IE862547L - Azetidinones - Google Patents

Abstract

Antibacterial activity is exhibited by 2-azetidinones having a 3-acylamino substituent and having an activating group in the 1-position of the formula <IMAGE> wherein <IMAGE> wherein A1 to A6 are selected from various defined divalent groups (including single bonds). [GB2181130A]

Description

r o c. Q •J ^ O u O -1- A Compounds having the formula I R2 R-, ~NH i R, 1 -C—»—-3N—C™&!H-'SO-^R , o* I - and such compounds in pharmaceutically acceptable salt farm, exhibit antibacterial activity. In formula I, and throughout the specification, the symbols ara as defined below. 0 1—i 5 JAr"QH R is -A,-N N-A^-C-Ag^N^ H / \ h ii i) i—i rrr -Aj-N N-A2-C~A^N^ , -AX~N ^N-A5- H OH -A. , -NH-Ar ^ N- U-^o5 1 3 ' or \ ■ -2- ~NH~ n 4 ° Cr- X V H is an acvl group derived from a carboxylic acid; R2 and R3 are the same or different and 5 each is hydrogen, alkyl, alkenyl, alkynyl, cyclo- alkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7-mexabered heterocycle (hereinafter referred to as Rx), or one of and R3 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, 10 alkoxycarbonyl, 2-phenylethenyl, 2-phenylethyny1, carboxyl, -CH7X1 [wherein Xn is azido, amino (-NH2), hydroxy, carboxyl, alkoxycarbonyl, alkanoylamino, phenyl carbonyl amino, (substituted phenyl)carbonylamino, alkylsulfonyloxy, phenyl-15 sulfonyloxy, (substituted phenyl)sulfonyloxy, 0 U phenyl, substituted phenyl, cyano, -A-C-NX6X7, -S-X^, or -0~X2 (wherein A, X2, X, and X„ are as hereinafter defined)], ~S~X2 or -0~X9 [wherein X2 is alkyl, substituted alkyl, phenyl, substituted 20 phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, phenylalkanoyl, (substituted phenyl)-alkanoyl, phenylcarbonyl, (substituted phenyl)- I 3 carbonyl, or heteroarylcarbonyl], -O-C-X^ or X- Xc | J D -S-C-X^ [wherein one of X3 and X^ is hydrogen and i5 25 the other is hydrogen or alkyl, or X3 and X^ when taken together with the carbon atom to which they are attached form a cycloalkyl group; and X^ is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted -3- phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl (HH2-1-), (substituted amino)- carbonyl, or cvano (-GhN) ], or -A~l-NXgX7 [wherein A is -CH-CH-, -(CH2)m-f -(CH2)m-0-f -(CH^-NB-, 5 or -CH2-S-CH?~, 31 is 0, 1 or 2, and Xg and X7 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl, or ~X& is hydrogen and X7 is amino, substituted amino, alkanoyl amino or alkoxy, or X, and X7 when taken together with 1 o the nitrogen atom to which they are attached form a 4, 5, 6 or 7-membered heterocycle]; o II A^ is a sxngle bond, -NH-C-, -NH~ or 0 -NH-NH-i!-; A2 is a single bond, -NH-, -CHj-CH^-NH-, or 0 II 1 5 -C-NH-NH-; Ag is -(CH^wherein p is 0 or 1, 0 0 1! ll -NH-C-NH-, -NH-C-NH- CH2~, -NH-CH,-, -0-CH,- fi._ ? -CH2-C-NH-, or ~CH2-C-NH-CH2-; A4 is -NH-, -(CH2)p-, -(CH2) -NH-, 0 0 " ch2x -NH-C-NH-NH-, -C-NH-NH-, or -A~ 20 wherein X is hydrogen, carboxyl or carbamoyl and p is 0 or 1, and y is 2, 3, or 4; is a single bond, -CH,~, -NH-CH2~, 0 -N=CH~, or -t-NH-.(CH2) - wherein q is 0 or 1; Ag is a single bond, -CH=CH- or ~(CH2) -25 wherein t is 1, 2, 3 or 4.

The above symbols (e.g. , A^ A2, A3, A^, A-and Ag) are used to represent groups of multiple -4~ atoms. These groups are inserted in the structural formulas shown herein in the order in which they are presented (i.e., from left to right). For I 1 example, if R is -A,-N 1 Y JJ and is yj ifV -NH u II I I |i'J H-C-, the R group would he -SMH-C-N N—, not r JL H s •C-NH-N The present invention accordingly provides a compound having the formula 10 SL C N-C-NS~SO,-R , y or such s compound in pharmaceuticElly acceptable salt fcrrc S (T Ti 03 R is -A^-N K-a -C-Ar-^N' i—I II u 2 6 | 6 "B r~\ * i 0 A_.

•A, -N N-A- ~ 1 \ / 2 o 0 (T ?!—03 i! .J.J r .N-A: rjr°3 6 /—s 9 |pJW)H -A, -N N~Ar"^*r , -NS-Ar—, or ^■ -a-c-nx6x7;. is .a-ido, amino, hydroxy, carboxyl, alkoxycarbonyl, alkanoyl amino, phenyl carbonyl amino, (substituted phenyl)carbonylamino, alkylsulfonyl- 15 oxy, phenylsulfonyloxy, (substituted phenyl)- sulfonyloxy, phenyl, substituted phenyl, cyano, 0 II -A-C-NXgX7, -S-X,, or -O-X, ; X9 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkvl, (substituted 20 phenyl)alkyl, alkanoyl, phenylalkanoyl, (sub stituted phenyl)alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, or heteroarvlcarbonyl; one of Xg and X^ is hydrogen and the other is hydrogen or alkyl, or X^ and X^ when taken 25 together with the carbon atom to which they are attached form a cycloalkvl group; X- is forjmyl, alkanoyl, phenylcarbonyl, r (substituted phenyl)carbonyl, phenyl alkyl carbonyl, *. (substituted phenyl) alkyl carbonyl, carboxyl, 4. 30 alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; X and X„ are the same or different and each 6 / is hydrogen, alkyl, phenyl or substituted phenyl, or Xg is hydrogen and X^ is amino, substituted amino, alkanoylamino or alkoxy, or Xg and X^ when together with the nitrogen atom to which they are attached form a 4, 5, 6 or 7-membered heterocycle A is -C3=CH~, -(CS2)a-f -(CS^-O-. ~ (^2 )jn~N5'" °r -ch2"S"CH2"; in is 0, 1 or 2; 0 An is a single bond, -NB-t-, -N3- or 0 II -NH-NH-C-;.

A? is a single'bond, -N3~, 0 -K-ME-NB-; 0 0 II II A3 is -(CH,) -fcua-C-NS*-, -Ns-C-NH-C^-, O O U !' .

-NH-CE^-, -0-CE?-, -CE,-C-N3-, or -CH^-C-his-CE^; ■ A. is -NH", ~(CE~)?~, -(CH2)y-NH-, O 0 * CE-X l| II I 2 -NE-C-N3-N3-, -C~NE-NS-, or -N~; A5 is a single bond, -CH?-, 0 -N-C5-, or -!|-NH-(CH?) is a single bond, -C3=CH- or *-(CH7)_ -; p is 0 or 1; y is 2, 3 or 4; g is 0 or 1; t is 1, 2, 3 or 4; and X is hydrogen, carboxyl or carbamoyl.

Listed below are definitions of various terms used to describe the ^-lactams of this invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.

The terms "alkyl" and "alkoxy" refer to both straight and branched chain groups. Those groups having 1 to 10 carbon atoms are preferred.

The terms "cycloalkyl" and "cycloalkenvl" refer to cycloalkyl and cycloalkenvl groups having 3,4,5,6 or 7 carbon atoms.

The term "substituted alkyl" refers to alkyl groups substituted with one or more (preferably 1, 2 or 3) azido, amino (-NH^), halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxv, alkoxy, phenyloxy, (substituted phenyl)oxy, mercapto, alkylthio, phenylthio, -5- (substituted phenyl)thio, alkylsulfinyl, or alkyl-sulfonyl groups.

The terms "alkanoyl", "alkenyl", and "alkynyl" refer to both straight and branched chain 5 groups. Those groups having 2 to 10 carbon atoms are preferred.

The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine.

The term "substituted phenyl" refers to a 10 phenyl group substituted with 1, 2 or 3 amino (-NE^), halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), alkanoyloxy, aminocarbonvl, or carboxy groups.

The expression "a 4,5,6 or 7-membered 15 heterocycle" (referred to as "R " ) refers to substituted and unsubstituted, aromatic and non-aromatic groups containing one or more (preferably 1, 2 or 3) nitrogen, oxygen or sulfur atoms. Exemplary substituents are oxo (=0), 20 halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl•, O^CH=N- 2-furfurylidenea.mino ( |J jj ), benzylideneamino and substituted alkyl groups (wherein the alkyl 25 group has 1 to 4 carbons). One type of "4,5,6 or 7-membered heterocycle" is the "heteroaryl" group. The term "heteroaryl" refers to those 4,5,6 or 7-membered heterocycles which are aromatic.

Exemplary heteroaryl groups are substituted and 30 unsubstituted pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triasolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, and tetrazolvl. Exemplary nonaromatic heterocycles (i.e., fully or partially saturated -s~ heterocyclic groups) are substituted and unsubstituted azetidinyl, oxetanyl, thietanyl, piperidinyl, piperazinvl, imidazolidinyl, ox.asolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, 5 dihydrothiazolvl and hexahydroazepinyl. Exemplary of the substituted 4,5,6 or 7-merobered heterocycles are l-alkyl-3-asetidinyl, 2~oxo»l-imidazolidinyl, 3~alkylsulfonyl~2-oxo-l~imidazolidinyl, 3-benzylideneamino-2-oxo-l-imida2olidinyi, 10 3~alkyl~2~oxo~l«~ imidazolidinyl, 3-phenyl (or substituted phenyl )~2~Qxo-l~ijnidazolidinyl, 3~benzyl~2«oxo-l~imida2;olidinyl, 3- (2-aminoethyl )~ 2-oxo-l-imidazolidinyl, 3-amino-2 ~ oxo-1-imidazolidinyl, 3- [ (alkoxycarbonyl)amino]-15 2-oxo-l-imidazolidinyl, 3~[2-[(alkoxycarbonyl)~ amino]ethyl]-2«oxo-l-imida2olidinyl, 2-oxo-l-pyrrolidinyl, 2-oxo~3~oxazolidinyl, 4-hvdroxy-6~ methyl-2-pyrimidinyl, 2-oxo-l-hexahydroazepinyl, 2-oxo~3-pyrrolidinyl, 2-oxo~3-tetrahydrofuranyl, 20 2,3-dioxo-l-piperazinyl, 2, 5-dioxo-l-piperazinyl, 4-alkyl-2,3-dioxo-l-piperazinyl, and 4-phenyl-2,3~ dioxo-l-piperazinyl.

The term "substituted amino" refers to a group having the formula -NXqXq wherein Xg is 25 hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Xg is alkvl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino (-NH,).

The term 8'acyl51 refers to all organic radicals derived from an organic acid (i.e., a carboxylic acid) by removal of the hydroxy 1 group. Certain acyl groups are, of course,, preferred but this preference should not be 5 viewed as a limitation of the scope of this invention. Exemplary acyl groups are those acyl groups which have been used in the past to acylate f! -lactam antibiotics including 6-aminopenicillanic acid and derivatives and including 7-asninocephalosporanic acid and derivatives; 10 see, for example? Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972), German Offenlegungsschrift 2,716,677, published October 10, 1978, Belgian patent 867,994, published December 11, 1978, United States Patent Specification No. 4,152,4.32 issued 15 May 1 , 1979, United States Patent Specification No. 3,971 ,778, issued July 27{, 1976, United States Patent Specification No. 4,172,199, issued October 23, 1979, and British patent 1,348,894, published March 27, 1974. The portions of these references describing various acyl 20 groups are incorporated herein by reference. The following list of acyl groups is presented to further exemplify the term "acyl"; it should not be regarded as limiting that term. Exemplary acyl groups are", (a) Aliphatic groups having the formula wherein Ra is alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenvl; cyclohexadienyl; or alkyl or alkenyl substituted -with one or more halogen, cyano, nifcro, amino, raercapto^ alkylthio, or cya.noraathy 11hio groups. (b) Carbocyclic aromatic groups having the formula e 9 - R, b 0 I II S-CH,-C- or % Rd ° ' G it —CiL>~S~C 10 15 20 25 30 wherein n is 0, 1, 2 or 3; R^, Rc, and Rj each is independently hydrogen,, halogen, hydroxyl, nitro, amino, cyano, trifluoraxnethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or amiss Diethyl; and is amino, hydroxyl, a carboxyl salt, protected carboxyl,, fonnyloxy, a sulfo salt, a sulf©amino salt, azido, halogen, hydrazine, alkylhydrazino, phenylhydrazino, or [ (alkylthio) thioxomethy 1 ] thio.

Preferred carbocyclic aromatic acyl groups include those having the formula ch2nh„ -10- &■ carboxyl salt, or sulfo salt) and O- 0 ei CH-C-I E (R is preferably carboxyl salt, or sulfo salt.) . (c) Beteroaroiaat.ic groups having the ronaula 0 !l B£- (CH_) -O, ~ 2 n 0 SI Rs-CE-C-* l K o ii Rf~0-CH,-C- , O II Rf-S-CH2-C- , 0 0 II II C- wherein n is 0, 1 , 2, or 3; Re is as defined above; and R^ is a substituted or unsubstituted 5-P 6- or 7-membered heterocyclic ring containing 1,2,3, or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms. Exemplary heterocyclic -11- rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl. Exemplary substituents are halogen, hydroxyl, nitro, amino, protected amino, 5 cyano,- trif luoromethyl, alkyl of 1 to 4 carbon atoms, i \ alkoxy of 1 to 4 carbon atoms, or 0 It HOOC -CH-CH _ -0—C -nk— .

I 2 NH, Preferred heteroaromatic acyl groups include those groups of the above formulas 10 wherein is 2-amino~4-thiazolyl, 2-amino-5-halo-4 —thiazolyl, 4-aminopyrimidin-2-yl, , 2,4-uniadiasol-3-vl, 2—thisnyl, 2—rur&nyl, or 6-aminopyridin"-2—yl. (d) fI(4—Substituted-2,3~dioxo—l—piper— 15 azmyl) carbonyl] ammo] ary lace tyl groups having the formula O 0 II II / \ -c-ch—nh-c~n n-r ' I \ / n • K //—* i g oo ! wherexn is an aromatic group (including carbocyclic aromatics such as those of the 20 formula and heteroaromatics as included within the definition of Rf); and Rh is alkyl, substitut ed -12- 10 alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mereapto groups), arylmethyleneamino (i.e., ~K=CH"R(? wherein is as defined above), [i.e., -NH-l-I arylcarbonylasiino (i.e., -NH-C-Rg. wherein R^ is as defined above) or alkylcarbonylamino.

Preferred [[(4~substituted~2,3-dioxo-l-piperazinyl)carbonyl3 amino]arvlacetyl groups include those wherein R^ is ethyl, phenyImethy1-eneamino or 2-furylmethyleneamino. (s) (Substituted oxiraino)arylacetyl groups having the formula ? -C-C—N-O-R.

I a- Rg 15 wherein Rg is as defined above and 'R- is hydrogen, alkyl, cycloalkyl, CH2~(CH2)1 9 Qr, 3, 2-pyrrazolylmethyl, ^•C-COOH (2-oxo-3-pyrrolidinyl)methyl, alkylaminocarbonyl, arvl amino carbonyl (i.e., -C-NH-R^ wherein R^. is as defined above) or substituted alkyl (wherein the 20 alkyl group is substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic group (as defined by R ), carbcxyl (including salts thereof), amido, alkoxycarbonyl, phenyImethoxycarbonyl, diphenylmethoxycarhonyl, 25 hydroxyalkoxvphosphinyl, dihydroxyphosphinyl, hydroxy(phenyImethoxy)phosphinvl, dialkoxyphosphinyl or tetrazolyl substituents). -13- Preferred (substituted oxyimino) arylacetyl groups include those wherein R is 2-amino—4-thiazolyle £>lso preferred are those groups wherein R. is methyl, ethyl, carboxymethyl, 5 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxyeyelopropyl. (f) (Acylamino)arylacetyl croups having the formula Q o ll II -C-CH-NH-C-R.

I 3 R g 10 wherein R is as defined above and R• is g j R V—/ 2) n~0~ • alkylamino, (cyanoalkyl) - aminoe amido, alkvlssuido, (cyanoalkyl) amido , WH NH_ O 51 /TTv I 2 || ~CH2 -NH-C —-CH-CH, -C-NH-CE3 , 14- Preferred (acylamino) arylacetyl groups of the above formula include those groups wherein Rj is amino or amido. Also preferred are those groups wherein R is phenyl or 2-thienyl. 5 (g) [ [ [3-Substituted-2-oxo-1-imidazoli- dinyl]carbonyl]amino]arylacetyl groups having the formula 0 II 0 0 C II »l / -C-CH-NH-C-N N-R.

I I I X R CH2~CH2 wherein R. is as defined above and R, is g k 10 hydrogen, alkylsulfonyl, arylmethyleneamino (i.e., -N=CH~R wherein R is as defined 9 g 0 91 above), -C-R^ (wherein R is hydrogen, alkyl or halogen substituted alkyl), aromatic group (as defined by R^ above), alkyl or substituted 15 alkyl (wherein the alkyl group is substituted with one or more halogen, cvano, nitre, amino or xnercapto groups).

Preferred [ [3~substitutad~2-oxo~l~:unidaKoli~ dinyl]carbonyl]amino]arylacetyl groups of the 20 above formula include those wherein R^ is phenyl or 2-thienyl. Also preferred are those groups wherein R^ is hydrogen, methylsulfonyl, phenyl-methyleneamino or 2-furylmethyleneamino. -15- The compounds of this invention form basic salts with various inorganic and organic bases which are also within the scope of this invention. Such salts include ammonium salts, 5 alkali metal salts, alkaline earth metal salts, salts with organic bases, e.g., dieyelohexylamine, benzathine,- N-methyl-D-glucamine, hydrabamine and the like. The pharmaceuticallv acceptable salts are preferred, although other salts are also 10 useful, e.g., in isolating or purifying the product.

Some of the compounds of this invention may be crystallized or recrystallized from solvents containing water. In these cases, water of 15 hydration may be formed. This invention contemplates stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilization. 2 0 The p-lactams of formula X contain at least one chiral center—the carbon atom in the 3-position of the p-lactam nucleus to which the acylamino sufastituent ("R^-NH-") is attached.

This invention is directed to those p-lactams 25 which have been described above, wherein the stereochemistry at the chiral center in the 3-position of the p-lactam nucleus is the same as the configuration at the carbon atom in the 6-position of naturally occurring penicillins 30 (e.g., penicillin G) and as the configuration at the carbon atom in the 7-position of naturally occurring cephamycins (e.g., cephamycin C). Also included within the scope of this invention are racemic mixtures which contain the above-described 35 0-lactams.

The p-lactams of formula I, and pharmaceutical^ acceptable salts thereof, have activity against gram-positive and gram-negative organisms. The compounds of this invention can be used as agents to combat bacterial infections (including.urinary tract infections and respiratory infections) in mammalian species, such as domesticated animals (e.g., dogs, cats, cows, horses, and the like) and humans.

For combating bacterial infections in mammals, a compound of this invention can be administered to a mammal in need thereof in an amount of about 1.4 mg/kg/day to about 350 mg/kg/day, preferably about 14 mg/kg/day to about 100 mg/kg/day. All modes of administration which have been used in the past to deliver penicillins and cephalosporins to the site of the infection are also contemplated for use with p-lactams of this invention. Such methods of administration include oral, intravenous, intramuscular, and as a suppository.

The present invention further provides a process for preparing compounds according to the invention comprising (1) acylating a compound of the formula i ' ""l3 13 jz U-C-NS-S0--R , X 4 - 16a - 30 with an acyl group derived from an Stj~ carboxylic acid, or (2) introducing a -CO-NH-SOjR activating group to a compound of the formula The p-lactams of formula I can he prepared from a 3-protected axn.ino-2-azetidinone having the formula In formula II, and throughout the specification, the symbol "R^" refers to an amino protecting group. These groups are well known in the field of p-lactam chemistry, and the particular group chosen is not critical. Benzyloxycarbonyl, ^2 I II 3 -17- trityl, and t-butoxycarbonyl are exemplary protecting groups. The reaction of a p-lactam of formula II with an isocyanats having the formula III o=c=n-so2-y , wherein Y is a leaving group such as chlorine, yields the corresponding compound having the formula IV R, \2 Ra-NH . 10 CH ^>R3 i N-C-NH-SO,-Y .

S 6 2 The reaction is preferably run in an inert organic solvent, e.g., ethyl acetate, tetrahydrofur&n, 15 dimethoxyethane, dichloromethane, acetonitrile or mixtures of these solvents. Displacement of the leaving group "Y" with the desired group "R" can be accomplished using the appropriate nucleophile having the formula 20 V EH, optionally in the presence of a base (e.g., triethylamine), and yields the corresponding compound having the formula VI R. i 2 25 Ra-NH- -R3 -N-C-NH-SO.-R II 2 O Alternatively, the displacement of the leaving 3 0 group can be accomplished by reaction of a compound of formula IV with a protected form of a compound of formula v. Following the displacement reaction, the protecting groups ean be removed using art-recognized techniques to yield a compound 3 5 of formula VI. -18- Protected forms of a compound of formula V, and of all reactants described herein which contain a 3-hydroxy-4-pyridone moiety, include those compounds wherein the hydroxyl group is 5 protected, those compounds wherein the hydroxyl group and the ring nitrogen are protected, and those compounds wherein both pyridone oxygens are protected. Exemplary protecting groups are silvl (e.g., trimethylsilyl), benzyl and. acyl (e.g., 10 acetyl). If silyl is used, later deprotection can be accomplished using hydrolysis or fluoride mediated cleavage. If benzyl is used, later deprotection can be accomplished by hydrogenolysis. If acyl is used, later deprotection can be 15 accomplished by hydrolysis.

Deprotection of a compound of formula VI using conventional techniques yields the corresponding key intermediate having the formula VII R7 20 NH, i C-R- I I 3 J2— .N-C-NH-S0,-R , J) or a salt thereof. The particular deprotection 25 reaction used will, of course, depend on the protecting group ("RA") present. If, for example, R4 is a t-butoxycarbonyl protecting group, deprotection can be accomplished by treatment of a compound of formula vi with acid (e.g., formic acid 30 or trifluoroacetic acid). If, for example, RA is a benzyloxycarbonyl protecting group, deprotection can be accomplished by catalytic hydrogenation of a compound of formula VI. Alternatively, the R^ protecting group can be removed simultaneously with the -19- other pyridone protecting groups immediately following the above-described displacement reaction.

Well known acylation techniques can be used 5 to convert an intermediate of formula VII to a corresponding product of formula I. Exemplary techniques-include reaction of a compound of formula VII with a carboxylic acid (R^-OH), or corresponding carboxylic acid halide or carboxylic 10 acid anhydride. The reaction with a carboxylic acid proceeds most readily in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming an active ester in situ such as N~hydroxybenzotriazole. In those 15 instances where the acyl group (R1 ) contains reactive functionality (such as amino or carboxyl groups) it may be necessary to first protect those functional groups, then carry out the acylation reaction, and finally deprotect the resulting 20 product.

An alternative procedure for preparing the compounds of formula I comprises first acylating . (acylation techniques have been described above) a 3-amino-2-azetidinone having the formula 25 VIII R„ NH 30 to yield an intermediate having the formula IX R, '2 Rj-NH | 35 CH (j-R 3 -nh -20- 0 |l A ~C-^3H-S02-H activating group can be introduced in the Imposition of a compound of formula IX (using the procedures described above) to obtain 5 the corresponding product of formula I. In those instances wherein the acyl side-chain "R^" contains reactive functionality (such as amino groups), it may be necessary to first protect those functional groups, then carry out the 10 addition of the activating group in the 1-position, and finally deprotect the resulting product.

Still another synthesis for the preparation of compounds of formula I comprises the use of a 3-a2idO"2~azetidinone having the formula X R, 1 5 20 30 '2 ' ^ CH C~R- ■Ah A -C-NH-SO,, -R activating group can be introduced in the 1-position of a compound of formula X (using the procedures described above) to obtain 25 the corresponding compound having the formula XI Reduction of an intermediate of formula XI yields the corresponding intermediate having the formula -21- VII 10 15 20 25 The reduction can be accomplished by catalytic (e.g., palladium on charcoal or platinum oxide) hydrogenstion or with reducing agents such as zinc or triphenylphosphine. As described above, from these key intermediates (compounds of formula VII), using conventional acylation techniques, it is possible to prepare the products of formula I.

Alternatively, a 3-a2ido~2<-azetidinone of formula X can be reduced to the corresponding 3-amino»2~asetidinone having the forraula viii ® The reduction can be accomplished by catalytic (e.g., palladium on charcoal or platinum oxide) hydrogenation or with reducing agents such as zinc or triphenylphosphine. A 3-amino-2~azetidinone of formula viii can be reacted as described above (i.e., first acylated and then treated as described above to introduce a -C-NH-SO^-R activating group in the 1-position) to yield the products of formula I.

Still another synthesis for preparing the compounds of formula I wherein R0 and Rg are each hydrogen utilizes a 6-acylaminopenicillanic acid 0 having the formula -22- XII (ch3)2 CH-COOH or a salt thereof, as the starting material. By adapting procedures described in the literature, 3-Ecylaiuino-2-a2et:idinone can be obtained from the corresponding 6-acylaminopenicillanic acid of 10 formula XII: see, for example, Chem. Soc. Special Publication Mo. 28, pg. 288 (1977), The Chemistry of Penicillins, Princeton University Press, pg. 257, and Synthesis, 494 (1977).

As described in the literature 6-acylamino-15 penicillanic acid, or a salt thereof, can be desul-furized to yield a compound having the formula XIII V1® CH CH, 2 0 N- Replacement of the carboxyl group of a 25 compound of formula XIII with an acetate group followed by hydrolysis yields the corresponding 3-acvlamino-2-azetidinone having the formula XIV 30 Treatment of a compound of formula XIII with cupric acetate and lead tetraacetate in an organic 35 solvent (e.g.', acetonitrile) replaces the carboxyl -23- group with an acetate group. Hydrolysis of the resulting compound can be accomplished using potassium carbonate in the presence of sodium borohydride. 0 II .

A ~C-NH-S02-R activating group can be . introduced -in the Imposition of a compound of formula XIV (yielding products of formula I wherein and R3 are each hydrogen) using the procedures described above.

Still another variation of the above-described synthetic routes for preparing a compound of formula I wherein R2 and are each hydrogen comprises first desulfurizing S-amino-penicillanic acid, acvlating the resulting compound to yield a compound of formula XIII and then proceeding as described above to obtain first a 3-acylamino-2~aEetidinone of formula XIV and then a product of formula I.

The azetidinones of formula I can also be prepared from amino acids having the formula XV OH The amino group is first protected (with a protecting group "R^", e.g., t-butoxycarbonyl). The carboxyl group of the protected, amino acid is then reacted with an amine having the formula wherein Z is alkyl, benzyl or triphenylmethyl, in the presence of a carbodiimide to yield a compound having the formula OH XVI Z-O-MH,, ~24 XVII OH 10 15 20 25 30 The hydroxyl group of a compound of formula XVII is converted to a leaving group ("OL) with a reagent, such as methanesulfonyl chloride or pyridine-S03 complex.

The fully protected compound having the formula XVIII OL is cyclized by treatment with base, e.g., potassium carbonate. The reaction is preferably carried out in an organic solvent or an organic solvent/water mixture under reflux conditions, and yields a compound having the formula XIX R -ww * Alternatively, cyclization of a compound of formula XVII can be accomplished without first converting the hydroxyl group to a leaving group. Treatment of a compound of formula XVII with triphenylphosphine and diethylazodicarboxylate, yields a compound of formula XIX.

Exemplary procedures for the conversion of a compound of formula XVIII to a compound of formula XIX are described in J. Amer. Chem. Soc., 102, 7026 (1980) and J. Org. Chem.. 47, 5160 (1982). -25- Both of the methods disclosed above for ring closure of a compound of formula XVII result in the inversion of the stereochemistry at the carbon atom bearing the R, and R3 substituents when R, 5 and R- are not the same. 3 Removal of the protecting group from the 1-position -of an azetidinone of formula XIX can be accomplished via sodium reduction when Z is alkyl, and yields an intermediate having the formula (at least one of R, and R3 is hydrogen). If Z is 15 benzyl, catalytic (e.g., palladium on charcoal) hydrogenation will initially yield the corresponding N-hydroxy compound, which upon treatment with titanium trichloride yields an intermediate of formula II. If Z is triphenylmethyl, formic acid 20 or 70% acetic acid/water will initially yield the corresponding N-hydroxy compound. 0 'I A -C-HH-SO^-R activating group can be introduced in the 1-position of a compound of 25 formula IX using the procedures described above, and the resulting compound can be deprotected and acylated. 10 II The nucleophiles of formula V wherein R is 0 30 —OH N^and A., and A_ are each a I 1 2 single bond can be prepared by reacting a 1 silylated derivative of 2~i:nidazolidinone (HN NH), 35 -26- or the anion of 2-imidazolidinone formed with a strong non-nucleophilic base, with an activated, suitably protected derivative of an acid having the formula 5 XX 0 10 to obtain, upon deprotection, the corresponding compound having the formula XXI 0 I 1 j? JU oh KNV^^N-C-Ag^v 15 0 ll The reaction can be run in an inert organic solvent such as dimethylformamide, acetonitrile, dichloromethane, or tetrahydrofuran. The acid of formula xx can be activated with dicyclohexyl-20 carbodiimide, or a combination of dicyclohexyl-carbodiimide and hydroxybenzotriazole. An activated and suitably protected derivative of a compound of formula xx can also be the corresponding acid chloride (prepared with reagents such as 25 phosphorus pentachloride, thionyl chloride, oxalyl chloride or triphenylphosphine/carbon tetrachloride) or a mixed anhydride (prepared with such reagents as diphenylphosphoryl chloride, pivaloyl chloride, or isobutyl chloroformate). 30 The compound of formula XX wherein A& is a single bond can be prepared as described in the literature; see Helv. Chem. Acta, 43, 469 (1960) and J. Med. Chem., 17, 1 (1974) .

The compound of formula XX wherein A^ is 35 »CH=CH- can be formed by oxidizing -27- XXII 10 15 20 25 30 cel,-oe (suitably protected) to the corresponding aldehyde having the -formula xxiii (suitably protected), reacting the aldehyde with a carboxyl protected derivative XXIV / —-\\ 0 \sL, n and deprotecting to yield xxv 0 HO 0 II ( CH=CH-C-OH M' I H The compounds of formula XX wherein Ag is ™(CH9)^- and t is 2, 3 or 4 can be formed by conjugation of a compound of formula xxiii (suitably protected) with a Wirtig reagent having the formula xxvi //"~\\ 0 ( W/73P=CH~(^2 } t-2 ^~0H (suitably protected at the carboxyl group), subsequent hydrogenation of the resulting exocyclic double bond, and deprotection to yield -28- XXVII 10 15 20 25 30 0 (CH,)t-C-0H wherein t is 2, 3 or 4.

The compounds of formula XX wherein A, is -(CH,)t~ and t is 1 can be formed by reaction of a suitably protected compound having the formula XXVIII o HO. (wherein L is a leaving group such as chloride, d " bromide, methanesulfony1oxy or toluenesulfonyl-oxy) with cyanide and subsequent hydrolysis and deprotection to yield the compound of formula XXVII wherein t is 1. A compound of formula XXVI11 can be prepared from a compound of formula XXII (suitably protected) by methods familiar in the art (such as thionyl chloride or methanesulfonylchloride/tri-ethylamine).

The nucleophile of formula v wherein R is O "VV I " N-A--C- 2 iW A 1 is a single bond and A, is -NH- can be prepared by reacting an activated and optionally protected derivative of a compound of formula XX with l-amino-2-imida2oli-dinone (EN ) to yield upon deprotection -29- 10 15 XXIX -A, H The nucleophiles of formula V wherein R is O I 1 ' ?\ -A, ~N. A- is a single bond and 1 2 5, 1 0 H A, is -CE2-CH2-NH~ can he prepared by reacting an activated and optionally protected derivative of a compound of formula XX with l-(2-aminoethyl)~2~ s 1 imidazolidinone (HN N-CHjCH^NH,) to yield upon deprotection XXX . , 0 fT >1—OH 6 HM N-CH, - CH,-ra-C-A&- 5 " k 20 The nucleophiles of formula V wherein R is 0 o rr^ri—OH -A--iT" ~L-A_-C-A; "^N-^ A. is a single bond and A- V I 1 25 0 11 is -C-NH-lMtf- can be prepared by reacting XXXI O O /TA •• n T y-fS2-0-C-NH-NH-C-Cl with a silylated form of 2~imidazolidinone, the 30 anion of 2-imi dazo1i dinone formed with a strong non-nucleophilic base, or with 2~imidazolidinone in the presence of an organic base to yield XXXII 0 0 35 ^V The nucleophiles of formula V wherein R is -A. -ll ^N-A0-J-A^-—A., is -KH-C- and A_ is 1 2 e | 1 2 25 O H a single bond can be prepared by reacting a compound having the formula XXXVI 30 6 (suitably protected) with hexamethyldisilazane to yield upon hydrolysis and deprotection a compound having the formula -31- XXXVII 0 15 0 eln-c-n js-c-ar^^n' 2 V ' i 5 The compounds of formula XXXVI (suitably protected) can be prepared by reacting a silylated forra of a compound of formula XXI (optionally protected) with phosgene.

Alternatively, a compound of formula XXXVII 10 can be prepared by reacting a protected form of a compound of formula XXI with chlorosulfonyl iso-cyanate followed by hydrolysis of the resulting intermediate and cleavage of the protecting groups.

The nucleophiles of formula V wherein R is 0 -A. ~N N-A.-C-Ar-'^N'' , A- is -NH-C- and A0 is -NH- can be prepared by reacting a silylated form 2 0 of the compound xxxviii | ( I-NH-Prot wherein the symbol Prot can be an amino protecting 25 group such as t-butoxycarbonyl or benzyloxycarbonyl, with phosgene to yield XXXIX 0 j- .L-NH-J Cl-C-N^^N-NH-Prot, d 30 which can be reacted with hexamethylsilaaane to yield upon deprotection XL 0 N-NH2. -32- Reaction of the compound of formula XL with an optionally protected activated form of a compound of formula XX yields upon deprotection XLI 0 t—, O r 7| OH ^N-NB-S-A, ■ 2 V ' i Alternatively, a compound of formula XL can be prepared by reacting the compound having the 10 formula XLI I p—( „ with chlorosulfonyl isocyanate to yield upon 15 hydrolysis xli 11 0 ^ H^N-C-N I~N=C&"V V Treatment of this compound with agueous. acid, yields. 20 a salt of the compound of formula XL.

The nucleophiles of formula V wherein R is »H 0 - —H JJ -NV.N-A2-C-Ag^v^, is -HH-C- and A, is 25 6 H ™CH,-CH,-NH- can be prepared by first deprotecting l-(aminocarbonyl)-3-[2-[[ (t-butoxy)carbonyl]amino]~ ethyl ]-2-imidaaolidinone and coupling the resulting compound with an activated form of a 30 compound of formula XX (optionally protected) to obtain after deprotection XLIV o 0 O (7]Y~0H II i I II IJ M .N~CH--CE0-NH-C-/tr^N> . 2 2 2 o I 35 6 H -33- The nucleophiles of formula V wherein R is 0 -OH 0 -A1-Nv^N-A2-C-A^ Ax is -NH-C- and A2 is 5 Cj> d H -t-NH-NH- can be prepared by reacting a silylated form of a compound of formula XXXIV (optionally protected) with phosgene followed by hexamethyl-disilazane to yield upon hydrolysis and 10 deprotection XLV cp it—19 8 H«,N-C~N -N-C-NH-NH-C-Ar"— N 2 V ° k 15 Alternatively, a compound of formula XLV can be prepared by reacting a protected form of a compound of formula XXXIV with chlorosulfonyl-isocyanate followed by hydrolysis of the resulting intermediate and cleavage of the protecting groups. 20 Alternatively, compound XXXII can be reacted with chlorosulfonyl isocyanate followed by hydrolysis of the resulting intermediate to yield XLV I , . o 0 .

I I II ll A 25 ^COR^N-C-NH-NH-C-O-CHjT _ ).

Deprotection of XLVI by hydrogenolysis yields r -34- 10 xxv n 01 — | 0 NH,OL .H-C-NE-NE, , - V which can be coupled with an activated and . optionally protected,derivative of a compound of formula XX .to yield upon deprotection a compound of formula XLV.

The nucleophiles of formula V wherein R is Q i—i A fr33 fcT -OA,.-"-*^N-r At IS -KB- ~A^—-t-Ag—^ Tiif A7 is -KB- and A, is 6 H a single bond can be prepared by coupling the 15 compound of formula XXXVIII to an activated form of a compound ox formula XX (optionally protected) and--cleaving the protecting group to.yield XLVIII 9 0 —OH I 1 " II 5 ° H The nucleophiles of formula v wherein R is j—| o 25 -A1 is -KB- and A, is ~NH- can be prepared by coupling a monoprotected (preferably with t~butoxycarbonyl or benzyloxy-carbonyl) derivative of 1,3-diamino-2-imidaaoli-30 dinone with an activated form of a compound of formula XX (optionally protected) and deprotecting the resulting compound to yield -35- XL IX )h h0n-n" l-ra-lr—h- 2 V ° i 5 Alternatively, a compound of formula XLIX can be formed by nitrosating a protected form of a compound, of formula XXIX followed by reduction of the nitroso group and cleavage of the protecting groups. 10 The nucleophiles of formula V wherein R is 0 rf^Sr-*OH -an -iSL JSJ~a_-c-ar—a, is -NH- and a- is 1 X/ 2d i X 2 6 H 15 -CH,-CHj-nh- can be prepared by nitrosating a compound of formula XXX (suitably protected) to yield a compound having the formula L 0 0 ffri—OH 20 0=n-n. ^n-ch_-ch_-nh-c-a,— 2 2 o | 1 . r1 (suitably protected) and reducing and deprotecting that compound to yield LI 0 25 , , o rTrr-oB h-n-n. CH. - chl-nh-c-a - n 2 2 2 t> | 0 H The nucleophiles of formula v wherein R is 0 30 i—i s iV°H -a. ™C-A^- a, is -NH- and A- is 1 2 o | 1 2 0 H 0 1 I -c-nh-ne- can be prepared by nitrosating, reducing 35 and deprotecting a protected derivative of a -So- compound of formula XXXIV. The resulting compound has the formula LII O [—i s a QrB 5 H-N-N. -N~C~NH-KS-C-A,-— 2 V 6 ^ Alternatively, a compound of formula LII can be prepared by reacting a compound of formula XXXVIII with phosgene to yield 10 LIII , , O 1 i I! Prot-NB-N N-C-Cl 0 which, on reaction with a monoprotected hydrazine in the presence of bass, yields 15 LIV | | O Prot-NB-N.^ N-C-NH-N3-Prot ; 6 (The two protecting groups must he different). Selective removal of the hvdraziae protecting 20 group yields LV O Prot-NH-N -N-i!-NE~NH2 <3 Coupling of a' compound of formula LV with an 25 activated optionally protected form of a compound of formula XX, followed by deprotection, yields a compound of formula LII.

The nucleophiles of formula V wherein R is 0 30 0 n/V-OH 0 1 0 'J II a1-nv^n-a2-c-a6--—a1 is -NH-NH-C- and a2 is 6 H a single bond can he prepared by reacting a compound of formula XXXVI (preferably a protected derivative 35 thereof) with hydrazine (preferably in monoprotected -37- fonti) in the presence of a base or with a silylated form of hydrazine or monoprotected hydrazine to yield a protected derivative of LVI 5 ' 0 t- - ■- ) Q r"OH 30 which can he deprotected using conventional techniques. 10 Alternatively, a compound of formula xxxv (either a silylated derivative tb.ereof or an anion thereof formed by reaction with a strong base) can he reacted with an activated form of formula XX (suitably protected) and deprotected to yield a 15 compound of formula LVI.

The nucleophiles of formula v wherein R is 0 ~A1-N>n^N-A, - c~a6~-—^ An is -NH-NH-C- a ad A, is 20 6 H -NH- can be prepared by selective removal of the -non-hydrazide protecting group of a compound of formula LIV, followed by coupling with an activated optionally protected compound of formula 25 XX and subsequent deprotection to yield a compound having the formula LVI I —o « I I 11 E~N-NB- C -NL .N-N3-OA, 2 \ / © V gl The nucleophiles of formula V wherein R is tfil 0H I I H Il 'J . LI ^-N .N-A9-C»A6-—, An IS -NH-NH-C- and H -38- and A, is -CHj-CH^-NH- can be prepared by sequentially reacting a compound of formula XXX (or a protected derivative thereof) with phosgene followed by hydrazine (or a monoprotected 5 derivative thereof) in the presence of a silylating agent such as N-methyl~N~(trimethyl-silyl)trifluoroacetamide to yield upon deprotection LVIII 0 ? t—1 I JlT°e 10 H2N-NE-C~Nv^x.N-CH2-CH7>-NH'-C-A6- IjK .

Alternatively, an amino protected derivative of 1-(2»aminoethy1)-2-imidazolidinone (optional1y silylated) can be reacted with phosgene, and then 15 with a monoprotected derivative of hydrazine in the presence of a base or a silylating agent (e.c., N-methyl-N-(trimethylsilyl)trifluoroacetamide or bis(trimethylsilyl)acetamide) to yield a protected derivative of the compound having the 20 formula LIX 0 II I 1 H7N-*NH~C-Nv^^N-CH7*-CH7-NH2 . 25 The groups used to protect the terminal amino groups in a compound of formula LIX should have been chosen so that the protecting group on the aminoethyl group can be selectively removed. The resulting mono-deprotected compound can be coupled 30 with an activated form of an acid of formula XX -39- (or a protected derivative thereof) to yield (after deprotection) a compound of formula LVIII. The nucleophiles of formula V wherein R is ll °a ? Nr is -NH-NH-C- and A, H O II is -C-NH-NH" can be prepared by reacting the 10 compound of formula XXXII (optionally as a silylated derivative thereof) with phosgene to yield a protected derivative of the compound having the formula LX 13 O ° r—i ? i-C~NVs^,N~C~( 6 ^N-NH-C-N^^N-C-Cl which can be coupled with a protected derivative of hydrazine to yield a protected derivative of 20 LXI O , 0 II Ii II H N-NH-C-N ^N-C-NH-NH, . 6 The groups used to protect the terminal amino groups in a compound of formula LXI should 25 be chosen so that one of the protecting groups can be selectively removed. The resulting mono-deprotected compound can be coupled with an optionally protected activated form of an acid of formula XX to yield (after deprotection) a compound 3 0 having the formula LXI I O JL 'OH II 1 I ll II I i jj E,N-NK-C-N. -N-C-NH-NH-CrA- Y ° & -40- The nucleophiles of formula V wherein R is 10 15 20 30 y ^ 0 -A^-N^ ^N-A^-cl-Ag^N-^can be prepared using the methodology described above for the preparation of the nucleophiles of formula v wherein R is I 1 0 -A^N^.N-A^-C-A ——"Nf but substituting the d appropriate 2,3-piperazinedione reactants for the 2-imidazolidinone reactants.

The nucleophiles of formula V wherein R is oh A^ is a single bond and Ag is 0 H a single bond can be prepared utilizing a suitably protected derivative of the compound LXI 11 HO—S S o -OH 25 A compound having the formula lxiv HO 0 ii "NH. can be prepared by converting a protected form of the compound having the formula -41- LXV HO [j l[ Wy "C-MH-NH. 0 -HH-NH.

I H to a protected form of the compound of formula LXIV 10 15 20 25 by the procedure of K. Heyns at al., Chem. Ber. , 87, 1440 (1954), followed by deprotection to yield the compound of formula LXIV, per se.

A compound of formula LXV can be prepared from a suitably protected form of a compound of formula LXIII by conversion to an ester (such as ethyl or methyl), reaction with hydrazine and deprotection. Alternatively, a suitably protected, activated form of a compound of formula LXIII can be reacted with a monoprotected hydrazine to yield upon deprotection a compound of formula LXV.

Reaction of the compound of formula LXIV (or a suitably protected derivative thereof) with 2-(chloro-ethyl)isocyanate optionally in the presence of a base (such as triethylamine) or a silylating agent yields upon deprotection the compound having the formula H Treatment of LXVI (or a suitably protected derivative thereof) with base yields upon deprotection the compound having the formula LXVI I 0 0 H -42 10 The nucleophiles of formula v wherein R is 0 m is a single bond and A& is ' ~ 6 3 H -CH9- can be prepared by reacting the compound having the.formula lxviii o BO ,ch2nh2 -N' I H (or an derivative in which the pyridone is suitably protected and the primary amine is unprotected) 15 with 2-(chloroethyi)isocyanate to obtain the compound having upon deprotection the formula LXIX 0 I 0 Cl~CH_~CH_-NH-t~NH-CH^ "^N' d Z | 20 H Treatment of LXIX (or a suitably protected derivative thereof) with base yields the compound having the formula LXX 0 25 , , rfTi—OK HNL ^N-CHr V i A compound of formula LXVIII can be prepared from a compound of formula XXVIII (suitably 30 protected) by treatment with aside, reduction of the aside, and deprotection. -43- Ths nucleophiles of formula V wherein R is 5 Nr is a single bond and is H -N=CH- or -NH-CHj can be prepared by condensing l-amino-2-imidazolidinone with. -Che aldehyde having the formula XXIII (optionally protected) to yield (after deprotection) the compound having the 10 formula (optionally protected) by catalytic hydrogenation or using sodiuxn cyanoborohydride yields the compound having the formula LXXI 15 Reduction of the compound of formula LXXI 20 The nucleophiles of formula V wherein R is 0 25 bond and A„ is O -d~NH-(CH? )g~ can he prepared by reacting 1-chloro- -44- 15 carbonyl-2~imidazolidinone with a compound having the formula LXXII1 0 -OH 5 H2N-(CH2)g H (or a suitably protected derivative thereof) in the presence of a base, or with a silylated derivative of a compound of formula lxxiii, to 10 yield following deprotection the compound having the formula LXXIV 0 « , o |^jj OH HN. .N-r-wn-rnp.. \ ~~— >^N-C-NH-(Ca2)q--^N- She nucleophiles of formula V wherein R is i—i oa « -A^ -N>S^J?-A5—-^^N-^and An is -NBC- can be prepared 20 d H by reacting ;a suitably protected derivative of a compound of formula lxvii, LXK, LXXI, LXXI I or LXXIV with, phosgene to yield a protected derivative of 25 LXXV 0 s I—l JfY"03 cl-c-kl fc-a 5 I d H which can be reacted with hexame thy1 s i 1 azane to 30 yield upon deprotection and hydrolysis LXXVI o O r^-OB -C-N^ J&-1 H-N-C-N. ^N-Ar 2 5 | 0 H 35 Alternatively, nucleophiles of formula V -45- 1 jfT! . 9 ^ N"and A, is -NHC- wherein R is A.. -N. Jn-Ac-—N"and A. is -NHC- A 5 can. be prepared by reacting a suitably protected derivative of a compound of formula LXVI I, LXX, LXXI, LXXI I-, or LXXIV with chlorosulfonyl isocyanate to yield upon hydrolysis and deprotection a compound of formula LXXVI. 10 The nucleophiles of formula V wherein R is ^ is -NH- can be prepared 15 by nitrosating a suitably protected derivative of a compound of formula LXVII, LXX, LXXI, LXXII or LXXIV (with, for example, nitrous acid), reducing the resulting compound (using, for example, zinc under acidic conditions) and deprotecting to yield 20 LXXVII ■OH H-N-M N-A £ ^N- 2 5 J. 0 a Alternatively, the compounds of formula 25 0 // LXXVII wherein A^ is -C-NH-(CH2)g- can be prepared by reacting a compound of formula XXXIX with a optionally protected form of a compound of formula LXIV or LXVIII in the presence of base or a 30 silylating agent to yield upon deprotection LXXVIII 0 , O u >— OH i \ i) j y . N-C~NH- ( CH2 ) 0 A -45- Alternatively, those compounds of formula LXXVII wherein Ag is -N=CH- or -NK-CH,,- can he prepared by reacting monoprotected 1,3-diamino~2~ iiaidazolidinone with a compound of formula XXIII (or 5 a protected derivative thereof) and deprotecting the product to yield the derivative of formula LXXVII wherein A5 is -N=CH-. Reduction of that derivative yields the compound of formula LXXVI I wherein is 10 The nucleophiles of formula V wherein R is 0 20 I—i IT j~°H ? ~A1~N— N^and A1 is -NH-nh-C- can be 15 prepared by reacting a compound of formula LXXV (suitably protected) with a monoprotected hydrazine in the presence of a base or a silylating agent. The products, after deprotection, have the formula LXX IX S The nucleophiles of formula V wherein R is 25 h2n~nh~c~nv N'T A, is a single bond and A- is i 1 a single bond or «CH2~ can be prepared by reacting a compound having the formula LXIV or LXVIII (or a 30 suitably protected, derivative thereof) with aziridine or an activated aziridine (activated with such groups as acyl or sulfonvl) to yield upon deprotection -47- 10 15 20 25 30 LXXX H2N-CH, -CH, -NH ( CH, ) ^^ H A compound of formula LXXX (or a suitably protected derivative thereof) ca.n be converted to the desired piperazinedione having the formula LXXXI o /~\ IljT°h HSv/1,-(CH2,OT'T ^0 a by reaction with a dialkyl oxalate (and subsequent deprotection if necessary).

The nucleophiles of formula V wherein R is -A. -N N-A..—A- is a single bond and A- is 0^-^' k 1 ~N=CH~ or can be prepared using the methodology described above for the preparation of the nucleophiles of formula V wherein R is -A., ""N, A., is a single bond and A^ is 0 H -N=CH- or but substituting l-amino-2,3- piperasinedione for l-amino-2-imidazolidinone. The resulting compounds would have the formulas LXXXII o /-\ jV® HN N-N=CH"~ and 0=^ 4=^0 t\ 10 25 **<48 •— LXXXIII Q /~~\ fijT0H HN N-NH-CH^ .

The nucleophiles of formula V wherein R is /~\ • (i if03 -A1 -N N-Ag-—sNr A^ is a single bond and A- is 1? -C-NH-(CE2) - can be prepared by reacting an optionally protected derivative of LXXXIV 15 HN N-C-Cl /~\ 8 1 N-C-C o with a compound of formula LXXI 11 (or a suitably protected derivative thereof) in the presence of a 20 base or a silylating agent. The resulting intermediate can be deprotected to yield LXXXV / \ 5 f^V-OH HN »-C-HH-(CH,)_ 0=^=0 9 The nucleophiles of formula v wherein R is 8 /~~\ |fjp0H -A- ~N N-A_-—"^N^and -N N-A_-—"^•N-'and An is -NH- can be prepared 1 A /> 5 I 1 * 30 ^==ro H by nitrosation of a protected derivative of a compound having the formula LXXXI, LXXXII, LXXXIII or LXXXV (with, for example, nitrous acid), reducing the resulting compound (using, for -49- example, zinc under acidic conditions) and deprotecting to yield LXXXVI /"A 5 ELN-N N-Ae—N Alternatively, those compounds of formula LXXXVI wherein Ag is -N=CB~ or -NH-CH,- can be prepared by reacting monoprotected, 1,4-diamino-10 2,3-piperazinedione with a compound of formula XXIII (or a protected derivative thereof) and deprotecting the product to yield a compound of formula LXXXVI, wherein Ag is ~N=CE~ which can then be reduced to a compound of formula LXXXVI wherein 15 Ag is ~NB~CH7-. Alternatively, reduction of -N=CH- can precede deprotection. which can be reacted with hex&methyldisilazar.e to 3 0 yield upon deprotection and hydrolysis LXXXVIII The nucleophiles of formula V wherein R is prepared by reacting a suitably protected derivative of a compound of formula LXXXI, LXXXI I, LXXXI 11, or LXXXV with phosgene to yield 25 -50- Alternatively, the nucleophiles of formula V / \ j jr°B i wherein E is -A, -N N-Ar^^»lrand A. is -NEC can 5 c /--Q ~ be prepared by reacting a suitably protected derivative .of a compound of formula LXXXI, LXXXII, LXXXIII, or LXXXV with chlorosulfonyl isocyanate to yield a compound of formula LXXXVIII 10 upon hydrolysis and deprotection.

The nucleophiles of formula V wherein H is 0 15 N'and A_ is - (CH- ) -have been described; •3 j_ 3 2 p see formula LXIV and LXVIII.

The nucleophiles of formula V v?herein R is 0 fjj^—OH 0 0 20 -NH-Aj-—N^and is -NE-H-NE- or -NE-S-NE-CH.,- H can be prepared by reacting a compound of formula XXXI with a compound of formula LXIV or LXVIII (optionally protected) in the presence of base or 25 a silylating agent, followed by removal of any protecting groups.

Alternatively, nucleophiles of formula V ii jTH . I 30 wherein R is -KB-A--—""^N-'and A, is -NH-c-NH- or o » 3 0 H can be prepared from a suitably protected form of a compound of formula LXIV or LXVIII by reaction with phosgene followed by 3 5 treatment with a monoprotected derivative of -51- hydrazine in the presence of base or a silylating agent and deprotection.

The nucleophiles of formula V wherein R is CJ -NB~A3-—^-"and A3 is -CH2-C-NH- or -CE2~CO~NH-CH2-H can be prepared by coupling an activated N~protected glycine derivative with a compound of 10 formula LXIV or LXVIII (optionally protected) followed by deprotection.

The nucleophiles of formula V wherein R is 0 iV0H IS -NE-A^-""-""^KKand A^ is -NE-CH,- can be prepared by H reacting an optionally protected derivative of the aldehyde of formula XXIII with .hydrazine or iaono-protected hydrazine followed by reduction of the 20 carbon-nitrogen double bond and subsequent deprotection.

Alternatively, a monoprotected hydrazine may be monoalkylated on the free amino group with a compound of formula XXVIII (suitably protected) 25 followed by deprotection to give a nucleophile of 9 ryH formula V wherein R is ~NH~A-~— vN-"and A, is 3 | 3 H 30 -NE-C3,-.

The nucleophiles of formula V wherein R is I! '0H -NE-Ag ^N^and is -O-CH,- can be prepared by 35 H reacting a suitably protected derivative of the -52- 10 15 20 25 30 35 compound of formula XXII with N-hydroxvphthalimide under Mitsunobu conditions (presence of triphenyl-phosphine and diethylasodicarboxylate) to yield a protected derivative of the compound LXXXIX which can be deprotected to the compound XC O HO CH,-0-NH? Alternatively, the compound of formula XC can be prepared by reacting a compound of formula XXVIII (suitably protected) with N-hydroxy-phthalimide in the presence of a base.

The nucleophiles of formula V wherein R is 0 0 I! -NH-A^-C-A-, I I ■OH N^and is -NH- can be prepared by A reacting a monoprotected hydrazine with an activated, optionally protected derivative of an acid of formula XX to obtain, after deprotection, a compound of the formula XCI 0 II NH2-NH-C-Ag Alternatively, the compounds of formula XCI can be prepared by reacting a carboxylic -53- acid ester of a suitably protected derivative of a compound of formula XX with hydrazine and then deprotecting.

The nucleophiles of formula V wherein R is 9 _iYH ~NE-A„-C-A~—"^N^and A. is -(CH- ) ~ and p is 0 4 o j 4 2 p H can be prepared by reacting ammonia or hexamethyl-10 disilizane with an activated, optionally protected derivative of an acid of formula XX to obtain, after deprotection, a compound having the formula XCI I Yd 15 The nucleophiles of formula V wherein R is 20 -NE-A-C-A,——^-N^and A„ is -(CH- ) - and p is 1 can be o | "s dp h prepared by treatment of a suitably protected activated derivative of a compound of formula XX with diazomethane followed by hydrochloric acid to 25 yield a protected derivative of a compound having the formula XCI 11 30 VCH2 wherein "L>>" is chlorine. a compound of formula XCIII wherein is chlorine can then be treated with an iodide or bromide salt (such as sodium iodide or lithium bromide) to give a protected 3 5 derivative of a cpmpound of formula XCIII wherein is bromine or iodine. Displacement of the -54- leaving group (wherein is chlorine, bromine or iodine) with azide followed by reduction and deprotection yields XCIV 5 0 ii nh--ck- — c-a/~" ^ n 2 ,1 o | h The nucleophile of formula V wherein R is 10 11 11 v N^and A„ is -(CH,) -NH- can be b '7 prepared by reacting a (optionally monoprotected) compound of formula 15 XCV nh2-(ch2)y-nh2 with an activated, optionally protected derivative of an acid of formula xx to obtain, after deprotection, a compound having the formula 20 XCVI 0 oh NH,-(ch, ) -NH-C-Ar*—"^N <£> £ V © | h The nucleophiles of formula V wherein R is 25 q 0 f^s—ob 0 II i[ jj \\ -MH-A.-C-Ar-—^N^and A. is -NH-C-NK~NB~ can be A prepared by reacting a compound of formula xci 30 (suitably protected) with a compound having the formula XCV11 o Prot~NH-NE~C~Cl in the presence of a silylating agent and than 35 removing the protecting groups. -55 The nucleophiles of formula V wherein R is -NH-A.'-C-Ar^^N^and A- is -C-MH-NH- can be 4 o | 4 prepared by reacting (in the presence of a base or a silylating agent) with an activated, optionally protected derivative of formula XX to obtain, after deprotection, 10 a compound having the formula XCVI1I p 0 ° fiii—0h 0 A 15 The nucleophile of formula V wherein R is 0 0 (iSr°H CB-X ii j .1 2 -NH~A4~C-Ag— ^N-^and is ~N~ can be prepared H 20 by reacting an optionally protected hydrazine derivative of the formula XCXX nh,-nh-ch7-x with an activated, optionally protected derivative 25 of an acid of formula XX to obtain, after deprotection, a compound having the formula f-2x rrV°H 2 ii i 30 OH Alternatively, compounds of formula C wherein X is hydrogen can be prepared by reacting methylhydrasine with a carboxylic ester derivative of the acid of formula XX (or a suitably protected 3 5 derivative thereof). -56- Th e compounds of formula I wherein R is 1 ^ -A, -N. i-A.-t-A. 1 V 2 0 A preferred are those compounds of formula 1 wherein R is i—i ? i[ jr°H ~KL .N-NH-C—. Also preferred are those !0 V S " 0 11 compounds of formula I wherein R^ is -C-C=N-0-R^ Rg and is 2«amino-4~thiazolyl and is methyl, ethyl, carboxymethyl, 1-carboxy-l-methylethyl, 15 %-s 1-carboxy-l-ethyl or "^C-COOH, wherein s is 1, 2 or 3. The use of these preferred acyl groups yields a product which exists as the syn or anti isomer or as a mixture of isomers. The syn isomer 20 exhibits greater activity than the anti isomer. The following examples are specific embodiments of this invention. -57- Example 1 [3S(Z)]-2-[[[l-(2-Amino-4-thiazolyl)~2-[ [l-[ [ [ [3-[[(l,4-dihydro~5~hydroxy~4-oxo-2-pyridinyl)carbonyl]-amino ]~2-oxo~l--imidazolidinyl ] sulfonyl ] amino ] » 5 carbonyl]-2-oxo-3-az eti dinyl]amino]-2-oxoethy1-idene]amino]oxy]-2-methylpropanoic acid, disodium salt A) 2»(Hydroxymethyl)-5-(phenylmethoxy)-4H- 10 pyran~4"one 69 g (3 mol) of sodium were dissolved in 5 1 of methanol. Subsequently 425.3 g (3 mol) of 5-hydroxy~2-(hydroxymethyl)-4H~pyran-4-one was added and stirred at 30°C until a clear 15 solution was obtained. 595 g (3.5 mol) of benzyl bromide was then added and stirred for 1 hour under reflux. The warm and very dark colored solution was poured into 15 1 of ice water. The product crystallized immediately. The crystals 20 were collected and washed first with 8 1 of water and then twice with 2.5 1 of ether. The product was left to stand overnight and finally dried at 50°C for 16 hrs. Yield: 646 g = 92.6%. 25 B) 4-Oxo-5~(phenylmethoxy)~4H-pyran~2-carboxylic acid 232 g (1 mol) of 2-(hydroxymethyl)-5-(pheny1-methoxy)-4H-pyran-4~one were put into a 10 1 stirring flask containing 6.61 of acetone and 30 400 ml of water. The clear solution was cooled to •*5°C by means of an ice-bath. While maintaining the temperature at +5° to 10 °C, 640 ml of Jones Reagent (202 g CrO^, 600 ml water, 174 ml E^SO^) was added dropwise over a period of l hr. Stirring 35 was continued for 2 hours without cooling. The -58- reaction mixture was filtered through a glass frit and the dark-green residue washed with 500 ml of acetone. The filtrate was then evaporated until all of the acetone was removed. To the aqueous, 5 partly crystalline product was added 1.2 1 of methanol, and this mixture was then heated to its boiling point. The resulting clear dark-green solution was placed in an ice-bath and the product allowed to crystallize. The crystalline product 10 was filtered and washed with 500 ml of a cold solvent mixture consisting of 250 ml methanol + 250 ml water and finally dried. Yield: 195 g = 79%. From the mother liquor a further 5% of the product could be isolated. 15 C) 1,4-Dihydro-4-oxo~5~ (pheny lmethoxy )-2-pyridine- carboxvlic acid 300 g (1.22 mol) of 4-oxo-5~(phenylmethoxy)-4H-pyran~2-carboxylic acid was put into a flask and 20 5 1 of 33% NH^OH was carefully added with stirring. The reaction mixture was then stirred under reflux. After 3 hours, one additional liter of 33% NH^OH was added slowly. Stirring was continued for further 2 hours under reflux. The reaction 25 solution was then evaporated until the product crystallised. The product was transferred back into the reaction flask and water added until a clear solution was obtained (approximately 5 1, pH 6.38). This solution was stirred vigorously while 30 concentrated hydrochloric acid was added dropwise until a pH of 3 was obtained. The precipitated white product was removed by filtration, thoroughly washed with water and dried. Yield: 273 g (1.12 mol) = 91.8%. -59- D) 1,4-Dihydro-4-oxo-N~(2-oxo~l~imidazolidinyl)~ 5- (phenvlmethoxy) - 2-pvri dinecarboxami da 1,4-Dihydro~4~oxo-5~(phenylmethoxy)-2-pyridinecarboxylic acid (12.26 g, 0.05 mol) and 5 l-amino-2~imidazolidinone (5.56 g, 0.055 mol) were suspended in 120 ml of dimethylformamide. To the suspension was added 0.3 g of dimethylaminopyridine and 0.4 g of N-hydroxybenzotriazole. After stirring for 30 minutes at room temperature, a solution of 10 11.35 g of dicyclohexvlcarbodiimide (0.055 mol) in 50 ml of dimethyl fonnamide was added dropwise and the mixture was stirred overnight at room temperature. The precipitate (dicyclohexylurea) was filtered off and the filtrate evaporated in vacuo. The 15 remaining syrup crystallized on treatment with aqueous sodium bicarbonate, yielding 11.7 g of the title compound, melting point 158-160°C. An additional crop of O.S g of product, melting point 162-164°C, crystallized from the aqueous filtrate. 20 E) 1,4-Dihydro-5~hydroxy-4~oxo-N~(2-oxo-l-imidazolidinvl )-2-pvridinecarboxamide To a suspension of 12 g (0.0365 mol) of 1,4-dihydro-4-oxo-N- (2~oxo-l-imidazolidinyl) -5-25 (pheny Ime thoxy) -2-pyridinecarboxamide in 150 ml of acetonitrile was added 36.1 ml (0.146 mol) of bis (trimethylsilyl )acetamide to form a slightly turbid solution. After filtration, 6 g of 10% palladium on charcoal was added and hydrogen was 30 passed through the stirred reaction mixture. After hydrogenation for 60 minutes, the catalyst was filtered off and 15 ml of methanol and 2 ml of acetic acid were added. Stirring was continued overnight; the title compound crystallized out, 35 yielding 6.6 g, melting point 270-275°C. -60- F) (3S)-[l-[[[[3-[[(l,4-Dihydro~5-hydroxv-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-l-imidazolidinyl]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phanvlmethvl ester 5 To a suspension of 13.8 g of (S)~3- [[(phenylmethoxy)carbonyl]amino]-2-azetidinone in 500 ml of ethyl acetate was added 5.63 ml (0.0626 mol) of chlorosulfonyl isocyanate. The mixture was stirred for 1 hour at room temperature 10 to form a solution of (S)-l-[[(chlorosulfonyl)amino]-carbonyl]-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone. The solution was cooled to 0°C, at which temperature a solution of silylated 1,4-dihydro~5-hvdroxy-4-oxo-N-(2-oxo-l-imidazolidinyl)-15 2-pyridinecarboxamide (prepared from a suspension of 14.9 g (0.0626 mol) of 1,4-dihydro-5-hvdroxy-4-oxo-N-(2-oxo-l-imidazolidinyl)-2-pyridine-carboxamide in 500 ml of ethyl acetate by the addition of 46.4 ml of N-methyl-N-(trimethylsilyl)-20 trifluoroacetamide (0.25 mol) and stirring for 30 minutes) was added slowly. Then 150 ml of dichloro-methane was added, and the mixture was stirred at room temperature overnight. To the clear solution was added 26.2 ml of triethylamine (0.188 mol), 25 followed by 300 g of ice and 200 ml of water. The pH was 6.5. After stirring for 1% hours, the two phases were separated and the aqueous phase was washed with three 200 ml portions of ethyl acetate. After removal of residual ethyl acetate in vacuo, 3 0 the pH of the aqueous phase was adjusted to 2 by the slow addition of 2 N hydrochloric acid (47 ml) with cooling. The crystals were filtered off, suspended in 200 ml of ethyl acetate and stirred for one hourk. Then the crystals were filtered off, 35 washed twice with 30 ml of ethyl acetate and twice with 50 ml of petroleum ether and dried in vacuo, -61- to yield 28.6 g of the title compound, melting point 190~200°C, dec.

G) (3S)-3-Amino~N-[[3~[[(1,4-dihydro~5~hydroxy~4- 5 oxo-2-pyridinyl)carbonyl]amino]-2-oxo-l-imidazolidinyl]-sulfonyl]-2-oxo»l-azetidinecarboxasnide, trifluoroacetate (1:2) salt " At room temperature, 4 g (0.00713 mol) of (3S)-[1-[[[[3-[[(1,4-dihydro~5~hydroxy-4-oxo-2-10 pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]-sulfonyl]amino]carbonyl]-2-oxo-3~azetidinyl]car-bamic acid, phenyImethy1 ester was added to a mixture of 15 ml of trifluoroacetie acid and 3.5 ml of thioanisole at 10°C. The clear solution was 15 stirred overnight at 10°C. After evaporation in vacuo at room temperature, the remaining syrup was treated with ether to yield the title compound as a yellowish solid. The yield was almost quantitative. 20 H) [3S(Z)]-2-[[[1-(2-Amino-4~thia2olyl)-2~[[1~ [ [ [ [3- [ [ (1,4-dihydro-5-hydroxy-4-oxo~2-pyridinyl')-carbonyl]amino]-2-oxo-l-imidazolidinyl]sulfonyl]-amino]carbonyl]~2-oxo-3-azetidinyl]amino]-2~oxo-25 ethylidene]amino]oxy]-2~methylpropanoic acid, diphenvlroethyl ester To a solution of 3.08 g (0.007 mol) of (2)-2-amino-a™[[2-(diphenyImethoxy)-1,1-dimethy1-2-oxoethoxy]imino]-4-thiazoleacetic acid in 70 ml 30 of dimethylfoimamide was added 2.9 ml (0.021 mol) of triethylamine followed, after cooling to -30°C under nitrogen, by 1.55 ml (0.007 mol) of diphenyl cb.lorophosp.hate. The mixture was stirred for 1 hour at -30°C. Then 1-95 ml of 35 triethylamine (0.014 mol) was added followed by -62- 0.007 mol of (3S)~3-amino-N~[[3~[[(1,4-dihydro-5-hydroxy~4-oxo-2-pyri dinyl)carbonyl]amino]-2-oxo-l-imidazolidinyl ] sulf onyl ] -2~oxo-l-azetidine-carboxamide, trifluoroacetate (1:2) salt. The 5 reaction mixture was stirred at -10°C for 2 hours and at 0°C for 1 hour. Then the solvent was removed in vacuo. Treatment of the residue with water and ethyl acetate yielded an insoluble product which solidified on treatment with ether 10 yielding 8.0 g of crude compound.

I) [3S(Z)]-2-[[[l-(2-Amino-4-thiazolyl)-2-[[1-[ [ [ [3- [ [ (1,4-dihydro-5~hydrox3'~4-oxo~2-pyridinyl )~ carbonyl]amino]-2-oxo-1-imi dazoli dinyl]sulfony1]-15 amino]carbonyl]-2-oxo~3-azetidinyl]amino]-2~oxo-ethylidene]amino]oxy]-2-methylpropanoic acid, disodimn salt Crude [3S(Z)]-2-[ [ [1~(2-amino~4~thiazolyl)-2-[[!"[[[[3-[[(l,4-dihydro-5~hydroxy-4-oxo-2-20 pyridinyl)carbonyl]amino]-2-oxo-l-imidasolidinyl]-sulfonyl]amino]carbonyl]~2-oxo-3~azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2~methylpropanoic acid, diphenvlmethyl ester (8 g) was suspended in 15 ml of anisole. After cooling to -10°C, 80 ml 25 of trifluoroacetic acid was added dropwise and the mixture was stirred at. -10°C for 1 hour. The addition of ether at 0°C precipitated the trifluoroacetate salt of the free acid of the product (4.1 g of crude material). The crude material was 30 suspended in water; the pH was adjusted to 5.5 by the addition of sodium bicarbonate solution and the solution formed was freeze dried. The crude sodium salt was then purified by chromatography on HP-20*. The product was eluted with water,' 35 -HP20: A macroreticular styrene-divinylbenzene copolymer resin sold by Mitsubishi Chemical Industries Ltd. -63- yielding 0.52 g of product.

JSMR (DMSOdg): 6 = 1.35 (s, 3 H); 1.40 (s, 3H), 3.37 (dd, 1H); 3.47 (t, 2H); 3.81 (t, 2H + ad, IB); 5.05 (m, 1H); 6.75 (S, 1H); 7.27 (s, 1H); 7.72 (s, 5 1H); 11.52 (broad s, IB).

Example 2 [3S(Z)]-2-[[[l-(2-Amino-4-thi£2olyl)-2-[[l-[[[[2-[ (1,4-dihydro-5~hydroxy~4-oxo-2-pyridinyl) carbonyl ] -10 hydrazino] sulf onyl] amino] carbonyl ] - 2-oxo-3-azetidinyl ]-amino ] -2-oxoethylidene ] amino ] oxy ]-2-methylpropanoic acid, disodium salt , .

A) l,4-Dihydro-4~oxo~5~ (pheny lmethoxy)-2-pyridine~ 15 carboxylic acid, 2- [(1,1-dimethylethoxy)carbonyl]- hvdrazide 1,4~Dihydro-4~oxo~5-(phenylmethoxy)-2-pyridinecarboxylic acid (61.3 g, 0.25 mol) was suspended in 500 ml of dimethylformamide at room 20 temperature, followed by the addition of 39.65 g (0.3 mol) of N-(t-buuoxycarbonyl)hydrazine, 1.5 g of dimethylaminopyridine and 2.0 g of N-hydroxy-b&nzotri&zole, and the mixture was stirred for 30 minutes at room temperature. Then, 57.7 g (0.28 mol) 25 of dicyclohexylearbodiimide, dissolved in 100 ml of dimethylformamide, was added dropwise with stirring over 30 minutes, and the mixture was stirred at room temperature overnight. The precipitate (dicyclohexylurea) was filtered off and the filtrate 30 evaporated in vacuo. The remaining syrup crystallized on treatment with diluted sodium bicarbonate solution. The dried crude product was recrvstall-ized from 2 liters of ethyl acetate to yield 69.5 g of the title compound, melting poir.t 173-175°C. 35 A second crop was obtained after evaporation of the mother liquor; 3.2 g, melting point 160-165°C. -64- B) 1,4-Dihydro~5-hydroxy-4-oxo~2-pyridine~ carboxvlic acid, hvdrazide 1,4-Dihydro-4~oxo~5-(phenylmethoxy )-2-pyridinecarboxylic acid, 2-1(1,1-dimethylethoxy)-5 carbonyl]hydrazi de (69 g, 0.191 mol) was added at 0°C to 370 ml of trifluoroacetic acid. The mixture was stirred for 1 hour at room temperature, then evaporated. The remaining syrup was treated with ether to yield 68.2 g of crude 1,4-dihydro-4-oxo-5-10 (phenylxnethoxy )-2-pyridineearboxylic acid, hydrazine, trifluoroacetate (1:2) salt as a solid.

The crude 1,4-dihydro-4-oxo~5~(phenylmsthoxy)-2-pyridinecarboxylic acid, hydrazine, trifluoroacetate (1:2) salt was dissolved in 250 ml of 15 acetoxxitrile and stirred with cooling for 1 hour.

The crystals were then filtered off and resuspended in 600 ml of acetonitrile. 3is(trimethvlsilyl)-acetamide (135 ml) was added followed by 28 g of 10% palladium on charcoal. Then hydrogen was 20 passed through the stirred solution- The hydrogenation was complete after 90 minutes. After filtration, 70 ml of methanol and 2 ml of acetic acid were added. After stirring overnight, the crystals formed were filtered off, yielding 19.4 g 25 of the title compound, melting point 290-340°C, dec.

C) (3S)-[!-[ [ [ [ [ [1,4~Dihydro-4~oxo-5~(phe=yl-methoxy)-2-pyridinyl]carbonyl]hydrazine]sulfonyl]- 30 amino]carbonyl]-2-oxo-3~azetidinyl]carbamic acid, nhenvlmethvl ester To a suspension of 5.19 g (0.0235 mol) of (S)-3~[[(phenyImethoxy)carbonyl]amino]-2-asetidinone in 160 ml of ethyl acetate was added 35 with stirring at room temperature 2.05 g (0.0236 mol) of chlorosulfonyl isocyanate. The -65- mixture was stirred for 1 hour at room temperature to form a solution of (S)-!-[[(chlorosulfonyl)-amino] carbonyl] - 3- [ [ (phenyImethoxy)carbonyl ] amino]-2-azet.idinone. The solution was cooled to 0°C, 5 BO ml of dichloromethane was added followed by 9.9 ml {0. 070/ mol) of txi ethyl amine and a solution of silylated 1,4~dihydro-5-hydroxy~4-,o3co«2«pyridinecarboxylic acid, hydrazide (obtained from a suspension of 3.99 g (0.0236 mol) of 10 1,4-dihydr o-5-hydroxy~4-oxo-2 -pyri dinecarboxyli c acid, hydraside in 50 ml of ezhvl acetate and B.7S nil of U~fflethyl»N~(trimethylsilyl)trifluoro-acetamide (8.75 ml = 0.0472 mol)). The mixture was stirred at. room temperature overnight, then ice 15 water was added and stirring was continued for an additional 30 minutes. The aqueous phase was layered with ethyl acetate and acidified to pH 2.5. 2!he precipitate crystallized after stirring for one hour, yielding 6.6 g of'the title compound. 20 Evaporation of the ethyl acetate phase and treatment with petroleum ether yielded a second crop of 1.4 g of the title compound.

D) (3S)-3~Amino-N-[[2-[(1,4-dihydro-S~hydroxy~4~ 25 oxo-2~pyridinyl) carbonyl] hydrazine] sulf onyl 3-2- oxo-l-azetidinecarboxamide, trifluoroacetate (1:2) salt (3S)-[1~[[[[[[1,4-Dihydro~4-cxo-5-(phenyl-methcxy) - 2 -pyri dinyl ] carbonyl ] hy dr az ino ] sulf onyl ] -30 ajnino]carbonyl]-2-oxo-3~azetidinyl]carbamic acid, phenyImethyl ester (6.6 g, 0.0133 mol) was added to a stirred mixture of 22 ml of trifluoroacetic acid and 5.3 ml of thioanisole at room temperature and stirred overnight at room temperature. The 35 trifluoroacetic acid was removed in vacuo and the -66- remaining syrup treated with ether to yield the title compound in guantitative yield.

E) [3S(2)]-2-[ [ [ 1- (2-&nino~4-thiazolyl )~2-[[l-[[ I [2- • 5 '[ (l,4-dihydro-5-hydroxy-4~oxo-2-pyridinyl Jcarbonyl hydraaino 3 sul f onyl 3 amino ] carbonyl 3-2-oxo-3-a2eti dinyl 3 -aadno}-2-oxoethylidene 3 amino 3 oxy3-2-methylpropanoic acid, diphenvlmethvl ester To a solution of 5.84 g (0.0133 mol) of 10 (Z)-2-amino-c-[ [2-(diphenyl»ethoxy)~l,l-diaiethyl~ 2-oxoethoxy]imi»o]-4-thia:2oleacetic acid in 135 ml of dimethylformamide v*as added 5.6 ml of triethyl-amine and (after cooling to -30®C).3.57 g (0.0133 mol) of diphenyl chlorophosphate. The 15 mixture was stirred, for 1 hour at- -30°C, then 3.72 ail of triethyl amine was added, followed by 0.0133 mol of (3S)-3-amiao-K-[ [2-[ (1,4-dihydro-5~hydroxy~4~oxo~2™pyridinyl ) carbonyl ] hydras in o 3 -sulf onyl ] -2 - oxo~ 1 ~ as e ti dine carbox ami de, tr i fl u or o-20 acetate (1:2) salt The mixture was stirred at -10°C for 2 hours and at 0°C for 1 hour, the solvent was removed in vacuo and the remaining syrup was treated with 150 ml of ethyl acetate and 70 ml of ice water, 25 which was adjusted to pH 1.5-2 by the addition of 2M hydrochloric acid. The insoluble material was removed and triturated with ether to yield 5.3 g of crude product. 30 F) [3S(2)3-2-[[[l-(2-Attiii0-4-this20lyl)-2-[[l-II [ [2-[(1,4-dihydro-5-hydroxy-4-oxo~2-pvridinyl) carbonyl3-hydrazine 3 sul f onyl 3 amino 3 c arb onyl ] ~ 2 -- oxo- 3 - as e ti diny 13 ~ amino3-2~oxoethylidene3 amino} oxy3 -2-me thy Ipropanoic acid, aisodium salt 35 [3S (2;)3-2- [ [ [l-(2-Amino-4-thiasolyl )~2~ [ [1- [ [ [ [2- 1(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl ]-hydratino3sulfonyl 3 amino3 carbonyl 3 -2-oxo-3-a:»etidinyl 3 ~ amino]~2-oxoethylidene] amino} oxy]~2-me thy lpropanoic acid, diphenylmethyl ester (5.3g, 0.0069 mol) was »67- suspended in 10.6 ml of anisole. The suspension was cooled to -10°C and 53 ml of trifluoroacetic acid was added with stirring,. The mixture was stirred at this temperature for 1 hour, then 200 ml of ether was added at -10°C to precipitate the trifluoroacetic acid,salt of the free acid of the title compound; the yield was 7.3 g„ The crude material was dissolved in a mixture of 100 ml of water and 50 ail of acetone. The pH was adjusted to 5 - 5.5 and the acetone was removed in vacuo. The remaining aqueous solution was lyophilized to yield 8.1 g of crude product, which was purified by EP-20 chromatography, eluting with water. The chromatography yielded 1.05 g of product.

NMR (DMSOd6): 6 ~ 1.40 (s, 33); 1.42 (s, 33); 3.25 (dd, IB); 3.70 (dd, 1H); 5.10 (m, 1H); 6.75 (s, IS); 7.40 (s, 1H); 7.B0 (s, IS); 11.32 (broad s, IS).

Example 3 [3S(Z)3-2-1 r [ 1-(2-Amino-4-thiasolyl)~2-[[1~ I [ [ [3- [ r (1,4-dihydro~5-hydroxy~4~oxo-2~pyridinyl )-c arbonyl ] amine ]-2-oxo-1- imi dis oli dinyl ] sul f onyl ] -amino ] carbonyl ] -*2-oxo-3»a2;etidinyl ] amino] -2- ox o~ ethvlidenelaminolosryl-2-acetic acid, disodiura salt A) [3S(2)]-2~[ [ [l~(2~Amino-4-thiazolyl}-2- [ [1-I [ [ [3- [ [ (l,4~dihydro-5~hydroxy~4-oxo-2-pyricinyl )~ carbonyl ] amino] -2«o3so~l~-imi&i2,olidi.-,yl l sulf onyl ] -amino] cartoonyl]-2-oxo-3-azeti dinyl] amino ]-2~oxo-ethylidane] amino] oxy ]-2-acetic acid, diphenyl- methvl ester To a solution of 2.06 g (0.005 mol) of (2)-2"amino-e- [ [2- (dipheny Isnethoxy)-2-oxoethoxy ]-imino]-4-thia2oleacetic acid in 100 ml of dimethyl- -68- formamide was added 2.1 ml (0.015 mol) of triethyl amine. The mixture was cooled to -30°C and 1.1 ml of diphenyl chlorophosphate (0.005 mol) was added with stirring. After stirring for 1 hour at S -30°C, an additional 1.4 ml of triethylamine (0,1 mol) was added at -30°C, followed by 2.7 g of (3S)-3-amino-N-[f3-[[(1,4-dihydro-5-hydroxy~4-0x0-2-pyri dinyl) carbonyl ] amino]-2-oxo-l-imidasoli-dinyl ] sulf onyl ] ~2~oxo-l~a2etidineearboxasiide, tri-10 fluoroacetate (1:2) salt.

The reaction mixture was stirred at -10°C for 2 hours and at 0°C for 1 hour. The solvent was evaporated off in vacuo, the oily residue suspended in water and the pH of the suspension 15 adjusted to 2 by the addition of 2N hydrochloric acid. The suspension was stirred .for 30 minutes, at room temperature, filtered off, the solid resuspended in water and filtered off again.

After drying in vacuo over phosphorous pentoxiae, 20 5.0 g of crude product were obtained. The material was used in the next step without further purification.

B) [3S(Z)]-2-[[[l-(2-Amino-4-thiazolyl)-2-[[1-[ 11[3-[[(1,4-dihyaro-5-hydroxy-4-oxo-2-pyridinyl)-25 ' carbonyl]amino]~2-oxo-l-imidizolidinyl]sulfonyl]- amino]carbonyl]-2-oxo-3«a2etidinyl]amino]-2-oxo-e thyli dene 1 amino "loxv 1-2-acetic acid, disodiuro salt 5.0 g of crude [3S(2)]-2-[[[1-(2-amin©-4-thiazolyl)~2~[[1-[[[[3-[[(1,4-dihydro-5-hydrexy~4-30 oxo-2-pyri dinyl)carbonyl] amino]-2-oxo-1-imi din oli-dinyl]sulfonyl]amino]carbonyl]-2-oxo-3-a:seti&inyi]-amino]-2-oxoethylidene]amino]oxy]-2-acetic acid, diphenylmethyl ester were suspended at -1D°C in a mixture of 10 ml of anisole and 50 ml of trifluoro-35 acetic acid. ■' The reaction mixture was stirred at -10cC for 1 hour, followed by the careful addition -69- of 100 nil of ether to precipitate the crude trifluoroacetate salt of the title compound. Yield 3.7 g. The crude material was dissolved in a mixture of 30 al of water and 60 ml of acetone, 5 and the pH of the mixture was adjusted to 5 - 5.5 by the addition of 0.1 N sodium hydroxide. The acetone was evaporated and the aqueous phase was lyophilized to yield 3.9 g of crude product. The crude material was purified by chromatography on 10 HP-20. The product was eluted with, water (fractions of 10 ml each). The fractions containing product were lyophilized to yield D.6 g of material which was rechromatographed on HP-20 to yield 0.25 g of pure product. 15 Sx amr>le 4 [3S(Z)]-2-[I[l-(2rAmino-4-thi&2olyl)-2-[[1~ 11111(1,4~dihy&ro~5~hydroxy~4-oxo-2-pyridi:nyl)~* methyl]amino]sulfonyl]amino]carbonyl]-2~oxo-3-2 0 azeti dinyl ] asaino ] - 2 -oxoethyli dene ] amino ] oxy] - 2-roethvlnropanoic acid A) 2~(Hydroxymethyl )-5-(phenyjLmethoxy)-4(lS)~ pvra dinone 25 A mixture of 2~(hydroxymethyl)-5-(phenyl- methoxy)-45-pyr art~4~one (9.65 g, 41.59 mole), 95 ml of concentrated ammonia and 20 sal of ethanol were heated at reflux overnight. An additional 75 ml of ammonium hydroxide was added, the mixture 30 was rafluxed for 2 hours and cooled. The resulting brown solid was filtered and washed with water until the washings were neutral. The crude product was suspended in ethanol, filtered, washed with ethanol and hexane and dried in vacuo. The 35 yield of the title compound was 7.61 g. -70- B) 2- (Chloromethyl) -5- (pheny Ime thoxy) (1H) — pyridinone f roonohvdrochlori de A suspension of 2-(bydroxymethyl)»5-(phenyl-methoxy)-4(1H)-pyridinone (3 g, 12.99 mmole) in 5 chloroform (15 ml) was cooled to 0° under argon sud treated with thionyl chloride (6.1 ml, 83.62 asnole). Within several minutes, a homogeneous solution was obtained. After stirring an additional 5 minutes, a crean colored solid 10 precipitated. The cooling bath was removed and the mixture was heated at reflux for 45 minutes. The mixture was cooled to 0° and the white precipitate was filtered, washed with chloroform asd hexane and dried in vacuo. The yield of the IS title compound was 3.65 g.

C) 2- (Aaidomethyl )~5~ (pheny Imethoxy)—4 (1H) -pyri dinone A mixture of 2-(chloromethyl )-5~ (phenyl-20 methoxy)-4(IS)-pyridinone, monohydrochloride (3.59 g, 12.54 mmole), sodium aside (4.08 g, 62.7 mmole) and diisopropylethylamine (2.19 ml, 12.54 mmole) in 70 ml of diaethylformaaide was stirred at room temperature under argon for 3.5 25 days. An additional 4.08 g of sodium aside was added arsd the mixture was heated at 45-50°C for 2 hours. After cooling, the reaction mixture was poured into 500 ml of water, producing an insoluble white solid. The pH of the supernatant liquid was 30 lowered from 8.5 to 7.5 vizh dilute hydrochloric acid, and the white solid was filtered. After washing with water, acetone, and hexane the solid was dried in vacuo. The yield of the title compound was 2.81 g. 35 -71- D) 2-(Atninomerhyl)- 5~( pheny line thoxy )-4{lH)~ pvridinone _ A mixture of 2-(azidomethyl)-5-(phenyl-methoxy)-4(IS)-pyridinone (2.03 g, 7.93 mmol) 5 and platinum oxide (200 mg) in 100 al ox dimethyl- formamide was stirred for 6 hours at room ; temperature.under one atmosphere of hydrogen. The catalyst was removed by filtration and the solution was concentrated in vacuo to afford 1.5 g (82% 10 yield) of the title compound as a grey powder.

S) (3S)-[l-[[[[[[1,4-Dihycro-4-oxo-S-(phenyl-methoxy) -2-pyridinyl ] methyl ] amino ] sulf onyl ] amino ] -carbonyl]-2-oxo-3~asetidinyl]carbaaic acid, 15 phenvlmethyl ester . .

To a stirred suspension of 2-{aainomethyl)~ 5- (pheny Ime thoxy) -4 (13 )-pyri dinone (2.330 g, 10.13 aaole) in 60 ml ethyl acetate was added N-methyl-N-(trimethylsilyl )tri£luoroacetamide 20 . (3.76 ml, 20.26 mmole). The resulting solution was stirred for 30 minutes at room temperature and then cooled to 0°C. Concurrently, to a stirred suspension of (S )-3-[ [ (phenylaiethoxy) c&rbonvl ]-amino]-2-azeti dinone (2.228 g, 10.13 ancle') in 60 ml 25 ethyl acetate was added chlorosulfonyl isocyanate (882 pi, 10.13 maol). The resulting solution was stirred for 30 minutes at room temperature, cooled to 0°C, and finally treated with triethylamine (4.23 ml, 30.39 mmole) followed by the solution of 3 0 ' silyl a tad 2 - (aainoxnethyl) -5 - (pheny Ime thoxy) -4 (IE) -pyri dinone described above. The mixture was stirred for two days at room temperature.

The mixture was concentrated in vacuo, the residue dissolved in CH^CN-water (40-60) and the ?H 35 lowered to 2.9 whereupon a thick oil separated.

' Upon cooling to 5®C, the oil solidified. The -72- solid was separated, washed four times with water, and dried in vacuo to afford 3.4 g crude product. The crude product was dissolved in a minimum volume dimethyl forinamide and. loaded on a column (1 1) of 5 BP-20 resin. The column was eluted with a stepwide acetone-water gradient. Desired materiel eluted with ca. 65% acetone. The relevant fractions were combined and lyophilized to afford 2.69 g of the title compound. 10 F) [3S(Z)]-2-[[ [1-(2-Amino-4-thiazolyl )-2- [ [1- [[[[[(1,4-dihydro»5-hydroxy»4-ozo-2-pyridinyl)-methyl]amino]sulfonyl]amino]carbonyl]~2-oxo-3«-azetidinyl ] amino] -2 -oxoethyli dene] amino] oxy] -2-1S methylpropanoic acid, diphenylmethyl ester, (as a mixture of monopotassium and monotriethylaaanoniuai salts) .

A mixture of (3S)-[1-I[[f[II,4-dihydro-4-oxo-5- (phenyImethoxy)-2-pyridinyl ] methyl ] amino ] -20 sulfonyl]amino3cai-bonyl]~2-oxo-3-a2etidinyl]-carbaaiic acid, phenylmethyl ester (912 mg, 1.64 Anmole), ©-toluenesulfonic acid monohydrate (625 mg, 3.2B mmole), and 10% palladium on charcoal (190 mg) in 16 ml of dimethylforniamide 25 was stirred under one atmosphere of hydrogen until 3.28 mmole (73 ml) of hydrogen was consumed (ca. 3 hours).

To a stirred solution of (Z )-2*-amino-e-[ [2-(diphenvImethoxy)~i,l-dimethyl-2-oxoethoxy]imino]-30 4-thiazoleaeetic acid (846 mg, 1.804 mmole) in 16 ml of dimethvlformamide at -20°C was added diphenyl chlorophosphate (374 pi, 1.BD4 mmole) followed by triethyl amine (450 jjI, 3.28 mmole). The solution was stirred for 1 hour at -20°C 35 whereupon the above-described mixture of hydrogenolyzed (35)~[i~[[[[[[1,4-dihydro-4- -73- oxo-5-(phenylmethoxy)-2-pyridinyl]methyl]amino]-sulfonyl]amino]carbonyl]-2-oxo~3-azetidinyl]-carbamic acid, phenvlmethvl ester was added. The resulting mixture was stirred at -20°C for one 5 hour and then at 5°C overnight. The catalyst was removed by filtration, volatiles were removed in vacuo and the resulting oil was dissolved in a minimum volume of acetone-water (75-25, pH 5.2) and added dropwise to a stirred suspension of 20 ml of. 10 *bowex 50x2-400 (K~) in acetone-water 35-65. After 40 minutes, the mixture was filtered and the filtrate lyophilized to afford 2.1 g of solid. The solid was dissolved in a minimum amount of acatonitrile-water (40-60, pH 5.6) and loaded onto 15 a column (800 ml) of HP-20 resin, eluting with a stepwise acetonitrile-water gradient. Desired material eluted with ca. 30% acetonitrile. The relevant fractions were combined and lyophilised to afford the impure title compound (254 mg). 20 G) [3S(Z)]-2-[[[l-(2-Amino-4-thiazolyl)-2-[lilt 11[(l,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)- methyl]amino]sulfonyl]amino]carbonyl]-2-oxo«3-azetidinyl]amino]~2~oxoethylidene]amino]oxy]-2- 25 methylpropanoic acid Trifluoroacetic acid (4.7 ml) was added dropwise to a stirred suspension of the above impure [3S(Z)]-2-[[[l-(2-amino-4-thiazolyl)-2-[.[1- [ [ [ [ [ (1,4-dihydro-5~hydroxy-4-oxo-2-pyridinyl )-30 methyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2 -oxoethy1idene]amino]oxy]-2-methylpropanoic acid, diphenylmethyl ester 35 *Dowex 50x2-400: 'Stvrene-divinylbenzene copolymer gel with -SO,- groups attached sold by Dow Chemical Co.

Dowex is a Trademark -74- (mixture of monopotassium and monotriethylammonium . salts) (131 mg) in 3 ml dichloromethane and 0.3 ml anisole at 0°C. After stirring 45 minutes at 5°C, 2 ml of toluene was added and the volatiles were 5 removed in vacuo. The resulting oil was washed with hexane (3x4 ml) and triturated to a solid with 10 ml ether.. The solid was washed once with ether (10 al) and dried in vacuo. The above reaction and vork-up were repeated on 166 mg of 10 [3S(Z)]-2- [ I [1- (2~amino~4~thia2olyl )-2-[ [1~ I [ I11 (1,4-dibydro-5~hydroxy-4-oxo-2-pyri&inyl )« methyl] amino] sulf onyl ] amino ] carbonyl ] - 2~oxo-3~ azeti dinyl ] amino ] -2-oxoe thy li dene ] amino] oxv]~2~ methylpropanoic acid, diphenyIme thy1 ester 15 (mixture of monopotassium and aonotriethyl- sunmonium salts). The crude products- vers combined, dissolved in 2 ml CE^CN-water 40-60 (pH 2.5) and chromatographed on a coluran (200 ml) HP-20 resin, using an acetonitrile-vater gradient. The desired 20 material eluted at ca^CN-water 20-80. The relevant fractions ware combined and lyophilized to afford 103 mg [3S(Z)]-2~[[[l-(2-amino~4-thiazolyl)-2-[[1-[[HI (1,4—dihydro-5-hycroxy-4-oxo-2-pyridinyl )-methyl ] amino] sulf onyl ] amino ] carbonyl ]-2-oxo-3~ 25 azeti dinyl ] amino ] -2 -oxoethyli dene ] amino ] oxy ] - 2 -me thyl -propanoic acid as a white solid. -75- Sxample 5 [3S(Z)]-2-[ [ [l-(2-Amino-4~thiazolyl )-2- [ [l-[ [ [ [2-[[2-[(1,4-dihydro-5-hydroxy-4-oxo~2~pyridinyl)~ carbonyl Jhydrasino] carbonyl]hydrazine]sulf onyl ] -5 amino] carbonyl ] -2~oxo-3-azetidinyl ] amino] -2-oxo-ethyli dene] amino] oxy] -2-methyIpropanoic acid, disodium salt ; A) 1,4-*Dihydro»4-oxo~5- (phenylmethoxy)-2-pyridine-10 carboxylic acid, 2-[ [ (4-methoxyphenyl )jnethoxy]- c&rbonvl 1 hvdr aside A solution of 4.54 g (0.022 moles) dicyclo-hexylearbodiimide in 25 ml dry of dimethylformamide was added to a stirred suspension of 4.90 g 15 (0.020 moles) of l,4~dihydro-4-oxo-5~(phenyl-methoxy)~2~pyridinecarboxylic acid, 4.50 g (0.022 moles) of 4~methoxybenzyl carbamate, 0.12 g (1.0 waiol) of 4-dimethylamino-pyridine and 0.2BS g (1,0 ssmol) of l-hydroxybenzotriazole hydrate in 20 ' 25 al of dry dime thy If ormami de at room temperature and stirring was continued overnight. The precipitate was filtered off and the filtrate was evaporated in vacuo. The residue solidified by stirring with ether and aqueous sodium bicarbonate 25 and the solid was collected, washed with water and finally dried in vacuo. !The crude material (B.14 g) was extracted in a soxhlet-app&ratus with 800 ml CBClj (7 hours). 5.70 g (67%) of pure 1,4-dihydro-4-oxo-5-(phenyimethoxy)-2-pyridine-30 carboxylic acid, 2~[[(4-methoxyphenyl)methoxyj- carbonyl] hydrazi de crystallized directly from the cold C3C13-extract, and an additional impure amount (1.5 g, 18%) of the title compound could be obtained by evaporation of the CHClg-solution 35 in vacuo; melting point 174.S-178°C. -76- B) l,4-Dihydro-4-oxo-5-(pheny line thoxy )~2~ pyridinecarboxylic acid, hydrazine, trifluoro- . acetate (1:2) salt A -10°C solution of 3.B1 ml 5 (35.04 xnmol) of anisole in 38 ml of trifluoro- acetic acid was added to an ice-cold suspension ox 3.71 g (8.76 Hanoi) of 1,4-dihydro~4-oxo~5~(phenyl-fflethoxy)-2-pyxi{3±aecarhoxylic: acid, 2-[[(4-xnethoxvphenyl)methoxy] carbonyl ]hydrazine in IS ml 10 dry dichloromethane. After stirring at 0°C for 20 minutes, the solution was evaporated in vacuo to leave the title compound as a solid which was stirred with few mis of dry ether, collected hv section and dried in vacuo. Yield; 3.25 g (99%); 15 melting point 173-175°c, dec.

C) 1,4-Dihydro-4-oxo-5- (phertylmetihoxy J^-pvridinecarboxvlic acid, hvdrazide . 3.84 ml (19.54 amol) of N~methyl-N~(tri- 20 methylsilyl )tri£luoroaeetamide was added to a suspension of 3.19 g (8.55 irnnol) of 1,4~dihydro~ 4-oxo- 5- (pheny Ime thoxy) -2 -pyri dine carboxy li c acid, hydrazide, trifluoroacetate (1:2) salt in 35 ml dry acetonitrile and stirring was continued for 30 25 minutes at room temperature. After evaporation in vacuo, the residue was taken up in ether, followed by a dropwise addition of 1 ml methanol. The precipitate was collected by suction, washed with ether and petroleum ether and dried in vacuo to 30 yield 2.05 g (92%) of the title compound (melting point 204~208°C, dec.). -77- d) l,4-Dihydro~4~oxo-5-(pheny lmethoxy)-2~pyridine-carboxylic acid, 2-f[2-(phenylaethoxy)carbonyl]- hvdrazinol carbonyl*! hydrazine - with cooling, 11.69 ml (0.060 mol) N-methyl-5 JW-triaethylsilyltxifluoroacetamide was added to a suspension of 5.19 g (0.020 mol) of 1,4-dibydro-4-oxo- 5- (pheny Imethoxy) -2 -pyri dine-carboxylic acid, hydraside in 20 ml dry acetoni-txiie, and stirring was continued for 30 minutes at 10 room temperature. The clear solution, was evaporated in vacuo, and the residue was re-dissolved in 30 ml dry di chl or ome thane. Then this solution was added dropvise to a stirred solution 0 IS of 4.57 g (0.020 mol) of ?hCE2OCNHNHCOCl (J. Gante, Chem. Ber. 97, 2551 (1964) in 60 ml of dichloromethane at 0-5°C„ After being stirred at this temperature for 2.S hours, the solution was evaporated in vacuo.and the solid foam was redissolved in 20 ml 20 methanol. Evaporation in vacuo gave the title compound as a solid foem which became crystalline by stirring with dry ether. Yield; 8.S7 g (98%); melting point >120eC, dec. 25 E) l,4-Dihydro-S-hydroxy-4-oxo-2-pyridine- carboxvlic acid, 2»(hydra%inocarbonyl)hydrazide, dihydrochloride A solution of 4.02 g (8.9 aaol) 1,4-dihyar£>'*• 4~oxo~5•- (phenyIme thoxy)- 2-pyri dine carb oxy1i c acid, 3 0 2-[[2- (pheny Ime thoxy) carbonyl ]hydrazine] carbonyl ] -hydrazide in 50 ml methanol containing 2.94 ml (35.6 snaol) conc- hydrochloric acid was hydrogenated in the presence of 0.4 g palladium (10%) on carbon for 10 minutes. tThe catalyst was 35 filtered off and the solvent was distilled off in vacuo to leave the title compound as a solid -78- (2.58 g) which was stirred with few ml dry ether, collected by suction and dried in vacuo. Yield: 2.47 g (92%); melting point 235-236°C, dec.

F) (3 S)—[1—[[[[2-[[2-[(1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazine]carbonyl]-hydras ino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinvl1carbamic acid, phenvlmethyl ester 4.86 ml (25.0 mrnol) of N-methyl-N-trimethyl-silyltrifluoroacetamide was added to a suspension of 1.5 g (5.0 mrnol) of 1,4-dihydro~5-hydroxy-4-oxo~2~pyridinecarboxylic acid, 2-(hydraaino-carbonyl)hydrazide, dihydrochloride in 20 ml of dry acetonitrile. After stirring for 45 minutes at rooxn temperature, the clear solution was evaporated in vacuo, and the residue was dissolved in 20 ml of dry ethyl acetate (Solution A).

To a suspension of 1.10 g (5.0 mmmol) of (S )~3- [ [ (phenylmethoxy)carbonyl]ajmino]-2-azetidinone in 40 ml dry ethyl acetate was added 0.45 ml (5.0 mmol) of chlorosulfonyl isocyanate with stirring, and the mixture was stirred for 1 hour at room temperature and then cooled to 0°C. After the addition of 10 ml of dry dichloromethane and 2.09 ml (15.0 mmol) of triethylamine, Solution A was dropped in with stirring at 0°C. After stirring overnight at 0°C, the reaction mixture was poured into ice water and the organic layer was separated. Acidification of the aqueous phase to pH 2 by the addition of IN hydrochloric acid gave the title compound as a sticky precipitate which was collected by suction, washed with water and dried in vacuo. Yield: 1.76 g (64%). -79- G) (3S )-3-Amino-N~[[2-[[2-[(1,4~dihydro-5-hydroxy-4-oxo-2-pyridinyl]carbonyl]hydrazino]-carbonyl]hydrazino]sulfonyl]-2-oxo-l-azetidine~ carboxamide, trifluoroacetate (1:2) salt 5 At 0°C 1.73 g (3.1 mmol) of (3S )-[1-[ [ [ [2- [[2—[(1,4-Dihydro~5~hvdroxy--4-oxo~2-pyridinyl)-carbonyl]hydrazino]carbonyl]hydrazino]sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenyImethyl ester were added to a mixture 10 of 5.13 ml trifluoroacetic acid and 1.21 ml thioanisole. After stirring overnight at room temperature, the solution was evaporated in vacuo and the residue was stirred with dry dichloro-methane. The precipitate was collected by 15 suction, washed with dichloromethane and dried in vacuo to yield 1.78 g (88%) of the title compound. h) [3s(2) ] -2- [ [ [1- (2-Amino~4-thiazolyl)-2- [ [ 1 •=• [ 11 [2-[[2-[(l,4~dihydro~5-hydroxy-4-oxo-2- 2 0 pyridinyl)carbonyl]hydrazino]carbonyl]hydrazine]- sulfonyl]amino]carbonyl]-2-oxo-3-azetidiny1]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, diphenvlmethvl ester Into a -30°C solution of 1.10 g 25 (2.5 mmol) of (Z)-2-amino-a-[(2-diphenylmethoxy)-1,l-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid in 22 ml of dry dimethylformamide was added 1.05 ml (7.5 mmol) of triethylamine followed by 0.53 ml (2.5 mmol) of diphenyl chlorophosphate. 30 After stirring at -30°C for 1 hour, 1.05 ml (7.5 mmol) of triethylamine was dropped in, followed by the addition of 1.62 g (2.5 mmol) of (3S)-3~ amino-N-[[2™[[2-[(1, 4-dihydro-5-hydroxy~4-oxo-2-pvridinyl]carbonyl)hydrazino]carbonyl]hydrazino]-35 sulfonyl]-2-oxo-l-azetidinecarboxamide, trifluoroacetate (1:2) salt. The mixture was stirred for 2 -80™ hours at -10°C and for an additional hour at 0°C. The solvent was removed in vacuo and the residue was taken up in few aT of ethyl acetate and ice ' water. The pH of the mixture was adjusted to 5 pH = 2 by the addition of dilute hydrochloric acid. The insoluble material was collected by suction and stirred with few ml ethyl acetate until it became crystalline to yield after drying in vacuo 1.72 g (82%) of the title compound. 10 I) [3S(Z)]-2~[[[1~ (2-Amino~4-thiazolyl )~2~ [ [1-[ I [ [2-[[2~[ (1,4~dihydro-5~hydroxy-4-oxo-2~ pyridinyl) carbonyl ] hydrazino ] carbonyl ] hydrazine ] -sulf onyl ] amino] carbonyl ] -2~oxo-3-azetidinyl ] amino ] -15 2-oxoethylidene]amino]oxy]-2-methylpropanoic acid; disodium salt To a suspension of 1,68 g (2.0 mmol) of crude [3S(2)]-2-[ [ [ 1 - (2 -amino-4-thiasoly 1)-2- [ [1- [ [ [ [2- [ [2- [ (l, 4-dihy£ro-5-hydroxy-4-oxo~2-2 0 pyri dinyl) carbonyl ] hydrazino ] carbonyl ] hydrazine ] - sulf onyl ] amino ] carbonyl ] - 2-oxo~3-a2etidinyl] amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, diphenyImethyl ester in 3 ail of dry dicfcloromethane was added 2.0 ml of anisole followed by 20 ml of 25 trifluoroacetic acid at -ID". After stirring at 0°C for 10 minutes, the solvent was removed in vacuo at 0c-5°C. The residue was taken up in ice water and ether and the pH was adjusted to 5.0 by the addition of dilute sodium hydroxide (1%). The 30 organic phase and insoluble material (0.38 g) were separated and the aqueous phase was freeze dried (2.65 g). The residue from lyophilization was purified on XAD-2 resin* (eluting with water) to yield upon, lyophilization 0.25 g (17%) of the title 35 compound as a colorless powder (melting point >213°C, dec.).

*XAD-2 resins Macroreticular styrene-divinylbenzene -81- Example 6 [3S~ [ 3a (2), 40 ] ] - 2- [ [ [1-(2-amino-4-thiazolyl)-2~ [ [1- [ [ [ [2- [ (1,4~dihydro»5-hydroxy-4-oxo~2~pyridinyl )-carbonyl ] hydrazino ] sul f onyl ] amino ] carbonyl ] -4-methyl-5 2~oxo-3~a2etidinyl ] amino ]-2-oxoethylidene] amino ]oxy] -2-methylpropionic acid, disodium salt A) (3S-trans )- [l-[ [ [ [2-[[1,4-Dihydro-4-oxo-5-hydroxy-2-pyridinyl] carbonyl] hydrazino] -10 sulfonyl] amino] carbonyl ]-4~methyl~2-oxo-3- azetidinvl 1 carbamic acid, phenylmethvl ester To a suspension of 2.34 g of (3S-trans)-(4-methyl-2-oxo-3-azetidinyl )carbamic acid, phenylmethyl ester in 50 ml of dry ethyl acetate 15 was added 1.41 g of chlorosulfonyl isocyanate.

After stirring for 1 hour at room temperature, a clear solution was formed (Solution A).

To a suspension of 1.70 g of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid, hydrazide 20 in 50 ml of dry ethyl acetate was added 6 g of N-methyl-N- (tr ime thy 1 silyl) trifluoroacetamide.

After stirring at 50°C for 1 hour, a clear solution formed (Solution B).

After cooling to ~10°C, Solution B was added 25 to Solution A, and the mixture was stirred overnight at room temperature. Upon cooling to -15°, 3 g of triethylamine was added, followed by 150 ml of ice water. After stirring for 1 hour at 0°, the organic phase was washed wirh 50 ml of 30 water. The combined water phases were adjusted to pU 2 with IN HCl and extracted three times with 100 ml of ethyl acetate. The combined organic phases were dried and the solvent was evaporated to yield 3.64 g of the title compound. 35 -82- B) (3S-trans)-3-Amino-N-[[2-[(1,4-dihydro~5~ hvdroxy~4~oxo-2-pyridinyl)carbonyl ]hydrazino] -sulfonyl]•~4-methyl~2-oxo-l-a2etidinecarboxamide, trifluoroacetate (1:2) salt To 3.5 g of (3S-trans)-[l-[[[[2-[[1,4-dihydro-4-oxo-5-hydroxy-2-pyridinyl ] carbonyl] -hydrazino ] s.ul fonyl ] amino ] carbonyl ] -4-methyl-2-oso-3-asetidinyl]carbamic acid, phenylmethyl ester in 20 ml of thioaaisole was added 50 ml of tri-fluoroacetic acid at room temperature, and the reaction was then stirred for 13 hours. After addition of 100 al of ether, 3.2 g of a crude precipitate was obtained. This precipitate was then stirred for 1 hour in 50 ml of isopropanol/ methylene chloride (1:1) to yield 2.21 g of the title compound.

C) [3S-[3a(Z),40]]-2~[[[1-(2-amino-4~thiazolyl)-2-[[!-[[[ [2-[(1,4-dihydro-5~hydroxy-4~oxo-2- pyr idinvl) carbonyl ] hydrazine ] sul fonyl ] amino ] -carbonyl]-4-methyl-2-oxo~3-azetidinyl]amino]-2-oxoethylidene] amino] oxy] ~2~methylpropionic acid, diphenvlmethvl ester To a solution of 1.8 g of (Z)-2-amino-a-[ [2-diphenylmethoxy)-l, l-dimethyl-2-oxoethoxy]-imino]~4~thiazoleacetic acid and 1.2 g of triethylamine in 30 ml of dimethylforxnamide at -30° were added 2.1 g of diphenyl chlorophosphate. After stirrng at -30° for 45 minutes, 1.95 g of (3S-trans )-3»amino-N~[[2-[(1,4-dihydro~5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]sulfonyl]-4-methyl-2-oxo-l-azetidinecarboxamide, trifluoroacetate (1:2) salt in 10 ml of dimethyl formamide tvas added, followed by 0.8 g of triethylamine. After stirring at ~10°C for 2 hours and at 0°C for 1 hour, the dimethylformamide was removed in -83- vacuo, the residue was stirred with 250 ml of ethyl acetate and 400 ml of ice water. The water phase was adjusted to pH 1.5 with 2N HCl and was extracted twice with 200 ml portions of ethyl 5 acetate. The organic phase was dried over sodium sulfate and evaporated to yield 1.3 g of the crude title compound.

D) [3S-[3a(Z),4p]]-2-[[[l-(2-amino-4-thiazolyl)-2-• 10 [[1-[[[[2-[(1,4~dihydro~5-hydroxy-4-oxo-2-pyridinyl)-carbonyl ] hydrazino ] sul fonyl ] amino ] carbonyl ] -4-methyl ~ 2-oxo-3-azetidinyl ] amino] -2-oxoethylidene ] amino ] oxy ] - 2-methylpropionic acid, disodium salt To a solution of 1.2 g of [3S~ [3cr (Z) ,40 ] ]-2-15 [[[l-(2~amino-4-thiazolyl)-2-[[1-[[[[2 - [ (l,4~dihycro~ 5-hydroxy-4-oxo-2-pyridinyl)carbonyl ]hydrazino] sulfonyl ] amino ] carbonyl ] -4~methyl-2-oxo-3-azetidinyl ] -amino]-2-oxoethylidene] amino] oxy] -2-methylpropionic acid, diphenylmethyl ester in a mixture of 10 ml 20 methylene chloride and 15 ml of anisole was added 30 ml of trifluoroacetic acid at ~5°C. After stirring for 30 minutes, 100 ml of ether was added to give 0.8 g of precipitate. This precipitate was suspended in 20 ml of water and the pH was 25 adjusted to 6.5 with sodium bicarbonate. The clear solution was then chromatographed on 3CAD-2 with water as the eluent to give 0.28 g of pure title compound. -84-Example 7 [3S(Z)]-l-[I[l-(2-Amin0-4-thia20lyl)-2- [ [!-[[[[3-[ [ (l,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl )earbonyl]--amino] -2-oxo~2~ijmidazoli dinyl] sulf onyl ] amino] carbonyl ]-5 2-oxo-3-azeti dinyl ] amino] -2-oxoethylidene] amino] oxy]-cyclopentanecarboxvlic acid, disodium salt A) [3S(Z)]-l-[[[1-(2-Aaino-4-thiazolyl )-2-[[l-[ [ [ [3- [ [ (l,4-dihydro~5~hydroxy~4-oxo-2-pyridinyl)-10 carbonyl ] amino ]-2~oxe>-l-imida2olidinyl ] sulfonyl ]- aaino ] carbonyl ] - 2 - oxo- 3 - as eti dinyl ] amino ] -2 - ox o-ethyli dene ] amino ] oxy] cycl open tanecarboxylic acid, dinhenvlmethvl ester To a suspension of 3.9 g (8.3 mmol) of (2)-2-15 amino-e -[[[1~(dipheny Ime thoxy) carbonyl ] cycl open tvl ] -oxy]imino]~4-thiazoleacetic acid in 100 ml of dry acetonitrile were added 3.5 ml (25 mmol) ox ■triethylamine to form a clear solution- After cooling to -30°C, 1.8 ml (8.3 mmol) of diphenyl 20 chlorophosphate were added, and the mixture was stirred at.~30°C for 1 hour (Solution A).

At the same time, 4.5 g (8.3 mmol) of (3S )-3-amino-N- [ [3- [ [ (1,4-dihydro-5~hydroxy~4-oxo-2-pyri dinyl) carbonyl ] amino ] - 2 - oxo-1 - imi das oli dinyl ] -25 sulfonyl]-2-oxo-l-azetidineearboxamide, trifluoroacetate (1:2) salt were suspended in 100 ml of dry ethyl acetate. Then, 7.2 ml of bis(trimethylsilyl)-acetamide were added at room temperature to give a clear solution after 5 minutes. After stirring 30 for 1 hour, the solution was cooled to 0° (Solution £).

Solution B was added dropwise with stirring to Solution A at -30° over 10 minutes. The mixture was' stirred for 1 hour at -10° C and for 35 1.5 hour at 0e. The volatiles were evaporated, -85- and the residue was triturated with water. The residue solidified, and the solids were collected and resuspanded in water at approximately pH 2. After stirring for 30 minutes, the solid was 5 collected and dried to give 12.0 g of the crude title compound. , 3). [3S(Z)]-l-[ T [l-(2-Amino~4~tiuazolyl)-2-[ [1-[ 11 [3- [ [ (l/4~dihydro-5~hydroxy~4~oxo-2-pyridinyl )- 10 carbonyl 3 amino] ~2-oxo-l-imida2olidinyl 3 sulfonyl 3 -amino 3 carbonyl 3 -2-oxo-3-a2eti dinyl 3 amino 3 -2-oxo-etbylidene3amino3oxy]eyclopantaneearboxylic acid, disodium salt Crude [3S (2) ]-l- [ [ [1- (2-amin.o~4-thia2olyl )- IS 2-[ [1-f [ f [3«[ [(l,4-dihydro-5-hydroxy-4-oxo-2- pyri dinyl) carbonyl] amino-3~2~oxo~l-imi dazolidinyl}-sulfonyl3 s^iino3 carbonyl]-2-oxo-3-azetidinyl3 axnino} - • 2-oxoethylidene] amino] oxy] eye 1 opentanec arb oxy lie acid, diphenylaethyl ester (12 g) was suspended. 20 in 20 al of anisole, and, upon cooling to -100C, 100 ml of trifluoroacetic acid was added. The -86- mixture was stirred at -10°C for 1 hour, and 300 ml of ether was added at -10° to yield a precipitate. After stirring for 1 hour c the precipitate was filtered off to give 5.7 g of 5 material. This material was dissolved in a mixture of 30 ml -of water and 60 ml ox acetone and the pH of the solution was adjusted to 5.S by the addition of 0.1N NaOH at 0° with stirring. The acetone was evaporated in vacuo, and the aqueous 10 solution was freeze-dried to yield 5.7 g of a solid residue. This residue was chroioatographed on HP-20 (eluting with water) to yield 1.69 g (27%) ox pure title compound. 15 (DMSO-d6 + CF3COOH): 6 = 1.67 (s, 4H); 2.07 (2, 43); 3.65 (t, 2H); 3.7S (dd, 1H); 3.97 (dd, 1H); 4.07 (t, 2H); 5.07 (dd, 1H); 7.00 (s, 1H); 7.67 (s, IE); 8.07 (s, IE); ppm. -87- Example 8 [3S(2)]~2~[[[l-(2-Amino-4-thiazolyl)~2~[[l-[[[[3-[ (1,4-dihydro-5~hydroxy~4-oxo-2-pyridinyl)methyl ] ~ 2-oxo-l.-imidazolidinyl ] sulfonyl ] amino ] carbonyl ] -2-oxo-3-azetidinyl ] amino] -2-oxoethylidene] amino ] -oxy 1-2-methylpropanoic acid, disodium salt A) 2-(Az i dome thy 1 )-5-(phenyImethoxy )-l-(phenyl-methyl) -4 (1H) -pyridinone To a suspension of 2.0 g (6 mmol) of 2- (chloromethyl )-5-(phenylmethoxy)-l-(phenyl~ methyl)-4(1H)-pyridinone in 20 ml of acetonitrile was added 3.9 g (.60 mmol) of sodium azide and 0.1 g of 18-crown-6, and the mixture was heated to reflux for four hours. The salts were filtered off by suction, and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-methanol 8:2) yielding 1.86 g of the title compound, melting point 120°C.

B) 2- (Aminomethyl) -5 - (pheny Ime thoxy) -1- (phenyl-methyl)-4(1H)-pyridinone 2 - (Az i dome thy 1) - 5 - (pheny Ime thoxy) -1 - (phenyl» methyl)-4(1H)-pyridinone (1.0 g, 2.89 mmol) was dissolved in 50 ml of methanol and 0.10 g of platinic oxide was added. Hydrogen was bubbled through the mixture for 30 minutes and the catalyst filtered off by suction over Hyflo*"- The filtrate was evaporated in vacuo and the oily residue triturated with ether to afford crystalline title compound (0.89 g), melting point 207°C.

* Hyflo is a Trademark -86- C) 2-[[[[(2-Chloroethyl) amino] carbonyl] amino ]-tnethvl ]- 5- (pheny Ime thoxy )-1 - (phenylmethyl )-4(lH)- •p'vri dinone _ To a suspension of 48.0 g (0.15 mol) of 2~(aiainomethyl)-5-(phenyImethoxy)-1-(phenylme thy 1 )-4 (13)-pyridinone in 1.5 1 of ethyl acetate was added 12.S ml (0.15 mol) of 2~chloroethyliso~ cyanate. The mixture was stirred overnight at room temperature, the product filtered off by suction, washed with ethyl acetate, and dried in vacuo, yielding 59.& g of the title compound, melting point 130°c.

D) 2~r (2-Oxo-l-imidasolidinyl )methyl]-5~ (phenylme thoxv )-!-(nhenvlmethvl) -4 (13) -pvri dinone A solution of 7.29 g (0.13 mol) ox potassium hydroxide in 500 ml of ethanol was added dropwise to a mixture of 50.8 g (0.13 mol) ox 2-['{[ I (2-chlorO' ethyl) amino ] carbonyl ] amino ] methyl ] -5- (pheny Ime thoxy )• (pheny line thy 1) -4 (IE) -pyri dinone and 1.3 1 of ethanol. The reaction mixture was heated to reflux for three hours and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (7:3) as eluent, yielding 23.1 g of product, which was further purified by reerystallization from acetonitrile, yielding 17.0 g of the title compound, melting point 2 90°C, -8 9- S) 5~Bydroxy~2-[(2-oxo-l-imida2olidinylJmethyl]- 4(1H)-Dvradinone, p-toluenesulfonate salt To a solution of 2-[(2~oxo~l-imidazolidinyl)« methyl ] ~5~ (pheny Imethoxy) -1- {phenyImethy1) -4 (IH) -5 pyri dinone (4.98 g; 12.8 mmol) in dimethylformamide (90 ml) was added p-toluenesulfonic acid, mono-hydrate (4.B6 g; 25.6 mmol) and palladium on charcoal (1.0 g), and hydrogen was bubbled through the mixture for 30 minutes. The catalyst was 10 filtered off by suction and the filtrate evaporated in vacuo. The residue was triturated with dichloro-me thane and ether, and the product filtered off by suction, yielding 4.12 g of the title compound, melting point 195°C. 2,5 F) 5-3ydroxy-2- [ (2~oxo~i~imidazolidinyl )methyl]-4 (IH)-pyridinone 5~Hydroxy-2-1 (2-oxo-1-imidazoli dinyl) me thyl]-4(IH)-pyridinone, p-toluenesulfonate salt (4.0 g; 20 10.5 saaol) was dissolved in wster (50 ml), and the pH was adjusted to 6.5 by the addition of 2N sodium hydroxide. The precipitate was filtered off by suction, washed with water, and dried in vacuo, yielding 1.5 g of the title compound, melting point 25 2B0eC, dec.

Si -90- G) (S)-[!-[[ [ [3-[(l,4-Dihydro~5-hydroxy-4-oxo-2~ pyridinyl )me thyl] -2-oxo-l-ijni dasolidinyl] sulf onyl] -amino ] carbonyl ] -2 - ox o~ 3 - az eti dinyl ] carb ami c acid, ohenvlmethyl ester 5 1.10 g (5 mmol) of (S )-3-[ [ (phenvlmethoxy)- c&rhonyl]aminG]-2«-a2etidinone was suspended in 20 ml ox dry ethyl acetate, and 0.44 ml (5 mmol) of chlorosulfonyl isocyanate added. The mixture was stirred at room temperature for one hour (solution a) 10 To a suspension of 1.04 g (5 mmol) of 5-hydroxy-2-1 (2-oxo-l-imida.zolidinyl)methyl ]-4(13)-pyridinone in 10 ml of dry ethyl acetate was added 3.70 ml (20 mmol) of N-snethyl-N-(trimethylsilyl)-trifluoroacetamiae, and the mixture was heated to 15 60®C. The resulting clear solution was evaporated in vacuo at 50°C and. the residue dissolved in-10 ml of dry ethyl acetate- (solution b)- Solution (b) was added T.o solution (a) and. the reaction mixture- stirred overnight at room-20 temperature. The solvent was removed in vacuo and. the residue triturated with ether, yielding 2.91 g of the title' compound, melting point 180eC, dec.

H) (S)-3~Ami»o-N~I [3-[ (l,4-dihydro-5-hydroxy-4-25 oxo-2-pyri dinyl )methyl]-2-oxo-l-imida2olidinyl]- sulfonyl] -2-oxo-l-azeti dine earbox amide, trifluoroacetate salt (S)-[!-[ [ [ [3-[ (1,4-Dihydro-5-hydroxy-4-oxo~2-pyri dinyl)methyl ]-2-oxo-1-imi daz o1i diny1]sulf onyl ] - 30 amino]carbonyl]"2-oxo-3-£zetidinyl]carbamic acid, phenyImethy1 ester (0.50 g, 0.93 mmol) was added to a mixture of 0.5 ml of thioanisole and 2 ml of trifluoroacetic acid . The solution was stirred overnight at room temperature and evaporated in 35 vacuo. The'residue was triturated with ether, -91- filtered off by suction, and dried in vacuo, yielding 0.49 g of the title compound, melting point 155°C. 5 2) [3S(Z)]-2-[[[l-(2-Amino-4-thiazolyl)-2~I[1-[ [I [3"Id#4-dihydro-5-hydroxy-4-oxo-2-pyridirjyl)~ methyl ] -2-Q3to-l-imifia2olidinyl ] sulfonyl ] amino ] -carbonyl]-2-oxo-3-&2etidinyl]amino]-2-oxoethyli-dene] amino]oxy]-2-methylpropanoic acid, diphenyl- 10 methvl ester To a suspension of 0.41 g (0.93 mmol) of (2 )-2-amino~e- [ [2- (diphenylmethoxy )~1,1-dimethy1-2-oxoethoxy]imino]-4-thia2oleacetic acid in 20 ml of dry aeetonitrile was added 0.39 ml (2.8 mmol) of 15 triethylamine. The mixture was cooled to -30°C, and 0.19 ml (0.93 nunol) of diphenylchlorophosphate were added dropwise. The reaction mixture was * stirred for one hour at -30eC (solution a).

(S)-3-Amino-N- [ [ 3—[ (1,4-dihydro-5-hydroxy-4-20 oxo-2-pyri dinyl) me thyl ] -2~oxo-l-imi dazolidinyl ] -sulfonyl ]-2-oxo-l-azeTidineearboxamide, trifluoroacetate salt (0.48 g, 0.93 mmol) was suspended in 20 ml of dry aeetonitrile, and 0.78 ml (3.2 mmol) of bis-trimethylsilylacetamiae added. The suspension 25 was stirred for 30 minutes at room temperature and then added to solution (a).

The reaction mixture was stirred for one hour at -10 °C and then for 1.5 hours at 0°C. The resulting clear solution was evaporated in vacuo, 30 and 50 ml of water was added to the oily residue. The mixture was adjusted to pS 2 by the addition ~92~ of 2N hydrochloric acid, and [3S(2)]-2-[ [[l-(2-amino-4-t±iia2olyl )-2- [[!-[[[ [3- [ (1,4-dihydro-5~ . hydroxy-4-oxo-2-pyridinyl)methyl3-2-oxo-l-. imidazolidinyl]sulfonyl3amino3carbonyl3~2-oxq-3-5 asetidinyl]amino3-2-oxoethylidene 3 amino3 -oxy]-2-methylpropanoic acid, disodium salt crystallised from the solution.. The product was filtered off by suction, washed with water, and dried in vacuo, yielding 0.7 g of the title compound. 10 J) [3S(2)]-2-[ [ [l-(2-Amino-4-thiasolyl)-2-[ [l-( [[[3-[(1,4-dihydro-5~hydroxv~4~oxo-2-pyridinyl)methyl3 - .2-oxo-1-imidazoli dinyl 3 sulfonyl 3 amino 3 carbonyl 3 -2-oxo-3-asetidinyl3 amino]-2-oxo-ethylidene]amino]- 15 oxvl~2-methvlt>ropanoic acid, disodium salt [3S(2) ]-2-[[[1-(2-Amino—4-thiazolyl)-2-[[1-[ I [ [3-[(1,4-dihydro-5-hyfiroxy-4-oxo-2-pyridinyl)~ methyl 3-2-oxo-1-imidazolidinyl]sulfonyl3 amino3-carbonyl]-2~oxo-3-azetidinyl]amino]-2-oxoethyli-20 dene]amino]oxy]-2-methylpropanoic acid, diphenyl-methyl ester (0.7 g, 0.85 nanol) was suspended in 1.4 ml of anisole and cooled to -10°C. Trifluoro-aeetic acid was added, and the solution was stirred for one hour at -10DC. Ether (100 ml) was 25 added, and the precipitate was filtered off by suction, washed with ether and dried in vacuo.

The trifluoroacetic acid salt was dissolved in a mixture of methanol and water and the pH adjusted to 6.5 by the addition of 2N sodium 30 hydroxide. Methanol was removed in vacuo and the aqueous solution freeze-dried, yielding 0.5 g of the title compound. This was purified by M?L,C: melting point 250°c, dec. ■c.l- £xample 9 [3S(Z)]-2-[[[1-(2-Amino~4-thiazolyl)-2-[[i-[[[[4-[ (1,4-dihydro-5-hydroxy-4-x>xo-2-pyridinyl )methyl]-2,3-di oxo-2 -piparazinyl ] sulfonyl ] amino] carbonyl ] - 5 2-oxo-3~azeti dinyl ] amino)-2-oxoethylidene) amino) -oxvl-2-methvlpropanoic acid, disodium salt .

' A) 2- (Chloromethyl)-5- (pheny ime thoxy )-l~(phenyl- methyl)-4(IH)-p vr idinone, hvdrochlori de 10 A suspension of 3.21 g (10 mmol) of 2-(hydroxymethyl )-5~(phenylmethoxy )-l-(phenyl-methyl)-4(IH)-pyridinone in 20 ml of chloroform was cooled to 0°C, and 4.65 ml (64 mmol) of thionyl-chloride was added dropwise. The mixture was 15 stirred for ten minutes at 0°c and then heated to reflux for one hour-. The solvent was evaporated- -in vacuo and the residue washed with petroleum ether and dried in vacuo, yielding 3/66 g of the-title compound, melting point S5°C, dec. 50 B) 2-(Chloromethyl )-5» (pheny Ime thoxy) -1 - (phenyl- methvl)-4(IH)-pvridinone 2-(Chioromethyl)-5- (phenyimethoxy)~1~(phenyl-methyl)-4(13)-pyridinone, hydrochloride (3.5 g, 25 9.3 snnol) was dissolved in a mixture of water/ethyl acetate and the layers separated. The organic phase was washed twice with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with petroleum ether, 3 0 filtered off by suction and dried in vacuo yielding 2.27 g of the title compound, melting point 115-120°C, dec. -94- C) N- (Triphenvlroethvl )piperazine-2, 3-dione A mixture of 2,3-piperazinedione (11.4 g, 100 mmol), bistrimethylsilylacetamide (55.7 g, 270 mmol) and 150 ml of acetonitrile was heated under reflux for one hour. Within 30 minutes, triphenylmethylchloride (22.2 g, 80 mmol) was added dropwise and the mixture was again refluxed for two hours. After stirring overnight at room temperature, 21.5 ml of water was added to the clear solution. The resulting precipitate (3.13 g) was filtered off and the filtrate concentrated in vacuo. The residue was triturated with water and dried to yield 25.5 g of crude title compound which was recrvstallized from ethanol. Yield of pure product: 12.19 g, melting point 230-235°C.

D) l-[ [l,4-Dihydro-4-oxo-5~ (pheny lmethoxy)-l- (phenylroethyl)-2-pyridinvl]methyl]-4—(triphenyl-tnethvl) '-2,3-pjperazinedione To a solution of N- (triphenylmethyl )pipera-sine-2, 3=-dione (4.19 g, 11.77 mmol) in 95 ml of dry dimethylformamide was added 0.35 g.(11.77 mmol) of sodium hydride (80% oil). After the hydrogen evolution had ceased, a solution of 2-(chloromethyl)-5- (pheny Ime thoxy )»1- (phenylme thyl) -4 (IH) -pvridinone (4.0 g, 11.77 nunol) in 25 ml of dry dimethylform-amide was added to the thick suspension which then turned into a clear solution. After one hour of stirring at room temperature, precipitation started. After two hours, the crystals were filtered off, washed and dried in vacuo, yielding 5.13 g of the title compound, melting point 165~168°C. -95- E) 1-[[1, 4-Dihvdro-4-oxo-5-(phenylmethoxy)-l- (phenyImethyl)-2-pyridinyl]methyl]~2,3-piperazine- dione To a solution of 1-[[1,4-dihydro-4-oxo-5-5 (phenylme thoxy) -1- (pheny Ime thyl)-2-pyri dinyl ] •=■ methyl ] -4- (tripheny Ime thyl )-2,3-piperazinedione (8.77 g, 13.23 mmol) in 65 ml of dichlororoethane was added dropwise at room temperature 65 ml of formic acid. After stirring for three days, the 10 volatiles were distilled off in vacuo and the residue triturated twice with ether to give 5.24 g of l-[[1,4-dihydro~4-oxo-5~(phenylmethoxy)-!-(pheny Ime thyl)-2-pyri dinyl ] methyl ]-2,3-piperazine-dione, melting point 260-265°C. 15 F) (S)-[l-[[[[4-[[l,4*-Dihydro-4-oxo-5~ (pheny 1-methoxy )-l- (phenylmethyl)-2-pyridinyl) methyl ] - 2,3-dioxo-l-piperazinyl ] sulfonyl ] amino) carbonyl ] -2-oxo-3-azetidinyncarbamic acid, phenylmethyl ester 20 To a solution of (S)-3-[[(phenylmethoxy)~ carbonyl]a^nino)-2-azstidinone (0.44 g, 2.0 mmol) in 25 ml of dry ethyl acetate was added 0.28 g (2.0 mmol) of chlorosulfonyl isocyanate and the solution was stirred for 30 minutes at room 25 temperature. To this were added 12 ml of dichloro-methane, 0.51 g (6 mmol) of triethylamine and a prestirred (three hours) mixture of 1-[[1,4-dihydro-4-oxo-5~ (pheny Ime thoxy) -1- (phenylmethyl) -2-pyridinyl ] -methyl]-2 ,3-piperazinedione (0.83 g, 2.0 mmol) and 30 N-methyl-N- (trimethylsilyl) trifluoro acetamide (1.59 g, 8.0 nunol) in 25 ml of dry ethyl acetate.

After stirring for three days at room temperature, ice water was added and the pH was adjusted to one with hydrochloric acid. The insoluble residue was — 96~ filtered off and dried in vacuo yielding 1.15 g of the title compound of 72% purity.

G) (S)-3-Amino-N-[[4-[(l,4-dihydro-5-hydroxy-4~ 5 oxo-2-pyridinyl )methyl]-2, S-dioxo-l-piperazinyl]- sulfonyl]-2~oxo-l~.azetidinecarboxamide, 4~methylbengenesulfonic acid salt To a solution of (S)~[1~[[[[4-[[1,4-dihydro-4-oxo-S- (pheny lmethoxy )-l-(phenylmethyl)-2-pyri dinyl ] 10 methyl ] -2,3-dioxo-l-piperazinyl ] sulfonyl 3 amino] - carbonyl]-2-oxo~3~azetidinyl3carbamic acid, phenylmethyl ester (0.98 g, 1.32 mmol) in 20 ml of dimethylformamide was added 0.5 g (2.64 mmol) of D-toluenesulfonic acid and O.S g of palladium on 15 charcoal (10%). For one hour, hydrogen was bubbled through the mixture. The catalyst was filtered off, the solvent distilled off in vacuo and the residue triturated with dichloromethane to yield, after drying, Q.B2 g of the title compound, melting 20 point 160-185°C, dec.

H) [3S(Z)3~2-[[ [1- (2-Aiaino-4~thiazolyl )-2~ [ [1- [ [ [ [4-[(1,4~dihydro-5-hydroxy~4-oxo-2-pyridinyl)methyl 3 ~ - 2,3-dioxo-l-piperazinyl3sulfonyl] amino3 carbonyl3-25 2-oxo-3-a2etidinyl]amino]-2-oxoethylidene] amino]-oxvT-2-methvlt>rot?anoic acid, diphenvlmethvl ester To a solution of (Z)-2-amino-c-[[2-(diphenvl-methoxy)-l,l-dimethyl-2~oxoethoxy]imino]-4-thiazole-acetic acid (0.57 g, 1.3 mmol) in 30 nil of dimethyl-30 formamide was added at ~30°C triethylamina (0.39 g, 3.9-mmol) and tripheny1chlorophosphate (0.31 g, 1.3 mmol). After stirring for one hour, triethylamine (0.39 g, 3.9 mmol) and (S)-3-amino-N-[[4-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]~ 35 2,3-dioxo-l-piperazinyl]sulfonyl3-2-oxo-l-azetidine- -97- carboxamide, 4-methylber.zenesulfonic acid salt (0.98 g, 1.3 mmol) were added. The mixture was stirred for two hours at -10°C and 1.5 hours at DcC. Water and ethyl acetate were added, and the 5 pH was brought to one with 3N hydrochloric acid.

The precipitate was filtered off, washed with ethyl acetate and dried in vacuo, yielding 0.85 g of the title compound, melting point 130-190°C, dec. 10 I) [3S(Z) ]-2-[[[1~(2-Amino-4~thiazolyl )»2-[[!-[[[[4-[ (1,4~dihydro-5-hydroxy~4~oxo~2-pyri dinyl) me thyl ] -2,3-di oxo-1-piperazinyl 3 sulfonyl ] amino 3 carbonyl 3 -2-oxo-3-azetidinyl 3 amino ] -2 -oxoethyli dene 3 amino 3 - oxvl-2-methvlpropanoic acid, disodium salt 15 To a suspension of [3S(2)]-2-[[[l-(2-amino-4- thiasolyl )~2~ [[!-[[[ [4- [ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl )methyl3-2,3-dioxo-l-piperazinyl3-sulfonyl ] amino 3 carbonyl 3-2-oxo-3-azeti dinyl ] amino 3-2-oxoethylidene]amino3oxy3-2-methylpropanoic acid, 2 0 diphenylmethyl ester (0.8 g, 0.94 mmol) in 1.4 ml of anisole was added at -10°c 7 ml of trifluoro-acetic acid. After stirring for one hour, 30 ml of ether was added and the resulting precipitate filtered off and dried in vacuo. This trifluoro-25 acetic acid salt was suspended in water and the pH adjusted to 6.5 with 2N sodium hydroxide. Freeze-drying of the solution gave 0.66 g of crude product which was chromatographed together with a second sample prepared in the same way (total: 1.55 g) on 30 macroreticular sytrene-divinylbenzene copolymer under MPLC conditions, yielding 0.34 g of the title -98- compound. A second column chromatography on macroreticular styrene-divinylbenzene copolymer furnished 0.18 g of the title compound, melting point 242~270°C. 5 Example 10 [3S(Z)]-2~[[[l-(2-Amino-4-thiazolyl)-2-[[1-[ [ [ [3- [[(l,4~dihydro-5-hydroxy-4-oxo-2-pvridinyl)methylene ]amino]-2-oxo-l-imidazolidinyl]sulfonyl]amino]~ 10 carbonyl]-2-oxo~3-azetidinyl]amino]-2-oxoethylidene] amino]oxy]-2-methylpropanoic acid, disodium salt A) 4,5-Bis(phenylmethoxy)-2-pyridinecarboxylic 15 acid, phenvlrnethyl ester 21.5 g (156 nunol) of potassium carbonate was added to a suspension of 29.4 g (120 mmol) of O-benzylcomenamic acid in 350 ml of dimethyl-form&mide and stirred for one hour at room 20 temperature. Benzylbromida (31 ml, 264 nunol) was added and the mixture was heated to 100°C under stirring for 25 hours. After cooling to room temperature, the dimethylformamide was distilled off in vacuo and the residue triturated with ethyl 25 acetate with short heating to 60°C. 40 g of inorganic salts were filtered off, the filtrate was concentrated to ca. 75 ml and chromatographed on silica gel with ethyl acetate:petroleum ether 50:10 as eluent, yielding 3 5.5 g of the title compound, 30 melting point 116.7°C. -99- B) 4, 5-Bis (phenvlmethoxv)-2-Pvridineniethanol To a suspension of 95 mg (25 mmol) of lithium aluminum hydride in 10 ml of ether and 10 ml of tetrahydrofuran was added 1.06 g (25 mmol) of 5 4,5-bis(phenylmethoxy)-2~pyridinecarboxylic acid, phenylmethyl ester in three portions at 0°C. After stirring for 20 minutes at 0°C, 0.2 ml of saturated sodium bicarbonate solution, 0.2 ml of 10% potassium hydroxide solution, and additional saturated sodium 10 bicarbonate solution were added until the inorganic precipitate flocked together. The clear organic phase was decanted and evaporated in vacuo to yield an oil which slowly crystallized. Yield: 0.6 g, melting point 9S.6°C. 15 C) 4,5-Bis(Phenylmethoxy)~2-pvridinecarboxaldehvde To a solution of 0.54 g (1.7 mmol) of 4,5-bis(phenyImethoxy)-2-pvridinemethanol in 15 ml of acetone was added 1.5 mg (17 mmol) of manganese 20 dioxide and the mixture was stirred overnight at room temperature. The mixture was then filtered over a silica gel column (70-250 mesh), and the aldehyde eluted with acetone. Evaporation of the eluent and trituration of the residue with petroleum 25 ether furnished 0.3 g of the title compound, melting point 104. 3°C. -100- D) 1,4-Dihydro-5-hydroxy-4-oxo-2~pyridinecarbox- aldehyde To a solution of 4,5-tais(phenyImethoxy)-2-pyridinecarboxaldehyde (1.9 g, 6.0 mmol) in 25 ml' 5 .of dry dimethvlformamide was added 0.2 g of palladium on charcoal catalyst and hydrogen was bubbled through the mixture for three hours. The catalyst was removed by filtration, the solvent distilled off in vacuo and the residue 10 triturated with ether to give 0.64 g of the title compound, melting point 174-177°C, dec.

E) [3S(Z)]-2-[[[l-(2-Amino-4-thiazolyl)-2-[ [1- [C C[3—[[(l,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)- 15 methylene ] amino] -2-oxo-l-imidazolidinyl ] sulfonyl]-suraino ] carbonyl ] -2-oxo-3-azetidinyl ] amino ]-2-oxoethylidene ]amino]oxy]-2-methylpropanoic acid, disodium salt To a solution of [3S(Z)]-2-[[[2-[[1-[[[(3-20 amino-2~oxo-l-imidazolidinyl) sulf onyl] amino]- carbonyl] -2-oxo-3-azeti dinyl ] amino] -1- (2-amino-4-thi azoly 1)-2-oxoethylidene ] ajcnino] oxy ] -2 -methylpropanoic acid, monosodium salt (0.64 g, 1.1 nunol) in 15 ml of dry dimethyl foraiamide 1,4-dihydro-25 5-hydroxy~4~oxo-2~pyridinecarboxaldehyde (0.18 g, 1.3 mmol) was added, and, after stirring for 4.5 hours, an additional 0.02 g (0.14 mmol) of 4 was added. After stirring overnight at room temperature, the solvent was evaporated in vacuo, the residue 30 taken up in 30 ml of water, filtered and the solution freese-dried. The crude material (0.82 g) was dissolved in 5 ml of water and chromatographed on macroreticular styrene-divinylbenzene copolymer resin with water as eluent, yielding 0.22 g of pure 35. product, melting point 248°C, dec. -101- Example 11 [3S(Z)]-2-[[[l-(2-Amino-4-thiazolyl)-2-[[1~[[[[4-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]• amino]~2,3-dioxo~l-piperazinyl]sulfonyl]amino]-5 carbonyl]-2-oxo~3-azetidinyl] amino] -2~oxoethyl i-dene] amino] oxy] -2-methylpropanoic acid, disodium salt A) 4. 5~Bis(phenylmethoxy )-2-pyridinecarboxvlic acid 10 To a solution of 11.8 g (28 mniol) of 4,5-his- (phenylme thoxy )-2~pyridinecarhoxylic acid, phenylmethyl ester in 115 ml of tetrahvdrofuran was added 16 ml of water and 35 ml of IN potassium hydroxide. After stirring overnight at room temperature, 15 115 ml of water was added and the pH was adjusted to 2.5 with IN hydrochloric acid. The acid was filtered off, washed with water and dried in vacuo, yielding 8.6 g of the title compound, melting point 203.6°C. 20 B) N- (2,3-Dioxo-l-piperazinyl)-4,5-bis(phenylme thoxy )-2~t>yridinecarboxamide To a suspension of 4,5~bis(phenylmethoxy)-2~pyridinecarboxylic acid (7.1 g, 21.17 mmol), 25 hydroxybenzotriazole (0.29 g, 2.12 mmol) and N-aminopiperazine-2,3-dione (2.73 g, 21.17 mmol) in 140 ml of dry dimethvlformamide was added, after 15 minutes of stirring, 4.80 g (23.3 mmol) of d~.:yclo-hexylcarbodiimide. After stirring for 21 hours at 30 room temperature, dicyclohexylurea was filtered off (4.0 g ) and the solvent was evaporated in vacuo.

The solid residue was triturated for 40 minutes with. 240 ml of tetrahvdrofuran. filtered, washed with tetrahyrofuran and dried in vacruo to yield 7.76 g of the title compound, melting point 231.1°C.

C) (S)- [!-.[[[ [4- [ [ [4,5-Bis (phenyImethoxy )-2~ pyridinyl ] carbonyl ] sjnino]~2,3-dioxo-l-piperazinyl J -sul f onyl ] amino ] c arb onyl ] - 2 ~ osc o- 3 » as e ti dinyl ] - c arb ami c acid, tahenvlmethvl ester To a suspension of (S )-3-[[(phenyImethoxy)~ carbonyl]amino]-2-azetidinone (2.02 g, 9.18 nunol) in 130 ml of ethyl acetate, chlorosulfonyl isocyanate (1.43 g, 10 mmol) was added, and, after stirring for one hour, triethylamine (2.79 g, 27.54 mmol) was added at Q°C„ To this mixture, a prestirrsd solution (1.5 hours) of N-(2,3-dioxo-l-pipera:zinyl)~ 4,5-his (pheny Imethoxy-) ~2-pyri&inscarhQxamide (4.10 g, 9.18 mmol) and N-aiethyl-N-(trixnethylsilyl)-trifluoroacetamide (5.4 g, 27.54 mmol) in 150 .ml of ethyl acetate was added. After stirring overnight at room temperature, 220 ml of ice water was added and the pB was adjusted to 2 (from 10.3) with 3N hydrochloric acid. When the separated organic phase was treated with brine, the title compound precipitated and was filtered, washed with water and dried in vacuo, yielding 5.35 g. When 2.5 g of this material was triturated for one hour with a mixture of 25 ml of water and 37.5 al of acetone at pB 5.3, 2.12 g of the title compound was obtained. -103- D) (S)-N-[4-[[[(3-Amino-2~oxo-l~azetidinyl)-carbonyl ] amino] sulfonyl ]~2,3-dioxo~l~piperazinyl ] ~ 1 t4~dihvdro-5-hydroxv-4-oxo-2-pyridinecarboxamide To a solution of (S)-[1-[[[[4-[[[4,5-bis-5 (phenyImethoxy)-2-pyri dinyl] carbonyl ] amino] -2,3-dioxo-l-piperazinyl ] sulfonyl ] amino] carbonyl ] ~2~ oxo-3~a:zetidinyl]carhamic acid, phenylmethyl ester (1.54 g, 2 mmol) in 30 ml of dimethylformamide was added 0.77 g of palladium on charcoal, and the 20 mixture was hydrogenolyzed for 45 minutes. The catalyst was removed by filtration over Hyflo and the resulting solution was used for the next step without isolation of the title compound. 15 e) [3S(2)]-2-[[[l-(2-Amino-4-thiasolyl)-2-[[l- [ 11 [4- [ [ (l,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl.)-carbonyl ] amino] -2,3-dioxo-l-piperazinyl ]sulf onyl ]-amino] carbonyl]-2-oxo-3-azeti dinyl] amino]-2-oxo-ethylidene] amino]oxy]-2-methylpropanoic acid, 20 diphenvlmethyl ester : " To a solution of (2)-2-amino-cr-[[2-(diphenyl-aethoxy )-l, l-dimethyl-2-oxoethoxy]imino]~4-thiazoleacetic acid (0.88 g, 2.0 mmol) in 20 ml of dimethyIfoimamide was added tr i e thy 1 amine 25 (0.60 g, 5.0 mmol) and, at -30°C and under nitrogen, triphenvlchlorophosphate (0.54 g, 2.0 mmol). After stirring for one hour at -30°C, triethylamine (0.20 g, 2 mmol) and the dimethyl-foraamide solution of (S)-N-[4-[[[(3-amino-2-oxo-l-3 0 azetidirvl) carbonyl ] amino] sulf onyl ] -2,3-dioxo-l- piperazinyl]-l,4-dihydro-5-hyeroxy-4«-oxo~2-pyridine- ► -104- carboxamide were added dropwise. The mixture was stirred for two hours at -1D°C and for 17 hours at 0°C, The solvent was distilled off in vacuo and ■ the residue partitioned between .40 ml of ethyl 5 acetate and 20 ml of ice water. When the pH was adjusted to 1.5 with dilute hydrochloric acid, an oil separated which was separated from the solvent and dried in vacuo, yielding 1.35 g of the title compound. 10 F) [3S(Z)]-2-[[[l-(2-Amino-4-thia2olyl)-2-[ [1- [ [ [ [4- [ [ (1 / 4-dihydro-5~hydroxy*-4-oxo-2-pyridinyl )-carbonyl ] amino] -2,3-dioxo-l-piperazinyl] sulfonyl] -amino] carbonyl ] - 2 - oxo- 3 - az e ti dinyl ] amino]~2-QSEo~ 15 ethylidene]amino]oxy]-2-methyIpropanoic acid, disodium salt __ To a mixture of 2.6 al of anisole and 13 ml of trifluoroacetic acid, [3S(Z)]-2-[[[l-(2~amiEto~ 4-thiazolyl )~2~ [ [1- [ [ [ [4- [ [ (1,4-dihydro-5-hydroxy-20 4~oxo-2~pyridinyl) carbonyl] amino]-2,3-dioxo-2-piperazinyl ] sulfonyl ] amino ] carbonyl ] -2-oxo-3-as eti dinyl ] amino ] -2-oxoethylidene ] amino] oxy] -2-methylpropanoic acid, diphenylmethyl ester (1.3 g, 1.48 amol) was added at <~10eC, and the mixture was 25 stirred for two hours at 0°C. The volatiles were distilled off in vacuo and the residue triturated with ether to give 1.05 g of trifluoroacetic acid salt after drying. This trifluoroacetic acid salt was suspended in 20 ml of water and the pH was 30 adjusted to 6.5 with IK sodium hydroxide. The frees® dried solution furnished 1.10 g of crude product which was chromatographed on macroreticular styrene-divinylbenzene copolymer under KPLC -105- conditions with water as eluent. Yield: 0.48 g.

This material was again chromatographed twice together with other samples, prepared in the same manner. The second column chromatography was run on macroreticular styrene-divinylbenzene copolymer the third on Organogen, each with water as eluent. Final yield 0.10 g, melting point > 300°C.

Example 12 [3S( 2) ]~3~ [ [ (2-Amino~4-thiazolyl) [ (2-fluoroethoxy )-imino]acetyl]amino]-N- [ [3-[ [ (1,4-dihydro-5-hydroxv-4~oxo~2-pyridinyl)carbonyl ] ammo]-2-oxo~l-imida2oli« dinyl ] sulfonyl ] -2-oxo-l-azetidinecarboxamide, ethvldiisooropvlainine salt To a solution of (Z)-2-amino~a~[(2-fluoroethoxy )imino]-4-thiasoleacetic acid (0.33 g, 1.4 mmol) in S ml of dry dimethylformamide was added N-hydroxybenzotriazole (0.19 g, 1.4 nunol) and N-ethyl-diisopropylamine (0.18 g, 1.4 mmol). At 0°C, dicyclohexylcarbodiimide (0.29 g, 1.4 mmol) was added and the mixture was stirred for one hour. A solution of (3S)-3~amino~N~[[3-[ [ (1,4-dihydro~5-hydroxy-4-oxo-2-pyridinyl)carbonyl J-amino ]-2-oxo~l~imidaEolidinyl] sulfonyl ]~2~oxo~l-azetidinecarboxamide, trifluoroacetate (1:2) salt (0.87 g, 1.6 mmol; see Example 1G) and N-ethyl-diisopropylamine (0.41 g, 3.2 mmol) in 3 ml of dry dimethylformamide was added and after stirring for 2 hours at 0°C, the mixture was stirred for an additional 16 hours at room temperature. The dicyclohexylurea was filtered off, ar.d the solvent distilled off in vacuo. The residual oil was triturated with water until completion of -106- crystallization. The solid (0.82 g) was collected by filtration, the filtrate brought to pH 6.1 and freeze dried. The solid was suspended in 40 ml of water and the pH brought to 6.0 with 0.25 N sodium hydroxide. Undissolved material was filtered off and the filtrate freeze dried. Two portions of freeze dried material were combined (ca. 0.6 g) and chromatographed on macroreticular styrene-divnylbenzene copolymer with water and water: acetonitrile 95:5 as eluent. After freeze drying, the appropriate fractions yielded 0.22 g of the title compound, melting point 163-165°C.

Example 13 [35(E)]-2-[[[l-(2~Amino-4-thiazolyl)-2-[ [1- [[[[2-(carboxymethyl)-2~[(1,4-dihydro-5~hydroxy-4~oxo~ 2-pyridinyl)carbonyl]hydrazino]sulfonyl] amino]-carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethyli- dene]amino]oxy]-2-methylpropanoic acid, trisodium salt A) N,O-Dibenzvl-comenamvl chloride, hydrochloride Into a suspension of 16.77 g (50.0 mmol) N,O-dibenzyl-comenamic acid in 360 ml of dry dichloromethane was added 11.45 g (55.0 mmol) of phosphorous pentachloride in portions at 0-5°C. Stirring was continued for 1 hour at room temperature, and the precipitate was collected by suction, washed with 20 ml of dry dichloromethane and dried in vacuo, yielding 15.02 g of the title compound, melting point 126-127°C, dec. -107- B) [2"[ (Pheny Imethoxy) carbonyl] hydrazino] ace tic acid, 1,l~diraethvlethvl ester Into a stirred solution of 6.65 g (0.040- mol) of N- [ (pheny Ime thoxy) carbonyl ] - hydrazine in 40 ml of dimethyl foriciamide was dropped a solution of B.58 g (0.04-4 mol) of t-butyl bromoacetate in 20 ml of dimethyl-formamide followed by a solution of 8.2 ml (0.048 mol) of N,N-diisopropylethylamine in 8 ml of dimethylformamide. After the mixture had been stirred at room temperature for one day, the solvent was distilled off in vacuo and the residue was taken up in ether and water. The organic layer was washed three times with water, dried (magnesium sulfate) and evaporated in vacuo to leave an oil (10.6 g), which was purified by column chromatography on silica gel eluting with ethyl acetate/toluene (1:1). The appropriate, fractions were evaporated in vacuo and the residue-was stirred with petroleum ether yielding 6.0 g of the title compound., melting point 61-62°C.

C) [l-[ [l,4-Dihydro~4-oxo-5-(phenyImethoxy)-2~ pyridinyl ] carbonyl ]-2- [ (phenylmethoxy)carbonyl ]- hvdrazinol acetic acid, 1,1-dimethvlethvl ester 15.6 ml (80.0 mmol') of N-Methyl-N-trimethyl-silyltrifluoroaeetaaide was added to a solution of 11.2 g (40.0 mmol) of [2~[(phenylmethoxy)carbonyl]-hydrazino]acetic acid, 1,1-dimethylethyl ester in 60 ail of dry acetonitrile. After stirring for 30 minutes at room temperature, the clear solution was -106- evaporated in vacuo and the residue was dissolved is 45 ml of dry di chl oromethane. This solution was dropped into a suspension of 15.61 g of N,0-dibcnzyl-coiaenamyl chloride, hydrochloride in 60 ml of dry di chl or ome'thane at room temperature. After stirring overnight, the reaction mixture was evaporated %in vacuo to leave a residue which was stirred with 10 ail of methanol, evaporated in vacuo again and then chromatographed on silica gel eluting with ethyl acetate and ethyl acetate/ methanol (10:1). After evaporation in vacuo, the appropriate fractions yielded a solid foam which became crystalline by stirring with ether. Yield: 12.7 g; melting point 177~178°C, dec.

D) [1-1(1,4~Dihydro-5-hyfiroxy-4-oxo~2-pyridinyl) - carbonyl] hydrazine] acetic acid, 1,1-dime thyl ethyl ester A suspension of 7.17 g (12.0 ssaol) of [1- [ [l,4-dihydro~4-oxo-5- (phenyImethoxy)-2-pyridinyl] carbonyl]-2- [ (phenyImethoxy)carbonyl]-hydrazino] acetic acid, 1,1-dime thyl ethyl ester in 400 al of methanol was hydrogenated in the presence of 1.6 g of palladium on charcoal (10%) for 40 minutes. The catalyst and the precipitated product were filtered off and washed well with 300 ml of dry dimethylformamide to dissolve the precipitated product. From the combined filtrates the solvents were removed in vacuo to leave a residue which crystallized by stirring with ether (1.68 g; melting point 221°C, dec.). Recrystallita-tion from methanol yielded the pure compound.

Yield: 1.26 g; melting point 225°C, sint. 229°C, i, -109- f E) (3S)-[l~[(l,4-Dihydro-5-hydroxy~4-oxo-2-pyridinyl)carbonyl]-2-[[[[2-oxo-3«[[(phenyl-methoxy)carbonyl]amino]-1-azetidinyl]carbonyl]-amino-] sul fonyl ] hydrazine ] acetic acid, 5 1,1-dimethvlethyl ester 9.0 ml (45.2 mmol) of N-methyl-N-trimethyl-silyltrifluoroacetamide was added to a suspension of 3.2 g (11.0 mmol) of [1-[(1,4-dihydro-5-hydroxy-4-oxo~2-pvridinyl)carbonyl]hydrazino]acetic acid, 10 1,1-dimethylethyl ester in 120 ml of dry ethyl acetate. At room temperature, stirring was continued for 1 hour to give a clear solution (solution A).

To a suspension of 2.42 g (11.0 mmol) (S)-3-15 [[(phenyImethoxy)carbonvl]amino]-2-azetidinone in 80 ml of dry ethyl acetate 0.99 ml (11.0 mmol) chlorosulfonyl isocyanate was added with stirring.

The mixture was stirred for 1 hour at room temperature and then cooled to 0°C. Solution A was dropped in 20 at 0°C and stirring was continued overnight at room temperature. After the addition of 4 ml of triethylamine, the mixture was evaporated in vacuo. The residue was dissolved in 10 ml of methanol-water (4:1). This solution was dropped into a mixture of 25 30 ml methanol/water, the pH of which was maintained at pH 2 to leave a residue (10.25 g) which became crystalline by stirring with few ml of water and methanol. The precipitate was purified by successive washing (stirring) with 30 isopropanol/water (4:1), methanol, methanol/ether (1:1) and ether. Yield after drying in vacuo: 2.39 g. -110- F) (S )-3~Amino-l- [ [ [ [2-(c&rboxymethyl )-2- [ (1,4-dihydro«5-hydroxy-4-oxo~2-pyridinyl) carbonyl ]-hydrazine]sulfonyl]amino]carbonylJ-2-azetidinone, ■ trifluoroacetate salt „ 5 At 0°C, 2.39 g (3.9 mmol) of (3S )-[l-[(1,4- dihy dr o- 5~hydroxy-4- oxo-2 -pyri dinyl) carbonyl ] -2-[ [ [ [2-oxo-3- [ [ (pheny Ime thoxy) carbonyl] amino ]-1-azeti dinyl] carbonyl ] amino] sulf onyl] hydrazino] acetic acid, 1, l-dimethylethyl ester was added to a 10 mixture of 7.0 ml of trifluoroacetic acid and 1.66 ml of thioanisole. After stirring overnight at room temperature, the solution was evaporated in vacuo. The residue was successively washed (stirred) with ethyl acetate, ethyl acetate/ 15 petroleum ether (1x1), petroleum ether and di chl oromethane- and then dried in vacuo. This • crude salt was used in the next step without any further purification. Yield: 2.15 g. 20 C) [3S(2)]-2'~[ [ [l-(2~Aadno~4-thiazolyl)-2-[■[!-IL[[2-(carboxymethyl)-2-[(1,4-dihydro-5-hydroxy-4-oxo-2~pyridinyl) carbonyl ] hydrazino ] sulfonyl ] -amino]carbonyl]-2-oxo-3~a2etidinyl]amino]-2-oxo-ethylidene]amino]oxy]-2-methylpropanoic acid, 25 diohenylmethvl ester 0.70 al (3.24 mmol) of diphenylchlorophos-phate was dropped into a -30°C cold mixture of 1.42 g (3.24 mmol) of (2)-2-amino~or-[ [2-(diphenyl-methoxy)-!, l-dimethyl-2-oxoethoxy]imino]~4-thia2ole-30 acetic acid and 1.81 ml (12.96 mm 1) of triethylamine in 30 ml of dry acetonitrile (solution A). 3.27 al (12.96 mmol) of bistrimethylsilyl acetamide was added to a suspension of 2.13 g (-3.3 mmol) crude (S)-3~amino-l-[[[[2-(carboxy-35 methyl )-2- [ (1 <4-difcydro-5-hvdroxy-4-oxo-2-pyridisyl )-c arb onyl]hydrazino]sulfonyl]amino]c arb onyl]-2-asetidinone, trifluoroacetate salt in 30 ml cf dry ethyl acetate at room temperature. After stirring for 1 hour, "he clear solution was cooled and dropped into the -30°C solution A. The mixture was stirred for 1 hour at -10°C, for an additional 1.5 hours at 0°C, and it was then 5 evaporated in vacuo. The residue was stirred with few ml of water, the pH; of which was adjusted to pB 2 by the addition of dilute hydrochloric acid. The precipitate was filtered off, washed with water, redissolved in water/acetone at pH S.5-5.0 10 (addition of dilute sodium hydroxide) and purified by MPLC on macroreticular styrane-divinylhenzane copolymer eluting with water-methanol gradient (0-100%). Freeze drying of the appropriate fractions yielded 270 mg of the purified products. A suspension 15 of this salt, in a few ml of cold water, was acidified with dilute hydrochloric acid at pH 2 to precipitate the free acid, which was collected by suction and dried in vacuo-; yielding 0.19 g; melting point >180°C, dec. 20 H) [3S(2)]-2-[[[1-(2-Amino-4-thiazolyl)~2~[[1-[ [ [ [2-(carboxymethyl)-2~[(1,4-dihyaro-5~hydroxy~ 4-0x0-2 -pyri dinyl) carbonyl ] hydrazino ] sul fonyl ] -amino]carbonyl]-2-oxo-3~a2stidinyl]amino]-2-oxo-25 ethylidene] amino]oxy]-2-aethylpropanoic acid, trifluoroacetic acid salt 0.17 g (0.2 mmol) of [3S(2)]-2-[[[l-(2-amino-4*-thiasolyl )-2- [ [1- [ [ [ [2-(c arb oxymethyl )-.2-r(l,4~dihydro-5-hydroxy-4~cxo-2-pyridinyl)-3 0 carbonyl]hydrazino]sulfonyl] amino]carbonyl]-2-oko-3-azeti dinyl ] amino ] -2-oxo-ethvi dene ] amino ] -oxy]-2~methyipropanoic acid, diphenylmethvl ester o -112- was slowly added to a -10°C cold, stirred solution of 0.62 ml (8.0 mmol) of trifluoroacetic acid and 0.087 ml (0.8 nunol) of thioanisole. Stirring was continued for 15 minutes at 0°C. The suspension 5 ' was evaporated in vacuo at 0-5°C, and the residue was stirred with dry ether, collected by suction, washed with dry ether and dried in vacuo, yielding 0.14 g; melting point >23 0°C, dec. 10 I) [3S(Z)]-2- [ [ [l-(2-Axnino-4-thiasolyl)-2-[ [1- [ [ [ [2-(carboxymethyl)~2-[ (1,4-dihydro~5-hydroxy~4-oxo-2-pyridinyl) carbonyl ] hydrazino ] sulfonyl ] amino3- carbonyl]-2-oxo-3-a2etidinyl] amino]-2-oxo-ethyli-dene 3 amino] oxy]-2-methylpropanoic acid, trisodium 15 salt . 115 mg (0.146 mmol) of [3S(Z)]-2-[[[l-(2-aauino-4-thia2olyl)-2-[ [1- [ [ [ [2-(carboxymethyl )-2-[ (l,4-dihydro~5-hydxoxy-4-oxo-2-pyridinyl)carbonyl3-hydrazino]sulfonyl ] amino] carbonyl ] -2~oxo-3-azetidinyl 2 0 saino 3 -2-oxoethyli dene 3 amino ] oxy 3 -2 -methylpropanoic acid, trifluoroacetic acid salt was suspended in 1.5 ail of water and the p3 ^*as adjusted to 5.5 by dropwise addition of dilute sodium hydroxide. The solution was passed through two successive columns 25 of macroreticular styrens-divinylhanzene copolymer (0.05 - 0.1 mm) and cross-linked dextran gel (25 -100 pm) eluting with water. The appropriate fractions were combined and lyophiliz sd yielding 100 mg of the title compound. 30 -113- Examole 14 [3S(2) ]-2-[[[l-(2~Amino~4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro-5-hydroxy~4-oxo-2-pyridinyl)acetyl]-amino]-2-oxo-l-imidazolidinyl]sulfonyl]amino]-5 carbonyl]~2-oxo-3~azetidinyl]amino]-2-oxoethylidene] amino] oxy] -2-methylpropanoic acid, disodium salt A) 2-(Cyanomethyl)-5-(phenyImethoxy)-l-(phenyl- 10 methyl) -4 (IH) -pyridinone .

To a suspension of 2.0 g (& mmol) of 2-(chloromethyl)-5-(phenyImethoxy)-1-(phenylmethyl ) -4 ( IH ) -pyri dinone in 20 ml of acetonitrile was added 3.9 g (60 mmol) of potassium cyanide and 15 0.1 g of 18-crown-6; the mixture was heated to reflux for 2.5 hours. The salts were filtered off by suction, and the filtrate was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel using ethyl 20 acetate/methanol (8:2) as eluent; yielding 0.55 g of the title compound, melting point 175-180°C.

B) 1,4-Dihydro-5-hydroxy-4-oxo-l-(phenylmethyl)- 2-pvridineaeetic acid 25 A mixture of 2.45 g (7.16 mmol) of 2-(cyano methyl )-5-(phenylmethoxy)-l-(phenylmethyl)-4(1H)~ pyridinone and 40 ml of concentrated hydrochloric acid (37%) was stirred for 4 hours at 70°C and then evaporated in vacuo. The residue was suspended in 30 15 ml of ice cold water and the pH was adjusted to 2.0 by the addition of 5N sodium hydroxide. The precipitate was filtered off, washed with ice water and ether and dried in vacuo (1.71 g). The crude acid was dissolved in 20 ml of 0.5N sodium hydroxide, reprecipirated by acidification (pH 1.8) with 2N hydrochloric acid, collected by suction and washed with ice water. Yield: 1.52 g; melting point 231-235°C.

C) 1,4"Dihydro~5~hydroxy-4~oxo«N~(2-oxo-l-iraidazolidinyl)-l~(phenylmethyl )-2~pyridine- acetamide 4.95 ml (35.83 nunol) of triethylamine was added to a suspension of 9.29 g (35.83 mmol) of 1,4~dihydro-5~hydroxy~4-oxo~l»(phenylmethyl)-2-pyridineacetic acid, 0.28 g (1.79 mmol) of N-hydroxybenzotriazole, 0.22 g (1.79 mmol) of N-dimethylaminopyridine, 3.62 g (35.83 mmol) of N-aminoimidazolidinone and 8.13 g (39.41 mmol) of di cyc1ohexy1c arb odi imi de in 115 ml of dry dimethyl-formamide. Stirring was continued overnight at room temperature. The precipitated dicyclohexylurea was filtered off, washed with dimethylform-amide, and the filtrate was evaporated in vacuo to leave a residue, which became crystalline by stirring with 110 ml of dichloromethane. The precipitate was collected by suction and dried in vacuo. To a suspension of this crude material in 65 ml of dry acetonitrile, 14.0 ml (71.6 nunol) of N-methyl-N-trimethylsilyltrifluoroacetamide was added. After having been stirred for 30 minutes at room temperature, the undissolved dicyclohexylurea was filtered off and the filtrate was evaporated in vacuo. The oily residue was boiled in 70 ml of methanol for 15 minutes and cooled. The precipitate was collected by suction, washed successively with methanol, methanol/ether (1:1) and ether and dried in vacuo.' Yield: 8.7 g; sint. 2€2°C, melting point 260-265°C dec. -115- D) (S)- [1-[[[[3-[[ [1,4~Pihydro~5-hydroxy~4»oxo--l~ (phenylmethyl)-2-pyridinyl}acetyl] amino]-2-oxo-l-imidasoli dinyl ] sulfonyl ] amino] carbonyl ] ~2-oxo~ 3~azetidinyl]carbamic acid, phenylmethyl ester, 5 monosodiuro salt 5.86 sal (30.0 mmol') of N-methyl-N-trimethyl-silyltxifluoroacetamide was added to a suspension of 3.42 g (10.0 mtnol) of 1,4-dihydro-5-hydroxy-4~ oxo-N-(2-oxo-l-imidasolidinyl )-l- (phenylmethyl )-10 2~pyridiaeacetamide in 50 ml of dry ethyl acetate • and stirring was continued for 1 hour at room temperature (solution A).

To a solution of 2.20 g (10.0 mmol) of (S) -3- [ [ (pheny Ime thoxy) carbonyl 3 .amino ]»2~ IS azetidinoiie in 50 ml of dry ethyl acetate, 0.90 ml (10.0 annol) of chlorosulfonyl isocyanate was added:, with stirring," and the mixture was stirred for 1 hour at room temperature and then, cooled , to D°C~ Solution A was dropped in with stirring at .0°C. 20 After stirring overnight at roosoa temperature, the .. mixture was evaporated in vacuo and the residue was taken up in a few ml of methanol and water. The pH was adjusted to 5.5 by the addition of dilute sodium hydroxide and the filtered solution was 25 freeze dried. MPLC on macroreticular styrene- divinylbeazene copolymer eluting with water/acetone (S.-l) and freeze drying of the relevant pure fractions yielded 0.40 g of the title compound. The impure fractions were purified by a second M?LC 30 using the same conditions. Yield: 0.60 g. -116- E) (S)-N~[3-[[[(3-Amino-2-oxo-l-azetidinyl)-carbonyl]amino]sulfonyl]-2-oxo-l-imida2olidinyl]- 1,4-dihydro-5»hydroxy~4~-ox0-2~pyridineaeetamide, trifluoroacetate salt 5 A solution of 0.90 g (1.3 nanol) of (S)~[1- I [ [ [3- [ [ [1,4-dihydro~5-hydroxy-4-oxo-l- (phenylmethyl ) - 2 -pyri dinyl ] acetyl ] aad.no ]-2-oxo~l-imi da2 oli dinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbarn:.c acid, phenylmethyl ester, 10 monosodium salt in 13 ml of dry dimethyl form amide containing 0.50 al (6.5 mmol) of trifluoroacetic acid was hydrogenated in the presence of 0.15 g palladium on carbon (10%) for 20 minutes. The catalyst was filtered off and washed with a few ml 15 of dimethylformaiaide. Evaporation of the; filtrate in vacuo gave an oily residue which became crystalline by stirring with a few ml of ethyl acetate.. Yield: 0.675 g; melting point >150°C, dec. 20 Simple stirring of this crude title compound in dry ethyl acetate for 1 hour, followed by filtration, washing with ethyl acetate and drying in vacuo improved the purity; yield: 80%, melting point >165®C, dec. 25 -117- F) [3S(2)]-2-[[[l-(2~Amino~4~thiazolyl)-2-[II-[ I [ £3—[[(l,4-dihydro-5-hydroxy-4-oxo-2~pyridinyl)-acetyl ] amino}~2-oxo-l-imidazolidinyl ] sulfonyl ] -amino ]carbonyl3-2-oxo-3~azetidinyl3 amino3-2~oxo-5 etJaylidene3amiao]oxy]-2-methylpropanoic acid. fljphenvlmethvl ester 1.1 ml (4.45 mmol) of bistrimethylsilyl acetamide was added to a suspension of 0.75 g (1.35 nanol) of (S)~N~ [3- [ [ [ (3-amino~2-oxo-l~ 10 azetidinyl)carbonyl3 amino3sulfonyl3-2-oxo~l- imidazolidinyl]-l,4-dihydro-5-hydroxy-4-oxo-2-pyridiaeacetamide, trifluoroacetate salt, in 12 ml of dry ethyl acetate. -After stirring for 1 hour at room temperature, the clear solution was 15 evaporated in vacuo and the oily residue was dissolved in 12 ml of dry ethyl acetate (solution A)..

Into a -30°C cold suspension of 0.60 g (1.35 mmol) of (2)-2~amino-cr- [ [2- (diphenylmethoxy)-l,l-dimethyl~2-oxoethoxy]imino]-4-thiazoleacetic. 20 acid in 12 ml of dry acetonitrile, 0.57 ml (5.4 sisnol) of triethylamine was dropped, followed by 0.29 ml (1.35 mmol) diphenylchlorophosphate.

Stirring was continued for 1 hour at -30°C and an additional hour at 0°C. The solvent was removed 25 in vacuo .and the residue was precipitated by stirring with a few ml of water (0°C). The precipitate was collected hy suction, washed with cold water, suspended in water at pH 2 (addition of few drops of dilute hydrochloric acid), filtered off, washed 30 successively with water, methanol and ether and dried in vacuo. Yield: 1.07 g; melting point >180°C, dec. This crude material was used in the next step without any further purification. -118- G) [3S(Z)]-2~ [ [ [l-(2-Amino»4-thia2olyl )-2-[ {1-[ [ [ [3- [ [ (1,4~dihydro-5-hydroxy~4-oxo-2-pyridinyl )- acetyl ] amino]-2-oxo-1- imidasolidinyl ] sulfonyl ]-amino ] carbonyl ]-2-oxo-3 ~ azeti dinyl ] amino ] - 2 -oxoethylidene] amino]oxy]-2~methylpropanoic acid, disodium salt 1.01 g (1.17 mmol) of crude [3S(2)]-2- [ [ [1-(2-aaiino-4-tJbiasolyl )-2~ [ [1- [ [ [ [3- [ [ (1,4-dihydro-5-hydroxy~4~oxo-2-pyridinyl) acetyl ] amino ]-2-oxo-l-iaii daz oli dinyl ] sulfonyl ] amino]carbonyl ] -2-oxo~3~ azeti dinyl] aminoJ-2-oxoethylidene] amino] oxy]-2-methylpropanoic acid, diphenylmethvl ester was added to a -10°C solution of 2.0 al of anisole in 10 ml of trifluoroacetic acid. After being stirred for 20 minutes at -10°c, the solvent was removed in vacuo at +10°C. The residue was .stirrec with a few ml of dichloromethane, filtered off, stirred once more with a few ml of dichloroiaethane,-: collected by suction, washed with hexane and dried in vacuo. This crude product (1.06 g) was suspended; in a few ml of watsr/acetonitrile and then dissolved by adjusting the pH to 6.0 by the addition of IN sodium hydroxide. After concentrating in vacuo, the aqueous solution was chromatographed (M?LC) on macroreticular styrene-divinylbenzene copolymer eluting with water. The appropriate fractions were combined and freeze dried. Yield: 0.10 g, melting point >2S5eC. -119- Example 15 [3S(Z)]-2-[ [ [l-(2-Amino-4-thia2olyl)-2-[ [1~[ [ [ [3-[ [3~(l,4-dihydLro-5-hydroxy-4~oxo-2-pyridinyl )~1-oxo~2.~propenyl ] amino] -2~oxo-l-imidazolidinyl ] -5 sul fonyl ] amino ] carbonyl ] ~2-axo~3-azetidinyl ] amino ] -2-oxoethylidene] amino] oxy]-2-methylpropanoic acid, disodium salt A) 2 = ((1 -Hydroxy-1 -methoxy)methyl )-5-(phenylmethoxy )-10 4 (IH) -pvridinone 9.0 g ox 2-(hvdroxymethyl)-5- (phenyImethoxy)~ 4(IH)-pyridinone and 26 g of manganese dioxide (activated) were stirred in 100 ml of methanol overnight at room temperature. Crystals of product 15 were formed. After boiling the reaction mixture for ten minutes, followed by hot filtration through Hyflo, and washing the filtercake two times with 50 al of boiling methanol, the combined filtrates were evaporated and the residue 20 stirred with 50 nil of ethyl acetate. White crystals of product were formed. Yield: 9.7 g, melting point 156°C dec.

B) 3- [ 1,4~Dihydro~4~cxo-5~ (phenylmethoxy)-2 ~ 25 pyridinvll-2-prot>enoic acid, ethvl ester 0.5 g of p-toluenesulfonic acid, 6.26 g of 2-(1-hydroxy-l-methoxymethyl )~5~(phenylmethoxy)-4(lH)-pyridinone and 8.35 g of carbethoxymethylene-triphenylphosphorane were stirred for 3 hours in 30 100 ml of dioxane at 70°C. A clear, dark-colored solution was formed. Evaporation of the solvent in vacuo yielded an oily residue of the title -120- compound and triphenylphosphine oxide. The residue was dissolved in 30 nil of isopropanol and crystals of product began to-separate. After standing in a refrigerator overnight, the crystals were filtered 5 off, washed with ether and recrystallized from isopropanol. Yield:"5.72 g, melting point 188°C.

C) 3 - f 1,4-Dihydro-4~oxo-5- (pheny Ime thoxy) -2~ pvridinvl]-2-propenoic acid 10 3-[1,4-dihydro-4-oxo-5~(phenylmethoxy)~2~ pyridinylj-2-propenoic acid/ ethyl ester (1.5g) and 0.29g of potassium hydroxide were stirred in 30 ml of ethanol for 2 hours at 50°C. After evaporation of the solvent, the residue was dissolved in 100 ml of IS water and filtered. I'o the filtrate was added 2N hydroehloz-ic acid until pH 5.0. Crystals of the title compound separated from the solution. They were filtered and washed with water and dried in vacuo. Yield: 1.14 g, melting point 236°C. 20 D) 3~[1,4-Dihydro-4-oxo-5-(phenyImethoxy)-2-pvridinvl 1 -N- (2"Oxo-l~imidagolidinvl )-2-propenamide 3-[1,4-Dihydro~4~oxo-5-(phenyImethoxy)-2~ pyridinyl]-2-propenoic acid (10.85 g), 1 g of 25 N-hydroxybensotriazole, 0.01 g of N,N-cimethyl~ aminopyridine and 8.24 g ox dicyclohexylcarbodiimide were stirred for 30 minutes in 100 ml of dimethvlformamide. After cooling to 0°C, 4 g of N-ainino-imidazolidinone.was added and stirring continued 30 for 1 hour at 0°C and 10 hours at room temperature. The resulting suspension was then heated to 60°C and filtered. It was again suspended in 50 ml of -121- dimethylformamide and heated to 60°C and filtered again. The combined filtrates were evaporated at 40°C (oil vacuo). The oily residue was stirred with 50 ml of water containing 2 g of sodium 5 bicarbonate. After the filtration, the solid was washed i*?ith water, acetone and ether. 12.3 g of solid was obtained after drying. It was stirred together with 8 g of p~toluenesulfonic acid in 100 ml of dichloromethane for 1 hour. Filtration 10 yielded 12.98 g of a white solid. This material was suspended in water. Recrystallization from water/dimethylformamide yielded 8.49 g of the title compound, melting point 271°C. 15 E) (3S)-[l-[[[[3-[[3-[l,4-Dihydro-4~oxo-5-(phenyl-methoxy)-2-pyridinyl]-l-oxo-2-propenyl]amino]-2-oxo-l-imidazolidinyl]sulfonyl]amino]carbonyl]~2~ oxo-3-azetidinyn carbamic acid, phenylmethvl ester 3-[1,4-Dihydro~4~oxo-5-(phenyImethoxy)-2-20 pyridinyl]-N-(2-oxo-l-imidazolidinyl)-2-propenamide (3.55 g) was suspended in 100 ml of ethyl acetate and 6.3 g of N-methyl-N-(trimethylsilvl)trifluoro-acetamide was added. After stirring for 1 hour, a clear solution was obtained. The solution was then 25 added within 10 minutes to a cooled solution (0°C) of 3.3 g of (S)-l~[[(chlorosulfonyl)amino]carbonyl]~ 3-[[(phenyImethoxy)carbonyl] amino]-2-azetidinone in 50 ml of ethyl acetate. After stirring overnight, the solvent was evaporated and the oily residue was 30 stirred for 1 hour with 50 ml of isopropanol The resultant precipitate was isolated by filtration and washed with isopropanol and ether. Yield: 5.91 g. -122- F) (3S)-3-Amino-N-[[3-[[(1,4-dihydro-5-hydroxy-4-OXO-2-pyridinyl]-l-oxo~2-propenyl] amino]~2-oxq-l~ imidasolidinyl] sulfonyl]- 2-oxo-1 -azetidinecarboxamide, trifluoroacetate salt . 5 ' (3S)-[!»[[[[3-[[3-[l,4-Dihydro~4-oxo-5-(pheny1~ methoxy)-2-pyridinyl]-l-oxo-2-propenyl]amino]-2-oxo~ 1- imi dazo li dinyl]sulfonyl] amino]carbonyl]-2-oxo~3-azetidinyl]carbamic acid, phenylmethyl ester (6.8 g) was stirred at room temperature overnight 10 in 60 ml of trifluoroacetic acid/thioanisole (3:1). After evaporation of the resulting solution to 1/3 of its volume, 50 ml of isopropanol and 10 ml of ether were added. (3S)-3-Amino-N«[[3-[[(1,4-dihydro-5-hydxoxy-4-oxo-2-pyridinyl]-l-oxo-2-15 propenyl ] amino] -2-03co-l-imidazolidinyl ] sulfonyl ] - 2-oxo~ 1-azetidinecarboxamide, trifluoroacetate salt was obtained as a white precipitate. It was washed with ether several times and dried. Yield: 4.30 g. 20 G) [3S(Z)]-2-[ I [l-(2-Amino-4-tliiazolyl)-2- [ [1- [ 11 [3"L [3-(l,4~dihydro~5-hydroxy-4-oxo~2-pyri dinyl )-l-oxo-2-propenyl ] amino ] -2—oxo-l--imidazolidinyl ] - sulfonyl]amino]carbonyl]~2-oxo-3-azetidinyl] amino]--2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, 25 disodium salt (Z)-2-amino-cr- [ [ 2 - (dipheny Ime thoxy) -1,1-dimethyl-2-oxoethoxy]imino ] -4-tbdazoleacetic acid (2.2 g) and 1.5 g of triethylamine was dissolved in 150 ml of acetonitrile. At -30°C, 1.4 g of dipheny1-30 chlorophosphate was added dropwise and the mixture was stirred for 1 hour. -123- (3S )-3-Amino-N~[[3-[[ (1,4-dihydro-5-hydroxy~ 4-0x0-2-pyridinyl ] -l-oxo-2-propenyl ] amino ] -2=oxo»l~ imidazolidinyl ] sulfonyl 3 -2-oxo~1 -azetidinecarboxamide, 2.0 trifluoroacet.ate salt (3.3 g) suspended in 5 100 ml of ethyl acetate was treated with 5 ml of N~methyl-N-(trimethylsilyl )trifluoroacetamide and stirred for 1 hour at room temperature. The solution was added dropwise to the activated acid at -30°C (15 minutes). It was then stirred for 1 • 10 hour at ~10°C, and 30 minutes at 0°C. The solvent was evaporated in vacuo and the remaining oil was stirred with ice water at pH 2 (2N phosphoric acid). The ice water was discarded and the residue washed 'with ice water again and then dissolved in IS 100 ml of tetrahydrofuran. The solution was dried over sodium sulfate and the filtrate evaporated. The diphenylmethvl ester of the title compound was isolated as a solid foam, 1.81 g. 1.5 g of the material was stirred in 30 ml 20 of trifluoroacetic acid/anisole at 0°C for 30 minutes and after adding 100 ml of ether, 1.7 g of the trifluoroacetic acid salt of the title compound was isolated by filtration. This was dissolved in 10 ml of water, and sodium bicarbonate 25 was added until the pH was 5.5. The filtered solution was chromatographed on macroreticular styrene-divinylbenzene copolymer (400 g) using water as the eluent. Appropriate fractions contained 0.64 g of product. Bioautography showed one minor 30 bioactive side product. The material was subjected to a second column chromatography on Merck Lobar using water as an eluent. Appropriate fractions contained 0.17 g of the title compound.

* Lobar is a Trademark -124- Sxample 16 [3S(Z)]-2-[[[1-(2-i=tfnino~4-thiazolyl)-2-[[l-[ [ [ [2-[3-(l,4~dihydro"-5-hydroxy-4-oxo-2-pyridinyl )-l~ - oxo-2-propenyl] hydrazino] sulf onyl] amino] carbonyl ]-5 2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] -oxy 1 "2-methylpropanoic acid, disodium salt A) 3- [l,4-Dihydro-4-oxo-'5~ (pheny Imethoxy)-2-pyridinyl]-2-propenoic acid, 2-[(1,1~dimethyl- 10 cthoxy)carbonvl1hvdrazioe 3-[1,4-Dihydro-4-oxo-5-(phenyImethoxy)-2-pyridinyl]-2-propanoic acid (1.36 g), 0.75 g of N-hvdroxybensotriazole, 0.01 g of N,N-dimethyl-aminopyridine and 1.06 g of dicyclohexylcarbo-15 diimide were stirred in 20 al of dimethyl-foraamide at D°C for 20 minutes. 0.56 g of K-(t-butoxycarbonyl)hydrazine was added. After stiri'ing overnight, the formed, dicyclohexylurea was filtered off and the filtrate was washed with 10 ml 20 of dimethylformamida. The filtrate "as evaporated to dryness and the residue was suspended in 30 ml of water, 1 g of sodium bicarbonate was added, and after stirring, the title compound was isolated by filtration. Recrystallisation from dimethyl form-23 amide/water gave white crystals. Yield: 1.47 g, melting point 141°C. -125- B) 3-[1,4-Dihydro-4~oxo-5-(phenyImethoxy)-2-•pvridinyn-2-propenoic acid, hvdrazioe 3- r 1,4-Dihydro-4-oxo-5- (phenyImethoxy)-2-pyridinyl]~2-propeno ic acid, 2-[ (1,1-diaethyl-5 etboxy)carbonyl]hydra2ide (3.86 g) was stirred for one-half hour is, 30 ml of trifluoroacetic acid at D-59C. The trifluoroacetic acid salt of the title ' compound precipitated after adding 50 al of diethyl-ether. The salt was suspended in 30 al of water, 10 stirred with 2 g of sodium bicarbonate for 20 minutes, and the title compound was filtered off, washed with water and dried yielding a beige powder. Yield: 2.75 g. 15 C) (3S )-l, 4-Dihydro~4-oxo-5-(pheny imethoxy)-2- pyridine-2-propenoic scad, 2™ f [{ [2-qxO"~3™£ [ (pnenyl~ methoxy) carbonyl] amino ] -l-azeti dinyl ] carbonyl ] - amino 1 sulf onvl 1 hvdrasi de 3- [1,4-Dihydro~4-oxD~'5- (pheny imethoxy )~2-20 pyridinyl ]-2-propenoic acid, hydrazi de (2.S6 g) and 8.1 g of N-methvl-N-(trimethylsilyl Jtrirluoro-acatamida were stirred for 1 hour in 50 ml of ethyl acetate. To the resulting clear solution was added a solution of 3.27 g of (S)-!»[[(chloro-25 sulfonyl)amino]carbonyl]-3-[ [ (phenylmethoxy)carbonyl]-amino]-2-azetidi.none in 3 0 al of ethyl acetate (addition within 10 minutes) at 0°C. After stirring overnight, the solvent was evaporated and the residue was stirred with 50 ml of isopropanol 30 and one drop of acid- The title compound was filtered off and washed with isopropanol and ether. Yield: 5.42 g. -126- D) (3S )~3- [1,4-Dihydro-5-hydroxy-4~oxo-2-pyridinyl]-2-propenoic acid, 2-[ [ [ (3-amino-2-oxo-l-azetidinyl )-carbonyl]amino]sulfonyl]hydraz ide, tr i fluoro-acetats salt (3S) -1,4-Dihydro~4-oxo-5- (pheny line thoxy) -2-pyridine-2-propenoic acid, 2- [ [ [ [2-oxo-3- [ [ (phenylme thoxy) carbonyl ] amino ]-l-azetidinyl ] carbonyl ] -amino]sulfonyljhydrazide (5.2 g) was stirred in 50 ml of trifluoroacetic acid/thioanisole (3:1) at room temperature overnight. To the clear solution was added a mixture of 100 ml of ether/isopropanol (8:2). The resultant precipitate was filtered off and washed with ether. Yield: 4.01 g after drying.

E) [3S(Z)]-2-[[[l-(2-Amino-4-thiazolyl)-2- [ [1- [ [ [ [2- [3-(1,4-dihydro-5-hydroxy-4-oxo~2-pyridinyl )- 1-oxo-2-propenyl ] hydrazino ] sulfonyl ] amino] carbonyl ] - 2-oxo-3-azeti dinyl ] amino] -2-oxoethylidene] amino]-oxvl-2-methvlpropanoic acid, disodium salt (Z)-2~Amino-c-[ [2-(diphenyImethoxy )-l, 1~ dimethy1-2-oxoethoxy]imino]-4-thiazo 1 eacetic acid (1.5 g) and 1 g of triethylamine were dissolved in 100 ml of acetonitrile. At ~30°C, 1 g of diphenyl-chlorophosphate was added dropwise and the mixture was stirred for 1 hour. (3S )-3-[l,4-Dihydro-5~hydroxy-4-oxo-2~ pyridinyl]-2-propenoic acid, 2- [[[(3-amino-2-oxo-l-azeti dinyl) carbonyl ] amino ] sul fonyl ] hydraz ide, trifluoroacetate salt (2.0 g) and 5.5 ml of N-methyl-N-(trimethylsilyl )trifluoroacetamide were stirred in 50 ml of ethyl acetate at room temperature -127- for 1 hour. A clear solution was formed and after cooling was added dropwise to the activated acid at -3D#C. The mixture was stirred for 1 hour at -30°C, 30 minutes at -10°C and 1 hour at 0°C. The 5 solvents were then evaporated in vacuo, and the residue stirred with 50 al of isopropanol. A solid was formed. It was isolated by filtration and stirred with 100 ml of ice water for 20 minutes at pH 2 (phosphoric acid). Filtration yielded the 10 diphanylmethvl ester of the title compound which was washed three times with 50 ml portions of ice water and dried (1.78 g). 1.5 g of the ester was stirred with 50 ml of trifluoroacetic acid/anisole (4:1) for 30 minutes at 0°C» After adding 150 ml 15 of ether, the trifluoroacetic acid salt of the free- acid of the title compound was isolated toy filtration (1.65 g). 1 g of that material was suspended in 5 ml of v-ster and the pH was adjusted to 6.0 (sodium 20 bicarbonate). The clear solution was then chroxnatographed on 400 g of macroreticular styrene-divinylbenzene copolymer using water as eluent, yielding 413 gm of the title compound. 400 mg of that material was rechromatographed on Merck Lobar C 25 using water as eluent; yield: ISO mg. -128- £xample 17 [3S(Z)]-2~[[[l~(2~Amino-4~thiazolyl)-2-[[!-[[[[[2-[ [ (1,4-dihydro~5-hydroxy--4~oxo~2-pyri dinyl)-• carbonyl]amino]ethyl]amino]sulfonyl]amino]-5 carbonyl ] -2-ojco-3-azetidinyl] amino ]-2~oxoethyli-dene]amino]oxy]-2~methylpropanoic acid, disodium salt A) N-(4*-Methoxybenzyl )-0~benzylcomenaniic acid 10 O-Benzylcomenic acid (10 g) and 10 ml of 4-methoxybenzylamine in 60 ml of water were refluxed for four hours. Acidification of the reaction mixture at room temperature with 2N hydrochloric acid to pH 2 yielded 15 g of crystals. 15 Recrystallization from dioxane yielded 12.3 g of the title compound, melting point 175°C.

B) 1,4-Dihydro-l-[(4-methoxyphenyl)methyl]-4~oxo- 5-(phenyImethoxy)-N-[2-[(phenylmethyl)amino]ethyl]-20 2-syyi dinecarboxamide N-f(4-Methoxyphenyl)methyl]-0-benzyl~comenamic acid (3.69 g), 1.50 g of N-hydroxybenzotriazole and 2.05 g of dicyclohexylcarbodiimide were stirred for 1 hour at room temperature in 50 ml of dioxane. A 25 solution of 1.35 g of N-benzylethylenediamine in 5 ml of dioxane was then added dropwise. After stirring overnight, the formed dicyclohexylurea was filtered off and the dioxane of the filtrate evaporated. The residue (oil) was dissolved in 30 50 ml of dichloromethane and extracted with two 50 ml portions of 10% sodium bicarbonate, and washed with water. After drying the dichloromethane solution over sodium sulfate and evaporation, the remaining solid was recrystallized from ethsnol 35 yielding crystals (4.2 g) of the title compound, melting point 112°C. -129- C) N-(2-Aminoethyl )-l, 4-dihydro-5~hydroxy~4--oxo-2-pvridinecarboxamide, p-toluenesulfonate salt 1,4-Dihvdro-l- [ (4-methoxyphenyl)methyl ] -4-oxo-5~(phenyImethoxy)-N~[2~ [ (phenylmethyl)amino]ethyl]- 5 2-pyridinecarboxamide (9.95 g) and 7.7 g of p-toluene-sulfonic acid in 100 ml of methanol were treated with 3 g of palladium on charcoal (10%) and hydrogen was bubbled through the reaction mixture at 45-5Q°C over six hours, A stream of argon was 10 then bubbled through the reaction mixture for 10 minutes. Filtration and evaporation of the filtrate yielded beige crystals of the title compound which ware washed first with 20 ml of cold methanol and then 50 ml of ether. Yield:. 15 10.5 g, melting point 271'°C.

D) N- (2-Aminoethyl) -1,4-dihydro-5-hydroxy-4-oxo-2 ~t> vri dinecarbox ami de, dihydrochloride N- (2-Aminosthyl )-l, 4-dihyciro~5~hydroxy-4~oxo-20 2-pyridinecarboxamide, p-toluenesulfonate salt (5.42 g) was dissolved in 50 ml of formic acid and 7.5 ml of formic acid/hydrochloric acid gas (2.2 equivalents hydrochloric acid) was added followed by 150 ml of ether; white crystals of were obtained. 25 Isolation by filtration and washing with 200 ml of ether yielded 2.SO g of the title compound, melting point 287°c. -130- E) (3S)-[!-[[[[[2—[[(1,4-Dihydro~5-hydroxy-4-oxo-2-pyridinyl)carbonylJ amino]ethyl]amino]-sulfonyl]amino]carbonyl]-2-oxo-3-a2etidinyl]- carbamic acid, phenylmethyl ester 5 To a 4.38 g of (S)~3~[[(phenyImethoxy)- carbonyl]amino]-2-azetidinone suspended in 50 ml of ethyl acetate was added 2.83 g of chlorosulfonyl isocyanate at room temperature. A clear solution was obtained after 30 minutes of stirring. 10 N~(2-Aminoethyl)-l,4-dihydro-5~hydroxy~4~oxo~ 2-pyridinecarboxamide, dihydrochloride (5.40 g) in 50 ml of acetonitrile was stirred together with 24 g (6 equivalents) of N-methyl~N-(trimethyl-silyl)trifluoroacetamide at 50°C for 1 hour. The 15 volatiles were then evaporated in vacuo. To the remaining oily residue was added 50 ml of ethyl acetate.

The above-prepared solutions were cooled to 0°C and the second solution was added to the first 20 while stirring. After stirring overnight, 200 ml of isopropanol was added under stirring at 0°C to yield the title compound in the form of beige crystals. Yield: 8.77 g, melting point 145°C. 25 F) (3S)-N-[[[[(3-Amino-2-oxo-l-azetidinyl)carbonyl]- amino]sulfonyl]amino]ethyl]-1,4~dihydro-5»hydroxy~ 4-oxo-2-pyridinecarboxainide, 2.0 trifluoroacetate salt (3S)-[1-[[[[[2-[[(1,4-Dihydro~5-hydroxy-4~ oxo-2»pyridinyl)carbonyl]amino]ethyl]amino]-30 sulfonyl]amino]carbonyl]-2-oxo-3-asetidinyl]- carbamic acid, phenylmethyl ester (2 g) was stirred -131- in 20 ml of thioanisole/40 al of trifluoroacetic acid at 0°C for 12 hours. After adding 100 al of ether, white crystals (fine) of the title compound were isolated by filtration. Washing with 50 al of 5 isopropanol and 100 ml of ether yielded 2.12 g of the title compound, melting point 136°C, dec.

G) [3S(Z)]-2-[[[1-(2-Amino—ft-thiasolyl)-2-[ [1-11 H [2-11(l,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl )- 10 carbonyl ] .amino ] ethyl ] amino ] sulfonyl ] amino ] carbonyl ] -2-oxo-3-azeti dinyl]amino]-2-oxoethyli dene]amino]-oxy]-2-methylpropanoic acid, diphenylmethyl ester (2 )-2-Amino-cr- [ [2- (diphenyImethoxy )~1, 1-15 diraethyl-2-oxoethoxy]imino]-4-thia2oleacetic. acid (4.40 g) and 3 g of triethylamine were dissolved in 150 ml of acetonitrile. At -30°C, 2.8 g of diphenyl chl or ophosphate was added dropwise and the mixture was stirred for 1 hour. 20 (3S)-N-[[[[(3-Aaino-2-cxo-l~a2etidinyl)carbonyl]- amino] sulfonyl]amino]ethyl]-1,4-dihydro~5-hydroxy-4-oxo-2-pyridinecarboxamiae, 2.0 trifluoroacetate salt (6.13 g) and 17 g of N-methyl~N~(trimethyl-silyl)trifluoroacetamide were stirred for 2 hours 25 in 100 ad of ethyl acetate. The solvent of the clear solution was distilled off in vacuo and the remaining oil was evaporated for 2 hours at 30°C (oil vacuo < 0.01 mm). The residue was dissolved again in 100 ml of ethyl acetate and added 30 dropwise to the activated acid at -30° C (30 minutes). The mixture was stirred for 1 hour at -10°C and 1 hour at 0°C. The solvent was evaporated and the remaining oily residue stirred with ice water at pli 3 (2N phosphoric acid). The ice water was discarded and the residue washed with ice water and dried. Yield: 7.8 g beige crystals.

H) [3S(Z)]-2~[[[l-(2~Amino~4~thiazolyl)-2-[[1-[[[[ [2-[[(1,4-dihydro-5-hydroxy~4-oxo~2-pyridinyl)-carbonyl]amino]ethyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]- oxy]-2-methvlpropanoic acid, disodium salt [3S(Z)]-2~[[[l-(2-Amino-4-thiazolyl)-2-[[1-[[[[2-iKl, 4-dihydro-5-hydroxy-4-oxo~2-pyridinyl )-carbonyl]amino]ethyl]amino]sulfonyl] amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]-oxy]-2-methylpropanoic acid, diphenylmethyl ester (3 g) was stirred for 3 0 minutes in 30 ml of trifluoroacetic acid/anisole. The trifluoroacetic acid salt of the free acid was isolated after precipitation with ether. 7.9 g of this material was suspended, in 20 ml of water and the pH was adjusted to 6.0 with sodium bicarbonate. After stirring for one-half hour, the suspension was filtered and the solution chromatographed on macroreticular stvrene-divinylbenzene copolymer with water as eluent yielding 0.24 g. This material was chromatographed again on a Merck Lobar C Column; yield: 0.078 g, melting point 275°C, dec. -133- Example 18 [2S [2a, 30 (2)] ]-2-[ [ [1-(2-Amino-4-thiazolyl )-2-[ [1- [ [ I [3- [ [ (l,4-dihydro~5-hydroxy~4-*oxc>-2-pyri dinyl) carbonyl ] amino ] - 2 ~ ox o-1 - imi das o1i diny1]~ 5 sulfonyl ] amino ] carbonyl} -2-methyl-4-oxo-3- ase ti dinyl ] amino ] - 2 - oxoethyl i dene ] amino ] oxy 3 - 2-methvloropanoic acid, disodium salt A) (2S-trans )-[!-[[ [ [3-[ [ [1,4-Dihydro-4-oxo-5-10 (phenylmethoxy )-2~pyridinyl] carbonyl] amino]»2-oxo-l-imidazolidinvl]sulfonyl]amino] carbonyl ]-2-methyl-4-oxo~3~azetidinyl') carbamic acid, •phenvlmethvl ester (3S«trans)-(4-methyl-2-oxo-3-asetidinyl )-carbamic acid, phenylmethyl ester (2.35 g) and 15 1.41 g of chlorosulfonyl isocyanate were stirred for 1 hour at 0®»5°C in 50 ml of ethyl acetate-. A clear solution was obtained, (solution A) - 1,4-Dihydro-4-oxo-N-(2-oxo-l-imida2oli dinyl )-5- (phenyl-methoxy)- 2-pyridinecarboxamide (3.28 g) and 5 g of 20 N-methyl-K-(trimethylsilyl)trifluoroacetamide were stirred in 50 ml' of ethyl acetate for 1 hour at 40°C (solution B).

To the cooled (0°C) solution A was added solution B during 30 minutes of stirring. After 25 continuous stirring overnight, the solvent was evaporated and the residue (oily) stirred with 50 ml of isopropanol and 1 drop of acetic acid. The title compound was formed as a beige precipitate; melting poir.t 1£3°C, dec. ; 4.3 g. 30 -134- B) (2S-trans)-N-[3-[ [ [(3-Amino-2~methyl-4-oxo-l~asetidinyl)carbonyl] amino]sulfonyl]-2-oxo- 1-imidazolidinyl ] -1 ,-4-dihydro~5-hydroxy>-4-oxo- 2-t>vr i dine carbox amide, di-p-toluenesulfonate (2S-trans)-[l-[[[[3~[[ [1,4-Dihydro-4-oxo-5-(pheny Imethoxy) -2-pyri dinyl ] carbonyl ] amino ] -2-oxo-l-imidazolidinyl] sulf onyl ] amino] carbonyl ] -2-methyl-4«oxo~3-a2etidiny3 ] carbamic acid, phenylmethyl ester (5.9 g) in 50 ml of dimethylformamide and 3.8 g of hydrated p-toluenesulfonic acid and 2.5 g of palladium on charcoal (10%) were hyfirogenated at room •temperature for 1 hour. After filtration over Hyflo, the dimethylformamide was distilled off in vacuo- The oily residue was stirred with 100 ml of dichloromethane. The title compound (5.8 g) was immediately formed as a white crystalline material.

C) [2S~ [2a ,33 (Z) ] ]-2~ [ [ [1- (2-Aminc-4-thiazolyl.)~ [l-[ [ [ [3-[ [ (1,4-dihydro~5~hydroxy-4-oxo~2- pyriditnyl) carbonyl] amino]-2-oxD-l-imi dazolidinyl]-sulfonyl] amino]carb onyl]-2-methyl-4-oxo~ 3 ~ aseti dinyl'] amino ] -2 - oxoethyli dene ] amino ] oxy ] - 2 - methvl?ror>anoic acid, disodium salt (2) -2-Amino-»cr -[[2-(dipheny Ime thoxy) -1,1-dimethyl-2-oxoethoxy]imino]-4-thia2oleacetic acid (4.40 g) and 3.0 g of triethylamine were dissolved in 150 ml of acetonitrile. At -30°C, 2.8 g of diphenyl chl or ophosphate was added dropwise and stirred for 1 hour. (2S-trar.s )~N~ [3- [ [ [ (3-Amino*-2-methyl-4-oxo-1 - az e ti dinvl) carbonyl ] amino]sulfonyl ] -2-oxo- -135- 1-imidazolidinyl ] -1,4-dihydro~5-hydroxy-4-oxo- 2-pyridinecarboxamide, di-p-toluenesulfonate (7.90 g) and 2.02 g of triethylamine ware stirred for 5 minutes at -20 °C in 50 ml of dimethylform- 5 amide.

The above-prepared suspension and solution ware combined at ~30°C and stirred for 1 hour at ~3Q®C, 1 hour at -1Q®C and overnight at 0-10oC. The solvents were than distilled off in vacuo and 10 the residue stirred with 100 ml of ice water at pH 3 (phosphoric acid). The dipheny Ime thyl ester of the title compound was filtered off and washed with water. Yield: 5.13 g, beige powder. 2 g of the ester was stirred in 30 ml of 15 trifluoroacetic acid/anisole (4:1) for 30 minutes-at 0°C. By adding 100 ml of ether, the trifluoroacetic acid salt of the free acid was precipitated-It was suspended in, 10 ml of water and the p3 was adjusted to 5.0. After filtration, the filtrate 20 was passed through an macroreticular styrene- divinylben2ezie copolymer column (water as eluent). Yield: 0.48 g.

A second column chromatography on Merck Lobar C with water as eluent gave 0.17 g of the 25 title compound. -136- Sxample 19 [3 S(2)]-2-Amino-N-[ 1- [ [[[3-[[(l,4-dihydro~5-hydroxy-4-oxo-2-pyridinyl)carbonyl3 amino 3-2-oxo-1-imidazolidinyl3 sulfonyl3 amino 3 carbonyl]~ 2-oxo-3-aseti dinyl ] -or- (methoxyimin© }-4~thiazole-acetamide, monopotassium salt To a suspension of 0.6 g of (Z)-2-amino~a~ (jnethoxyiminoJ^-tJaiazoleacetic acid (0.003 mol) was added, at room temperature, 2.14 ml (0.009 mol) of tributylamine. The suspension was cooled to -30°C, at which temperature 0.66 ml of diphenyl-chlorophosphate (0.003 mol) was added. The reaction mixture was stirred at -30°C for 1 hour (mixture A).

To a suspension of 1.62 g of (3S)-3-amino~N-I [3-11(1,4-dihydro- 5-hv dr oxy-4-cxo-2-pyridinyl )-carbonyl] amino3-2-oxo-l-ijnida2oliditsyl] sulf onyl J-2-oxo~l-azetidinecarboxamide (0.003 mol) in 20 ml of ethyl acetate was added, at room temperature, 2.6 ml of bis-trimethylsilylacetamide to form a clear, brownish solution, which was stirred for 1 hour at room temperature, then cooled to 0°C (solution B).

Solution B was added dropwise wi-^h stirring to mixture A, while the temperature was maintained at -30® C (ca. 10 minutes). The mixture was stirred at -10°c for 1 hour and at 0°C for an additional l*s hours and evaporated in vacuo. The remaining syrup was dissolved in 50 ml of -137- acetone. To the solution was added 6 ml of 1-molar potassium ethylhexanoate to precipitate 3 „ 0 g of crude product- Addition of ether to the filtrate provided an additional 0.2 g of crude S material. Chromatography of the crude material on macroreticular styrene-divinylbenzene copolymer yielded 1.85 g of the title compound.

Example 20 10 [3S(Z) ]»2~[[Il-(2-Amino-4-thiazolyl )-2-[[1-[[f[3~ [ [ (1,4-dihvdro-5-hycroxy-4-oxo~2-pyri dinyl) carbonyl ] amino ] - 2 - oxo-1 - imi daz oli dinyl ] sul f onyl ] amin o ] -carbonyl 3-2~oxo~3-a2eti dinyl ]amino] »2«oxoe thy li- dene 1 amino 1 ox v 1 - 2 -me th vlp r op an o i c acid [3S(Z)]-2-[ [ [l-(2-Amino-4-thia2olvl )-2-III-1 [ 113- [ [ (1,4-dihydxo~5-hydroxy-4-oxo~2~ pyridinyl)carbonyl] amino]-2-oxo-l-imid£2olidinyl]-' sulfonyl] amino] carbonyl ]-2~oxo-3~a2eti dinyl] amino]— 2-oxoethyli dene] amino] oxy-]-2-me thy lpr opanoic. acid, disodium salt (2.2 g; see Example 1) was dissolved in 20 ml of acetone/water (1:1) and the pH was adjusted to pH 2 with 2N hydrochloric acid. Chromatography using macroreticular s tvrene- di vinyl -benzene copolymer yielded 0.7 g of the title compound. 15 20 25 -138- Example 21 [3 S(Z)]-2-[[[l-(2~Amino-4~thiazolyl)~2-[[l-[[[[3-[ [ (1,4-dihydro-5-hydroxy-4~oxo-2~pyridinyl) carbonyl ]- amino ] ~2 -oxo-1- imidazoli dinyl ] sulfonyl ] amino ] carbonyl*] -2-oxo~3~azetidinyl ] amino] -2-oxoethylidene ] amino ] oxy ] -N-hydroxy-2-methylpropanamide, monosodium salt (Z)-2-Amino-o-[[1,l-dimethyl-2-oxo-2~[(tri-pheny Ime thoxy) amino Jethoxy ] imino ] -4-thiazoleacetic acid (4.72 g) was suspended in 65 ml of acetonitrile and, at ~30°C, 3.72 ml of triethylamine was added.

After 10 minutes of stirring, 1.97 ml of diphenyl-chlorophosphate v/as dropped in. Stirring was then continued for 90 minutes (solution A). (3 S)-3-amino-N-[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl ] amino]-2-oxo-l-imidazoli-dinvl]sulfonyl]-2-oxo-l-azetidinecarboxamide (8.9 ml) was suspended in 70 ml of acetonitrile, and 7.7 ml of bis-trimethyls'ilylacetamide was added. A clear solution was obtained after stirring for 1 hour at -10°C and hours at 0°C. The solvent and formed trifluoroacetic acid trimethyl-silyl ester were evaporated in vacuo and the remaining oil was dissolved in 70 ml of ethyl acetate (solution B).

Solution A was then dropped into the stirred solution B at -20°C during 30 minutes. Continuous stirring at -10°C for 1% hours and at 0°C for 1 hour finished the reaction.

The solvents were then distilled off in vacuo and the oily residue vas stirred with 3 00 ml of ice water whose pH was adjusted to 4.0 with phosphoric acid (10%). The forjned solid was then filtered off, washed with water and dried in vacuo overnight. Yield: 9 g of crude.

The crude product (4.5 g) was stirred with 45 ml of formic acid (98%) and 4.5 ml of dichloromethane at 0°C for one hour, -he title compound (2.3 g) vas obtained toy precipitation with diethyl-ether- £xample 22 [3S(2)3-2-[ r [1-{2-Amino-4~thiatolyl)-2-[[l-[ I [ [2- [ 13" [ I (1,4~dihydro-5"hydroxy-4-oxo-2»pyridinyl )-carbonyl ] amino ] -S-oxo-l-imidazolidinyl ] carbonyl ] -hydrazino] sulfonyl ] amino] carbonyl]~2-oxo-3~ aseti dinyl] amino]~2-oxoethylidene] amino] oxy ] -2-methylpropanoic acid, disodium salt A) *'"[[( Pheny las thoxy) earn onyl ] amino ] - 2 - imidazolidinone l-Amiao-2-imidasolidinone (26 g, 0.257 mol) was dissolved in 200 ml of water. The solution was layered -with 200 ml of ethyl acetate and 43.8 g of chl or o formic acid, bensyl ester (0.257 mol) was dropped into the mixture wirh. stirring while maintaining the pH of 8.5-9 by the addition of saturated sodium bicarbonate solution. After stirring overnight'at room temperature, the -140" title compound was filtered off, washed first with water and then with ethyl acetate. Yield: 46.7 g, melting point 140~144°c. 5 B) 1~[ [ (Phenylmethoxy)carbonyl]amino]-3-(chloro- carbonvl)-2-imidazoli dinone To a .suspension of 69.9 g (0.297 mol) of 1-[ [ (pheny lmethoxy)carbonyl]amino]~2-imidazoli-dinone in 1 liter of dichloromethane was added a 10 solution of 35 g of phosgene in 200 mi of dichloromethane . The mixture was stirred overnight at room temperature to form a clear solution. The solvent was removed in vacuo and the remaining syrup triturated with ether. Yield: 76.0 g, melting point 15 102-105°C.

C) 3- [ [ (Pheny Ime thoxy) carbonyl ] amino ]-2-oxo-l-imidazolidinecarboxylic acid, 2-[(1,1-dimethyl- ethoxv) carbonvl 1 hvdrazide 20 l-[[(PhenyImethoxy)carbonyl]amino]-3-(chloro- carbonyl)-2~imi daz o1i dinone (76 g, 0.255 mol) was added at room temperature to 1.5 liters of ethyl acetate. After cooling to 0~5°C, a solution of 39.S g (0.9 mol) of N-(t-butoxycarbonyl)hydrazide 25 and 41.8 ml of triethylamine (0.3 mol) in 150 ml of ethyl acetate wftre dropped in within 30 minutes. The mixture was stirred overnight. The precipitate was filtered off, dried, stirred with 300 ml of water to remove triethylamine hydrochloride, 30 filtered, washed with water and dried. Yield: 71.2 g, melting point 195-198°C. -141- D) 2- [ [3-[III,4~Dihydro-4-oxo-5-(phenyImethoxy)-2-pyri dinyl] carbonyl] amino ]-2~oxo-l-imi da2oli dinyl ]-' carbonyl3hydrasinecarboxylic acid, 1,1-dixnethyl-ethyl ester S 3~[[(Pbenylmethoxy)carbonyl]amino]-2-oxo-l- imidazelidinecarboxylic acid, 2-[ (1,l~dimethyl~ ethoxy)carbonyl]hydrazide (31.5 g, 0.08 mol) was dissolved in 400 ml of dimethylformamide, 16 g of palladium on charcoal (10%) was added and hydrogen 10 was passed through the stirred reaction mixture." After 1 hour, the catalyst was filtered off. To the filtrate was added 19.62 g of C-henzyl-comenamic acid (0.08 mol), 0.48 g of dimethylamino™ pyridine and 0.54 g of N-hydroxybensotriazole. The 15 ' mixture was stirred for one hour at room temperature. A solution of 18.13 g of dicyclobexylcarbodiimiae (0.0S8 mol) was added at room.temperature and the. mixture was stirred overnight.• The precipitate (dicyclohexylurea) was filtered off, the filtrate 20 evaporated in vacuo, and the residue triturated ■ with water to which sodium bicarbonate was added to adjust the pH to 7.5. The precipitate was filtered off to yield 36 g of the title compound. 25 E) 3- [ [[1,4-Dihydro-4-oxo«5~(phenyImethoxy)-2-pyri dinyl 3 carbonyl ] amino ] - 2 -oxo-l-imi daz oli dine- carboxvlic acid, hvdrazide 2-[I3~[[[1,4-Dihydro-4-oxo~5-(phenyImethoxy)-2 -pyri dinyl ] carh onyl ] amino ] - 2 - ox o-1 - imi das o1i dinyl3 -30 carbonyl]hydra2inecarbo5Tvlic acid, 1,1-dimethyl- ethyl ester (3 6 g) was added, at ~1Q6C with stirring, to 300 ml of trifluoroacetic acid. The mixture was stirred at OeC for 1 hour, the trifluoroacetic acid was removed in vacuo and the residue triturated with ether to yield 41 g of the trifluoroacetate salt of the title compound. The trifluoroacetate salt was suspended with cooling in water and the pH was adjusted to 7 by the addition of 2N sodium hydroxide. The precipitate was filtered off to yield 21-9 g of the title compound. ?) 3- [ [ (1,4-Dihydro~5-hydroxy-4-oxo~2-pyridinyl )~ carhonyl ] amino]-2-oxo-l~ imidazoli dine carboxylic acid, hydrazide 3-[ {[1,4»Dihydro-4~oxo-5-(phenyImethoxy )-2~ pyridinyl]carbonyl]amino]-2-oxo-l-i2nidasolidine- ' carboxylic acid, hydrazide (21.9 g) was suspended in 250 ml of acetonitrile. To the suspension was added 75 ml of bis-trimethylsilylacetamide and the mixture was stirred to form a solution. To the solution was added 10 g of palladium on charcoal (10%) and hydrogen was passed through the vigorously'stirred mixture. The debenzylation was complete after 1 hour. After filtration, 15 ml of methanol and 10 drops of acetic acid were added to precipitate the title compound. Yield: 10.8 g.

This crude material was stirred with 150 ml of ethan^l to yield 8.8 g of the title compound, melting point <205°C, dec. -243- G) (S)~[l~[[[[2"[[3-[[(l,4-Dihydro»5-hydroxy»4~ oxo"2-pyridinyl)carbonyl] amino]-2-oxo-l-imidazoli- dinyl ] carbonyl ] hydrazine ] sulfonyl ] amino ] carbonyl 3 ~ 2-oxo~3-a2etidinvl"l carbamic acid, ohenvlmethvl ester 5 ■ To a suspension of 5.9 g (0.02 mol) of crude 3-[[(1,4-dihydro~5~hydroxy--4~o:KO~2-pyridinyl)-carbonyl] amino 3-2-oxo-i-imidazolidinecarboxylic acid, hydrazide, 14.9 ml (0.08 mol) of N-methyl N-(trimethylsilyl )trifluoroaeeta»iide was added and 10 the mixture was stirred at 50°c to form a solution (solution A).

To a suspension of 4.4 g ox (S )-3-[ [ (phenv1-methoxy)carbonyl]amino]-'2-a2etidinone (0-02 mol) in 160 ml of ethyl acetate, 1.76 al of chlorosul-15 fonyl isocyanate was added at room temperature. The mixture «a,s stirred for 1 hour (solution 3).

Solution A was added- (with cooling, ice) to solution B. After stirring fox 1 hour, 2.8 ml (0-02 mol) of triethylamine was added to the 20 mixture, which was then stirred overnight at room temperature. An additional 2.8 ml of tri ethyl amine (0.02 mol) was added, followed by ice water. The mirrors was stirred thoroughly for 1 hour and the layers ware separated. The aqueous phase was 25 acidified to pH 3 and the precipitate isolated by filtration. Yield: 5.3 g of crude title compound.

The crude material was dissolved in acetone/ water and the.pH of the solution was adjusted to 6.5 by the addition of "2N sodium hydroxide. After 30 removal of "the acetone in vacuo, the acueous solution was filtered and lyophilized to yield -144- 5.5 g of the crude sodium salt, of the title compound. Chromatography of the crude sodium salt 02* macroreticular styrene-divinylbenzene copolymer yielded 0.64 g of purified material. This was 5. dissolved in water axs,d acidified with 2N hydrochloric acid to precipitate the title compound. Yield;'' O.S g.

H) (s J-N-[3-[ [2~[ [ [(3-toino-2-oxo-l-azetidixiyl)~ 10 carbonyl ] amino ] sulf onyl ] hydrazino ] carbonyl ] -2~oxo-l~in.idazolidinyl]~l, 4-dihydro-5-hydroxy-4-oxo-2- pyri dine c arboxami de 0.5 g of (S)~[1-[[[[2-[[3-[[(1,4-dihydro-5~ hydroxy-4-axo-2-pyridinyl)carbonyl ] amino]-2-oxo-l-15 imidazolidinyl3 carbonyl ] hydrazino] sulf onyl] amino] -carbonyl]~2-oxo-3-azetidinyl]carbamic .acid, phenylmethyl ester »as added to a mixture of 0.5 ml of thloanisole and 2 ail of trifluoroacetic acid. The atixfore was stirred overnight at room temperature. ■ 20 and evaporated in vacuo. The residue was triturated' with ethyl acetate to provide the title compound in Quantitative yield.

I) [3S (2) ]-2~ [ [ [1- [ 2 - Amino-4- thi azolyl]-2~ [ [ 1-25 [ [ [ [2- [ [3-1 [ (1,4-dihydro-5-hydroxy-4-oxo-2- pyridiayl) carbonyl ] amino ]-2-oxo~l-imidazolidiayl ] -carbonyl ] hydrazino] sulfonyl ] amino] carbonyl ] -2-oxo-3-azetidinyl ] amino ] -2-oxoethylidene 3 amino] cxy ] - 2- methvlnronanoic acid, diohenvlmethvl ester 30 To a solution of 0.35 g (0.0008 mol) of (2 )-2-eunino~e- [ [2 - (diphenyImethoxy )~1,1-dimethyl-2-oxoethoxy] imino]-4-thiazoleacetic acid in 10 ml of acetonitrile, 0.34 ml of triethvlamine was added. *•145- The mixture was cooled to -30°C and 0.17 ml of diphenylchlorophosphate was added. The reaction nisture was stirred at -30"C for 1 hour (solution A).

To a suspension of 0.008 mol (S)~N~[3™[[2-f [ [ (3-amino~2-ox:©~l-a2etidinyl)carbonyl]amino]~ sulfonyl ] hydrazino 3 carbonyl ] -2-oxo-l-imidasolidinyl ] -1,4-dihydrci-5-hyciroxy-4~oxo-2-py:ricLi:aecarboxamide in 6 ml of ethyl acetate, 0.7 al of bis-trixnethyl-silylacetamide was added (solution B).

Solution B was added to solution A at ~3Q®C. The mixture was stirred at -10°C for 2 hours and at 0°C for 1 hour and evaporated in vacuo. After treatment of the residue with water, 0.7 g of crude title compound was obtained, melting point 155cC, dec.

J) [3S (2) ]-2-1 r [1~(2-Amino-4-thiazolyl )-2-{[1-I [ [ [2- [ 13— £ [ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl )-carbonyl] amino]-2-oxo-l-iaidasolidinyl'] carbonyl]- hydrazino ] sulfonyl ] amino ] carbonyl ] -2-oxo-3 - azeti dinyl]-amino]-2-oxoethylidene] amino] oxy]-2-methylpropanoic acid, disodium salt To a suspension of 0.7 g [3S(Z)]~2~[I[l-[2-amino-4~thia2olyl]-2-[[1-[[ [ [2-[[3-[[(1,4-dihydro-5-hydroxy~4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]carbonyl] hydrazino]sulfonyl]amino]-carbonyl ] ~2~oxo~3~a2eti&inyl ] amino] -"2-oxoethylidene ] -amino]oxy]-2-methylpropanoic acid, diphenylmethvl ester (0.00077 mol) in 1 ml of anisole, 6 ml of trifluoroacetic acid was added at -10°C. ~he mixture was kept at -106C for 1 hour. At -10°C, ether was added to precipitate the trifluoroacetate of the free acid of the starting material, yield D. 5 g. -146- The precipitate was suspended in water with cooling and the pH was adjusted to 5.5 bv the addition of 2N sodium hydroxide. Freeze drying-yielded 0.55 g of crude material. The crude material was purified by chromatography on macroreticular styrane-divinylbenzene copolymer to yield. 0.1 g of purified title compound.

Example 23 [3S(2)]-2-[[[l-(2-Amino-4-thiazolyl)-2-[[1~[[[[2-[ (1,4-dihydro-5-hydroxy-4~oxo-2-pyridinyl)carbonyl]- 2-methylhydrazino]sulfonyl]amino]carbonyl]~2-oxo- 3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, disodium salt A) 1,4-Dihydro-4-oxo-5~(phenyImethoxy)-1-(phenylmethyl )-2~-pyridinecarboxylic acid, l~methvlhvdrazide N,O-Dibenzylcomenamyl chloride (0.15 mol) was suspended in 150 ml of dichloromethane with ice cooling. To the suspension, 26.2 ml (0.5 mol) of methylhydrazine was added, followed by 150 ml of acetonitrile. The mixture was stirred overnight at room temperature. The turbid solution was evaporated in vacuo and triturated with 300 ml of water. The solid material obtained was filtered and dried to yield 26.3 g of crude material. Recrystallization of the crude material from water yielded 12.7 g of pure title compound, melting point 138-142°C. -147- B) (S )-l,4-Dihvdro-4-oxo-5~(phenylmethoxy )-l-(phenylmethyl)-2-pyri dinecarboxylic acid, l-methyl-2-[[[[2- oxo-3- [ [ (phenyImethoxy)carbonyl]amino]-l-asetidinyl]- carbonvllamino1sulfonvlIhvdrazide 5 ' 1,4-Dihydro-4-oxo-5-(pheny Ime'thoxy )-l- (phenyl-methyl) -2-pyridinecarboxy 1 i c acid, 1 ~methylhydr&zi de (1.82 g, 0-005 mol) was suspended in 20 ml of ethyl acetate. At room temperature, a total of 1.85 ml of N-methyl~N-(trii»ethylsilyl)trifluoroacetami.de 10 (0.01 mol) was added. The mixture was stirred for 4 hours at 60°C (suspension A).

(S)-3-[[(PhenyImethoxy)carbonyl]amino]-2-azetidinone (1.1 g, 0.005 mol) was suspended in 40 ml of ethyl acetate at room temperature and 15 0.5 ml of chlorosulfonyl isocyanate was added.

The mixture was stirred at room temperature for 1 ■ hour to form a solution (solution 3).

To solution B., 1.2 ml of triethylamine was added (with ice cooling) followed by 20 ml of 20 dichloromethane- and suspension A. The suspension was stirred overnight at room temperature. To the slightly turbid solution, 30 ml of dichloromethane and 20 al of water was added and the mixture was stirred for 1 hour at room temperature. 25 The pB of the aqueous phase was 6.5-7. 60 ml of ethyl acetate was added, the organic layer separated and the aqueous phase washed twice with a mixture of di chl or ©methane/ethyl acetate (1:3). The combined organic phases were dried 30 (magnesium sulfate) and evaporated to yield 4.5 g of a syrup which crystallized on standing over the weekend. After treatment with ether, 2.6 g of crude title compound was obtained. -148- C) 1,4-Dihydro-5-hydroxy-4-oxo-2~pyridinecarboxylic acid, 2-[[[(3-amino~2-oxo-l-azetidinyl)carbonyl]-amino]sulfonyl]-1-methylhydrazide, trifluoro-acetate salt 5 ' To a solution of 2 g of (S)-l,4-dihydro-4-oxo- 5- (phenv Ime tho sty) -1 - (phenylme thyl) - 2 -pyri dine-carboxylic.acid, l-methyl-2™[[[[2-oxo-3-[[(phenyl-methoxy)carbonyl]amino]-1-azeti dinyl]carbonyl]-amino]sulfonyl]nydrazide in 60 ml of dimethyl-10 formamide, 1.1 ml of trifluoroacetic acid was added, followed by one gram of palladium on charcoal (10%). After flushing with nitrogen, hydrogen was passed through the solution for 60 minutes with stirring, the catalyst was removed by 15 filtration, the filtrate evaporated in vacuo and the residue triturated with ether to yield 1.1 g of crude title compound. Yield: 86.6%.

D) [3S(Z)]-2-[[[l-(2-Amino-4-thiaaolyl)-2-[[1-20 [[[[2-[(l,4~dihydro-5-hydroxy~4-oxo-2-pyridinyl)- carbonyl]-2~methylhydrazino]sulfonyl]amino]carbonyl]-2-0x0-3-azetidinyl]amino]-2-oxoethylidene]amino]-oxy1-2-methylpropanoic acid, dinhenvlmethvl ester To a suspension of 0.88 g of (Z)-2-amino-a-25 [[2-(diphenyImethoxy)~1,l-dimethyl-2-oxoethoxy]-imino]-4-thiazoleacetic acid (0.002 mol) in 30 inl of acetonitrile 0-7 ml (0.005 mol) of triethylamine was added, followed, at -30°C, by 0.44 ml of diphenylchlorophosphate (0.002 mol). The mixture 30 was stirred at -30°C for 1 hour (solution A).

To a suspension of 1.2 g (0.002 mol) of 1,4-dihydro-5~hydroxy-4-oxo-2-pyridinecarboxylic acid, 2-[[[(3-amino-2-oxo-1-azetidinyl)carbonyl]- -149- amino]sulfonyl3~l-methylhydra2ide, trifluoroacetate salt in 30 ml of ethyl acetate, 2 ml of bis-trimethvlsilylacetamide (ca. 0.008 mol) was added at i-oobi temperature to form, after 30 5 minutes, a clear solution (solution 3).

At »30°C, solution B was added dropwise to solution A .(ca. 10 minutes). The temperature was kept at -1Q6C for 1 hour and at DeC for another hour. The solvent was evaporated and the residue 10 treated with water, to yield, after filtration and drying, 2.4 g of crude title compound.

E) [3S(2)]-2-[ [ [1- (2-Amino-4-thiasoly 1 )-2~[[1-I [ [ f2~ [ (l,4-dihydro-5-hydroxy-4~oxc>~.2-pyridinyi )-15 carbonyl 3 -2-methylhydra2ino] sulf oayl ] amino ] carbonyl 3 ~ 2-oxo-3-azeti dinyl 3 amino 3 - 2 - ox oe thyli dene ] amino 3 ~ oryl-2-methvlpropanoic acid, disodium salt At ~10°C, 2.4 g of crude I3S(2)3-2-[[Il-(2-amino-4-th.iazolyl )-2- [ [1- [ f [ [2- {(1,4~dihydro-5-20 hydroxy-4-oxo-2-pyridinyl )carbonyl] -2-methyl-hydrasiao 3 sulfonyl 3 amino 3 carbonyl 3 ~2-oxo-3~ azetidinyl3amino3-2-oxoethyliaene3 amino 3 oxy}- 2-methylpropanoic acid, dipheny Ime thyl ester was added to a mixture of 20 ml of trifluoroacetic acid 25 and 4 ml of anisole. The mixture was stirred at -10°C for 1 hour and the reaction product was precipitated by the addition of ether at -10°C; Yield; 1.12 g of the crude trifluoroacetate of the title compound. 30 The crude material was .converted to the sodium salt by the addition of 2W sodium hydroxide to a suspension in acetone-water and lyophilization. The sodium salt was purified by chromatography on macroreticular styrene-divinylbenzene copolymer 35 (elution with water). Yield: 0.25 g. -150- Example 24 (3S)-2-[[[l-(2~Amino-4-thiazolyl)-2-[[1-[[[[[(1,4-di.hydro-5~hydroxy-4~oxo-2-pyridinyl)methyl ] amino]~ sulfonyl]amino]carbonyl]-2~oxo~3~azetidinyl]amino]~ 5 2-oxoethvliaenelamino]oxy]-2-methylpropanoic acid A) 2-(Hydroxvmethvl)-5-(phenylmethoxy)~4H-pvran-4-one A suspension of 5-hydroxy~2-(hydroxymethyl)-4H- pyran-4-one (56.8 g, 0.4 mole) in 400 ml of methanol 10 was treated with sodium hydroxide, (16 g, 0.4 mole) in 200 ml of warm methanol followed bv 50.6 g (46 ml, 0.4 mole) of benzyl chloride. The mixture was heated, to reflux for 3.5 hours, cooled, and poured in 1 L of water. The resulting solid was 15 filtered and washed with ca. 1.5 L of water, 200 ml of ethanol and 400 ml of hexane. After drying under high vacuum, the weight of product was 55.7 g. 20 B) l,4-Dihydro~2-(hydroxymethyl)-5~(phenyImethoxy)- 4-pvridinone A mixture of 2-hydroxymethyl-5-(phenyImethoxy)~ 4H-pyran-4-one (9.65 g, 41.59 mmole), 95 ml of concentrated ammonia and 20 ml of ethanol and 25 heated at reflux overnight. An additional 75 ml of ammonium hydroxide was added, the mixture was refluxed for 2 hours and cooled. The resulting brown solid was filtered and washed with water until the washings were neutral. The crude product: 30 was suspended in ethanol, filtered, washed with ethanol and hexane and dried in vacuo. The yield of the title compound was 7.61 g. -151- C) 2- (chloromethyl)-l, 4-dihydro~5~ (phenylme thoxy-) - 4-pyridinone, hydrochloride A suspension of 1,4-dihydro~2-(hydroxymethyl) - 5-(phenyImethoxy)-4-pyridinone (3 g, 12.99 ©mole) 5 in chloroform (15 ml) was cooled to 0°C under argon and treated with thionyl chloride (6.1 ml, 83.62 mmole). Within several minutes, a homogeneous solution was obtained. After stirring an additional 5 minures, a cream colored solid precipitated. The cooling 10 bath was removed and the mixture was heated at reflux for 45 minutes. The mixture was cooled to 0°C and the white suspended material was filtered, washed with chloroform and hexane and dried in vacuo. The yield of the title compound was 3.65 g. 15 D) 2-(Azidomethyl)-l,4-dihydro-5-(phenoxymethyl )« 4-pvr i dinone A mixture of 2 -(chloromethyl)-1,4-dihydro-5-(phenyImethoxy)-4-pyridinone, hydrochloride 20 (3.59 g, 12.54 mmole), sodium aside (4.08 g, 62.7 mmole) and diisopropylethylamine (2.19 ml, 12.54 mmole) in 70 ml of dimethyl forrnamide was stirred at room temperature under argon for 3.5 days. An additional 4.08 g of sodium azide was 25 added and the mixture was heated at 45-50°C for 2 hours. After cooling, the reaction was poured into 500 ml of water, producing an insoluble white solid. The pH of the supernatant liquid was lowered from 8.5 to 7.5 with dilute hydrochloric 30 acid, and the white solid was filtered. After washing with water, acetone, and hexane, the solid was dried in vacuo. The yield of the title compound was 2.81 g. -152- 10 E) 2- (Aminosaethvl )"4-oxo"5- (phenvlmethoxv )pvridine h suspension of 2«(azidomethyl)-l,4~dihydro-5~ (phenoxymethyl)-4~pyridinone (2.030 g, 7.93 mmole) •and platinum oxide (200 mg) in 100 al of dimethyl- fonuaiflids was stirred for sis hours at room : tempera-cure under one atmosphere of hydrogen. The catalyst was removed by filtration and the solution was concentrated in vacuo to afford 1.5 g of the title compound as a grey powder.

F) (3S)-l-[[[f[(l,4-Dihydro-5-hydroxy-4-oxo-2- pyri dinyl) methyl ] amino ] sulfonyl ] amino ] carbonyl 3 -2"QXo»3~ f f(phenyImethoxv)carbonvl1 amino1azetidine To a stirred suspension of 2- (aminomethyl)-4-15 oxo-5-(pheaylxae thoxyJpyridine. (2.330 g, 10.13 imnole) in SO al of ethyl acetate, was added N-methyl-N-(trims thyl silyl) tri fluor o a cetami de (3. 7d ml, 20.26 aaaole). The resulting solution was stirred for 30 minutes at room temperature and then cooled 20 to 0°C. Concurrently, to a stirred suspension of (S )-3- [ [ (pheny Imethoxy) carbonyl ] amino J -2-aseti dinone (2.228 g, 10.13 sanole) in 60 ml of ethyl acetate was added chlorosulfonyl isocyanate (8B2 ul, 10.13 nanol). The resulting solution was stirred 25 for 30 minutes at room temperature then cooled to 0aC and treated with triethyl amine (4.23 ml, 30.39 mmole) followed by the solution of silylated 2- (aminomethyl)-4-oxo-5- (pheny Ime thoxy )pyri dine described above. The mixture was stirred for two 30 days at room temperature.

The mixture was concentrated in vacuo, the residue dissolved in acetonitrile-vrater (40-60) -153- and the pH lowered to 2.9 whereupon a thick oil separated. Upon cooling to 5°C, the oil solidified. The solid was separated, washed four times with water, and dried in vacuo to afford 5 3.4 g of cmde title compound. The crude was dissolved in a minimum volume of dime thy 1 f o rm ami de aad loaded .on a column (IL) of macroreticular styrene-divinylbenzene copolymer. The column ■ was eluted with a stepwise acetone-water gradient. 10 Desired material eluted with ca. 65% acetone. The relevant fractions were combined and lyophilized to afford 2.69 g of the title compound.

G) (3S)—2—[[[l-(2-Amino-4-thiazolyl)-2-[[1-15 111 [ [ (1 / 4-dihyaro-5-hydroxy-4~oxo-2-pyridinyl )-methyl ] amino] sulfonyl] amino] carbonyl ]-2~oxo~3-azeti dinyl ] amino]-2-oxoethylidene ] amino ] oxy] -2- methvlDrooanoic acid, dinhenvlmethvl ester- (3S )-l-[1111(1,4-Dihyaro-5-hydroxy~4-*oxo-2-20 pyridinyl )methyl ] amino] sulfonyl] amino] carbonyl] ~" 2-oxo-3-{ [ (pheny Imethoxy) carbonyl ] amino] as eti dine (912 mg, 1.64 mmole), p~toluetnesulfonic acid mono-hydrate (625 mg, 3.28 mmole) and 10% palladium on charcoal (190 mg) in 16 ml of dimethylformamide 25 were stirred under one atmosphere of hydrogen until 3.2S mmole (73 ml) of hydrogen was consumed (ca. 3 hours).

To a stirred solution .of (2 )-2-amino-cr-[ [2-(diphenylmethoxy)~1, l-dimethyl-2-oxoethoxy] imino ] -30 4-thiazoleacetic acid (846 mg, 1.B04 mmole) in 16 ml of dimethyIformamide at »20°C was added diphenylchlor©phosphate (374 1, 1.804 mmole ) followed by triethylamine (450 jjI, 3.2B nanole). -254- The solution was stirred for 1 hour at -20°C whereupon the above-described mixture of hydrogen-olyzed compound was added.- Triethylamine (921 ul, 6.6 mmole) was then added. The resulting mixture 5 was stirred ax -20*C for one hour and then at S®C overnight. The catalyst was removed by filtration, volatiles were removed in vacuo and the resulting oil was dissolved in a minimum volume of acetone-water (75-25) (pH S.2) and added dropwise to a 10 stirred suspension of 20 ml of Dowex 50x2-400 (K ) in acetone-water (35-65). After 40 minutes, the mixture was filtered and the filtrate lyophilised to afford 2.1 g of solid. The solid was dissolved in a minimum amount of acetonitrile-watsr (40-60) 15 (pB 5.6) and loaded onto a colujan (800 ml) of macroreticular styrene-divinylbenzene copolymer, eluting with a stepwise acetooxtrile-water gradient.,. Desired snaterial eluted with ca. 30% acetonitrile. The relevant fractions were combined and lyophilized 20 to afford the title compound.

E) (3S)-2-[[[l-(2-Aaino-4-thiasolyl)-2-[ [1-[[[[[(1 / 4-dibycbro-5~hydroxy~4*-oxo-2-pyri dinyl )-methyl] amino] sul fonyl] amino] carbonyl ] -2-oxo-3- 2 5 azeti dinyl ] aai.no ] -2 - oxoethy li dene ] amino ] oxy ] - 2 - methvlpro^anoic acid Trifluoroacetic acid (4.7 ml) was added dropwise to a stirred suspension of (3S )-2-[[[1-(2-amino~4-thia2olyl)-2-[[1-[[[[[(l,4-dihydro-5- 3 D hydroxy-4-oxo-2~pyridinyl )methyl ] amino ] sulfonyl ] - amino] carbonyl ] -2~oxo-3--azeti dinyl ] amino] -2-oxo-ethylidene]amino]oxy]-2-methylpropanoic acid, -155- diphenylmethyl ester (131 rng, 0.113 mmole) in 3 ml of dichloromethane and 0.3 ml anisole at. 0°C«, After stirring <45 minutes at Ssc, 2 ml of toluene was added and the volatiles were removed in vacuo. 5 The resulting oil was washed with hexane (3^4 ml) and triturated to a solid with 10 ml of ether. The solid was washed once with ether (10 ml) and • dried in vacruo. The above reaction and work-up were repeated on 0.166 mmole of (3S)-2-[[[1-(2-10 amino-4-thiazolyl)~2-[ [1«[ [[[ [ (l,4-dihydro~5~ hydroxy-4-oxo-2-pyridinyl)methyl ] amino]sulfonyl ]-amino ] carbonyl ]-2-oxo~3-aseti dinyl ] amino ] -2- oxo-ethylidene]amino]oxy]-2-methylpropanoic acid, diphenylmethyl ester. The crude solids were 15 combined, dissolved in 2 sal of acetonitrile- water (40-60) (pH 2.5) and chromatographed on a column (200 ml) of macroreticular styrene-di'vinyl-benzene copolymer, using an acetonixrile-watex' gradient. The desired material eluted.at 20 acetonitxile-water (20~80). The relevant fractions were combined and 'lyophilized to afford 103 rag of the title compound as a white solid, melting point 180°C, dec. -156-

Claims (25)

1. claims: 1. A compound having the formula 'CH. s ,2 I r3 A 7 -N-C-NE-SO^-R or such a compound in pharmaceutical}.y acceptable salt form wherein 0 R is -An-N^^W-A^-C-Ar^N 6 H -A-, -N N I it U 0B i—i -A.,-C-A^N , -An -N^^N-A? D: iQ H 6 10 15 -NH-A or 0 0 a II li u is an acyl group derived from a carboxylic acid; R, and R^ are same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7-membered heterocycle or one of R^ and Rg is -157- hydrogen and the other is azido, halomethyl, dihalomethyl, tribalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethyuyl, carboxyl, I 3 | 3 -ch2x1 , -s-x,, -o-x,, -o-c-x4, -s-c-x4 or 0 ' xc x. II 5 5 -A-C-NX6X7^ 5 Xn is asido, amino, hydroxy, carboxyl, alkoxycarbonyl, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyl-oxy, phenylsulfonyloxy, (substituted phenyl)-sulfonyloxy, phenyl, substituted phenyl, cyano, 0 II 10 -A-C-NX6X?, -S~X2, or -0-x, ; X9 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, pheny1alkanoyl, (substituted phenyl)alkanoyl, phenylcarbonyl, (sub-15 stituted phenyl)carbonyl, or heteroarylcarbonvl; one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X^ and X^ when taken together with the carbon atom to which they are attached form a cycloalkyl group; 20 X5 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino) carbor.y 1, or cyano ; 25 X, and X7 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl, or Xg is hydrogen and X7 is amino, substituted amino, alkanoylamino or alkoxy, or X, and X7 when taken together with the nitrogen atom to which they are 30 attached form a.4, 5, 6 or 7-membered heterocycle; -158- A is -CH=CH-, -(CK0) -, -(CH_) -0-, •4 IH Gm ill -(CH~) -NH- or -CH,-S-CH--; 2 IB 2 2 n is 0, 1 or 2; o A., is a single bond, -NE-U-, -KH- or 0 -NH-NH-C-;. A, is a single bond, -NH-, or 0 -S-NB-NH-; 0 0 A3 is -(CH,) -, -N3-S-NH- , -NH-S-NH-CH,-, 0 0 -NH-CH7~, -O-CH,-, -CE,~c!-NH-, or -CH2~t!-NH-CH2-; a4 is -NH-, -(CH2)p-, -(CH^) -N5-, O 0 " CH-X 11 It I 2 -NH-C-NH-NE-, -C-NE-NE-, or -N-; Ag is a single bond, -CH,-, 0 -n=ch-, or -H-NH-(CH,) *. 9 afi is a single bond, ~C3~CH» or ~(CH, p is 0 or 1; y is 2, 3 or 4; q is 0 or 1; t is 1, 2, 3 or 4; and X is hydrogen, carboxyl or carbamoyl.

2. A compound in accordance wirh claim 1 -159-

3. A compound in accordance with claim 1 (j fl jj °d wherein R is -A., -N M-A,-C-A^W' ~0^ ^0 ~ ° H

4. A compound in accordance with claim 1 1 JU °H wherein R is -An ~N^ ^N-A--~"~^£K 3 I p

5. A compound in accordance with claim 1 - A- wherein R is -An-N N-Ag— H

6. A compound in accordance with claim 1 o- i OH wherein R is -NH-A-r-^N- ■5 j H

7. A compound in accordance with claim 1 0 H (fV°H 10 wherein R is -NS-A4-C-Ag— H

8. A compound in accordance with claim 2 wherein A_, is a single bond.

9. A compound in accordance with claim 2 wherein A, is -NH-. 15

10. A compound in accordance with claim 2 wherein A& is a single bond. -160-

11. A compound in accordance with claim 1 . [ 1 1 °H is -lL -N-NH-C*— wherein R., is 1 I O H

12. A compound in accordance with claim 1 wherein R,.and R^ are each hydrogen. 5

13. A compound in accordance with claim 1 0 II wherein R, is -C~C=N-0-R. and R. is 2-anu,no~4~ 1 | i g R * 9 thiazolyl and is methyl, ethyl, carboxvmethyl, l-carboxy-l-methylethyl, l~carboxy~l~ethyl, or ch2-(ch2)s 10 -C-COOH, wherein s is 1, 2 or 3.

14. A compound in accordance with claim 1 0 wherein R. is -£-c=N-0-R•, R is 2-amino~4~thia2olyl 1 K 9 and is carboxymethyl, 1-carboxy-l-methylethyl, c^-(ch2)s 1-carboxy-l-ethyl, or -C-CQOB, wherein s is 1, 2 or 3. 15

15. A compound in accordance with claim 2 0 If wherein R, as -C-C=N-0-R. and R is 2-aaino-4- K thiazolvl and R^ is methyl, ethyl, carboxymethyl, l-carboxy-i-methylethyl, l-carboxy-l~ethyl or CEL-(CH_) ' 2 ;s -u-COOH, wherein s is 1, 2 or 3. -161-

16. A compound in accordance with claim 2 0 wherein Rn is -C-(p=N-0-R^, is 2-amino-4~thiazoly 1 Rg and is carboxymethyl, l~carboxy-l-methylethyl, C52"VCH2}s l-carboxy~l~ethyl or -C-CQQH, wherein s is l, 2 or 5 3.

17. A compound in accordance with claim 11 0 II wherein R. is -C^-C-h-0-R. and K is 2-amino—4~ 1 | i g * <3 thiazolyl and Rs is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethy1, 1-carboxy-l-ethyl or 10 -C-COOH, wherein s is 1, 2 or 3.

18. h compound in accordance with claim 11 0 wherein is -li-C-N-O-R. , R is 2-amino-4~thiazolvl x i i g *g and R^ is carboxymethyl or 1-carbcxy-l-methylethyl.

19. A compound in accordance with claim 11 15 wherein R, and R^ are each hydrogen.

20. The compound in accordance with claim 1, [3S(Z)]-2-[[[l-(2-amino-4-thiazolyl)-2-[[l-[[ [ [3- [ [ (1,4-dihydro-5~hydroxy-4-oxo-2~pyridinyl)carbonyl]-amino]-2-oxo-l-imidazolidinyl]sulfonyl]amino]-20 carbonyl]-2-oxo-3-aaetidinyl] amino]-2-oxoethyl idene] amino] oxy]-2-methylpropanoic acid, or a pharmaceutical^ acceptable salt thereof. -162-

21. The compound in accordance with claim 1, [3S(Z)]-2-[[ [l-(2~amino-4~thia2olyl )-2-[[l-[I[[2-[(1,4-dihvdro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]-hydrasino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl] ■ 5 amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, or a pharmaceutical^ acceptable salt thereof.

22. .The compound in accordance with claim 1, [3S(2) ]-2-[[[l-(2-amino-4-thia2olyl)-2-[ [1- [ [ [ [3- [ [ (l,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)~ 1 o carb ony 1 ] amino ] - 2 -- oxo-1 - imi diz o 1 i diny 1 ] sul f ony 1 ] - amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy]~2-acetic acid, or a pharmaceutical^ acceptable salt thereof.

23. The compound in accordance with claim 15 1, [3S(Z)]-2-[ [[l-(2~amino-4~thiazolyl)-2- [ [1- [ [ [ [ [ (1,4-dihydro~5-hydroxy-4-oxo-2~pyridinyl )-methyl ] amino ] sulfonyl ] amino ] carbonyl ] ~2~oxo-3~ azeti dinyl ] amino ] -2 - oxoethyli dene ] amino ] oxy ] -2-roathylpropanoic acid, or a pharmaceutical^ 20 acceptable salt, thereof.

24. The compound in accordance with claim 1, [3S(Z)]-2-[[[l-(2-amino-4-thia2olyl)-2~[[l-[[[[2-[ [2- [ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl )-carbonyl] hydrazino] carbonyl] hydrazine] sulfonyl]-25 amino ] carbonyl ]-2-oxo-3-azeti dinyl ] amino ] -2-oxo ethylidene] amino] oxy]-2-methylpropanoic acid, or a pharmaceutically acceptable salt thereof.

25. The compound in accordance with claim 1, [3S~[3a(Z),4P]]-2-[[[1-(2-&mino-4-thiazolvl)-2- 30 I[1~[tI[2-[(1,4-dihydr -5-hydroxy-4-oxo-2~pyridinyl)- carbonyl]hydrazine]sulfonyl] amino]carbonyl]-4-methyl-2-oxo-3-azetidinyl ] amino] -2-oxoethylidene ] amino] oxy ] -2-methylpropionic acid, or a pharmaceutically acceptable salt thereof. 25. The compound in accordance with claim 1, [3S(2)]-1-[[[l-(2-amino-4-thiazolyl)-2-[[l-[[[{3-[ [ (1', 4-dihydro-5-hydroxy-4-oxo-2 -pyridinyl) carbonyl ] -amino]-2~oxo-l-imida2olidinyl ] sul fonyl ] amino ] carbonyl ] -2-oxo-3-azeti dinyl] amino]-2-oxoethylidene] amino] oxy]-cyclopentanecarboxylie acid, or a pharmaceutical^ acceptable .salt thereof. 27. A process for preparing compounds according to claims 1-2 6 comprising (1) acvlating a compound of the formula NH2 ' i-r, I I 3 "" "-NH-SO,-R , with an acyl group derived from an R1-carboxylic acid, or (2) introducing a -CO-NH-SOjR activating group to a compound of the formula VNH - 164 - 28. A compound in accordance with Claim 1 substantially as herein described. 29. A 2-oxo-l[[(substituted sulfonyl)amino]-carbonyl] azetidine in accordance with Claim 1„ substantially as described in any of the Examples. maclachlan & DONALDSON, Applicants® Agents, 47 Merrion Square,, DUBLIN 2.