CA1253501A - Azetidinyl sulfonic acid and analogs - Google Patents

Abstract

ABSTRACT Antibiotic activity is exhibited by .beta.-lactams having the formula , or an ester or salt thereof, wherein R1 is an acyl group.

Description

~L2~3~
~ GCl98 ~ AZETIDINYL SULFONIC ACID AND ANALOGS
._ This invention is directed to a novel family of ~-lactam antibiotics, and to the use of such compounds as antibacterial agents.
It has been discovered that the B-lactam nucleus can be biologically activated by a subs~ituent R R
5~ ~ 6 havi~g the formula -O-C S03H (or salt thereof) attached to the nitrogen atom i.n the nucleus.
R5~ ~ 6 ~-Lactams having a -O-C~03H substituent (or pharmaceutically acceptable sal~
thereof) in the l-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 ~-lactam antibiotics of this invention are those encompassed by the formula Rl-NH- I F 3 ~ ~R6 ~C - N - O -C-SO H

or an ester or salt thereofO

3~ .

. 35 ~.2535~3~

As used in formula I and throughout the specification, the symbols are as defined below.
Rl 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,~,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 2-phenylethenyl,

2-phenylethynyl, carboxyl, -CH2X~ X2, 13 X3 1l - -X2 -o -f -x4 - S -f -X4 or -A-C-NX6X7 ;
lS X5 X5 Xl is azido, amino (-NH2), hydroxy, alkanoyl-amino, 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 alkanoylj 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, alkanoyl, phenylcarbonyl,

3~ (substituted phenyl)carbonyl, phenylalkylcarbonyl, ~substituted phenyl~alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl (NH2-C~ substituted amino~oarbonyl, or cyano l-C--N);

~ 3~

A is -CH=CH-, CH2-CH=C~ (C~2)-n , -(C~ ) , O-~ -tCH2)n~-NH-~ or (C~2~n, 2 n i~ 0, 1, 2 or 3;
n' is 1 or 2;
X6 and X7 are the same or different and each is hydrogen or alkyl, or X6 is hydro~en and X7 is amino, substituted amino, acylamino or alkoxy; and ~5 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 R5 and R6 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, lS alkoxycarbonyl, 2-pheny~eth~nyl, 2-phenylethynyl, carbOxyl~ -CH2Xl, -S-X2~ --X2' or -A-C-NX~X7-Listed below are definitions of various terms used to describe the B-lactams of this invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific ins~ances) 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 7 carbon atoms.
The term "substituted alXyl" refers to alkyl groups substituted with one, or more, azido amino(-NH2), halogen, hydroxy, carboxy, cyano ~i3~

alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy~ (substituted phenyl)oxy, R7-oxy, mercapto, al~ylthio, phenylthio, (suhstituted phenyl)-t~io, alkylsulfinyl, 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 iodi.ne.
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 4,14~,333, issued March 13, 1979. The preferred protected carboxyl groups are benzyl, benzhydryl, t-butyl, and ~-nitrobenzyl esters.
The term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino(-NH2~, halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alko~y (of 1 to 4 carbon atoms), or carboxyl groups.
The expression "a 4,5,6 or 7-membered heterocycle" (referred to as "~ ") refers to substituted and unsubstituted, aromatic and non-aromatic groups containing one or more nitrogen, oxygen or sulfur atoms~ Exemplary substituents are oxo~=O), halogen, hydroxy, nitro, 30- amino, cyano, trifluoromethyl, alkyl of 1 to 4 . 35 ~ ;3~
GCl9 carbons, al~oxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 2-furylimino O~_CH=N-( ~ ), benzylimino and substituted alkyl groups (wherein the alkyl group has 1 ~o 4 carbons)~
One type of 1-4,5,6 or 7-membered heterocycle" is the "heteroaryl n . group. The term "h,eteroaryl n 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, imiaazolyl, 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 heterocy~les are 1-alkyl-3-azetinyl, 2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-l-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~ C198 3-(2-aminoethyl)-2-oxo-1-imidazolidinyl, 3-amino-2-oxo-1-imidazolidinyl, 3-I (alkoxycarbonyl)amino~-2-oxo-1-imidazolidinyl, 3-~2- I (alkoxycarbonyl~-amino~e~hyl~-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-Euranyl, 2,3-dioxo-l-piperazinyl, 2,5-dioxo-1-piperazinyl, 4-alkyl-2,3-dioxo-1-piperazinyl, and 4-phenyl-2,3-dioxo-l-piperazinyl.
The term "substituted amino" refers to a group having the formula -NYlY2 wherein Yl is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Y2 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)-C- (wherein "substituted alkyl" is defined above) and phenylalkanoyl.

~ 7 ~~

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 no-t be viewed as a limi-tation of -the scope of this invention. Exemplary acyl groups are those acyl groups which have been used in the past to acylate ~-lactam antibiotics including 6-aminopeni-cillanic acid and derivatives and 7-aminocephalosporanic acid and derivatives; see, for example, ~halosporins and Penicillins, edited by Flynn, Academic Press (1972), German Ofenlegungsschrift 2,716,677, published October 10, 1978, Belgian patent 867,994, published December 11, 1978, United States patent 4,152,432, 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. Portions oE these references describe various acyl groups. 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 Ra 1,!
wherein Ra is alkyl; cycloalkyl; alkoxy; alkenyl;

f~
~ i ,,~,~, ( ~3~
_ -8- GC198 ~ycloalkenyl; cyclohexadienyl; or alkyl or alXenyl substituted with one or more halogen, cyanor nitro~ amino, mercapto, alkylthio, or cyanomethyl-thio groups.
(b) Carbocyclic aromatic groups ha~ng theformula RC
Rb~-~CH2)n-C-~

Rb ~ CH-C- , Re 2 D Rb ~<Rd ~1 Rc b ~ C 2 ~s6~ _ 3~

_g_ .

R
Rb~d 2 ~ S-CH~-C- c>r ~ H -S-C-wherei~ n is 0, 1, 2 or 3; Rb, Rc, 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 i5 amino, hydroxyl, a carboxyl salt, protected carboxyl, foLmyloxy, a sulfo salt, a sulfoamino salt, azido, halogen, hvdrazino, alkylhydrazino, phenylhydrazino, or ~(alkylthio)thioxomethyl]thio.
20Preferred carbocyclic aromatic acyl groups include those having the I ormula 25HO ~ CH -C-, O

.. ~H2-C-, 30 ~

3~

. HO ~ H-C- (R~ is preferably ~e a carboxyl salt or sulfo salt) and CH-C- (Re is preIerably a carboxyl salt or sulfo salt~. .
(c) Heteroaromatic yroups haviny ~he formula R~ ICH2)n Rf-CH-C-e Rf--O--CH2--C-- ~
O

Rf-S-CH7-C- , O O
ll ~I
Rf-C -C-wherein n is 0, 1, 2 or 3; Re is as aefined ab~ve; and R~ 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 .G3~

~ ~3~

rings are thienyl ! furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl. Exemplary substituents are halogenl hydroxyl, nitro, amino, protected S amino~ cyano, trifluoromethyl, alkyl~of 1 to 4 carbon atoms, alkoxy of 1 ~o 4 carbon atoms, or R

HOOC - f H - C~2 - o-c -NH-Preferred heteroaromatic acyl yroups include those groups of the above formulas wherein Rf is 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 1~ 5-amino-1,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl, or 6-aminopyridin-2-yl.
(d) [~(4-Substituted-2,3-dioxo-1-piper-azinyl)carbonyl~amino]arylacetyl groups having the formula ll f--~
-C-CH-NH-C-N N-R O ~ 0 wherein Rg is an aromatic group (including carbocyclic aromatics such as those of the formula Ic and heteroaromatics as included within the definition of Rf); and Rh is alkyl, substituted ~53~

_ GC198 alXyl ~wherein the alkyl group is substituted with one or more halogent cyano, nitro~ amino or mercapt~ groups), arylm~thyleneamino (i.e., -N=CH-Rg wherein R~ is as defined above), Ol arylcarbonylamino (i~e., -NH~C~Rg wherein R
is as defined above) or alkylcarbonylamino.
Preferred [[(~-substituted-2,3-dioxo-1-piperazinyl)carbonyl~amino]arylacetyl groups include those wherein ~ is ethyl, phenylmethylene-amino or 2-furylmethyleneamino.
(e) ~Substituted oxyimino)arylacetyl groups havinq the formula O
--C-C=N-O-Ri g wherein R is.as de~ined above and Ri is hydrogen, Rc, alkyl, cycloalkyl, al~ylaminocarbonyl, arylamino-carbonyl (i.e., ~C~NH~Rg 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, alXoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxvcarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl, or dialkoxy-. phosphinyl substituents).

,~ .

5;3~

Preferred ~substituted oxyimino)arylacetyl groups include those wherein R~ is 2-amino-4-thiazolyl. Also preferred are those groups wherein Ri is methyl, ethyl, carbo~yme~hyll 5 l-carboxy-l-methylethyl~ ~,2,2-trifluoroethyl or l-carbo~ycyclopropy~. .. .
(~-3 (Acylamino)arylacetyl groups having the formula o O
-C-CH-NH-C-R
R~

wherein Rg is as defined above and Rj is Rb ~ (CH2)n-O-, ~mino, alkylamino, (cyanoalkyl)-amino, amido, alkylamido, (cyanoalkyl)amido, -cH2-NH-C ~ N ~CH-CH2--NH-CH

HO

~ \ ~ ~ ~ro2-N(CH2 C~2 OH)2, ~ rCH3, OH

~ CH, or ~~ ~
HO ~ C-o o _ ~Cl9~ ~

Preferred (acylamino~arylacetyl groups of the above formula incl~de those groups wherein R is amino or amido~ Also preferred are those groups wherein R is phenyl or 2-thienyl.
(g~ [[[3-Substituted-2-oxo-l-imidazoli-dinyl]carbonyl]amino]arylacetyl groups having the formula I I
O O C
- C - C~-NH -C-N N-Rk wherein R is as defined above and Rk is hydrogen, alkylsulfonyl, arylmethyleneamino lS ~i.e., ~N=CH-Rg wherein R~ is as defined above), -C-Rm (wherein Rm is hydrogen, alkyl or halogen substituted alkyl), aromatic group (as de~ined by Rg above), alky~ or substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino vr mercapto groups).
Preferred [[3-substituted-2-oxo-l-imidazoli-dinyl]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, phenyl-methyleneamino or 2-furylmethyleneamino.

3~

~5350~ .

_ 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 potassilIm salts (which are preferred)l alkaline earth metal salts like the calcium and magnesiwn salts~ salts with organic bases, e.~., 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, ~, in isolating or purifying the product.

The salts are formed in conventional manner by reactin~ 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 ~he hydrogen form (e.g., polystyrene sulfonic acid resin like Dowex 50, or with an aqueous acid and extraction with an organic solvent, ~ ~, ethyl aceta~e, dicloromethane or the like, the free acid form can be obtained, and, if desired, another salt formed.

3~

3~

.

~ -Lactarns having a -O-~C~SO H substituent (or salt thereof) in the l-position and an amino or acylamino substituent in the 3-posltion contain at least one chiral center - the carbon atom (in the 3-position of the ~-lactam nucleus) to which the amino or acylamino substituent is attached.
This invention is directed to those 3-lactams which have been described above, wherein the stereochemistry at -the chiral center in the 3-position of the B-lactam nucleus is the same as the configuration at the carbon atom in the

6-position of naturally occurring penicillins ~ ~, penicillin G) and as the configuration lS at the carbon atom in the 7 position of naturally occurring cephamycins, (e.g., cephamycin C).
With respect to the preferred ~-lactams of 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 above-described 3-lactams.

~ 2~ GC198 ..

~-Lactams having a -O-C-SO3H substituent (or salt thereof) in the 1-position of the ~-lactam nucleus and an acylamino substituent in the 3-position of the ~-lactam nucleus have activity against a range of gram negative and 5~ ~ ~
gram-positive organisms. The O-C-SO3H
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 infections) in mammalian species, such as domesticated animals (e.g., dogs, cats, cows, horses, and the like) and humans.
For combating bacterial infections in mammals a compound of this invention can be administered to a mammal in need thereof in an amount of about 1.4 mg/kg/day to about 35Q mg/kg/day, preferably about 14 mg/~g/day ; to about 100 mg/kg/day. All modes of adminis-tration which have been used in the past to deliver penicillins and cephalosporins to the site of the infection are also contemplated for use with the novel family of ~-lactams of this invention. Such methods of administration include oral, intravenous, intramuscular, and as a suppository.

535 ~ ~ GC198 The ~-lactams of this invention can be prepared from an amino acid having the formula II OH
~R

~C - OH .
O
The amino group is first protected with a classical protecting group (e.g., t-butoxycarbonyl, benzyloxy-carbonyl, _-nitrophenylsulfenyl, etc.), ylelding a compound having the formula III
Al-NH-CH - C -R3 ~C OH
O~

In formula III, and throughout the specification, the symbol "Al" refers to a nitrogen protecting group.
The carboxyl group of a protected amino acid of formula XII is then reacted with an amine having the formula IV ~ 6 NH3-O ~C - SO3 The reaction proceeds in the presence of a coupling agent such as l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide or dicyclohexylcarbodiimide, and yields a salt of the compound having the formula ~25350:~ GC198 vIOH~\ R4 Al-NH-CH - C R3 C--NH O 5`c'R6o H
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 VI ~ 4 Al-NH-CH- C - R3 ~C - NH-O - C -SO3H , O
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 VII _4 Al-N~-CH - C-R
¦ ¦ R5~ ~R~
~5 0 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 triphenylphosphine and diethyl-azodicarboxylate or carbon tetrachloride and ~riethylamine, yields a compound of formula VII.

~2535~ GC198 Both of the methods disclosed above for ring closure of a compound of formula V result in the inversion of the stereochemlstry at the carbon bonded to the R3 and R4 subs-tituents.
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 (~ , palladium on charcoal) hydrogenation can be used. If the protecting group is o-nitrophenylsulfenyl, ~-toluenesulfonic acid can be used in combination with ~-thiocresol. The deprotected compound has the formula VIII

NH2~fH - IC R3R~ R6 ~C - N -O - C - SO3H
or a salt thereof, f~2~

and is a key intermedia~e for preparing the compounds of this lnvention. 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 Rl~NH-CH - C-R
~C - N -O-~C~ ~O H
or a salt thereof.
Exemplary teehniques include reaction with a carboxylic aeid (Rl-OH) or eorresponding carboxylic aeid halide or earboxylie aeid anhydride. The reactions with a earboxylie aeid proeeed most readily in the presenee of a carbodiimide such as dicyelohexylcarbodiimide and a substance capable of forming a reaetive intermediate in situ sueh as N-hydroxybenzotriazole or 4-dimethyl-aminopyridine. In those instanees wherein the acyl group (Rl) contains reactive functionality (such as amino or carboxyl groups) lt may be neeessary to first proteet these functional groups, then carry out the aeylation reaetion, and finally deproteet the resulting produet.

~2535~:~ GCl 9 8 The products of formula I wherein R2is methoxy can be prepared from the corresponding compound of formula VII wherein Al is benzyloxy-carbonyl~ Halogenating (preferably chlorinating) the amide nitrogen of a compound of formula VII
(Al is benzyloxycarbonyl) yields a compound having the formula ~ CH2~O-C-N-CH - C-R3 1 - I o~-~C'R~O H

or a salt thereof.
Reagents and procedures of N-chlorinating amides are known in the art. Exemplary reagents are tert. - butyl hypochlorite, sodium hypochlorlte, and chlorine. The reaction can be run in an organic solvent (~ , a lower alkanol 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, ~y~, an alkali metal methoxide, yields a compound (in combination wi~h its enantiomer if R3 and R4 are the same or if X is a racemic mixture) having the formula XI

CH2-O-C-NH-l ¦ 3R R
~ C N -O - C - ~O H , or a salt thereof.

~35~

The reaction can be run in an organic solvent, e.g., a polar organic solvent such as tetra-hydrofuran, at a reduced ternperature.
Alternatively, a compound of formula VII, wherein A1 ls benzyloxycarbonyl, can be converted to a compound of formula XI using a single step procedure. The methoxylating agent can first be mixed with a compound of formula VII (Al 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 VII to a product of this invention.
The starting materials oE formula II
are readily obtainable using art-recognized procedures; see, for example Synthesls, pg. 216 (1979) and J. Org. Chem., 44:3967 (1979).
The following examples are specific embodiments of this invention.

~ 3~ GC1~8 Example 1~3S-[3~(Z),4~]]-2 i [[1-(2-Amino-4-thiazolyl)-2-[~4-methyl-2-oxo-1-(sulfome_noxy)-3-azetidinyl]-amino]-2-oxoeth~lidene]amino]oxy]-2-methylpropanoic acid, di~otassium salt . .
A) minoxymethanesulfonic 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 90-95C 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 P205 to yield 15.3 g of crude material. This was dissolved in 20 ml of water, and tetra-butylammonium 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 drled (Na2SO4, and concentrated _ vacuo. Hydrolysis of the acetone oxime was accomplished by heating in 120 ml of 2N ~Cl at 130C for 4 hours. This solu-tion was concentrated ln vacuo from water twice and then from acetonitrile. The product solidified upon addition of dichloromethane, and was fil~ered and dried in vacuo to yield 2.5 g of the title compound.

~2535~ GC198 -~5-B) O-Sulfomethyl-~-N-_-butoxycarbonyl-L-__ threonine hydroxamate,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 16 ml of water and 4 ml of tetrahydrofuran at 0C.
The pH was adjusted to 4.5 wi~h lN ROH, and l-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 lN H2SO~.
The product was ion paired with tetrabutyl-ammonium hydrogensulfate (3.05 g, 8 mmole) at pH 2.8 and extracted from the aqueous solution wi ~ four 100 ml portions of dichloro~
methane. The dichloromethane solution was dried (Na2SO4) and concentrated ln 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 50X
(0.7 meq K~/ml), and after lyophilization, 2.63 g of th.e title compound was obtained.

~2~

Ç) O-Sulfomethyl-a-N-t-butoxycarbonyl-L~
(O-methanesulfonylthreonine)hydroxamate,_ tetrabutylammonium salt To a parkial solution of O-sulfomethyl-~-N-t-butoxycarbonyl-L-threonine hydroxamate, potassium salt (2.37 g, 6.5 mmole) in 50 ml of dry pyridine at 0-5C 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 lO ml __ of water, and 2.0 g (6 mmole).of tetrabutyl ammonium hydrogensulfate was added at pH 2.8.
The ion paired material was extracted with chloroform. The chloroform was dried and concentrated ln vacuo to yield 2.6 g of crude product.

D) ~3S-(3a,4~?_]-3-~[(l,1-Dimeth~lethoxy~-carbonvl]amino]-4-methY1-2-oxo-l-(sulfomethoxy)-azetidine, potassium salt O-Sulfomethyl-~-N-t-butoxycarbonyl-L-(O-methanesulfonylthreonine)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 ml of acetone.
Refluxing was continued for 3.5 hours and the reaction was cooled, filtered, and concentrated 3~ in vacuo. The residue was dissolved in 10 ml .
of 5 M pH 5.5 KH2PO4, and the pH was adjusted to 2.~. Product was extracted four times with lO0 ml portions of dichloromethane, and the combined extract was dried and concentrated ~535~ GC198 -27~

in vacuo to yield 1.52 g of crude tetrabutyl-ammonium lon paired B-lactam salt. The potassium salt was obtained by ion exchange through 50 ml of Dowex 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 conbined and lyophilized to yield 0.245 g of product.
Analysis Calc'd for ClOH17N27SK 1 2 H2O
C, 32.46; H, 5.28; N, 7.57; S, 8.66 Found: C, 32.52; ~, 4.76; N, 7.43; S, 8.30 E) [3S-(3~,4~)]-1-Sulfomethyl-3-amlno-4-methyl-2-_o l-azetidine [3S-(3~,43)]-3-[[(1,1-Dimethylethoxy~carbonyl]-amino]-4-methyl-2-oxo-1-(sulfomethoxy)azetidine, potassium salt (0.245 g, .68 mmole) was suspended in 0.5 ml of dichloromethane and 0.5 ml of anisole. mhe reaction mixture was cooled to 0 C, and trifluoroacetic acid (1.0 ml) was added under nitrogen. The reaction mixture was s~irred 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.

i3~

F) L3S-~3~(Z),4~]~-2-~L~1-(2=Ami 4-thiazolyl)-2-[[4-methyl-2-oxo l-(sulfomethoxy)- _azetidinyl]-_ninol-2-oxoethylidene]amino]oxy]-2-methylpropionic acid, dlphenylmethyl ester, potassium salt (Z)-2-Amino-~-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxyl-imino]-4-thiazoleacetic acid (0.30 g, .68 mmole) and 1-hydroxybenzotriazole hydrate (0.10 g, .68 mmole) were dissolved in ~ ml of dry dimethylformamide under nitgoren.
This was cooled to 0 C, and N,N'-dicyclohexyl-carbodiimide (0.14 g, .68 mmole) was added portionwise. After addition, the reaction was stirred at 0C for 1 hour. To this was added a solution of the above crude 3-amino-1-(sulfo-lS methoxy)azetidine (ca. 0.68 ~mole) in 10 ml of dimethylformamide and O.S ml of N,N-diisopropyl-ethylamine at 0 C. The reaction was stirred at 0C 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 S0 (0.7 meq K~/ml) using water, to yield upon lyophilization 0.211 g of crude product, contaminated with hydroxybenzotriazole.

3~

G) ~3S-~3~(Z),4~]]-2-l[~1-(2-Amino-4-thiazolyl)-2-[[4-methyl-2-oxo-1-(sulfomethoxy)-3-azetidinyl]-amino]-2-oxoeth.ylldene]amino]oxy]-2-methyl-propanoic acid, dipotassium salt [3S-[3~(Z),4~]]-2~~I[1-(2-Amino-4-thiazolyl)-2-[[4 methyl-2-oxo-1-(sulfomethoxy)-3-azetidinyl]-amino]-2-o~oethylidene]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 0C for 2 hours. The reaction mixture was condentrated _ vacuo and evaporated from benzene twice.
The residue was washed with ether: ethyl acetate lS (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 lN KOH, and chromatographed through 40 ml of HP-20 with water to give 53 mg of the title compound, melting point 200C, dec.
AnalysiS Calc'd for C14H17N5OgS2 2 2 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-[2~,3~(Z)]]-[[3-[[(2~Amino-4-thiazolyl)-(methoxyimino)ace-tyl]amino3-2-methyl-4-oxo-l-azetidinyl]oxy]methanesulEonic acid Following the procedure of ~xample 1, and substituting an equimolar amount of (2)-2-amino-~-[(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 - SO3 (1030 cm ); ~-lactam (1778 cm Analysis: calc. for C11l114N5O7S2 3 calc. C-38.11; H-4.82; ~-15.92; S-12.56 found: C-37.94; H-5.36; N-15.92; S-12.56 Example 3 [2S-[2~,3~(R)]]-[[3-[[[[(4-Ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-2-methyl-4-oxo-1-azetidinyl]oxy-meth~esulfonic acid Following the procedure of Example 1 and substituting ~-[[(4-ethyl-2,3-dioxo-1-piperazinyl)-carbonyl]amino]-phenylacetic acid for the thiazole-acetic acid used in paxt (F) of Example 1, the ~itled compound is obtained as the monopotassium salt as a hygroscopic solid. IR - SO3 (1038 cm );
~-lactam (1775 cm 1) 30 Analysis calc- for C20H24N5O9SK-1-6~12O
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-ben~oxycarbonylamino)-4-methyl-2-oxo-1-(sulfomethoxy)-azetidine Following the procedure of Example 1, parts (A) through (D) and substituting benzyloxy-carbonylserine for the t-butoxycarbonyl-L-threonine used in part (B), the titled compound is prepared as a potassium salt, IR --SO3 (1025 cm );
~-lactam (1775 cm ).

Example 5 (2~, 3~ sulfomethoxy-2-(aminocarbonyl)--3-[[(l,l-dimethy].ethoxy)carbonyl]amino]-4-oxoazetidine A. Er~thro-3-hydroxy-dl-aspartic acid Erythro 3-hydroxy-dl-aspartic acid was prepared from trans-epoxysuccinic 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 ~-methyl erythro-3-hydroxy-dl-asparate To a suspension of 5.0 g (33.5 mmol) of erythro-3-hydroxy-dl-aspar-tic 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. 210C. dec.
C. _Erythro-3-hydroxy-dl-asparagine The above ~-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 ho-t water.
The pEI was adjusted to 5.0 using 6NHCl, and the solution was concentrated in vacuo to about 20 ml and then left ~253~

overnight at 5C. The white crystalline mass was collec-ted and dried to give 3.4 g (95 percent yield) of desired product having m.p. 233C dec.
D N-T-butoxycarbonyl-erythro-3-hydroxy-dl-asparagine, potassium salt Erythro-3-hydroxy-dl-asparagine (710 g, 47 mmol) was suspended in 50 ml of water and solubilized by addition of 3 N 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 ~ICl. The solution was con-centrated in vacuo to a small volume, and then the pH
was adjus-ted to 3.0 (6N HCl). Removal of solvent in vacuo gave a solid (20 g) containing the desired product in free acid form and in about quantitive 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 0.635G15 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-alpha-n-t-butoxycarbonyl-ery-thro-3-hydroxy-dl-asparagine hydroxamate, ~otassium 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. H2S04). The solution was concentrated in vacuo to a residue, which was concentra-ted from water (2 times~ and then from benzene (2 times). Thls residue was dissolved in dry acetonitrile (4 ml) and dry tetrahydrofuran (8 ml) and cooled to 0C. To this stirred solution was added 0.424 g (2.77 mmol) of l-hydroxybenzotriazole monohydrate followed by 0.572 g (2.77 mmol) of n,n'-dicyclohexyl-carbodiimide. The mixture was stirred at 0C for 2 hours, and then the above aminoxymethanesulfonic acid, tetra-butylammonium salt (1.06 g, 2.88 mmol) in 5 ml of acetonitrile was added dropwise. After the addition, the reaction was stirred at 0C 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 0C until it solidiEied. 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 fraction-ation 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. 145C dec.
~nal. Calcd. for ClOH18N309SK.).71Il20: C, 29.42: H,4.80 N, 10.29: S,7.85 Found: C,29.42: H~.73: M, 10.04: S, 7.45 F O-sulfomethyl-alpha-n-t-butoxycarbonyl-erythro-3-hydroxy-dl-asparagine hydroxamate, tetrabutyl-ammonium 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 O.lm tetrabutylammonium hydrogen sulfate in 0.5m ph 5.5 KH2P04 buffer. The solution was concen-trated to dryness, and the residue was tritura-ted with methylene chloride. Filtration and evaporation of the methylene chloride gave the desired product as a residue (156 mg, 0.26 mmol).
G. (2~, 3~)-1-sulfomethoxy-2-(aminoc_rbonyl)-3-[[(l,l-dimethylethoxy)carbonyl]amino]-4-oxo-azetidine, potassium salt The above 0-sulfomethyl hydroxamate, tetrabutylammonium salt (1~0 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 0.8 ml of dry methylene chloride. To this stirred solution at -50C under argon was added 0.12 ml (0.85 mmol) of triethylamine followed by dropwise addition of 0.08 ml ~0.42 mmol) of trifluoro-methanesulfonic anhydride. The reaction was allowed to warm to -30C over 1 hour, and then 0.06 ml of triethylamine was added. ~fter 5 minutes, the reaction was concentrated in vacuo, and the residue was dissolved in 2 ml of acetone.
The solution was cooled to 0C, 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, fil-tration 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. 149C dec. and IR(KBR) 1786 reciprocal cm (~-lactam carbonyl) and 1696 reciprocal cm (broab, amide and carbamate carbonyl).

GCl98 Bv followinq the procedures previously descrikeA
the followinq comPounds are PrePared:
(3S-trans)-[[(2-Amino-4-thiazolyl)(methoxy-imlno)acetyl]amino]-4-methyl-2-oxo-l-azetidinyl]-oxy]methanesulfonic acid, monopotassium salt (3S-trans)-[[(2-Amino-4-thiazolyl)[(2,2,2-tri~luoroethoxy)imino]acetyl]amino]-4-methyl-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, mono-pOtasSiUJn salt (3S-trans)-[[(2-Amino-4-thiazolyl)[(2-amino-2-oxoethoxy)imino]acetyl]amino]-4-methyl-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-trans)-[[(2-Amino-4-thiazolyl)[(carboxy-methoxy)imino~acetyl]amino]-4 methyl-2-oxo-l-azetidinyl]-oxy]methanesulfonic acid, dipotassium salt (3S-trans)-[[(2-Amino-4-thiazolyl)[[(l-carboxy-cyclopropyl)oxy]imino~acetyl]amino]-4-methyl-2-oxo-l-azetidinyl]-oxy]methanesulfonic acid, dipotassium salt [3S-¦3~(R),4B]]-[[3-[(Aminophenylacetyl)-amino]-4-methyl-2-oxo-l-azetidinyl]oxy]methane-sulfonic acid, monopotassium salt (3S-trans)-[[3-[(Phenylacetyl)amino]-4-methyl-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-trans)-[[3-[(2-Thienylacetyl)amino]-4-methyl-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-trans)-[[3-[(2,6-Dimethoxyphenyl)acetyl~-amlno]-4-methyl-2-oxo-l-azetidinyl]oxy]methane-sulfonic acid, monopotassium salt ~ ~i35~3~

-36- G~198 [3s-[3~(R)~4B]]-[[3-[[[[(Aminocarbonyl)-amino]-2-thienylacetyl-amino]-4-methyl-2-oxo-1-azetldinyl]-oxy]methanesulfonic acid, monopotassium salt [3S-[3(R),4~]]-[[3-[(Carboxyphenylacetyl)-amino]-~-methyl-2-oxo-1-azetidinyl~oxy]methane-sulfonic acid, dipotassium salt [3S-[3~(+),4~]]-[[3-[(Phenylsulfoacetyl)-amino]-4-methyl-2-oxo-1-azetidinylloxy]methane-sulfonic acid, dipotassium salt (3S-trans)]-[[3-¦[(2-Amino-4-thiazolyl)-oxoacetyl]amino]-4-methyl-2-oxo-1-azetidinyl]-oxy]methanesulfonic acid, monopotassium salt [3S-[3a(R),4~]]-[[3-l[[[[2-Oxo-3-[(phenyl-methylene)amino]-l-imidazolidinyl]carbonyl]amino]-phenylacetyl]amino]-4-methyl-2-oxo-1-azetidinyl~oxy]--methanesulfonic acid, monopotassium salt [3S-[3~(Z),4~]]-[[3-[[2-Furanyl(methoxy-imino)acetyl~amino]-4-methyl-2-oxo-1-azetidinyl]oxy]-methanesulfonic acid, monopotassium salt [3S(Z)]-[[3-l[(2-Amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]oxy]methane-sulfonic acid, monopotassium salt [3S(Z)]-[[3-[[(2-Amino-4-thiazolyl)[(l-carboxy-l-methylethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyl~oxy]methanesulfonic acid, dipotassium salt [3S(Z)]-[[3-[[(2-Amino-4-thiazolyl)[(2,2,2-trifluoroethoxy)imino]acetyl]amino~-2-oxo-1-azetidinyl]oxy]methanesulfonic acid, monopotassi~m salt -37- GCl9~

[3S~)]-[ L3-E [ (2-Amino-4-thiazolyl)[(2-amino-?-oxoethoxy)imino]acetyl]amino]-2-oxo-1-azeti~inyl]-oxy~methanesulfonic acid, monopotassium salt [ 3s- [3~(5),4g]]-[[3-[[[(Aminocart)onyl)aminoJ-2-thienylacetyl]amino]-2-oxo-1-azetidinyl]oxy]-methanesul~onic acid, monopotassium salt [ 3s- 13~ ( ~), 4 ~] ] - [ [ 3-[(Phenylsulfoacetyl)-amino]-2-oxo-1-azetidinyl]oxy]methanesulfonic acid, dipotassium salt [3S-[3a(R),4B]]-[[3-[[[[(4-Ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-2-oxo-l-azetidinyl]oxy]methanesulfonic acid,monopotassium salt [(3S(Z)]-i[3-[(Phenoxyacetyl)amino]-2-oxo-1-azetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-cls)-[[(2-Amino-4-thiazolyl)~methoxy-imino)acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]-oxy]methanesulfonic acid, monopotassium salt (3S-cis)-[[(2-Amino 4-thiazolyl)[(2,2,2-trifl~oroethoxy~imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methanesulfonic acid, mono-potassium salt (3S-cis)-[[(2-Amin~-4-thiazolyl)i(carboxy-methoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]-o~y]methanesulfo.nlc acid, dipotassium salt (3S-cls)-[[3-[[(2-Amino-4-thiazolyl)](l-carboxy-l-methylethoxy)imino]accetyl]amino]-2-oxo-4-methyl-l-azetidinyl]oxy]methanesulfonic acid, dipotassium salt (3S-cis)-[[(2-Amino-4-thiazolyl)[[(l-carboxy-cyclopropyl)oxy]imino]acetyl]aminoJ-4-methyl-2~oxo-1-azetidinyl]-oxy]methanesulfonic acid, dipotassium salt ~ ~35~

-3~- GC198 (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(R),4a]]-[[3-[[[[(4-Ethyl-2,3-dioxo-l-piperazinyl)carbonyl]amlno]phenylacetyl]amino]-4-methyl-2-oxo-1-azetiainyl]oxy]methanesulfonic acid, monopotassium salt [3S-[3a(S),4a]]-[[3-[[[(AminocarbonylJ-amino]-2-thienylacetyl]-amino]-4-methyl-2-oxo-1-azetidinyl]-oxy]methanesulfonic acid, monopotassiun, salt [3S-[;a(R),4a]]-[[3-[(Aminophenyl-acetyl)-amino]-4-methyl-2-oxo-1-azetidinyl]oxy]-methanesulfonic acid, monopotassium salt

Claims (30)

The embodiments of the invention in which an exclusive property or privilege is claimed are de-fined as follows:

1. A process for preparing a .beta.-lactam having the formula or a pharmaceutically acceptable salt thereof, wherein R1 is an acyl group derived from a carboxylic acid;
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, 2-phenylethynyl, carboxyl, -CH2-X1, -S-X2, -O-X2, or -A-?-NX6X7;
R5 and R6 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 R5 and R6 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, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2-X1-, -S-X2, -O-X2 or -A-?-NX6X7 X1 is azido, amino, 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 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;
A is -CH=CH-, -CH2-CH=CH-, -(CH2)n-, -(CH2)n'-O-, -(CH2)n'-NH-, -(CH2)n'-S-CH2;
n is 0, 1, 2 or 3;
n' is 1 or 2; and 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;
wherein the terms "alkyl and "alkoxy" refer to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to cycloalkyl groups having 3, 4, 5, 6 or 7 carbon atoms;
the term "substituted alkyl" refers to alkyl groups substituted with one, or more azido, amino, halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenoxy, (substituted phenyl)oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl, or alkylsulfonyl groups;
the terms "alkanoyl", "alkenyl" and "alkynyl"
refer to groups having 2 to 10 carbon atoms;

the term "substituted alkanoyl" refers to a group having the formula (substituted alkyl) -?-or phenylalkanoyl;
the term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms) or carboxyl groups;
the term "substituted amino" refers to a group having the formula -NY1Y2 wherein Y1 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Y2 is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy or amino;
the term "heteroaryl" refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, tetrazolyl or one of the above groups substituted with one or more halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substituted phenyl, 2-furylmethyleneamino, phenylmethyleneamino, substituted alkyl, wherein the alkyl groups has 1 to 4 carbon atoms, groups;
the term "a 4, 5, 6 or 7-membered heterocycle" refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, tetrazolyl, azetinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydro-pyrimidinyl, dihydrothiazolyl, hexahydro-azepinyl or one of the above groups substituted with one or more oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substituted phenyl, 2-furylmethyleneamino, phenylmethyleneamino or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, groups, characterized by reacting a compound of the formula with a R1 carboxylic acid or a reactive derivative thereof.

2. A process in accordance with claim 1 wherein R1 is (Z)-2-amino-.alpha.-[(1-carboxy-1-methyl-ethoxy)imino]-4-thiazoleacetyl.

3. A process in accordance with claim 1 wherein R2, R3, R4, R5 and R6 are each hydrogen

4. A process in accordance with claim 1 wherein R2, R3, R5 and R6 are each hydrogen and R4 is methyl.

5. A process in accordance with claim 1 wherein R2, R4, R5 and R6 are each hydrogen and R3 is methyl.

6. A compound having the formula or a pharmaceutically acceptable salt thereof, wherein R1 is an acyl group derived from a carboxylic acid;
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, 2-phenylethynyl, carboxyl, -CH2-X1, -S-X2, -O-X2, or -A-?-NX6X7;

R5 and R6 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 R5 and R6 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, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2-X1-, -S-X2, -O-X2 or -A-?-NX6X7 X1 is azido, amino, 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 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;
A is -CH=CH-, -CH2-CH=CH-, -(CH2)n-, -(CH2)n'-O-, -(CH2)n'-NH-, -(CH2)n'-S-CH2;
n is 0, 1, 2 or 3;
n' is 1 or 2; and 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;
wherein the terms "alkyl and "alkoxy" refer to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to cycloalkyl groups having 3, 4, 5, 6 or 7 carbon atoms;
the term "substituted alkyl" refers to alkyl groups substituted with one, or more azido, amino, halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenoxy, (substituted phenyl)oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl, or alkylsulfonyl groups;
the terms "alkanoyl", "alkenyl" and "alkynyl" refer to groups having 2 to 10 carbon atoms;
the term "substituted alkanoyl" refers to a group having the formula (substituted alkyl) -?-or phenylalkanoyl;
the term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms) or carboxyl groups;

the term "substituted amino refers to a group having the formula -NY1Y2 wherein Y1 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Y2 is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy or amino;
the term "heteroaryl" refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, tetrazolyl or one of the above groups substituted with one or more halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substituted phenyl, 2-furylmethyleneamino, phenylmethyleneamino, substituted alkyl, wherein the alkyl groups has 1 to 4 carbon atoms, groups;
the term "a 4, 5, 6 or 7-membered heterocycle" refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4 triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, tetrazolyl, azetinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydro-pyrimidinyl, dihydrothiazolyl, hexahydro-azepinyl or one of the above groups substituted with one or more oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substituted phenyl, 2-furylmethyleneamino, phenylmethylene-amino or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, groups, whenever prepared by the process of claim 1.

7. A compound in accordance with claim 6, wherein R1 is (Z)-2-amino-.alpha.-[(1-carboxy-1-methyl-ethoxy)imino]-4-thiazoleacetyl, whenever prepared by the process of claim 2.

8. A compound in accordance with claim 6, wherein R2, R3, R4, R5 and R6 are each hydrogen, whenever prepared by the process of claim 3.

9. A compound in accordance with claim 6, wherein R2, R3, R5 and R6 are each hydrogen and R4 is methyl, whenever prepared by the process of claim 4.

10. A compound in accordance with claim 6, wherein R2, R4, R5 and R6 are each hydrogen and R3 is methyl, whenever prepared by the process of claim 5.

11. A .beta.-lactam having the formula or a pharmaceutically acceptable salt or ester thereof, wherein R1 is an acyl group derived from a carboxylic acid;
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-mem-bered heterocycle, or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2-X1, -S-X2, -O-X2, or -A-?-Nx6X7;

R5 and R6 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, phenyl, substitu-ted phenyl, cycloalkyl or a 4, 5, 6 or 7-membered heterocycle, or R5 and R6 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, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2-X1-, -S-X2, -O-X2 or -A-?-NX6X7;
X1 is azido, amino, hydroxy, alkanoylamino, al-kylsulfonyloxy, phenylsulfonyloxy, (substituted phe-nyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2 or -O-X2;
X2 is alkyl, substituted alkyl, phenyl, substi-tuted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, (sub-stituted 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, alkanoyl, phenylcarbonyl, (substi-tuted phenyl)carbonyl, phenylalkylcarbonyl, (substi-tuted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano;
A is -CH=CH-, -CH2-CH=CH-, -(CH2)n-, -(CH2)n'-O-, -(CH2)n'-NH-, or -(CH2)n'-S-CH2;
n is 0, 1, 2 or 3;
n' is 1 or 2; and 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;

wherein the terms "alkyl" and "alkoxy" refer to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to cycloalkyl groups having 3, 4, 5, 6 or 7 carbon atoms;
the term "substituted alkyl" refers to alkyl groups substituted with one or more azido, amino, halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenoxy, (sub-stituted phenyl)oxy, mercapto, alkylthio, phenyl-thio, (substituted phenyl)thio, alkylsulfinyl, or alkylsulfonyl groups;
the terms "alkanoyl", "alkenyl" and "alkynyl"
refer to groups having 2 to 10 carbon atoms;
the term "substituted alkanoyl" refers to a group having the formula (substituted alkyl) -?-or phenylalkanoyl;
the term "substituted phenyl" refers to a phe-nyl group substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms) or carboxyl groups;
the term "substituted amino" refers to a group having the formula -NY1Y2 wherein Y1 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Y2 is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phe-nyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy or amino;
the term "heteroaryl" refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, py-rimidinyl, oxazolyl, triazinyl, tetrazolyl or one of the above groups substituted with one or more halogen, hydroxy, nitro, amino, cyano, trifluoro-methyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substitu-ted phenyl, 2-furylmethyleneamino, phenylmethylene-amino, substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, groups; and the term "a 4, 5, 6 or 7-membered heterocycle"
refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thia-zolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazi-nyl, tetrazolyl, azetinyl, oxetanyl, thietanyl, pi-peridinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazo-lyl, hexahydroazepinyl or one of the above groups substituted with one or more oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alk-ylsulfonyl, phenyl, substituted phenyl, 2-furylme-thyleneamino, phenylmethyleneamino or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms.

12. A compound in accordance with claim 11, wherein R1 is (Z)-2-amino-.alpha.-[(1-carboxy-1-methyl-ethoxy)imino]-4-thiazoleacetyl.

13. A compound in accordance with claim 11, wherein R2, R3, R4, R5 and R6 are each hydrogen

14. A compound in accordance with claim 11, wherein R2, R3, R5 and R6 are each hydrogen and R4 is methyl.

15. A compound in accordance with claim 11, wherein R2, R4, R5 and R6 are each hydrogen and R3 is methyl.

16. A .beta.-lactam in accordance with claim 11, a salt of [3S-[3.alpha.(Z),4.alpha.]]-[[3-[[(2-amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-4-methyl-2-oxo-1-azeti-dinyl]oxy]methanesulfonic acid.

17. A .beta.-lactam in accordance with claim 11, a salt of [3S-[3.alpha.(Z),4.alpha.]]-2-[[[1-(2-amino-4-thiazolyl)-2-[[4-methyl-2-oxo-1-(sulfomethoxy)-3-azetidinyl]am-ino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid.

18. A .beta.-lactam in accordance with claim 11, a salt of [3S-[3.alpha.(Z),4.beta.]]-2-[[[1-(2-amino-4-thiazolyl)-2-[[4-methyl-2-oxo-1-(sulfomethoxy)-3-azetidinyl]am-ino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid.

19. A .beta.-lactam in accordance with claim 11, a salt of [3S-[3.alpha.(R),4.beta.]]-[[3-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methanesulfonic acid.

20. A .beta.-lactam in accordance with claim 11, a salt of [3S-[3.alpha.(Z),4.beta.]]-[[3-[[(2-amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-4-methyl-2-oxo-1-azeti-dinyl]oxy]methanesulfonic acid.

21. A pharmaceutical composition comprising a .beta.-lactam having the formula or a pharmaceutically acceptable salt or ester there-of, in admixture with a pharmaceutically acceptable carrier therefor, wherein R1 is an acyl group derived from a carboxylic acid;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phe-nyl, 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, trihalome-thyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethy-nyl, carboxyl, -CH2-X1, -S-X2, -O-X2, , , or -A-?-NX6X7;

R5 and R6 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, phenyl, substitu-ted phenyl, cycloalkyl or a 4, 5, 6 or 7-membered heterocycle, or R5 and R6 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, 2-phe-nylethenyl, 2-phenylethynyl, carboxyl, -CH2-X1-, -S-X2, -O-X2 or -A-?-NX6X7;
X1 is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2 or -O-X2;
X2 is alkyl, substituted alkyl, phenyl, sub-stituted phenyl, phenylalkyl, (substituted phenyl)-alkyl, alkanoyl, substituted alkanoyl, phenylcarbo-nyl, (substituted phenyl)carbonyl or heteroarylcar-bonyl;
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, alkanoyl, phenylcarbonyl, (sub-stituted phenyl)carbonyl, phenylalkylcarbonyl, (sub-stituted phenyl)alkylcarbonyl, carboxyl, alkoxycar-bonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano;
A is -CH=CH-, -CH2-CH=CH-, -(CH2)n-, -(CH2)n'-O-, -(CH2)n'-NH-, or -(CH2)n'-S-CH2;

n is 0, 1, 2 or 3;
n' is 1 or 2; and 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;
wherein the terms "alkyl" and "alkoxy" refer to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to cycloalkyl groups having 3, 4, 5, 6 or 7 carbon atoms;
the term "substituted alkyl" refers to alkyl groups substituted with one or more azido, amino, hal-ogen, hydroxy, carboxy, cyano, alkoxycarbonyl, amino-carbonyl, alkanoyloxy, alkoxy, phenoxy, (substituted phenyl)oxy, mercapto, alkylthio, phenylthio, (substi-tuted phenyl)thio, alkylsulfinyl, or alkylsulfonyl groups;
the terms "alkanoyl", "alkenyl" and "alkynyl"
refer to groups having 2 to 10 carbon atoms;
the term "substituted alkanoyl" refers to a group having the formula (substituted alkyl) -?-or phenylalkanoyl;
the term "substituted phenyl" refers to a phe-nyl group substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms) or carboxyl groups;
the term "substituted amino" refers to a group having the formula -NY1Y2 wherein Y1 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Y2 is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phe-nyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy or amino;
the term "heteroaryl" refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, py-rimidinyl, oxazolyl, triazinyl, tetrazolyl or one of the above groups substituted with one or more halo-gen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 car-bon atoms, alkylsulfonyl, phenyl, substituted phenyl, 2-furylmethyleneamino, phenylmethyleneamino, substi-tuted alkyl, wherein the alkyl group has 1 to 4 car-bon atoms, groups; and the term "a 4, 5, 6 or 7-membered heterocycle"
refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thia-zolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazi-nyl, tetrazolyl, azetinyl, oxetanyl, thietanyl, pi-peridinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazo-lyl, hexahydroazepinyl or one of the above groups substituted with one or more oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alk-ylsulfonyl, phenyl, substituted phenyl, 2-furylmeth-yleneamino, phenylmethyleneamino or substituted al-kyl, wherein the alkyl group has 1 to 4 carbon atoms.

22. A composition in accordance with claim 21, wherein R1 is (Z)-2-amino-.alpha.-[(1-carboxy-1-methyl-ethoxy)imino]-4-thiazoleacetyl.

23. A composition in accordance with claim 21, wherein R2, R3, R4, R5 and R6 are each hydrogen

24. A composition in accordance with claim 21, wherein R2, R3, R5 and R6 are each hydrogen and R4 is methyl.

25. A composition in accordance with claim 21, wherein R2, R4, R5 and R6 are each hydrogen and R3 is methyl.

26. A composition in accordance with claim 21, wherein the .beta.-lactam is a salt of [3S-[3.alpha.(Z),4.alpha.]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]am-ino]-4-methyl-2-oxo-1-azetidinyl]oxy]methanesulfonic acid.

27. A composition in accordance with claim 21, wherein the .beta.-lactam is a salt of [3S-[3.alpha.(Z),4.alpha.]]-2-[[[1-(2-amino-4-thiazolyl)-2[[4-methyl-2-oxo-1-(sul-fomethoxy)-3-azetidinyl]amino]-2-oxoethylidene]am-ino]oxy]-2-methylpropanoic acid.

28. A composition in accordance with claim 21, wherein the .beta.-lactam is a salt of [3S-[3.alpha.(Z),4.beta.]]-2-[[[1-(2-amino-4-thiazolyl)-2-[[4-methyl-2-oxo-1-(sul-fomethoxy)-3-azetidinyl]amino]-2-oxoethylidene]am-ino]oxy]-2-methylpropanoic acid.

29. A composition in accordance with claim 21, wherein the .beta.-lactam is a salt of [3S-[3.alpha.(R),4.beta.]]-[[3-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]am-ino]phenylacetyl]amino]-4-methyl-2-oxo-1-azetidinyl]-oxy]methanesulfonic acid.

30. A composition in accordance with claim 21, wherein the .beta.-lactam is a salt of [3S-[3.alpha.(Z),4.beta.]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]am-ino]-4-methyl-2-oxo-1-azetidinyl]oxy]methanesulfonic acid.