GB2129428A

GB2129428A - Azetidinyl sulfonic acid and analogs

Info

Publication number: GB2129428A
Application number: GB08326626A
Authority: GB
Inventors: William A Slusarchyk; David R Kronenthal
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1982-10-06
Filing date: 1983-10-05
Publication date: 1984-05-16
Also published as: SU1318146A3; IE56600B1; JPS5988462A; NO833626L; GR79704B; SE8305509L; PH24175A; ZA837491B; GB2129428B; DK457983A; DK457983D0; IL69917A; DD222016A5; PT77458B; FI833631A0; CA1253501A; DE3336262A1; IE832354L; CH658858A5; AU1993983A

Abstract

Antibiotic activity is exhibited by beta -lactams having an <IMAGE> 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:- <IMAGE> or salts or esters thereof, R1 being hydrogen or acyl and R2, R3 and R4 being hydrogen atoms or substituents.

Description

SPECIFICATION Azetidinyl sulfonic acid and analogs This invention is directed to a novel family of p-lactam antibiotics, and to the use of such compounds as antibacterial agents. It has been discovered that the p-lactam nucleus can be biologically activated by a substituent having the formula

(or salt thereof) attached to the nitrogen atom in the nucleus.

,-Lactams having a

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 p-lactam antibiotics of this invention are those encompassed by the formula

or an ester or salt thereof.

As used in formula I and throughout the specification, the symbols are as defined below.

R1 is acyl; R2 is hydrogen or methoxy; R3 and R4 are the same or different and each hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6, or 7-membered heterocycle (referred to hereinafter as R7) or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2phenylethenyl, 2-phenylethynyl, carboxy, -CH2X1,-S-X2, -O-x2,

X1 is azido, amino (-N H2), hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2 or -O-X2; X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl or heteroarylcarbonyl;; one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X when taken together with the carbon atom to which they are attached form a cycioaikyl group; X5 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl; phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, a minocarbonyl

(substituted amino)carbonyl, or cyano (-C-N); A is -CH=CH-, H 2-CH=CH-, (CH2) (CH2) -0-, (CH2)nNH^ or -(CH2),-S-CH2; nisO, 1,2or3; no is 1 or2; X6 and X7 are the same or different and each is hydrogen or alkyl, or X6 is hydrogen and X7 is amino, substituted amino, acylamino or alkoxy; and R5 and R6 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or R7, or R5 and R6 together with the carbon atom to which they are attached are cycloalkyl or R7, or one of P5 and R6 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2X1, -S-X2 -O-X2,or

Listed below are definitions of various terms used to describe the p-iactams 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 "cycloalkenyl" refer to cycloalkyl and cycloalkenyl groups having 3, 4, 5, 6 or carbon atoms.

The term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido amino (-N H2), halogen, hydroxy, carboxy, cyano alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, R7-oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, aikylsulfinyl, or alkylsulfonyl groups.

The terms "alkanoyl", "alkenyl", "alkenyl" and "alkynyl" refer to both straight and branched chain 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 "protected carboxyl" 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, 1 979. 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 amino (-N K2), 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 "R7") refers to substituted and unsubstituted, aromatic and non-aromatic groups containing one or more nitrogen, oxygen or sulfur atoms. Exemplary substiituents are oxo(=0), halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 2-furylimino

b'enzylimino and substituted alkyl groups (wherein the alkyl 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 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, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl and hexahydroazepinyl.Exemplary of the substituted 4,5,6 or 7-membered heterocycles are 1 -alkyl-3- azetinyl, 2-oxo-1 -imidazolidinyl, 3-alkylsulfonyl-2-oxo-1 -imidazolidinyl, 3-benzylimino-2-oxo-1 - imidazolidinyl, 3-alkyl-2-oxo-1 -imidazolidinyl, 3-phenyl (or substituted phenyl)-2-oxo-1 -imidazolidinyl, 3-benzyl-2-oxo-1 -imidazolidinyl, 3-(2-aminoethyl)-2-oxo-1 -imidazolidinyl, 3-amino-2-oxo-1 - imidazolidinyl, 3-[(alkoxycarbonyl)amino]-2-oxo-1 -imidazolidinyl, 3-[2-[(alkoxycarbonyi)-amino]ethyl]- 2-oxo- 1 -imidazolidinyl, 2-oxo-1 -pyrrolidinyl, 2-oxo-3-oxazolidinyl, 4-hydroxy-6-methyl-2-pyrimidinyl, 2-oxo-1 -hexahydroazepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-3-furanyl, 2,3-dioxo-1 -piperazinyl, 2,5-dioxo1 -piperazinyl, 4-alkyl-2,3-dioxo-1 -piperazinyl, and 4-phenyl-2,3-dioxo- 1 -piperazinyl.

The term "substituted amino" refers to a group having the formulaNY,Y2 wherein Y, is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyi or (substituted phenyl)alkyl, and Y, is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, - or amino (-NH2).

The term "substituted alkanoyl" includes within its scope compounds having the formula (substituted alkyl)

(wherein "substituted alkyl" is defined above) and phenylalkanoyl.

The 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, of course, preferred but this 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 p-lact,am 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, 1 978, Belgian patent 867,994, published December 11, 1 978, United States patent 4,152,432, issued May 1, 1 979, United States patent 3,971,778, issued July 27, 1976, United States patent 4,172,199, issued October 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"; 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; cycloalkenyl; 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

wherein n is 0,1,2 or 3; Rb, Pc, and Rd each is independently hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethyl; and Re 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

(Re is preferably a carboxyl salt or sulfo salt) and

(Re is preferably a carboxyl salt or sulfo salt).

(c) Heteroaromatic groups having the formula

wherein n is 0,1,2 or 3; Re is as defined above; and Rf is substituted or unsubstituted 5-, or 7-membered heterocyclic ring containing 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms. Exemplary heterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazoiyl, 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

Preferred heteroaromatic acyl groups include those groups of the above formuias wherein of is 2 amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino- 1 ,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl, or 6-aminopyridin-2-yl.

(d) [[(4-Substituted-2,3-dioxo- 1 -piperazinyl)ca rbonyl] amino] arylacetyl groups having the formula

wherein Rg is an aromatic group (including carbocyclic aromatics such as those of the formula

and heteroaromatics as included within the definition of Rf); and Rh is alkyl, substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups), arylmethyleneamino (i.e., N=CHRg wherein Rg is as defined above), arylcarbonylamino (i.e.,

wherein Rg is as defined above) or alkylcarbonylamino.

Preferred [[(4-substituted-2,3-dioxo- 1 -piperazinyl)carbonyl]a mino]arylacetyl groups include those wherein Rh is ethyl, phenylmethyleneamino or 2-furylmethyleneamino.

(e) (Substituted oxyimino)arylacetyl groups having the formula

wherein Pg iS as defined above and Rj is hydrogen, Pc, alkyl, cycloalkyl, alkylaminocarbonyl, arylaminocarbonyl (i.a,

wherein Rg is as defined above) or substituted alkyl (wherein the alkyl group is substituted with 1 or more halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic group (as defined by Rg), carboxyl (including salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl, or dialkoxyphosphinyl substituents).

Preferred (substituted oxyimino)arylacetyl groups include those wherein Rg is 2-amino-thiazolyl.

Also preferred are those groups wherein Rj is methyl, ethyl, carboxymethyl, 1 -carboxy-1 -methylethyl, 2,2,2-trifluoroethyl or 1 rboxycyclopropyl.

(f) (Acylamino)arylacetyl groups having the formula

wherin Rg is as defined above and Rj is

amino, alkylamino, (cyanoalkyl)amino, amido, alkylamido, (cyanoalkyl)amido,

Preferred (acylamino)arylacetyl groups of the above formula include those groups wherein Rj is amino or amido. Also preferred are those groups wherein Rg is phenyl or 2-thienyl.

(g) [[[3-Substituted-2-oxo- 1 -imidazolidinyl]ca rbonyl] amino]arylacetyl groups having the formula

wherein Rg is as defined above and Rk is hydrogen, alkylsulfonyl, arylmethyleneamino (i.e., N=CHRg wherein Rg is as defined above),

(wherein Rm is hydrogen, alkyl or halogen substituted alkyl), aromatic group (as defined by Rg above), alkyl or substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups).

Preferred [[3-substituted-2-oxo- 1 -imidazolidinyl]carbonyl]amino]arylacetyl groups of the above formula include those wherein Rg is phenyl or 2-thienyl. Also preferred are those groups wherein Rk is hydrogen, methylsulfonyl, phenylmethyleneamino or 2-furylmethyleneamino.

The 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 Dowes 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.

p-Lactams having a

substituent (or salt thereof) in the 1-position and an amino or acylamino substituent in the 3-position contain at least one chiral center - the carbon atom (in the 3-position of the ,B-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 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 (e.g., penicillin G) and as the configuration at the carbon atom in the 7-position of naturally occurring cephamycins, (e.g., cephamycin C).

With respect to the preferred -lactamsof formula I, the structural formulas have been drawn to show the stereochemistry at the chiral center in the 3-position.

Also included within the scope of this invention are racemic mixtures which contain the abovedescribed B-lactams.

p-Lactams having a

substituent (or salt thereof) in the 1-position of the ,B-Lactam nucleus and an acylamino substituent in the 3-position of the p-lactam nucleus have activity against a range of gram-negative and gram-positive organisms. The

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 bacteriai 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 bacteriai 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 cise with the novel family of ,l3-lactams of this invention. Such methods of administration include oral, intravenous, intramuscular, and as a suppository.

The ,B-lactams of this invention can be prepared from an amino acid having the formula

The amino group is first protected with a classical protecting group (e.g., t-butoxycarbonyl, benzyloxycarbonyl, o-nitrophenylsulfenyI, etc.), yielding a compound having the formula

In formula III, and throughout the specification, the symbol "A" refers to a nitrogen protecting group.

The carboxyl group of a protected amino acid of formula Ill is then reacted with an amine having the formula

The reaction proceeds in the presence of a coupling agent such as 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide or dicyclohexylcarbodiimide, and yields a salt of the compound having the formula

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 methanesulfonyl chloride (methanesulfonyl is referred to hereinafter as "Ms").

The fully protected compound having the formula

or a salt thereof, is cyclized 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 compound having the formula

or a salt thereof.

Alternatively, cyclization 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 triephenylphosphine and diethylazodicarboxylate or carbon tetrachloride and triethylamine, yields a compound of formula VII.

Both of the methods disclosed above for ring closure of a compound of formula V result in the inversion of the stereochemistry at the carbon bonded to the R3 and R4 substituents.

Deprotection of the 3-amino substituent of a compound of formula VII can be accomplished using art-recognized techniques. If, for example, the protecting group is t-butoxycarbonyl, trifluoroacetic acid can be used to deprotect the amino group. If the protecting group is benzyloxycarbonyl, catalytic (e.g., palladium on charcoal) hydrogenation can be used. If the protecting group is o-nitrophenylsulfenyl, p-toluenesulfonic acid can be used in combination with p-thiocresol. The deprotected compound has the formula

or a salt thereof; and is a key intermediate for preparing the compounds of this invention. The compounds of formula VIII form an integral part of this invention.

Well known acylation techniques can be used to convert a compound of formula VIII to the corresponding compound having the formula

or a salt thereof.

Exemplary techniques include reaction with a carboxylic acid (P1-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 dicyclohexylcarbodiimide and a substance capable of forming a reactive intermediate in situ such as N-hydroxybenzotriazole or 4-dimethylaminopyridine. In those instances wherein the acyl group (R1) contains reactive functionality (such as amino or carboxyl groups) it may be necessary to first protect these functionai groups, then carry out the acylation reaction, and finally deprotect the resulting product.

The products of formula I wherein R2 is methoxy can be prepared from the corresponding compound of formula VII wherein A1 is benzyloxycarbonyl. Halogenating (preferably chlorinating) the amide nitrogen of a compound of formula VII (A1 is benzyloxycarbonyl) yields a compound having the formula

or a salt thereof. Reagents and procedures of N-chlorinating amides are known in the art. Exemplary reagents are tert.-butyl hypochlorite, sodium hypochloride, and chlorine. The reaction can be run in an organic solvent (e.g. a lower alkanoi such as methanol) or in a two phase solvent system (e.g., water/methylene chloride) in the presence of a base such as sodium 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 R3 and R4 are the same or if X is a racemic mixture) having the formula

or a salt thereof. The reaction can be run in an organic solvent e.g., a polar organic solvent such as tetrahydrofuran, at a reduced temperature.

Alternatively, a compound of formula VII, wherein A1 is benzyloxycarbonyl, can be converted to a compound of formula Xl using a single step procedure. The methoxylating agent can first be mixed with a compound of formula VII (A1 is benzyloxycarbonyl) and the N-chlorinating reagent then added to the reaction mixture.

Conversion of a compound of formula XI to the desired products of formula I can be accomplished using the procedures described above for the conversion of an intermediate of formula Vll to a product of this invention.

The starting materials of formula II are readily obtainable using art-recognized procedures; see, for example Synthesis, pg. 216 (1979) and J. Org. Chem., 44:3967 (1979).

The following examples are specific embodiments of this invention.

Example 1 f3S-[3 a(Z), 4,B7-2-[[[1 -(2-A mino-4-thiazolyl)-2 -[[4 -meth yl-2-oxo- 1 -(sulfomethoxy)-3-azetidin yl]amino]-2-oxoe thylldene]amino]oxy]-2-methylpropanoic acid, dipotassium salt A) Aminoxymethanesulfonic acid Acetone oxime (1.46 g, 20 mmole) was added to a suspension of a 60% mineral oil dispersion of sodium hydride (0.8 g, 20 mmole) in 16 ml of dry dimethylsulfoxide. This was followed by the portionwise addition of sodium bromomethane sulfonate (3.94 g, 20 mmole). The reaction was heated at 90-950C for 4 hours under nitrogen, cooled and washed twice with 250 ml of ether. Product solidified, was washed with 100 ml of dichloromethane, filtered and dried over P2O5 to yield 15.3 g of crude material.This was dissolved in 20 ml of water, and tetrabutylammonium hydrogen sulfate (7.5 g, 22 mmole) was added. The resulting ion paired product was extracted twice with 200 ml of dichloromethane. The dichloromethane solution was dried (Na2SO4, and concentrated in vacuo.

Hydrolysis of the acetone oxime was accomplished by heating in 120 ml of 2N HCI at 1 300C for 4 hours. This solution was concentrated in vacuo from water twice and then from acetonitrile. The product solidified upon addition of dichloromethane, and was filtered and dried in vacuo to yield 2.5 g of the title compound.

8) O-Sulfomethyl-ct-N-t-butoxyca rbonyl-L-threonine hydroxa mate, potassium salt Aminoxymethanesulfonic acid (1.14 g, 8.9 mmole) was added to a solution of t-butoxycarbonyl-L- threonine (1.96 g, 8.9 mmole) in 1 6 ml of water and 4 ml of tetrahydrofuran at OOC. The pH was adjusted to 4.5 with 1 N KOH, and 1-ethyl-3-(3-dimethylaminopropyl)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 1N SO4. The product was ion paired with tetrabutylammonium hydrogensulfate (3.05 g, 8 mmole) at pH 2.8 and extracted from the aqueous solution with four 100 ml portions of dichloromethane.The dichloromethane solution was dried (Na3SO4) and concentrated in vacuo to yield 4.5 g of product as the tetrabutylammonium salt. This was converted to the potassium salt by ion exchange on 150 ml of Dowex 50 X (0.7 meq K&commat;/ml), and after lyophilization, 2.63 g of the title compound was obtained.

C) O-Sulfomethyl-α-N-t-butoxyCarbonyl-L-(O-methanesulfonylthreonine)hydroxamate, tetrabutylammonium salt To a partial solution of O-sulfomethyl--N-t-butoxywarbonyl-L-threonine hydroxamate, potassium salt (2.37 g, 6.5 mmole) in 50 ml of dry pyridine at 0--5 C under nitrogen was added dropwise 0.8 ml (excess) of methanesulfonyl chloride. The reaction was stirred at room temperature for 4 hours, and then concentrated in vacuo. The residue was dissolved in 10 ml of water, and 2.0 g (6 mmole) of tetrabutylammonium hydrogensulfate was added at pH 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) 3 [3S-(3α,3ss][-3[[1,1 -Dimethylethoxy)-carbonyl]amino-4-methyl-2-oxo-1 -(sulfomethoxy)-azetidine, potassium salt O-Su If omethyl-cr-N-t-butoxycarbonyl-L-(O-methanesulfonylth reonine)hydroxamate, tetrabutylammonium salt (2.6 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 65 mt of acetone. Refluxing was continued for 3.5 hours and the reaction was cooled, filtered, and concentrated in vacua. The residue was dissolved in lOmlof.5MpH5.5KH2P04, and ml of.5 M H 5.5 KH2PO4, and the pH was adjusted to 2.8.Product was extracted four times with 100 ml portions of dichloromethane, and the combined extract was dried and concentrated in vacuo to yield 1.52 g of crude tetrabutylammonium ion paired ,-lactam salt. The potassium salt was obtained by ion exchange through 50 ml of Dowes 50X (0.7 meq K+/ml) to yield upon lyophilization 0.53 g of crude material, which was further purified by chromatography through 100 ml of HP-20 using water. The appropriate fractions were combined and lyophilized to yield 0.245 g of product.

Analysis Calc'd for CtoH17N207SK 1.2 H20 Calc: C, 32.46; H, 5.28; N, 7.57; S, 8.66 Found: C, 32.52; H,4.76; N,7.43; S,8.30 E) {3 S-(3 a,4,8)]- 1 -Sulfomethyl-3-amino-4-methyl-2-oxo-1 -azetidine.

[3 S-(3α,4ss)]-3-[[(1,1 1 1 -Di ethyl ethoxy)ca rbo nyl] ,1 -Dimethylethoxy)carbonyl]-amino]-4-methyl-2-oxo-1 sulfomethoxy)azetidine, potassium salt (0.245 9, .68 mmole) was suspended in 0.5 ml of dichloromethane and 0.5 ml of anisole. The reaction mixture was cooled to OOC, and trifluoroacetic acid (1.0 ml) 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 with ether, and the ether was decanted to give the desired product as a white solid.

F) [3 S-[3 a(Z),4B]1-2-[[[1 -(2-Amino-4-thiazolyl)-2-[[4-methyl-2-oxo- 1 -(su Ifomethoxy)-3-azetidinyl]- amino]-2-oxoethylidene]amino]oxy]-2-methylpropionic acid, diphenylmethyl ester, potassium salt (Z)-2-Amino--[[2-(diphenylmethoxy)-1,1-dimethyl-2-oXoethoxy]-imino]-4-thiazoleacetic acid (0.30 g, .68 mmole) and 1-hydroxybenzotriazole hydrate (0.10 g, .68 mmole) were dissolved in 4 ml of dry dimethylformamide under nitrogen. This was cooled to 00 C, and N,N'-dicyclohexylcarbodiimide (0.14 g, .68 mmole) was added portionwise. After addition, the reaction was stirred at OOC for 1 hour.

To this was added a solution of the above crude 3-amino-1-(sulfomethoxy)azetidine (ca. 0.68 mmole) in 10 ml of dimethylformamide and 0.5 ml of N,N-diisopropylethylamine at OOC. The reaction was stirred at 0 C for 1 hour and then at room temperature overnight. The solution was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in 50 ml of dichloromethane and washed with 2 ml of water. Upon evaporation of dichloromethane, 0.372 g of crude product was obtained. This was passed through 30 ml of Dowex 50 (0.7 meq K /ml) using water, to yield upon lyophilization 0.211 g of crude product, contaminated with hydroxybenzotriazole.

G) [3 S-[3 α(Z),4ss]-2-[[[1 -(2-Amino-4-thiazolyl)-2-[[4-methyl-2-oxo-1 -(sulfomethoxy)-3-azetidinyl]- amino]-2-oxoethylidene]amino]oxy]-2-methyl-propanoic acid, dipotassium salt [3 S-[3α(Z),4α]-2-[[[1 -(2-Amino-4-thiazolyl)-2-[[4-methyl-2-oxo-1 -(su lfomethoxy)-3-azetidinyl]- amino]-2-oxoethylidene]amino]oxy]-2-methylpropionic acid, diphenylmethyl ester, potassium salt (0.211 g) was dissolved in 1.8 ml of dichloromethane, 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 was 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 KH2PO4, adjusted to pH 6.5 with 1 N KOH, and chromatographed through 40 ml of HP-20 with water to give 53 mg of the title compound, melting point 2000 C, dec.

Analysis Calc'd for C14H17NsOgS2K2 .2.75H20: Calc: 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 Example 2 [2S-[2α,3ss(3(z)[[[3[[2-Amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-2-methyl-4-oxo- 1- azetidinyl]oxy]methanesulfonic acid Following the procedure of Example 1, and substituting an equimolar amount of (2)-2-amino-a [(methoxy)-imino]-4-thiazoleacetic acid for the thiazoleacetic acid used in part (F) of Example 1 ,the titled compound is prepared as the mono-potassium salt as a hygroscopic solid after dissolving in acetonitrile and removing the acetonitrile under vacuum several times IR--SO,-(1030 cm~1);; -lactam (1778 cm~1) Analysis Calc'd for Cr1H,4NsO7S2K 0.1 CH3CN Calc: C, 38.11; H, 4.82; N, 15.92; S, 12.56 Found: C,37.94; H,5.36; N,15.92;S,12.56 Example 3 [2S-[2 tr, 3/5(R)]]-[[3-[[[[(4-Eth yl-2,3-dioxo- i-pip erazinyl)carbonyl]amino]phenylacetyl]amino]-2-methyl- 4-oxo- 1 -azetidinylloxy-methanesulfonic acid Following the procedure of Example 1 and substituting cr-[[(4-ethyl-2,3-dioxo-1-piperazinyl)- carbonyl]amino]-phenylacetic acid for the thiazoleacetic acid used in part (F) of Example 1, the titled compound is obtained as the monopotassium salt as a hygroscopic solid. IR-SO3 (1038 cm-1); ,B- lactam (1775 cm~1) Analysis Calc'd for C20H24NsOgSK 1.6H,O Calc: C, 41.53; H, 4.74; N, 12.11; S, 5.54 Found: C,41.53; H,4.46; N,11.13; S,5.61 Example 4 (S)-3-benzyloxycarbonylamino)-4-methyl-2-oxo- I -sulfomethoxyJ-azetidine Following the procedure of Example 1, parts (A) through (D) and substituting benzyloxycarbonylserine for the t-butoxycarbonyl-L-threonine used in part (B), the titled compound is prepared as a potassium salt, lP-S03-(1 025 cm-1); p-lactam (1775 cm-1).

Example 5 (2,3J- 1 -sulfomethoxy-2-(aminocarbonyl)-3-((( 1,1 -dimethylethoxy)carbon yl)amino)-4-oxoazetidine A. Erythro-3-hydroxy-dl-aspartic acid Erythro-3-hydroxy-dl-aspartic acid was prepared from transepoxysuccinic acid as described by C.

W. Jones et al. (Can. J. Chem. 47,4363 (1969)). Trans-epoxysuccinic acid was prepared from fumaric acid as described by G. B. Payne et al. (J. Org. Chem. 24, 54 (1959)).

B. p-methyl erythro-3-hydroxy-dl-aspartate To a suspension of 5.0 g (33.5 mmol) of erythro-3-hydroxy-dl-aspartic 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 taken 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 percent yield) of desired methyl ester having m.p. 2100 C dec.

C. Erythro-3-hydroxy-dl-asparagine The above p-methyl aspartate (4.0 g, 24.5 mmol) was dissolved in 40 ml of conc. 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 5X0 using 6N HCI, and the solution was concentrated in vacuo to about 20 ml and then left overnight at 50C. The white crystalline mass was collected and dried to give 3.4 g (95 percent yield) of desired product having M.P. 2330C dec.

D. N-t-Butoxycarbonyl-erythro-3-hydroxy-dl-aspa ragine, potassium salt Erythro-3-hydroxy-dí-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-butyldicarbonate (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 HCI. The solution was concentrated in vacuo to a small volume, and then the pH was adjusted to 3.0 (6N HCI). Removal of solvent in vacuo gave a solid (20 g) containing the desired product in free acid form and in about quantitative yield, along with inorganic salts.A portion (2.9 g) of this solid was taken up in water and dilute KOH at pH 6.5 and chromatographed through 100 ml of HP20 resin using water and then acetone-water (1:9) to give the desired potassium salt as a residue (1.8 g).

E. Aminoxymethanesulfonic acid, tetrabutylammonium salt Tetrabutylammonium hydrogen sulfate (1.02 g, 3 mmol) was added to a solution of 0.635 g (5 mmol) of aminoxymethane-sulfonic acid in 2 ml of water, and the pH was adjusted to 10.0 using dilute KOH. The water was removed in vacuo, and the residue was triturated with methylene chloride.

After filtration, the filtrate was dried over sodium sulfate and evaporated to give the desired product as a residue (1.06 g, 2.88 mmol).

F. 0-Sulfomethyl-a-N-t-butoxycarbonyl -erythro-3-hydroxy-dI-asparagine hydroxamate, potassium salt N-t-butoxycarbonyl -erythro-3-hydroxy-dl-asparagine, potassium salt (0.792 g., 2.77 mmol) was dissolved in water (3 ml) and adjusted to pH 2.4 (dil. H2SO4). 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 (8 ml) and cooled to OOC. To this stirred solution was added 0.424 g (2.77 mmol) of 1 -hydroxybenzotriazole monohydrate foliowed by 0.572 g (2.77 mmol) of N,N'-dicyclohexylcarbodiimide.The mixture was stirred at OOC for 2 hours, and then 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 OOC for 4 hours. The reaction was filtered and concentrated in vacuo to a residue. Water (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. 1 450C dec.

Analysis Calc'd for CaoH18N3OgSK 0.71 H2O: Calc: C, 29.42; H, 4.80; N, 10.29; S, 7.85 Found: C, 29.42; H, 4.73; -N, 10.04; S, 7.45 G. O-sulfomethyl-a-N-t-butoxycarbonyl -erythro-3-hydroxy-dl-aspa ragine hydroxa mate, tetrabutylammonium salt To a solution of the above asparagine hydroxamate, 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 0.5 M pH 5.5 KH2PO4 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, HZO.26 mmol).

H. (2a,3a)-1 -sulfomethoxy-2-(aminocarbonyl)-3-((( 1 ,1 -dimethylethoxy)carbonyl)amino)-4oxoazetidine, potassium salt The above O-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 3A molecular sieves overnight. The solution was removed via syringe and diluted with 0.8 ml of dry methylene chloride. To this stirred solution at -5O0C under argon was added 0.12 ml (0.85 mmol) of triethylamine followed by dropwise addition of 0.08 ml (0.42 mmol) of trifluorcmethanesulfonic 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 vacua, and the residue was dissolved in 2 ml of acetone.The solution was cooled to OOC, 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 water gave 15 mg (20 percent yield) of desired potassium salt, after lyophilization having m.p. 1 490C dec. and IRIKBR) 1786 reciprocal CM (Beta-lactam carbonyl) and 1696 reciprocal CM (broad, amide and carbonate carbonyl).

By following the procedures previously described the following compounds are prepared: (3 S-trans)-[[(2-Amino-4-thiazolyl) (methoxyimi no)acetyl] amino]-4-methyl-2-oxo-1 azetidinyl]oxymethanesulfonic acid, monopotassium salt (3S-trans)-[[(2-Amino-4-thiazolyl) [(2 ,2,2-trifluoroethoxy)imino] acetylja mino]-4-methyl-2-oxc- 1- azetidinyl]oxy] methanesulfonic acid, monopotassium salt (3 S-trans)-[[(2-Amino-4-thlazolyl) [(2-amino-2-oxoethoxy)imino]acetyl] a amino]4-methyl-2-oxo-1 1 - azetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-trans)-[[(2-Amino-4-thiazolyl) [(carboxymethoxy)imino]acetyl amino]-4-methyl-2-oxo-1 azetidinyl]-oxy]methanesulfonic acid, dipotassium salt (3S-trans)-[[(2-Amino-4-thiazolyl) [[( 1-ca carboxycyclopropyl)oxy]imino]acetyl]amino]-4-methyl-2- oxo- 1 -azetidinyl]-oxy] methanesulfonic acid, dipotassium salt [3S-[3a( R),4P]1-[[3-[(Aminophenylacetyl) am ino)-4-methyl-2-oxo- 1 -azetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-trans)-[[3-[(Phenylacetyl)amino]-4-methyl-2-oXo-1 -azetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-trans)-[[3-[(2-Thienylacetyl)amino]-4-methyl-2-oXo-1-azetidinyl]oxy]methanesulfonic acid monopotassium salt (3 S-trans)-[[3-[(2, 6-Dimethoxyphenyl)acetyl]-a minol-4-methyl-2-oxo- 1 -azetidinyl]oxy]methanesulfonic acid, monopotassium salt [3 S-[3(R)Aj-[[3-[[[[(Aminocarbcnyl)-amino]-2-thienylacetyLaminc]-4-methyl-2-cxo-1 azetidinyl]oxyj methanesulfonic acid, moncpotassium salt [3 S-[3a(R)Aj]-[[3-[(Carboxyphenylacetyl)-aminoj4-methyl-2-oxo- 1 -azetidinyljoxy]methanesulfonic acid, dipotassium salt [3 S-[3a(+),4j]-[[3-[(P henylsulfcacetyl)-ami nc]-4-methyl-2-cxc- 1 -azetidinyl]oxy]methane- sulfonic acid, dipotassium salt (3S-trans)]-[[3-[[(2-Amino-4-thiazclyl)-cxcacetyl]aminc]-4-methyl-2-oxc- 1 -azetidinyl]oxy]methanesulfonic acid, monopotassium salt [3S-[3(r(R),4X3]]-[[3-[[[[[2-Oxo-3-[(phenyimethylene)amino]-1 -imidazolidinyl]carbonyl]amino]- phenylacetyl]amino]-4-methyl-2-oxo- 1 -azetidinyl]oxy] methanesulfonic acid, monopotassium salt [3S-[3(Z),4j]-[[3-[[2-Furanyl(methcxyiminc)acetyl]amino]-4-methyl-2-cxc-1 -azetidinyl]oxy]methanesulfonic acid, monopotassium salt 3S(Z)]-[[3-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-oxo-1 -azetidinyi]- oxyjmethanesulfonic acid, monopotassium salt [3 S(Z)]-[[3-[[(2-Amino-4-thiazolyl) [(1 1-ca rboxy- 1 -methylethoxy)imino]acetyl]amino]-2-oxo- 1 azetidinyl]oxylmethanesulfonic acid, dipotassium salt [3S(Z)]-[[3-[[(2-Aminc4-thiazolyl)[(2,2,2-trrnucrnethoxy)iminojacetyl]amino-2-oxo-1 -azetidinyl]oxy]methanesulfonic acid, monopotassium salt 3S(Z)]-[[3-[[(2-Aminc-4-thiazolyl)[(2-amino-2-oxoethcxy)iminc]acetyl]amino]-2-oxo-1 -azetidinyl]- oxy]methanesulfonic acid, monopotassium salt [3S-[3α(S S),4p] 1-[[3-[[[(Aminocarbonyl)amino]-2-thienYlacetYI]amino]-2-oXo- 1 -azetidinyl]- oxy]methanesulfonic acid, monopotassium salt [3S-[3a(+),4p|]-[[3-[(Phenylsulfoacetyl)amino]-2-oXo-1-azetidinyl]oxy]methanesulfonic acid, dipotassium salt [3S-[3(R),4/3]]-[[3-[[[[(4-Ethyl-2,3-dicxo-1 -piperazinyl)ca rbonyl]amino] phenylacetyl]amino]-2- oxo-1 -azetidinyl]oxy] methanesulfonic acid, monopotassium salt [(3S(Z)]-[[3-[(Phenoxyacetyl)aminc]-2-cxc- 1 -azetidinyl]oxy]methanesulfcnic acid, monopotassium salt (3S-cis)-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-4-methyl-2-oXo-1 -azetidinyl] oxylmethanesulfonic acid, monopotassium salt (3S-cis)-[[(2-Amino-4-thiazolyl)[(2,2,2-trifiuoroethoxy)imino]acetyl]amino]-4-methyl-2-oXo-1 azetidinyl]oxy] methanesulfonic acid, monopotassium salt (3S-cis)-[[(2-Aminc-4-thiazolyl)[(carboxymethcxy)iminc]acetyl]aminoj-4-methyl-2-oxo-1 azetidinyljoxy]methanesulfcnic acid, dipotassium salt (3S-cis)-[[3-[[(2-Amino-4-thiazolyl)](1 carboxyl1 -methylethoxy)imino]acetyl]amino]-2-oxo-4- methyl -azetidinyl]oxy]methanesulfonic acid, dipotassiu m salt (3S-cis)-[[(2-Amino-4-thiazolyl)[[( 1- rboxycyclopropyl)oxy] imino]acetyl]amino]-4-methyl-2-oxo- 1 -azetidinyl]-oxy]methanesulfonic acid, dipotassium salt (3S-cis)-[[(2-Amino-4-thiazolyl)[(2-amino-2-oXoethoxy)imino]acetyl]amino]-4-methyl-2-oXo-1 azetidinyl]oxy] methanesulfonic acid, monopotassium salt [3S-[3a(R),4]]-[[3-[(Carboxyphenylacetyl)amino]-4-methyl-2-oXo-1 -azetidinyl]oxy]methane- sulfonic acid, dipotassium salt [3S-[3a( P),4a]]-[[3-[[[[(4-Ethyl-2,3-dioxc-1 -piperazinyl)carbonyl]amino]phenylacetyl]amino]-4- methyl-2-oxo-1 -azetidinyl]oxy] metha nesu If onic acid, monopotassium salt [3 S-[3α(S),4α-[[3-[[[(Aminocarbonyl)amino]-2-thienylacetyl]-amino]-4-methyl-2-oxo-1 azetidinyl]-oxy]methanesulfonic acid, monopotassium salt [3S-[3a(R),4a]]-[[3-[(Aminophenylacetyl)-aminc]-4-methyl-2-oxc-l -azetidinyl]oxy]methanesulfonic acid, monopotassium salt

Claims

1. A-ss-lactam having an

substituent in the 1-position and an acylamino substituent in the 3-position; wherein Re and Re are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or a 4,5,6 or 7-membered heterocycle, or Re and Re together with the carbon atom to which they are attached are cycloalkyl or a 4,5,6 or 7-membered heterocycle, or one of Re and Re is hydrogen and the other is azido, halomethyl, dihalomethyl, thihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2- phenylethynyl, carboxyl,-CH2X1,-S-X2,-O-X2, or

X1 is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyi, substituted phenyl, cyano, -S-X2, or -O-X2; X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, (substituted phenyl)-carbonyl, or heteroarylcarbonyl; A is -CH=CH-, --CH2,-CH=CCH-, --(CH,),,-I --(CH,),,OO-, --(CH,),,NHH-, or -(CH2),-S-CH2-; n is 0, 1,2 or 3; n' is 1 or 2; and Xe and X7 are the same or different and each is hydrogen or alkyl, or Xe is hydrogen and X7 is amino, substituted amino, acylamino or alkoxy, or a salt or ester thereof.

2. A ,B-lactam in accordance with claim 1 wherein P5 and Re are each hydrogen.

3. A ss-lactam in accordance with claim 1 having the formula

or a salt or ester thereof, where R1 is acyl; R2 is hydrogen or methoxy; R3 and R4 are the 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 R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2phenylethynyl, carboxyl, -CH2-X1 -S-X2, -O-X

wherein P5, Re, X1,X2,A, and X7 are as defined in claim 1; and one of X2 and X4 is hydrogen and the other is hydrogen or alkyl, or X2 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group; X5 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl or cyano.

4. A ss-lactam in accordance with claim 3 wherein R2 is hydrogen.

5. A /3-lactam in accordance with claim 4 wherein one of R3 and P4 is other than hydrogen.

6. A p-lactam in accordance with claim 4 wherein P3 is hydrogen and P4 is methyl.

7. A p-lactam in accordance with claim 4 wherein P3 is methyl and P4 is hydrogen.

8. A p-lactam in accordance with claim 4 wherein R5 and R6 are each hydrogen.

9. A ss-lactam in accordance with claim 4 wherein Re and Re are each methyl.

10. A ss-lactam in accordance with claim 4 wherein P1 is (Z)-2-amino-α-[(1-carboxy-1 -methyl- ethoxy)imino)-4-thiazoleacetyl.

11. A ,B-lactam in accordance with claim 3 wherein R2,Rs and Re are each hydrogen and one of R3 and P4 is alkyl and the other is hydrogen.

12. A ,B-lactam in accordance with claim 3 wherein R2,R3,R and R6 are each hydrogen and R4 is methyl.

13. A p-lactam in accordance with claim 3 wherein R2,R4,Rs and Re are each hydrogen and P2 is methyl.

14. A ,B-lactam having the formula

or a salt thereof, wherein R3 and R4 are the 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 R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2phenylethenyl, carboxyl,--CH2X1,-S-X2,-O-X2,

R5 and Re are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or a 4,5,6 or 7-membered heterocycle, or P5 and Re together with the carbon atom to which they are attached are cycloalkyl or a 4,5,6 or 7-membered heterocycle, or one of R5 and R6 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, alkenyl, alkynyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl -CH2-X1, -S-X2,-0-X2,

X, is azido, amino, hydroxy, aikanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2or-O-X2; X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl or heteroarylcarbonyl; one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group;; X5 is formyl, alkancyl, phenylcarbonyl (substituted phenyl)carbony, phenylajkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonvl, or cvano: A is -CH=CH-, -CH2-C H=CH-, (CH2) (CH2)O (CH2)NH, -(CH2),-S-CH2-; nisi, 1,2 or 3; n' is 1 or 2; and X5 and X7 are the same or different and each is hydrogen or alkyl, or X6 is hydrogen and X7 is amino, substituted amino, acylamino or alkoxy.

15. A ss-lactam in accordance with claim 1 a salt of [3S-[3α(Z)Ass-2-[[[1 -(2-amino-4-thiazolyl)2-[[4-methyl-2-oxo- 1 -(sulfomethoxy)-3-azetidinyl]amino]-2-oxoethylidene]a mino]oxy-2methylpropanoic acid.

16. A p-lactam in accordance with claim 14, [3S-(3α,4ss)]-1-sulfomethoxy-3-amino-4-methyl-2- oxo-1 -azetidine.