IE56600B1 - Azetidinyl sulfonic acid and analogs - Google Patents

Abstract

Antibiotic activity is exhibited by beta -lactams having an substituent in the 1-position and an acylamino substituent in the 3- position, R<5> and R<6> being hydrogen atoms at various defined substituents or R<5> and R<6> together completing a ring. The corresponding 3-amino compounds may be produced as intermediates. The compounds may be of the formula:- or salts or esters thereof, R1 being hydrogen or acyl and R2, R3 and R4 being hydrogen atoms or substituents.

Description

This invention is directed to a nov^l family of S-lactam (2-azetidinone) antibiotics, end to use of such compounds as antibacterial agents.

It has been discovered that the 2-lactam nucleus can be biologically activated by a substituent RC X X 6 having the formula «O-OSO^H (or salt thereof) attached to the nitrogen atom in the nucleus.

TO S-Lactams having a -O-C-SOjH substituent (or pharmaceutically acceptable salt thereof) in the 1-position and an acylamino substituent in the 3-position exhibit activity against a range of gram-negative and gram-positive bacteria.

Illustrative members of the novel family of β-lactam antibiotics of this invention are those encompeissed by the formula R, r2 R.-NH-C-C-R, „ 1 ι ι 0*c so^a or a diphenylmethyl ester or salt thereof. -2As used in formula I and throughout the specification, the symbols are as defined below. is acyl; R, is hydrogen or methoxy; R, and Rn are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4,5,6 or 7-membered hetorocycle (referred to hereinafter as £U) or one of and Rc is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, *<Η2Χχ, -S-X,, X, X, 0 13 13 II -0-X2, -O-C-X^, -S-C-X^, os: -A-C-NXgX? ; X5 X5 Χχ is azido, amino (-NH^), hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2 or -O-X, · X^ is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl or heteroarylcarbonyl; one of X^ and 2L is hydrogen and the other is hydrogen or alkyl, or X, and ΧΛ when taken together with the carbon atom fo which they are attached fora a cycloalkyl group; is formyl, alkanoyl, phenylc&rbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl lalkylcarbonyl, carboxyl, II alkoxycarbonyl* aminocarbony! (NH?-C-), (substituted amino)carbonyl, or cyano (-C5^); -3A is -CH«CH, -CH^CHCH-, "2)-n , n is 0, It 2 or 3; n' is 1 or 2; * Xg and X7 are the same or different and each is hydrogen or alkyl, or Xg is hydrogen and X? is amino, substituted amino, acylamino or alkoxy; and * and Rg are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or Ry, or Rg and R. together with the carbon atom to which they o are attached are cycloalkyl or R?, or one of Rg and Rg is hydrogen and the other is azido, halomethyl, dihaloraethyl, trihalomethyl, alkoxyearbonyl, 2-phenylethenyl, 2-phenylethynyl, II carboxyl, "CH2X1' ’SX2' °X2' ΟΓ · .Listed below are definitions of various terms used to describe the S-lactarns 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 croups having 1 to 10 carbon atoms.

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

The term ^substituted alkyl refers to alkyl groups substituted with one, or mere, azido aminohalogen, hydroxy, carboxy, cyano, * -4alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy# (substituted phenyljoxy, R-y-oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl, or alkylsulfonyl groups.

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

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

The term protected carboxylw refers to a carboxyl group which has been esterified with a conventional acid protecting group.

These groups are well known in the art; see, for example, United States patent 4,144,333, issued March 13, 1979. The preferred protected carboxyl groups are benzyl, benzhydryl, t-butyl, and p-nitrobenzyl esters.

The term substituted phenyl refers to a phenyl group substituted with 1, 2 or 3 2θ amino (-NH^), halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), or carboxyl groups.

The expression a 4,5,6 or 7-membered heterocycle (referred to as EL) refers to substituted and unsubstituted, aromatic and non-aromatic groups containing one or more nitrogen, oxygen or sulfur atoms. The substituents are oxo(^0), halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 -510 carbons, alkoxy of X to 4 carbona, alkylsulfonyl, phenyl, substituted phenyl, 2-furylimino (I1 *1 ), benzyl imi no and substituted alkyl groups (wherein the alkyl group has 1 to 4 carbons). One type of 4,5,5 or 7-membered heterocycle is the heteroaryl11 group. Th® term heteroaryl" refers to those 4,5,6 or 7-membered heterocycles which are aromatic. Exemplary heteroaryl groups are substituted and unsubstituted pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, and tetrazolyl. Exemplary nonaromatic heterocycles (i.e., fully or partially saturated heterocyclic groups) are substituted and unsubstituted azetinyl, oxetanyl, uhietanyl, piperidinyl, piperazinyl, imida zo1id inyl, oxa zolidinyl; pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl and hexahydroa2epinyl. Exemplary of the substituted 4,5,6 or 7-membered heterocycles are l-alkyl-3azetinyl, 2-oxo-l-imidazolidinyl, 3-alkylsulfonyl-2oxo-l-imidazolidinyl, 3-benzylimino-2-oxo-limidazolidinyl, 3-alkyl-2-oxo-l-imidazolidinyl, 3-phenyl (or substituted phenyl)-2-oxo-limidazolidinyl, 3-benzyl-2-oxo-=l-imidazol idinyl, ~s3-(2-awino9 3- [2~ [ (alkoxycarbonyl) amino] ethyl J -2-oxo-l-ixnidasolidinyl, 2-oxo-X S pyrrolidinyl, 2"OXO-3-oxa3olidinyl, 4-hydro5iy-6~ methyl-2-pyrimidinyl, g-oxo-X-hexahydroaxepinyl, 2-oxo-3-pyrrolidiny!, 2-oxO3-£uranyl, 2,3-dioxol-piperasinyl, 2,5-dioxo-X-pipera2inyl, 4-alkyl 2,3-diojto-l-piperaginyl, and 4-phenyX-2,3-dioxo10 l~piperasinyl, The term substituted amino refers to ® group having the formula -NY^Y, wherein Y^ is hydrogen? alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Y, is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino (-NH,).

The term "substituted alkanoyl includes within its scope compounds having the formula {} (substituted alkyl)«C- (wherein substituted alkyl is defined above) and phenylalkanoyl. -ΊThe term acyl refers to all organic radicals derived from an organic acid (i.e., a carboxylic acid) by removal of the hydroxyl group. Certain acyl groups are, or course, preferred butthis preference should not be 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 β-lactam antibiotics including 6-aminopenicillanic acid and derivatives and 7-aminocephalosporanic acid and derivatives; 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 4,125,432, issued May 1, 1979, United States patent 3,971,778, issued July 27, 1976, United States patent 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 groups are incorporated herein by reference. The following list of acyl groups is presented to further exemplify the term acyl*1? it should not be regarded as limiting that term. Exemplary acyl groups are: (a) Aliphatic groups having the formula II R -Ca wherein R, is alkyl? cycloalkyl? alkoxy; alkenyl; a -8eyeloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, or cyanomethylthio groups. (b) Carbocyclic aromatic groups having the formula IL lcb^VcH,-oi, c wherein n is 0, 1, 2, or 3; R^, Rc, and R^ each is independently hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoro -methyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethyl? and Ηθ is amino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, a sulfo salt, a sulfoamino salt, azido, halogen, hydrazino, alkylhydrazino, phenylhydrazino, or [(alkylthio)thioxomethyl]thio.

Preferred carbocyclic aromatic acyl groups include those having the formula HO II II -10" -οfc.

(Re ie preferably a carboxyl salt or sulfo salt) and (Re is preferbly a carboxyl salt or sulfo salt). (c) Heteroaromatic groups having the formula ff Rf-lCH2>n~C15 II R--CH-C1 I Rf-O-CH2-C-, ff Rf-S"CH2-C", O 0 II II Rf-C—Cwherein n is 0, 1, 2 or 3; Rg is as defined above; and Rf is a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms. Exemplary heterocyclic -11rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl. Exemplary substituents are halogen, hydroxyl, nitro, amino, protected amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or II HOOC-CH-CH--O-C-NHAh2 Preferred heteroaromatic acyl groups include those groups of the above formulas wherein is 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, - amino-1,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl, or 6- aminopyridin-2-yl. (d) [[(4-Substituted-2,3-dioxo-1-piperazinyl) carbonyl]amino]arylacetyl groups having the formula 0 , , u n / \ 'C-CH-NH-C-N N-Rn f)? and R^ is alkyl, substituted -13Preferred (substituted oxyimino)arylacetyl groups include those wherein Rg is 2-aminoM-thiazolyl. Also preferred are those groups wherein Is methyl, ethyl, carboxymethyl, Ί-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxycyclo propyl. (f) (Acylamino)arylacetyl groups having the formula 0 II H -C-CH-NH-C-Rj ΊΟ as defined above and Rj is amino, amido, alkylamido, NH tt -CH2-NH-C-C xn (cyanoalkyl)amido, -ch-ch2-c-nh-ch3.

HO c~ II -12alkyl (wherein the alkyl group Is substituted with one or more halogen, cyano, nitro, amino or mercapto groups), arylmethyleneamino (i.e., -NCH-Rg wherein R^ is as defined above), II arylcarbonylamino (i.e., -NH-C-Rg wherein R^ is as defined above) or alkylcarbonylamino.

Preferred [[(4-substituted-2,3-dioxo-1-piperazinyl) carbonyl]amino]arylacetyl grouDs include those wherein R^ is ethyl, phenyImethyleneamino or 2-fury Imethy leneamino. (e) (Substituted oxyimino) arylacetyl groups having the formula -C-C=M-O-R.

I, 1 wherein is as defined above and R^ is hydrogen, Rc, alkyl, cycloalkyl, alkylaminocarbonyl, arylaminoO II carbonyl (i.e., -C-NH-R wherein R is as defined above) g or substituted alkyl (wherein the alkyl group is substituted with 1 or more halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic group (as defined by R^), carboxyl (including salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy)phosphinyl, or dialkoxyphosphinyl substituents). -14Preferred (acylamino)arylacetyl groups of the above formula include those groups wherein IC is amino or amido.

Also preferred are those groups wherein Rg is phenyl or 2-thienyl. (g) I[[3-Substituted-2-oxo-1-imidazolidinyl]carbonyl] amino]arylacetyl groups having the formula 0 /c\ -C-CH-NH-C-N N-R I I I I ch2-ch2 g wherein R is as defined above and R. is hydrogen, alkylsulfonyl, g K arylmethyleneamino (i.e., -N«CH-R wherein R is as defined above) , *C'-RJn (wherein Rm is hydrogen, alkyl or halogen substituted alkyl), aromatic group (as defined by R^ above), alkyl or substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups).

Preferred I[3-substituted-2-oxo-1-imidazolidinyl]car-fc bonyl]amino]arylacetyl groups of the above formula include those wherein R^ is phenyl or 2-thienyl. Also preferred are those groups wherein R^ is hydrogen, methylsulfonyl, phenylmethyleneamino or 2-furyImethyleneamino. -15The terms salt and salts refer to basic salts formed with inorganic and organic bases. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, salts * with amino acids like arginine, lysine and the like. The nontoxic, pharmaceutically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.

The salts are formed in conventional manner by reacting the free acid form of the product with one or more equivalents of the appropriate base providing the desired cation in a solvent or medium in which the salt is insoluble, or in water and removing the water by freeze drying. By neutralizing the salt with an insoluble acid like a cation exchange resin in the hydrogen form (e-g., polystyrene sulfonic acid resin like Dowex (Trade Mark) 50) or with an aqueous acid and extraction with an organic solvent, e.g., ethyl acetate, dicloromethane or the like, the free acid form can be obtained, and, if desired, another salt formed. -16e-Lactams having ¢1 -0-C-SO3H substituent (os· inait thereof) An the Imposition and an amino or acylamino ©ubuttituent in the ^position contain at least on& chiral center the carbon atom (in the 3-position of the d-lactam nucleus) to which the amino or acylamino substituent is attached this invention is directed to those B~lactams which have been described above, wherein the stereochemistry at th& chiral center in the 3®po$ition of the S"lactea nucleus is the aam as the configuration at tha carbon atom in the Opmition of naturally occurring penicillins (e.g., penicillin G) and a& the configuration at the carbon atom in the 7-po@ition of naturally occurring c<3phamycins, (e_«.g_»_* cephamycin C).

With respect to the pr^fe^red 0~l&ctams of formula X, the structural formulas have been drawn to show the stereochemistry at the chiral center in th& l-positioa.

Also included within the scope of this invention are racemic mixtures which contain the above-dwscrihed e-lactams. 3\ / 0 8-Lactams having a -O-C-SO^H substituent (or salt thereof) in the 1-position of the B-lactam nucleus and an acyl amino substituent in the 3-position of the β-lactam nucleus have activity against a range of gram-negative and The -O-C-SO3H gram-positive organisms XO substituent (or salt thereof) is essential to the activity of the compounds of this invention.

The compounds of this invention can be used as agents to combat bacterial infections (including urinary tract infections and respiratory X5 infections) in mammalian species, such as domesticated animals (e.g., dogs, cats, cows, horses, and the like) and humans.

For combating bactex^ial infections in mammals a compound of this invention can be administered to a messaal in need thereof in an amount . of 1.4 mg/kg/day to 350 mg/kg/day, preferably 14 mg/kg/day to 100 mg/kg/day.

All modes of administration which have been used in the past to deliver penicillins and cephalosporins to the site of infection are also contemplated for use with the novel family of β-lactams of this invention. Such methods of administration include oral, intravenous, intramuscular, and as a suppository. -18° The of thi® invention can hs prepared frcai an amino acid having the formula .-CH* 03 a _4£!· ,C——OH The amino group is first protected with a classical XO protecting group (e.g._, t-butoxycarbonyl, bengylosty carbonyl, ©"nitrophenylsulfanyl, etc.), yielding a compound having ths formula Κ\Ά; cs—c~a; Xn formula XXX, and throughout the specification, the symbol refers to a nitrogen protecting group.

The carboxyl group of a protected amino acid of formula XXX is than reacted with an amine having the formula XV a, X S * ί so The reaction proceed® in ths presence of a coupling agent such a® X^ethyX^S-O-dlmethyl&minopropyl)c&rbodiimide or dicyclohaxylcarbodihaide, and irielda a ®sXt of the ccmpound having the formula ’ -19XO ^«NU-CHΝΗ-Ο—C teiX The hydroxyl group of a compound of formula V (or a salt thereof) is converted to a leaving group, using, for example, a classical reagent such as wsth&nesulfonyl chloride (methanesulfonyl is referred to hereinafter as m&s).

The fully protected compound having the formula vx OMsK„ lK\x * ^"NH-CH*-C—R3ZC"to. 0Z or a salt thereof, is cyclised by treatment with base, e.g., potassium carbonate. The reaction is preferably carried out in an organic solvent such as acetone, under reflux conditions, and yields a coapound having the formula VXX 5x z% CSO3H or a salt thereof.

Alternatively, cyclisation of a compound of formula V can be accomplished without first converting the hydroxyl group to a leaving group. Treatment of a compound of formula V (or a salt thereof) with triphenylphosphine aad di®thyl« osodicarboxylato or carbon tetrachlorides and triathylamin®, yields a compound of formula VXX. -30Both οί th® methoda di®cloi»«d above) for ring clomur* of a compound of formula v result in tha invention of tha ^tereocheaisttry at th<$ carbon bonded to tha and substituent®.

Oaprotaction of tha 3-aiaino substituent of a compound of formula ^TtX can be accomplished using art-reseognised techniques. Xf, for example, the protecting group is t"butoxycarbonyl, trifluoroacetic acid can bo used to doprotect £3 the amino group. Xf the protecting group is boasy loxycarbonyl, catalytic (e.g., p&Iladiisa on charcoal) hydrogens tion can b Vaaa Ο- ο? a salt thereof -21and ί® a key intermediate; for preparing the compounds of this invention. The compounds of formula VIZI form an integral part of this invention. ®ell known acylation techniques can he used to convert a compound of formula VIZI to the corresponding compound having the formula IX XO R, NR· •CH-C I I R. or a salt thereof.

Exemplary techniques include reaction with a carboxylic acid (R^-OH) or corresponding carboxylic acid halide or carboxylic acid anhydride. The reactions with a carboxylic acid proceed most readily in the presence of a carbodiimide such as dicyclohexylcarbodiiaide and a substance capable of forming a reactive intermediate in situ such as N-hydroxybensotrissole or 4-dimethylaminopyr idine. Xn those instances wherein the acyl group (R^) contains reactive functionality (such as amino or carbonyl groups) it may be necessary to first protect these functional groups, then carry out the acylation reaction, and finally deprotect the resulting product.

The products of formula Ϊ wherain R, is methoxy can be prepared from the corresponding compound of formula VXX wherein A, is benzyloxy» Λ carbonyl. Balogonating (preferably chlorinating) the amide nitrogen of a compound of formula VIX (A^ is bensyloxycarbonyl) yields a compound having the formula Cl ii ι Hj-O-C^-CH—c-a I "MS—O^C—S 03H or a salt thereof.

Reagents and procedures of ^-chlorinating amides are known in the art. Sx^pl&ry reagents are tert.Mautyl hypochlorite, sodiisa hypochlorite, and chlorine. The reaction can be run in an organic solvent (e.c., ® lower alkanol such a© methanol) or in a two phase solvent system (e.g., water/methylene chloride) in the presence of a base such as ©odium borate decahydrate.

The reaction is preferably run at a reduced temperature.

Reaction of a compound of formula x with a methoxylating agent, e.g., an alkali metal methoxide, yields a compound (in combination with its enantiomer if &3 and R^ are the same or if X is a racemic mixture) having the formula XX CH , ~O-C-HH«C—C‘ I I Or ίθ3Η or a salt thereof. -23Th« reaction can be run in an organic wolvent, t-s.t?., & P°i&7 organic solvent such as tetra*» hydrofuran, at a reduced eompcrature.

Alternatively, a compound of formula VXX, sj wherein is benzyloxycarbonyl, can be converted to. & compound of foraula XX using , a single step procedure. The methoxylating agent can first be mixed with a compound of formula VXX (Αη is Conversion of a compound of foraula XX to the desired products of formula X can be accoaplished using tho procedures described above for the conversion of an intermediate of formula νχχ to a product of this invention.

The starting materials of formula XX are readily obtainable using art-recognised procedures; ne£, for example Synthesis, pg. 216 (1979) and J. Org. Chem., 44x3967 (1979). 3Q The following examples are specific embodiments of this; invention. -24Bxaaple 1 J3S-(3a(2) ,48) )-3^1[(l^(2"AMino-4-thiasolyl)-2[ [^aethyl^l-OKO-IHaulfogaethoxy)S-agetidinyl]·*· arainoj 3-oxoethyiidene] aaino )οκν H2-m^thylpropanoic acid, dipotaasiua salt A) ftgainoxymethanesulfonic acid Acetone oxime (1.46 g, 20 mmole) was added to a suspension of a 50¾ Mineral oil dispersion of sodium hydride (0.8 g, 20 mmole) in 15 ml of dry dimethylsulfoxide. This was followed by the portionwise addition of sodiisa bromomethane sulfonate (3.94 g, 20 mmole). The reaction was heated at 90"95°C for 4 hours under nitrogen, XS cooled and washed twice with 250 ml of ether. Product solidified, was washed with 100 ml of dichlorornethane, filtered and dried,over w yiQl^ 15.3 g of crude material. This was dissolved in 30 ml of water, and tetra20 butylammonium hydrogen sulfate (7.5 g, 22 mmole) was added. The resulting ion paired product was extracted twice with 200 ml of dichlorornethane. The dlchloromethane solution was dried (Na_SOa, 3.5 g of the title compound. -25S) O-Sulfomethyl-a-N-t-butoxycarbonyl-Lthreonine hydroxamate, potassium salt ftwinoxymethanesulfonic acid (1.14 g, 8.9 mmole) was added to a solution of t-butoxycarbonyl-Lth reo nine (1.96 g, 8.9 mmole) in 16 ml of water and 4 ml of tetrahydrofuran at 0°C.

The pH was adjusted to 4*5 with IN KOH, and l~ethyl-3- (3«dimethyliaminopropyl) carbodiimide hydrochloride (1.87 g, 9.7 mmole) in 8 ml of water was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, and during this time, the pH was maintained at 4 to 4.5 by occasional addition of IN H^SO^,.

The product was ion paired with tetrabutylammonium hydrogensulf&to (3.05 g, 8 mmole) at pH 2.8 and extracted from the aqueous solution with four 100 ml portions of dichloromethane. The dlchloromethane solution was dried (Na^SO^) and concentrated In vacuo to yield 4.5g of product as the tetrabutylammonium salt. This was converted to the potassium salt by ion exchange on 150 ml of Dowex 50 X ra (0.7 meq K /ml), and after lyophilization, 2.63 g of the title compound was obtained. -26C) 0-Sulfoagthyl-g~®~£"butoxycarbonyi~L (O^me thanasulf onyl threonine) hydroxama to, tetrabutylaEKaoaiwa malt To a partial solution of O-sulfomothyl-a3 N^t^butoxycarbonyl^L^threonine hydroxasaate, potassium salt (2.37 g, 6.5 mmole) in 50 ml of dry pyridine at 0-5°C under nitrogen was added dropwi0.8 ml (excess) of methanesulfonyl chloride. The reaction was stirred at room temperature for 4 hours, and then concentrated ia vacuo. The residue wars dissolved in 10 ml of water* and 2.0 g (6 mmole), of tetrabutyl» asmaonium hydrogensulfate was added at pa 2.8.

The ion paired material was extracted with chloroform. The chloroform was dried and concentrated in vacuo to yield 2.6 g of crude product.

D) (3S°(3a,43))-3-([(1,1-Dimethylethoxy)20 carbonyl) amino) -4 -ang^xyl-2-oao-l- (sul fome thoxy) ~ atetidlne* potassium salt O-Sul fome thyl-a-N"t"buto3tycarbonyl -L(O-meth&nesulf onyl threonine) hydroxamate, tetrabutylammonium salt (2.5 g, 4.0 mmole) was dissolved in 5 ml of acetone and added dropwise to a refluxing suspension of 2.2 g of potassium carbonate in 55 ml of acetone. Refluxing was continued for 3.5 hours and the reaction was cooled, filtered, and concentrated in vacuo. The residue was dissolved in 10 ml of .5 H pH 5.5 and the pH was adjusted <& «3 to 2.8. Product was extracted four times with 100 ml portions of dichloromethane, and the combined extract was dried and concentrated -27in vacuo to yield X.52 g of crude tetrabutylammonium ion paired β-lactara salt. The potassium salt was obtained by ion exchange through 50 ml fix of Dowex SOX (0.7 meg K /ml) to yield upon 5 lyophilization 0.53 g of crude material, which was further purified by chromatography through 100 al of HP-20 using water. The appropriate fractions were ’combined and lyophilized to yield 0.245 g of product.

Analysis Calc'd for C,qH^N^O^SK 1.2 HoO: C, 32.46? H, 5.28? ¢3, 7.57; S, 8.66 Found: C, 32.52; H, ^.76; N, 7.43; S, 8.30 E) [ 3S- (3o,4 8) 1 -l-Sulfomethoxy-3~aminp-4-methyl-2 IS oxo-l-azetidine (3S~ (3α, 4 8) ] -3~ [ ((1,1 «Dimethylethoxy) carbonyl ] amino ] -4-methyl-2-oxo-l* (sulf oraethoxy) azetidine, potassium salt (0.245 g, .68 mmole) was suspended in 0.5 ml of dlchloromethane and 0.5 ml of anisole. The reaction mixture was cooled to 0°C, and trifluoroacetic acid (1.0 al) was added under nitrogen. The reaction mixture was stirred for 1 hour and then concentrated in vacuo to a residue which was evaporated from benzene twice. This was triturated wi^h ether, and the ether was decanted to give the desired product as a white solid. -28F) |3S-[3a(2) r4S]J-5-nn-(g-2^ino-4-thjlasolyl)^2[ (4-methyl-2-oxoml-(sulfoaethoxy) -3-a8etldlayl) amino] 2-oxogthylldenel aminojoxyl ^a-methylpropionlc acid, diphenylmethyl potassium salt (2)-2-Amino~e-[ [2-(diphenyImethoxy)-1,1dim This was cooled to 0°C, and N,N'-dicyclohexy 1carhodiimide (0.14 g, .68 mmole) was added portionwise. After addition, the reaction was stirred at 0°C for 1 hour. To this was added a solution of the above crude 3-aminoe»l-(sulfo15 methoxylazetidine (ca. 0.68 wsaole) in 10 ml of dimethylformamide and 0.5 ml of H,N-diisopropyIethylamine at 0°C. The reaction was stirred at 0°C for 1 hour and then at room temperature overnight. The solution wan filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in 50 ml of dichloromethane and washed with 2 ml of wat@r. Upon evaporation of dichloromethane, 0.372 g of crude product was obtained. This was passed through 30 ml of β Dowex 50 (0.7 meg K /ml) using water, to yield upon lyophilisation 0.211 g of crude product, contaminated with hydroxybensotriazole. -29G) [3S-I3q(Z) ,4s] ]-2-{[f1-(2-Amino-4-thia2Qlyl)-2[ [4-methyl-2~oxo~l~(sulfomethoxy) -3-azetidinvl ] amino]-2-0xoethylidenelamino]oxy]-2-methylpropanoic acid, dipotassium salt 5 [3S-[3o(2),4 fl]]-2-11[l-(2-Amino-4-thiazolyl)-2([4-methyl"2~oxo-l"(sulforaethoxy)-3-azetidinyl1 amino]-2-oxoethylidene]amino]oxy]-2-methylpropionic acid, diphenylmethyl ester, potassium salt (0.211 g) was dissolved in 1.8 ml of dlchloromethane, 0.5 ml of anisole, and 1.5 ml of trifluoroacetic acid, and stirred under nitrogen at 0°C for 2 hours. The reaction mixture vas concentrated in vacuo and evaporated from benzene twice.

The residue was washed with ether: ethyl acetate (1:1) and with ether: acetonitrile (1:1) to give a white solid. This was dissolved in 1.0 ml of pH 5.5 0.5 M ΚΗ-,ΡΟ^, adjusted to pH 6.5 with IN KOH, and chromatographed through 40 ml of HP-20 with water to give 53 mg of- the title compound, melting point 200°C, dec.

Analysis Calc'd for cxJsH£7N5OgS2K2’2·75 H2O: C, 28.44; H, 3.84; N, 11.85; S, 10.84 Found: C, 28.32; H, 3.36; N, 11.90; S, 10.37 -30Example 3 [2S-[2q,3s(2)11-((3-([(2-&mino-4-thiazolyi)(msthoxy imino) acetyl) amino] -2-roethyl-4-oxo1-aaetidlnyl] oxy] methanesulfonic acid S Following the procedure of Example 1, and substituting an equimolar amount of (2)-2-aminoα~( (methoxy)-iaino]-4-thia2oleacetic acid for the thiazoleacetic acid used in part (F) of Example 1, the titled compound is prepared as the mono10 potassium salt as a hygroscopic solid after dissolving in acetonitrile and removing the acetonitrile under vacuum several times XS - S03(1030 cm1); β-lcctem (1778 cm1) Analysis: calc, for ^NgO^SjK-O.ICH^CN calc. C-38,XI;~H-4.82? N-15.92? S-12.56 found: C-37.94? 0-5.36; N-15.92? S-12.56 Example 3 (2S-[2a,36(R)]1 -[[3-[[[((4-Ethyl-2,3-dioxo-l20 piperazinyl) carbonyl] amxno]phenylacetyl]ainino]^^mathyl-^-oro-l-axetidinylioxy-methanesulfonic acid Following the procedure of Example 1 and substituting a-4 ((4-ethyl~2,3-dioxO"X-pipera2inyl) 35 carbonyl]amino]'-phenylacetic acid for the thiazoleacetic acid used in part (?) of Example 1, the titled compound is obtained as the monopotassium salt &s a hygroscopic solid. IR - S03~ (1038 cm ? 0-lactam (1775 cm Analysis: calc, for Ο^θΗ,^Ο^δΚ-Ι.δ^Ο c&lc.: C-41.53r H-4.74; N-12.11? S-5.54 found: C-41.53; H-4.46; N-11.13; S-5.61 -31Example 4 (S) -3-benzy loxycarbonylami.no) -4-inethy 1-2-oxo-l(sulfomethoxy)-azetidinc Following the procedure of Example 1, parts (A) through (D) and substituting benzyloxy5 carbonylthreonine for the t-butoxycarbonyl-Lthreonine used in part (Β), the titled compound is prepared as a potassium salt, IR -SO3"(1O25 cm"1); B-lactam (1775 cm A).

Example 3 (2tf ,3c^)-l-suIfomettioxy-2-(aminocarbonyl)-3-(((lgl-dimefhykthoxy) _____ carbonyDam ino)-4-oxoazet idine A. Erythro-3-hydroxy-dl-aspartic acid Erythro-3-hydroxy-dl-a$parfic acid was prepared from transepoxysuccinic acid as described by C.W. Jones et at (Can. J. Chem. 47,4363 (1%$)). Trans-epoxysuccinic acid was prepared from fumaric acid as described by G.B. Payne ef al. (3. Org. Chem. 24, 54 (1959)).

B. >& -methyl erythro-3-hydroxy-dl-aspartate To a suspension of 5.0 g (33°3 mmol) of eryfhro-3-hydroxy-dlaspartic acid in 50 ml of dry methanol was added 6 ml of conc.hydrochloric acid® The mixture was refluxed for 3 hours, cooled to room temperature, and evaporated in vacuo. The residue was fallen up In 95 percent ethanol, and the pH was adjusted to 8.0 by addition of pyridine® The white solid was filtered and dried to give 5.2 g (95 peroenf yield) oi desired methyl ester having m.p« 210°C dec. -32 C. Erythro-3-hydroxy-dl-asparagine The above $ -methyl aspartate (4.0 g, 24.5 mmol) was dissolved in 40 ml of cone, ammonia and stirred overnight at room temperature. The reaction mixture was evaporated in vacuo to a solid which was dissolved in hot water. The pH was adjusted to 5.0 using 6N HCl, and the solution was concentrated in vacuo to about 20 ml and then left overnight at 5°C. The white crystalline mass was collected and dried to give 3.4 g (95 percent yield) of desired product having frl.P. 233°C dec: D. N-t-Butoxycarbonyl-srythro-3-hydroxy-dl-asparagine, potassium salt Erythro-3-hydroxy-dl-asparagine (7.0 g. 47 mmol) was suspended in 50 ml of water and solubilized by addition of 3N KOH. This solution was adjusted to pH 10.0 and maintained at this pH while adding dropwise a solution of di-t-butyldicarbonats (15.5 g, 71 mmol) in 20 ml of t-butanol. The reaction mixture was stirred at pH 10.0 overnight at room temperature. The t-butanol was removed in vacuo, and the aqueous remainder was adjusted to pH 5.0 using 6N HCl. The solution was concentrated in vacuo to a small volume, and then the pH was adjusted to 3.0 (6N HCl). Removal of solvent in vacuo gave a solid (20g) containing the desired product in free acid form and in about quantitative yield, along with inorganic salts. A portion (2.9g) of this solid was taken up in water and dilute KOH at pH 6.5 and chromatographed through 100 ml οί HP20 resin using water and then acetone-water (1:9) to give the desired potassium salt as a residue (l.Sg).

E. Aminoxymethanesulfonic acid, tetrabutylammonium salt Tetrabutylammonium hydrogen sulfate (1.02g, 3 mmol) was 3O added to a solution of 0.635g (5 mml) of aminoxymethane-sulfonic acid in 2 ml of water, and ths pH was adjusted to 10.0 using dilute KOH. Ths water was removed in vacuo, and the residue was triturated with methylene - 33 chloride. After filtration, the filtrate was dried over sodium sulfate and evaporated to give the desired product as a residue (1.06 g., 2.83 mmol).

F. 0-Sulfornethyl-Q(-N-t-butoxycarbonyl-erythro-3"hydroxy-dl..asparaRine hydroxamate, potassium salt N-t-butoxycarbonyl-erythro-3-hydroxy-dl-asparagine, potassium salt (0.792 g., 2*7 7 mmol) was dissolved in water (3 ml) and adjusted to pH 2.4 (dil. H^SO^). The solution was concentrated in vacuo to a residue, which was concentrated from water (2 times) and then from benzene (2 times).

This residue was dissolved in dry acetonitrile (4 ml) and dry tetrahydrofuran (8mi) and cooled to 0°C. To this stirred solution was added 0.424 g (2.77 mmol) of i-hydroxybenzotriazole monohydrate followed by 0.572 g (2.77 mmol) of Ν,Ν’-dicyclohexylcarbodiimide. The mixture was stirred at O°C for 2 hours, and tnen the above aminoxymethanesulfonic acid, tetrabutyl ammonium salt (1.06 g, 2.88 mmol) in 5 ml of acetonitrile was added dropwise. After the addition, the reaction was stirred at 0°C for 4 hours. The reaction was filtered and concentrated in vacuo to a residue, E/ater (10 ml) was added, and the residue was triturated at 0°C-until it solidified. The solid was removed by filtration, and the aqueous filtrate was concentrated to about 3 ml. the pH was adjusted to 4.0, and the fractionation was performed over 80 ml of Dowex 50 (K) ion exchange resin. Appropriate fractions were collected and concentrated to a small volume. The pH was adjusted to 3.4, and the solution was chromatographed over HP20 resin to give, after lyophilization, 502 mg (46 percent) of desired product as a solid having m.p. 145°C dec.

Anal. Calcd. for C10H18N3095K.0.71H20! C, 29Λ2:Η, 4.80 Ν,ΙΟ^ώ, 7.85 Found: C,29.42: H,4.73: N, 10.04: S, 7.45 G. Q~sulfomethyl-0(-N-t-butoxycarbonyl-erythro-3"hydroxy-dl-asparagine hydroxamate, tetrabutyl-ammonium salt To a solution of tbs above asparagine hycroxamatc, potassium salt (104 mg, 0.263 mmol) in 1 ml of water was added 2.63 ml of 0.1 M tetrabutylammonium hydrogen sulfate in 0.5M pH 5.5 KH^PO^ buffer. The solution was concentrated to dryness, and the residue was triturated with methylene chloride. Filtration and evaporation of the methylene chloride gave the desired product as a residue (156 mg, Η£θ.26 mmol).

H. (2 (X ,3O()- l-sulfomethoxy-2-faminocarbonyl)-3-((( 1,1 -dimethyiethoxy) carbonyl)amino)4«oxoazetidine, potassium salt The above 0-sulfomethyl hydroxamate, tetrabutylammonium salt (140 mg, 0.234 mmol) was dissolved in 1.6 ml of dry methylene chloride and stirred with 1 g of dried 3 A molecular sieves overnight. The solution was removed via syringe and diluted with O.S ml of dry methylene chloride. To this stirred solution at -50°C under argon was added 0.12 ml (0.85 mmol) of triethylamine followed by dropwise addition of 0.0S ml (0.42 mmol) of trifuoromethanesuifonic anhydride. The reaction was allowed to warm to -30°C over 1 hour, and then 0.06 ml of triethylamine was added. After 5 minutes, the reaction was concentrated in vacuo, and the residue was dissolved in 2 ml of acetone. The solution was cooled to 0°C, and a solution of 79 mg of potassium perfluorobutane sulfonate in 1 ml of acetone was added. Ether was then added, and the solids were collected by centrifugation. Treatment of this solid by stirring with 2 ml of Dowex 50 (K) resin in water, filtration and removal of the water in vacuo gave crude desired potassium salt containing no amines. Chromatography of this crude potassium salt on HP20 resin using wafer gave 15 mg (20 percent yield) of desired potassium salt, after lyophilization having m.p. 149°C dec- and IR(KBR) 1786 reciprocal CM (Beta-lactam carbonyl) and 1696 reciprocal CM (broad, amide and carbamate carbonyl). - 35 Bv following the procedures previously described the following compounds are prepared: (3S-trans)-([(2-Amino-4-thi6solyl)(methoxyimino)acetyl)amino] «4-methyl-2-oxo-l-azetidinyl) oxyjmethanesulfonic acid, monopotassium salt (3S-trans]-[((2-Amino-4-thiazolyl)ί(2,2,2tr ifluoroethoxy)imino]acetyl] amino]-4-raethyl-2-oxo-lazetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-trans) - (((2-Aaino-4-thiazolyl) ((2-amino-2oxoethoxy) imino]acetyl] amino] -4~methyl-2-oxo-lazetidinyl]oxy]methanesul£onic acid, monopotassium salt (3S-trans) - I ((2-Amino-4-thiazolyl) [ (car'boxymethoxy)imino]acetyl]amino] "4-methyl~2-oxo-lazetidinyl]-oxy]methanesulfonic acio, dipotassium salt (3S-trans)-1 ((2-Amino~4~thiazolyl)[((l-carboxycyclopropyl)oxyJ imino]acetyl]amino] -4"methyI-2-oxo-lazetidinyl]-oxyjmethanesulfonic acid, dipotassium salt Ϊ 3S-[3a(RJ,4 6]]- ([3-((Aminophenylacetyl)amino] -4-raethyl-2-oxo-l-azetidinyl] oxy] methanesulfonic acid, monopotassium salt (3S-trans)«I(3-1(Phenylacetyl)amino]-4methyl-2-oxo-l-azetidinyl] oxy] methanesulf onic acid, monopotassium salt (3S-trans)-((3-((2-Thienylacetyl)amino]-4methyl-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-trans)-[(3-((2,6-Dimethoxypnenyl)acetyl]amino]-4-methyl-2-oxo-l-azetidinyl]oxy)methanesulfonic acid, monopotassium salt - 36 (3S-(3e(R),4 β]]-((3-((((( Aminocarbonyl)5 amino] -2-thienylacetyl-amino] -4-methyl"2-oxo-lazetidinyl]-oxy]methanesul£onic acid, monopotassium sale 13S-13o(R),4 9]]- ((3-((Carboxyphenylacetyl)aminoj «4-methyl-2-oxo-l-axetidinyl]oxy]aethane10 sulfonic acia, dipotassium salt (3S-[3 g(±) ,4 3] 1-((3-( (Phenylsulfoacetyl)amino)-4-methyl-2-oxo-l-a2®tidinyl]oxy]methanesulfonic acid, dipotassium salt *(3S-trans)1-((3-((<2-Amino-4-tni£2olyl)X5 oxoacetyl]amino]-4-methyl-2-oxo-l-asetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-OMR) ,4B] 1-((3-( ([ ((2-ΟΧΟ-3-((phenylmethylene)amino]-l-imidasolidinyl]carbonyl]amino]phenylacetyljamino]-4-methyl-2-oxo-l-asetidinyl]oxy]20 aethanesulfonic ^cid, monopotassium salt (3S-[3o(3),43]]-((3-([2~Furanyl(methoxyimino)acetyl] amino]-4-methyl-2-oxo-l-£zetidinyl]oxy]aethanesulfonic acid, monopotassium salt (3S (Z)]-((3-(((2-Araino-4-thiazolyl)(methoxy25 imino)acetyl]amino]-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S(Z)]-I(3-(((2-Amino-4-thiazolyl)((1-carboxy1-methylethoxy)imino]acetyl]amino]-2-oxo-lazetidinyl]oxy]methanesulfonic acid, dipotassium salt (35(2)1-((3-(((2-Amino-4-thiazolyl)((2,2,2trifluoroethoxy)imino]acetyl]amino]-2-oxo-1azetidinyl]oxy]raethanesulfonie acid, monopotassium salt - 37 (3$(Z)) -( 13-( ( (2-Amino-4-thia2olyl) ( (2-amino-2owoethoxy)imino]acetyl) amino]-2-oxo-1-ajetioinyl]oxy)methanesulfonic acid, monopotassium salt (3S-(3 o(S),4β)J-I (3-([I(Aminocarbonyl)amino]2-thienylacetyl]amino]-2-oxO"l-a2ctxdinyl]oxy]methanesulfonic acid, monopotassium salt [3S-(3a (?),4B)) -[(3-1(Phenylsulfoacetyl)amino]-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, dipotassium salt (3S-(3a(R),46]]-((3-(((((4-Ethyl-2,3-dioxo-lpiperazinyl)carbonyl]amino]phenylacetyl)amino]-2-oxo1-azetidinyl]oxy]methanesulfonic acid,monopotassium salt ((3S (Z) ] - [ (3- ((Phenoxyacetyl) amino] -2-oxo-lazetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-cis)-[((2-Amino-4-thiazolyl)(methoxyimino)acetyl] ammo] -4-methyl-2-oxo-l-a2etidinyl] oxy]methanesulfonic acid, nonopotassium salt (3S-cis)-[((2-Amino-4-thiazolyl)((2,2,2trifluoroethoxy)imino]acetyl]amino]-4-methyl-2-oxo-lazetidinyl]oxy)methanesulfonic acid, monopotassium salt (3S-cis)- (I(2~Amino-4-thiazolyl)i(carboxymethoxy)imino]acetyl]amino]-4-aethyl-2-oxo-lazetidinyl]-oxy]methanesulfonxc acid, dipotassium salt (3S-cis)-((3-(((2-Amino-4-thiazolyl)](1carboxy-l-methylethoxy)imino)accetyl]amino]-2-oxo-4methyl-l-azetidinyl)oxy]methanesulfonxc acid, dipotassium salt (3S-cis)- (((2-Amino-4-thiezolyl)(((1-carboxycyclopropyl)oxy]imino]acetyl]amino]-4-methyl-2-oxo-lazetidinyl]-oxy]methanesulfonic acid, dipotassium salt - 38 (3S-cis) " (((2~&mino-4-thAei8olyl) ((2~amino~2~ oitoethoxy) Amino] acetyl]amino] "«s-methyl^-oxo-iazetidinyljoxyjfiieth&nesulfonic acid, monopotaisaium salt [3S-[3o(R) ,4a] ]-([3-( (Carboxyphenylacetyl)amino] -4-meehyl"2-oxo"l-as?st id inyl] oxy] me thanesulfonic acid, dipotassium salt (3SH3«W r«e| ]-[ [3-((( ((4-Ethyl-2,3-dioxol-pipesr&sinyl) carbonyl] amino] phenylacetyl) amino] -4XO wethyI-2-ojiO-i-asistieinylJoxy]methanesulfonic acid, monopotassium salt (3S-[ 3o(S) ,4 a] J - [ (3-( ([ (Aminocarbonyl) amino]"2-thienylacetyl]-amino]-4-methyl-2-oxo-lazetidinyl]-oxylmethanesulfonic acid, monopotassium salt (3S-(3a(R),4a] ] - ((3-((Aminophenylacetyl) -amino]"4-raethyl-2-oxo-l-asetidinyl]oxy]methanesulfonic acid, monopotassium salt

Claims (1)

1.CLAIMS 1. A S-X&ctaa having tin -0—C—SO^E substituent in the Imposition and an acylamino substituent in the 3-position? therein R5 and Rg are the same or different end each is hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, eycloalkyl or a 4,5,6 or 7-membered heterocycle, or and together with the carbon atom to which they are attached are cycloalkyl or a 4,5,6 or 7-membered heterocycle, or one of R^ cn< ^ hydrogen and the other is azido, halomethyl, dihalomethy1, · trihalomethyl, alkoxycarbonyl, 2. -phenylethenyl, 2-phenylethynyl, carboxyl. sulfonyloxy, phenylsulfonyloxy, {substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -S-Xj, or -O-X^j &lkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl) ti Iky 1, alkanoyl, substituted alkanoyl, phenylcarbonyl, (substituted phenyl)- V carbonyl, or heteroiirylearboaylj A is -ea,~ca-cs~, ~(ch 0 ) -(cs,) ,-ο-, ~ a η & λ β> χλ or «(CR,) ,-5-00.,-1 a is θ, 1, 2 or 3; a' is 2'a 1 2 1 or 2; and X- and and each is hydrogen or alkyl, or X g is hydrogm and Χγ is amino, substituted amino, acylamino or alkoxy, the stereochemical configuration at the 3. -position of the β-lactan nucleus being the same as the configuration at the 6-position of naturally occurring penicillins, or a salt or a diphenylmethyl ester thereof. * 40wherein 2. A β-lactam in accordance with claim 1 and Rg are each hydrogen. 3. A β-lactam in accordance with claim 1 having the formula R^NH-C *4 C-R. R 5y* 6 •N—0—C—SO 3 H 10 or a salt or ester thereof, wherein R 1 is acyl? R 2 is hydrogen or methoxy? and R^ are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, 15 substituted phenyl or a 4,5,6 or 7-membered heterocycle, or one of R^ and is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH^X^, -S-X 2 , 20 X 3 X 3 0 I J I J π -O-X_, -O-C-X,, -S-C-X, , or -A-C-NX c X-; 2 I 4 I 4 Ο 7 X 5 X 5 wherein Rg, Rg, , X 2 , A, Xg and X? are as defined in claim 25 1; and one of Xg and X^ is hydrogen and the other is hydrogen or alkyl, or Xg and when taken together with the carbon atom to which they are attached form a cycloalkyl group? Xg is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl) 30 alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, * (substituted amino) carbonyl or cyano. 4. A β-lactam in accordance with claim 3 wherein Rj is hydrogen. - 41 5. a 3~lact&ga iw accordance with claim 4 wher&in one of R3 and R<$ is oth^r than hydrogen. 6. A S^Iiaeta® in accordance with claim 4 wherein 83 ii*> hydrogen and in aethyl . ?. & 8-Xactaa ia accordance with claim 4 * wherein Rg is aethyl and is hydrogen. 0. A 3lactam in accordance with claim 4 wherein and are each hydrogen. £θ A a-laetcm· ia accordance with claim 4 wherein and ar© each aethyl. 10. Λ ^X&ctasa in accordance with claim 4 wherein &, ia tS)«2«aminO“©“i ll~earboxy«!-iaethyX 11. A S-lecfesa in accordance with claira 3 wherein H2, RS end RS are £&ch hydrogen md ene of R3 end R4 is ali^X ©sd the other is hydrogen. 12. A fi-lact&m in iseecrdmce with claim 3 therein Ra, R3, RS md R$ tsra eadi hydrogel send R4 is irathyX. 13. A Wactssa in accordance with claim 3 wherein R^, R^, Rg and are each hydrogen and Rg is asthyl* 14. A Slactam having the foraula ,1—§ ' 8 I Xa O—c—§o^s cr 4 or a isialt thereof, wharein Rg and R^ are as defined in claim 3 and R c and -R c are as defined in claim 1. t -4215. Α β-lactam ln accordance with claim 1, which is a salt of (3S-[3α(Ζ)]-2-[[ί1-(2-amino-4-thiazolyl) -2“[[4-methyl-2-oxo-1-(sulfomethoxy)-3-azetidinyl]amino] -2-oxoethylidene]amino]oxo]-2-methylpropan0ic acid. 5. 16. Α β-lactam in accordance with claim 14, which is (3S-(3ft,4β)]-1-sulfomethoxy-3-amino-4-methyl-2-oxo1-azetidine. 17. A process substantially as herein described with reference to the Examples, for preparing a 6. 10 compound as defined in claim 1 or claim 14. 18. A β-lactam compound, whenever prepared by a process in accordance with claim 17.