[[(3-Acylamino-2-oxo-1-azetidinyl)oxy]methyl]phosphinic acids

Abstract: Antibacterial activity is exhibited by β-lactams having a 3-acylamino substituent and in the 1-position a substituent having the formula wherein 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, alkenyl, alkynyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH₂X₁ -S-X₂, -O-X₂, or -A--NX₆X₇; R₇ is hydrogen, alkyl, substituted alkyl, phenyl, substi­ tuted phenyl, 1-(ethoxycarbonyloxy)ethyl, 1,3-dihydro-3-­ oxo-1-isobenzofuranyl, wherein R′ is hydrogen or alkyl, R″ is alkyl or phenyl, R‴ is hydrogen, methyl or phenyl, and R iv is hydrogen or together with R‴ is -(CH₂)₃- or -CH₂)₅-; and R₈ is hydroxy, alkoxy, (substituted alkyl)-oxy, phenyloxy, (substituted phenyl)oxy, alkyl, substituted alkyl, phenyl, sub­ stituted phenyl, heteroaryl, amino, substituted amino, alkyl­ thio, (substituted alkyl)thio, phenylthio, (substituted phenyl)thio, or R″--O-CH₂-CH₂-O.

Description: Antibacterial activity is exhibited by fl-lactams having the formula EMI1.1 and pharmaceuticallytacceptable salts thereof As used in formula I, and throughout the specification, the symbols are as defined below. R1 is acyl; R2 is hydrogen or methoxy: R3 and R4 are the same or different and each is hydrogen, alkyl alkenyl, alkynyl. cycloalkyl, phenyl. substituted phenyl or a 4,5,6 or 7-membered heterocycle (refetred to hereinafter as R9) or one of R3 and R4 is hydrogen and the other is azido. halomethyl, dihalomethyl, trihalomethyl, alkoxyearbonyl, alkenyl. alkynyl. 2-phenylethenyl. 2-phenylethynyl. carboxyl, -CH2X1 [wherein X1 is azido. amino (-NK2), hydroxy. alkanoylaminol. phenylcarbonylamino. (substituted phenyl)carbonylamino. alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl) sulfonyloxy, phenyl. substituted phenyl, cyano, EMI1.2 -S-Xz, or -O-X2 (wherein A. X2. X6 and X7 are as hereinafter defined)J. -S-Xz or -O-X2 twherein X2 is alkyl. substituted alkyl. phenyl. substituted phenyl. phenylalkyl. (substituted phenyl)alkyl. alkanoyl. phenylalkanoyl, (substituted phenyl)alkanoyl. phenylcarbonyl. (substituted phenyl)carbonyl. or heteroarylcarbonyl], EMI2.1 ±wherein 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: and X5 is formyl, alkanoyl. phenylcarbonyl, (substituted phenyl)carbonyl. phenylalkylcarbonyl. (substituted phenyl) alkylcarbonyl. carboxyl. alkoxycarbonyl. aminocarbonyl EMI2.2 (substituted amino) carbonyl. or cyano (-C=N)1, or EMI2.3 (wherein A is -CH=CW. -(CH2)n-. -CH2-O-. -CH2-NH-. or -CH2-S-CH2-. n is 0. 1 or 2. and X6 and X7 are the same or different and each is hydrogen. alkyl. phenyl or substituted phenyl. or X6 is hydrogen and X7 is amino. substituted amino. acylamino or alkoxy. or X6 and K when taken together with the nitrogen atom to which they are attached form a 4. 5. 6 or 7-membered heterocycle): R5 and R6 are the same or different and each is hydrogen, alkyl. alkenyl, alkynyl. phenyl. substituted phenyl, cycloalkyl or R9. or R5 and R6 together with the carbon atom to which they are attached are cycloalkyl or R9. or one of R5 and R6 is hydrogen and the other is azido. halomethyl. dihalomethyl. trihalomethyl, alkoxycarbonyl. alkenyl. alkynyl. 2-phenylethenyl, 2-phenylethynyl. carboxyl. -Ch2X1. -S-X2. EMI2.4 R7 is hydrogen, alkyl1 substituted alkyl. phenyl. substituted phenyl. l-(ethoxyearbonyloxy) ethyl, l,3-dihydro-3-oxo-l-isobenzofuranyl, EMI3.1 wherein R' is hydrogen or alkyl. R" is alkyl or phenyl. R"' is hydrogen. methyl or phenyl and Riv is hydrogen or together with R"' is -(CH2)3- or -(CH2)5-: and R8 is hydroxy. alkoxy. (substituted alkyl)oxy, phenyloxy. (substituted phenyl)oxy. alkyl. substituted alkyl. phenyl, substituted phenyl. heteroaryl. amino. substituted amino. alkylthio. (substituted alkyl)thio. phenylthio, (substituted phenyl)thio, or EMI3.2 Listed below are definitions of various terms used to describe the ss-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)a halogen. hydroxy, carboxy. cyano, alkoxycarbonyl. aminocarbonyl. alkanoyloxy. alkoxy. phenyloxy. (substituted phenyl)oxy. Rg-oxy, mercapto. alkylthio. phenylthio. (substituted phenyl)thio. alkylsulfinyl. or alkylsulfonyl gruops. The terms "alkanoyl". "alkenyl". and "alkynyl" refer to both straight and branched chain groups. Those groups having 2 to 10 carbon atoms are preferred. The tetms "halogen" and "halo" refer to fluorine. chlorine. bromine and iodine. 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). alkoxy (of 1 to 4 carbon atoms). carbamyl. or carboxyl groups. The expression "a 4.5,6 or 7-membered heterocycle" (referred to as wRgn) refers to substituted and unsubstituted. aromatic and nonaromatic 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 carbons, alkoxy of 1 to 4 carbons. alkylsulfonyl. phenyl. substituted phenyl. 2-furylimino EMI4.1 benzylimino and substituted alkyl groups (wherein the alkyl group has l to 4 carbons). One type of "4.5.6 or 7-membered heterocycle" is the Wheteroaryl" group. The term "heteroaryl" refers to those 4.5,6 or 7-membered heterocycles which are aromatic. Exemplary heteroaryl groups are substituted and unsubstituted pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3,-triazolyl. 1,2,4-triazolyl. imidazolyl, thiazolyl. thiadiazolyl. pyrimidinyl, oxazolyl, triazinyl, and tetrazolyl. Exemplary nonaromatic heterocycles (i.e., fully or partially saturated heterocyclic groups) are substituted and unsubstituted azetinyl, oxetanyl. thietanyl, piperidinyl. piperazinyl. imidazolidinyl, oxazolidinyl. pyrrolidinyl, tetrahydropyrimidinyl. dihyrothiazolyl and hexahydroazepinyl. Exemplary of the substituted 4.5.6 or 7-membered heterocycles are l-alkyl-3-azetinyl, 2-oxo-l-imidazolidinyl, 3-alkylsulfonyl-2-oxo-l-imidazolidinyl. 3-benzylimino-2-oxo-l-imidazolidinyl. 3-alkyl2-oxo-l-imidazolidinyl, 3-phenyl (or-substitutd phenyl)-2-oxo-l-imidazolidinyl, 3-benzyl-2-oxol-imidazolidinyl, 3-(2-aminoethyl)-2-oxo-limidazolidinyl, 3-amino-2-oxo-1-imidazolidinyl, 3-( (alkoxycarbonyl)aminoi-2-oxo-l-imidazolidinyl. 3-[2-[(alkoxycarbonyl)amino]ethyl]-2-oxo-1 imidazolidinyl. 2-oxo-l-pyrrolidinyl. 2-oxo-3oxazolidinyl, 4-hydroxy-6-methyl-2-pyrimidinyl. 2-oxo-l-hexahydroazepinyl, 2-oxo-3-pyrrolidinyl. 2-oxo-3-furanyl. 2,3-dioxo-l-piperazinyl, 2,5-dioxo-1-piperazinyl. 4-alkyl-2,3-dioxo-l piperazinyl. and 4-phenyl-2,3-dioxo-l-piperazinyl. The term "substituted amino" refers to a group having the formula -NY1Y2 wherein Y1 is hydrogen, alkyl. phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and is alkyl, phenyl, substituted phenyl. phenylalkyl. (substituted phenyl)alkyl. hydroxy, cyano. alkoxy. phenylalkoxy, or amino The term "acyl" refers to all organic radicals derived from an organic acid (i.e., a carboxylic acid) by removal of the hydroxyl group. Certain acyl groups are, of course, preferred but this preference should not be viewed as a limitation of the scope of this invention Exemplary acyl groups are those acyl groups which have been used in the past to acylate B-lactam antibiotics including 6-aminopenicillanic acid and derivatives and 7-aminocephalosporanic acid and derivatives; see, for example, Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972), German Offenlegungsschrift 2,716,677, published October 10, 1978, Belgian patent 867,994, published December 11, 1978, United States patent 4,152,432, 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. The portions of these references describing various acyl groups are incorporated herein by reference. The following list of acyl groups is presented to further exemplify the term "acyl"; it should not be regarded as limiting that term. Exemplary acyl groups are: (a) Aliphatic groups having the formula EMI6.1 wherein Ra is alkyl; cyclcr.lkyl; alkoxy; alkenyl; cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, or cyanomethylthio groups. (b) Carbocyclic aromatic groups having the formula EMI7.1 EMI8.1 wherein n is 0, 1, 2 or 3; Rb, Rct 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, alkyihydrazino, phenylhydrazino, or r (alkylthio) thioxomethyli thio. Preferred carbocyclic aromatic acyl groups include those having the formula EMI8.2 EMI9.1 (Re is preferably a carboxyl salt or sulfo salt) and EMI9.2 (Re is preferably a carboxyl salt or sulfo salt). (c) Heteroaromatic groups having the formula EMI9.3 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 containing 1,2,3 or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms. Exemplary heterocyclic 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 I to 4 carbon atoms, or EMI10.1 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-dioxo-1-piperazinyl)carbonyl]amino]arylacetyl groups having the formula EMI10.2 wherein R is an aromatic group (including g carbocyclic aroma tics such as those of the formula EMI10.3 and heteroaromatics as included within the definition of Rf) ; and Rh is alkyl, substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups), arylmethyleneamino (i.e., -N=CH-Rg wherein Rg is as defined above), arylcarbonylamino (i.e., EMI11.1 wherein Rg is as defined above) or alkylcarbonylamino. Preferred ((4-substituted-2 ,3-dioxo-1- piperazinyl)carbonylaamino]arylacetyl groups include those wherein Rh is ethyl, phenylmethyleneamino or 2-furylmethyleneamino. (e) (Substituted oxyimino)arylacetyl groups having the formula EMI11.2 wherein Rg is as defined above and Ri is hydrogen, alkyl, cycloalkyl; alkylaminocarbonyl, arylamino carbonyl (i.e., EMI11.3 wherein Rg is as defined above) or substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic group (as defined by Rg), carboxyl (including salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) phosphinyl, or dialkoxyphosphinyl substituents). Preferred (substituted oxyimino)arylacetyl groups include those wherein Rg is 2-amino -4- thiazolyl. Also preferred are those groups wherein Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl. (f) (Acylanino)arylacetyl groups having the formula EMI12.1 wherein Rg is as defined above and Rj is EMI12.2 amino, alkylamino, (cyanoalkyl)amino, amido, alkylamido, (cyanoalkyl)amido, EMI12.3 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 (g) [[[3-Substituted-2-oxo-1-imidazoli- dinyl]carbonyl]amino]arylacetyl groups having the formula EMI13.1 wherein Rg is as defined above and Rk is hydrogen, alkylsulfonyl, arylmethyl eneamino (i.e., -N=CH-R wherein Rg is as defined above), EMI13.2 (where in Rm is hydrogen, alkyl or halogen substituted alkyl), aromatic group (as defined by Rg above), alkyl or substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups). Preferred [[3-substituted-2-oxo-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, methylsulfonylr phenylmethyleneamino or 2-furylmethyleneamino. The compounds of this invention form basic salts with various inorganic and organic bases which are also within the scope of this invention. Such salts include ammonium salts. alkali metal salts. alkaline earth metal salts. salts with organic bases. e.q. dicyclohexylamine. benzathine. N-methyl-D-glucarnine. hydrabamine and the like. The pharmaceutically acceptable salts are preferred. although other salts are also useful. e.a., in isolating or purifying the product. Some of the compounds of this invention may be crystallized or recrystallized from solvents containing water. In these cases water of hydration may be formed. This invention contemplates stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilization. B-Lactams having an EMI14.1 substituent in the l-position and an amino or acylamino substituent in the 3-position contain at least one chiral center - the carbon atom in the 3-position of the B-lactam nucleus) to which the amino or acylamino substituent is attached. This invention is directed to those B lactams which have been described above, wherein tbj stereochemistry at the chiral center in the 3-position of the ss-lactam nucleus is the same as the configuration at the carbon atom in the 6-posi:ion of naturally occurring penicillins te.a., pen.cillin G) and as the configuration at the carbon om in the 7-position of naturally occurring cephamycins (e.q.. cephamycin C). Also included within the scope of this invention are racemic mixtures which contain the above-described 13-lactams. ss-Lactams having an EMI15.1 substituent in the l-position of the fl-lactam nucleus and an acylamino substituent in the 3-position of the ss-lactam nucleus have activity against a range of gram-negative and gram-positive organisms. The compounds of this invention can be used as agents to combat bacterial infections (including urinary tract infections and respiratory infections) in mammaliam species. such as domesticated animals (e.a., 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 mgSkgOday to about 100 mg/kg/day. All modes of administration which have been used in the past to deliver penicillins and cephalosporins to the site of the infection are also contemplated for use with the novel family of ss-lactams of this invention. Such methods of administration include oral, intravenous. intramuscular. and as a suppository. The B-lactams of this invention can be prepared from an amino acid having the formula EMI16.1 The amino group is first protected with a classical protecting group (e.g.1 t-butoxycarbonyl. benzyloxycarbonyl. 2-nitrophenylsulfenyl. etc.). yielding a compound having the formula EMI16.2 In formula III. and throughout the specification. the symbol "A1" 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 EMI16.3 In formula IV, and throughout the specification. the symbol XYZ refers to benzyl. pivaloyl, -CH2 CH(NHA2)CO2alkyl (A2 is an amino protecting group), t-butyl, p-nitrobenzyl. benzhydryl. 2-cyanoethyl. 2-trimethylsilylethyl. trichloroethyl. E-anisyl. inter alia. The reaction proceeds in the presence of a coupling agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbociimide or dicyclohexylcarbodiimide, and yields a copound having he formula EMI17.1 The hydroxyl group of a compound of formula V is converted to a leaving group, using. for example, a classicai reagent such as methanesulfonyl chloride (methanesulfonyl is referred to hereinafter as "MS"). The fully protected compound having the formula EMI17.2 is cyclized by treatment with base, e.s., 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 EMI17.3 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. yields a compound of formula VII. Both of the methods disclosed above for ring closure of a compound of formula V result in the inversion of the stereochemistry of the R3 and R4 substituents. Selective reduction of a compound of formula VII (using catalytic hydrogenation if Y is benzyl or by treatment with a base such as sodium sulfide or sodium hydroxide if Y is pivaloyl, or with DBU if Y is -CH2CH(NHZ2)CO2alky1 yields the corresponding compound having the formula EMI18.1 Compounds of formula VIII are described in copending United States patent application serial number 404.945. filed August 4. 1982 and some are also described in J.A.C.S.. 102:7to26 (1980). Alkylation of a hydroxanic acid of formula VIII with an activated form of a compound having the formula EMI18.2 can be accomplished by first generating the anion of the hydroxamic acid with a suitable base. and then reacting the resulting compound with an activated form of an acetic acid derivative of formula fX. Activated and protected forms of compounds of formula IX have the formula EMI18.3 wherein Y is a suitable leaving group. such as a triflate group, or other reactive leaving group well known in the art. The above alkylation procedure has been described as a two step sequence, but both steps can be performed simultaneously. The resulting product has the formula EMI19.1 Deprotection of the 3-amino substituent of a compound of formula X can be accomplished using art-recognized techniques. If, for example. the protecting group is t-butoxycarbonyl, trifluoroacetic acid can be used to deprotect the amino group. If the protecting group is benzyloxycarbonyl, catalytic (e,q., palladium on charcoal) hydrogenation can be used. If the protecting group is o-nitrophenylsulfenyl. - toluenesulfonic acid can be used in combination with E-thiocresol. The deprotected compound has the formula EMI19.2 and is a key intermediate for preparing the compounds of this invention. The compounds of formula XI form an integral part of this invention. Well known acylation techniques can be used to convert a compound of formula XI to the corresponding compound having the formula EMI20.1 Exemplary techniques include reaction with a carboxylic acid (R1-OE) or corresponding carboxylic acid halide or carboxylic acid anhydride. The reactions with a carboxylic acid proceed most readily in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming a reactive intermediate in situ such as N-hydroxybenzotriazole or 4-dimethylaminopyridine. In those instances wherein the acyl group (R1) contains reactive functionality (such as amino or carboxy groups) it may be necessary to first protect these functional groups. then carry out the acylation reaction. and finally deprotect the resulting product. Alternatively. the compounds of this invention can be prepared by reacting a compound of formula III with an amine having the formula EMI20.2 The reaction proceeds in the presence of a coupling agent such as dicyclohexylcarbodiimide and yields a compound having the formula EMI21.1 The amine of formula XIIf can be prepared by reacting N-hydroxyphthalimide with an alcohol having the formula EMI21.2 under Mitsunobu conditions (triphenylphosphinediethyldiazodicarboxylate) or with an activated form of the alcohol having the formula EMI21.3 to yield a compound having the formula EMI21.4 Cleavage of the phthalimide group in a compound of formula XVT with hydrazine or an alkylhydrazine yields the corresponding amine of formula XI II. A compound of formula XIV can be cyclized to give a compound of formula X using the procedures described above for the cyclization of a compound of formula VI. Those compounds of formula XII wherein R7 is alkyl and R8 is alkoxy can be coverted to the corresponding diacid having the formula EMI22.1 providing another route for the preparation of the products of formula I wherein > is hydrogen and R8 is hydroxyl. Conversion to the diacid can be accomplished using trimethylsilyl bromide in the presence of bis-trimethylsilylacetamide as a drying agent and acid scavenger, and then solvolyzing the resulting bis-silyl ester with water or an alcohol. Those compounds of formula XII wherein N is alkyl and R8 is alkoxy can be heated with thiourea to yield the corresponding monoacid having the formula EMI22.2 providing another route for the preparation of the products of formula I wherein R7 is hydrogen and R8 is alkoxy. Alternatively, mono-acidic phosphorous derivatives can be obtained from the corresponding monoalkyl esters of formula XII. wherein R8 is alkyl. substituted alkyl. phenyl. substituted phenyl. heteroaryl. amino. or substituted amino. (this subgrouping is referred to hereinafter as R10). by treatment with an acid- scavenger and drying agent such as bis-trimethylsilylacetamide followed by treatment with trimethylsilyl bromide to yield an intermediate silyl ester having the formula EMI23.1 An intermediate of formula XIX can be treated with an organic or inorganic base in the presence of water or an alcohol to yield a salt of a compound having the formula EMI23.2 The tetraalkylammonium salt of a compound of formula XX can be treated with an alkyl halide. (substituted alkyl)halide, l-(ethoxycarbonyloxy)ethyl halide, 1,3-dihydro-3-oxo-1-isobenzofuranyl EMI23.3 EMI23.4 to obtain an ester having the formula EMI23.5 wherein R11 is alkyl, substituted alkyl. 1-(ethoxycarbonyloxy)ethyl. 1.3-dihydro-3-oxo-r- isobenzofuranyl, EMI24.1 EMI24.2 When R10 is methoxy or ethoxy i.e.. a compound of formula XVIII. this process results in transesterification. yielding the tetraalkylammonium salt of a compound having the formula EMI24.3 A compound of formula XXII can be converted to the corresponding compound of formula XXI wherein R10 is methoxy or ethoxy by treating the tetraalkylammonium salt of the compound of formula XXII with methyl or ethyl sulfate. Alternatively. the tetraalkylammonium salt of the compound of formula XXII can be converted to the corresponding acid on ion-exchange resin and then treated with diazomethane or diazoethane to yield the desired compond of formula XXII wherein R10 is methoxy or ethoxy. The products of formula I wherein R2 is methoxy can be prepared from the corresponding compound of formula VII. Halogenating (preferably chlorinating) the amide nitrogen of a compound of formula VII yields a compound having the formula EMI25.1 Reagents and procedures of N-chlorinating amides are known in the art. Exemplary reagents are tert.-butyl hypochlorite. sodium hypochlorite, and chlorine. The reaction can be run in an organic solvent (e.a.. a lower alkanoyl such as methanol) or in a two phase solvent system (e,s,, 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 XXIII with a methoxylating agent. e.a., an alkali metal methoxide. yields a compound (in combination with its enantiomer if R3 and R4 are the same or if XXIII is a racemic mixture) having the formula EMI25.2 The reaction can be run in an organic solvent, e.g.. a polar organic solvent such as tetrahydrofuran. at a reduced temperature. Alternatively, a compound of formula VII can be converted to a compound of formula XXIV using a single step procedure. The methoxylating agent can first be mixed with a compound of formula VII and - the N-chlorinating reagent then added to the reaction mixture. Conversion of a compound of formula XXIV 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 following examples are specific embodiments of this invention. Example 1 [3S-[3&alpha;(Z), 4ss]]-[[[3-[[(2-Amino-4-thiazolyl) (methoxyimino)acetyl)amino]-4-methyl-2-oxo-1 azetidinyl)oxy)methyl)phosphonic acid a potassium salt A) N-[(Diethoxyphosphinyl)methoxy]-Nê-[(1,1 dimethvlethoxy)carbonyl-l-threoninamide To a solution of N-t-butoxycarbonylamino-Lthreonine (3.20 g, 14.6 inmol) in dimethylformamide (35 ml) was added N-hydroxybenzotriazole (1.97 g. 14.6 mmol). The resulting solution was cooled to OOC, and dicyclohexylcarbodiimide (3.30 g, 16 mmolj was added. The ice bath was removed and the solution was stirred for thirty minutes at room temperature. After re-cooling the solution to OOC. diethyl aminooxymethyl phosphonate (2.67 g. 14.6 mmol) in dimethylformamide (25 ml) was added. The solution was then stirred at room temperature for 16 hours After removal of dimethylformamide at reduced pressure. the crude product (10.6 g) was purified by two successive chromatographies on silica gel (40% acetone/methylene chloride. and 33% acetone/methylene chloride) to afford 1.76 g of the title compound. B) (3S-trans)-[[[3-[[(1.1-Dimethylethoxy)carbonyl] amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methyl] phosphonic acid, diethyl ester N-[(Diethoxyphosphinyl)methoxy]-Nê-[(1.1dimethylethoxy)carbonyl]-l-thrsoninamide (1.38 g, 3.62 =sol) and triphenylphosphine (0.97 g, 3.7 mmol) were placed in a round-bottomed flask. which was dried in vacuo for thirty minutes at room temperature. Argon was introduced into the flask. followed by dry tetrahydrofuran (30 ml). The solution was cooled to 0 C and diethyfazodi- carboxylate (585 pl, 3.7 mmol) was added dropwise. The cooling bath was removed and the solution stirred at room temperature for 16 hours. Tetrahydrofuran was evaporated at reduced pressure, and the residue triturated with cold ether (30 ml. -10 C) to precipitate triphenylphosphine oxide. Filtration and evaporation at reduced pressure afforded the crude product (1.96 g) which was purified by chromatography on silica gel, eluting with 20% acetone/methylene chloride. The product obtained in this manner is conveniently separated from the 4-hydroxy-4-methyl-2-pentanone (aldol product) by crystallization from ether:pentane(1.l). The first crop of crystals thus obtained gave 0.61 g of the title compound. melting point 76-800C, Recrystallization from etherf pentane afforded the product. melting point 85-880C. C) [3S-(3&alpha;(Z), 4ss]]-[[[3-[[(2-Amino-4-thiazolyl) (methoxyimino)acetyl)amino)-4-methyi-2-oxo-l- azetidinyl)oxy)methyl)phosphonic acid, diethyl ester (3S-trans)-[[[3-[[(1.1-Dimethylethoxy)carbonyl] amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methyl] phosphonic acid, diethyl ester (0.85 g. 2.32 mmol) was weighed into a round-bottomed flask under argon. and cooled to -10 C. A solution of 10% anisole in trifluoroacetic acid at -10 C was added. and the resulting solution was stirred at that temperature for thirty minutes. Evaporation of the volatiles at room temperature with a vacuum pump afforded the crude trifluoroacetic acid salt of the deprotected azetidone starting material which was used directly in the next step. The activated ester of (Z)-2-amino-- (methoxyimino)-4-thiazoleacetic acid was prepared by dissolving the acid (0.47 g. 2.32 mmol) and hydroxy benzotriazole (0.31 g. 2.32 mmol) in dimethylformamide (8 ml). This solution was cooled to OOC, and dicyclohexylcarbodiimide (0.48g. 2.3 mmol) was added. The solution was stirred at room temperature for thirty minutes. and then cooled to OOC. To this solution of activated ester was added the trifluoroacetic acid salt prepared above, as a solution in dimethylformamide (2.5 ml). followed by two rinses of 2.5 ml and 1.0 ml of dimethylformamide. To this solution was added triethylamine (1.0 ml. 7.2 mmol). The pH was found to be ca. 9. and the ice bath was removed. After stirring for 16 hours at room temperature, dimethylformamide was evaporated in vacuo. The residue was treated with 5 ml of acetone. and solid potassium bicarbonate was added to adjust the pH to 6 on moist litmus paper. After filtering the solution to remove inorganic salts and hydroxybenzotriazole salt, the acetone solution was chromatographed on a reverse-phase HP-20 column (25mm x 15") using 50% acetone/water to elute 0.47 g of the title compound. melting point 74-780C. D) [3S-[3&alpha;(Z),4ss]]-[[[3-[[(2-Amino-4-thiazolyl] (methoxyimino)acetyl]amino]-4-methyl-2-oxo-1 azetidinyl3oxy3methyl3phosphonic acid. potassium salt [3S-3&alpha;(Z),4ss]]-[[[3-[[(2-Amino-4-thiazolyl) (methoxyimino)acetyl]amino]-4-methyl-2-oxo-1 azetidinyl)oxy3methyl Iphosphonic acid, diethyl ester (0.10 g. 0.22 mmol) was dissolved in dry methylene chloride (2.0 ml) under argon and cooled to OOC. To this solution was added bis(trimethylsilyl)acetamide (0.20 m. 1.12 mmol) and the solution was stirred for thirty minutes at OOC. Trimethylsilylbromide (0.20 ml. 1.5 mmol) was added. and the cooling bath removed. Thin layer chromatography (silica. 50% acetone/methylene chloride) showed no remaining starting material after 2.5 hours. and the volatiles were evaporated in wacuo, followed by azeotropic removal of residual trimethylsilyl bromide (two times with 2 ml of toluene) at low pressure. To the residue thus obtained was added pH 4.0 buffer (10 ml). followed by methylene chloride (10 ml). The mixture was stirred vigorously for fifteen minutes. and the aqueous layer separated. washed with methylene chloride (15 ml) and lyophilized to afford the crude product (0.11 g) which consisted predominantly of one spot by thin layer chromatography (Rf=0.05, 3:1:1 n-butanol: water:acetic acid). Chromatography on HP-20 (25mm x 12") using water as the eluting solvent afforded the title compound. melting point 220-2250C. dec. Example 2 [3S-[3&alpha;(Z),4ss]]-[[[3-[[(2-amino-4-thiazolyl)- (methoxyimino)acetyl]amino]-4-methyl-2-oxo-1azetidinyl]oxy]methyl]phosphonic acid. methyl ester, Potasstua salt A) [3S-trams)[[[3-[[(1,1-Dimethylethoxy)carbonyl] amino]-q-methyl-2-oxo-1-azetidinyl]oxy]methyl] Phosphoric acid. dimethyl ester [3S-trans)-[[[3-[[(1,1-Dimethylethoxy)carbonyl] amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methyl] phosphonic acid. diethyl ester (250 mg. 0.68 mmol) was dissolved in dry methylene chloride (5 ml) and cooled to 0 C under an argon atmosphere. Bis trimethylsilylacetamide (0.5 ml) was added. After stirring for 15 minutes. trimethylsilyl bromide (0.5 ml) was added to the solution. the ice bath removed. and the reaction mixture allowed to warm to room temperature over two hours. The volatiles were removed in vacuo, followed by azeotropic removal with toluene (two times with ml). The crude phosphonate bis-trimethylsilyl ester thus prepared was dissolved in dry ether (15 ml). and added to a stirring olution of diazomethane in ether/methanol (ca. 3 miol. ether/methanol/20 ml/ 10 ml) at -10 C. After stirring for fifteen minutes. three drops of acetic acid were added. which failed to further discharge the pale yellow color of the reaction mixture. The solvent was then removed at reduced pressure. affording 0.40 g of the crude title compound. The crude dimethyl phosphonate was purified by chromatography on silica gel (25 mm x 8"), eluting with 4% methanol/ethyl acetate, yielding 170 mg of the title compound of sufficient purity to be used in the next step. B) (3S-trans)-[[[3-[[(1,1-dimethylethoxy)carbonyl] amino]-4-methjyl-2-oxo-1-azetidinyl]oxy]methyl] Phosphonic acid, methvl ester. potassium salt (3S-trans)-[[[3-[[(1,1-dimethylethoxy)carbonyl] amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methyl] phosphonic acid. dimethyl ester (170 mg. 0.50 mmol) was dissolved in deuterated acetonitrile (2.5 ml). and thiourea (45 mg. 0.59 mmol) was added. The mixture was heated in a sealed tube overnight at 800C. Chromatography on Dowex K (200-400 mesh, 25 mm x 6"), using water as the eluant, followed by lyophilization of the appropriate fractions afforded the title compound (70 mg). C) [3S-[3&alpha;(Z),4ss]]=[[[3-[[(2-amino-4-thiazolyl)- (methoxyimino)acetyl]amino]-4-methyl-2-oxo-1 azetidinyl)oxyjmethyliphosphonic acid, methyl ester. potassium salt (3S-trans)-[[[3-[[(1,1-dimethylethoxy)carbonyl] amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methyl] phosphonic acid, methyl ester. potassium salt (70 mg, 0.19 mmol) was dissolved in'a solution of 10% anisole in trifluoroacetic acid (2 ml) at -10 C. The solution was stirred for thirty minutes and the volatiles removed at room temperature on a vacuum pump for three hours. to give the crude trifluoroacetic acid salt of the starting azetidinone. Activated (Z)-2-amino--(methoxyimino) 4-thiasoleacetic acid was prepared by dissolving the acid (40 mg. 0.20 mmol) and hydroxybenzotriazole (27 mg. 0.20 mmol) in dimethylformamide (1 ml). After cooling the solution to -10 C. dicyclohexylcarbodiimide (45 mg, 0.22 mmol) was added and the ice bath removed. Stirring was continued for 90 minutes. after which the solution was recooled to -100C. and the crude trifluoroacetic acid salt prepared above. was added in dimethylformamide (1 ml). followed by two rinses of dimethylformamide (1 ml. 0.5 ml). To this solution was added triethylamine (120 1, 0.86 mmol). The solution was found to be basic by pH paper. the cooling bath was removed and the solution stirred overnight at room temperature. Dimethylformamide was removed from the reaction mixture in vacuo, and the resulting product treated with water (1.5 ml) to afford a slurry of pH 4. Potassium bicarbonate was added to adjust the pH to 8.5. and the material was chromatographed on Dowex K+ resin (200-400 mesh. 25 mi x 6"). Lyophilization of the fractions containing W active material afforded 0.70 g of product. This material was further purified by chromatography on HP-20 resin (25 mm x 8"). Lyophilization of the appropriate fractions afforded 30 mg of the title compound. Analysis of the spectral data for this material indicated contamination of the product by hydroxybenzo- triazole and dicyclohexylurea. The product browned at 164 C and decomposed at 210 C. ExamPle 3 [3S-[3&alpha;(Z),4ss]]-[[[3-[[(2-Amino-4-thiazolyl) (methoxyimino)acetyl)amino]-4-methyl-2-oxo-1azetidinyl]oxy]methyl]methylphosphinic acid. potassium salt A) [Hydroxymethylamethylphosphinic acid, ethyl ester Ethyl methylphosphinate (9.41 g, .087 mole) was heated to 850C under nitrogen. Dried paraformaldehyde (2.61 g, .078 mole) was added. and the reaction mixture was heated at 85-950C for- 5 minutes and then at 780C for 2 hours. The product was distilled at 1280C/0.9mm to yield 7.92 g of the title compound. B) [[[(Trifluoromethyl)sulfonyl)sulfonyl]oxy]methyl]methyl ahosPhinic acid. ethyl ester A solution of dichloromethane (2 ml). pyridine (0.23 ml. 2.65 mmole). and (hydroxymethyl) methylphosphinic acid, ethyl ester (0.37 g, 2.65 mmole) was added dropwise to triluoformethanesulfonic anhydride (2.65 mmole. 0.45 ml) in 2 ml of dry dichloromethane at -10 C under nitrogen. The reaction was stirred for 20 minutes at -100C, diluted with 20 ml of dichloromethane and washed twice with 5 ml portions of water. The organic layer was dried (sodium sulfate) and concentrated in vacuo to yield 0.16 g of the title compound. C) [3S-[3&alpha; ,4ss]]-3-[(1,1-Dimethylethoxycarbonyl] amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methyl] methylphosphinic acid, ethyl ester A solution of [3S-(3&alpha;, 4ss]]-3-[(2,2dimethylethoxycarbonyl0amino]-4-methyl-2-oxo-1hydroxyazetidine (0.155 g, 0.62 mmole) and triethylamine (0.11 ml, 0.77 mmole) in dimethylformamide (1 ml) was added to [[[(trifluoromethyl0sulfonyl]oxy]methylphosphinic acid, ethyl ester (0.21 g. .77 mmole) at -10 C under nitrogen. The reaction was stirred at 00C for 1 hour and then concentrated in vacuo. The residue was dissolved in dry dichloromethane and washed successively with pH 5.5 0.5M KH2PO4. pH 3.0 KH2PO4 buffer. and water. It was then dried (sodium sulfate) and concentrated in vacuo to yield 0.175 g of crystalline product. melting point 84-890C. D) [3S-[3&alpha; ,4ss]]-3-[(1,1-Dimethylethoxycarbonyl] amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methyl] methylphosphinic acid, potassium salt [3S-[3&alpha; ,4ss]]-3-[(1,1-Dimethylethoxycarbonyl]amino]-4-methyl-2-oxo-1-azetidinyl] oxyjmethyl3methylphosphinic acid. ethyl ester (0.175 g. 0.52 mmole) was dissolved in 1.5 ml of dry dichloromethane and cooled to -10 C under nitrogen. Bistrimethylsilylacetamide (BSA, 1.25 ml. 3.9 mmole) was added, and the reaction was stirred for 30 minutes at 0 C. Trimethylsilylbromide (TMSBr, O.17 ml, 1.3 mmole) was added. and the reaction was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was evaporated twice from toluene. The residue was dissolved in 2 ml of tetrahydrofuran and 2 ml of 0.5M KH2PO4 (pH 5.5) buffer and stirred at room temperature for 1 hour at pH 5. The tetrahydrofuran was removed in vacuo and the crude aqueous solution was washed with dichloromethane. The dichloromethane solution was concentrated in vacuo to yield 77 mg of azetidinyl phosphinate starting material, and the aqueous layer was chromatographed on 60 ml of HP-20 with water and then with 10% acetone-water. The appropriate fractions were combined and lyophilized to yield 52 mg of the title compound as a solid. E) [3S-[3&alpha; ,4ss]]-3-Amino-4-methyl-2-oxo-1 azetidinyl]oxy]methyl]methylphosphinic acid. trifluoroacetic acid salt [3S-[3&alpha; ,4ss]]-3-[(1,1-Dimethylethoxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl] oxy)methyl)methylphosphinic acid. potassium salt (50 mg. 0.15 mmole) was suspended in 0.5 ml of dichloromethane and 0,5 ml of anisole at 0 C under nitrogen, Trifluoroacetic acid (1.0 ml) was added, and the reaction was stirred at 0 C for 2 hours. The solution was concentrated in vacuo to a residue. which was evaporated twice from toluene to give a viscous oil This was triturated with ether to give a white solid. The NMR spectrum of this solid in D2 0 was consistent with that expected fpr the product. The D20 solution was concentrated in vacuo to dryness and used in thefollowing step. F) [3S-[3&alpha;(Z),4ss]]-[[[3-[[(2-Amino-4-thiazolyl) methoxyimino)acetyl]amino]-4-methyl-2-oxo-1 azetidinyl]oxy]methyl]methylphosphinic acid. potassium salt. (Z)-2-Amino-&alpha;-(methoxyimino)-4-thiazoleacetic acid (30.9 mg, 0.15 mmole) and l-hydroxybenzo- triazole (23.2 mg. 0.15 mmole) were dissolved in 1 ml of dimethylformamide at 0 C under nitrogen. N.N'-Dicyclohexylcarbodiimide (DCC, 31.2 mg, 0.15 mmole) was added. and the reaction was stirred at 0 C for 2 hours. [3S-(3&alpha;, 4ss)]-3-Amino-4-methyl2-oxo-1-azetidinyl]oxy]methyl]methylphosphinic acid. trifluoroacetic acid salt was dissolved in 3 ml of pH 5.5 0.5M KH2PO4 buffer. and the pH was adjusted to 5.5 with 1M potassium hydroxide. This was added to the activated ester. and the reaction was stirred at ambient temperature overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was washed with dichloromethane, dissolved in water. and passed through 10 ml of Dowex 50K resin (0.7 m eq/ml). Fractions (4ml) were collected, and the appropriate fractions were combined and lyophilized to a residue. which was chromatographed through 30 ml of HP-20 using water to elute the product. After lyophilization. 21 mg of desired product was obtained. melting point 192-202 C. dec. Example 4 [2S-[2&alpha;,3ss(Z)]]-[[[3-[[(2-Amino-4-thiazolyl) (methoxyimino)acetyl]amino]-2-methyl-4-oxo-1-azetidinyl]oxy- methyl] phosphonic acid, 2-amino-2-oxoethyl ester, monopotassium salt A) [ (Hydroxy)methyl]phosphonic acid, dimethyl ester Dimethyl phosphite (12.02 g, .11 mole) and triethylamine (1.0 g, .01 mole) were heated to 400C under N2. Paraformaldehyde (3.28 g, .11 mole) was added portionwise and the reaction mixture was heated up to 550C. Immediate reaction occurred, and a clear solution was formed. After reaction subsided, heating was continued at 550C for 15 minutes. The crude reaction mixture was used as is in step B. B) [[[(Trifluoromethyl)sulfonyl]oxy]methyl]phosphonic acid, dimethyl ester l(Hydroxy)methyl]phosphonic acid, dimethyl ester (2.10 g, 15 mmole) was dissolved in 3 ml of dry CH2C12 and cooled to -600C. Triethylamine (1.52 g, 15 ininole) was added followed by the slow dropwise addition of trifluoromethanesulfonic anhydride (4.23 g, 15 mmole). The reaction was stirred until the temperature reached -250C., CH2C12 (10 ml) was added, and the reaction mixture was washed with two 5 ml portions of cold water. The dichloromethane solution was dried with Na2S04, and concentrated in vacuo to yield 3.0 g (83%) of the triflate ester. C) [2S-[2&alpha;,3ss)]-[[(1,1-dimethylethoxy)carbonyl]- amino]-2-methyl-4-oxo-1-azetidinyl]-oxy]-methyl phosphonic acid, dimethyl ester The above triflate (2.2 g, 8.1 rurnole) was added dropwise to a solution of 12S-(2a,38)-3-If(l,l-dimethyl- ethoxy)carbonyl]amino]-2-methyl-4-oxo-1-hydroxyazetidine (1.77 g, 8.2 mmole) and triethylamine (1.28 ml, 8.1 mmole) in 5 ml DMF at -10 C. The reaction was stirred under N2 at -100C for 4 hrs. and then concentrated in vacuo. The residue was dissolved in dry dichloromethane (150 ml) and washed successively with pH 5.5 0.5 M KH2PO4, Ph 3.0 KH2PO4, and water. It was then dried (Na2S04) and concentrated in vacuo to a volume of 4 ml. This was placed on 50 ml of SilicAR CC-7 and then filtered through with 400 ml CH2Cl2. The filtrate was concentrated to yield 1.59 g (57%) of crystalline product having M.P. 51-55 C. D) [2S-[2&alpha;,3ss)]-[[[3-[[(1,1-Dimethylethoxy)carbonyl]- amino] -2-methyl-4-oxo-l-azetidinyl 1 oxy] -methyl]- phosphonic acid, monomethyl ester, monopotassium salt The above azetidinyl phosphonate (1.08 g, 3.2 imnole) and thiourea (0.24 g, 3.2 mmole) were refluxed in 2 ml of dry acetonitrile under N2 overnight. The solution was cooled, and the crude thiuronium salt of the product oiled out. The supernatant was decanted, and the residue was dissolved in water and passed through 70 ml of Dowex 50 in K+ form (0.7 meq/ml). The product was chromatographed on 100 ml of HP-20 with water and then with 10t acetone-water. The appropriate fractions were combined and lyophilized to yield 0.53 g (48%) of product as the potassium salt. E) [2S-[2&alpha;,3ss)]-[[[3-[[(1,1-Dimethylethoxy) carbonyl]amino]-2-methyl-4-oxo-l azetidinyl]oxy]methyllphosphonic acid, 2,-amino-2-oxoethyl ester, monopotassium salt The above monomethyl ester, potassium salt (0.5 g, 1.4 mmole) was ion-paired with tetrabutylammonium sulfate (0.14 ml of 0.1 M in pH 5.5 buffer). Product was extracted with six 50 ml portions of CH2C12, dried and concentrated in vacuo to yield 0.85 g of tetrabutylammonium salt. This was dissolved in 4 my of 1,1, l-trichloroethane. Iodoacetamide (0.57 g, 3.1 mmole) was added, and the reaction mixture was refluxed under nitrogen for 6 hrs. Volatiles were evaporated in vacuo, and the residue was passed through 50 ml of Dowex 50 2X400 .7 meq/ml in the K form. The eluent was lyophilized and chromatographed on 70 ml of HP-20 with water and then 5% acetone-water to yield upon lyophilization 0.10 g (16%) of desired product. F) [2S-[2&alpha;,3ss)]-[[[3-Amino-2-methyl-4-oxo-1- azetidinyl)oxy3methyl]phosphonic acid, mono (2-amino-2-oxoethyl)ester, trifluoroacetic acid salt The above azetidinyl phosphonic acid, potassium salt (82 mg, .20 mmole) was suspended in 0.2 ml of CH2C12 and 0.2 ml of anisole at -100C under N2. Trifluoroacetic acid (0.4 ml) was added, and the reaction was stirred at 0 C for 1.5 hrs. The solution was concentrated in vacua to a residue, which was evaporated from benzene (2X) to give a viscous oil. This was triturated with ether to give crude desired product as a white solid. G. [2S-[2&alpha;,3ss(Z)]-[[[3-[[(2-Amino-4-thia- zolyl)(methoxyimino)acetyl3amino]-2- methyl-4-oxo-1-azetidinyl]oxy]methyl] phosphonic acid, 2-amino-2-oxoethyl ester, monopotassium salt (Z)-(2-Amino-4-thiazolyl)methoxyimino)acetic acid (40.8 mg, .20 mmole) and l-hydroxybenzotriazole (31.1 mg, 0.20 mmole) were dissolved in 0.4 ml of DMF at 0 C under N2. N,NÚ-Dicyclohexsylcarbodiimide (DCC, 41.9 mg, 0.29 mmole) was added, and the reaction was stirred at 0 C for 2 hrs. The above crude TFA salt was dissolved in 2 ml of pH 5.5 0.5 M KH2PO4 buffer, and the pH was adjusted to 6.0 with 1 N KOH. This was added to the activated ester, and the reaction was stirred at ambient temperature overnight. The react-ion mixture was filtered and concentrated in vacuo. The residue was dissolved in water and passed through 80 ml of Dowex 50K resin (0.7 meq/ml). Five ml fractions were collected, and the appropriate fractions were combined and lyophilized to a residue, which was chromatographed through 80 ml of HP-20 using water to elute the product. After lyophilization, 19 mg (19%) of desired product was obtained having m.p. 165-175 dec. Anal. Calc'd. for C13H18N608SPK-2. 9H20 C,28.87; H,4.44; N,15.54; S,5.90; P,5.70 Found: C,29.27; H,3.79; N,14.13; S,5.60 P,5.30 Example 5 [2S-(2&alpha;,3ss)]-1-([[3-Amino-2-methyl-4-oxo-1- azetidinyl]oxy]ethyl]phosphonic acid, monomethyl ester, trifluoroacetic acid salt A. ll-Hydroxyethyl]phosphonic acid, dimethyl ester Dimethyl phosphite (2.34 g, 0.021 mole) acetaldehyde (0.89 g, .020 mole) and potassium fluoride (1.90 g, .020 mole) was stirred at 0 C for 2 hrs. under N2. The reaction mixture was then diluted with 50 ml of CH2C12 and filtered to remove potassium fluoride, The filtrate was concentrated in vacuo to yield 3.02 g (98%) of product. B. C1-CI(TrifluoromethyI)sulfonyl]oxy]ethyl phosphonic acid, dimethyl ester fl-Hydroxyethyljphosphonic acid, dimethyl ester (2.11 g, 13,7 mmole) was dissolved in 3 ml of dry CH2C12 and cooled to -40 C under N2. Triethylamine (1.39 g, 13.7 mmole) was added, followed by the slow dropwise addition of trifluoromethanesulfonic anhydride (3.87 g, 13.7 mmole). Stirring was continued until the reaction temperature reached -25 C. Dichloromethane (20 ml) was added and washed with two 4 ml portions of water. The CH2C12 solution was dried (Na2SO4) and concentrated in vacuo to yield 3.62 g (92%) of desired triflate. C. [2S-(2&alpha;,3ss)]-1-[[[3-[(1,1-Dimethylethoxy- carbonyl0amino]-2-methyl-4-oxo-1-azetidinyl] oxy]ethyl]phosphonic acid, dimethyl ester The above triflate ester (2.68 g, 94 mmole) was added dropwise in two portions (30 minutes apart) at -10 C under N2, to a 4 ml DMF solution of 12S-(2a,3ss)]- 3-[1,1-dimethylethoxycarbonyl)amino]-2-methyl-4-oXo 1-hydroxyazetidine (1.35 g, 6.3 mmole) (see SQ 28,085) and triethylamine (1.3 ml, 9.5 mmole). The solution was stirred at ambient temperature for 1 hr. then concentrated in vacuo. The residue was dissolved in dry CH2C12 and washed successively with pH 2.8 0.5 M RH2P04, pH 5.5 KH2P04 buffer and water. The CH2C12 was dried tNa2SO4) and concentrated in vacuo to yield 2.4 g (theory) of product as a light yellow oil. D. [2S-(2&alpha;,3ss)]-[[[3-[(1,1-Dimethylethoxy- carbonyl)amino]-2-methyl-4-oxo-1-azetidinyl] oxy]ethyl]phosphonic acid, monomethyl ester, monopotassium salt The above azetidinyl phosphonate (1.35 g, 3.8 mmole) and thiourea (0.58 g, 7.7 mmole) were dissolved in 1 ml dry acetonitrile and refluxed under N2 for 6 hrs. The reaction mixture was cooled and diluted with 2 ml of ether. The thiuronium salt of the product oiled out and was dissolved in 2 ml of water. This solution was passed through 100 ml of Dowex 50 resin (0.7 meq/ml). Twenty ml fractions were collected, and the appropriate ones were combined and lyophilized to a residue, which was chromatographed through 100 ml of HP-20 using water. After lyophilization of the appropriate fractions, 0.89 g (68%) of desired product was obtained. E. [2S-(2&alpha;,3ss)]-1-[[[3-Amino-2-methyl-4-oxo-1- azetidinyl]oxylethylIphosphonic acid, mono methyl ester, trifluoroacetic acid salt The above azetidinyl phosphonic acid, monomethyl ester, potassium salt (0.34 g, 0.9 mmole) was suspended in 3 ml of CH2C12 and 3 ml of anisole at -100C under N2. Trifluoroacetic acid (6 ml) was added, and the reaction was stirred at 0 C for 2 hrs. The solution was concentrated in vacuo to a residue, which was evaporated from benzene. This was triturated with ether and dried in vacuo to give a white solid. F. [2S-12a,3ss(Z)]]-[l-[t-3-[[(2-Amino-4- thiazolyl)methoxyimino)acetyl]amino]-2 methyl-4-oxo-1-azetidinylAoxy]ethyl]- phosphonic acid, monomethyl ester, mono potassium salt (Z)-(2-Amino-4-thiazolyl)methoxyimino)acetic acid (183 mg, 0.92 mmole) and l-hydroxybenzotriazole (139 mg, 0.92 mmole) were dissolved in 1.2 ml of DMF at 0 C (under N2). N,N1-Dicyclohexylcarbodiimide (DCC, 188 mg, 0.92 mmole) was added, and the reaction was stirrediat 0 C for 2 hrs. The above crude TFA salt was dissolved in 4 ml of pH 5.5 0.5 M KH2PO4 buffer. This was added to the activated ester, and the pH was adjusted to 4.6 with 1 M KOH. The reaction was stirred at ambient temperature overnight, filtered and concentrated in vacuo. Hydroxybenzotriazole precipitated out of the reaction mixture upon addition of ice water (5 ml pH 4.3) and was filtered The filtrate was chromatographed through 150 ml of HP-20. Product was eluted with 5% acetone in water to yield 117 mg of desired material in the acid form after lyophilization. This was redissolved in 2 ml 0.5 M KH2PO4 buffer, and the pH was adjusted to 4.9 with 1 N KOH. This was rechromatographed through 80 ml of HP-20. The potassium salt eluted with water and was lyophilized to yield 91 mg (30%) of desired material having a m.p. 182-2004C. Calc'd. for C13H19N5O7PSK.1.77H2O: C,31.78, H,4.62; N,14.25; S,6.53; P.6.30 Found: C,31.78; H,4.34; N,14.12; S,6.61; P,6.2 Example 6 [3S-[3&alpha;[Z),4ss]]-[[3-[[(2-amino-4-thiazolyl)[(1- diphenylmethoxycarbonyl-1-methylthoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methyl]phosphonic acid, diethyl ester By substituting (Z)-2-amino-&alpha;-[(1-diphenyl- methoxycarbonyl-1-methylethoxy)imino]-4-thiazoleacetic acid for the (Z)-2-amino-&alpha;-(methoxyimino)-4- thiazoleacetic acid used in example (cf), the above titled compound is obtained.

Claims: What is claimed is: 1. A compound having the formula EMI47.1 or a pharmaceutically acceptable salt thereof. wherein R1 is acyl; R2 is hydrogen or methoxy: R3 and R4 are the same or different and each is hydrogen, alkyl. alkenyl. alkynyl. cycloalkyl, phenyl, substituted phenyl or a 4,5,6 or 7-membered heterocycle or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl. alkenyl. alkynyl. 2-phenylethenyl, 2-phenylethynyl. carboxyl. -CH2X1. -S-X2. -O-X2, EMI47.2 wherein X1 is azido, amino. hydroxy, alkanoylamino, phenylcarbonylamino, (substituted phenyl) carbonyl- amino. alkylsulfonyloxy, phenylsulfonyloxy. (substituted phenyl0sulfonyloxy. phenyl. substituted phenyl, cyano, EMI47.3 or -O-X2: X@ is alkyl. substituted alkyl, phenyl. substituted phenyl, phenylalkyl. (substituted phenyl)alkyl. alkanoyl. phenylalkanoyl, (substitued phenyl) 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 formed. alkanoyl. phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl. carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; A is -CH-CH-. -(cH2)n-, -CH2-O-. or -CH@-S-CH@-: n is O. 1 or 2: and X6 and t7 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl, or X6 is hydrogen and X7 is amino. substituted amino. acylamino or alkoxy. or X6 and Z7 when taken together with the nitrogen atom to which they are attached form a 4, 5, 6 or 7-membered heterocycle; 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. alkenyl, alkynyl, 2-phenylethenyl. 2-phenylethynyl, carboxyl. -CH2Xl, -S-X2. EMI48.1 R7 is hydrogen. alkyl. substituted alkyl, phenyl, substituted phenyl. l-(ethoxycarbonyl oxy)ethyl, 1,3-dihydro-3-oxo-l-isobenzofuranyl, EMI49.1 wherein R' is hydrogen or alkyl, R" is alkyl or phenyl. R"' is hydrogen, methyl or phenyl, and RiV is hydrogen or together with Rt" is -(CH2)3- or -(CH2)5-; and R8 is hydroxy. alkoxy. (substituted alkyl)oxy, phenyloxy, (substituted phenyl)oxy. alkyl. substituted alkyl. phenyl, substituted phenyl, heteroaryl. amino. substituted amino. alkylthio. (substituted alkyl)thio. phenylthio. (substituted phenyl)thio, or EMI49.2 2. A compound in accordance with claim 1 wherein R2 is hydrogen. 3. A compound in accordance with claim 1 wherein R3 and R4 are the same or different and each is hydrogen or alkyl. 4. A compound in accordance with claim 2 wherein R3 and R4 are the same or different and each is hydrogen or alkyl. 5. A compound in accordance with claim 1 wherein R5 and R6 are the same or different and each is hydrogen or alkyl. 6. A compound in accordance with claim 2 wherein R5 and R6 are the same or different and each is hydrogen or alkyl. 7. A compound in accordance with claim 1 wherein R7 is hydrogen or alkyl and R8 is hydroxy or alkoxy. 8. A compound in accordance with claim 2 wherein R7 is hydrogen or alkyl and R 8 is hydroxy or alkoxy 9. A compound in accordance with claim 1 wherein R2 is hydrogen: R3 and R4 are the same or different and each is hydrogen or alkyl: R5 and R6 are the same or different and each is hydrogen or alkyl: R7 is hydrogen or alkyl; and R8 is hydroxy or alkoxy. 10. A compound in accordance with claim 1. [3S-[3&alpha;(Z),4ss]]-[[[3-[[(2-amino-4-thiazolyl) (metylxyimino)acetyl]amino]-4-methyl-2oxo-1-azetidinyl]oxy]methyl]phosphonic acid. or a salt thereof. 11. A compound in accordance with claim 1, [3S-[3&alpha;(Z),4ss]]-[[[3-[[(2-Amino-4-thiazolyl) (metylxyimino)acetyl]amino]-4-methyl-2oxo-1-azetidinyl]oxy]methyl]phosphonci acid. methyl ester. or a salt thereof. 12. A compound in accordance with claim I. [3S-[3&alpha;(Z),4ss]]-[[[3-[[(2-Amino-4-thiazolyl) (metylxyimino)acetyl]amino]-4-methyl-2oxo-1-azetidinyl]oxy]methyl]phosphonic acid, diethyl ester or a salt thereof. 13. A compound in accordance with claim 1. [3S-[3&alpha;(Z),4ss]]-[[[3-[[(2-Amino-4-thiazolyl) (metylxyimino)acetyl]amino]-4-methyl-2-oxo-1 azetidinylloxylmethyllmethylphosphinic acid. or a salt thereof. 14. A compound having the formula EMI51.1 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. alkenyl, alkynyl. 2-phenylethenyl. 2-phenylethynyl. carboxyl, CH2 18 a SX2a -O-X2. EMI51.2 wherein X1 is azido. amino. hydroxy, alkanoylamino, phenylcarbonylamino. (substituted phenyl)carbonylamino. alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy. phenyl, substituted phenyl, cyano. EMI51.3 or -O-X2: X2 is alkyl, substituted alkyl. phenyl. substituted phenyl. phenylalkyl. (substituted phenyl)alkyl. alkanoyl. phenylalkanoyl, (substitued phenyl)- 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)carbonyi. phenylalkylcarbonyl. (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl. (substituted auino)carbonyl, or cyano: A is -CH-CH-, -(CH2)n-. -CH2 -O-. -CH2-NH- or -CH2-S-CH2-; n is 0. 1 or 2; and X6 and X7 are the same or different and each is hydrogen. alkyl. phenyl or substituted phenyl, or X6 is hydrogen and X7 is amino, substituted amino, acylamino or alkoxy. or X6 and X7 when taken together with the nitrogen atom to which they are attached form a 4. 5. 6 or 7-membered heterocycle; 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, alkenyl. alkynyl. 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2X1. -S-X2, EMI52.1 R7 is hydrogen, alkyl. substituted alkyl. phenyl. substituted phenyl. l-(ethoxycarbonyloxy)ethyl. 1.3-dihydro-3-oxo-l-isobenzofuranyl. EMI52.2 wherein R' is hydrogen or alkyl, RZ is alkyl or phenyl. R"' is hydrogen. methyl or phenyl. and Riv is hydrogen or together with R"' is or -(CH2)5-: and R8 is hydroxy. alkoxy, (substituted alkyl)oxy, phenyloxy, (substituted phenyl)oxy. alkyl. substituted alkyl. phenyl, substituted phenyl, heteroaryl. amino. substituted amino, alkylthio. (substituted alkyl)thio. phenylthio, (substituted phenyl)thio. EMI53.1

Inventors: BREUER, HERMANN, KOSTER, WILLIAM H.
Applicants: E.R. SQUIBB & SONS, INC.
Application year: 1984
Main classification: C07F9
IPC codes: C07F9, C07D205