CA1268763A - 3-acylamino-2-oxo-1-azetidinyl esters of phosphonic acids, phosphoric acid and phosphoric acid esters - Google Patents

Abstract

ABSTRACT
Novel .beta.-lactams having the formula:

Description

6~3763 3-ACY ~ ~I~10-2-OXO-l-AZETIDINYL ESTERS
OF PHOSPHONIC ACIDS, PHOSPHO~IC PCID A~D
PHOSPHORIC ACID ESTERS
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 substituent y having the formula -O-P-R5, and pharmaceutically OH
acceptable salts thereof, attached to the nitrogen atom in the nucleus.

3-Lactams having a -O-P-R5 substituent OH
(or a pharmaceutically acceptable salt 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

-2 R4 Rl-NH-C f R3 y l 11 ~C N--O - P - R5 O OH

or a pharmaceutically acceptable salt ~lereof.
This application is a divisional application from patent application No. 435,268 filed August 24, l983.
The invention as described and claimed herein, is for those compounds or formu]a I above wherein Rl and R2 both stand for hydrogen, such compounds being useful as intermediates in the preparation of the ~-lac-tam antibiotics of formula I.

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 4,5,6 or 7-membered heterocycle (referred to hereinafter as ~6) or one of R3 and R4 is hydrogen and the o~her is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2Xl, -S-X2, X~3 Xl3 l -O-X2, -O-C-X4, -S-C-X4, or -A-C-NX6X7 ;

X1 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 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, phenyicarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, o alkoxycarbonyl, aminocarbonyl (NH2-C-), (substituted amino)carbonyl, or cyano (-C--N);

-3- 1 2l6 8 7 6 3 A is -CH=CH-, -CH2-CH=CH-, -(CH2)n, (C~ ) -O-, -(CH2)n,NH-, or (CH2)n, 2 n is 0, 1, 2 or 3;
n' is 1 or 2;
X6 and X7 are the s.ame or different and each is hydrogen or alkyl, or X6 is hydrogen and X7 is amino, substituted amino, acylamino or alkoxy;
R5 is hydroxyl, alkyl, substituted alkyl, phenyl, substituted phenyl, alkoxy, alkylthio, (substituted alkyl)oxy, (substituted alkyl)thio, phenyloxy, phenylthio, (substituted phenyl)oxy or (substituted phenyl)thio; and Y is oxygen or sulfur.
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 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 7 carbon atoms.
The term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido, amino (-NH2), halogen, hydroxy, carboxy, cyano,

-4- ~26~763 alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, P6-oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)-thio, alkylsulfinyl, or alkylsulfonyl groups.
The terms "alkanoyl", "alkenyl", "alkenyl"
and "alkynyl" refer to both stra-ght and branched chain groups. Those groups ha~ing 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, 1979. The preferred protected carboxyl groups are benzyl, benzhydryl, t-butyl, E-methoxybenzyl, and ~-nitrobenzyl esters.
~he term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino(-NH2), halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 ca~bon atoms), alkoxy (of 1 to 4 carbon atoms), or carboxyl groups.
The expression "a 4,5,6 or 7-membered heterocycle" (referred to as "R6") 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, amino, cyano, trifluoromethyl, alkyl of 1 to 4

-5- ~2G8~63 carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 2-Eurylimino O~_CH=N-( ~ ), benzylimino and substituted alkyl groups (wherein the alkyl group has 1 to 4 car~ons).
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 lS (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-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,

- 6- 126~763 3-(2-aminoethyl)-2-oxo-1-imidaæolidinyl, 3-amino-2-oxo-1-imidazolidinyl, 3-I(alkoxycarbonyl)amino~-2-oxo-1-imidazolidinyl, 3-[2-l~alkoxycarbonyl)-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-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 -NYlYz wherein Yl is hydrogen, alkyl, phenyl, substitùted 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 O
(substituted alkyl) -C- (wherein "substituted alkyl"
is defined above) and phenylalkanoyl.

-7_ ~Z68~63 The term "acyl" refers to all organic radi-cals derived from an organic acid (i.e., a car-boxylic acid) by removal of the hydroxyl group.
Certain acyl groups are, of course, preferred but this preference should not be viewed as a limita-tion 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-aminopenicillanic acid and derivatives and 7-aminocephalosporanic acid and derivatives;
see, for example, Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972), German Of-fenlegungsschrift 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, is-sued July 27, 1976, United States patent 4,172,199, issued October 23, 1979, and British patent 1,348, 894, published March 27, 1974. The following list of acyl groups is presented to further exemplify the term "acyl"; it should not be regarded as lim-iting that term. Exemplary acyl groups are:
(a) Aliphatic groups having the formula R -C-wherein Ra is alkyl; cycloalkyl; alkoxy; alkenyl;

GCl95 -8- ~268763 cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, or cyanometh~l-thio groups.
(b) Carbocyclic aromatic groups having the formula Rb~(CH2 ) n~C~, Rb ~ CIH-C- , Rb~ CH2-o-c-, b ~ O-CH2-C- , - 9- ~,61 3763 b ~ d 1l b~Rd ~ -CH -S-C-wherein 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 is amino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, a sulfo salt, a sulfoamino salt, azido, halogen, hydrazino, alkylhydrazino, phenylhydrazino, or l(alkylthio)thioxomethyl]thio.
20Preferred carbocyclic aromatic acyl groups include those having the formula .

HO ~ CH -C-, ~ H -C-, -10- ~,2~763 O
HO ~ H-C- (Re is preferably Re s a carboxyl salt or sulfo salt) and ~ CH-C- (Re is preferably Re a carboxyl salt or sulfo salt).
(c) Heteroaromatic groups having the formula Rf (CH2)n o Rf-CH-C-Re Ol Rf-O--CH2-C- ~
O

Rf-S-CH2-C-O O
ll ll Rf-C -C-wherein n is 0, 1, 2 or 3; Re is as defined above; and Rf is a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring (heteroaryl group) containing 1,2,3 or 4 tpref~ably 1 or 2) ni~gen, oxygen and ~fur aboms. Exem~lary heb~lic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl. Exemplary substituents are halogen, hydroxyl, nitro, amino, protected amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or R

Preferred heteroaromatic acyl groups include those groups of the above formulas wherein Rf 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-dio~o-1-piper-azinyl)carbonyl]amino]arylacetyl groups having the formula O
-c-cH-NH-c-N~ _~N Rh g O O
wherein Rg is an aromatic group (including carbocyclic aromatics such as those of the formula Rc and heteroaromatics as included within the definition of Rf); and Rh is alkyl, substituted . GC195 -12- ~26~763 alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups), arylmethyleneamino (i e., ~N=CH~Rg wherein Rg is as defined above), O
arylcarbonylamino (i e., ~NH~C~Rg wherein R
is as defined above) or alkylcarbonylamino.
Preferred [[(4-substituted-2,3-dioxo-l-piperazinyl)carbonyl]amino]arylacetyl groups include those wnerein Rh is ethyl, phenylmethylene-amino or 2-furylmethyleneamlno.
(e) (Substituted oxyimino)arylacetyl groups having the formula -C-C=N-O-Rg wherein Rg is as defined above and Ri is hydrogen, R6, alkyl, cycloalkyl, alkylaminocarbonyl, arylamino-carbonyl (i.e., ~C~NH~Rg wherein Rg is as defined above) or substituted alkyl (wherein the alkyl group is substituted with l 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 dialkoxy-phosphinyl substituents).

-13- ~ ~ 6 ~ 7 6 3 Preferred (substituted oxyimino)arylacetyl groups include those wherein Rg is 2-amino-4-thiazolyl. Also preferred are those groups wherein Ri is methyl, ethyl, carboxymethyl, l-carboxy-l-methylethyl, 2,2,2-trifluoroethyl or l-carboxycyclopropyl.
~ f) (Acylamino)arylacetyl groups having the formula O O
Il 11 -C-CH-NH-C-R
Rg wherein Rg is as defined above and Rj is Rc Rb ~ (CH2)n-O-, amino, alkylamino, (cyanoalkyl)-amino, amido, alkylamido, (cyanoalkyl)amido, -CH -NH-C ~ N -CH-CH2-C-NH-CH3, HO
~N(CH2~CH2 OH~2' ~ CH3, OH
QH OH

N ~_J

~ f ~1 HO ~ C-O O

-14- ~ 76~

Preferred (acylamino)arylacetyl groups of the above formula include those groups wherein Rj is amino or amido. Also preferred are those groups wherein R is phenyl or 2-thienyl.
(g) [[[3-Substituted-2-oxo-1-imidazoli-dinyl]carbo~yl]amino]arylacetyl groups having ~ the formula O O C
Il 11 ~ ~
-C-CH-NH-C-N N-Rk Rg CH --CH2 wherein Rg is as defined above and Rk is hydrogen, alkylsulfonyl, arylmethyleneamino (i.e., ~N=CH~Rg wherein Rg is as defined above), -C-Rm (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 groupsl.
Preferred [[3-substituted-2-oxo-1-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.

-15- ~2~8763 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 5 (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts wlth 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 is 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 insolùble acid - like a cation exchange resin in the hydrogen form (e.g., polystyrene sulfonic acid resin llke Dowex 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.

GCl9~
-16- ~2~763 y ~-Lactams having a -O-P-R5 substituent OH
(or a pharmaceutically acceptable salt thereof) in the l-position and an amino or acylamino substituent in the 3-position contain at least o~e &hiral 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 ~-lactams which have been described above, wherein the stereochemistry at the chiral center in the 3-position of the 3-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.q., cephamycin C).
With respect to the preferred 3-lactams of formula I, the structural formulas have been drawn to show the stereochemistry at the chiral center in the 3-position. Because of the nomenclature convention, those compounds of formula I wherein R2 is hydrogen have the S-configuration and those compounds of formula I
wherein R2 is methoxy have the R-configuration.
Also included within the scope of this invention are racemic mixtures which contain the above-described ~-lactams.

--17- ~26~763 ~-Lactams having a -O-P-R5 substituent OH
(or a pharmaceutically acceptable salt thereof) in the 1-position of the ~-lactam nucleus and an acylamino substituent in the 3-position of the 3-~actam nucleus have activity against a range of gram-negative and gram-positive organisms.

The -O-P-R5 substituent (or a pharmaceuticall~
0~
acceptable 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 350 mg/kg/day, preferably about 14 mg/kg/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.

The B-lactams of this invention can be prepared from hydroxamic acids of formula VIII
(infra.), which are obtainable from an amino acid having the formula II OH~R4 NH2-1H C R~
~C OH
o utilizing the methodology disclosed in U. S.
patent 4,337,197. As disclosed therein, the amino group is first protected with a classical protecting group (e.g., t-butoxycarbonyl, benzyloxycarbonyl, _-nitrophenylsulfenyl, etc.), yielding a compound having the formula III IOH~R4 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 III is then reacted with an amine salt having the formula IV
Y~O-NH3Cle, In formula IV, and throughout the specification, the symbol "Y3' refers to benzyl, pivaloyl, -CH2(NHA)CO2alkyl, t-butyl, ~-nitrobenzyl, benzhydryl, 2-cyanoethyl, 2-trimethylsilylethyl, trichloroethyl, inter alia. The reaction proceeds in the presence of a coupling agent such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide or dicyclo-hexylcarbodiimide, and yields a compound having the formula ~68763 A1NH-fH C - R3 ~ NH-O-Y3 .
o The hydroxyl group of a compound of formula V
is converted to a leaving group, using, for example, a classical reagent such as methane-sulfonyl chloride (methanesulfonyl is referred to hereinafter as "Ms").
The fully protected compound having the formula VI OM~s~R4 AlNH-IH - C - R3 ~ - NH-O-Y3 O
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 Al-NH-CH Cl-R3 ~C N-O-Y3 .
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 with triphenylphosphine and diethylazodicarboxylate or carbon tetrachloride, triphenylphosphine and a base such as triethylamine, yields a compound of formula VII.

~6876~

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 substituents.
Selective reduction of a compound of formula VII (using catalytic hydrogenation if Y3is benzyl or by treatment with a base such as sodium sulfide or sodium hydroxide if Y3is pivaloyl or with DBU if Y3is -CH2CH(NHA)CO2alkyl) yields the corresponding compound having the formula Al-NH-CH C-R3 O~ N-OH
Phosphorylation of a hydroxamic acid of formula VIII can be accomplished by first treating the compound with base (e.g., 2,6-lutidine or trie.thylamine) to generate the corresponding anion and then reacting the salt with a phosphorous derivative having the formula IX IYI
(Act) -P-R

wherein the activating group "Act" is, most preferably, chlorine to yield the corresponding compound having the formula X

Al-NH~-2 C4~R3 l l ll~ Rs ,C N -O - P~
o~ Act 1,2~,8763 . Hydrolysis of a compound of formula X under neutral or mildly acidic conditions yields the corresponding compound having the formula NH CH C R
~C - N -O -P\

Alternatively, phosphorylation of a hydroxamic acid of formula VIII can be accomplished by first treating the compound with a base (e g., 2,6-lutidine) and then reacting it with a phosphorous derivative having the .
formula XII 1l R' Act-P ~ S
O-alkyl , wherein R5 is alkyl or alkoxy, to obtain the corresponding compound having ~he formula XIII _4 Al-NH-CH C-R3 y C N -O -P ~ 5 O~ \ O-alkyl .

~Z~7~3 Treatment of a compound of formula XIII with an acid-scavenger and drying agent such as bis-trimethylsilylacetamide,followed by treatment with trLmethylsilyl bromide, yields an intermediate silyl ester having the formula Al-NH-CH f-R3 0 l I Il ~ R5 , C--N--O--P
~' ~o-si (CH3)3 wherein R5 is alkyl or -O-Si(CH3)3.
A compound of formula XI~ is readily converted to a salt of the corresponding compound of formula XI by treatment with aqueous buffer in the range of pH 2.5 to pH 6, with or without an alcohol.
Deprotection of the 3-amino substituent of a compound of formula XI can be accomplished using art-recognized techniques. If, for example, the protecting group is t-butoxycarbonyl, trifluoroacetic acid-anisole 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, ~-toluenesulfonic acid can be used in combination with ~-thiocresol. The deprotected compound has the formula ~26~3763 =4 NH -CH --C-R
~C N -O -P\
O OH
and is a key intermediate for preparing the compounds of this invention.
Well known acylation techniques can be used to convert a compound of formula XV to the corresponding compound having the formula XVI =R4 Rl-NH-CH C-R
I l ll ~ R5 ~C N -O - P~
O~ OH
Exemplary techniques include reaction with a carboxylic acid (Rl-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 reactlve intermediate in situ such as ~-hydroxybenzotriazole or 4-dimethyl-aminopyridine. In those instances wherein the acyl group (Rl) contains reactive functionality (such as amino or carboxyl groups) it may be necessary to first protect these functional groups, then carry out the acylation reaction, and finally deprotect the resulting product.

~6S763 --2g--The products of formula I wherein R2 is methoxy can be prepared from the corresponding compound of formula XI wherein Al is benzyloxy-carbonyl. Halogenating (~referably chlorinating) the amide nitrogen of a compound of formula XI
yields a compound having the formula XVII

~C - I_O _ p ~ 5 O OH .
Reagents and procedures of N-chlorinating amides are known in the art. Exemplary reagents are tert. -butyl hypochlorite, sodium hypochl.orite, and chlorine. The reaction can be run in an organic solvent (e.g., a lower alkanol such as methanol) or in a two phase solvent system (e.q., 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 XVII
with a methoxylating agent, e.~., an alkali metal methoxide, yields a compound (in combination with its enantiomer if R3 and R4 are the same or if XVII is a racemic mixture) having the formula XVIII
oCH3 R4 ~ CH2-O-C-NH-C C-R3 y ~,C N-O -P~

~Z6~3~63 The reaction can be run in an organic solvent, e.g., a polar organic solvent such as tetra-hydrofuran, at a reduced temperature.
Aiternatively, a compound of formula XI, wherein ~1 is benzyloxycarbonyl, can be converted to a compound of formula XVIII
using a single step procedure. The methoxylating agent can first be mixed with a compound of formula XI and the N-chlorinating reagent then added to the reaction mixture.
Conversion of a compound of formula XVIII
to the desired products of formula I can be accomplished using the procedures described above for the conversion of an intermediate of formula XI to a product of this invention.
The following examples are specific embodiments of this invention.

~6~763 Example 1 .

Me~hylphosphonic acid,[3S-[3~(Z),4B]]-3-[[t2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-4-methyl-2-oxo-l-azetidinyl ester, potassium salt A) O-Benzyl--N-t-butoxycarbonyl-L-threonine hydroxamate To a stirred solution of 10.95 g (50 mmol) of N-t-butoxycarbonyl-L-threonine in 50 ml of water was added a solution of 8.75 g tS5 mmol) of O-benzylhydroxylamine hydrochloride and 50 ml of water, which had been adjusted to pH 4.0 using 2N KOH. After the addition, the pH was adjusted to 4.0, and a solution of 10.55 g (55 mmol) of l-ethyl-3-[(3-dimethyl-amino)propyl]carbodiimide hydrochloride (water soluble carbodiimide, in 50 ml of water was added over 10 minutes while maintaining the pH
at 4.0 - 4.5 using lN HCl. The reaction was continued for 20 minutes in this pH range, and then extracted with ethyl acetate. The ethyl acetate extract was washed at pH 8.5 (aqueous NaHCO3) and then at pH 3.0 (lN HCl), dried (Na2SO4), and evaporated to a crystalline residue. Treatment with ethyl acetate-hexane gave 9.60 g of crystalline product.

~;~6~763 B) O-Benzyl-a-N-t-butoxycarbonyl-L-(O-mesyl-threonine)hydroxamate To a stirred solution of O-benzyl-~-N-t-butoxycarbonyl-L-threonine hydroxamate (0.60 g, 29.6 mmol) in 24 ml of dry pyridine at 0-5C under nitrogen was added dropwise 2.63 ml (34 mmol) of methylsulfonyl chloride.
The reaction was stirred at this temperature for 4 hours, poured into 250 ml of water, adjusted to pH 3.5 (3 N HC1), treated with saturated NaCl solution, and extracted repeatedly with ethyl acetate. The combined ethyl acetate extract was washed with water, then water at pH 7, dried !Na2SO4), and evaporated to give 11.68 g of desired product as a crystalline mass.

C) [3S- ( 3a, 4 B) ] -3- [ [ (1, l-Dimethylethoxy)carbonyl]-amino]-4-methyl-2-oxo-1-(phenylmethoxy)azetidine Potassium carbonate (12 g, 0.087 mol) wa added to a stirred solution of 11.65 g (0.029 mol) of O-benzyl-~-N-t-butoxycarbonyl-L-(O-mesylthreonine)hydroxamate in 490 ml of acetone under nitrogen and the reaction was refluxed. After 6 hours, the reaction mixture was cooled and filtered through ~elite.
Evaporation of the filtrate gave a crystalline residue, which was recrystallized from ethyl acetate-hexane to give 4.65 g of crystalline product.

* Trade-mark ,ci~.
~Z6~3763 D) ~3S-(3~,4~)]-3-[~(1,1-Dimethylethoxy)carbonyl]-amino]-4-methyl-2-oxo-1-hydroxyazetidine To a solution of [3S-(3~,4~)]-3-[[(1,1-dimethylethoxy)carbonyl]amino~-4-methyl-2-oxo-l-(phenylmethoxy)azetidine (1.22 g, 4 mmole) in 40 ml of methanol was added 10~ palladium on charcoal (0.8 g), and the reaction mixture was reduced at atmospheric pressure for 15 minutes (until hydrogen uptake stopped). ~he reaction mixture was filtered through Celite and concentrated in vacuo. The solid that was obtained, was dried over P2OS at 45C to yield 0.75 g of product.

E) Methylphosphonic acid, [3S-(3a,4~)]-3{[(1,1-dimethvlethoxy)carbonyl]aminq~4-methyl-2-oxo-1-azetidinyl ester, potassium salt [3S-(3a,43]-3{[(1,1-Dimethylethoxy)carbonyl]-amino]-4-methyl-2-oxo-1-hydroxyazetidine (1.02 g, 4.7 mmole) was partially dissolved in 14 ml of dry dichloromethane and cooled to -10C under nitrogen. 2,6-Lutidine (0.6 ml, 4.9 mmole) was then added followed by the dropwise addition of methylphosphonic dichloride (O.62 g, 4.6 ~mole) in 5 ml of dichloromethane. After addition, the reaction was stirred at -10C for 1 hours.
The termperature was allowed to rise to 0C, and then 20 ml of 0.5 ~ KH2PO4 containing 2 ml of 2 N KOH and 15 ml of tetrahydrofuran was added (pH 6.6). This solution was stirred at 0-15C for 5 hours, and the pH was maintained lX 61~7 63 at 4.2 by the addition of 1 N KOH. The reaction mixture was concentrated _ vacuo to remove solvent and the remainder was lyophilized. The lyophilate was washed with two 200 ml portions of dichloromethane, and the dichloromethane was concentxated in vacuo to yield 1.63 g of crude material. This was dissolved in 5 ml of water (pH 4.5) and passed through 60 ml of ~owex 50 resin (K~, 0.7 meq/ml) to yield 1.03 g of crude product. The product was further purified by chromatography through 80 ml of ~P-20 resin using water as eluent. The product which was found to elute in a wide band ~500 ml) gave, after lyophilization, 0.4 g of hygroscopic material.
F) Methylpho~phonic acid, t3S-(3~,4B~]-3-amino-2-methyl-4-oxo-1-azetidinyl ester, trifluoroacetic acid salt Methylphosphonic acid, [3S-(3,4B)]-3-[~(l,l-dimethylethoxy)carbonyl]amino~4-methyl-2-oxo-l-azetidinyl ester, potassium salt (0.35 g, 1 mmole) was suspended in 1.5 ml of dichloromethane and 1.25 ml of anisole. The reaction mixture was cooled to -1~C, and trifluoroacetic acid (0.95 ml) was added. This was stirred under nitrogen at -10C for 1 hour. The reaction mixture was evaporated in vacuo to a residue, which was evaporated from toluene (twice) to give a viscous oil. Ether was added, and the oil solidified. The ether was decanted and the product was dried _ vacuo.

7 * Trade-mark l~' . lZ687~3 ~195 G) Methylphosphonic acid, [3S-[3(Z),4B~]-3-[~(2-amino-4-thiazolyl)tmeth ~ zetyl]-amino]-4-methyl-2-oxo-1-azetidinyl ester, potassium salt l-Hydroxybenzotriazole (.169 g, 1.1 mmole) and (Z)-(2-amino-4-thiazolyl)(methoxyimino) acetic acid (.223 g, 1.1 mmole) were dissolved -in 3 ml of dry dimethylformamide under nitrogen.
This was cooled to 0C, and N,N'-dicyclohexyl-carbodiimide (.228 g, 1.1 mmole) was added portionwise. After addition, the reaction was stirred at 0C for 1 hour. To this was added a solution of methylphosphonic acid, ~3S-(3~,4B)]-- 3-amino-2-methyl-4-oxo-1-azetidinyl ester., trifluoroacetic acid salt in 2 ml of dimethyl-formamide and 1.1 ml of N,N-diisopropylethylamine at 0C. 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 water (pH 4.5), and the solution was washed with dichloromethane. The aqueous solution was passed through 80 ml of Dowex 50 (K~ .7 meq/ml). Partial purification of product was obtained by taking 8 ml fractions.
Those fractions that contained product (4-8, 40 ml) were pooled and lyophilized to yield 0.4 g of material which was purified further by chromatography through 150 ml of HP-20 resin using water as eluent. Lyophilization ~2~;8763 ~, gave 32 mg of desired product containing ca. 0.1 - 0.2 equivalents of l-hydroxy-benzotriazole; melting point 160 - 180C, dec.
~nalysiS Calc'd- for CllH15N56SPK C~ 31-81;
H, 3.64; N, 16.86; S, 7.72; P, 7.46 Found: C, 30.24; H, 3.71; N, 16.22; S, 7.23; P, 5.6 Example 2 [35-[3~(Z),43]]-2-[[[1-(2-Amino-4-thiazolyl)-2-r [1- t (hydroxymethylphosphinyl)oxy]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidine]amino]-oxy]-2-methylpropanoic acid, dipotassium salt A) Methylphosphonic acid, ~3S-(3,4~)]-3.amino-4-methyl-2-oxo-1-azetidinyl ester, trifluoroacetic acid salt Methylphosphonic acid, [3S-(3~,43)]-3-[Ul,l-dimethylethoxy)carbonyl]amino}4-methyl-2-oxo-l-azetidinyl ester, potassium salt (0.223 g, 0.7 mmole; see example lE) was suspended in 0.53 ml of anisole and 0.53 ml of dry dichloro-methane under nitrogen. Trifluoroacetic acid (1.0 ml) was added dropwise at 0C, and the reaction mixture was stirred at 0C to 5C
for 2 hours. This was concentrated in vacuo to a residue, which was dried by concentration two times from 30 ml portions of toluene. The crude reaction product was triturated twice with ether to give, upon drying, a solid.

~26~3763 B) [3S-[3~(Z),43]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[[1-[(hydroxvmethYlphosphinyl)oxy]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidine~amino]-ox~}2-methylpro ~noic acid, diphenylmethyl ester, potassium salt (z)-(2-Amino-4-thiazolyl)[~2-(diphenyl-methoxy)-l,l-dimethyl-2-oxoethoxy]imino]acetic acid (0.310 g, 0.7 mmole) and l-hydroxybenzotriazole (0.108 g, 0.7 mmole) were dissolved in 4 ml of L0 dry dimethylformamide under nitrogen. This was cooled to 0C, and N,N'-dicyclohexylcarbodiimide (0.145 g, 0.7 mmole) was added portionwise.
After addition, the reaction was stirred at 0C for 1 hour. To this was added a solution lS of methylphosphonic acid, L3S-(3~,4~)]-3-amino-4-methyl-2-oxo-l-azetidinyl ester, trifluoro-acetic acid salt (ca. 0.7 mmole) in 2 ml of dimethylformamide and 0.5 ml of N,N-diisopropyl-ethylamine at 0C. The reaction was stirred at 0C for l hour and then at room temperature overnight. The solution was filtered and the filtrate was concentrated ln vacuo. The residue was dissolved in 50 ml of dichloromethane and washed with 2 ml of water (pH 4.5). The dichloromethane was concentrated in vacuo to yield 0.581 g of crude product. This was purified partially by dissolving in 20 ml of ethyl acetate and washing with 5 ml portions of KH2PO4 buffer a~ pH 4.5 (four times). The ~26~3763 aqueous washes were lyophilized overnight to give 0.261 g of a residue which was passed through 10 ml of Dowex 50 (K~ 0.7 meq/ml) using water, and lyophilized to give 0.233 g of crude product contaminated with hydroxy-benzotriazole.

C) [3S-[3~(Z),4B]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[[l-[(hydroxYmethylphosphinyl)oxv]-4-methvl-2-oxo-3-azetidinyl]amino]-2-oxoethylidine]amino]-oxy]-2-methyl~ropanoic acid, dipotassium salt [3S-[3~(Z),43]]-2-[[[l-(2-Amino-4-thiazolyl)-2-[[1-(hydroxymethylphosphinyl)oxy]-2-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidine~aminol-oxy-2-methylpropanoic acid, diphenylmethyl ester, potassium salt (0.223 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 concentrated in vacuo and evaporated from toluene twice. The residue was washed with ether:ethyl acetate (l:l) (three times) to give the trifluoroacetic acid salt as a white solid.
This was dissolved in 1.5 ml of pH 4.5 0.5 M KH2PO4, and the pH was adjusted to 6.5 with lN KOH.
This aqueous fraction was chromatographed through 80 ml of HP-20 resin with water to give 94 mg of desired product, melting point 60-70C.
Analysis Calc'd for C14H18N5O8PS 2K-3.75 H2O:
C, 28.35; H, 4.33; N, 11.80; P, 5.22 Found: C, 28.61; H, 3.76; N, 11.45; P, 4.9 ~Z6~763 ~C195 Exam~le 3 Methylphosphonic acid,[3S-[3~(R),43~]-3-[ f [ ~ (4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino~-phenyIacetyl]amino]-4-methyl-2-oxo-1-azetidinyl ester potassium salt (3S-trans)-3-[[[[(4-Ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino~phenylacetyl]amino]-l-hydroxy-4-methyl-2-azetidinone (0.22 g, .53 mmol; see U. S. patent 4,337,197) was suspended in 8 ml of dry dichloromethane at -10C under nitrogen. 2,6-Lutidine (.07 ml, .6 mmol) was added followed by the dropwise addition of methylphosphonic dichloride in 0.5 ml of dichloromethane. After addition,the reaction was stirred at -10C for 2 hours. The temperature was allowed to rise to 0C, 8 ml of 0.5 M KH2PO4 containing 0.6 ml of 2N KOH
(pH 6.6) was added and the reaction was stirred at room temperature for 2 hours. The organic layer was separated and the aqueou~ layer was lyophilized. The lyophilate was washed (3 times) with 100 ml portions of dichloromethane.
These washes were concentrated in vacuo, dissolved in 2 ml of water (pH 4.5) and passed through 10 ml of Dowex 50 resin (K~, 0.7 meq/ml) to yield 120 mg of crude product. This was chromatographed through 50 ml of HP-20 resin packed in water; product was eluted with 20 acetone:water. After lyophilization, 62 mg of analytical product was obtained, melting point 175-180C, dec.
Analysis Calc'd for C20H25N5O8P 2 C, 41.85; H, 5.18; N, 12.20; P, 5.40 Found: C, 42.05; H, 5.01; N, 12.08; P, 5.0 126~3763 ~ J~

Example 4 Methylphosphonic acid, (S)-2-oxo-3-[(phenylacetyl)-amino]-l-azetidinyl ester, potassium salt (S)-N-(l-Hydroxy-2-oxo-3-azetidinyl)-2-phenylacetamide (0.119 g, 0.55 mmole; see U. S. patent 4,337,197) was dissolved in 3 ml of dry dichloromethane and the solution was cooled to -10C under nitrogen. 2,6-Lutidine (0.065 ml, 0.56 mmole) was added, followed by the dropwise addition of a solution of methyl-phosphonic dichloride in 1 ml of dichloromethane.
After addition, the reaction was stirred at -10 C for 2 hours. The remaining chloro group was hydrolyzed at room temperature with 8.ml of 0.5 M KH2PO4 containing 0.6 ml of lN KOH
(pH 6.0). The solution was stirred vigorously for 2 hours. The dichloromethane layer was separated and the aqueous layer was lyophilized.
The lyophilate was washed 3 times with 100 ml portions of dichloromethane and with 100 ml of ethanol. These washes were concentrated in vacuo, combined and dissolved in 2 ml of water. The pH of this solution was adjusted to 4.5 with lN KOH from pH 2.5. This material was passed through 8 ml of Dowex resin (K~, 0.7 meq/ml) to yield 67 mg of crude product.
This was placed on 15 ml of HP-20 resin and product was eluted with water. After lyophili-zation, 20 mg of analytical product was obtained, melting point 135-140C, dec.
Analysis Calc'd for C12H14N2O5PK H2 H, 4.56; N, 7.90; P, 8.73 Found: C, 40.64; H, 4.47; N, 1.89; P, 8.4 ~6~3763 Example 5 ~3S-[3a(Z),4s~]-2-[[[1-(2-Amino-4-thiazolyl)-2-[[l-~(hydroxymethoxyphosphinyl)oxy]-4-methyl-2-oxo-3-a~etidinyl]amino]-2-oxoethylidine]amino]-oxy]-2-methylpropanoic acid, dipotassium salt A) Methylphosphoric acid,[3S-(3~,4~)]-3-U(l,l-dimethylethoxy)carbonyl]amino}4-methyl-2-oxo-1-azetidinyl ester, potassium salt [3S-(3,43)]-3-[[(1,l-Dimethylethoxy)carbonyl]-amino]-4-methyl-2-oxo-1-hydroxyazetidine (1.18 g, 5.46 mmole, see example lD) was partially dissolved in 14 ml of dry dichloromethane and cooled to -70C under nitrogen. TriethylaMine (.78 ml, 5.46 mmole) was added followed by the dropwise addition of methyl phosphonic dichloride (0.79 g, S.46 mmole) in 6 ml of dichloromethane.
The reaction mixture was stirred for 1.2 hours while warming from -60 to -30 C. A solution of 0.5 M KH2PO~ pH 5.5 buffer (55 ml) was added, and the reaction was stirred vigorously. The reaction flask was removed from the cooling bath and the solution was stirred at ambient temperature for 45 minutes. The pH during this time was maintained at 3.5 to 4.0 by occasional addition of 2 N KOH. The aqueous layer was lyophilized.
The lyophilate was washed with three 150 ml portions of dichloromethane, and the dichloro-methane was concentrated in vacuo to yield the crude triethyl ammonium salt (1.8 g). This was 126~3763 dissolved in water (pH 4.2) and passed through 90 ml of Dowex 50 resin (K , 0.7 meq/ml) to yield 0.87 g of crude material, which was purified further by chromatography through 100 ml of HP-20 resin packed in water. The product eluted with 20% acetone-water (170 ml) to yield, after lyophilization, 0.22 g of analytically pure material, melting point 143,dec.

B) Methylphosphoric acid, [3s-(3~,43)]-3-amino-4-methyl-2-oxo-1-azetidinyl ester, trifluoro-acetic acid salt Methylphosphoric acid, ~3S-(3~,4B)]-3-[[(l,l-dimethylethoxy)carbonyl]amino}4-methyl-2-lS oxo-l-azetidinyl ester, potassium salt (0.20 g, .57 mmole) was suspended in 0.65 ml of dichloro-methane and 0.65 ml of anisole. The reaction mixture was cooled to -10C, and trifluoroacetic acid (1.3 ml) was added. This was stirred at 0C for 1 hoùr. The solution was concentrated in vacuo to a residue, which was evaporated from benzene (twice) to give a viscous oil.
This was triturated with ether to give a white solid, which was dried ln vacuo.

~z6a~763 '~

C) ~3S-[3(Z),4B]]-2-[[[l-(2=Amino-4-thiazolyl)-2-[[l-[(hydroxymethoxy~hosphinyl)oxy]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidine]amino]-oxy]-2-methylpropanoic acid, diphenylmethyl ester, potassium salt (z)-(2-Amino-4-thiazolyl)[[2-diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]acetic acid (.29 g, 0.66 mmole) and l-hydroxybenzotriazole (0.10 g, 0.66 mmole) were dissolved in 8 ml of dry dimethylformamide (DMF) nitrogen. This was cooled to 0C, and N,N-dicyclohexylcarbodiimide (0.14 g, 0.66 mmole) was added portionwise.
After addition, the reaction was stirred at 0C for 1 hour~ Methylphosphoric acid, L3S-(3,4~)]-3-amino-4-methyl-2-oxo-1-azetidinyl ester, trifluoroacetic acid salt (0~57 mmol) in 2 ml of DMF and 0~5 ml of N,N-diisopropylethylamine were added to the activated acid side chain, and the reaction was stirred overnight at room temperature. The solution was filtered, and the filtrate was concentrated in vacuo~ The residue was dissolved in 8 ml of water, and the pH was adjusted to 4~5 with 1 N KOH~ This solution was passed through 100 ml of Dowex 50 (K~, 0~7 meq/ml) using water, and lyophilized to give 0~202 g of crude material contaminated with hydroxybenzotriazole~

~26~7~;3 D) f 3s- [ 3 ( z), 4~]]-2-~[[1-(2-Amino-4-thiazolyl)-2-.

[[l-[(hydroxymethoxyphosphinyl)oxy]-4-methyl-2-oxo-3-azetidinyl]amino~-2-oxoethylidine]amino]-oxy]-2-methylpropanoic acid, dipotassium salt s [3s-[3(Z) ,4B]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[~1-[(hydroxymethoxyphosphinyl)oxy]-4-methyl-2-oxo-3-azetidinyl]amino~-2-oxoethylidine]amino]-oxy]-2-methylpropanoic acid, diphenylmet'nyl ester, potassium salt was dissolved in 1.8 ml of dichloromethane, 0.5 ml of anisole, and 1.5 ml of trifluoroacetic acid, and stirred under N2 at -10C for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was evaporated from benzene (three times). T4e residue was washed with ether: ethyl acetate (1:1) and ether:acetonitrile (1:1) to give a white solid. This material was dissolved in 2 ml of pH 5.5, 0.5 M KH2PO4 and the pH was adjusted to 6.5 with 1 N KOH. This was chromatographed through 100 ml of HP-20 resin with water to give 77 mg of desired product, melting point 178-185C, dec.
Calc'd- for C14H18N5SPOgK2 2 4H20 H, 3.92; N, 11.96; S, 5.47; P, 5.29 Found: C, 28.72; H, 3.73; N, 11.86;
- S, 5.51; P, 5.0 ~Z6~ ~

Addi~ional embodiments of compounds following within the scope of this invention are: -[ 3S- [ 3a ( Z), 4]~-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[(hydroxymethylphosphinyl)oxy]-4-methyl-2-oxo-3-azetidinyl~amino~-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, dipotassilLm salt [3S-~3a(Z),4]~-2-~[1-(2-amino-4-thiazolyl)-2-[[1-(hydroxymethoxyphosphinyl)oxy]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acld, dipotassium salt methylphosphonic acid, [3S-[3~(Z),4B]]-3-[[(2-aminothiazolyl)(2,2,2-trifluoroethoxy-imino)acetyl]amino]-4-methyl-2-oxo-1-azetidinyl ester [3S-~3~(Z),4B]]-[[[1-(2-amino-4-thiazolyl)-2-~[l-[(hydroxymethylphosphinyl)oxy]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]-amino]oxy]acetic acid methylphosphonic acid,[3S-[3~(Z),4B]]-3-[[(2-amino-4-thiazolyl)[(2-amino-2-oxoethoxy)-imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinyl ester ~ 26~3763 methylphosphonic acid,[3S-(3~,4B)]-3-~[(S)-~-[(aminocarbonyl)amino]-2-thiopheneacetyl]amino]-4-methyl-2-oxo-1-azetidinyl ester s methylphosphonic acid,[3S-(3~,4B)]-3-[(aminophenyacetyl)amino]-4-methyl-2-oxo-l-azetidinyl ester methylphosphonic acid,[2S-(2~,3B)]-3-[[(phenylsulfo)acetyl]amino]-2-methyl-4-oxo-l-azetidinyl ester methylphosphonic acid,[3S-[3(Z),4~]]-3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1-azetidinyl ester [3S-[3(Z),4]]-[t[1-(2-amino-4-thiazolyl)-2-~[1-[(hydroxymethylphosphinyl)oxy]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]acetic acid methylphosphoric acid,[3S-[3~(Z), 4a ] ] -3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1-azetidinyl ester methylphosphoric acid,[3S-~3~(Z) ,4~] ]-3-[~(2-amino-4-thiazolyl)~(2-amino-2-oxoethoxy)imino]acetyl]amino]-4-methyl-2-oxo-l-azetidinyl ester ~z~763 ~C195 [35-[3(z),4g]]-2-[[[1-(2-amino-4-~hiazolyl)-2-[[1-[(hydroxyphenylphosphinyl)cxy]-4-me~hyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy-2-me~hylp!opanoic acid [3S-[3~(Z),4~]]-2-[~[1-(2-amino-4-~hiazolyl)-2-[[1-[[hydroxy(4-methoxyphenyl)phosphinyl]oxy]-4-methyl-2-oxo-3-azecidinyl]amino]-2-oxoethylidene]amino]oxy-2-methylpropanoic acid [3S-[3~(Z),4~]]-2-~[[1-(2-amino-4-thiazolyl)-2-[[1-[[hydroxy(4-dimethylaminophenyl)phosphinyl]oxy]-4-methyl-2-oxo-3-aze~idinyl]amino]-2-oxoethylidene]-amino]oxy-2-methylpropanoic acid [3S-[3~(Z),4~]]-2-~[[1-(2-amino-4-thiazolyl)-2-~[[hydroxy(phenylmethyl)phosphinyl]oxy]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoe~hylidene]amino]oxy-2-methylpropanoic acid [35-[3(Z),4~]~-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[(azidomethyl)hydroxy]phosphinyl]oxy]-4-methyl-2-oxo-3-aze~idinyl]amino]-2-oxoe~hylidene]amino]oxy-2-methylpropanoic acid [3S-[3(z),4~]]-2-[[[1-(2-amino-4-~hiazolyl)-2-[[1-[[hydroxy(methoxymethyl)phosphinyl]cxy]-4-methyl-2-Gxo-3-azetidinyl]aminG]-2-oxoethylidene]amino]ox~-2-methylpropanoic acid l~Z68763 Gclgs [3S-[3~(Z),4B]]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[(hydroxyethylphosphinyl)oxy]-4-methyl-2-oxo-3-aze~idinyl]amino]-2-oxoethylidene]aminojoxy-2-me~hyl-propanoic acid [3s-[3 a( Z ) ,4B]]-2-[[[1-(2-amino-4-thiazolyl) 2-[[1-[[hydroxy(2-propenyl)phosphinyl]oxy]-4-methyl-2-oxo-3-azetidir.yl]amino]-2-oxoethylidene]aminG]oxy-2-r,le~hyl-propanoic acid [3S-[3~(Z),4g]]-2-[[[1-(2-amino-4-~hiazolyl)-2-[[1-[(hydroxyphenoxyphosphinyl)oxy]-4-me~hyl-2-oxo-3-azetidinil]amino]-2-oxoethylidene]amino]oxy-2-me~hyl-propanoic acid ~3S-[3(Z),4g]~-2-~[1-(2-amino-4-thiazolyl)-2-[[1-~hydroxy(4-methylphenoxy)phosphinyl]oxy]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino,oxy-2-methylpropanoic acid [3S-[3(2),4B]]-2-[~[1-(2-amino-4-thiazolyl)-2-[[1-[[hydroxy(phenylmethoxy)phosphinyl]oxy]-4-methy1-2-oxo-3-azetidinyl]ar,lino]-2-Gxoethylidene]amino]oxy-2-methylpropanoic acid [3S-[3~(Z),4B]]-2-~[[1-(2-amino-4-thiazolyl)-2-[[1-[(hydroxyethoxy)phosphinyl]oxy]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy-2-methylpropanoic acid [3S-[3~(Z),4B]]-2-[[[1-(2-amino-4-~hiazolyl)-2-[[1-[[(2-fluoroethoxy)hydroxyphosphinyl]oxy]-4-me~hyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene~amino]oxy-2-me~hylpcopanoic acid _4~

[3S-[3(2),4~]]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[hydroxy(methylchio)phosphinyl]oxy]-4-me~hyl-2-oxo-3-aze~idinyl]amino]-2-oxoethylidene]amino]oxy-2-me~hylpcopanoic acid [3S-[3~(2),4~]]-2-[[[1-(2-amino-4-~hiazolyl)-2-[[1-~[(hydroxyme~hyl)~hiophosphinyl]oxy]-4-me~hyl-2-oxo-3-aze~idinyl]amino]-2-oxoe~hylidene]aminG~ox~-2-methylpropanoic acid [3S-[3(Z),4B]]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[(hydroxyphenyl)thiophosphinyl]oxy]-4-methyl-2-oxo-~-azetidinyl]amino]-2-oxoe~hylidene]aminG]oxy-2-methylpropanoic acid [3S-[3 a( Z ) ,4B]]-2-[[[l-~2-amino-4-thiazolyl)-2-[[
[[(hydroxymethoxy)chiophosphinyl~oxy]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy-2-methylpropanoic acid [3s-[3~(z)~4B]]-2-[[[l-(2-amino-4-thiaol~l)-2-[[
[[(hydroxyphenoxy)thiophosphinyl]oxy]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoe~hylidene]amino]oxy-2-me~hylpropanoic acid

Claims (14)

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

1. A .beta.-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, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2X1, -S-X2, X1 is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl) sulfonyloxy, phenyl, substituted phenyl, cyano, X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, substituted phenyl)carbonyl or hetero-arylcarbonyl;

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, phenyl-alkylcarbonyl, (substituted phenyl)-alkylcarbonyl, carboxyl, alkoxy-carbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano;
A is ;

n is 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 hydrogen and X7 is amino, substituted amino, acylamino or alkyoxy;
R5 is hydroxyl, alkyl, substituted alkyl, phenyl, substituted phenyl, alkoxy, alkylthio, (substituted alkyl)oxy, (substituted alkyl)thio, phenyloxy, phenylthio, (substituted phenyl)oxy or (substituted phenyl)thio; and Y is oxygen or sulfur;
wherein the terms "alkyl" and "alkoxy" refer to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to groups having 3, 4, 5, 6, or 7 carbon atoms;
the terms "alkanoyl", "alkenyl" and "alkynyl"
refer to groups having 2 to 10 carbon atoms;
the term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino, halogen, hydroxyl, tri-fluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or carboxyl groups;
the term "substituted alkyl" refers to alkyl groups substituted with one or more azido, amino, halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenloxy, (substituted phenyl)oxy, (4, 5, 6 or 7-membered heterocycle)oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl or alkylsulfonyl groups;
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-furylimino, ben-zylimino or substituted alkyl, wherein the alkyl group 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, aze-tinyl, oxetanyl, thietanyl, piperidinyl, pipertazinyl, imidazolidinyl, oxa-zolidinyl, pyrrolidinyl, tetrahydro-pyrimidinyl, dihydrothiazolyl or hexa-hydroazepinyl 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, sub-stituted phenyl, 2-furylimino, benzylimino or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, 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 "substituted alkanoyl" refers to a group having the formula:

(substituted alkyl)

2. A .beta.-lactam in accordance with claim 1 wherein Y is oxygen.

3. The .beta.-lactam in accordance with claim 2 wherein R4 is hydrogen and R3 and R5 are each methyl, or a salt thereof.

4. The .beta.-lactam is accordance with claim 2 wherein R3 is hydrogen, R4 is methyl and R5 is methoxy, or a salt thereof.

5. A .beta.-lactam in accordance with claim 2 wherein R3 and R4 are each hydrogen, or a salt thereof.

6. The .beta.-lactam in accordance with claim 2 wherein R3 and R4 are each hydrogen and R5 is methyl, or a salt thereof.

7. The .beta.-lactam in accordance with claim 2 wherein R3 is hydrogen and R4 and R5 are each methyl, or a salt thereof.

8. A pharmaceutical composition comprising a -lactam having the formula:

or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier therefor, 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, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2X1, -S-X2, -O-X2, , or X1 is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl) sulfonyloxy, phenyl, substituted phenyl, cyano, ;
X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, substituted phenyl)carbonyl or hetero-arylcarbonyl;
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, phenyl-alkylcarbonyl, (substituted phenyl)-alkylcarbonyl, carboxyl, alkoxy-carbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano;
A is ;

n is 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 hydrogen and X7 is amino, substituted amino, acylamino or alkyoxy;
R5 is hydroxyl, alkyl, substituted alkyl, phenyl, substituted phenyl, alkoxy, alkylthio, (substituted alkyl)oxy, (substituted alkyl)thio,phenyloxy, phenylthio, (substituted phenyl)oxy or (substituted phenyl)thio; and Y is oxygen or sulfur;
wherein the terms "alkyl" and "alkoxy" refer to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to groups having 3, 4, 5, 6, or 7 carbon atoms;
the terms "alkanoyl", "alkenyl" and "alkynyl"
refer to groups having 2 to 10 carbon atoms;
the term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino, halogen, hydroxyl, tri-fluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or carboxyl groups;
the term "substituted alkyl" refers to alkyl groups substituted with one or more azido, amino, halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenloxy, (substituted phenyl)oxy, (4, 5, 6 or 7-membered heterocycle)oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl or alkylsulfonyl groups;
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-furylimino, ben-zylimino or substituted alkyl, wherein the alkyl group 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, aze-tinyl, oxetanyl, thietanyl, piperidinyl, pipertazinyl, imidazolidinyl, oxa-zolidinyl, pyrrolidinyl, tetrahydro-pyrimidinyl, dihydrothiazolyl or hexa-hydroazepinyl or one of the above groups substituted with one or more xo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, sub-stituted phenyl, 2-furylimino, benzylimino or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, 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 "substituted alkanoyl" refers to a group having the formula:

(substituted alkyl).

9. A composition in accordance with claim 8 wherein Y is oxygen.

10. A composition in accordance with claim 9 wherein R4 is hydrogen and R3 and R5 are each methyl, or a salt thereof.

11. A composition in accordance with claim 9 wherein R3 is hydrogen, R4 is methyl and R5 is methoxy, or a salt thereof.

12. A composition in accordance with claim 9 wherein R3 and R4 are each hydrogen, or a salt thereof.

13. A composition in accordance with claim 9 wherein R3 and R4 are each hydrogen and R5 is methyl, or a salt thereof.

14. A composition in accordance with claim 9 wherein R3 is hydrogen and R4 and R5 are each methyl, or a salt thereof.