NZ335892A

NZ335892A - Cephalosporin derivatives for treating bacterial infections

Info

Publication number: NZ335892A
Application number: NZ335892A
Authority: NZ
Inventors: Dane M Springer; Bing Y Luh; Andrea Stanley V D; Thomas W Hudyma; Oak K Kim
Original assignee: Bristol Myers Squibb Co
Priority date: 1996-11-27
Filing date: 1997-11-21
Publication date: 2001-07-27
Also published as: EP0966472A1; KR20000057283A; CN1238775A; HUP9903621A3; AU734948B2; CA2272717A1; IL129437A0; BR9713350A; AR010650A1; WO1998023621A1; CZ185399A3; HUP9903621A2; TW414796B; ZA9710662B; NO992526D0; PL334558A1; EP0966472A4; JP2001506607A; NO992526L; AU5365298A

Abstract

A compound of the Formula (IA) are gram-positive antibacterial agents useful for the treatment of diseases caused by methicillin-resistant Staphylococcus aureus. Wherein; X is halogen; Y is hydrogen or halogen; A is CO2H, PO3H2, SO3H or tetrazolyl; L1 is a furylene group, a thienylene group, a C2-10alkylene group, or a C2-10alkylene group interrupted by one or more groups independently selected from vinyl, S, SO, SO2, SO2NH, Formula (II) or Formula (III); n is 0 or 1; R3 and R4 are each independently selected from hydrogen or C1-6alkyl; R2 is hydrogen, NH2, pyrrolidinyl, C3-6cycloalkyl, C1-6alkyl, C2-6alkyl substituted by one or more substituents independently selected from OH, NR5R6 in which R5 and R6 are each independently hydrogen or C1-6alkyl, CO2H, morpholinyl, morpholinyl quaternized by a C1-6alkyl group, oxo, halogen, SO3H, PO3H2, imidazolyl, imidazolyl substituted by 1-2 C1-6alkyl groups, tetrazolyl, tetrazolyl substituted by 1-2 C1-6alkyl groups or N=CR7 in which R7 is a furan or thiophene ring optionally substituted by either -CO2H or -SO3H, phenyl or phenyl substituted by 1-3 substituents independently selected from OH, NR5R6, CO2H, morpholinyl, morpholinyl quaternized by C1-6alkyl group, oxo, halogen, SO3H, PO3H2, imidazolyl, imidazolyl substituted by 1-2 C1-6alkyl groups, tetrazolyl, tetrazolyl substituted by 1-2 C1-6alkyl groups or N=CR7; M is hydrogen, a carboxyl-protecting group or a negative charge; XÈ is a counter anion; and M is 0 or an integer selected so as to make the molecule as a whole electrically neutral.

Description

<div class="application article clearfix" id="description"> GG289A K0 ^r ^1 W /' ' j J el. 10 CEPHALOSPORIN DERIVATIVES 1. Field of the Invention The present invention is directed to new cephem derivatives represented by the general formula ys „ © coom wherein Q is an optionally substituted pyndinmm group connected to the sulfur atom via a ring carbon atom; X is halogen; Y is hydrogen or halogen; A is C02H, P03H2, S03H or tetrazole; L1 is a furylene group, a thienylene group, a C2-C10 alkylene group, or a C2-CI0 alkylene group interrupted by one or more groups independently selected from vinyl, S, SO, S02, S02NH, ° H An-' " : H s n is 0 or 1; M is hydrogen, a negative charge or a carboxyl-protectmg group; m is 0 or an © integer selected so as to make the molecule as a whole electncally neutral; and x is a counter anion; or a pharmaceutical^ acceptable salt thereof. 15 The derivatives are gram-positive antibacterial agents especially useful in the manufacture of medicaments for the treatment of diseases caused by methicillin-resistant Staphylococcus aureus (also referred to below as MRSA or methicillin-resistant aureus). intellectual property office of n.z. 2 4 MAY 2001 RECEIVED WO 98/23621 PCT/US97/21785 2 2. Description of the Prior Art The literature discloses a vast number of cephem derivatives having a wide variety of C-3 and C-7 substituents. 5 With respect to the C-7 substituents of the present invention, U.S Patent 3,345,366 discloses cephem derivatives of the type o 11 o R2-C-ch2^^ 1/h z-ch2-c-n s Rl /{(-Nn^-CH2-A co2M 10 wherein R, is hydrogen or chloro, Rj is hydroxy or amino, Z is oxygen or sulfur, A is acetoxy or N-pyridinium and M is hydrogen, pharmaceutical^ acceptable non-toxic cations or an anionic charge when A is N-pyridinium. This approach was also discussed in Antimicrob. Ag 15 Chemother. Meeting. 1968, pgs 109-114 (Hobby, G.L.) and JP 50083383. EP 638,574 A1 discloses cephem derivatives of the general formula Y.wR /CH (CH^ (f~y-X-CH2 L-N Printed from Mimosa WO 98/23621 wherein 5 10 15 PCT/US97/21785 3 X = absent, -O-, -S-, -SO-, -S02-, -NH-; Y = -CH, N-; Z = -H, halogen, -OH, CrC5 O-alkyl, -OCH2CONH2, -OCONH2, -OSOzNH2, -OCH2CN, -NH2 either as such or substituted with Q-Q alkyl radicals, -NHCOCH3, - nhso2ch3, —nhso2 —^ y— ch3 ^t amides of Q-Q, linear acids, amides of benzene and toluene derivatives, -N02, -NO, -CHO, -CH2OH, -COOH, -SH, -SOH, -S02H, -S03H, -S-alkyl where the alkyl residue is Q-C.,, -CF3; R = -H, -OH, Cj-Cg-O-alkyl with the alkyl residue possibly containing halogens, acid functionalities either free or salified with alkaline or alkaline earth metals, basic functions such as -OCH2CH2NH2, -OCH2CH2NH-CH3, - OCH2(o, m, p)-pyridmyl, -OCH2CN, -OCH2CONH2, - 0ch2s02nh2; n = 0 to 4; A = -S-, -O-, -CH2-, -SO-, S02-; Rj = a structural group characteristic of cephalosporins such as -CI, -H, -OCH3, -CH2OCH2NH2, -CH2OCHv -CH3, -CH=CH-CH3, -CF3, -C02R2, -S02R where R2 is an alkyl or aryl radical Printed from Mimosa WO 98/23621 4 PCT/US97/21785 n-n -ch2-ococh3 , -ch2-s—^ .n ch-i ¥ | (ch2)2-n-ch3 ©/ -ch2 n (°> n"n -ch2-s—^ ,n n ch3 -ch= ch2 ch3^n-Ny°h cHa6-4N-l0 5 -ch2-s ,s ch3 ch,cooh o ch2cooh nh. ^n-m ^ sACHj their pharmaceutically acceptable salts and their C6 and C7 epimers. 10 The C-3 substituents employed in the compounds of the present invention are known in the cephem art, but have not previously been combined with the C-7 substituents of the present invention. Applicants have discovered that the combination of C-3 and C-7 substituents 15 provided in the compounds of the present invention unexpectedly gives the desired solubility, activity and toxicity profile needed for commercially viable anti-MRSA cephem products. SUMMARY OF THE INVENTION The present invention provides a novel series of cephem 20 derivatives of the general formula Printed from Mimosa GG289A 5 33 S 5 g coom 1 wherein Q is an optionally substituted pyndinium group connected to the sulfur atom via a ring carbon atom; X is halogen; Y is hydrogen or halogen; A is C02H, P03H2, S03H or tetrazole; L1 is a furylene group, a thienylene group, a C2-C,0 alkylene group, or a C2-C10 alkylene group interrupted by one or more groups independently selected from vinyl, S, SO, S02, S02NH, 0 h or ^Nv" : H 0 n is 0 or 1; M is hydrogen, a negative charge or a carboxyl-protecting group; m is 0 or an © integer selected so as to make the molecule as a whole electrically neutral; and x is a counter anion; or a pharmaceutical^ acceptable salt thereof The compounds of formula I are antibacterial agents useful in the manufacture of medicaments for the treatment of infections in humans and other animals caused by a variety of gram-positive bacteria, particularly methicillin-resistant S. aureus Also included in the invention are processes for preparing the compounds of formula I and pharmaceutical compositions containing said compounds in combination with pharmaceutical^ acceptable carriers or excipients. intellectual property office of n.z. 2 4 MAY 2001 RECEIVED GG289A 6 DETAILED DESCRIPTION The present invention provides novel cephem derivatives of general formula I above which are antibacterial agents useful in the manufacture of medicaments for the treatment of infectious diseases in humans and other animals The compounds exhibit good activity against a wide variety of gram-positive microorganisms, e.g. S pneumoniae, S pyogenes. S aureus. E. faecalis. S. epidermidis and S. hemolvticus. and are particularly useful against strains of methicillin-resistant S. aureus. The compounds of formula I are characterized by an optionally substituted pyridinium thiomethyl group of the type wherein X is halogen; Y is hydrogen or halogen; A is C02H, P03H2/ SOsH or tetrazole; L1 is a furan group, a thiophene group, a C2-C10 alkyl group, or a C2-C10 alkyl group interrupted by one or more (preferably 1 or 2) groups © chrs—'{/ n at the 3-position of the cephem ring and a 7-substituent of the type A-(LJ)n independently selected from vinyl, S, SO, S02, SOzNH, intellectual property office of n.z. 2 4 MAY 2001 RECEIVED GG289A 10 <^J( H a 7 ^ <& ? H or -V H O 15 and n is 0 or 1. A preferred embodiment of the present invention comprises a compound of the formula (X)m° coom ia wherein X is halogen; Y is hydrogen or halogen; A is C02H, P03H2, S03H or tetrazolyl; L1 is a furylene group, a thienylene group, a C2-C10 alkylene group, or a C2-CI0 alkylene group interrupted by one or more groups independently selected from vinyl, S, SO, S02, S02NH, h or v N H O n is 0 or 1; R3 and R4 are each independently selected from hydrogen or C,-Cs alkyl; R2 is hydrogen, NH2, pyrrolidinyl, C3-C6 cycloalkyl, C,-C6 alkyl, C2-C6 alkyl substituted by one or more substituents independently selected from OH, NRJR6 in which R5 and R6 are each independently hydrogen or C,-C6 alkyl, C02H, morpholinyl, morpholinyl quaternized by a C,-C6 alkyl group, oxo, halogen, S03H, P03H2, imidazolyl, lmidazolyl substituted by 1-2 C,-C6 alkyl groups, tetrazolyl, tetrazolyl substituted by 1-2 C,-C5 alkyl groups or N=CR7 in which R7 is a furan or thiophene ring optionally substituted by either -C02H or -S03H, phenyl or phenyl substituted by 1-3 substituents independently selected from OH, NR5R6 in which R3 and R6 are as defined above, C02H, morpholinyl, GG289A % *1 ^ 5-' 0 9 8 morpholinyl quatemized by a C,-C6 alkyl group, oxo, halogen, S03H, P03H2, limdazolyl, imidazolyl substituted by 1-2 C,-C5 alkyl groups, tetrazolyl, tetrazolyl substituted by 1-2 C,-C6 alkyl groups or N=CR7 in which R7 is as defined above; M is hydrogen, a carboxyl- © . protecting group or a negative charge; X is a counter anion; and m is 0 or an integer selected so as to make the molecule as a whole electrically neutral; or a pharmaceutically acceptable salt thereof. Another preferred embodiment comprises a compound of the formula x. h c r3 w- N- -R A-<^ * S 'Or 10 - d" T ■CH^I^R 7Q COOM r4 IA wherein X is halogen; Y is hydrogen or halogen; A is C02H, P03H2, S03H or tetrazolyl; L1 is a furylene group, a thienylene group, a C2-C10 alkylene group or a C2-C10 alkylene group interrupted by one or two groups independently selected from vinyl, S, SO, S02, S02NH, or -V : H o n is 0 or 1; R3 and R4 are each independently selected from hydrogen or C,-C6 alkyl, R2 is 15 hydrogen, NH2, pyrrolidinyl, C^Cg alkyl, C,-Cs alkyl substituted by one or two substituents independently selected from OH, NR5R6 in which R5 and R6 are each independently hydrogen or C,-C6 alkyl, C02H, morpholinyl, morpholinyl quatemized by a Cj-Cg alkyl group, oxo, halogen, S03H, P03H2, tetrazolyl, ch3 -Nf N—CH3 or N R intellectual property office of n.z. 2 4 MAY 2001 RECEIVED in which R7 is a furan or thiophene radical optionally substituted by a -C02H or -S03H group, phenyl or phenyl substituted by 1-2 substituents independently selected from OH, NR5R6 in which R5 and R6 are as defined above, C02H, S03H, P03H2, tetrazolyl, ch3 ©A — n— ch3 or © halogen; M is hydrogen, a carboxyl-protecting group or a negative charge; X is a counter anion; and m is 0 or an integer selected so as to make the molecule as a whole electrically neutral; or a pharmaceutically acceptable salt thereof 10 Particularly preferred groups of the formula x - Y a~(L1),, in the above-described compounds of formula I and formula IA include 15 intellectual property office of n.z. 2 4 MAY 2001 RECEIVED WO 98/23621 PCT/US97/21785 10 Particularly preferred groups of the formula yf-i® —^rvi-R2 R4 include Printed from Mimosa WO 98/23621 PCT/US97/21785 11 <y^o. c ch, // ' n- nh2 ch3 ch3 ch3 ■ oe-o. cty™- W N ii T ch3 IT nh3 ^ oh ch3 ✓=\© © nh3 oh ch3 ^^^^m-ch3 ch3 _^. ©/—\ // / h3c ch3 o oh co2h OH N or ch3 ch, M L=J ch3 Specific preferred embodiments of the present invention include the following: Printed from Mimosa WO 98/23621 PCT/US97/21785 12 „ , NL ^S> V/s 1 o /- chrs-q coor1 wherein R1 is hydrogen or a carboxyl-protecting group x ^ Y y^—s- ^ q (a) ci ci co2h G /T^©_ <©/—\ / — h,c l-[3-[N-(N-methyl) morpholino)]-prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2-carboxyethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt co2h Printed from Mimosa WO 98/23621 PCT/US97/21785 13 2,6-dimethyl-l-[ammo]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2/5-dichloro-4-(2-carboxyethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt co2h l-[amino]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2-carboxyethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt cojh l-[N-pyrrolidino]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2-carboxyethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4 2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt Printed from Mimosa WO 98/23621 PCT/US97/21785 l-[methyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2-carboxyethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio] pyridinium inner salt 2,6 dimethyl-l-[2-hydroxy ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2-[[(lS)-(carboxy-l-ethyl(amino)carbonyl)phenylthio) acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio] pyridinium inner salt Printed from Mimosa WO 98/23621 15 PCT/US97/21785 CO2H 1 - [ammo]-4- [ [(6R)-trans-2-carboxy-8-oxo-7- [ (2,5-dichloro-4-(carboxymethyl thio)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt cozh l-[aminocarbonyl methyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(carboxymethylthio)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyndimum inner salt co2h Printed from Mimosa WO 98/23621 16 PCT/US97/21785 l-[2-hydroxy-3-amino-prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2-carboxyethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4 2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt co2h l-[3-hydroxy-4-carboxyphenyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2/5-dichloro-4-(2-carboxyethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt l-[5-(sulfonylfuran-2-yl)-methylimine]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2-carboxyethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt Printed from Mimosa WO 98/23621 PCT/US97/21785 17 ch, ct NH2 oh ch, COjH 2,6-dimethyl-l-[2-hydroxy-3-amino-prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-5 oxo-7-[(2,5-dichloro-4-(2-carboxyeth-l-yl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt ch3 /==<© /—s© ch3 Q© /—\ts y N-/ W vn- ch3 ' ch3 co2h 10 l-[3-(l,2 dimethyl-lH-imidazol-3)prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-carboxyphenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt s' (n) ci /=\© /—oh !_/- ci O 1 co2h 15 Printed from Mimosa WO 98/23621 PCT/US97/21785 18 l-[2-hydroxyethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2/5-dichloro-4-(carboxymethysulfonyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridmium inner salt (o) ci co2h ch 2,6-dimethyl-l-[3-(3-(l,2 dimethyl-lH-imidazol-3)prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(carboxymethysulfonyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyndinium inner salt (p> « 'CI o nh k COjH l-[2-hydroxyethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-((( carboxymethyl)amino)carbonyl)acetamido)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt Printed from Mimosa WO 98/23621 PCT/US97/21785 19 (q) ci C^OH ho,c n o h l-[2-hydroxyethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2-(((carboxymethyl)amino)carbonyl)ethenyl)phenylthio)acetamido]-5-thia-l-5 azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt (r) ,ch3 =^© 'ch3 % N VN ch3 co2h l-[3-(3-(l,2 dimethyl-lH-imidazol-3-yl)prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(5-carboxy-2-thiophene)phenylthio)acetamido]-5-10 thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt (s) ho2c n o h ch3 /=(® n-nh2 ch, Printed from Mimosa WO 98/23621 PCT/US97/21785 20 2/6-dimethyl-l-[amino]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2-(((carboxymethyl)amino)carbonyl)ethenyl)phenylthio)acetamido]-5-thia-l-azabicyclot4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt 2,6-dimethyl-l-[ N-(N-methyl) morpholino]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2-(((carbonylmethyl)amino) carbonylethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt k co2h 2,6-dimethyl-l-[ l,2-dimethyl-lH-imidazol-3-yl)prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(N-carboxymethyl aminosulfonyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt Printed from Mimosa WO 98/23621 21 PCT/US97/21785 or co2h l-[2-hydroxyethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(5-5 carboxy-2-furan)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt; or pharmaceutically acceptable salts and/or prodrugs thereof. To elaborate on the definitions for substituents of the formula I and formula IA compounds. 10 (a) "Halogen" includes chloro, bromo, fluoro and iodo, and is preferably chloro or bromo and most preferably chloro. (b) The aliphatic "alkyl" groups may be straight or branched chains containing the specified number of carbon atoms. 15 The term "pharmaceutically acceptable salt" as used herein is intended to include the nontoxic acid addition salts with inorganic or organic acids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p-toluenesulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoracetic, Printed from Mimosa WO 98/23621 PCT/US97/21785 22 hydroiodic, hydrobromic, and the like. Some of the compounds of the present invention have an acidic hydrogen and can, therefore, be converted with bases in a conventional manner into pharmaceutically acceptable salts. Such salts, e.g. ammonium, alkali metal salts, particularly 5 sodium or potassium, alkaline earth metal salts, particularly calcium or magnesium, and salts with suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines (e.g. hydroxyl-substituted alkylamines such as diethanolamine, triethanolamine or tris-(hydroxymethyl)amino-10 methane), or with bases such as piperidine or morpholine, are also intended to be encompassed by the term "pharmaceutically acceptable salt". Compounds of the present invention in the form of acid addition 15 salts may be written as coor1 where X represents an acid anion and R1 is hydrogen or a carboxyl- 20 protecting group The counter anion X ^ may be selected so as to provide pharmaceutically acceptable salts for therapeutic administration. Printed from Mimosa WO 98/23621 23 PCT/US97/21785 The carboxyl-protecting group R1 is intended to include readily removable ester groups which have been conventionally employed to block a carboxyl group during the reaction steps used to prepare the 5 compounds of the present invention and which can be removed by methods which do not result m any appreciable destruction of the remaining portion of the molecule, e.g. by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, irradiation with ultraviolet light or catalytic hydrogenation. 10 Examples of such protecting groups include benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allyl, benzyl, p-methoxybenzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and Cj-C6 alkyl such as methyl, ethyl or t-butyl. Included within such protecting groups are those which are hydrolyzed under physiological 15 conditions such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, a-acetoxyethyl, a-pivaloyloxyethyl and methoxymethyl. Compounds of the present invention with such physiologically hydrolyzable carboxyl protecting groups are also referred to herein as "prodrugs". Compounds of the present invention where R1 is a 20 physiologically removable protecting group are useful directly as antibacterial agents. Compounds where an R1 protecting group is not physiologically removable are useful intermediates which can be easily converted to the bioactive form by conventional deblocking procedures well-known to those skilled m the art. Printed from Mimosa WO 98/23621 24 PCT/US97/21785 Compounds of the present invention wherein a hydroxyl substituent is esterified with a group hydrolyzable under physiological conditions are also included within the scope of the term "prodrug" as 5 used herein. Such hydroxyl-protecting groups may be employed, for example, to increase the solubility of a cephem derivative Illustrative of suitable ester "prodrugs" of this type are compounds wherein one or more hydroxy substituent groups are converted to sulfate (-0S03H) or phosphate (-0P03H2) groups. 10 The compounds of the present invention can be made by conventional methods. A suitable procedure is summarized by the following reaction scheme: Printed from Mimosa WO 98/23621 25 PCT/US97/21785 A (L')„ £ VI OH H,N. oKjXc, COjR acylation x _ Y A— O-'C 'I H CI CO,R IV IV deprotection x y H N. co2h IV' CI R3 S=/ N-R2 R4 III X Y ^P-or IA To elaborate on the above process, intermediates of type VI are first prepared, for example, analogous to the process illustrated below: Printed from Mimosa WO 98/23621 PCT/US97/21785 CI CI CI 26 C02t-Bu Bu3N,DMF, 80°C Ph3P, Pd(OAc)2 s^co2CH3 NaSN^CQ2CH3 DMF C02t-Bu C02t-Bu NaOH ?^co2H C02t-Bu Acid intermediate VI is then coupled with a suitable cephem intermediate having a 3-substituent leaving group. For example, the 5 leaving group may be acetoxy or halogen. In the preferred embodiment illustrated by the reaction scheme, the cephem intermediate is the 3-chloromethyl cephem V, but other suitable cephem intermediates with equivalent leaving groups at the 3-position could also be employed. The cephem intermediate V may be acylated with VI or a reactive derivative 10 thereof by conventional acylation procedures well-known in the cephalosporin art to give N-acylated intermediate IV. In addition to using the free arylthioacetic acid, e.g. with a suitable condensing agent such as Printed from Mimosa WO 98/23621 PCT/US97/21785 27 dicyclohexylcarbodiimide, acylating agent VI may also be employed m the form of equivalent acylating derivatives such as an acid anhydride, mixed anhydride, activated ester, or acid halide. The cephem intermediate preferably has the carboxyl group protected by a conventional carboxyl-5 protecting group which can be readily removed. Examples of such protecting groups are discussed above and include benzyl, 4-mtrobenzyl, 1,1 dimethylethyl, 4-methoxybenzyl, diphenylmethyl, allyl, and the like. Other examples of suitable protecting groups are disclosed in Protective Groups in Organic Synthesis. 2nd Ed., Theodora W. Greene (John Wiley 10 & Sons, 1991), Chapter 5 In one embodiment, intermediate V may be acylated with acid VI in the presence of dicyclohexylcarbodiimide and in an inert solvent such as tetrahydrofuran or dichloromethane. The reaction temperature is typically between -20 °C and 50 °C. Upon completion of the reaction, insoluble material is removed by filtration, 15 the filtrate is concentrated, and the residue is treated with a relatively non-polar solvent such as diethyl ether or ethyl acetate resulting in precipitation of the desired product. Alternatively, acid VI may be converted to the corresponding acid chloride, for example by treatment with thionyl chloride with or without a solvent such as dichloromethane, 20 followed by coupling with cephem amine V in the presence of a base such as tnethylamine or N-methylmorpholine to give intermediate IV. Cephem IV is typically isolated after aqueous work-up and evaporation of volatile solvents followed by trituration of the compound with a relatively non-polar solvent such as diethyl ether or ethyl acetate. This Printed from Mimosa WO 98/23621 PCT/US97/21785 28 intermediate may be used in the next reaction step as the X = chloride derivative, or can be converted to the X = bromide or X = iodide derivative by treatment with the appropriate metal halide m a solvent such as acetone. 5 To prepare the quaternary cephem I, intermediate IV is deprotected under acidic conditions, followed by reaction of the resulting intermediate IV' with a thiopyridone derivative HI. For example, when R is diphenylmethyl or 4-methoxybenzyl, cephem acid IV' is obtained upon 10 treatment of IV with trifluoroacetic acid neat or in an inert solvent such as methylene chloride. A reagent such as anisole may also be employed to scavenge the liberated ester protecting group. The reaction temperature is usually at or below room temperature. The deprotection may also be carried out by treatment with other protic acids such as hydrochloric acid 15 in a solvent such as methanol. The final product is typically isolated by precipitation or crystallization. Reaction of IV' with a thiopyridone derivative ffl in a solvent such as dimethylformamide, dimethyl sulfoxide, ethanol, methanol, or other appropriate solvents at a temperature between -20 °C and 100 °C affords target quaternary cephem I 20 The final product is isolated as described above Thiopyridones ffi are typically prepared according to a method analogous to that described in T. Takahashi et al., European Patent Application No. 209751 and in I.E. El-Kholy et al., J. Heterocyclic Chem. Vol. 11, p. 487 (1974). This procedure entails reaction of 4-thiopyrone (European Patent No. 209751) with an Printed from Mimosa WO 98/23621 PCT/US97/21785 29 appropriate primary amine m a solvent such as aqueous methanol or ethanol at a temperature ranging between 0 °C and 78 ° C. The primary amine may be in the form of a zwitterion m examples where there is a free acid group present in the molecule In these cases, a base such as 5 sodium hydroxide, sodium bicarbonate, or pyridine is added to form the free amine in situ. The product may be isolated as its sodium salt by evaporation of volatile solvents, followed by trituration with a solvent such as diethyl ether or ethyl acetate. Alternatively, the reaction mixture may be acidified and extracted with an organic solvent to afford the 10 product as the free carboxylic acid. If the carboxylate group is protected as an ester, the amine may be free or present as an acid salt. In the latter case, a base such as sodium hydroxide, sodium bicarbonate, or pyridine is added to form the free amine in situ. The product is typically isolated by precipitation or by reversed phase column chromatography following 15 removal of volatile solvents. Other representative intermediate VI groups may be prepared as described in the preparation of starting materials section below. It will be understood that where the substituent groups used in the 20 above reactions contain certain reaction-sensitive functional groups such as ammo or carboxylate groups which might result in undesirable side-reactions, such groups may be protected by conventional protecting groups known to those skilled in the art. For example, thiopyridone Printed from Mimosa WO 98/23621 PCT/US97/21785 30 intermediates of formula III may have an amine functional group protected as the t-butyloxycarbamate. Suitable protecting groups and methods for their removal are illustrated, for example, in Protective Groups in Organic Synthesis. 2nd Ed., Theodora W. Greene (John Wiley 5 & Sons, 1991). It is intended that such "protected" intermediates and end-products are included within the scope of the present disclosure and claims. The desired end-product of formula I may be recovered either as 10 the zwitterion or in the form of a pharmaceutically acceptable acid addition salt, e.g. by addition of the appropriate acid such as HC1, HI or methanesulfonic acid to the zwitterion. Compounds of formula I where Rl is hydrogen or an anionic charge, or a pharmaceutically acceptable salt thereof, may be converted by conventional procedures to a correspondmg 15 compound where Rl is a physiologically hydrolyzable ester group. It will be appreciated that certain products within the scope of formula I may have a C-3 substituent group which can result in formation of optical isomers. It is intended that the present invention 20 include within its scope all such optical isomers as well as epimeric mixtures thereof, i.e. R- or S- or racemic forms. The novel cephalosporin derivatives of general formula I (including the IA compounds) wherein R* is hydrogen, an anionic charge Printed from Mimosa WO 98/23621 PCT/US97/21785 31 or a physiologically hydrolyzable carboxyl-protecting group, or the pharmaceutically acceptable salts or prodrugs thereof, are potent antibiotics active against many gram-positive bacteria. While they may be used, for example, as animal feed additives for promotion of growth, as 5 preservatives for food, as bactericides in industrial applications, for example in water-based pamt and in the white water of paper mills to inhibit the growth of harmful bacteria, and as disinfectants for destroying or inhibiting the growth of harmful bacteria on medical and dental equipment, they are especially useful in the treatment of infectious 10 disease in humans and other animals caused by the gram-positive bacteria sensitive to the new derivatives. Because of their excellent activity against MRSA organisms, they are particularly useful in the treatment of infections resulting from such bacteria. 15 The pharmaceutically active compounds of this invention may be used alone or formulated as pharmaceutical compositions comprising, in addition to the active cephem ingredient, a pharmaceutically acceptable carrier or diluent. The compounds may be administered by a variety of means, for example, orally, topically or parenterally (intravenous or 20 intramuscular injection). The pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions. Compositions for injection, the preferred route of delivery, may be prepared in unit dose form m ampules or in multidose containers and may contain additives such as suspending, Printed from Mimosa WO 98/23621 PCT/US97/21785 32 stabilizing and dispersing agents. The compositions may be in ready-to-use form or in powder form for reconstitution at the time of delivery with a suitable vehicle such as sterile water. 5 The dosage to be administered depends, to a large extent, on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of 10 the physician or veterinarian. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 50 mg/day to about 20 g/day. Administration is generally carried out in divided doses, e.g., three to four times a day, analogous to dosing with a cephalosporin such as cefotaxime. 15 in vitro acttvtty Samples of the compounds prepared below in Examples 1-22 after solution in water and dilution with Nutrient Broth were found to exhibit 20 the following Minimum Inhibitory Concentrations (MIC) values versus the indicated microorganisms as determined by tube dilution The MICs were determined using a broth micro dilution assay in accordance with that recommended by the National Committee for Clinical Laboratory Standards (NCCLS). Mueller-Hinton medium was used except for Printed from Mimosa WO 98/23621 PCT/US97/21785 33 Streptococci which was tested in Todd Hewitt broth. The final bacterial inoculate contained approximately 5 x 10^ cfu/ml and the plates were incubated at 35°C for 18 hours in ambient air (Streptococci in 5% C02). The MIC was defined as the lowest drug concentration that prevented 5 visible growth. Microorganism MIC value in ug/ml s aureus methicillin resistant A27223 <8 10 s pneumoniae A9585 <2 s. pyogenes A9604 <2 E faecalis A20688 <8 s. aureus A9537. penicillinase negative <1 s aureus A15090. penicillinase positive <1 15 S. epidermidis A24548 <1 S. epidermidis A25783. methicillin resistant <2 S. hemolyticus A21638 <8 Printed from Mimosa WO 98/23621 34 PCT/US97/21785 tn vtvo activity The in vivo therapeutic efficacy of the compounds prepared in Examples 1-22 below after intramuscular injection to mice 5 experimentally infected with the representative MRSA stram A27223 was also measured. The determination of the effectiveness of antimicrobial agents in Staphylococcus aureus systemic infection in mice 10 Organisms: The test organism, MRSA strain A27223 used to generate systemic infection in mice, is grown on two large Brain Heart Infusion Agar plates. On each plate, 0.5 ml of frozen stock culture is plated out. Plates are then incubated for 18 hours at 30°C. The next day each plate is 15 washed with 20 ml of Brain Heart Infusion Broth and then pooled together. A microscopic direct count of microorganism is done using a 1:1000 dilution of plate wash. After a direct count is obtained, the number of organisms per milliliter is calculated. The count is adjusted to the desired amount of moculum by diluting in 4% hog mucin. The desired 20 challenge (amount of organisms given to mice) is 2.4 x 10® cfu/0.5 ml/mouse for MRSA strain A27223. The mice are infected intraperitoneally with 0.5 ml of challenge. Ten non-treated infected mice are used as controls Printed from Mimosa WO 98/23621 PCT/US97/21785 35 Mice: Mice used are male ICR mice. The average weight of the animals is from 20 to 26 grams. Drug preparation and treatment: Compounds are tested at 4 dose levels, 5 (25, 6.25,1.56, and 0.39 mg/kg) and prepared in 5% cremophor, unless otherwise specified. Vancomycin is used as the control compound, and is dosed at 6.25,1.56, 0.39, and 0 098 mg/kg. It is prepared m 0 1M phosphate buffer. There are five infected mice per dose level, and they are treated with 0.2 ml of the test compound, preferably by intramuscular injection 10 Treatment begins 15 minutes and 2 hours post-infection. Test duration: A PD50 (the dose of drug given which protects 50% of mice from mortality) experiment runs for 5 days. During this time, mortality of mice are checked every day and deaths are recorded. The 15 cumulative mortality at each dose level is used to calculate a PD50 value for each compound. Survivmg mice are sacrificed at the end of day 5 by CO2 inhalation. Calculation: Actual calculation of PD50 is performed with a computer 20 program using the Spearman-Karber procedure. Results: The in vivo efficacy, expressed as the PD50 value, ranged from about 0.8 to 22.0 mg/kg (for certain compounds, more than one test was Printed from Mimosa WO 98/23621 PCT/US97/21785 36 carried out; the indicated range is for at least one test result when multiple tests were done). ILLUSTRATIVE EXAMPLES 5 The following examples illustrate the invention, but are not intended as a limitation thereof. The abbreviations used in the examples are conventional abbreviations well-known to those skilled in the art. Some of the abbreviations used are as follows: h = hour(s) mol = mole(s) mmol = mmole(s) g = gram(s) THF = tetrahydrofuran L = liter(s) mL = milliliter(s) Et20 = diethyl ether EtOAc = ethyl acetate BOC = butoxycarbonyl DCC = dicyclohexylcarbodiimide DPM = diphenylmethyl Ph3P = triphenylphosphine t-Bu = tertiary-butyl EtOH = ethanol Printed from Mimosa WO 98/23621 PCT/US97/21785 37 Bu3N tributylamine MeOH methanol 5 TFA DMF DABCO dimethylformamide 1,4-diazabicyclo[2.2.2]octane trifluoroacetic acid DMS dimethylsulfide m-CPBA meta-chloroperoxybenzoic acid trifluoroacetic anhydride triethylamine TFAA TEA 10 In the following examples, all temperatures are given in degrees Centigrade. Proton nuclear magnetic resonance (JH NMR) spectra were recorded on a Bruker AM-300 or a Varian Gemini 300 spectrometer. All spectra were determined in CDCI3, DMSO-d6, CD3OD, or D2O unless 15 otherwise indicated. Chemical shifts are reported in 8 units relative to tetramethylsilane (TMS) or a reference solvent peak and interproton coupling constants are reported in Hertz (Hz). Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; dd, doublet of doublets; dt, doublet of triplets; 20 and app d, apparent doublet, etc. Mass spectra were recorded on a Kratos MS-50 or a Finnegan 4500 instrument utilizing direct chemical ionization (DCI, isobutene), fast atom bombardment (FAB), or electron ion spray (ESI). Printed from Mimosa WO 98/23621 PCT/US97/21785 38 Analytical thin-layer chromatography (TLC) was carried out on precoated silica gel plates (60F-254) and visualized using UV light, iodme vapors, and/or staining by heating with methanolic phosphomolybdic acid Column chromatography, also referred to as flash chromatography, 5 was performed in a glass column using finely divided silica gel at pressures somewhat above atmospheric pressure with the indicated solvents. Reversed-phase analytical thin-layer chromatography was carried out on precoated reverse phase plates and visualized using UV light or iodme vapors. Reversed-phase column chromatography was 10 performed in a glass column using Baker Octadecyl (Cis), 40 mm. 15 Printed from Mimosa WO 98/23621 PCT/US97/21785 39 Preparation of Starting Materials scheme 2 Sv^co2H scheme 3 ii CI CH2C12 S^.C02Me QH s co2m0 i v CC^t-Bu Sv/c°2Me DCC.THF cozh 5 Oa^^sO OOgt'BlJ s. .c02me CL 1 NaS^COzMe DMF Printed from Mimosa WO 98/23621 PCT/US97/21785 40 scheme 5 CI, S % ^C02Me TFA |-s/C°2Me H2NvC02t-Bu S ^,C02Me CI C02t-Bu 11 CI co2h DCC 12 HN O 13 ^CQ2t-Bu NaS^COzMe CI C02t-Bu DMF S ^^2^® CI O o-S^COjt-Bu 17 Nal TFAA O ■ PO2M8 20 S^C02t-Bu s c02ma CI ' NaS^COjMe DMF 0_s=0 I HN^C02t-Bu HN^C02t-Bu 23 Printed from Mimosa WO 98/23621 PCT/US97/21785 41 scheme 8 OH ?" oV sV Ckj. 8 " ClvK M„NC(S)CI 0kJ^ 1 A 220°C CI, I 1 C| CH2CI2 li ci 24 I 25 I 26 I SH S ^p02Me s ^.COzMe KOH Clv#k. TEA CIN^k n Rl. qn^~\ — ulci—- ri n-Bu3sn29oA^ th t CI BrCH2C02Me Cl I I 27 28 jr\ n-Bu3Sn —co2t-Bu S^COgMe \ 31 CV A. Synthesis of acid 2 Acid 1 (2.00 g., 0.006 mol) is dissolved in 50 mL EtOH, and PtC>2 (1.00 5 g., 0.004 mol) is added. The mixture is hydrogenated at 20 psi for 18 hours. iH-NMR analysis indicates that the reaction has only proceeded to 30% conversion. More Pt02 (0.400 g., 0.002 mol) is added, and hydrogenation at 20 psi is continued another 6 hours. At this time the reaction is only 50% complete. The solids are filtered, and the filtrate is treated with fresh 10 Pt02 (1.00 g., 0.004 mol) and hydrogenated at 20 psi for another 20 hours. The reaction still shows some starting olefin. At this point the mixture is filtered, and the filtrate is concentrated. The residue is chromatographed on silica using CH2CI2 as eluant, followed by a gradient elution with Printed from Mimosa WO 98/23621 PCT/US97/21785 42 methanol/CH2Cl2 (up to 15% MeOH). Acid 2 is obtained (0.750 g., 0.002 mol; 33% yield) as a white solid. iH-NMR (300 MHz, CDCI3): 5 7.40 (s, 1H, ArH), 7.30 (s, 1H, ArH), 3.72 (s, 5 2H, SCH2), 2.96 (t, 2H, J = 8 Hz, A1CH2), 2.54 (t, 2H, J = 8 Hz, CH2CO2R), 1.43 (s, 9H, C(CH3)3). B Synthesis of acid 4 Diester 3 (7.00 g., 0.019 mol) is suspended in 40 mL CH2CI2. Anisole 10 (1 mL) is added, followed by 15 mL of trifluoroacetic acid. The mixture is stirred for 1 hour at room temperature. The solvents are concentrated to ~15 mL, and excess ether is added to precipitate a white solid. The solid is collected, washed with ether, and dried under vacuum to yield acid 4 (4.85 g., 0.015 mol; 79% yield). 15 iH-NMR (300 MHz, DMSO-d6): 5 8.08 (s, 1H, ArH), 7.71 (d, 1H, J = 16 Hz, ArCH=C), 7.43 (s, 1H, ArH), 6.69 (d, 1H, J = 16 Hz, C=CHCC>2), 4.19 (s, 2H, SCH2), 3.66 (s, 3H, OCH3) 20 Printed from Mimosa WO 98/23621 PCT/US97/21785 43 C. Synthesis of hydroxysuccinimide ester 5 Acid 4 (8.75 g, 0.027 mol) is suspended in 55 mL THF under an atmosphere of nitrogen. Dicyclohexylcarbodiimide (1M in CH2CI2, 28.7 mL, 0.029 mol) is added, followed by N-hydroxysuccmimide (3.14 g., 0.027 5 mol). The reaction is allowed to stir for 3 hours at room temperature. The mixture is diluted with ~30 mL acetone, filtered to remove dicyclohexylurea, and concentrated to -25 mL. A solid forms which is filtered off, and the filtrate is evaporated to dryness. Crude 5 is obtamed as a white solid (12.3 g.) which is of sufficient purity for use in subsequent 10 reactions. iH-NMR (300 MHz, DMSO-d6): 5 8.27 (s, 1H, ArH), 8.01 (d, 1H, J = 16 Hz, ArCH=C), 7.50 (s, 1H, ArH), 7.17 (d, 1H, J = 16 Hz, C=CHCC>2), 4.23 (s, 2H, SCH2), 3.68 (s, 3H, OCH3), 2.84 (m, 4H, CH2CH2). 15 D. Synthesis of amide 6 tert-Butylglycine hydrochloride (5.19 g., 0.031 mol) is suspended under a nitrogen atmosphere in 60 mL dry DMF. N-Methylmorpholine (3.90 mL, 0.036 mol) is added, and then the mixture is cooled to 0°C. 20 Crude hydroxysuccinimide ester 5 (12.3 g.) is added, and the mixture allowed to stir for 10 minutes at 0°C. The cooling bath is removed and the reaction is stirred for 1 hour. The mixture is concentrated, and the residue dissolved in ethyl acetate and placed in a separatory funnel. The solution is washed with 0.4 N aqueous HC1, 0.1 N aqueous NaHC03, Printed from Mimosa WO 98/23621 PCT/US97/21785 44 water and then brine. The organic phase is dried (MgSC>4) and evaporated to afford clean amide 6 as a light yellow solid (10.4 g., 0.024 mol; 89% yield from acid 4). 5 iH-NMR (300 MHz, DMSO-d6): 8 8.42 (t, 1H, J = 8 Hz, NH), 7.81 (s, 1H, ArH), 7.59 (d, 1H, J = 16 Hz, ArCH=C), 7.47 (s, 1H, ArH), 6.80 (d, 1H, J - 16 Hz, C=CHCONH), 4.20 (s, 2H, SCH2), 3.85 (d, 2H, J = 8 Hz, NCH2CO2), 3.67 (s, 3H, OCH3), 1.41 (s, 9H, C(CH3)3). 10 E. Synthesis of 2.4.5-trichlorobenzaldehvde 8 Ester 7 (1.03 g., 3.35 mmol) is dissolved m 200 mL CH2CI2 and 100 mL methanol. The mixture is cooled to -78°C, and ozone is bubbled through the solution until it turns blue. The mixture is purged with oxygen, and then 1.3 mL of methyl sulfide is added. The mixture is 15 allowed to warm to room temperature, and the solvents are evaporated The crude residue is partitioned between ether and water The ether layer is washed with water and brine, and then dried (MgSC>4) Concentration of the ether layer, followed by chromatography on silica using 25% CH2Cl2/hexane as eluant, affords 8 (0.55 g., 2.63 mmol; 79% yield) as a 20 white solid. iH-NMR (300 MHz, CDCI3): 8 10.34 (s, 1H, CHO), 7.98 (s, 1H, ArH), 7.58 (s, 1H, ArH). Printed from Mimosa 10 WO 98/23621 PCT/US97/21785 45 F Synthesis of 2.4.5-trichlorobenzoic acid 9 2,4,5-Trichlorobenzaldehyde (0.275 g., 1.31 mmol) is dissolved in 8 mL acetone. A slight excess of Jones Reagent is added, and the mixture stirred at room temperature for 1 hour. Methanol (~6 mL) is added, and after 5 minutes the mixture is partitioned between methylene chloride and water. The aqueous phase is extracted with chloroform (2X), and the combined organic extracts are washed with water, then brine. The organic phase is dried (MgSC>4), and concentrated to afford pure 2,4,5-trichlorobenzoic acid 9 (0.285 g., 1.26 mmol; 96% yield) as a white solid. iH-NMR (300 MHz, CDC13): 5 8.01 (s, 1H, ArH), 7.61 (s, 1H, ArH). G. Synthesis of 2.4.5-trichlorobenzoic acid, tert-butvl ester 10 Acid 9 (2.93 g., 13.0 mmol) placed in a Parr hydrogenation bottle 15 (under an atmosphere of nitrogen) is dissolved in 55 mL of dioxane. The bottle is cooled to -78°C, and 5 mL conc. sulfuric acid is added cautiously, followed by ~50 mL liquid isobutylene (cooled to -78°C). The bottle is sealed and agitated on a Parr shaker overnight (~19.5 hours). The sealed bottled is vented, and the solution slowly added to a separatory funnel 20 containing half-saturated aqueous NaHCC>3 and ether. The aqueous layer is extracted with ether, and the combined organic phase was dried (MgS04) and concentrated. Chromatography on silica using hexane, followed by 25% CH2CI2/hexane, affords ester 10 as a pale yellow oil (2.56 Printed from Mimosa WO 98/23621 PCT/US97/21785 46 g., 9.10 mmol; 70% yield) which solidifies overnight in the refrigerator to an off-white solid. iH-NMR (300 MHz, CDCI3): 5 7.81 (s, 1H, ArH), 7.53 (s, 1H, ArH), 1.58 (s, 5 9H,C(CH3)3) H. Synthesis of diester 11 Using the method described below for the synthesis of diester 3, ester 10 (2.5 g., 11.3 mmol) is converted to diester 11 (3.20 g., 9.12 mmol; 10 81% yield). Diester 11 was obtained as a white solid by chromatography on silica gel using 80% methylene chloride/hexane. iH-NMR (300 MHz, CDCI3): 6 7.75 (s, 1H, ArH), 7.30 (s, 1H, ArH), 3.75 (s, 3H, OCH3), 3.72 (s, 2H, SCH2), 1 58 (s, 9H, C(CH3)3). 15 I. Synthesis of acid 12 Diester 11 (1.60 g., 4.56 mmol) is dissolved in 5 mL methylene chloride. Trifluoroacetic acid (2 mL) is added, and the mixture stirred for 4 hours at room temperature. The solvents are evaporated to provide 12 20 (1.24 g., 4.20 mmol; 92% yield) as a tan solid of sufficient purity for use in the next reaction. Printed from Mimosa WO 98/23621 PCT/US97/21785 47 1H-NMR (300 MHz, DMSO-d6): 8 7.87 (s, 1H, ArH), 7.46 (s, 1H, ArH), 4.23 (s, 2H, SCH2), 3.68 (s, 3H, OCH3). J. Synthesis of amide 13 5 Acid 12 (1 24 g., 4.20 mmol) is dissolved in 14 mL dry THF. Dicyclohexylcarbodiimide (0.866 g., 4.20 mmol) is added, followed by tert-butyl glycine (0.550 g., 4.20 mmol), and the mixture stirred at room temperature for 2 hours. Ether is added to the flask, and the solids removed by filtration. The filtrate is evaporated to yield 1.96 g. of crude 10 material. Chromatography on silica using 80% CH2Cl2/hexane, followed by a second chromatography using 20% ethyl acetate/hexane affords amide 13 (0.844 g., 2.07 mmol; 49% yield) as a white solid. iH-NMR (300 MHz, CDCI3): 8 7.78 (s, 1H, ArH), 731 (s, 1H, ArH), 4.12 (d, 15 2H, J = 6 Hz, NCH2CO2), 3.77 (s, 3H, OCH3), 3.72 (s, 2H, SCH2), 1.48 (s, 9H, C(CH3)3). K. Synthesis of ester 15 2,4,5-Trichlorothiophenol (35.0 g., 0.166 mol) is dissolved in 500 mL 20 methylene chloride and cooled to 0°C. Triethylamine (22.0 g., 0.217 mol) is added, followed by a solution tert-butyl bromoacetate (35.1 g., 0.180 mol) in 100 mL methylene chloride (over 5 minutes). After stirrmg for 20 minutes at 0°C, the ice-bath is removed, and stirring continued for Printed from Mimosa WO 98/23621 PCT/US97/21785 48 another hour. The mixture is placed in a separatory funnel and washed with water (2X), 10% aqueous H3PO4, and then brine. The organic phase is dried (MgS04), and evaporated to afford a white solid, which is washed with hexane. Ester 15 (51 g., 0.156 mol; 94%) as obtained is of suitable 5 purity for subsequent reactions. 1H-NMR (300 MHz, CDC13): 8 7.47 (s, 1H, ArH), 7.45 (s, 1H, ArH), 3.66 (s, 2H, SCH2), 1.43 (s, 9H, C(CH3)3). 10 L. Synthesis of sulfoxide 16 Ester 15 (50.0 g., 0.153 mol) is dissolved in 500 mL chloroform and cooled to 0°C. m-Chloroperoxybenzoic acid (50-60% from Aldrich, 48.0 g., 0.140-0.168 mol) is added in small portions over 30 minutes. The ice bath is removed and stirring continued for 2.5 hours at room temperature. 15 The solids were removed by filtration, and the filtrate washed with dilute aqueous NaHSC>3, 5% aqueous Na2CC>3, saturated aqueous NaHCC>3, and then brine. The organic phase is dried (MgSC>4), and evaporated. The crude material is chromatographed twice on silica gel using methylene chloride and then 3% methanol/methylene chloride to afford sulfoxide 16 20 (35.0 g., 0.102 mol; 67% yield) as a white solid. Printed from Mimosa WO 98/23621 PCT/US97/21785 49 iH-NMR (300 MHz, CDCI3): 5 7.95 (s, 1H, ArH), 7.53 (s, 1H, ArH), 4.05 (d, 1H, J = 14 Hz, CH2S(0)), 3 70 (d, 1H, ] = 14 Hz, CH2S(0)), 1.43 (s, 9H, C(CH3)3). 5 M. Synthesis of diester 17 Using the procedure described below for the synthesis of diester 3, sulfoxide 16 (35.0 g., 105 mmol) is converted to diester 17 (32.5 g., 78.7 mmol; 75% yield). The compound is isolated as a white solid after chromatography on silica using methylene chloride then 3% 10 methanol/methylene chloride. iH-NMR (300 MHz, CDC13): 8 7.83 (s, 1H, ArH), 7.28 (s, 1H, ArH), 3.92 (d, 1H, J = 14 Hz, CH2S(0)), 3.77 (s, 3H, OCH3), 3.71 (s, 2H, SCH2), 3.57 (d, 1H, J = 14 Hz, CH2S(0)). 15 N. Synthesis of diester 20 Diester 17 (28.0 g., 67.8 mmol) is dissolved in 500 mL acetone. Sodium iodide (48.7 g., 325 mmol) is added, followed by trifluoroacetic anhydride (40.0 g., 191 mmol) over 5 minutes. After stirring at room 20 temperature for 1 hour, the solvents are evaporated. Methylene chloride is added and evaporated twice. The residue is taken up in methylene chloride and washed with aqueous NaHS03 solution (3X), water, and then brine. The organic phase is dried (MgSC>4), and evaporated. Printed from Mimosa WO 98/23621 PCT/US97/21785 50 Chromatography of the residue on silica using methylene chloride affords diester 20 (23.5 g., 59.2 mmol; 87 % yield) as a white solid. iH-NMR (300 MHz, CDCI3): 8 7.38 (s, 1H, ArH), 7.35 (s, 1H, ArH), 3.74 (s, 5 3H, OCH3), 3.66 (s, 2H, SCH2), 3.60 (s, 2H, SCH2). O Synthesis of sulfone 18 Ester 15 (7.00 g., 21.4 mmol) is dissolved in 40 mL chloroform and treated with m-chloroperoxybenzoic acid (~60% from Aldrich, 12.0 g., -42 10 mmol). After stirring for 1 hour at room temperature, the solids are removed by filtration, and the filtrate is washed with dilute aqueous NaHSC>3, 5% aqueous Na2CC>3, saturated aqueous NaHCC>3, and then brme. The organic phase is dried (MgS04), and evaporated. Chromatography of the residue on silica using methylene chloride then 15 3% methanol/methylene chloride affords sulfone 18 (7.00 g., 19.5 mmol; 93% yield) as a white solid. iH-NMR (300 MHz, CDCI3): 8 8.17 (s, 1H, ArH), 7.67 (s, 1H, ArH), 4.32 (s, 2H, SCH2), 1.33 (s, 9H, C(CH3)3). 20 P. Synthesis of diester 19 Using the procedure described below for the synthesis of diester 3, sulfone 18 (7.20 g., 20.0 mmol) is converted to diester 19 (8.05 g., 18.8 Printed from Mimosa WO 98/23621 PCT/US97/21785 51 mmol; 94% yield). The compound is isolated as a white solid after chromatography on silica using methylene chloride then 3% methanol/methylene chloride. 5 iH-NMR (300 MHz, CDCI3): 8 8.05 (s, 1H, ArH), 7.40 (s, 1H, ArH), 4.28 (s, 2H, SO2CH2), 3.78 (s, 3H, OCH3), 3.77 (s, 2H, SCH2). Q. Synthesis of sulfonamide 22 tert-Butyl glycme (2.62 g, 20.0 mmol) and tnethylamine (2.50 g., 25.0 10 mmol) are dissolved in 20 mL chloroform under a nitrogen atmosphere The solution is cooled with an ice-bath, and 2,4,5- trichlorobenzenesulfonyl chloride (5.60 g., 20.0 mmol) dissolved in 30 mL chloroform is added over 5 minutes. The cooling bath is removed and the mixture allowed to stir at room temperature for 1 hour. The solution 15 is washed with 10% aqueous H3PO4, water, and then brine. The organic phase is dried (MgSC>4), and evaporated to afford clean sulfonamide 22 (7.00 g., 18.8 mmol; 94% yield) as a white solid. 1H-NMR (300 MHz, CDCI3): 8 8.10 (s, 1H, ArH), 7.63 (s, 1H, ArH), 3.72 (s, 2H, NCH2CO2), 1.33 (s, 9H, C(CH3)3). 20 R. Synthesis of diester 23 Using the procedure described above, sulfonamide 22 (3.70 g., 10.0 mmol) is converted to diester 23 (2.37 g., 7.40 mmol; 74% yield). The Printed from Mimosa WO 98/23621 PCT/US97/21785 52 compound is isolated as a white solid after chromatography on silica using methylene chloride then 5% methanol/methylene chloride. iH-NMR (300 MHz, CDCI3): 8 7.96 (s, 1H, ArH), 7 36 (s, 1H, ArH), 5.65 (t, 5 1H, J = 5 Hz, NH), 3.85 (s, 3H, OCH3), 3.78 (s, 2H, SCH2), 3.71 (d, 2H, J = 5 Hz, NCH2CO2), 1-34 (s, 9H, C(CH3)3). S. Synthesis of 2.5-dichloro-4-iodophenol 24 2,5-Dichlorophenol (20.4 g., 0.125 mol) is placed in a 1L round 10 bottom flask equipped with a large egg-shaped stir bar and is dissolved in 307 mL CH2CI2. With rapid stirring, iodine (46.6 g., 0.183 mol) is added, followed by silver sulfate (42.3 g., 0.136 mol). The purple solution is stirred 1 day, at which point NMR analysis of an aliquot indicates the reaction is complete. 15 The reaction is diluted with CH2CI2 (-200 ml) and filtered through a fritted Buchner funnel to remove silver salts. The salts are washed with additional CH2CI2 (-100 mL). The organic filtrate is transferred to a separatory funnel and is washed first with a solution of sodium thiosulfate (~40 g. in -200 mL water; this removes excess I2), and then 20 brine. The organic phase is dried (MgS04), and evaporated to give 24 (34.59 g., 0.108 mol; 86% yield) as a pale pink/yellow solid. The material is sufficiently pure to carry forward. Printed from Mimosa WO 98/23621 PCT/US97/21785 53 iH-NMR (300 MHz, CDCI3): 8 7.75 (s, 1H, ArH), 7.14 (s, 1H, ArH), 5.62 (br, 1H, OH) T. Synthesis of thiocarbamate 25 5 Iodophenol 24 (34.59 g., 0.108 mol) is placed mto a 500 mL round bottom flask equipped with septa, N2 inlet, and a stir bar. The phenol is then dissolved in 130 mL DMF. DABCO (24.2 g., 0.216 mol) is added followed by dimethylthiocarbamyl chloride (21.6 g., 0.175 mol). The mixture is stirred at room temperature for ~ 1 hour, then diluted with 10 EtOAc (-400 mL) and poured into a separatory funnel containing - 300 mL of ice-water. The phases are separated, and the aqueous extracted twice with - 200 mL of EtOAc. The combined organic extracts are washed twice with water (~ 100 mL), and then brine. The organic phase is dried (MgS04), and evaporated to afford 25 as a dark oil. This material is 15 dissolved in CH2CI2 and dried again (MgS04). After evaporation a yellow solid (-35 g.) is obtained. The compound was of sufficient purity to be used in the next reaction. iH-NMR (300 MHz, CDCI3): 8 7.90 (s, 1H, ArH), 7.24 (s, 1H, ArH), 3.46 (s, 20 3H, CH3), 3 37 (s, 3H, CH3). Printed from Mimosa WO 98/23621 PCT/US97/21785 54 U. Synthesis of 26 The crude material obtained above (~35 g.) was heated neat under N2 at 220°C for two hours. After cooling, the material was dissolved in CH2CI2 and filtered through a plug of silica gel. The fractions containing 5 the product are evaporated to afford 30.2 g. of a brown solid. This material was chromatographed on silica (in portions) using a gradient elution starting with 1:1 CH2Cl2/hexane (material dissolved in a minimum amount of CH2CI2 for column loading), and then -70% CH2CI2/ hexane Compound 26 is obtained as a yellow crystalline solid (13.0 g., 36.0 mmol, 10 33% yield from 2,5-dichlorophenol). iH-NMR (300 MHz, CDCI3): 5 7.95 (s, 1H, ArH), 7.62 (s, 1H, ArH), 3.10 (br s, 3H, CH3), 3.00 (br s, 3H, CH3). 15 V. Synthesis of 2.5-dichloro-4-iodothiophenol 27 Carbamate 26 (9.80 g, 0.026 mol) is dissolved in 40 mL EtOH and treated with 30 mL 3N aqueous KOH. The mixture is heated to reflux with stirring under nitrogen for 3 hours. The solution is allowed to cool and is then acidified with 3 N HC1 until pH -3. The mixture is extracted 20 with CH2CI2 (thrice), and the combined organic phase washed with water and then brine. The extracts are dried (MgS04) and evaporated. The crude material is chromatographed on silica using 1:1 CH2Cl2/hexane. Thiol 27 (6.43 g., 0.021 mol; 81% yield) is obtained as a white solid. Printed from Mimosa WO 98/23621 55 PCT/US97/21785 1H-NMR (300 MHz, CDCI3): 5 7.83 (s, 1H, ArH), 7.56 (s, 1H, ArH) W. Synthesis of ester 28 5 Thiol 27 (6.43 g., 0.021 mol) is dissolved in 50 mL CH2CI2 and triethylamine (2.52 g., 0.025 mol) is added. Methyl bromoacetate (3.82 g., 0.025 mol) is then added over 5 minutes. The resultant mixture is stirred at room temperature for 1.5 hours, at which time ^H-NMR analysis indicated the reaction was complete. The mixture was diluted with 10 CH2CI2 (-200 mL) and was washed with water, IN HCl, water, and then brine. The organic layer was dried (MgSQj) and evaporated. The crude material is chromatographed on silica using 70% CH2CI2/hexane. Ester 28 is obtained as a white solid (7.20 g., 0.019 mol; 90% yield). 15 iH-NMR (300 MHz, CDCI3): 5 7.82 (s, 1H, ArH), 7.42 (s, 1H, ArH), 3.75 (s, 3H, OCH3), 3.68 (s, 2H, SCH2). X. Synthesis of stannane 29 Bis(tributyltin) (29.5 g., 50.9 mmol) is dissolved under a nitrogen 20 atmosphere in 70 mL dry THF. The solution is cooled to -20°C, and butyllithium (1.6 M in hexane, 31.2 mL, 49.9 mmol) is added dropwise over 20 minutes, maintaining the temperature of the bath at -20°C. The solution is then cooled to -50°C, and then copper(I) bromide Printed from Mimosa WO 98/23621 PCT/US97/21785 56 methylsulfide complex (5.10 g., 24.8 mmol) is added. The mixture is allowed to stir at -40°C for 15 minutes, and is then cooled to -78°C. 5-Bromofuroic acid tert-butyl ester (4.10 g., 16.6 mmol) dissolved in 15 mL THF is added, and the mixture allowed to stir for 3 hours at -78°C. The 5 reaction mixture is poured into 1 L of ether and -300 mL half-saturated aqueous ammonium chloride solution. After stirring for 5 minutes the ether layer is decanted onto another -300 mL of half-saturated aqueous ammonium chloride solution. After 5 minutes the biphasic mixture is separated, and the organic phase is washed with brine, dried (MgS04) and 10 evaporated. Chromatography on silica using hexane, then 25% methylene chloride/hexane affords stannane 29 (5.05 g., 11.1 mmol; 67% yield) as a clear oil. !H-NMR (300 MHz, CDCI3): 8 7.04 (d, 1H, J = 4 Hz, HetArH), 6.56 (d, 1H, J 15 =4 Hz, HetArH), 1.59-1.47 (m, 3 H, SnBu3), 1.37-1.24 (m, 9 H, SnBu3), 1.13-1.05 (m, 6 H, SnBu3), 0.89 (t, 9H, J = 6 Hz, SnBu3). Y. Synthesis of diester 30 Stannane 29 (1.50 g., 3.28 mmol) is dissolved in 8 mL dry THF. Aryl 20 iodide 28 (0.928 g., 2.46 mmol) is added, followed by bis(triphenylphosphine)-palladium(II) chloride (0.160 g., 0.228 mmol). The solution is heated to reflux for 6 hours. The mixture is diluted with -15 mL THF, 4 mL conc. aqueous KF is added, and the mixture is stirred for 20 minutes. Ether is added, and the mixture is then filtered to remove Printed from Mimosa WO 98/23621 PCT/US97/21785 57 insoluble tin solids. The biphasic filtrate is separated, and the aqueous layer is extracted with ether. The combined organic phases are washed with brine, dried (MgSC>4) and evaporated. Durmg evaporation crystals began to form, and when only ~5 mL of liquid remains it is decanted. The 5 solids are washed with hexane and then pumped dry. Diester 30 (0.793 g., 1.91 mmol; 78% yield) is obtained as a white solid. iH-NMR (300 MHz, CDCI3): 8 7.99 (br s, 1H, ArH), 7.40 (br s, 1H, ArH), 7.19 (d, 1H, J = 2 Hz, HetArH), 7.13 (d, 1H, J = 2 Hz, HetArH), 3.75 (s, 3H, 10 OCH3), 3.71 (s, 2H, SCH2), 1.60 (s, 9H, C(CH3)3). Z. Synthesis of stannane 31 Using the method described above, 5-bromo-2-thiophenecarboxylic acid, tert-butyl ester (4.52 g., 17.2 mmol) is converted to stannane 31 (4.33 15 g., 9.16 mmol; 53% yield). The compound is isolated as a light yellow oil after chromatography on silica using 25% methylene chloride/hexane. iH-NMR (300 MHz, CDCI3): 8 7.80 (d, 1H, J = 3 Hz, HetArH), 7.12 (d, 1H, J = 3 Hz, HetArH), 1.58 (m, 15H, SnBu3), 0.92 (t, 9H, J = 6 Hz, SnBu3), 0.85-20 0.80 (m, 3H, SnBu3). Printed from Mimosa WO 98/23621 PCT/US97/21785 58 AA. Synthesis of diester 32 Using the method described above for the synthesis of diester 30, stannane 31 (1.70 g., 3.60 mmol) and aryl iodide 28 (1.03 g., 2.73 mmol) are converted to diester 32 (0.920 g., 2.13 mmol; 78% yield as a light yellow 5 solid). iH-NMR (300 MHz, CDCI3): 8 7.66 (d, 1H, J = 3 Hz, HetArH), 7.55 (s, 1H, ArH), 7.44 (s, 1H, ArH), 7.27 (d, 1H, J = 3 Hz, HetArH), 3.78 (s, 3H, OCH3), 3.73 (s, 2H, SCH2), 1.58 (s, 9H, C(CH3)3). Printed from Mimosa WO 98/23621 PCT/US97/21785 59 Example 1 l-f2-hydroxy-3-ammo-prop-l-yll-4-|'[f6R')-trans-2-carboxy-8-oxo-7-fC2.5-dichloro-4-(2-carboxyethenyl')phenylthio')acetamidol-5-thia-l-azabicyclor4.2.01-oct-2-en-3-yl1methylthio|pyridinium inner salt. scheme 1 CI S £02M© c, J! <*JL n^co,m. ajr BUiN, DMF, 80°C "V^CI dmf I Phj P, Pd(OAc>2 7 3 COjt-Bu C02t-Bu Sv/C°2h „ N* *S cljy NaOH ^ 1 1 1 lc, Cl VV" 0^V^C' TFA Cl u T coodpm * V COgDPM ^ 'CI C02DPM COrf-Bu ^ nc02,Bu IV" s ci s HO NHBOC CI C02H ^ kAcl CO2H rn m iv" ^ hrix^nhboc C02H CO2H H0 ?^S¥NV-f*Svl 2TFA-TFA Cl^k A 2h ci c02l CO.H "" h0'^'r' A. Synthesis of olefin 7 2,4,5-Trichloroiodobenzene (25 g., 81.3 mmol) is dissolved in 80 mL DMF. tert-Butyl acrylate (48 mL, 328 mmol), tributylamine (58 mL, 243 10 mmol), triphenylphosphine (4.08 g., 15.5 mmol), and palladium acetate (3.23 g., 14.4 mmol) are added, and the mixture heated to 80°C for three Printed from Mimosa WO 98/23621 PCT/US97/21785 60 hours. The solvents are evaporated and the residue is partitioned with EtOAc and water. The aqueous phase is extracted with EtOAc, and the combined organic phase is washed with brine, dried (MgS04), and evaporated. The dark red-brown oil is chromatographed on silica in a 5 fritted Buchner funnel using vacuum filtration, with 30% CH2Cl2/hexane followed by 50% CH2Cl2/hexane as eluant. Acrylate 7 is obtained (18.7 g., 60.8 mmol; 75% yield) as a mauve solid. 1H-NMR (300 MHz, CDCI3): 8 7.82 (d, 1H, J = 16 Hz, ArCH=C), 7.67 (s, 1H, 10 ArH), 7.51 (s, 1H, ArH), 6.34 (d, 1H, J = 16 Hz, C=CHC02t-Bu), 1.51 (s, 9H, C(CH3)3). B. Synthesis of diester 3 Acrylate 7 (21.23 g., 69 mmol) is dissolved in 131 mL DMF The 15 sodium salt of methyl mercaptoacetate (17.7 g., crude: see note below) is added and the mixture stirred at room temperature for one hour. The mixture is partitioned with EtOAc and water. The aqueous phase is extracted with EtOAc, and the combined organic phase is washed with brine, dried (MgS04), and evaporated. Chromatography on silica in a 20 fritted Buchner funnel (vacuum filtration) using 50% CH2CI2/hexane followed by 90% CH2Cl2/hexane as eluant affords diester 3 (19 6 g., 52.0 mmol; 75% yield). Printed from Mimosa WO 98/23621 PCT/US97/21785 61 IjH-NMR (300 MHz, CDC13): 8 7.86 (d, 1H, J = 16 Hz, ArCH=C), 7.60 (s, 1H, ArH), 7.36 (s, 1H, ArH), 6.35 (d, 1H, J = 16 Hz, C=CHC02t-Bu), 3.77 (s, 3H, OCH3), 3.72 (s, 2H, SCH2), 1.51 (s, 9H, C(CH3)3). 5 Note: The sodium salt of methyl mercaptoacetate is best made fresh before use. Approximately 30 mL of methyl mercaptoacetate is dissolved in -250 mL THF. One equivalent of 5 N NaOH is added slowly in pipetfulls, and the mixture allowed to stir for 5 minutes. The solvents are removed in vacuo (including water) and the sticky solid is co-evaporated 10 with ether (~200 mLs) and then dry THF (2 x 200 mLs). The solid is pumped dry for several hours under high vacuum until the flask is no longer cool due to evaporation. The freely mobile white solid is used as obtained. Excess of this reagent (1.5 to 2 equivalents) is generally used. 15 C. Synthesis of acid 1 Diester 3 (4.40 g., 0.012 mol) is dissolved in 30 mL THF. To this solution is added 13 mL of IN NaOH, and the mixture is allowed to stir at room temperature for 1.5 hours. At this time ^H-NMR analysis of an aliquot indicates that the reaction is complete The THF is removed 20 under vacuum, and the concentrate is diluted with water and extracted with EtOAc. The aqueous layer is then acidified with IN HCl to pH 4, and then extracted with CH2CI2 The organic phase is washed with brine, dried (MgS04), and then evaporated. Acid 1 is obtained as a tan solid (3 80 g., 0.011 mol; 92% yield). Printed from Mimosa WO 98/23621 PCT/US97/21785 62 iH-NMR (300 MHz, CDC13): 8 7.82 (d, 1H, J = 16 Hz, ArCH=C), 7.56 (s, 1H, ArH), 7.33 (s, 1H, ArH), 6.29 (d, 1H, J = 16 Hz, C=CHC02t-Bu), 3.72 (s, 2H, SCH2), 1.51 (s, 9H,C(CH3)3) 5 D. Synthesis of cephem IV" Cephem amine V' (15.04 g., 0.035 mmol) is suspended under a nitrogen atmosphere in 65 mL THF. A solution of DCC in methylene chloride (1M, 36.2 mL, 0.036 mmol) is added, and the mixture allowed to stir for 5 minutes. Acid 1 (13.15 g., 0.035 mmol) is added and the mixture 10 is stirred for 1.5 hours. Ether (-30 mL) is added, and the solids (mostly DCU) are filtered off. The red-colored filtrate is evaporated to -25-30 mL and ether and pentane are added to precipitate the cephem product. The solid cephem is collected, washed with ether, and dried under vacuum to afford diester IV" (14.2 g., 0.019 mmol; 54% yield). 15 iH-NMR (300 MHz, CDC13): 8 7.53 (d, 1H, J = 16 Hz, ArCH=C), 7.45-7.20 (m, 12H, ArH), 6.98 (s, 1H, Ph2CH), 6.35 (d, 1H, J = 16 Hz, C=CHCC>2t-Bu), 5.82 (dd, 1H, J = 5, 8 Hz, R1R2CHNR3), 4.97 (d, 1H, J = 5 Hz, CH(NR)(SR)), 4.37 (m, 2H, CH2CI), 3.76 (d, 1H, J = 16 Hz, ArSCH2), 3.55 (d, 1H, J = 16 Hz, 20 ArSCH2), 3.40 (d, 1H, J = 16 Hz, RSCH2R), 1.54 (s, 9H, C(CH3)3). Printed from Mimosa WO 98/23621 PCT/US97/21785 63 E. Synthesis of diacid IV'" Diester IV" (0.760 g., 1.00 mmol) is dissolved in 4 mL CH2CI2 and 0.8 mL anisole. Trifluoroacetic acid (2 mL) is added, and the mixture is stirred for 4 hours. The solvents are evaporated, and the residue 5 triturated with CH2CI2/ether. The solid is collected, washed with EtOAc and then dried under vacuum. Diacid IV'" is obtained (0.420 g., 0.780 mmol, 78% yield) as a light yellow solid. iH-NMR (300 MHz, DMSO): 8 9.30 (d, 1H, J = 8 Hz, RC(O)NH), 8.07 (s, 1H, 10 ArH), 7.72 (d, 1H, J = 16 Hz, ArCH=C), 7.54 (s, 1H, ArH), 6.68 (d, 1H, J = 16 Hz, C=CHC02H), 5.71 (dd, 1H, J = 5,8 Hz, R1R2CHNR3), 5.13 (d, 1H, J = 5 Hz, CH(NR)(SR)), 4.55 (m, 2H, CH2CI), 3.97 (m, 2H, ArSCH2), 3.70 (d, 1H, J = 16 Hz, RSCH2R), 3.53 (d, 1H, J = 16 Hz, RSCH2R) 15 F. Synthesis of cephem IA' Diacid IV"' (0.780 g., 1.45 mmol) is dissolved in 3 mL methanol and 8 mL CH2C12- Thiopyridone III' (0.395 g., 1.45 mmol) is added, and the mixture is stirred at room temperature for 4 hours. The flask is then placed in a refrigerator at 4°C overnight. The solvents are concentrated, and the product 20 precipitated with ether. The solid is filtered, then suspended in EtOAc and stirred for 30 minutes. The product is then filtered, and the solid dried under vacuum. Cephem IA' is obtained as a tan solid (0.690 g., 0.850 mmol; 59% yield of a mixture of two diastereomers). Printed from Mimosa WO 98/23621 PCT/US97/21785 64 iH-NMR (300 MHz, DMSO, partial): 5 9.31 (d, 1H, J = 8 Hz, RC(O)NH), 8.67 (d, 2H, J = 7 Hz, SpyrH), 7.98 (d, 2H, J = 7 Hz, SpyrH), 8.07 (s, 1H, ArH), 7.72 (d, 1H, J = 16 Hz, ArCH=C), 7.54 (s, 1H, ArH), 6.69 (d, 1H, J = 16 Hz, C=CHC02H), 5.70 (dd, 1H, J = 5,8 Hz, R1R2CHNR3), 5.14 (d, 1H, J = 5 Hz, 5 CH(NR)(SR)), 4.59-4.45 (m, 2H, CH2Spyr), 4.40-4.32 (m, 2H, pyrCH2R), 4.05-3.95 (m, 2H, ArCH2S), 1.38 (s, 9H, C(CH3)3). G Synthesis of cephem IA" Cephem IA' (0.605 g., 0.747 mmol) is suspended in 3 mL CH2CI2, 10 and 1 mL of trifluoroacetic acid is added. The solution is stirred for two hours and the solvents evaporated. The crude material is dissolved in CH2CI2 and precipitated with ether. The solids are collected, suspended in EtOAc and stirred for 30 minutes. The solids are collected and dried under vacuum (P2O5). Cephem IA" is obtained (0.410 g., 0.609 mmol; 82% 15 yield). iH-NMR (300 MHz, DMSO, partial): d 9.40-9.35 (m, 1H, RC(O)NH), 8.77-8.72 (m, 2H, SpyrH), 8.23-8.18 (m, 2H, SpyrH), 8.12 (s, 1H, ArH), 7.77 (d, 1H, J = 16 Hz, ArCH=C), 7.62 (s, 1H, ArH), 6.75 (d, 1H, J = 16 Hz, C=CHC02H), 5.68-5.61 (m, 1H, R1R2CHNR3), 5.11 (d, 1H, J = 5 Hz, CH(NR)(SR)), 4.07-20 3.97 (m, 2H, ArSCH2). Printed from Mimosa WO 98/23621 PCT/US97/21785 65 Following the general procedures and using the appropriate starting materials described above, the following additional compounds were prepared: Example No. PL. a (l)n r3 r4 2 co2" ch3 ( oh ch3 3 "t- co2" 4 s' > co2" ch3 w© v n-nh2 ch3 Printed from Mimosa WO 98/23621 PCT/US97/21785 66 5 "4- co2" r^® v n— nh2 6 s"' co2" C®t2i 7 s' co2" fi \=/N~CH3 8 CIYS y^ci c^c^n^o h ch3 y— oh ch3 9 A si c02" f-\® v n-nh2 Printed from Mimosa WO 98/23621 PCT/US97/21785 67 10 A S1 CO{ o ry_J~N H> 11 s^ > co2" 12 s' col oh ^ c°2 13 s'' co2" ch3 ^ Vn-CH ch3 3 14 A ^S—1 0" 1 co2" 0 o X 15 °"<x o0r"cl o*H co2_ ch3 ch3 v 3 Printed from Mimosa WO 98/23621 68 PCT/US97/21785 16 s"' ct nh c02" <ry^oH 17 s' atl ^Y^c\ ks ' o2c^sn"^o h 18 C,A yxi \° co2" 19 CI r^S K c02' ch3 /ity-A®/"1 ^={ 4, n ch3 ^ ch3 20 A s-" ' o2c^n^"o h ch3 w® ^ n- nh2 ch3 Printed from Mimosa WO 98/23621 PCT/US97/21785 69 21 C'A cl ■ o2c^n o h ch3 ch3 hsc 22 °Cl^C1 o'\„ k co2 ,ch3 ^ Vn-ch ch3 v 3 Printed from Mimosa TABLE: NMR DATA 3 o \o 00 n Kji Os *1 ^0 1-5 h 3 ft CD a t-h H o B B o w ArS ^ At 6^s C02H V tint's f -5 ili j|!" Compd. of i:f®feyd?si i„ Sf „ -i" «■ ' ^ " -fi "w >?bA 'Tr^5-^ If j 4",,y">1^■ ^ ^ f vX ' '> mT! «-} ? vfi <>.?L S XS* *J< 1 '">(■ f-~ \ A?*, %X t%~t- ")*»»(■ H-.i <■ •»'W < 5 A -rH^f ■■>, P?:,, I 4 ii'f- -iih* »'<• ls*?5iESi2l!' ■yJ-4S<f»>*><s "K.■! i A>~ _y< > Jv?J , «I Sc!4 "?•<5 > x| W " ' iisr^is-s^t - ^5-3 w 1 i j j ^ ;• ',>. 5 3 ,w If *1 X ' \i ^ V x !' :-«- !! W-'&j' ^ " } ^ »■ ^ £ -,"i Li f (<|r5 •»ts 4>5s(T4 *•."-:• = JfSiSlp > ^ .-j- s'T'"' <• i i-WS' <?<>v v x V!;.' '" A 1 '< ii !;-f "V^ " ~ 1 k~1»S^ S-PyrH " Sfv "'T- . 1 ti?r-?r 'h ' . < >' S>is s y ,i.v( J i f;-^ '^V;4rS* " -V~ .,1" ■Afr%_ -- s'f<-;; J-< f - s Form -;';5'MS •"'' Data 1 3 70-3 54 (m) 511 (d, J = 5) 5.68-5 61 (m) 4 40-4 39 (m) 397 (br s) 9 40-9 35 W 8 12 (s) 7 77 (d, J = 16) 7 62 (s) 6 75 (d, J = 16) 8 77-8 72 (m) 8 23-818 (m) 4 80-4 60 (m) 4 40-4 24 (m) 4 23-410 (m) 3 10-3 00 (m) 2 80-265 (m) bis TFA salt M+ = 685 2 3 74 (d, J = 18) 349 (d, J = 18) 513 (d, J = 5) 569 (dcU = 5,8) 4 41-4 37 (m) 3 95-383 (m) 9 24 (d, J = 8) 747 (s) 745 (s) 284 (t, J = 7) 2 48 (t, J = 7) 8 62 (d, J = 6) 8 05 (d, J = 6) 4 62-4 57 (m) 4 30-4 23 (m) 4 09-3 98 (m) 3 10-2 98 (m) 2 80-2 64 (m) bis TFA salt MH+ = 687 3 3 92-3 77 (m) 4 86 (d, J =5) 5 39 (d, J = 5) 4 41 (d, J = 13) 4 29 (d, 1 = 13) 4 09 (br s) DjO exch 7 74 (s) 741 (s) 7 39 (d, J = 16) 6 39 (d, I = 16) 8 54 (d, J = 7) 7 97 (d, J = 7) 4 50-4 40 (m) 3 92-3 77 (m) 349-3 21 (m) 2 40-2 30 (m) bis zwitterion M* = 752 3 i-0 0 1 ve s k> h- 00 vi •X) n h 3 rt n> a hh n s h 3 o w 4 3 44 (d, J = 17) 3 26 (d, J = 17) 4 90 (d, J = 5) 5 41 (dd, J = 5, 8) 4 37 (s) 3 96 (d, J =15) 3 88 (d, J = 15) 9 23 (d, J = 8) 7 81 (s) 7 51 (s) 7 33 (d, J = 16) 7 02 (s) 6 51 (d, J = 16) 8 02 (s) monoNa salt / zwitterion M* = 654 5 3 45 (d, J = 17) 329 (d, J = 17) 4 94 (d, J = 5) 5 41 (dd, J = 5, 8) 4 64 (d, J = 14) 4 27 (d, 1 = 14) 3 92-3 83 (m) 9 23 (d, J = 8) 782 (s) 750 (s) 7 35 (d, J = 16) 6 53 (d, I = 16) 861 (d, J = 7) 8 23 (d, J = 7) monoNa salt / zwitterion M* = 626 6 3 46 (d, J = 17) 3 36(d, J = 17) 4.95 (d, J = 5) 5 45 (dd, J = 5, 8) 465 (d, J = 14) 4 44 (d, J = 14) 395 (s) 9 21 (d, J = 8) 8 03 (s) 768 (d, J = 16) 7 56 (s) 6 68 (d, J = 16) 8 92 (d, J = 7) 833(d,J = 7) 3 42-3 32 (m) 2.20-190 (m) monoNa salt / zwitterion M* = 680 7 3.76 (d, J = 18) 356 (d, J = 18) 516 (d, J = 5) 5 72 (dd, J = 5,8) 4 18 (s) 4 00 (s) 9 27(d, J = 8) 8 10 (s) 757 (s) 7 74 (d, I = 16) 6 72 (d, J = 16) 8<&(dJ = 6) 8 00 (d, J = 6) 3.45 (s) chloride salt M* = 628 8 3 45 (d, J = 16) 3.24 (d, ] = 16) 4 85 (d, J = 5) 540 (d, J = 5) 4 28-4 21 (m) 405 (br s) obscured 7 83 (s) 7 55 (d, J = 16) 7 48(s) 6 81 (d, J = 16) 3 83 (q, J = 8) 119 (a, J = 8) 7 75 (br s) 2 68 (s) 4 45-4 37 (m) 3 80-3 75 (m) zwitterion sodium salt MH* = 754 9 3 6-3 2 (m) 4 92 (d, J = 5) 5 39 (dd, J = 5, 8) 4 65 (d, J = 13) 4 25 (d, J = 13) 3 90-3 70 (m) 9.28 (d, J = 8) 7 47 (s) 7 36 (s) 8 58 (d, J = 7) 8 23 (d, J = 7) monoNa salt / zwitterion M* = 646 10 3 75 (d, J = 18) 3 53 (d, J = 18) 513 (d, J = 5) 5.68 (dd, J = 5,8) 4 40 (d, J = 14) 4 36 (d, J = 14) 396 (s) 907 (d, J = 8) 7 65 (s) 7 39 (s) 3 87 (s) 8 63 (d, J = 7) 8 01 (d, J = 7) 7 65 (br s) 5 20 (s) chloride salt MH* = 689 11 3 6-3.2 (m) 4 96 (d, J = 5) 5 42 (d, J = 5) 4 42-419 (m) 3 95 (d, J =14) 3 78 (d, J =14) DjO exch 7 60 (d, J = 16) 8 00-707 (m) 6 38 (d, J = 16) 8 62 (d, J = 7) 8 36 (d, J = 7) 8 88 (s) monoNa salt / zwitterion V© 00 u 9\ h> si *0 o h co no bj m* 00 U\ *0 H h 3 r+ (d a i-h 3 h 3 o w 0) 12 3 76 (d, ] = 18) 3 56 (d, J = 18) 515 (d, J = 5) 5 69 (dd, J = 5, 8) 4 46 (d, J = 10) 4 44 (d, J = 10) 3 98 (s) 00 \o a ii 8 07 (s) 7 71 (d, J = 16) 755 (s) 6 70 (d, ] = 16) 9 34 (d, J = 6) 814 (d, J = 6) 8 04 (d, J = 8) 7 46 (d, J = 2) 7.31 (dd, ] = 2, 8) sodium salt MH* = 748 13 3 74 (d, J = 12) other obscured 515 (d,J =5) 5 70 (dd, J = 5, 8) 4 36-4 31 (m) 4 05-3 95 (m) 934 (d, J = 8) 7 86 (s) 7 56 (s) 7 83 (s) 2 75 (s) 7.80 (d, J = 2) 768 (d, J = 2) 4.40-4 31 (m) 3 77 (s) 2.66 (s) zwitterion chloride salt MH* = 752 14 3 75 (d, J = 18) 3 47 (d, J = 18) 5 14 (d, J = 5) 5 68 (dd, J = 5, 8) 4 40 (d, J = 14) 4 34 (d, J = 14) 4 02 (s) 9.35 (d, J = 8) 7 87 (s) 7 71 (s) 4 61 (s) 8 89 (d, J = 7) 801 (d, J = 7) 4.45 (br s) 3 80 (br s) chloride salt MH* = 710 15 3 50-3 20 (m) 5.13 (d, J = 5) 5 66 (dd, J = 5, 8) 4 40-425 (m) 4 08 (s) 9 35 (d, J = 8) 7 88 (s) 768 (s) 4 59 (s) 7 81 (s) 2 73 (s) 7 76 (d, J = 2) 7.66 (d, J = 2) 4.65-4 50 (m) 3.80-360 (m) 2 70-250 (m) 2.48 (s) 2 30-2 10 (m) chloride salt MH' = 829 16 3 69 (d, J = 16) 348 (d, J = 16) 5 12 (d, J = 6) 5 64 (dd, J = 6, 8) 4 41 (d, J = 13) 4 35 (d, J = 13) 3 96 (br ») 928 (d, J = 8) 8 83 (t, J = 8) 7 50 (s) 747 (s) 3 88 (d, J = 8) 867 (d, J = 8) 8 08 (d, J = 8) 4.51-4 45 (m) 3 83-3 77 (m) chloride salt MH* = 688 17 3 72 (d,J = 17) 3 49 (d, J = 17) 5 12 (d, J = 6) 5 66 (dd, J = 6, 8) 441 (d, J = 11) 4 34 (d, J = 11) 3 96 (br s) $36(d,J=$) 8 42 (t, J = 6) 781 (s) 7 56 (d, J = 16) 755 (s) 6 81 (d, J = 16) 3 86 (d, J =6) 8 68 (d, J = 8) 8 02 (d, J = 8) 4 48-4 42 (m) 3 81-375 (m) chloride salt MH* = 714 18 3 76 (d, J = 17) 351 (d,J = 17) 5 15 (d, J = 5) 5 66 (dd, J = 5, 8) 4 42 (d, J = 12) 4 35 (d, J = 12) 4 03-3 93 (m) 931 (d, J = 8) 7 86 (s) 7 61 (s) 7 35 (d, J = 3) 7 24 (d, J = 3) 8 66 (d, J = 7) 8 02 (d, J = 7) 4.53-445 (m) 3.83-3 76 (m) chloride salt M* = 696 00 & s vi n> ►ti o h vo ft VI 19 3 74 (d, J = 16) 3 49 (d, J = 16) 514(41=5) $76tf«U = 5, 8) 4 39-4 29 (m) 398 (s) 9 31 (d, J = 8) 7 82 (s) 7 73 (d, J = 3) 763 (s) 7 51 (d, J = 3) 7 80 (s) 2 74 (s) 7 79 (d, J = 1) 7 66 (d, J = 1) 4 46-4 35 (m) 438-431 (m) 3 76 (s) 2 64 (s) 2 30-218 (m) chloride salt M' = 832 20 3 45 (d, J = 17) 3 26 (d, J = 17) 4 85 (d, J = 5) 5 41 (dd, J = 5, 8) 4 42 (d, J = 14) 4 22 (d, J = 14) obscured 9 22 (d, J = 8) 781 (s) 7 53 (d, J = 16) 749 (s) 6 83 (d, J = 16) 7 81 (s) monoNa salt / zwitterion M* = 712 21 3 95-3 87 (m) 4.86 (d, J =5) 5 40 (dd, J = 5,8) 4 48 (d, J = 13) 4.34 (d, J = 13) 3 92 (br s) 919 (d, J = 8) 810 (s) 752 (s) 7 46 (d, J = 16) 7 03 (d, J = 16) 7 83 (s) 4 37-425 (m) 3 95-3 85 (m) 3 65-360 (m) 3 45-315 (m) 2 75 (s) 2.25-215 (m) bis zwitterion M* = 837 22 3 48 (d, J = 18) 3.20 (d, J = 18) 5.12 (d, J = 5) 5 68 (dd, J = 5, 8) 4 40-425 (m) 4 06-3 92 (m) 9 36(d, J = 8) 835 (t, J = 4) 7 87 (s) 760 (s) 3 70 (d, J = 4) 7 80 (s) 776 (d, J = 2) 761 (d, J = 2) 4 65-4 50 (m) 3 80-3 66 (m) 2.72 (s) 2.65 (s) 2 14-2 07 (m) chloride salt MH* = 847 GG289A 74 </div>

Claims

1. claims We claim: 5 1. A compound of the formula K " ^ o m t- )' w >>'/ f ^ [j r3 (x)m0 n o J—chj-s4 ,n-r2 0^^chrs^,, coom r4 ia wherein X is halogen; Y is hydrogen or halogen; A is C02H, P03H2, S03H or tetrazolyl, L1 is a furylene group, a thienylene group, a C2-CI0 alkylene group, or a C2-C10 alkylene group interrupted by one or more groups independently selected from vinyl, S, SO, S02, S02NH, a" or -V : h o n is 0 or 1; R3 and R4 are each independently selected from hydrogen or C,-C6 alkyl; R2 is 25 hydrogen, NH2, pyrrolidinyl, C3-C6 cycloalkyl, C,-C6 alkyl, C2-C6 alkyl substituted by one or more substituents independently selected from OH, NR5R6 m which R5 and R6 are each independently hydrogen or C,-C6 alkyl, C02H, morpholinyl, morpholinyl quatermzed by a Cj-C6 alkyl group, oxo, halogen, S03H, P03H2, imidazolyl, lmidazolyl substituted by 1-2 C,-C6 alkyl groups, tetrazolyl, tetrazolyl substituted by 1-2 C,-C6 alkyl groups or N=CR7 in which R7 is a furan or thiophene ring optionally substituted by either 20 -C02H or -S03H, phenyl or phenyl substituted by 1-3 substituents independently selected from OH, NR3R6 in which R3 and R6 are as defined above, C02H, imoiuholinyl, umpnoimyl INTELLECTUAL property office of N.Z. 2 4 MAY 2001 RECEIVED GG289A 75 morpholinyl quatemized by a C,-C6 alkyl group, oxo, halogen, S03H, P03H2, lmidazolyl, 33 imidazolyl substituted by 1-2 C,-C6 alkyl groups, tetrazolyl, tetrazolyl substituted by 1-2 C,-Cs alkyl groups or N=CR7 in which R7 is as defined above; M is hydrogen, a carboxyl- © protecting group or a negative charge; X is a counter anion; and m is 0 or an integer selected so as to make the molecule as a whole electncally neutral; or a pharmaceutically acceptable salt thereof.

A compound of the formula xv/vy © |X)- /=<© ■ 1ljn o COOM r4 IA 10 wherein X is halogen; Y is hydrogen or halogen; A is C02H, P03H2, S03H or tetrazolyl; V is a furylene group, a thienylene group, a C2-C10 alkylene group or a C2-C10 alkylene group interrupted by one or two groups independently selected from vinyl, S, SO, S02, S02NH, 15 H o n is 0 or 1; R3 and R4 are each independently selected from hydrogen or C,-C6 alkyl, R2 is hydrogen, NH2, pyrrolidinyl, C,-C6 alkyl, C,-C6 alkyl substituted by one or two substituents independently selected from OH, NR5R6 in which R5 and R6 are each _ XI UAL PROPER i office of n.z. 2 4 MAY 2001 received GG289A 76 c 'l^3& independently hydrogen or C,-C6 alkyl, C02H, morpholinyl, morpholinyl quatemized by a C,-C6 alkyl group, oxo, halogen, S03H, P03H2, tetrazolyl, CH3 ©A -N-"' N— CH3 or N' in which R7 is a furan or thiophene radical optionally substituted by a -C02H or -S03H group, phenyl or phenyl substituted by 1-2 substituents independently selected from OH, NR5R6 in which R5 and R6 are as defined above, C02H, S03H, P03H2, tetrazolyl, ch3 ©A — N— CH, or L=J © . halogen; M is hydrogen, a carboxyl-protecting group or a negative charge; X is a counter anion; and m is 0 or an integer selected so as to make the molecule as a whole electncally neutral; or a pharmaceutically acceptable salt thereof. w

3 A compound of claim:2 wherein — is A—(La)n intellectual property office of n.z. 2 4 MAY 2001 RECEIVED GG289A 77 cl cl cl cl co2h cl cl o=s co2h o=s co2h co2h cl co2h cl ci co2h cl or cl o=s = o hn cozh

A compound of claim 2 or claim 3 wherein r3 (/ n-r2 r is intellectual property office of n.z. 2 4 MAY 2001 RECEIVED GG289A 78 v> h3c ch3 /t~^© f n-nh2 ch3 ch3 0?^°h ch3 /~^© V n-nh2 o- w nh, o lkt^/°^so3h LJ /=\© <^n-n ch r& v/4 t nh3 \ oh ch3 © \ /a t nh3 oh © CH, ch, ch3 dP^xy h3c n ch, ch3 oh '/n~<^3~c0!h ch3 \J or ch3 ch3 ch,

A compound of the formula INi iZLLCCTU/ 1 PROPERTY OFFICE OF NZ 2 4 may 2001 p t 0 eiv e d GG289A 79 5 ij $ w a (l>1 H -N\r_>S\ S^Y rr l © ° n^>l— CH2-S-Q (X)„ © o' t COOM >* L [ wherein A and Q are as defined below: x Y x<^ /^-s- A—(L!)n Q intel rctual ppoperty office of n.z. 2 4 MAY 2001 -TCEIVED £ intei1 rctual ppoperty office of n.z. 2 4 MAY 2001 RECEIVED (i) cl (k) Cl co2h OH C© ^ .o^sojh n-n' j_j IIM I LL'.ECI UAL PROPERTY OFFICE OF N.Z. 2 4 MAY 2001 ~ IVED GG289A 82 / (m) ci ci co2h (n) Cl cl o ] co2h C© / oh (o) cl o., -c o l c02h (p) Cl cl o nh k co2h rctual property office of n.z. 2 4 MAY 2001 """CEIVED 83 ho,c C^OH 84 _ gg289a € j ^ © and M is hydrogen, a negative charge or a carboxyl-protecting group; x is a counter anion; and m is 0 or an integer selected so as to make the molecule as a whole electncally neutral; or a pharmaceutically acceptable salt thereof

7. The compound of the formula ci ho. O Cl h © o co2h © n—nh? wherein x 1S a counter anion; or a pharmaceutically acceptable salt thereof. © wherein x 1S a counter anion, or a pharmaceutically acceptable salt thereof. 85 The compound of the formula rr= fr ft f"" v? v_ o i © coo o © wherein X js a counter anion ; or a pharmaceutically acceptable salt thereof. 20 The compound of the formula ho' © ch3 nh2 ch3 © wherein X }$ a counter anion ; or a pharmaceutically acceptable salt thereof. 11 The compound of the formula © © wherein x JS a counter anion; or a pharmaceutically acceptable salt thereof. intellectual property office of n.z 2 4 MAY 2001 R E C EIV L D 86 5 13 14 • o 15 15 16 17 20 18 A pharmaceutical composition comprising an effective antibacterial amount of a compound of claim 1 and a pharmaceutically acceptable carrier or excipient. The use of an effective antibacterial amount of a compound of claim 1 m the manufacture of a medicament for treating a bacterial infection. The use of an effective antibacterial amount of a compound of claim 1 in the manufacture of a medicament for treating a bacterial infection caused by a strain of methicillin-resistant Staphylococcus aureus. A compound of claim 1, as specifically set forth herein. A composition of claim 12, where the compound is specifically set forth herein. The use of either claim 13 or claim 14, where the compound is specifically set forth herein. A compound of claim 1, substantially as herein described with reference to any one of Examples 2-22. END OF CLAIMS intellectual property OFFICE OF N.Z. 2 4 MAY 2001 RECEIVED END