NZ525401A - Prodrugs of a 7-acylamino-3-heteroarylthio-3-cephem carboxylic acid antibiotic - Google Patents

Abstract

Prodrug of 7-acylamino-3-heteroarylthio-3-cephem carboxylic acid having formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof are disclosed, wherein R'2 is an acyl group that is cleaved by an enzyme found in mammals; A, B, L, G, E, and J are each independently nitrogen or carbon, wherein the specific juxtaposition of groups A, B, and L forms a heterocyclic group as shown in the specification; and Q is selected from the group consisting of nitrogen and -CX, wherein X is selected from the group consisting of hydrogen and chlorine. These prodrugs are substantially more water soluble at or near neutral pH than the parent compound.

Description

525 WO 02/24708 PCT/USO1/08980 DESCRIPTION PRODRUGS OF A 7-ACYLAMINO-3-HETEROARYLTHIO-3-CEPHEM CARBOXYLIC ACID ANTIBIOTIC FIELD OF THE INVENTION The present invention relates to organic chemistry, medicinal chemistry, biochemistry and medicine. In particular it relates to prodrugs of a cephalosporin antibiotic wherein the prodrugs are substantially more water soluble than the 10 parent antibiotic which, among other benefits, aids parenteral administration. The prodrugs convert readily under physiological conditions to provide the parent antibiotic.

BACKGROUND OF THE INVENTION The following is provided to help understand of present invention. Nothing 15 in this section is admitted, nor should be construed to be, prior art to the present invention.

Over the past three decades a variety of antibiotics has become available for clinical use. However, the indiscriminant use of these antibiotics has given rise to resistance among a number of clinically important bacterial strains such as 20 Salmonella, S. pneumoniae, Enterobacteriaceae, Staphylococcus aureus, and Pseudomonas. The rate of development of resistance has increased alarmingly in recent years. Among the various classes of antibiotics that have encountered this rise in development of resistance, the cephalosporins have been particularly hard hit.

Since 1965, over 70 cephalosporins have become available for clinical use in the treatment of bacterial infections. Their mode of action involves inhibition of the biosynthesis of bacterial peptidoglycan biosynthesis, an important step in cell wall manufacture. Resistance to cephalosporins occurs primarily by three mechanisms: (a) the development of ^-lactamases, which cleave p-lactam rings 30 thereby deactivating the antibiotic; (b) changes in cell wall composition resulting in decreased penetration by the antibiotic; and, (c) changes in penicillin-binding proteins (PBPs) resulting in reduced binding of the PBPs with p-lactams, the binding being essential to the inhibition of cell-wall biosynthesis by (J-lactams.

Examples of bacteria whose resistant is due to poor PBP binding are methicillin-resistant Staphylococcus aureus ("MRSA") and the Enterococci. Resistance in MRSA is due to the presence of high levels of an altered PBP, PBP2a, which has been shown to bind very poorly to p-lactams. Attempts to circumvent this 5 mechanism of resistance has led to the discovery of a host of new antibacterial compounds.

Among the compounds shown to be effective against bacteria whose resistance has been shown to be related to poor PBP binding are those described in commonly owned International Application No. PCT/US95/03976 and U.S. 10 patent applications Serial Nos. 08/222,262, filed April 1,1994; 08/369,798, filed January 6,1995; 08/413,713, 08/413,714, 08/415,065, 08/413,712, 08/415,064, and 08/415,069, ail of which were filed on March 29,1995; 08/455,969, filed May 31,1995; 08/457,673, filed June 1,1995; 08/940,508 and 08/937,812, both of which were filed September 29,1997; 08/730,041, 08/730,039, 08/728,232, 15 08/430,042, 08/728,233, and 08/730,040, all of which were filed October 11, 1996; and 08/842,915, filed April 17,1997; all of which are incorporated herein by reference in their entirety, including any drawings.

A class of compounds which have demonstrated activity against p-lactam, in particular, cephalosporin resistant, bacteria is the 7-acyIamino-3-heteroarylthio-20 3-cephem carboxylic acids, described in U.S. Patent No. 6,025,352, which is likewise incorporated by reference, includign any drawings, as if fully set forth herein. Of the 7-acylamino-3-heteroarylthio-3-cephem carboxylic acids, a particularly active compound is (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-(2-aminoethylthiomethyl]-pyrid-4-ylthio}-3-cephem-25 4-carboxylic acid (1): However, while exhibiting a high level of activity against p-lactam resistant bacterial strains in vitro, the utility of 1 in vivo is limited due to its relatively low .OH 1 water solubility which limits the available modes of administration. That is, the water solubility of 1 at or near neutral pH, i.e., from about pH 5 to about pH 7, is insufficient for parental administration.

What is needed is a version of 1, which is more water soluble at or near neutral pH but which has the same high bactericidal activity as 1 or which readily reverts to 1 itself in vivo. The present invention provides such a version of 1.

SUMMARY OF THE INVENTION In one aspect the invention provides a compound of formula III or formula IV: (IV) or a pharmaceutically acceptable salt thereof, wherein: intellectual property office of n.z. 3 I AUG 2005 R'2 is an acyi group that is cleaved by an enzyme found in mammals; A, B, L, G, E, and J are each independently nitrogen or carbon, wherein said specific juxtaposition of groups A, B, and L forms a heterocyclic group selected from the group consisting of wherein said specific juxtaposition of groups E, G, and J forms a heterocyclic group selected from the group consisting of provided that the group -CH2-S-CH2CH2NHR'2 is attached only to a carbon atom of said heterocyclic group; and, Q is selected from the group consisting of nitrogen and -CX, wherein X is selected from the group consisting of hydrogen and chlorine.

In another aspect the invention provides an intermediate compound having the following formula: and NHR*2 ;'WBIfcU UAL PROPERTY OFFICE Of N.l ;3a ;31 AUG 2005 ;RECEIVED ;wherein R'2 is selected from the group consisting hydrogen -C(0)-R88, -C(0)-0R89, ;-C(0)-CH(NHR'3)-alk4, and ;-C(0)-0-CH2 ;wherein: ;R88 is ^ or ^ ;m/) mp ;R'3 is selected from the group consisting of hydrogen, -C(0)-0R89, and -C(0)-CH(NH2)-alk4; ;alk4 is selected from the group consisting of hydrogen, and optionally substituted alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, phenyl, -COOH, ;-C(0)-0R89, -C(0)NH2, -OH, -SH, -NH2, and ;R89 is selected from the group consisting of benzhydryl, f-butyl, ally), p-nitrobenzyl, benzyl, p- or o-nitrobenzyl, 2,2,2-tnchloroethyl, allyl, cinnamyl, benzhydryl, 2-chloroallyl, f-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, (3-(trimethylsilyl)ethyl, 4- or 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, and 3,3-dimethylallyl. ;In another aspect the invention provides a compound selected from the group consisting of: ;(7R)-7-((Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido-3-[4-(2-aminoethylthio-1,3,4-thiadiazol-5-ylthio)]-3-cephem-4-carboxylic acid, ;3b ;(7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-methyl-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7-((Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamidol-3-(4-(2-aminoethylthiomethyl)-1,3-thiazol-2-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-methoxy-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethyithio)-pyridazin-6-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthio)-pyridazin-3-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthio)-pyrimidin-4-ylthio]-3-cephem-4-carboxyiic acid, ;(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)-pyridazin-3-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl-1,3,4-thiadiazol-5-yithio)]-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazoi-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-aminoethylthio- 1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yi)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)-1,2,4-thiadiazol-5-ylthio]-3-cephem-4-carboxylic acid, ;3c ntellectual property office OF n.z ;3 1 AUG 2005 ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-aminoethylamino-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-(2-aminoethylthio-1,3,4-thiadiazol-5-ylthio)-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-guanidinoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid, and ;(7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-chloro-4-(2-aminoethylthiomethyl)-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid. ;In another aspect the invention provides a compound selected from the group consisting of: ;(7R)-7[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-amino-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethyithiomethyl)pyrid-3-ylthiol-3-cephem-4-carboxylic acid, ;3d intellectual property office of n.z. ;31 AUG 2005 ;(7R)-7[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-guanidinoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-guanidinoethylthiomethyl) pyrid-3-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid, ;(7R)-7[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-guanidinoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid, and ;(7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyi)pyrid-3-ylthio]-3-cephem-4-carboxylic acid. ;In another aspect the invention provides a use of a compound or salt thereof of the invention in the manufacture of a medicament for treating a mammal suffering from a methicillin-resistant Staphylococcal bacterial infection. ;In another aspect the invention provides an antibacterial composition for treating a methicillin-resistant Staphylococcal bacterial infection, comprising a therapeutically effective amount of a compound or salt thereof of the invention in a pharmaceutically acceptable carrier. ;ntellectual property office of n.z. ;3 1 AUG 2065 ;In another aspect the invention provides a compound selected from the group consisting of: ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-ornithylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-prolylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-N-(L)-alanylamino-5-chlorothiazol-4-yl)-2- ;(hydroxyimino)acetamido]-3-{3-(2-aminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z-2-(2-amino-5chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L,L)-alanylalanylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-glycylaminoethylthiomethyl]pyrid-4-ylthio)-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-aspartylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-alanylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N- ;(L)-(Na-methyl)alanylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-histidylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;intellectual property office of n.z. ;3 1 AUG 2005 ;RECEIVED ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-valylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-asparagylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-lysylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chiorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-serylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-glutaminylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-glutamylaminoethylthiomethyl]pyrid-4-yithio}-3-cephem-4-carboxylic acid; and, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-((5-methyl-1,3-dioxolan-4-en-2-on-4-yl)methoxycarbonyl) aminoethyithiomethyl]pyrid4-yithio}-3-cephem-4-carboxylic acid. ;In another aspect the invention provides a compound selected from the group consisting of: ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-ornithylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L, L)-alanylalanylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid; ;intellectual property office of n.z. ;31 AUG 2005 ;-BiG&iysn ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-aspartylaminoethyIthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-aianylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-lysylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-glutamylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid; and, ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-((5-methyl-1,3-d ioxolan-4-en-2-on-4-yl)methoxycarbonyl) aminoethylthiomethyi]pyrid-4-ylthio}-3-cephem-4-carboxylic acid. ;In another aspect the invention provides a compound (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-(2-N-(L)-aspartylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, which corresponds to the structure: ;vOH, ;H ;vAyCOjH ;3h ntellectual property office of n.z ;3 1 AUG 2005 RECilVlP ;In another aspect the invention provides a compound (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-aspartylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, which corresponds to the structure: ;o ;The present invention relates to prodrugs of 1 that exhibit surprising water solubility and which are readily bioconverted in vivo to the parent compound. Thus, described herein are compounds having the chemical structure: ;wherein: ;R'1 is selected from the group consisting of hydrogen and -C(0)CH(NH2)CH3; and, R'2 is selected from the group consisting of hydrogen and an acyl group that is cleaved by an enzyme found in mammals. ;ntellectual property office of n.z ;3 1 AUG 2005 ;received ;Also described herein is a compound wherein: ;R'2 is selected from the group consisting of hydrogen, -C(0)-R88, -C(O)-0R89, ;R88 is ^ or ; ;R'3 is selected from the group consisting of hydrogen, -C(C>)-OR89, and -C(0)-CH(NH2)-alk4; ;alk4 Is selected from the group consisting of hydrogen, and optionally substituted alkyl, wherein said alkyl is optionally wherein ;3j ;.'ntellectual property office of m.z. ;31 AUG 2005 ;10 ;15 ;substituted with one or more substituents selected from the group consisting of hydrogen, phenyl, -COOH, -C(0)-0R89, -C(0)NH2, ;ff—"NH ;JL> ;-OH, -SH, -NH2, and ^ N ;and, ;R89 is selected from the group consisting of benzhydryl, f-butyl, aliyl, p-nitrobenzyl, benzyl, p- or o-nitrobenzyl, 2,2,2-trichloroethyl, cinnamyl, 2-chloroallyl, f-amyl, trityi, 4-methoxytrityl, 4,4,-dimethoxytrityl, trimethylsilyl, f-butyldimethylsilyl, p-(trimethylsilyl)ethyl, 4- or 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dImethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, and 3,3-dimethylalIyl. ;Also described herein, in the above compound R'3 is selected from the group consisting of hydrogen, methyl, and -C(0)CH(NH2)CH3. ;Furthermore, as described herein, in the above compounds, ;alk4 is selected from the group consisting of hydrogen, -CH3, ;-CH(CH3)2, -CH2OH, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2i -CH2CH2CH2CH2NH2i -CH2COOH, -CH2CH2COOH, -CH2-C(0)NH2, -CH2CH2- ;•NH ;C(0)NH2, and -CH2 N ;Pharmaceutically acceptable salts of any of the above compounds are 20 also described. ;Described herein is a compound selected from the group consisting of: consisting of: ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-omithylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic 25 acid: ;h nh2 ;k a ^—^nh2 ;30 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3- ;{3-[2-N-(L)-prolylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid: ;[ntellectual property office of n.z. ;3 1 AUG RECEIVED ;WO 02/24708 ;PCT/US01/08980 ;t,oh ;10 ;h2n- ;(7R)-7-[(Z)-2-(2-N-(L)-alanylamino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-aminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid: ;„oh nh2 h s ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L,L)-alanylalanylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-15 4-carboxylic acid: ;h2n—^ ;25 ;30 ;20 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yi)-2-(hydroxyimino)acetamido]-3- ;{3-[2-N-glycylaminoethyithiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid: ;h2n—^ ;nh. ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-aspartyIaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid: ;.OH ;h nh2 o ;5 ;WO 02/24708 ;PCT/US01/08980 ;15 ;20 ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-alanylaminoethyIthiomethyl3pyrid-4-ylthio}-3-cephem-4-carboxylic acid: ;.OH ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-(Na-methyl)alanylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-10 carboxylic acid: ;(7R)-7-[(Z)-2-(2-amino-5-ch!orothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-histidylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid: ;t,oh ;HjN— ;h n=\ ;NyOv'® ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-valylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxyiic acid: ;r,OH ;25 ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-asparagylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic ;„oh h2n—^ ;NHi ;6 ;WO 02/24708 PCT/USO1/08980 ;acid: ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-lysylaminoethyIthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid: ;r„oh h ^ ;nh2 ;10 ;15 ;20 ;25 ;30 ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-serylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid: ;_,0h ;,0h ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-glutamylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid ;(7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-glutaminylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid: ;,,0H ;h2n—^ ;nh2 ;VW*' and, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-((5-methyl-1,3-dioxoian-4-en-2-on-4-yl)methoxycarbonyl)aminoethyl-thiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxy!ic acid: 7 Also described herein is a compound selected from the group consisting of: group consisting of: (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-ornithylaminoethylthiomethyI]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-'(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L,L)-alanylalanylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-aspartylaminoethylthiomethyiJpyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido)-3-{3-[2-N-(L)-alanylaminoethylthiomethyl]pyrid-4-yIthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido)-3-{3-[2-N-(L)-lysylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-glutamylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid; and, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-((5-methyl-1,3-dioxolan-4-en-2-on-4-yl)methoxycarbonyI)aminoethyl-thiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxy)ic acid. 1 Finally, an aspect of this invention is the compound (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-aspartylaminoethylthiomethyl3pyrid-4-ylthio}-3-cephem-4-carboxylic acid: intellectual property office OF n.z. 3 1 AUG 2005 received n2H-^ s n o Also described herein is a pharmaceutically acceptable salt of any of the compounds of this invention.

Another aspect described herein is a composition for use in the treatment of a bacterial infection in a patient comprising one or more compounds of this invention.

A still further aspect described herein is a composition comprising a compound of this invention and a pharmaceutically acceptable carrier or excipient.

An aspect described herein is a composition for use in the treatment of a bacterial infection in a human being comprising one or more compounds of this invention It is likewise an aspect described herein that the composition for use in treatment of a bacterial infection in a human being further comprises a pharmaceutically acceptable carrier or excipient.

As described herein the above compositions are useful in the treatment of a p-lactam antibiotic resistant bacterial infection.

The p-lactam antibiotic resistant bacterial infection is a methicillin, ampicillin or vancomycin resistant bacterial infection in another aspect of this invention.

Furthermore, the bacterial infection is caused by a Staphylococcus or Entercoccus species bacteria as described herein.

The Staphylococcus or Enterococcus species are resistant to some, or all, other P-lactam antibiotics as described herein.

The resistant Staphylococcus species is S. aureus Col (MethR)(bla-), S. aureus 76 (MethR) (bla+), S. aureus ATCC 29213, S. Aureus ATCC 25913, S. Aureus ATCC 32432 or S. Aureus ColBA as described herein.

The resistant Enterococcus species is E. feecium ATCC 35667 or E. faecalis ATCC 29212 as described herein. intellectual property office of n.z 3 1 AUG 2005 9 RECEIVED WO 02/24708 PCT/USO1/08980 Finally, a composition for use in the prophylactic treatment of a patient for the prevention of a bacterial infection is described herein. [ intellectual property office i of N.z 3 ! AUG 2005 RECEIVED WO 02/24708 PCT/USO1/08980 DETAILED DESCRIPTION OF THE INVENTION Brief description of the Figures.

Figure 1 shows the water solubility of the parent antibiotic, compound 1, in its zwitterionic form (2) compared to that of a prodrug of this invention, compound 3: „oh Definitions As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group 15 has 1 to 20 carbon atoms (whenever a numerical range; e.g. "1-20", is stated herein, it means that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms. The alkyl group 20 may be substituted or unsubstituted. Examples, without limitation, of unsubstituted alkyl groups are methyl, ethyl, n-propyl, Jso-propyl, n-butyl, sec-butyl, /so-butyl, ferf-butyl, and 2-methylpentyl. When substituted, the substituent group(s) may be, without limitation, one or more independently selected from the group consisting of halo, hydroxy, cyano, nitro, lower alkoxy, 25 carboxy, carbonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, alkylthio, amino, amido, isothioureido, amidino, guanidino, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted 6-member heteroaryl having from 1 to 3 nitrogen atoms in the ring, optionally substituted 5-member heteroaryl having from 1 to 3 heteroatoms in the ring 30 selected from the group consisting of nitrogen, oxygen and sulfur, and optionally substituted 5- or 6-member heteroalicyclic group having from 1 to 3 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur. Examples, without limitation of substituted alkyl groups include trifluoromethyl, 11 WO 02/24708 PCT/USO1/08980 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, 4-cyanobutyl, 2-guanidinoethyl and 3-N,N'-dimethylisothiouroniumpropyl.

A "cycloalkyl" group refers to a 3 to 8 member all-carbon monocyclic ring, an all-carbon 5-member/6-member or 6-member/6-member fused bicyciic ring or 5 a multicyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, 10 cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane and, cycloheptatriene. A cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) may be, without limitation, one or more independently selected from the group consisting of halo, hydroxy, alkoxy, mercapto, alkylthio, cyano, nitro, optionally substituted aryl, optionally substituted 15 aryloxy, mercapto, alkylthio, optionally substituted arylthio, amino, amido, carboxy, carbonyl, alkylcarbonyl, alkoxycarbonyl, optionally substituted 6-member heteroaryl having from 1 to 3 nitrogen atoms in the ring, optionally substituted 5-member heteroaryl having from 1 to 3 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur, and optionally 20 substituted 5- or 6-member heteroalicyclic group having from 1 to 3 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur.

An "alkenyl" group refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond.

An "alkynyl" group refers to an alkyl group, as defined herein, consisting of 25 at least two carbon atoms and at least one carbon-carbon triple bond.

An "aryl" group refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be 30 substituted or unsubstituted. When substituted, the substituting group(s) may be, without limitation, one or more independently selected from the group consisting of alkyl, (haIo)3C-, halo, hydroxy, alkoxy, mercapto, alkylthio, cyano, nitro, amino, amido, carboxy, carbonyl, alkylcarbonyl, alkoxycarbonyl, optionally substituted 6- 12 WO 02/24708 PCT/USO1/08980 member heteroaryl having from 1 to 3 nitrogen atoms in the ring, optionally substituted 5-member heteroaryl having from 1 to 3 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur, and optionally substituted 5- or 6-member heteroalicyclic group having from 1 to 3 heteroatoms 5 in the ring selected from the group consisting of nitrogen, oxygen and sulfur.

Examples, without limitation, of substituted aryl groups are biphenyl, iodobiphenyl, methoxybiphenyl, anthryl, bromophenyl, iodophenyl, chlorophenyl, hydroxyphenyl, methoxyphenyl, formylphenyl, acetylphenyl, trifluoromethylthiophenyl, trifluoromethoxyphenyl, alkylthiophenyl, 10 trialkylammoniumphenyl, amidophenyl, thiazolylphenyl, oxazolyl phenyl, imidazolylphenyl, imidazolylmethylphenyl, cyanophenyl, pyridyiphenyl, pyrrolylphenyl, pyrazolylphenyl, triazolylphenyl and tetrazolylphenyl.

As used herein, a "heteroaryl" group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one 15 or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, having a conjugated pi-electron system. Examples, without limitation, of heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine and carbazole. A heteroaryl group may be substituted or unsubstituted. When 20 substituted, the substituted group(s) may be, without limitation, one or more independently selected from the group consisting of alkyl, (halo)3C-, halo, hydroxy, lower alkoxy, mercapto, alkylthio, arylthio, cyano, nitro, amino, amido, carboxy, carbonyl, alkylcarbonyl and alkoxycarbonyl. Examples of substituted heteroaryl groups are, without limitation, 2-aminothiazol-4-yl, 2-amino-5-25 chIorothiazol-4-yl, 5-amino-1,2,4-thiadiazol-3-yl, 2,3-dioxopiperazinyl, 4-alkylpiperazinyl, 2-iodo-3-dibenzfuranyl and 3-hydroxy-4-dibenzthienyl.

A "heteroalicydic" group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. 30 However, the rings do not have a completely conjugated pi-electron system. The heteroalicyclic ring may be substituted or unsubstituted. When substituted, the substituting group(s) may be, without limitation, one or more independently selected from the group consisting of alkyl, (halo)3C-, halo, hydroxy, alkoxy, 13 WO 02/24708 PCT/USO1/08980 mercapto, alkylthio, cyano, nitro, amino, amido, carboxy, carbonyl, alkylcarbonyl and alkoxycarbonyl.

A "hydroxy" group refers to an -OH group.

An "alkoxy" group refers to both an -0-(unsubstituted alkyl) and an -O-5 (unsubstituted cycloalkyl) group.

An "aryfoxy" group refers to both an -O-aryl and an -O-heteroaryl group, as defined herein.

A "mercapto" group refers to an -SH group.

A "alkylthio" group refers to both an (unsubstituted alkyl)S- and an 10 (unsubstituted cycloalkyl)S- group.

A "arylthio" group refers to both an -S(aryl) and an -S(heteroaryl group), as defined herein.

A "halo" group refers to fluorine, chlorine, bromine or iodine.

A "cyano" group refers to a -CsN group.

A "nitro" group refers to a -NOz group.

An "amino" group refers to an NRR' group wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heteroalicyclic.

An "amido" group refers to a -C(0)NRR', wherein R and R' have the above 20 meaning.

A "carboxy" group refers to a -C0(0)H group.

A "carbonyl" group refers to a -C(0)H group.

An "acyl" group refers to a -C(0)R group, in which R is hydrogen or alkyl as defined above, such as formyl, acetyl, propionyl, or butyryl. 25 An "alkylcarbonyl" group refers to a -C(0)(alkyl) group.

An "alkoxycarbonyl" group refers to an -C(0)(0-alkyl) group.

A "trialkylsilyl" groups refers to an RR'R"Si- group, where R, R' and R" are alkyl as defined above.

A "trialkylammonium" group refers to a [RR'R"N-]+, where R, R' and R" are 30 alkyl as defined above.

The term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from those 14 WO 02/24708 PCT/USO1/08980 manners, means, techniques and procedures known to practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts.

A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or physiologically acceptable salts thereof, with 5 other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

As used herein, a pharmaceutically acceptable salt refers to any of the compounds of this invention in its cationic or anionic form together with an 10 appropriate counterion. A compound of this invention may exist as a singly or a doubly charged species, in the latter instance it will form a salt with two counterions, which may be the same or different. Preferred pharmaceutically acceptable salts include (1) inorganic salts such as sodium, potassium, chloride, bromide, iodide, nitrate, phosphate or sulfate; (2) carboxylate salts such as 15 acetate, trifluoroacetate, propionate, butyrate, maleate, or fumarate; (3) alkyisulfonates such as methanesulfonate, ethanesulfonate, 2-hydroxyethylsulfonate, n-propylsuifonate or isopropyisulfonate; and (4) hydroxycarboxylates such as lactate, malate, and citrate. Salts in which a compound of this invention is the cationic species are prepared by reacting the 20 compound with an organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. The acid used provides the anionic counterion. Salts in which a compound herein is the anionic species of the pair are prepared by reacting any one of the compounds of 25 the invention with an organic or inorganic base, such as benzathene, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procain, and the hydroxide, alkoxide, carbonate, bicarbonate, sulfate, bisulfate, amide, alkylamide, or the dialkylamide salts of lithium, sodium, potassium, magnesium, calcium, aluminum, and zinc. The base supplies the cation.

A "prodrug" refers to an compound which is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also WO 02/24708 PCT/USO1/08980 have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but then 5 is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial.

A further example of a prodrug might be a single amino acid or a short polypeptide, for example, without limitation, a 2 -10 amino acid polypeptide, bonded through a terminal amino group to a carboxy group of a compound or 10 through a carboxy group of the amino acid to an amino group of a compound, as is the case with the compounds of this invention. The compound thus formed is then converted in vivo to release the active molecule.

As used herein, a "physiologically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not 15 abrogate the biological activity and properties of the administered compound.

An "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and 20 polyethylene glycols.

"In vitro" refers to procedures performed in an artificial environment such as, e.g., without limitation, a test tube or a petri dish containing a culture medium.

"In vivo" refers to procedures performed in a living organism such as, without limitation, a mouse, rat, dog, cat, rabbit, cow, pig, horse or a human. 25 As used herein, a "bacterial infection" refers to the establishment of a sufficient population of a pathogenic bacteria in a patient to have a deleterious effect on the health and well-being of the patient and/or to give rise to discernable symptoms associated with the particular bacteria.

As used herein, the terms "prevent", "preventing" and "prevention" refer to 30 a method for barring an organism from acquiring a bacterial infection in the first place. 16 WO 02/24708 PCT/US01/08980 As used herein, the terms "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a bacterial infection and/or its attendant symptoms.

As used herein, "administer," administering," or "administration" refers to 5 the delivery of a compound, or salt thereof, or a pharmaceutical composition containing a compound or salt thereof to an organism for the purpose of treating or preventing a bacterial infection.

The term "patient" refers to any living entity capable of being infected by bacteria. In particular, a "patient" refers to a mammal such as a dog, cat, horse, 10 cow, pig, rabbit, goat or sheep. Most particularly, a patient herein refers to a human being.

The term "therapeutically effective amount" as used herein refers to that amount of a compound being administered that will relieve, to some extent, one or more of the symptoms of the disorder being treated. In reference to the 15 treatment of a bacterial infection, a therapeutically effective amount refers to that amount of a compound that (1) reduces, preferably eliminates, the population of the bacteria in the patient's body, (2) inhibits (that is, slows to some extent, preferably stops) proliferation of the bacteria, (3) inhibits to some extent (that is, slows to some extent, preferably stops) spread of the infection caused by the 20 bacteria, and/or, (4) relieves to some extent (preferably, eliminates) one or more symptoms associated with the bacterial infection.

The term "prophylactically effective amount" refers to that amount of a compound that (1) maintains a reduced level of a population of a bacteria; (2) maintains the level of inhibition of proliferation of the bacteria; (3) maintains the 25 level of inhibition of spread of the infection and/or (4) maintains the level of relief of one or more symptoms associated with the baterial infection, achieved by the adminstration of a therapeutically effective amount of the compound.

The term "beta-lactam resistant bacteria" refers to bacteria against which a beta-lactam antibiotic has a minimum inhibitory concentration (MIC) of greater 30 than 32 jag/mL.

Synthesis Compound 1 is synthesized using well-known organic chemistry reactions and procedures from readily available materials. Texts such as, without limitation, 17 WO 02/24708 PCT/USO1/08980 March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure (McGraw-Hill, latest edition); Larock, Comprehensive Organic Transformations (VCH Publishers, latest edition); Greene and Wuts, Protective Groups in Organic Synthesis (John Wiley & Sons, latest edition) and G.I. Georg, The Organic 5 Chemistsry of p-Lactams (VCH Publishers, latest edition) provide ample direction for the synthesis of 1. A method for the preparation of 1 can also be found in U.S. Patent No. 6,025,352, which is incorporated, including any drawings, as if fully set forth herein. The following is representative of that synthesis: A. (Z)-2-(2-Amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino)- acetic 10 acid.

To a solution of (Z)-2-(2-aminothiazol-4-yl)-2-(triphenylmethoxy-imino)acetic acid (5.81 g, 13.47 mmol) in DMF (30 mL) at room temperature was added N-chloro- succinimide (1.80 g, 13.47 mmol). After stirring overnight, the reaction mixture was poured into water (500 mL) and the resulting precipitate was 15 filtered, washed with water and ethyl acetate, and dried under vacuum to afford 4.43 g (71%) of the title compound: 13C NMR (CDCI3) 8 108.5, 125.6, 126.2, 126.6,127.3, 134.7,141.8,146.5,162.1, 163.3.

B. (7R)-7-[(Z)-2-(2-Amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxy-imino)-acetamido]-3-chloro-3-cephem-4-carboxylate diphenylmethyl ester.

To a solution of 7-amino-3-chlorocephalosporanic acid diphenylmethyl ester toluenesulfonic acid salt (5.0 g, 8.72 mmol) in dry THF (100ml) at room temperature was added pyridine (0.63 g, 10.0 mmol), followed by (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino)aceticacid (5.81 g, 13.47 mmol). The resulting slurry was cooled to -15° C and additional pyridine (1.42 g, 22.5 25 mmol) was added followed by dropwise addition of phosphorous oxychloride (1.64 g, 17.5 mmol), while maintaining reaction temperature below -10° C. After 30 min, ethyl acetate (200 mL) was added followed by water (150 mL). The aqueous layer was thoroughly extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate and concentrated under vacuum 30 to yield the crude product, which was purified by flash column chromatography on silica gel (ethyl acetate/hexane 3:1) to afford the title compound (5.37 g, 65%): 1H NMR (CDCI3 /CD3OD) 8 3.35 (d, 1H, J=18), 3.68 (d, 1H, J=18), 5.07 (d, 18 WO 02/24708 PCT/USO1/08980 1H, J=5), 5.80 (br s, 2H), 6.04 (dd, 1H, J=9, 5), 7.03 (s, 1H), 7.06 (d, 1H, J=9), 7.22-7-50 (m, 25H).

C. (7R)-7-[(Z)-2-(2-Amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxy-imino)-acetamido]-3-mercapto-3-cephem-4-carboxylate diphenylmethyl ester.

To a solution of (7ft)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenyl-methoxyimino)acetamido]-3-chloro-3-cephem-4-earboxylate diphenylmethyl ester (4.0 g, 4.72 mmol) in DMF (30 mL) at -20° C was added, in one portion, powdered sodium hydrogen sulfide hydrate (1.10 g, 19,6 mmol). After 15 min the 10 reaction mixture was poured into 0.5 M monosodium phosphate (about 100 mL). The mixture was extracted with ethyl acetate, and the organic layer was washed thoroughly with water. After concentrating under vacuum, the crude title product was obtained as a yellow foam 3.8 g (95%): 1H NMR (CDCIS / CD3OD) 5 3.38 (d, 1H, J=15), 4.43 (d, 1H, J=15), 5.03 (d, 15 1H, J=5), 5.80 (d, 1H, J=5), 5.99 (brs, 1H), 6.80 (s, 1H), 7.05-7.50 (m, 25H).

D. 3-ChIoromethyl-4-chloropyridine hydrochloride Thionyl chloride (0.714 mL, 9.78 mmol) was added at room temperature to dry DMF (7 mL). After 30 min, the solution was cannulated into a solution of 3-hydroxymethyl-4-chloropyridine (700 mg, 4.89 mmol) in DMF (3 mL). After 45 20 min, the product was precipitated by addition of dry ether (100 ml), washed with ether, and dried under vacuum to yield 813 mg (84%) of the title compound: 1H NMR (CDgOD) 5 5.00 (s, 2H), 8.31 (d, 1H, J=5), 8.99 (d, 1H, J=5), 9.18 (s, 1H).

E. 3-(N-ferf-Butoxycarbonylaminoethylthiomethyl)-4-chloropyridine.

To a solution of 3-chloromethyl-4-chloropyridine hydrochloride (513 mg, 2.59 mmol) in DMF (6 mL) at room temperature were added sodium iodide (386 mg, 2.59 mmol), diisopropylethyl- amine (1.12 mL, 6.47 mmol) and 2-(N-tert-butoxycarbonylamino)ethanethiol (458 mg, 2.59 mmol). After 2 h, the reaction mixture was partitioned between dilute HCI and ethyl acetate. The organic layer 30 was washed with water, dried over sodium sulfate, and concentrated to yield 750 mg of the oily product (96%), which was used in the next step without further purification: 19 WO 02/24708 PCT/USO1/08980 1H NMR (CDCI3) 5 1.43 (s, 9H), 2.61 (m, 2H), 3.35 (m, 2H), 3.81 (s, 2H), 4.90 (br s, 1H), 7.35 (d, 1H, J=4), 8.40 (d, 1H, J=4), 8.57 (s, 1H).

F. (7/?)-7-[(Z)-2-(2-Amino-5-chlorothiazo!-4-yl)-2-(triphenyImethoxy-imino)-acetamido]-3-[3-(N-fert-butoxycarbonylaminoethylthiomethyl)pyrid-4- ylthio]-3-cephem-4-carboxylate diphenylmethyl ester.

To a solution of (7R)-7-[(Z)-2-(2-amino~5-chlorothiazo!-4-yl)-2-(triphenylmethoxy- imino)acetamido]-3-mercapto-3-cephem-4-carboxylate diphenylmethyl ester (650 mg, 0.777 mmol) in DMF (3 mL) was added 3-(N-ferf-butoxycarbonylaminoethylthiomethyl)-4-chloropyridine (242 mg, 0.80 mmol) at 10 room temperature. After stirring overnight, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was thoroughly washed with water, dried over sodium sulfate, and concentrated to yield the crude product which was purified by radial chromatography on silica gel (dichloromethane / methanol; v/v, 50/1) to afford 220 mg of the title compound (26%): 15 1H NMR (CDCI3/CD3OD) 5 1.23 (s, 9H), 2.32 (t, 2H, J=6), 2.98 (d, 1H, J=18), 3.06 (m, 2H), 3.40 (d, 1H, J=18), 3.46 (s, 2H), 5.03 (d, 1H, J=5), 5.52 (br s, 1H), 5.94 (d, 1H, J= 5), 6.80 (s, 1H), 6.90 (d, 1H, J=6), 7.00-7.22 (m, 25H), 8.01 (d, 1H, J=6), 8.08 (s, 1H).

G. (7/?)-7-[{Z)-2-(2-Amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)-20 acetamido]-3-[3-(aminoethylthiomethyl)pyrid-4-ylthio]-3-eephem-4- carboxylate, methanesulfonic acid salt.

To a cold solution (0° C) of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino)acetamido]-3-[3-(N-ferf-butoxycarbonylaminoethylthio methyl)-pyrid-4-ylthio]-3-cephem-4-carboxylate diphenylmethyl ester (1.00 g, 25 0.907 mmol) in dichloromethane (10 mL) and anisole (1.0 mL) was added trifluoroacetic acid (13 mL). After 1.5 hr, the reaction mixture was concentrated under vacuum at room temperature, and the oily residue was dissolved in 98% formic acid (20 mL). After 4 hr at room temperature, formic acid was removed under vacuum, and the residue was dissolved in water (25 mL). Insoluble material 30 was removed by centrifugation. The supernatant was purified on an HP20 column by elution with water, then 0.1 M aqueous ammonium acetate, then finally eluting the product with 1:4 acetonitrile/water. The eluate was concentrated to about 1/10 original volume, and the resulting precipitate was filtered, washed with PCT/USO1/08980 water and dried in vacuum to yield a zwitterionic product (260 mg). The methanesulfonate salt was prepared by suspending the zwitterionic product in water (15 mL) followed by addition of methanesulfonic acid (1.0 M in water, 0.98 eq) and acetonitrile (5 mL). After evaporation of the resulting solution to dryness, the residue was dissolved in water (30 mL) and centrifuged to remove insoluble material, and the supernatant was lyophilized to give the title compound (274 mg, 44%). 1H NMR (D20) 8 3.11 (s, 3H), 3.19 (m, 2H), 3.52 (m, 2H), 3.67 (d, 1H, J=17), 4.22 (d, 1H, J=17), 4.33 (s, 2H), 5.76 (d, 1H, J=4), 6.29 (d, 1H, J=4), 7.93 (d, 1H, J=4), 8.78 (d, 1H, J=4), 8.87 (s, 1H).

Prodrugs of 1, which are the subject of this invention, can also be prepared by standard organic synthetic procedures found in the above-referenced texts. The following are examples of such preparations. The syntheses shown are not to be construed as limiting the scope of this invention in any manner whatsoever. That is, other prodrugs and other approaches to sythesizing them will become apparent to those skilled in the art based on the disclosures herein; all such prodrugs and syntheses are within the scope of this invention. 1. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazoI-4-yl)-2-(hydroxyimino)-acetamido]-3-{3-[2-N-(L)-a-glutamylaminoethyl thiomethyl] pyrid-4-ylthio}-3-cephem-4-carboxylate, bis trifluoroacetic acid salt A solution of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino)acetamido]-3-mercapto-3-cephem-4-carboxylate, diphenylmethyl ester (354 mg, 0.41 mmol) and 4-chloro-3-{2-[N-(L)-a-(N-t-butoxycarbonyl)-(y-t-butoxy)-glutamyl]-aminoethylthiomethyl}pyridine (183 mg, 0.41 mmol) in DMF (2.5 mL) was stirred under nitrogen for 3 h., and was diluted with ethyl acetate (25 mL). The reaction mixture was thoroughly washed with water and dried over anhydrous sodium sulfate. The mixture was subjected to 21 column chromatography on silica gel (eluting with 2:1 hexane/ethyl acetate, followed by 1:3) to afford the desired coupling product as an oily solid (107 mg). Standard deprotection (trifluoroacetic acid, dichloromethane, triethylsilane) was conducted, and the title product was precipitated by addition of diethyl ether. The precipitate was filtered, washed thoroughly with diethyl ether and dried to afford the title compound (48 mg). 1H NMR (CD3OD): 5 2.25-2.37 (m, 2H), 2.65 (t, 2H, J = 8), 2.80-2.96 (m, 2H), 3.58-3.78 (m, 3H), 4.08-4.20 (m, 4H), 5.58 (d, 1H, J = 8), 6.20 (d, 1H, J = 8), 7.80 (d, 1H, J = 8), 8.62 (d, 1H, J = 8), 8.91 (s, 1H). 2. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino) acetamido]-3-{3-[2-N-(L)-a-(N-t-butoxycarbony[)-(y-t-butoxy)aspartyl-aminoethyl-thiomethyl]pyrid-4-ylthio}-3-cephem-4«carboxylic acid To a stirred suspension of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yI)-2-(hydroxyimino)acetamido]-3-{3-[2-aminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid (8.6 g, 14.28 mmol) in DMF (25 mL) at room temperature was added triethylamine (2.0 mL, 14.5 mmol), followed by addition of a solution of aspartic acid, N-t-butoxycarbonyl-[a-(N-hydroxysuccinimide)-ester]-y-t-butyl ester (5.5 g, 14.28 mmol) in DMF (25 ml). After 30 min., ice cold water (200 mL) was added to the reaction mixture followed by addition of hydrochloric acid (1.0 M, 14.3 mL). A precipitate formed, which was filtered, washed thoroughly with water and dried under reduced pressure to yield the crude product as a yellowish solid 3. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino) acetamido]-3-{3-[2-N-(L)-y-aspartylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylate, sodium salt (10.0 g). o 22 WO 02/24708 PCT/USO1/08980 To a stirred suspension of crude (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-a-(N-t-butoxycarbonyl)-(y-t-butoxy)-aspartyl-aminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid (11.8 g, 13.52 mmol) in dichloromethane (200 mL) at room temperature was added 5 triethylsilane (66 mL) followed by trifluoroacetic acid (200 mL). The resulting clear solution was stirred for 2.5 hr. After removing the solvents under reduced pressure, the oily residue was re-dissolved in ethyl acetate (50 mL), and the trifluoroacetate salt of the product was precipitated with addition of diisopropyl ether (100 mL). The precipitate was filtered, thoroughly washed with diisopropyl ether, and dried under 10 reduced pressure to produce the crude trifluoroacetate salt as a yellow solid (15.0 g). A solution of the crude product (in 600 mL water, adjusted with aqueous sodium bicarbonate to pH 6.0) was loaded onto a reverse phase preparative column, which was eluted with an acetonitrile/phosphate buffer mixture. The fractions containing pure product (800 mL) were combined, the acetonitrile was removed by evaporation 15 under reduced pressure, and the aqueous solution of the product was desalted by loading it onto a column containing HP20 resin and washing thoroughly with water. The product was eluted with 20% aqueous acetonitrile, and the fractions containing pure desalted product were concentrated under reduced pressure to remove the acetonitrile. The remaining water was removed from the resulting cloudy solution by 20 lyophilization. The lyophilized material was redissolved in water and the cloudy solution was adjusted to pH 6.1 with addition of sodium bicarbonate solution. The resulting clear solution was lyophilized to yield the pure title product as a pale yellow solid (3.99 g.). 1H NMR (D20): 8 2.50-2.70 (m, 3H), 3.21 (d, 1H, J =16), 3.30 (t, 2H, J = 8), 3.70 25 (d, 1H, J = 16), 3.78 (s, 2H), 4.04-4.10 (m, 1H), 5.27 (d, 1H, J = 8), 5.80 (d, 1H, J = 8), 7.18 (d, 1H, J = 8), 8.19 (d, 1H, J = 8), 8.23 (s, 1H).

Pharmaceutical Applications and Preparations A prodrug of the present invention or a physiologically acceptable salt thereof can be administered as such to a patient or can be administered in 30 pharmaceutical compositions in which the foregoing materials are mixed with suitable carriers or excipient(s). Techniques for formulation and administration of drugs may be found in Remington's Pharmacological Sciences (Mack Publishing Co., Easton, PA, latest edition). 23 WO 02/24708 PCT/USO1/08980 Routes of Administration.

Suitable routes of administration may include, without limitation, oral, rectal, transmucosal, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intravitreal, intraperitoneal, intranasal, or intraocular.

The preferred routes of administration are oral and intravenous.

Alternatively, one may administer the compound in a local rather than systemic fashion, for example, topical application onto or injection directly into an infected area of a patient's body.

Compositions/Formulations 10 Pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions may be formulated in conventional manner 15 using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen; such formulations are well-known to those skilled in the art and include, without limitation, the following; For injection, compounds may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient. Pharmaceutical 30 preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding other suitable auxiliaries, if desired, to obtain tablets or dragee cores. Some useful excipients, without limitation, are fillers such as sugars such as lactose, sucrose, 24 WO 02/24708 PCT/USO1/08980 mannitol, or sorbitol, cellulose preparations such as maize starch, wheat starch, rice starch and potato starch and other materials such as gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, 5 such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid. Salts such as sodium alginate may also be used.

Dragee cores are normally provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or 10 titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical compositions which can be used orally include push-fit 15 capsules made of gelatin, soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol, and the like. Push-fit capsules may contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in 20 suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Stabilizers may be added in these formulations, also.

For administration by inhalation, the compounds are conveniently delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, dichlorodifluoromethane, 25 trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. 30 The compounds may also be formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, WO 02/24708 PCT/USO1/08980 solutions or emulsions in oily or aqueous vehicles, and may contain formulating materials such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active 5 compound. Additionally, suspensions of the active compounds may be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium 10 carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use. 15 The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.

In addition, compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example, 20 subcutaneously or intramuscularly) or by intramuscular injection. A compound may be formulated for this route of administration with suitable polymeric or hydrophobic materials (for instance, in an emulsion with a pharmacologically acceptable oil), with ion exchange resins, or as a sparingly soluble derivative such as, without limitation, a sparingly soluble salt.

. The pharmaceutical compositions herein also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

The compounds of the invention may be provided as physiologically acceptable salts wherein the claimed compound may form the negatively or the positively charged species. Examples of salts in which the compound forms the positively charged entity include, without limitation, quaternary ammonium salts 26 WO 02/24708 PCT/USO1/08980 such as the hydrochloride, sulfate, carbonate, lactate, tartrate, maleate, succinate wherein the nitrogen atom of the quaternary ammonium group is a nitrogen of the compound herein which has reacted with the appropriate acid. Salts in which a compound of this invention forms the negatively charged species include, without 5 limitation, the sodium, potassium, calcium and magnesium salts formed by the reaction of a carboxylic acid group of a compound herein with an appropriate base, e.g., sodium hydroxide (NaOH), potassium hydroxide (KOH), Calcium hydroxide (Ca(OH)2), etc.

A therapeutically effective amount of a p-lactam antibiotic compound of this 10 invention can be administered to a patient to ameliorate or eliminate a methicillin or other p-lactam, such as vancomycin or ampicillin, resistant bacterial infection. In particular, infections caused by resistant S. aureus species, such as, without limitation, S. aureus Col (MethR)(bla-), S. aureus 76 (MethR) (bla+), S. aureus ATCC 29213, S. Aureus ATCC 25913, S. Aureus ATCC 32432 and S. Aureus 15 ColBA or resistant Enterococcus species such as E. faecium ATCC 35667, or E. faecalis ATCC 29212, may be treated using a therapeutically effective amount of a compound of this invention. Of course, the compounds of the present invention may be used against bacteria which are susceptible or sensitive to methicillin, vancomycin, ampicillin or other antibiotic, also.

The compositions containing a compound or compounds of the invention can be administered for prophylactic or therapeutic treatment. In therapeutic applications, the compositions are administered to a patient already suffering from an infection, as described above, in an amount sufficient to cure or at least partially arrest the symptoms of the infection. An amount adequate to accomplish 25 this is defined as "therapeutically effective amount or dose" and will depend on the severity and course of the infection, previous therapy, the patient's overall health status and response to the drugs, and the judgment of the treating physician. In prophylactic applications, compositions containing a compound or compounds of the invention are administered to a patient who is who has 30 previously been treated with a therapeutically effective amount of a compound to prevent recurrence of the infection, or they may be adminstered to a patient who, for one reason or another, may be susceptible to infection but is not yet infected such as the case of presurgical adminstration an antibiotics. Such an amount is 27 WO 02/24708 PCT/US01/08980 defined to be a "prophylactically effective amount or dose." The precise amounts again depend on factors such as those described above.

Dosage The proper dosage will depend on the severity and course of the infection, 5 previous therapy, the patient's general health status, his or her response to the drugs, etc., all of which are within the knowledge, expertise and judgment of the treating physician.

In general, a suitable effective dose of the compound of the invention will be in the range of 0.1 to 10000 milligram (mg) per recipient per day, preferably in 10 the range of 20 to 2000 mg per day. The desired dosage is preferably presented in one, two, three, four or more subdoses administered at appropriate intervals throughout the day. These subdoses can be administered as unit dosage forms, for example, containing 5 to 1000 mg, preferably 10 to 100 mg of active ingredient per unit dosage form. Preferably, the compounds of the invention will be 15 administered in amounts of between about 2.0 mg/kg to 250 mg/kg of patient body weight, between about one to four times per day.

Once improvement of the patient's condition is observed, a maintenance dose may be administered if desired by the treating physician. The dosage, frequency, or both, can be reduced as a function of the patient's response to a 20 level at which the improvement persists. When the symptoms have been alleviated to the desired level, treatment may be stopped although some patients may require intermittant treatment on a long-term basis should flare-ups of the symptoms reccur.

Biological Evaluation 25 The biological activity of compound 1 was previously reported as compound 16 in U.S. Patent No. 6,025,352, which is incorporated by reference, including any drawings, as if fully set forth herein. Thus, the biological activity of the prodrugs described herein are expected to be the same since they hydrolyze readily to the parent compound in vivo. However, the prodrugs and salts thereof 30 described in the present invention are substantially more water soluble at or near neutral pH that the parent compound of its salts. It is this surprisingly enhanced solubility that is the focus of this invention. The solubility of any of the prodrugs herein can be determined using the following procedure: 28 A small amount (5-8 mg) of a salt of a compound of this invention is weighed into a screw cap vial. Water is added to dissolve the salt at a high concentration (50-75 mg/mL). To this" solution is added small amounts (1-5 pL increments) of 0.1 N aqueous sodium hydroxide until a faint precipitate remains 5 after mixing. The suspension is maintained at room temperature for 15 minutes with periodic vortexing. An aliquot of the suspension is then transferred to an Eppendorf tube and centrifuged at 14000 rpm for 1.5 minutes. A portion of the supernatant is diluted with water, filtered and quantified by HPLC against a standard calibration curve. The pH of the supernatant is measured using a fine 10 needle probe. For each subsequent determination, using a new sample, more 0.1 N sodium hydroxide is added to increase the pH just slightly, and the rest of the procedure is repeated. Five to seven determinations are used to prepare the pH vs. concentration curve.

When starting with a zwitterion, the zwitterion is suspended in water and 15 0.1 N sodium hydroxide or 0.1 N hydrochloric acid is added to begin to dissolve the solid. The suspensions are held at room temperature for 15 minutes with frequent stirring and then are subjected to the same treatment described above (centrifugation, dilution and quantitation).

An example of the vastly greater water solubility at or near neutral pH of 20 the compounds of this invention compared to that of 1 is shown in Figure 1. In Fig. 1, the water solubility of 1, in its zwitterionic form (2) is compared to that of its L-aspartyl prodrug (3): h,n—^ Determination of prodrug cleavage in serum Of course, the key to the utility of the prodrugs of this invention is their ready conversion to the parent active compound, 1, under physiological conditions. The ability of a prodrug herein to revert to 1 can be evaluated using the following protocol: 29 WO 02/24708 PCT/USO1/08980 Fresh control human serum, fresh control rat serum, and rhesus monkey plasma (heparinized and stored frozen) are preincubated at 37 °C for 15 min in a shaking water bath. The pH of the serum or plasma is measured using test strips. Then 25 |xL aliquots of a solution in water of a prodrug of this invention (2 mg/mL) 5 are added to each matrix resulting in a final solution volumn of 1 mL. The solutions are incubated at 37° C for 1 hr, removing 100 jxL aliquotes at 0,15, 30, and 60 min post dosing. The aliquotes are added to 200 j-iL 4% trichloroacetic acid, vortexed, and centrifuged for 10 min at 14,000 rpm in an Eppendorf microcentrifuge. Then 25 |j,L of each supernatant is analyzed via HPLC 10 (Beckman Ultrasphere C18 column, 5 micron, 4.6mm x 25cm and 1 mL/min of 95% 0.1 M ammonium acetate, pH = 6, 5% acetonitrile ramping to 25% acetonitrile over 20 min with peak detection at 254 and 280 nM).

CONCLUSION One skilled in the art would readily appreciate that the present invention is 15 well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The molecular complexes and the methods, procedures, treatments, molecules, specific compounds described herein are presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other 20 uses will occur to those skilled in the art which are encompassed within the spirit of the invention are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention.

All patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms WO 02/24708 PCT/USO1/08980 "comprising", "consisting essentially of and "consisting of may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents 5 of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the 10 art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of 15 members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims forX being bromine and chlorine are fully described.

The invention has been described broadly and genetically herein. Each of the narrower species and subgeneric groupings falling within the generic 20 disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

Other embodiments are contained within the following claims. 31

Claims (25)

WHAT WE CLAIM IS:

1. A compound of formula III or formula IV: hon nhr'2 (III) h,n nhr'2 (IV) or a pharmaceutically acceptable salt thereof, wherein: R is an acyl group that is cleaved by an enzyme found in mammals; A, B, L, G, E, and J are each independently nitrogen or carbon, wherein said specific juxtaposition of groups A, B, and L forms a heterocyclic group selected from the group consisting of jo jo * and * 32 intellectual property office of n.z. 3 1 AUG 2005 D wherein said specific juxtaposition of groups E, G, and J forms a heterocyclic group selected from the group consisting of provided that the group -CH2-S-CH2CH2NHR'2 is attached only to a carbon atom of said heterocyclic group; and, Q is selected from the group consisting of nitrogen and -CX, wherein X is selected from the group consisting of hydrogen and chlorine.

2. A compound or salt thereof of claim 1, wherein R'2 is selected from the group consisting of -C(0)-R88, -C(0)-0R89, -C(0)-CH(NHR'3)-alk4, and R'3 is selected from the group consisting of hydrogen, -C(0)-0R89, and -C(0)-CH(NH2)-alk4; alk4 is selected from the group consisting of hydrogen, and optionally substituted alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, phenyl, -COOH, o wherein O ■ntellectual property office OF HI 3 1 AUG 2005 33 vv -C(0)-0R89, C(0)NH2, -OH, -SH, -NH2, and R89 is selected from the group consisting of benzhydryl, t-butyl, allyl, p-nitrobenzyl, benzyl, p- or o-nitrobenzyl, 2,2,2-trichloroethyl, allyl, cinnamyl, benzhydryl, 2-chloroallyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, trimethylsilyl, t-butyldimethylsisyl, 0-(trimethylsilyl)ethyl, 4- or 2-methoxybenzyl, 2,4-d imethoxybenzyl, 3,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, and 3,3-dimethylallyl.

3. A compound or salt thereof of claim 1, wherein said compound has the structure set forth in formula V: nhr'2 or a pharmaceutically acceptable salt thereof wherein R is an acyl group that is cleaved by an enzyme found in mammals.

4. A compound or salt thereof of claim 3, where R'2 is selected from the group consisting of -C(0)-R88, -C(0)-0R89, -C(0)-CH(NHR'3)-alk4, and A -cioychcaf \ wherein 34 intellectual property office of n.z. 3 1 AUG 2005 RECEIVED 'ntellectual PROrEHTY office r,c hi R«is^ or RECEIVED 3 I AUG 2005 R'3 is selected from the group consisting of hydrogen, -C(0)-0R89, and -C(0)-CH(NH2)-alk4; alk4 is selected from the group consisting of hydrogen, and optionally substituted alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, phenyl, -COOH, -C(0)-0R89, -C(0)NH2, -OH, -SH, -NH2, and R89 is selected from the group consisting of benzhydryl, t-butyl, allyl, p-nitrobenzyl, benzyl, p- or o-nitrobenzyl, 2,2,2-tnchloroethyl, allyl, cinnamyl, benzhydryl, 2-chloroallyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, (3-(trimethylsilyl)ethyl, 4- or 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-d imethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, and 3,3-dimethylallyl.

5. A compound or salt thereof of claim 4, wherein R'3 is selected from the group consisting of hydrogen, methyl, and -C(0)-CH(NH2)CH3.

6. A compound or salt thereof of claim 4, wherein alk4 is selected from the group consisting of hydrogen, -CH3, -CH(CH3)2, -CH2OH, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, -CH2COOH, -CH2CH2COOH, -CH2-C(0)NH2, -CH2CH2-C(0)NH2, and

7. A compound of claim 3 selected from the group consisting of: (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-ornithylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, 35 (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-prolylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-(2-N-glycylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-aspartylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-(2-N-(L)-(Na-methyl)alanylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-histidylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-valylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazoi-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-asparagylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-lysylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-serylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-glutaminylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamidol-3-{2-[2-(5-methyl-1,3-dioxolan-4-en-2-on-4-yl)methoxycarbonyl)aminoethylthiomethyl] pyrid-3-ylthio}-3-cephem-4-carboxylic acid, and 36 intellectual property office of n.z. 3 1 AUG 2005 RECEIVED (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-(2- N-(L)-pyroglutamylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid.

8. An intermediate compound having the following formula: H^si ,s^ss^NHR'2 wherein R'2 is selected from the group consisting hydrogen -C(0)-R88, -C(O)- R'3 is selected from the group consisting of hydrogen, -C(0)-0R89, and -C(0)-CH(NH2)-alk4; alk4 is selected from the group consisting of hydrogen, and optionally substituted alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, phenyl, -COOH, OR89 o -C(0)-CH(NHR'3)-alk4, and wherein: intellectual property office of n.z. 3 1 AUG 2005 RECEIVED -C(0)-0R89, -C(0)NH2, -OH, -SH, -NH2, and R89 is selected from the group consisting of benzhydryl, f-butyl, allyl, p-nitrobenzyl, benzyl, p- or o-nitrobenzyl, 2,2,2-tnchloroethyl, allyl, cinnamyl, benzhydryl, 2-chloroallyl, f-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, (3-(trimethylsilyl)ethyl, 4- or 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, and 3,3-dimethylallyl.

9. A compound or salt thereof of claim 1 having the chemical structure: h,n nhr wherein R'2 is an acyl group that is cleaved by an enzyme found in mammals.

10. A compound or salt thereof of claim 9, where R'2 is selected from the group consisting of -C(0)-R88, -C(0)-0R89, -C(0)-CH(NHR'3)-alk4, and O a -C(0)-0-CH2 x wherein: HN R88 is ^ or P. R'3 is selected from the group consisting of hydrogen, -C(O)-OR0a, and -C(0)-CH(NH2)-alk4; 89 38 intellectual property office of n.z. 3 t AUG 2005 RECEIVED 3 1 AUG 2005 RECEIVED alk4 is selected from the group consisting of hydrogen, and optionally substituted alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, phenyl, -COOH, -C(0)-0R89, -C(0)NH2, -OH, -SH, -NH2, and R89 is selected from the group consisting of benzhydryl, £-butyl, allyl, p-nitrobenzyl, benzyl, p- or o-nitrobenzyl, 2,2,2-trichloroethyl, allyl, cinnamyl, benzhydryl, 2-chloroallyl, f-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, P-(trimethylsilyl)ethyl, 4- or 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, and 3,3-dimethylallyl.

11. A compound selected from the group consisting of: (7R)-7-((Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido-3-[4-(2-aminoethylthio-1,3,4-thiadiazol-5-ylthio)]-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-methyl-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid, (7R)-7-((Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamidol-3-(4-(2-aminoethylthiomethyl)-1,3-thiazol-2-ylthio]-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-methoxy-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthio)-pyridazin-6-ylthio]-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthio)-pyridazin-3-ylthio]-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthio)-pyrimidin-4-ylthio]-3-cephem-4-carboxylic acid, 39 INTELLECTUAL property office of n.z. 3 1 AUG 2005 RECEIVED (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)-pyridazin-3-ylthio]-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl-1,3,4-thiadiazol-5-ylthio)]-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimirio)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-aminoethylthio- 1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)-1,2,4-thiadiazol-5-ylthio]-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-aminoethylamino-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid, (7R)-7-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-(2-aminoethylthio-1,3,4-thiadiazol-5-ylthio)-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-guanidinoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-amirioethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid, and (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-chloro-4-(2-aminoethylthiomethyl)-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid. 40 intellectual property office of HZ 31 AUG 2005 RECEIVED

12. A compound selected from the group consisting of: (7R)-7[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-amino-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid, (7R)-7[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)pyrid-3-ylthiol-3-cephem~4-carboxylic acid, (7R)-7[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-guanidinoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid, (7R)-7[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-guanidinoethylthiomethyl) pyrid-3-ylthio]-3-cephem-4-carboxylic acid, (7R)-7[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid, (7R)-7[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid, (7R)-7[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid, (7R)-7[(Z)-2~(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-guanidinoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid, and (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid.

13. A compound or salt thereof of claim 1, wherein said compound is active against methicillin-resistant Staphylococcal bacteria selected from the group consisting of S. aureus Col (MethR)(lac-), S. aureus 76 (MethR){lac+), S. aureus ATCC 33593 (MethR), S. aureus Spain #356 (MethR), and S. haemolyticus 05 (MethR). 41 INICUUtV/iunw 0 31 i I REC

14. A use of a compound or salt thereof of claim 1 in the manufacture of a medicament for treating a mammal suffering from a methicillin-resistant Staphylococcal bacterial infection.

15. An antibacterial composition for treating a methicillin-resistant Staphylococcal bacterial infection, comprising a therapeutically effective amount of a compound or salt thereof of claim 1 in a pharmaceutically acceptable carrier.

16. A compound or salt thereof of claim 10, wherein R'3 is selected from the group consisting of hydrogen, methyl, and -C(0)-CH(NH2)CH3.

17. A compound or salt thereof of claim 10, wherein alk4 is selected from the group consisting of hydrogen, -CH3, -CH(CH3)2, -CH2OH, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, -CH2COOH, -CH2CH2COOH, -CH2-C(0)NH2, -CH2CH2-C(0)NH2, and ^ N .

18. A compound selected from the group consisting of: (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-ornithylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-prolylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-N-(L)-alanylamino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-(2-aminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z-2-(2-amino-5chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L,L)-alanylalanylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, 42 (7R)-7-[(Z-2-(2-amino-5-chiorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-glycylaminoethylthiomethyl]pyrid-4-ylthio)-3-cephem-4-carboxylic acid, (7R)-7-[(Z-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-aspartylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-alanylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N- (L)-(Na-methyl)alanylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-histidylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-valylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-asparagylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-lysylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-ch!orothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-serylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-glutaminylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-glutamylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid; and, intellectual property office of n.z 31 AUG 2005 RECEIVED (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-((5-methyl-1,3-dioxolan-4-en-2-on-4-yl)methoxycarbonyl) aminoethylthiomethyl]pyrid4-ylthio}-3-cephem-4-carboxylic acid.

19. A compound selected from the group consisting of: (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-omithylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L,L)-alanylalanylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid; (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-aspartylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-alanylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-lysylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-(L)-glutamylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid; and, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-[2-N-((5-methyl-1,3-d ioxolan-4-en-2-on-4-yl)methoxycarbonyl) aminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid.

20. A compound (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-{3-(2-N-(L)-aspartylaminoethylthiomethyl]pyrid-4-ylthio}-3-cephem-4-carboxylic acid, which corresponds to the structure: intellectual property office of n.z. 3 1 AUG 2005 RECEIVED 44 H2N—^ H tfH3+

21. A compound (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-aspartylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, which corresponds to the structure: o

22. A compound as claimed in any one of claims 1, 11, 12, 18, 19, 20 and 21 substantially as herein described with reference to any example thereof.

23. An intermediate compound as claimed in claim 8 substantially as herein described with reference to any example thereof.

24. A use as claimed in claim 14 substantially as herein described with reference to any example thereof.

25. An antibacterial composition as claimed in claim 15 substantially as herein described with reference to any example thereof. END OF CLAIMS intellectual property office of n.z 3 1 AUG 2665 RECEIVED 45