel (1% methanol / dichloromethane) to give 105 mg (85%) of the title compound. 1 H NMR (CDCl ₃ ) δ 2.93 (d, 1H, J = 18), 3.09 (d, 1H, J = 18), 3.40 (s, 2H), 3.81 (s, 3H) , 4.67 (d, 1H, J = 4), 5.20 (d, 1H, J = 12), 5.22 (d, 1H, J = 12), 5.61 (dd, 1H, J = 4.9) 6.72 (d, 1H, J = 2), 6.87 (d, 2H, J = 10) 7.10 (d, 1H, J = 9), 7.3-7.5 ( m, 7H), 7.76 (d, 1H, J = 2).

Example 175 Sodium salt of (7R) -7- [cyanoacetyl) amino] -3- (T-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid

To a stirred mixture of (7R) -7 - [(cyanoacetyl) amino] -3- (1-phenylpyrazol-5-ylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (105 mg, 0.187 mmol) and anisole (O, Trifluoroacetic acid (0.5 mL) was added at 0 ° C to a solution of 2 mL) in dichloromethane (2 mL). After 1 or. At 0 ° C, the solvent is removed by rotary evaporation. The residue is dissolved in aqueous sodium bicarbonate solution and chromatographed by reverse phase chromatography over Cis, eluting with water followed by 20% acetonitrile / water. The fractions containing the desired product are lyophilized to give 47.5 mg (50%) of the desired product. For NMR analysis, the product was treated with HCl and dried. ¹ H NMR (d _{3 in} acetone) δ 3.24 (d, 1H, J = 18), 3.30 (d, 1H, J = 18), 3.79 (s, 2H), 5.06 (d, 1H, J = 4), 5.76 (d, 1H, J = 4), 6.87 (d, 1H, J = 2), 7.4-7.6 (m, 5H), 7.82 ( d, 1H, J = 2).

Example 176 (7R) -7-Methylphenylacetyl) aminol-3 - ('1- (pyrid-2-yl') pyrazol-5-ylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

To a stirred solution of 2-pyridylhydrazine (3.30 g, 30.2 mmol) and malonaldehyde bis (dimethylacetal) (4.96 g, 30.2 mmol) in absolute ethanol (60 mL) was added concentrated HCl at room temperature until the mixture became acidic. (3 mL). The mixture is refluxed for 3 hours. and leave to cool to room temperature. The mixture is concentrated by rotary evaporation and the residue is triturated with ether and filtered off. The remaining solid was dissolved in water, basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic extracts are washed with water and brine, dried (sodium sulfate) and concentrated by rotary evaporation. 3.10 g (70%) of 1- (pyrid-2-yl) pyrazole are obtained. ¹ H NMR (CDCl ₃ ) δ 6.48 (dd, 1H, J = 1.2), 7.20 (dd, 1H, J = 8, 10), 7.75 (d, 1H, J = 1). , 7.82 (dt, 1H, J = 2.10), 8.00 (d, 1H, J = 10), 8.42 (dd, 1H, J = 2.8), 8.59 (d, 1H, J = 2).

To a stirred solution of 1- (pyrid-2-yl) pyrazole (1.00 g, 6.88 mmol) in THF (20 mL) at -78 ° C was added a solution of n-butyllithium in hexane (4.70 mL, 1.6M, 7.52 mmol). After 15 minutes Sulfur (243 mg, 7.59 mmol) was added at -78 ° C. The mixture was stirred at -78 ° C for 15 min, warmed to 0 ° C and stirred for 30 min. Water was added and THF was evaporated on a rotary evaporator. The residue is washed with ethyl acetate, acidified to pH 6 and extracted with ethyl acetate. The latter organic extract was washed with brine, dried (sodium sulfate), and concentrated by rotary evaporation to give 873 mg (73%) of 5-mercapto-1- (pyrid-2-yl) pyrazole. 1 H NMR (CDCl ₃ ) δ 6.30 (m.p. 1 H), 6.30 (d, 1H, J = 2), 7.22 (dd, 1H, J = 8, 10), 7.63 (d, 1H, J = 2), 7.87 (dt, 1H, J = 2, 10), 8.01 (d, 1H, J = 10), 8.44 (dd, 1H, J = 2, 8).

To a stirred solution of 5-mercapto-1- (pyrid-2-yl) pyrazole (95 mg, 0.540 mmol) in DMF (2 mL) at 0 ° C was added a solution of sodium bis (trimethylsilylamide) in THF (0.40 mL, 1M, 0 mL). , 40 mmol). this solution was added to a solution of (7R) -7 - [(phenylacetyl) amino] -3- (trifluoromethanesulfonyloxy) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (235 mg, 0.400 mmol) in DMF (12 mL) at -40 ° C. At C. After 20 min. At -40 ° C, quench the reaction with saturated ammonium chloride solution (2 mL) and water. The mixture was extracted twice with ethyl acetate, the organic extracts were washed with water and brine, dried over sodium sulfate and concentrated by rotary evaporation. 240 mg (98%) of the title compound is obtained, containing about 10% of the Δ2 isomer.

Ή NMR (de-acetone) δ 3.54 (d, 1H, J = 18), 3.63 (d, 1H, J = 16), 3.70 (d, 1H, J = 16), 3.78 (s, 3H), 3.80 (d, 1H, J = 18), 5.17 (d, 1H, J = 10), 5.21 (d, 1H, J = 10), 5.25 (d , 1H, J = 4), 5.90 (dd, 1H, J = 4, 9) 6.33 (d, 1H, J = 2), 6.80 (d, 2H, J = 12) 7.2 -7.4 (m, 8H), 7.74 (d, 1H, J = 2), 7.94 (d, 1H, J = 10), 8.03 (dt, 1H, J = 2.10). , 8.20 (d, 1H, J = 9), 8.46 (dd, 1H, J = 2.8).

Example 177 (7R) -7-l (Phenylacetyl) amino-3- (1- (pyrid-2-yl) pyrazol-5-ylthio) -3-cephem-4-carboxylic acid

To a stirred mixture of (7R) -7 - [(phenylacetyl) amino] -3- (1- (pyrid-2-yl) pyrazol-5-ylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (100 mg, 0.16) of a suspension of mmol) and anisole (0.6 mL) in dichloromethane (1.2 mL) at 0 ° C was added trifluoroacetic acid (1.2 mL). After 30 minutes At 0 ° C, the solvent is removed by rotary evaporation. The residue is dissolved in ethyl acetate and extracted with a saturated aqueous solution of sodium bicarbonate. The aqueous extracts are washed with ether and the aqueous HCl is acidified to pH 4-5. This solution is extracted with ethyl acetate, the organic extracts are washed with water and with brine, dried (sodium sulfate) and concentrated. The resulting oil was triturated with hexane to give the title compound (60 mg, 75%) as a slightly yellow solid. 4Ί NMR (dg-acetone) δ 3.55 (d, 1H, J = 16), 3.63 (d, 1H, J = 16), 3.71 (d, 1H, J = 16), 3.79 (d, 1H, J = 18), 5.25 (d, 1H, J = 4), 5.89 (dd, 1H, J = 4, 9), 6.44 (d, 1H, J = 2) , 7.2-7.4 (m, 6H), 7.78 (d, 1H, J = 2), 7.92 (d, 1H, J = 10), 8.02 (dt, 1H, J = 2, 10),

8.18 (d, 1H, J = 9), 8.48 (dd, 1H, J = 2, 8).

Example 178 ('7R) -7- (Phenylacetyl) amino] -3- (2- (pyrazol-1-yl) pyrid-3-ylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

A mixture of 2-chloro-3-nitropyridine (942 mg, 5.94 mmol), pyrazole (967 mg, 14.2 mmol) and potassium carbonate powder (2 g) in DMF (10 mL) was stirred vigorously at room temperature for 4 days. After diluting the mixture with water, a solid precipitates, which is filtered off and dried. 670 mg (63%) of 3-nitro-2- (pyrazol-1-yl) pyridine are obtained. ¹ H NMR (CDCl ₃ ) δ 6.51 (m, 1H), 7.37 (dd, 1H, J = 5, 8), 7.76 (m, 1H), 8.03 (dd, 1H, J = 2.8, 8.40 (m, 1H), 8.60 (dd, 1H, J = 2.5).

To a suspension of 3-nitro-2- (pyrazol-1-yl) pyridine (670 mg, 3.72 mmol) in ethanol (10 mL) was added 1M solution of SnCF.FbO in 6N aqueous HCl (14.5 mL, 14.5 mmol). . The mixture is refluxed for 10 minutes and the solvent is evaporated off on a rotary evaporator. 10% aqueous sodium hydroxide solution is added until most of the material is dissolved and the mixture is extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated. 376 mg (68%) of 3-amino-2- (pyrazol-1-yl) pyridine are obtained in the form of a brown oil. ⁴ Η NMR (CDCl ₃ ) δ 5.62 (m.s, 2H), 6.46 (m, 1H), 7.05 (dd, 1H, J = 5, 8), 7.24 (dd, 1H) , J = 2.8, 7.74 (m, 1H), 7.85 (dd, 1H, J = 2.5), 8.54 (d, 1H, J = 3).

To a stirred solution of 3-amino-2- (pyrazol-1-yl) pyridine (376 mg, 2.50 mmol) in 3M aqueous HCl (4.3 mL) at 0 ° C for 10 min. add a solution of sodium nitrite (181 mg, 2.63 mmol) in water (1 mL). After 30 minutes this solution was added to a solution of potassium ethylxanthate (800 mg, 5.0 mmol) in a mixture of water and saturated aqueous sodium bicarbonate (1: 1, 22 mL) at 60 ° C. The mixture was heated at 60 ° C for 10 min. and extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product is purified by chromatography on silica gel (hexane / ethyl acetate 4: 1) to give 250 mg of the ethylxanthate derivative. This material was dissolved in ethanol (4 mL) and treated with 30% aqueous sodium hydroxide solution (2 mL). After 3 or. the mixture was neutralized by addition of 0.5M citric acid solution, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product is purified by silica gel chromatography to give 166 mg (40%) of 3-mercapto-2- (pyrazol-1-yl) pyridine. * Η NMR (CDCl ₃ ) δ 5.92 (m.s, 1H), 6.47 (m, 1H), 7.08 (dd, 1H, J = 5.8), 7.72 (dd, 1H) , J = 2, 8), 7.78 (m, 1H), 8.21 (dd, 1H, J = 2.5), 8.42 (d, 1H, J = 3).

To a solution of 3-mercapto-2- (pyrazol-1-yl) pyridine (77 mg, 0.435 mmol) in DMF (1 mL) was added 1M sodium bis (trimethylsilyl) amide in THF (0.42 mL, 0.42 mmol) at room temperature. ). After 10 minutes. place this solution through a funnel into a solution of (7R) -7 [(phenylacetyl) amino] -3- (trifluoromethanesulfonyloxy) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (267 mg, 0.457 mmol) in DMF (2 mL) -40 ° C. After 1 or. The mixture was poured into water at 40 ° C and extracted with ethyl acetate. The organic extracts were washed with water, dried over sodium sulfate and concentrated by rotary evaporation. The residue is triturated with 1: 1 hexane / ethyl acetate, dried to give 291 mg of the title compound. ¹ H NMR (CDCl ₃ ) δ 3.10 (d, 1H, J = 18), 3.52 (d, 1H, J = 18), 3.65 (d, 1H, J = 16), 3.69 (d, 1H, J = 16), 3.75 (s, 3H), 5.01 (d, 1H, J = 4), 5.26 (d, 1H, J = 12), 5.28 (d) , 1H, J = 12), 5.89 (dd, 1H, J = 4, 9), 6.05 (d, 1H, J = 9), 6.50 (m, 1H), 6.72 (d) , 2H, J = 10), 7.13 (dd, 1H, J = 5, 8), 7.20 (d, 2H, J = 10), 7.2-7.4 (m, 5H), 7 , 59 (dd, 1H, J = 2.8), 7.78 (m, 1H), 8.28 (dd, 1H, J = 2.5), 8.40 (m, 1H).

Example 179 Sodium salt of (7R) -7 - [(phenylacetyl) aminol-3- (2- (pyrazol-1-yl) pyrid-3-ylthio) -3-cephem-4-carboxylic acid

To a stirred mixture of (7R) -7 - [(phenylacetyl) amino] -3- (2- (pyrazol-1-yl) pyrid-3-ylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (80 mg) and anisole ( To a solution of 0.1 ml) in dichloromethane (1 ml) was added trifluoroacetic acid (1 ml) at 0 ° C. After 30 minutes At 0 ° C, the mixture is concentrated to an oil and partitioned between water and saturated aqueous sodium bicarbonate solution. The aqueous phase is subjected to reverse phase chromatography over Gs eluting with water followed by acetonitrile / water. The fractions containing the product are lyophilized to give 43 mg of the desired product. ¹ H NMR (D ₂ O) δ 3.10 (d, 1H, J = 18), 3.50 (d, 1H, J = 18), 3.64 (d, 1H, J = 16), 3, 69 (d, 1H, J = 16), 5.10 (d, 1H, J = 4), 5.62 (d, 1H, J = 4), 6.61 (m, 1H), 7.2-. 7.4 (m, 5H), 7.52 (m, 1H), 7.82 (m, 1H), 7.93 (dd, J = 8), 8.14 (m, 1H), δ , 37 (m, 1H).

Example 180 (7R) -7 - [(Phenylacetyl) amino] -3- [2- (N, N'-fbis) tert-butyloxycarbonylguanidiniomethyl) phenylthiol 3-cephem-4-carboxylic acid 4-methoxybenzyl ester

To a stirred solution of 2-mercaptobenzyl alcohol (1.00 g, 7.10 mmol) in dichloromethane (20 mL) at 0 ° C was added methyl acrylate (0.70 mL, 7.70 mmol) followed by triethylamine (50 μ, Ι , 0.35 mmol). The mixture was allowed to warm to room temperature and stirred for 4 hours and then the solvent was evaporated on a rotary evaporator. The residue was chromatographed on a silica gel column (0-10% ethyl acetate in dichloromethane) to give 1.40 g (86%) of 3- (2-hydroxymethylphenylthio) methylpropionate. Ή NMR (CDCl ₃ ) δ 2.63 (t, 2H, J = 7), 3.18 (t, 2H, J = 7), 3.68 (s, 3H), 4.79 (s, 2H) , 7.27 (m, 2H), 7.43 (m, 2H).

To a stirred mixture of 3- (2-hydroxymethylphenylthio) methylpropionate (1.40 mg, 5.10 mmol), triphenylphosphine (2.00 g, 7.60 mmol) and N, N '- (bis) tert-butyloxycarbonylguanidine (2.60) g,

A solution of 10.2 mmol) in THF (30 mL) was added slowly at 0 ° C to diisopropyl azodicarboxylate (1.50 mL, 7.60 mmol). The mixture was allowed to warm to room temperature and stirred for 5 hours. The solvent is evaporated on a rotary evaporator and the residue is chromatographed on a silica gel column. 1.62 g (68%) of 3- [2- (N, N '(bis) tert-butyloxycarbonylguanidinomethyl) phenylthio] methylpropionate are obtained. ^! 1 H NMR (CDCl ₃ ) δ 1.25 (s, 9H), 1.46 (s, 9H), 2.62 (t, 2H, J = 7), 3.13 (t, 2H, J = 7). , 3.69 (s, 3H), 5.39 (s, 2H), 7.0-7.4 (m, 4H), 9.42 (ss, 1H), 9.53 (ss) , 1H).

To a stirred solution of 3- [2- (N, N '- (bis) tert-butyloxycarbonylguanidine methylphenylthio] methylpropionate (63 mg, 0.13 mmol) in DMF (1 mL) was added potassium tert-butoxide (15 mg, 0.13) at room temperature. After 4 hours, the mixture was poured through a funnel into stirring (7R) -7 - [(phenylacetyl) amino] -3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylic acid 4-methoxybenzyl ester (79 mg, 0.13 mmol). DMF (0.5 mL) at -40 [deg.] C. The mixture was stirred at -40 [deg.] C. for 40 min and quenched by addition of a saturated ammonium chloride solution. The mixture was extracted with ethyl acetate / hexane, the organic phase dried over sodium sulfate and concentrated by rotary evaporation. . Column chromatography on silica gel (50% ethyl acetate in hexanes) gave 44 mg (40%) of the title compound. ^X H NMR (CDC1 ₃₎ δ 1.28 (s, 9H), 1.42 (s, 9H), 3.05 (d, 1H, J = 18), 3.33 (d, 1H, J = 16), 3.59 (d, 1H, J = 16), 3.62 (d, 1H, J = 16), 3 , 81 (s, 3H), 5.00 (d, 1H, J = 4), 5.07 (d, 1H, J = 18), 5.26 (s, 2H), 5.32 (d, 1H) , J = 18), 5.78 (dd, 1H, J = 4, 9), 6.15 (d, 1H, J = 9), 6.89 (d, 2H, J = 12), 7.03 (d, 1H, J = 10), 7.2-7.4 (m, 9H), 7.52 (d, 1H, J = 10), 9.39 (m.s, 1H), 9.44 (m.p. s, 1H).

Example 181 Internal salt of (7R) -7 - [(phenylacetyl) amino] -3- [2- (guanidiniomethyl) phenylthio] -3-cephem-4-carboxylic acid

To the stirred (7R) -7 - [(phenylacetyl) amino] -3- [2- (N, N '- (bis) tert-butoxycarbonylguanidinomethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (44 mg) , 0.055 mmol) and anisole (0.2 mL) in dichloromethane (0.4 mL) at 0 ° C were added trifluoroacetic acid (1 mL). The mixture was allowed to warm to room temperature and stirred for 40 min. The solvent is removed in vacuo, the residue is triturated with ether and filtered. The title compound (25 mg, 95%) is obtained as a yellowish powder. ^X H NMR (CD3OD) δ

3.10 (d, 1H, J = 17), 3.41 (d, 1H, J = 17), 3.54 (d, 1H, J = 12), 3.58 (d, 1H, J = 12) ), 4.48 (s, 2H), 5.04 (d, 1H, J = 5), 5.59 (d, 1H, J = 5), 7.2-7.4 (m, 9H).

Example 182 4-Methoxybenzyl ester of (7R) -7 - [(phenylacetyl) amino] -3- (2-chloromethylphenylthio) -3-cephem-4-carboxylic acid

Thionyl chloride (1.3 mL, 17.8 mmol) was added to dry DMF (100 mL) at 0 ° C. After 30 minutes (7R) - [(Phenylacetyl) amino] -3- (2-hydroxymethylphenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (6.90 g, 12.0 mmol) was added at 0 ° C. The resulting solution was stirred at 0 ° C for 30 min. and poured into ice water (800 mL). After 30 minutes the mixture is filtered, the precipitate is washed with water and air dried. The resulting brownish solid was dissolved in dichloromethane (500 mL), washed with water and brine, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue is triturated with ether, filtered and dried. The title compound (4.35 g, 61%) is obtained as an off-white solid. ¹ H NMR (CDCl ₃ ) δ 3.08 (d, 1H, J = 18), 3.25 (d, 1H, J = 18),

3.60 (d, 1H, J = 16), 3.63 (d, 1H, J = 16), 3.81 (s, 3H), 4.75 (d, 1H, J = 14), 4, 79 (d, 1H, J = 14), 4.94 (d, 1H, J = 4), 5.25 (s, 2H), 5.75 (dd, 1H, J = 4, 9), 6, 04 (d, 1H, J = 9), 6.86 (d, 2H, J = 10), 7.2-7.6 (m, 11H).

Example 183 Trifluoroacetic acid salt of (7R) -7-amino-3- (2-chloromethylphenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

To a stirred mixture of (7R) -7 - [(phenylacetyl) amino] -3- (2-chloromethylphenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (11.6 g, 19.5 mmol) and pyridine (3, A solution of 20 ml, 39.6 mmol) in dichloromethane (50 ml) is slowly added at 0 ° C to a solution of phosphorus pentachloride (6.40 g, 30.7 mmol) in dichloromethane (75 ml). After 2 or. Isobutanol (1.82 mL, 19.8 mmol) was added at 0 ° C. The mixture is stirred for 2 hours. At 0 ° C, dichloromethane (500 mL) was added and the resulting solution was washed with saturated aqueous sodium bicarbonate (2x400 mL), water (2x400 mL), 1M aqueous HCl (2x400 mL) and table salt (2x400 mL). The organic phase is dried (sodium sulfate), trifluoroacetic acid (1.6 mL, 20.8 mmol) is added and the mixture is concentrated by rotary evaporation. The resulting off-white solid was triturated with ether and dried. The title compound (6.53 g, 57%) is obtained as a brownish solid. Ή NMR (CDCl ₃ / CD ₃ OD) δ 2.85 (d, 1H, J = 18), 3.34 (d, 1H, J = 18), 3.72 (s, 3H), 4.62 ( d, 1H, J = 8), 4.74 (d, 1H, J = 8), 4.74 (m, 1H), 5.06 (m, 1H), 5.17 (s, 2H), 6 , 80 (d, 2H, J = 10), 7.2-7.6 (m, 6H).

Example 184 (7R) -7- [f ('2-N, N ^, - (' bis) -Tert-Butyloxycarbonylguanidineethylthio) acetyl) amino] -3- [2-chloromethyl) phenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

To a stirred solution of N, N '- (bis) -di-tert-butyloxycarbonyl-S-methylisothiourea (2.37 g, 8.17 mmol) and 2-mercaptoethylamine hydrochloride (0.88 g, 7.78 mmol) in THF ( 40 mL) at room temperature was added triethylamine (1.2 mL, 8.56 mmol). The reaction mixture was heated at 45-50 ° C for 7 hours, after which the solvent was evaporated on a rotary evaporator. The residue is triturated with hexane / ethyl acetate and the triethylamine hydrochloride is filtered off. The filtrate was concentrated and chromatographed on a silica gel column (2-5% ethyl acetate / hexane). 1.08 g (44%) of 2- (N, N'-di-tert-butyloxycarbonylguanidine) ethanediol are obtained. ¹ H NMR (CDCl ₃ ) δ 1.43 (t, 1H, J = 8), 1.48 (s, 18H), 2.73 (dt, 2H, J = 8.6), 3.63 (s) , 2H, J = 6), 8.67 (m.p., 2H).

To a stirred solution of 2- (N, N'-di-tert-butyloxycarbonylguanidine) ethanediol (1.08 g, 3.37 mmol) and methyl bromoacetate (516 mg, 3.37 mmol) in THF (10 mL) was added at 0 ° C. triethylamine (0.56 mL, 4.04 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture is partitioned between ethyl acetate and water and the aqueous layer is extracted with ethyl acetate. The combined organic phases are washed with water and brine, dried over sodium sulfate and concentrated. The residue is chromatographed on a silica gel column (5-10% ethyl acetate / hexane) to give 1.24 g (95%) of methyl [2- (N, N'-di-tert-butyloxycarbonylguanidine) ethyl] thioacetate. Ή NMR (CDCl ₃ ) δ 1.48 (s, 18H), 2.83 (t, 2H, J = 8), 3.26 (s, 2H), 3.65 (s, 2H, J = 8). , 3.73 (s, 3H), 8.59 (s, 2H).

To a stirred solution of methyl [2- (N, N'-di-tert-butyloxycarbonylguanidine) ethyl] thioacetate (1.24 g, 3.17 mmol) in ethanol (15 mL) was added 10% aqueous sodium hydroxide solution (3 mL) at room temperature. ml). After 2 or. the mixture is concentrated and the residue is treated with 10% aqueous HCl. The resulting mixture was extracted with ethyl acetate, and the organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated. 1.06 g of [2- (N, N'-di-tert-butyloxycarbonylguanidine) ethyl] thioacetic acid is obtained in the form of a white solid. ¹ H NMR (CDCl ₃ ) δ 1.50 (s, 18H), 2.89 (t, 2H,

J = 8), 3.34 (s, 2H), 3.72 (m, 2H), 8.82 (s, 2H).

To a stirred mixture of [2- (N, N'-di-tert-butyloxycarbonylguanidine) ethyl] thioacetic acid (153 mg, 0.406 mmol) and (7R) -7-amino-3- (2-chloromethylphenylthio) -3-cephem-4 A solution of trifluoroacetic acid salt of 4-carboxylic acid 4-methoxybenzyl ester (200 mg, 0.0334 mmol) in THF (8 mL) at -20 ° C was added diisopropylethylamine (233 μΐ, 1.34 mmol) followed by phosphorus oxychloride (39 μΐ, 0.406 mmol) ). After 2 or. the mixture is partitioned between ethyl acetate and water, the layers are separated, and the organic layer is washed with a saturated aqueous solution of sodium bicarbonate, water, 10% aqueous HCl, and brine. After drying over sodium sulfate, the mixture is concentrated on a rotary evaporator and the residue is chromatographed on silica gel (0-3% MeOH / dichloromethane). 228 mg (82%) of the title compound are obtained. 1 H NMR (CDCl ₃ ) δ 1.51 (s, 18H), 2.80 (t, 2H, J = 8), 3.22 (d, 1H, J = 18), 3.30 (d, 1H , J = 18), 3.34 (s, 2H), 3.62 (m, 2H), 3.82 (s, 3H), 4.80 (s, 2H), 5.01 (d,

1H, J = 4), 5.31 (s, 2H), 5.75 (dd, 1H, J = 4, 9), 6.90 (d, 2H, J = 10), 7.3-7, Δ (m, 7H), 8.60 (m.p., 2H).

Example 185 (7R) -7-i ((2-N, N '- (Bis) -tert-Butyloxycarbonylguanidine ethylthio) acetyl) airunol-3- [2 (lodmethyl) phenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

To a stirred mixture of (7R) -7 - [((2-N, N '- (bis) -tert-butyloxycarbonylguanidinoethylthio) acetyl) amino] -3- [2- (chloromethyl) phenylthio] -3-cephem-4-carboxylic acid 4 Sodium iodide (205 mg, 1.34 mmol) was added at room temperature to a solution of -methoxybenzyl ester (228 mg, 0.273 mmol) in acetonitrile (3 mL). After stirring overnight, the mixture is partitioned between water and ethyl acetate and the organic layer is washed with water and brine. The solvent was evaporated on a rotary evaporator to give 239 mg (94%) of the title compound. 1 H NMR (CDCl ₃ ) δ 1.51 (s, 18H), 2.80 (t, 2H, J = 8), 3.28 (d, 1H, J = 18), 3.35 (s, 2H) ), 3.37 (d, 1H, J = 18), 3.62 (m, 2H), 3.82 (s, 3H), 4.60 (d, 1H, J = 9), 4.63 ( d, 1H, J = 9), 5.06 (d, 1H, J = 4), 5.29 (s, 2H), 5.77 (dd, 1H, J = 4, 9), 6.89 ( d, 2H, J = 10), 7.3-7.6 (m, 7H),

8.60 (m.p., 2H).

Example 186 (7R) -7 - [((2-N, N '- (Bis) -tert-Butyloxycarbonylguanidineethylthio) acetyl) aminol-3- [2- (isothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid 4-methoxybenzyl ester

To a stirred mixture of (7R) -7 - [((2-N, N '- (bis) -tert-butyloxycarbonylguanidinoethylthio) acetyl) amino] -3- [2- (iodomethyl) phenylthio] -3-cephem-4-carboxylic acid 4 A solution of -methoxybenzyl ester (239 mg, 0.258 mmol) in acetonitrile (2 mL) was added at room temperature with thiourea (19 mg, 0.258 mmol). After 4 or. the solvent was evaporated on a rotary evaporator and the residue was triturated with ether, filtered, dried to give 240 mg (9%) of the title compound. Ή NMR (CDCl ₃ ) δ 1.48 (s, 18H), 2.81 (m, 2H), 3.21 (d, 1H, J = 18), 3.40 (s, 2H), 3.42 (d, 1H, J = 18), 3.60 (m, 2H), 3.80 (s, 3H), 4.70 (d, 1H, J = 11), 4.87 (d, 1H, J) = 11), 5.12 (d, 1H, J = 4), 5.27 (s, 2H), 5.56 (dd, 1H, J = 4, 9), 6.50 (e.g. s, 1H ), 6.89 (d, 2H, J = 10), 7.3-7.6 (m, 6H), 8.15 (d, 1H, J = 9), 8.50 (very broad, m.p. 1H), 8.66 (s, 1H).

Example 187 Trifluoroacetic acid salt of (7R) -7 - [((2-guanidinoethylthio) acetyl) amino] -3- [2- (isothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid

To (7R) -7 - [((2-N, N '- (Bis) -tert-Butyloxycarbonylguanidinoethylthio) acetyl) amino-3- [2- (isothiuronomethyl) phenylthio] -3-cephem-4-carboxylic acid 4-methoxybenzyl ester (240 mg, 0.240 mmol) and anisole (100 µl) were added trifluoroacetic acid (1.5 mL) at room temperature. After 1.5 or. volatiles are evaporated in vacuo and the residue is triturated with ether. The resulting solid was dried, suspended in water (50 mL), filtered and lyophilized. 131 mg (82%) of the title compound are obtained. ¹ H NMR (D ₂ O) δ 2.83 (t, 2H, J = 7), 3.25 (d, 1H, J = 18), 3.38 (s, 2H), 3.42 (t, 2H, J = 7), 3.48 (d, 1H, J = 18), 4.59 (s, 2H), 5.20 (d, 1H, J = 4), 5.59 (d, 1H, J = 4), 7.2-7.6 (m, 4H).

Using essentially the same procedures as described in Examples 184-187, the compounds of Examples 188-219 can be prepared.

Example 188 (7R) -7 - [((3-Guanidinopropylthio) acetyl) amino] -3- [2- (isothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 189 Trifluoroacetic acid salt of (7R) -7 - [((4-guanidinobutylthio) acetyl) amino-3- [2- (isothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid

Example 190 (7R) -7 - [((2-N, N ^, -Dimethylguanidine ethylthio) acetyl) amino] -3- [2- (isothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 191 (7R) -7 - [((3-N, N'-Dimethylguanidinepropylthio) acetyl) amino] -3- [2- (isothiuronomethyl) phenylthio) 3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 192 (7R) -7 - [((4-N, N'-Dimethylguanidine butylthio) acetyl) amino] -3- [2- (isothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 193 Trifluoroacetic acid salt of (7R) -7-N - ((2-isothiuronium) ethylthioacetyl) amino] -3- [2- (isothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid

Example 194 (7R) -7 - [((3-Isothiuronium) propyl) thioacetyl) amino-3- [2- (isothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 195 (trifluoroacetic acid salt of (7R) -7- [f (4-isothiuronium) butyl) thioacetyl) aminol-3- (2-isothuronomethyl) phenylthio) -3-cephem-4-carboxylic acid

Example 196 (7R) -7 - [((2-N, N'-Dimethylisothiuronio) ethylthioacetyl) amino] -3- [2- (isothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 197 (S, 7R) -7- ((3-N, N'-Dimethylisothiouronium) propylthioacetyl) amino] -3- [2- (isothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 198 ^(, 7R) -7-f (f4-N, N'-dimetilizotiuronio) butiltioacetil) aminol-3- [2- (izotiuroniometil ') phenylthio) 3 CEFEM-4-carboxylic acid trifluoroacetic acid salt

Example 199 ('7R) -7- [(2-Tetramethylisothiuronio) ethylthioacetyl) amino] -3- [2-physiothiuronomethyl) phenylthio] -3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 200 trifluoroacetic acid salt of N, N-N-tetramethylisothiothuronolpropylthioacetamino-B-p-physothiuronomimethylphenylthiol-Scefem-4-carboxylic acid

Example 201 (7R) -7 - [((4-Tetramethylisothiuronium) butylthioacetyl ') aminol-3- [2-physiothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 202 S, trifluoroacetic acid salt of (7R) -7- [(2-f (iminomethyl) arruno) ethylthioacetyl) amino] -3- [2- ('isothiuronion'-ethyl) phenylthio] -3-cephem-4-carboxylic acid

Example 203 Trifluoroacetic acid salt of (7R) -7 - [(2-N-methyliminomethyl) amino) ethylthioacetyl) aninol-3- [2- (isothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid

Example 204 Trifluoroacetic acid salt of ('7R) -7- [β-fiminomethyl') amino) propylthioacetyl) aminol-3- [2-physiothiuronomethyl) phenylthio) -3cephem-4-carboxylic acid

Example 205 (trifluoracetic acid salt of (7R) -7- [f- (N-methyliminomethyl) amino ') propylthioacetyl) amino] -3- [2- (isothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid

Example 206 Trifluoroacetic acid salt of (7R) -7- [f - ((iminomethyl) amino) butylthioacetyl) amino] -3- [2- (isothiuronomethyl) phenylthio) -3cephem-4-carboxylic acid

Example 207 (7R ') - 7 - [(' 4-f (N-Methyliminomethyl) amino) butylthioacetyl ⁽ amino) -3- [2-physiothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 208 Trifluoroacetic acid salt of (7R) -7 - [((2-amide) ethylthioacetyl) amino] -3- [2-physothiuronomethyl) phenylthio] -3-cephem-4-carboxylic acid

Example 209 trifluoroacetic acid salt of (7R) -7- [f (3-amidiniopropyl) thioacetyl) amino] -3- [2-physothiuronomethyl ') phenylthio] -3-cephem-4-carboxylic acid

Example 210 ( ^, 7R ') - Trifluoroacetic acid salt of 7- [((4-amidinobutyl) thioacetyl) amino] -3- [2-physothiuronylmethyl) phenylthio] -3-cephem-4-carboxylic acid

Example 211 (7R ') - 7 - [(2- (N, N'-Dimethylamidino) ethylthioacetyl) arninol-3- [2-physothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 212 Trifluoroacetic acid salt of (7R) -7- [[beta] -N, N'-dimethylamidine) propyl (thioacetyl) amino] -3- [2-physiuronomethyl) phenylthio] -3-cephem-4-carboxylic acid

Example 213 (R) -7- [(4- (N, N ^, -Dimethylamidine ^, ) butyl) thioacetyl) amino] -3- [2- ('isothiuroniomethyl ·') phenylthio ') 3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 214 f7R ') - 7 - [((' 2- ^(, tetrametilamidinio) etiltioacetil) amino] -3- [2-fizotiuroniometil) phenylthio) -3cefem-4-carboxylic acid trifluoroacetic acid salt

EXAMPLE 215 Trifluoroacetic acid salt of (7R ') - 7 - [(3-tetramethylamido) propyl) thioacetyl) amino] -3- [2 - (' isothiuroniomethyl) phenylthio] -3-cephem-4-carboxylic acid

Example 216 Trifluoroacetic acid salt of (7R) -7- [f- (4- (tetramethylairmium) butyl) thioacetyl) amino] -3- (f-physiuroniomethyl) phenylthio) -3cephem-4-carboxylic acid

Example 217 (7R) -7 - [('((2-Amino) methylthioacetyl) amino] -3- [2-physothiuronomethyl) phenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 218 (7R ') - 7 - [(2- (N, N ^, -Dimethylamidine) methylthioacetyl) amino] -3- [2- (' isothiuroniomethyl) phenylthio) -3-cephem-4-carboxylic acid trifluoroacetic acid salt

Example 219 Trifluoroacetic acid salt of (7R) -7- ((2-tetramethylamido) methylthioacetyl) amino] -3- [2-physothiuronomethyl) phenylthio] -3cephem-4-carboxylic acid

Thus, it should be noted that the compounds, methods and compositions of the present invention are effective against a variety of bacterial strains resistant to β-lactams, which pose an increasing risk to human health.

Although certain embodiments and examples have been used in the description of the present invention, it will be understood by those skilled in the art that modifications may be made to the embodiments and examples given without departing from the spirit or scope of the invention.

Literature sources which have not previously been included in the bibliography, including both patents and non-patent literature, are specifically included herein as references for all purposes.

Other embodiments are included in the definition below.

Claims (34)

DEFINITION OF INVENTION 1. A compound having the formula: R * O S '(CH ₂ ) _n Y co ₂ r ^{2 in} which R ¹ is -NHC (O) ZR ³ or -NR ⁴ R ⁵ where Z is -CH 2 (X) m -, -C (NOR ⁶ ) -, -CH (OR ⁷ ) -, -C (CHCO ² R ⁸ ). - or -CH (NR ⁹ R ¹⁰ ) -, wherein X is O or S and m is 0 or 1; R ³ is selected from the group consisting of cyano, alkyl, aryl, heterocycle and heteroaryl; R ⁴ ' ⁷ are independently selected from the group consisting of hydrogen, alkyl, aryl and acyl; R ⁸ is selected from the group consisting of hydrogen, alkyl and aryl; and R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, alkyl, acyl, and heterocyclylcarbonyl; or R ¹ is -NHC (O) S R ² is hydrogen, alkyl, alkenyl, aryl, heterocycle, aralkyl, heteroaralkyl or trialkylsilyl; n is 0 or 1; and Y is selected from the group consisting of aryl and heterotricyclic; with the proviso that when n is 0 and R ¹ is selected from the group consisting of phenylacetamide, phenylthioacetamide, phenyloxyacetamide, Da-aminophenylacetamide, thienylacetamide and D-mandeloylamide, Y is not phenyl substituted with C _1-4 alkyl, C ₄ -alkoxyl or halogen other than 2-bromo and 2-iodo; and provided that when n is 1, Y is not phenyl, wherein R ³ is 4- (2-amino) thiazolyl, and Z is -C (NOCH ₂ CO ₂ H) -; and pharmaceutically acceptable salts and prodrugs thereof. A compound according to claim 1, wherein R ¹ is NHC (O) ZR ³ or O R 'is -NHC (O) A-S 3. A compound according to claim 2 wherein R ³ is alkyl, cyano, aryl or heterocycle. 4. A compound according to claim 2 wherein R ³ is selected from the group consisting of methyl, cyano, phenyl, thienyl, furanyl and 2-aminothiazolyl. 5. A compound according to claim 2 wherein Z is -CH 2 (X) _m -, X is S, om is 0 or 1. 6. A compound according to claim 5, wherein m is 1 and R ³ is alkyl substituted with a group consisting of guanidine, isothioureid and amidine. 7. A compound according to claim 2 wherein Z is -C (NOR ⁶ ) -, R ⁶ is selected from the group consisting of hydrogen and alkyl, and R ³ is aryl or heterocycle. 8. A compound according to claim 2 wherein R ⁶ is selected from the group consisting of 2-fluoroethyl, cyclopropylmethyl, allyl, dichloralyl and cyclopentyl, and R ³ is selected from the group consisting of phenyl, 2-thienyl, 2- furyl and 2-aminothiazol-4-yl. 9. The compound of claim 1, wherein Y is selected from the group consisting of 1-dibenzfuranyl, 2-dibenzfuranyl, 3-dibenzfuranyl, 4-dibenzfuranyl, 1-dibenzthienyl, 2-dibenzthienyl, 3-dibenzthienyl, 2 -biphenyl, 3-biphenyl and 4biphenyl. 10. A compound according to claim 1 wherein Y is optionally substituted with acyl, alkyl, hydroxyl, halogen, carbonyl, thioalkyl, amido, alkoxy, trialkylammonium, cyanoalkylamide, imidazolyl, thiazolyl, oxazolyl, imidazolyl, oxazolylmethyl, imidazole group, imidazolomethyl, thienyl, thienylmethyl, furyl, furylmethyl, pyridine group, cyano, pyridyl, pyrrolyl, pyrazolyl, triazolyl and tetrazolyl. 11. A compound according to claim 1 wherein Y is optionally substituted phenyl, biphenyl, dibenzfuranyl or dibenzthienyl; n is 0; and said substituent is optionally in the substituted ring at the 2-position relative to the attachment of the ring to the sulfur atom. 12. A compound having the formula: in which R ¹ is -NHC (O) Z R ³ or -NR ⁴ R ⁵ where Z is -CH 2 (X) m -, -C (NOR ⁶ ) -, CH (OR ⁷ ) -, -C (CHCO ² R ⁸ ) - or -CH (NR ⁹ R ¹⁰ ) -, wherein X is O or S, om is 0 or 1; or R ¹ is -NHC (O) / $; R ² is hydrogen, alkyl, alkenyl, aryl, heterocycle, aralkyl, heteroaralkyl or trialkylsilyl; R ³ may be cyano, alkyl, aryl, heterocycle and heteroaralkyl; R ⁴ ' ⁷ may be independently hydrogen, alkyl, aryl and acyl; R ⁸ may be selected from the group consisting of hydrogen, alkyl and aryl; R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, alkyl, acyl and heterocyclylcarbonyl; p = 1 or 2; R ¹¹ is H or halo; N ⁺ R ¹³ R ¹⁴ R ¹² is W W ^{, 5} r '. where W = S, NH or CH ₂ and R ⁱ³ R ¹⁶ is H, hydroxy, amino, amidino, alkyl, cycloalkyl, acyl, or phosphoryl and taken together may form a 5- or 6-membered ring; or R ¹² is SR ¹⁷ , wherein R ¹⁷ is alkyl, cycloalkyl, or a 5- or 6-membered heterocyclic ring having 0-4 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms, which may be substituted such as alkyl, hydroxyl, alkoxyl, amino, hydroxymethyl, aminomethyl or mono- or dialkylaminomethyl; and pharmacologically acceptable salts and prodrugs thereof. 13. The compound of claim 12, characterized in that R ¹ is -NHC (O) ZR ³ or s / R ¹ is -NHC (O) '- S. 14. A compound according to claim 13 wherein R ³ is alkyl, cyano, aryl or heterocycle. T 15. A compound according to claim 13 wherein R is selected from the group consisting of methyl, cyano, phenyl, thienyl, furanyl and 2-aminothiazolyl. 16. A compound according to claim 13 wherein Z is -CH ₂ (X) _m -, X is S, om is 0 or 1. 17. The compound of claim 16, wherein m is 1 and R ³ is alkyl substituted with a substituent selected from the group consisting of guanidine, isothioureid or amidine. 18. A compound according to claim 13 wherein Z is -C (NOR ⁶ ) -, R ⁶ is selected from the group consisting of hydrogen and alkyl, and R ³ is a heterocycle. 19. The compound of claim 13, characterized in that R ⁶ is selected from the group consisting of 2-fluoroethyl, cyclopropylmethyl, allyl, dichloralilo and cyclopentyl, and R ³ is selected from the group consisting of phenyl, 2-thienyl, 2- furyl and 2-aminothiazol-4-yl. 20. A compound according to claim 12 wherein p is 0, 1 or 2, R ¹¹ is H n ⁺ r ¹³ r ¹⁴ JL or halogen, R ¹² is> W NR ¹ 'R, w is g, NH or CH 2, and R ¹³ -R ¹⁶ are hydrogen or lower alkyl. The compound of claim 20, wherein p is 1, R ¹¹ is hydrogen, R ¹² NR ¹³ R ¹⁴ [Is SW NR ¹⁵ R where w = S or NH and R ¹³ -R ¹⁶ are hydrogen. 22. A compound having the formula: in which R ¹ is -NHC (O) Z R ³ or -NR ⁴ R ⁵ where Z is -CH 2 (X) m -, -C (NOR ⁶ ) -, CH (OR ⁷ ) -, -C (CHCO ² R ⁸ ) - or -CH (NR ⁹ R ¹⁰ ) -, wherein X is O or S, om is 0 or 1; or R ¹ is -NHC (O) / $; R ² is hydrogen, alkyl, alkenyl, aryl, heterocycle, aralkyl, heteroaralkyl or trialkylsilyl; R ³ may be cyano, alkyl, aryl, heterocycle and heteroaralkyl; R ⁴ ' ⁷ may be independently hydrogen, alkyl, aryl and acyl; R ⁸ may be selected from the group consisting of hydrogen, alkyl and aryl; R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, alkyl, acyl and heterocyclylcarbonyl; R ¹⁸ is phenyl optionally substituted, heteroaryl, or cyano; V = C or N; AC is CR ¹⁹ , N or S, wherein R ¹⁹ is hydrogen, alkyl, hydroxyl, amino, cyano, hydroxymethyl or mono- or dialkylaminomethyl; DG is CR ¹⁹ or N, wherein R ¹⁹ is hydrogen, alkyl, hydroxyl, amino, cyano, hydroxymethyl or mono- or dialkylaminomethyl; and pharmacologically acceptable salts and prodrugs thereof. A compound according to claim 22, wherein R ¹ is -NHC (O) ZR ³ or R 'is -NHC (O) The compound of claim 23, wherein R ³ is alkyl, cyano, aryl, or heterocycle. 25. A compound according to claim 23 wherein R ³ is selected from the group consisting of methyl, cyano, phenyl, thienyl, furanyl and 2-aminothiazolyl. The compound of claim 23, wherein Z is -CH ₂ (X) _m -, X is S, om is 0 or 1. 27. The compound of claim 26, wherein m is 1 and R ³ is alkyl substituted with a substituent selected from the group consisting of guanidine, isothioureid or amidine. 28. The compound of Claim 23 wherein Z is -C (NOR ⁶ ) -, R ⁶ is selected from the group consisting of hydrogen and alkyl, and R ³ is aryl or heterocycle. 29. The compound of claim 23, characterized in that R ⁶ is selected from the group consisting of 2-fluoroethyl, cyclopropylmethyl, allyl, dichloralilo and cyclopentyl, and R ³ is selected from the group consisting of phenyl, 2-thienyl, 2- furyl and 2-aminothiazol-4-yl. 30. The compound of claim 22, wherein AC, Y and DG are optionally substituted pyrazole, thiadiazole, and pyridine, and wherein R ¹⁸ is optionally substituted phenyl, pyridyl, pyrazolyl, or cyano. Use of a compound according to any one of claims 1, 12 or 22 in the preparation of a pharmaceutical composition for the treatment of mammalian diseases caused by β-lactam antibiotic resistant bacteria. 32. The use of claim 31, wherein said animal is infected with β-lactam resistant staphylococcal or enterococcal organisms. 33. An antibacterial composition for treating bacterial infections resistant to β-lactam antibiotics, comprising a therapeutically effective amount of a compound of claim 1, 12 or 22 in a pharmaceutically acceptable carrier. 34. The composition of claim 33, wherein said bacterium is a lactam-resistant staphylococcal or enterococcal organism.