NZ205642A

NZ205642A - Beta-lactams and pharmaceutical compositions

Info

Publication number: NZ205642A
Application number: NZ205642A
Authority: NZ
Inventors: W A Slusarchyk; D R Kronenthal
Original assignee: Squibb & Sons Inc
Priority date: 1982-10-06
Filing date: 1983-09-19
Publication date: 1986-08-08
Also published as: ZA837491B; NL8303410A; DK457983D0; CA1253501A; AU1993983A; SE8305509D0; KR900005132B1; ES8504814A1; LU85033A1; IT8323172A0; SE8305509L; GB8326626D0; DD222016A5; DK457983A; ES526282A0; FI833631A0; FI833631A; NO833626L; JPS5988462A; CH658858A5

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £05642 S I 205642 Priority Datfi(s}: .. Complete Specification Filed: □ass: Publication Date: f. P.O. Journal. No: i: L_ir L ii»» m V ;1 C' Li fcituiqil NEW ZEALAND PATENTS ACT. 1953 No.: Date: COMPLETH SPECIFICATION AZETIDINYL SULFONIC ACID AND ANALOGS XI We, E. R. SQUIBB & SONS, INC., a corporation of Delaware, USflj having its offices at Lawrenceville-Princeton Road, Princeton, New Jersey, United States of America hereby declare the invention for which £ / we pray that a patent may be granted to nax/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (followed by page la) 10 15 20 ' > 1' '' ■. - / 2iQ 5 6 4 2 - la* ftBETIDIHYIi CULFOHIC ACID AMD ANAi^CS This invention is directed to a novel family of S-lactam antibiotics, and to the use of such compounds as antibacterial agents. It has been discovered that the S-lactam nucleus can be biologically activated by a substituent Rs Rs 5n / 6 having the formula -O-C-SO^H (or salt thereof) attached to the nitrogen atom in the nucleus. R* Rfi 5y f 6 B-Lactams having a -O-C-SO^H substituent (or pharmaceutically acceptable salt thereof) in the 1-position and an acylamino substituent in the 3-position exhibit activity against a range of gram-negative and gram-positive bacteria . Illustrative members of the novel family of 3-lactam antibiotics of this invention are those encompassed by the formula §2 §4 R,-NH-C C-R-a d 1 I i \/< S— 0— C-SO H 3 0 or an ester or salt thereof. 30 { GC 205642 -2- As used in formula I and throughout the specification, the symbols are as defined below, is acyl; R2 is hydrogen or methoxy; 5 and R^ are the same or different and each is hydrogen, alkyl, alkenyl, alkvnyl, cvcloalkyl, phenyl, substituted phenyl or a 4,5,6 or 7-mcinbered hetorocycle (reforrod to hereinafter as ) or one of and is hydrogen 10 and the other is azido, halomethyl, dihalomethyl, tr ihalomethy1, alkoxycarbonyl, 2-phenylethenyl, 2-ohenylethynyl, carboxyl, -CI^X^, -S-X2, X, X, 0 I 3 1 3 || -0-X-, -O-C-X., -S-C-X., or ~A-C-NX,X_ ; . I | 4 | 4 6 7 15 X5 X5 is azido, amino (-Nf^) , hydroxy, alkanoyl-amino, aIkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2 or -0-X2 ; 20 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanovl, substituted alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl or heteroarvicarbony1 ; 25 one of X^ and X^ is hydrogen and the other is hydrogen or alkyl, or X^ and X^ when taken together with the carbon a torn to which they are attached form a cycloalkyl group; X^ is formyl, alkanoyl, phenylcarbonyl, 30 (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, O II alkoxycarbonyl, ajninocarbonyl (Nf^-C-) , (substituted amino)carbonyl, or cyano (-C=N); 35 GC198 205642 -3- A is -CH=CH-, -CH_-CH=CH-/ -(CH.)- , » b n -(CH2)n,-0-, -(CH2)n,-NH-, or -<CH2)n,-S-CH2 ; n is 0, 1, 2 or 3; n1 is 1 or 2; 5 Xg and X? are the same or different and each is hydrogen or alkyl, or Xg is hydrogen and X^ is amino, substituted amino, acylamino or alkoxy; and Rc and R,. are the same or different and b b each is hydrogen, alkyl, alkenyl, alkynyl, phenyl, 10 substituted phenyl, cycloalkyl or R?, or R^ and Rg together with the carbon atom to which they are attached are cycloalkyl or R?/ or one of R^ and R- is hydrogen and the other is azido, o halomethyl, dihalomethyl, trihalomethyl, 15 alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, 0 II carboxyl, -CH^, -S-X2< -0-X2, or -A-C-NXgX.,. Listed below are definitions of various terms used,to describe the 2-lactams of this 20 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. 25 The terms "alkyl" and "alkoxy" refer to both straight and branched chain groups. These groups having 1 to 10 carbon atoms are preferred. The terms "cycloalkyl" and "cycloalkenyl" refer to cycloalkyl and cycloalkenyl groups 30 having 3,4,5,6 or 7 carbon atoms. The term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido amino(-NH^), halogen, hydroxy, carboxy, cyano 2105642 -4- alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, R^-oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)-thio, alkylsulfinyl, or alkylsulfonyl groups. The terms "alkanoyl", "alkenyl", "alkenyl" and "alkynyl" refer to both straight and branched chain groups. Those groups having 2 to 10 carbon atoms are preferred. The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine. The term "protected carboxyl" refers to a carboxyl group which has been esterified with a conventional acid protecting group. These groups are well known in the art; see, for example, United States patent 4,144,333, issued March 13, 1979. The preferred protected carboxyl groups are benzyl, benzhydryl, _t-butyl, and g-nitrobenzyl esters. The term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino (-Nf^), halogen, hydroxvl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), or carboxyl groups. The expression "a 4,5,6 or 7-membered neterocycle" (referred to as "R^") refers to substituted and unsubstituted, aromatic and non-aromatic groups containing one or more nitrogen, oxygen or sulfur atoms. Exemplary substituents are oxo(=0), halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 2-furylimino groups (wherein the alkyl group has 1 to 4 carbons). One type of "4,5,6 or 7-membered heterocycle" is the "heteroaryl" group. The term "heteroaryl" refers to those 4,5,6 or 7-membered heterocycles which are aromatic. Exemplary heteroaryl groups are substituted and unsubstituted pyridinyl, furanyl, pvrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiaaiazolyl, pyrimidinyl, oxazolyl, triazinyl, and tetrazolyl. Exemplary nonaromatic heterocycles (i.e., fully or partially saturated heterocyclic groups)are substituted and unsubstituted azetinyl, oxetanyl, thietanyl, piperidinvl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrol idinyl, tetrahydropyrimidinyl, dihydrothiazolyl 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-imida zo1idinyl, 3-benzylimino-2-oxo-l— imidazolidinyl, 3-alkyl-2-oxo-l-imiaa zolid inyl, 3-phenyl (or substituted phenyl)-2-oxo-l-imidazolidinvl, 3-benzyl-2-oxo-l-imidazolidinyl, -5- ), benzylimino and substituted alkyl ^ | tp- •-♦"t "i lit' * -%, TO 5 6 4 2 -6- 3-(2-aminoethyl)-2-oxo-l-imidazolidinyl, 3-amino-2-oxo-l-imidazolidinyl, 3-1(alkoxycarbonyl)aminoJ -2-oxo-l-imidazolidinyl, 3-[2-[(alkoxycarbonyl)-amino]ethyl]-2-oxo-l-imidazolidinyl, 2-oxo-l-5 pyrrolidinyl, 2-oxo-3-oxazolidinyl, 4-hydroxy-6-methyl-2-pyrimidinyl, 2-oxo-l-hexahydroazepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-3-furanyl, 2,3-dioxo-1-piperazinyl, 2,5-dioxo-l-piperazinyl, 4-alkyl-2 , 3-dioxo-l-piperazinyl, and 4-phenyl-2,3-dioxo-10 1-piperazinyl. The term "substituted amino" refers to a group having the formula -NY^Y2 wherein Y^ is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and 15 Y2 is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino (-MH^)- The term "substituted alkanoyl" includes within its scope compounds having the formula 2 0 0 II (substituted alkyl)-C- (wherein "substituted alkyl" is defined above) and phenylalkanoyl. { 205642 GC198 The term "acyl" refers to all organic radicals derived from an organic acid (i.e., a carboxylic acid) by removal of the hydroxy1 group. Certain acyl groups are, or course, 5 preferred but this preference should not be viewed as a limitation of the scope of this invention. Exemplary acyl groups are these acyl groups which have been used in the past to acylate B-lactam antibiotics including 10 6-aminopenicillanic acid and derivatives and 7-aminocephalosporanic acid and derivatives; see, for example, 15 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, 20 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 25 term "acyl"; it should not be regarded 3S limiting that term. Exemplary acyl yrc;ps are: (a) Aliphatic groups having the formula O If Ra~C~ 30 wherein R is alkyl; cycloalkyl; alkoxy; alkenyl; a " 2056 42 GC19 3 V *m 8- cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, or cyanomethyl-thio groups. 5 (b) Carbocyclic aromatic groups having the formula p- R R, 0 bWi-CH X , o-< - Y - \V^| •• t -9- g2€)564'2 o II S-CH2-C- or 10 15 20 -CH2-S-C- wherein n is 0, 1, 2 or 3; R^, Rc, and each is independently hydrogen, halogen, hydroxyl, nitro, amino, cyano, trif 1 uoromethy 1, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethvl; and Rg is imino, hydroxyl, a carboxyl salt, protected carboxyl, for;nylexy, a sulfo salt, a sulfoantino salt, azido, halogen, hyarazino, alkylhyarazino, phenylhydrazino, or [(alkylthio)thioxomethyl]thio. Preferred carbocyclic aromatic acyl groups include those having the formula -10- g2.BQ 5 6 4^ 2 o // w " HO—(f —CH-C- (Rg is preferably R e a carboxyl salt or sulfo salt) and O II . . CH-C- (R is preferably 10 \ / [ s R e 15 O- a carboxyl salt or sulfo salt). (c) Heteroaromatic groups having the formula O Rf-(CH2)n-C-, O II Rp-CH-C- , r I R 20 e O II Rf-0-CH2-C- , O II Rf-S-CH2-C- , O 0 25 II II Rf-C—C- vherein n is 0, 1, 2 or 3; Rg is as defined above; and R^ is a substituted or unsubstituted 5-, 6- or 7-membered heterocvclic ring containing 30 1,2,3 or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms. Exemplary heterocyclic 10 GC1 -11- £05642 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 O II H00C-CH-CHo-0-C-NH- . I 2 NH2 Preferred heteroaromatic acyl groups include those groups of the above formulas wherein R^ is 2-amino-4-thiazolyl, 2-amino-5- halo-4-thiazolyl, 4 -aminopyrimidin-2-yl, 15 5-amino-1,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl, or 6-aminopyridin-2-yl. (d) ([(4-Substi tuted-2,3-dioxo-l-piper- azinyl)carbonyl]amino]arylacetyl groups having the formula 20 0 0 . |l II / \ -C-CH-NH-C-N N-R. i >-i g oo wherein is an aromatic group (including 25 carbocyclic aromatics such as those of the D formula ic Wv Rd and heteroarcmatics as included within the 30 definition of Rf); and R^ is alkyl, substituted V "~r- 15 20 25 -12- ;2>© 56 alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or inercapto groups), ary lmethy leneamino (i.e. , -N=CH-R wherein R is as defined above), 9 9 5 0 5 II arylcarbonylamino (i.e., -NH-C-R wherein R g g is as defined above) or alkylcarbonylamino. Preferred [[(4-subst i tuted-2,3-d icxo-1-piperazinyl)carbonyl]amino]arylacetyl groups 10 include those wherein is ethyl, pheny line thy lene amino or 2-furylmethyleneamino. (e) (Substituted oxyimino)arylacetyl groups having the formula O 30 -C-C~N-0-R. I 1 R g wherein R is as defined above and R. is hvdrocen, R„ g i - - ' c alkyl, cycloalkyl, alkylaminocarbonyl, arylamino- O II carbonyl (i.e., -C-NH-R wherein R is as defined 9 9 above) or substituted alkyl (wherein the alkyl group is substituted with 1 or more halogen, cyano, nitro, amino, rnercaoto, alkylthio, arc;natic group (as defined by Rg)' carbcxvl (including salts thereof), omido, alkoxycarbonyl, pheny lmet'noxycarbonvl , d ipheny line thoxycarbonyl, hydroxyalkoxypnosphinyl, dinydroxyphcsphinyl, hydroxy(phenylmethoxv)phcsphinyl, or dialkcxy- phcsphinyl substituents) . X 2s0 5 6 4 2 GC -13- Preferred (substituted oxyimino)arylacetyl groups include those wherein is 2-amino-4- thiazolyl. Also preferred are those groups wherein is methyl, ethyl, carboxymethyl, 5 1-carboxy-l-methylethyl, 2 , 2,2-trifluoroethyl or 1-carboxycyclopropyl. (f) (Acylamino)arylacetyl groups having the formula o 0 II II -c-ch-nh-c-r . I 3 10 r g wherein r is as defined above and r. is g j r 15 Rb^cb^Rd (Cf^^-O-, amino, alkylaxnino, (cyanoa 1 kyl) amino, amido, alkylamido, (cyanoalkyl)amido, 20 nh nh_ 0 II /-A I 2 II -ch2-nh-c—n -ch-ch2-c-nh-ch3 , GC -14- £056 4 2 Preferred (acylamino)arylacetyl groups of the above formula include those groups wherein Rj is ajnino or amido. Also preferred are those groups wherein R^ is phenyl or 2-thienyl. 5 (g) [ [ [3-Substituted-2-oxo-l-imidazoli- dinyl]carbonyl]amino]arylacetyl groups having the formula O II O 0 C II II ^ ^ 10 -C-CH-NH-C-N N-R. I I I k d CH-, —CH_ g 2 2 wherein R is as defined above and R, is g k hydrogen, alkylsulfonyl, arylnethyle.noamino 15 (i.e., -N=CH-R wherein R is as defined 13 g g O II above), -C-R (wherein R is hydrooen, alkyl m m or halogen substituted alkyl), aromatic group (as defined by R^ above), alkyl or substituted 20 alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups). Preferred [ [ 3-substituted-2-o.\o-l-imidazoli-dinyl]carbonyl]amino]arylacetyl groups of the 25 above formula include those wherein R^ is phenyl or 2-thi&ny1. Also preferred are these groups wherein R^ is hydrogen, methylsulfonyl, phenyl-methyleneamino or 2-furylmethyleneamino. 30 -15- 205642 The terms "salt" and "salts" refer to basic salts formed with inorganic and organic bases. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, e.g. , dicyclohexylamine salt, benzathine, N-methy1-D-glucam1ne, hydrabamlne salts (hydrabamine being an Involved amino acid, the proper name being N,N-bis(dehydrab1etyl)ethylened1amino), salts with amino acids like arginlne, lysine and the like. The nontoxic, pharmaceutically acceptable salts are preferred, although other salts are also useful, e.g., 1n isolating or purifying the product. The salts are formed in conventional manner by reacting the free acid form of the product with one or more equivalents of the appropriate base providing the desired cation in a solvent or medium in which the salt is insoluble, or in water and removing the water by freeze drying. By neutralizing the salt with an insoluble acid like a cation exchange resin in the hydrogen form (e.g., polystyrene sulfonic acid resin like Dowex 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. 10 15 20 GC198 -16- 205642 Rfi 5S / 6 b-Lactams having a -O-C-SO^H substituent (or salt thereof) in the 1-position and an amino or acylamino substituent in the 3-position contain at least one chiral center — the carbon atom (in the 3-position of the 3-lactam nucleus) to which the amino or acylamino substituent is attached. This invention is directed to those s-lactams which have been described above, wherein the stereochemistry at the chiral center in the 3-position of the 6-lactam nucleus is the same as the configuration at the carbon atom in the 6-position of naturally occurring penicillins (e.g., penicillin G) and as the configuration at the carbon atom in the 7-position of naturally occurring cephamycins, (e.g., cephamycin C). With respect to the preferred s-lactams of formula I, the structural formulas have been drawn to show the stereochemistry at the chiral center in the 3-position. Also included within the scope of this invention are racemic mixtures which contain the above-described s-lactams. 5 10 15 20 25 30 GC198 205642 6-Lactams having a -O-C-SO-jH substituent (or salt thereof) in the 1-position of the 8-lactam nucleus and an acylainino substituent in the 3-position of the s-lactam nucleus have activity against a range of gram-negative and V A gram-positive organisms. The -O-C-SO^H substituent (or salt thereof) is essential to the activity of the compounds of this invention. The compounds of this invention can be used as agents to combat bacterial infections (including urinary tract infections and respiratory infections) in mammalian species, such as domesticated animals (e.g. , dogs, cats, cows, horses, and the like) and humans. For combating bacterial infections in mammals a compound of this invention can be administered to a mammal in need thereof in an amount of about 1.4 mg/kg/day to about 350 mg/kg/day, preferably about 14 mg/kg/day to about 100 mg/kg/day. All modes of administration which have been used in the past to deliver penicillins and cephalosporins to the site of the infection are also contemplated for use with the novel family of s-lactams of this invention. Such methods of administration include oral, intravenous, intramuscular, and as a suppository. / ■ , ..... ' 30 TO 5 6 4 2 -18- The 8-lactams of this invention can be prepared from an amino acid having the formula ii oh p I R4 nh2-ch—c—r* The amino group is first protected with a classical 10 protecting group (e.g., t-butoxycarbonyl, benzyloxy-carbonyl, o-nitrophenylsulfenyl, etc.), yielding a compound having the formula III 15 oh „ Ins\r4 a.-nh-ch c—r, 1 I 3 .c oh v 0 20 In formula III, and throughout the specification, the symbol "A^" refers to a nitrogen protecting group. The carboxyl group of a protected amino acid of formula III is then reacted with an amine 25 having the formula Iv Rs Rfi NH®-0—C—SO® The reaction proceeds in the presence of a coupling agent such as l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide or dicyclohexylcarbodiimide, and yields a salt of the compound having the formula 35 GC198 -19- 2056-42 V OH. R, I 4 A, -NH-CH C —R7 I *5s ^6 yC NH-O—C—S0,H . O J 5 The hydroxyl group of a compound of formula V (or a salt thereof) is converted to a leaving group, using, for example, a classical reagent such as methanesulfonyl chloride (methanesulfonyl is referred to hereinafter as "Ms"). 10 The fully protected compound having the formula VI OMs R, I v\y 4 A,-NH-CH C—R3 I JZ NH-O—C—SO-H , 15 0 or a salt thereof, is cyclized by treatment with base, e.g., potassium carbonate. The reaction is preferably carried out in an organic solvent such as acetone, 2o under reflux conditions, and yields a compound having the formula VH r =4 A. -NH-CH C-R., 1 i I "I- ^ .C N-O—C—S0,H , & 3 25 0 or a salt thereof. Alternatively, cyclization of a compound of formula V can be accomplished without first converting the hydroxyl group to a leaving group. 30 Treatment of a compound of formula V (or a salt thereof) with triphenylphosphine and diethyl-azodicarboxylate or carbon tetrachloride and triethylamine, yields a compound of formula VII. 35 -20- GC198 2056 10 IS Both of the methods disclosed above for ring closure of a compound of formula V result in the inversion of the stereochemistry at the carbon bonded to the and substituents. Deprotection of the 3-amino substituent of a compound of formula VII can be accomplished using art-recognized techniques. If, for example, the protecting group is t-butoxycarbonyl, trifluoroacetic acid can be used to deprotect the amino group. If the protecting group is benzyloxycarbonyl, catalytic (e.g., palladium on charcoal) hydrogenation can be used. If the protecting group is o-nitrophenylsulfenyl, ]3-toluenesulfonic acid can be used in combination with £-thiocresol. The deprotected compound has the formula VIII NH2-CH c or a salt thereof GC1?20 5642 21- and is a key intermediate for preparing the compounds of this invention. The compounds of formula VIII form an integral part of this invention. 5 Well known acylation techniques can be used to convert a compound of formula VIII to the corresponding compound having the formula IX R, s4 10 R,-NH-CH C-R, I I ^C N—0—-*C—SO-H , 0y J or a salt thereof. Exemplary techniques include reaction with, a 15 carboxylic acid (R^-OH) or corresponding carboxylic acid halide or carboxylic acid anhydride. The reactions with a carboxylic acid proceed most readily in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance 2o capable of forming a reactive intermediate in situ such as N-hydroxybenzotriazole or 4-dimethyl-aminopyridine. In those instances wherein the acyl group (R^) contains reactive functionality (such as amino or carboxyl groups) it may be 25 necessary to first protect these functional groups, then carry out the acylation reaction, and finally deprotect the resulting product. { G T05642 -22- The products of formula I wherein R2 is methoxy can be prepared from the corresponding compound of formula VII wherein is benzyloxy-carbonyl. Halogenating (preferably chlorinating) the amide nitrogen of a compound of formula VII (A^ is benzyloxycarbonyl) yields a compound having the formula or a salt thereof. Reagents and procedures of N-chlorinating amides are known in the art. Exemplary reagents are tert.—butyl hypochlorite, sodium hypochlorite, "m t 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.g., water/methylene chloride) in the presence of a base such as sodium borate decahydrate. The reaction is preferably run at a reduced temperature. Reaction of a compound of formula X with a rnethoxylating agent, e.g., an alkali metal methoxide, yields a compound (in combination with its enantiomer if R, and R. are the same 3 4 or if X is a racemic mixture) having the formula X 0 CI II I 0 XI o C N—0—C — I I 3S5s s* or a salt thereof. / GC198 -23- 205642 The reaction can be run in an organic solvent, e.g., a polar organic solvent such as tetra-hydrofuran, at a reduced temperature. Alternatively, a compound of formula VII, 5 wherein A1 is benzyloxycarbonyl, can be converted to a compound of formula XI using a single step procedure. The methoxylating agent can first be mixed with a compound of formula VII (A^ is benzyloxycarbonyl) and the N-chlorinating 2o reagent then added to the reaction mixture. Conversion of a compound of formula XI to the desired products of formula I can be accomplished using the procedures described above for the conversion of an intermediate 25 of formula VII to a product of this invention. The starting materials of formula II are readily obtainable using art-recognized procedures; see, for example Synthesis, pg. 216 (1979) and J. Org. Chem., £4:3967 (1979). 2o The following examples are specific embodiments of this invention. GC198 -24- 205642 Example 1 I3S-[3a(Z),4b]1—2—[ [ [l-(2-Amino-4-thiazolyl)-2-[[4-methyl-2-oxo-l-(sulfomethoxy)-3-azetidinyl]-amino]-2-oxoethylidene]aminojoxy]-2-methylpropanoic 5 acid, dipotassium salt A) Aminoxymethanesulfonic acid Acetone oxime (1.46 g, 20 mmole) was added to a suspension of a 60% mineral oil dispersion 10 of sodium hydride (0.8 g, 20 mmole) in 16 ml of dry dimethylsulfoxide. This was followed by the portionwise addition of sodium bromomethane sulfonate (3.94 g, 20 mmole). The reaction was heated at 90-95°C for 4 hours under nitrogen, 15 cooled and washed twice with 250 ml of ether. Product solidified, was washed with 100 ml of dichloromethane, filtered and dried over P2O2 to yield 15.3 g of crude material. This was dissolved in 20 ml of water, and tetra-20 butylammonium hydrogen sulfate (7.5 g, 22 mmole) was added. The resulting ion paired product was extracted twice with 200 ml of dichloromethane. The dichloromethane solution was dried (Na2SO^, and concentrated in vacuo. Hydrolysis of the 25 acetone oxime was accomplished by heating in 120 ml of 2N HC1 at 130°C for 4 hours. This solution was concentrated _in vacuo from water twice and then from acetonitrile. The product solidified upon addition of dichloromethane, 3q and was filtered and dried in. vacuo to yield 2.5 g of the title compound. GC198 2 0 5 6 B) O-Sulfomethyl-a-N-t-butoxycarbonyl-L-threonine hydroxamate, potassium salt Aminoxymethanesulfonic acid (1.14 g, 8.9 mmole) was added to a solution of t-butoxycarbonyl-L-threonine (1.96 g, 8.9 mmole) in 16 ml of water and 4 ml of tetrahydrofuran at 0°C. The pH was adjusted to 4.5 with IN KOH, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.87 g, 9.7 mmole) in 8 ml of water was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, and during this time, the pH was maintained at 4 to 4.5 by occasional addition of IN HjSO^. The product was ion paired with tetrabutyl-ammonium hydrogensulfate (3.05 g, 8 mmole) at pH 2.8 and extracted from the aqueous solution with four 100 ml portions of dichloromethane. The dichloromethane solution was dried (Na2SO<j) and concentrated iri vacuo to yield 4.5g of product as the tetrabutylammonium salt. This was converted to the potassium salt by ion exchange on 150 ml of Dowex 50X 0 (0.7 meq K /ml), and after lyophilization, 2.63 g of the title compound was obtained. GC198 -26- 2 0 5 6 4 2 C) O-Sulfomethyl-a-N-£-butoxycarbonyl-L-(O-methanesulfonylthreonine)hydroxamate, tetrabutylammonium salt To a partial solution of O-sulfome thyl-a-5 N-t-butoxycarbonyl-L-threonine hydroxamate, potassium salt (2.37 g, 6.5 mmole) in 50 ml of dry pyridine at 0-5°C under nitrogen was added dropwise 0.8 ml (excess) of methanesulfonyl chloride. The reaction was stirred at room 10 temperature for 4 hours, and then concentrated in vacuo. The residue was dissolved in 10 ml of water, and 2.0 g (6 mmole). of tetrabutylammonium hydrogensulfate was added at pH 2.8. The ion paired material was extracted with 15 chloroform. The chloroform was dried and concentrated in vacuo to yield 2.6 g of crude product. D) [ 3S- ( 3a , 4 8) ] — 3 — f [ (1,1-Dimethylethoxy) - 20 carbonyl]amino]-4-methyl-2-oxo-l-(sulfomethoxy)- azetidine, potassium salt 0-Sulfomethyl-a-N-_t-butoxycarbonyl -L-(O-methanesulfonylthreonine)hydroxamate, tetrabutylammonium salt (2.6 g, 4.0 mmole) 25 was dissolved in 5 ml of acetone and added dropwise to a refluxing suspension of 2.2 g of potassium carbonate in 65 ml of acetone. Refluxing was continued for 3.5 hours and the reaction was cooled, filtered, and concentrated 3q in vacuo. The residue was dissolved in 10 ml of .5 H pH 5.5 KH^PO^, and the pH was adjusted to 2.8. Product was extracted four times with 100 ml portions of dichloromethane, and the combined extract was dried and concentrated 35 GC198 2 0 5 6 in vacuo to yield 1.52 g of crude tetrabutylammonium ion paired 8-lactam salt. The potassium salt was obtained by ion exchange through 50 ml 0 of Dowex 50X (0.7 meq K /ml) to yield upon lyophilization 0.53 g of crude material, which was further purified by chromatography through 100 ml of HP-20 using water. The appropriate fractions were conbined and lyophilized to yield 0.24 5 g of product. Analysis Calc'd for C^qH^^O^SK • 1. 2 H^O: C, 32.46; H, 5.28; N, 7.57; S, 8.66 Found: C, 32.52; H, -4.76; N, 7.43; S, 8.30 E) [3S-(3 a,4 8)]-l-Sulfomethyl-3-amino-4-methy1-2-oxo-l-azetidine [3S-(3a,4 6) ]-3-[[(1,1-Dimethylethoxy)carbonyl]-amino)-4-methyl-2-oxo-l-(sulfomethoxy)azetidine, potassium salt (0.245 g, .68 mmole) was suspended in 0.5 ml of dichloromethane and 0.5 ml of anisole. The reaction mixture was cooled to 0°C, and trifluoroacetic acid (1.0 ml) was added under nitrogen. The reaction mixture was stirred for 1 hour and then concentrated in vacuo to a residue which was evaporated from benzene twice. This was triturated with ether, and the ether was decanted to give the desired product as a white solid. 5 10 15 20 GC198 2 0 5642 F) 13S- [3a(Z)> 4 8]J —2 — I[11—(2-Amino-4-thiazolyl)-2-[f 4-methyl-2-oxo-l-(sulfomethoxy)-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2-methylpropionic acid, diphenylmethyl ester, potassium salt (Z)-2-Amino-a- [ [2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]-imino]-4-thiazoleacetic acid (0.30 g, .68 mmole) and 1-hydroxybenzotriazole hydrate (0.10 g, .68 mmole) were dissolved in 4 ml of dry dimethylformamide under nitgoren. This was cooled to 0°C, and N,N'-dicyclohexyl-carbodiimide (0.14 g, .68 mmole) was added portionwise. After addition, the reaction was stirred at 0°C for 1 hour. To this was added a solution of the above crude 3-amino-l-(sulfomethoxy) azetidine (ca. 0.68 mmole) in 10 ml of dimethylformamide and 0.5 ml of N,N-diisopropyl-ethylamine at 0°C. The reaction was stirred at 0°C for 1 hour and then at room temperature overnight. The solution was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in 50 ml of dichloromethane and washed with 2 ml of water. Upon evaporation of dichloromethane, 0.372 g of crude product was obtained. This was passed through 30 ml of A Dowex 50 (0.7 meq K /ml) using water, to yield upon lyophilization 0.211 g of crude product, contaminated with hydroxybenzotriazole. ' ... '"*'A 1 " 1 . GC19 -29- ^2 056 42 G) [3S-[3a(Z),4 3]]-2-[ [ [1-{2-Amino-4-thiazolyl)-2-[ [4-methyl-2-oxo-l-(sulfomethoxy)-3-azetidinyl)-amino]-2-oxoethylidene]amino]oxy]-2-methy1-propanoic acid, dipotassium salt 5 [3S-[3a(Z),4 3]]-2-fI [1-(2-Amino-4-thiazolyl)-2- [[4-methyl-2-oxo-l-(sulfomethoxy)-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2-methylpropionic acid, diphenylmethyl ester, potassium salt (0.211 g) was dissolved in 1.8 ml of dichloromethane, 10 0.5 ml of anisole, and 1.5 ml of trifluoroacetic acid, and stirred under nitrogen at 0°C for 2 hours. The reaction mixture was condentrated in vacuo and evaporated from benzene twice. The residue was washed with ether: ethyl acetate 15 (1:1) and with ether: acetonitrile (1:1) to give a white solid. This was dissolved in 1.0 ml of pH 5.5 0.5 M Kf^PO^, adjusted to pH 6.5 with IN KOH, and chromatographed through 40 ml of HP-20 with water to give 53 mg of the 20 title compound, melting point 200°C, dec. Analysis Calc'd for C^H^N^Oj^I^ ■ 2 . 75 H20: C, 28.44; H, 3.84; N, 11.85; S, 10.8 4 Found: C, 28.32; H, 3.36; N, 11.90; S, 10.37 25 Gcig2 0 56 -30- Example 2 [2S-[2g,3g(Z)]1 -[[3-[[(2-Amino-4-thiazolyl)- (methoxyimino)acetyl]amino]-2-methvl-4-oxo- 1-azetidinyl]oxy]methanesulfonic acid Following the procedure of Example 1, and substituting an eauimolar amount of (2)-2-amino- a-[ (methoxy)-imino]-4-thiazoleacetic acid for the thiazoleacetic acid used in part (F) of Example 1, the titled compound is prepared as the mono- potassium salt as a hygroscopic solid after dissolving in acetonitrile and removing the acetonitrile under vacuum several times IR - SO^ (1030 cm ^); s-lactam (1778 cm ^) Analysis: calc. for C.. . Hn . Nc0_.SoK • 0 . lCH^CN J 11 14 5 7 2 3 calc. C-38.11; H-4.82; N-15.92; S-12.56 found: C-37.94; H-5.36; N-15.92; S-12.56 Example 3 [2S-[2a,3S(R)]]-[[3-[[[[(4-Ethyl-2,3-dioxo-l-piperaziny1)carbonyl]amino]phenylacetyl]amino]-2-methy1-4-oxo-l-azetidinyl]oxy-methanesulfonic acid Following the procedure of Example 1 and substituting a-[ [ (4-ethy1-2,3-dioxo-l-piperazinyl)-carbonyl]amino]-phenylacetic acid for the thiazoleacetic acid used in part (F) of Example 1, the titled compound is obtained as the monopotassium salt as a hygroscopic solid. IR - SO^ (1038 cm ; B-lactam (1775 cm ^) Analysis: calc. for C^qH,,^N^O^SK • 1. 6^0 calc.: C-41. 53 ; H-4.74; N-12.11; S-5.54 found: C-41.53; H-4.46; N-11.13; S-5.61 : ■' -*-Vj ■ --i. GC198 -31- 205b4 2 Example 4 (S)-3-benzyloxycarbonylamino)-4-methyl-2-oxo-l- (sulfomethoxy)-azetidine Following the procedure of Example 1, parts (A) through (D) and substituting benzyloxy- carbonylserine for the t-butoxycarbonyl-L- threonine used in part (B), the titled compound is prepared as a potassium salt, IR -SO,"(1025 cm "*") ; -1 n-lactam (177 5 cm ). r'A.r^VSM^r v.--: .■ 205642 GC198 -32- Bv followinq the procedures previously described the followinq compounds are prepared: (3S-trans)-({(2-Amino-4-thiazolyl)(methoxy-imino)acetyl J amino]-4-methyl-2-oxo-l-azetidinyl]-5 oxy]methanesulfonic acid, monopotassium salt (3S-trans)-[[(2-Amino-4-thiazolyl)[(2,2,2-tr ifluoroethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetiainyl]oxylmethanesulfonic acid, mono-potassium salt 10 (3S-trans)-([(2-Amino-4-thiazolyl)[(2-amino-2- oxoethoxy)imino]acetyl]amino]-4-methyl-2-oxo-l-azetidinyl]oxy)methanesulfonic acid, monopotassium salt (3S-trans) - [ [ (2-Amino-4-thiazolyl) [ (car'boxy-15 methoxy)imino]acetyl]amino]-4-methyl-2-oxo-l- azetidinyl]-oxy]methanesulfonic acia, dipotassium salt (3S-trans)-([(2-Amino-4-thiazolyl) [ [ (1-carboxy-cyclopropyl)oxy]imino]acetyl]amino]-4-methyl-2-oxo-l-20 azetidinyl]-oxy]methanesulfonic acid, dipotassium salt I3S-[3a(R),48]]-([3-[(Aminophenylacetyl)-amino]-4-methyl-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, monopotassium salt 25 (3S-trans)-[[3-[(Phenylacetyl)amino]-4- methyl-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-trans)-[[3-((2-Thienylacetyl)amino]-4-methy1-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, 30 monopotassium salt (3S-trans)-[(3-((2,6-Dimethoxyphenyl)acetyl]-amino]-4-methyl-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, monopotassium salt 35 V -33- GC198 205642 ( 3S- [3 a(R) , 4 B] ] - [ [3- [ [ [ [ ( Aminocarbony 1) -5 amino)-2-thienylacetyl-amino]-4-methyl-2-oxo-l- azetidinyl)-oxy]methanesulfonic acid, monopotassium salt [3S-[3 a(R),46)]-[(3-[(Carboxyphenylacetyl)-amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methane-10 sulfonic acid, dipotassium salt [ 3S- ( 3 a[t) , 4 6] ] - [ [3 - [ (Phenylsulf oacetyl) -amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methanesulfonic acid, dipotassium salt (3S-trans)J—[[3—([(2-Amino-4-thiazolyl)-15 oxoacetyl]amino]-4-methyl-2-oxo-l-azetidinyl]-oxy]methanesulfonic acid, monopotassium salt [3S-f 3 a(R) ,4 6]]-[[3-[[[([2-Oxo-3-[(phenyl-methylene )amino]-1-imidazolidinyl]carbonyl]amino]-phenylacetyl]amino]-4-methyl-2-oxo-l-azetiainyl]oxy]-20 methanesulfonic acid, monopotassium salt [3S-[3 a(2),46]]-[[3-[[2-Furanyl(methoxy-imino)acetyl]amino]-4-methy1-2-oxo-1-azetidinyl]oxy]-methanesulfonic acid, monopotassium salt [3S(Z)]-[[3-[[(2-Amino-4-thiazolyl)(methoxy-25 imino)acetyl]amino]-2-oxo-1-azetidinyl]oxy]methanesulfonic acid, monopotassium salt [3S ( Z)]-[[3-([ (2-Amino-4-thiazolyl) [(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, dipotassium 30 salt [3S(Z)]-[[3-[[ (2-Amino-4-thiazolyl) [ (2,2,2-tr ifluoroethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyl]oxy]methanesulfonic acid, monopotassium salt 35 2 0 56 4 2 34- GC198 [3S(2)]-([3-[[{2-Amino-4-thiazolyl)((2-amino-2-oxoethoxy)imino]acetyl)amino]-2-oxo-l-azetiainyl]-oxy]methanesulfonic acid, monopotassium salt [3S-[3 a( S),4 8)]-[[3 -f[[(Aminocarbony1)amino]-5 2-thienylacetyl]amino]-2-oxo-l-azetidinyl]oxy]-methanesulfonic acid, monopotassium salt [3S- [ 3a (±) ,4 6] ] - [ [3 - ( (Pheny lsul foace tyl) -amino]-2-oxo-l-azetidinyl)oxy]methanesulfonic acid, dipotassium salt 10 [3S-[3a(R),48]]-[(3-[[[[(4-Ethyl-2,3-dioxo-1- piperaz inyl)carbonyl]amino]phenylacetyl]amino]-2-oxo-l-azetidinyl] oxy ] methanesulfonic acid,monopotassium salt [ (3S (Z) ] - [ (3- ( (Phenoxyacetyl) amino] -2-oxo-l-15 azetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-cis)-([(2-Amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-4-methyl-2-oxo-l-azetidinyl]-oxy]methanesulfonic acid, monopotassium salt 20 (3S-cis)- [((2-Amino-4-thiazolyl)[(2,2,2- tri£luoroethoxy)imino]acetyl]amino]-4-methyl-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, monopotassium salt (3S-c is)-[[(2-Amino-4 -thiazolyl) ((carboxy-25 methoxy)imino]acetyl]amino]-4-methyl-2-oxo-l- azetidinyl]-oxy]methanesulfonic acid, dipotassium salt (3S-cis)- [ [3-[[(2-Amino-4-thiazolyl)] (1-carboxy-l-methylethoxy)imino]accetyl]amino]-2-oxo-4-30 methy1-1-azetidinyl]oxy]methanesulfonic acid, dipotassium salt (3S-cis)-[[(2-Amino-4-thiazolyl) ( [ (1-carboxy-cyclopropyl)oxy]imino]acetyl]amino]-4-methyl-2-oxo-l-azetidinyl] -oxy] methanesulfonic acid, dipotassium 35 salt ! I I i { m _ *3 c _ ' r> n - JJ -WU1 J ll 205642 (3S-cis) - [ [ (2-Ajnino-4-thiazolyl) [ (2-amino-2-oxoethoxy)iminoJ acetyl)amino]-4-methy1-2-oxo-1-azetidinyl]oxy]methanesulfonic acid, monopotassium salt 5 [3S-[ 3 a (R),4 a]]-[(3-((Carboxyphenylacetyl)- amino]-4-methy1-2-oxo-1-azetidinyl)oxy]methanesulfonic acid, dipotassium salt [3S-[3a(R),4a]]-{(3-[[[((4-Ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-4-10 methyl-2-oxo-l-azetidinyl]oxy]methanesulfonic acid, monopotassium salt [3S-[3 a(S),4a]]-[[3 —{[[(Aminocarbonyl)-amino]-2-thienylacetyl]-amino]-4-methyl-2-oxo-l-azetidinyl]-oxy]methanesulfonic acid, monopotassium 15 salt (3S-[3a(R),4a]]-[(3 - [(Aminophenyl-acetyl)-amino]-4-methyl-2-oxo-l-azetidinyl]oxy]-methanesulfonic acid, monopotassium salt EXAMPLE 5 (2a, 3a)-l-sulfomethoxy-2-(aminocarbonyl )-3-(((1,1-dimethylethoxy)carbonyl)amino)-4-oxoazetidine A) Erythro-3-hydroxy-dl-aspartic acid Erthro-3-hydroxy-dl-aspartic acid was prepared from trans-epoxy-succinic acid as described by C.W. Jones et al. (Can. J. Chem. 47,4363 (1969)). Trans-epoxysuccinic acid was prepared from fumaric acid as described by G.B. Payne et al. (J. Org. Chem. 2A, 54 (1959)). B) g-methyl erthro-3-hydroxy-dl-aspartate To a suspension of 5.0 g (33.5 mmol) of erythro-3-jhydroxy-dl-aspartic acid in 50 ml of dry methanol was added 6 ml of conc. hydrochloric acid. The mixture was refluxed for 3 hours, cooled to room temperature, and evaporated in vacuo. The residue was taken up in 95 percent ethanol, and the pH was adjusted to 8.0 by addition of pyridine. The white solid was filtered and dried to give 5.2 g (95 percent yield) of desired methyl ester having m.p. 210 °C. - 36 - 205642 < C) Erthro-3-hydroxy-dl-asparacine The above g-methyl aspartate (4.0 g, 24.5 mmol) was dissolved in 40 ml of conc. ammonia and stirred overnight at room temperature. The reaction mixture was evaporated in vacuo to a :solid which was dissolved in hot water. The pH was adjusted to 5.0 using 6NHC1, and the solution was concentrated in vacuo to about 20 ml and then left overnight at 5 °C. The white crystalline mass was collected and dried to give 3.4 g (95 percent yield) of desired product having m.p. 233 °C. D) N-t-butoxycarbonyl-erythro-3-hydroxy-dl-asparaqine, potassium . salt Erythro-3-hydroxy-dl-asparagine (7.0 g, 47 mmol) was suspended in 50 ml of water and solubilized by addition of 3 N KOH. This solution was adjusted to pH 10.0 and maintained at this pH while adding dropwise a solution of Di-t-butyldicarbonate (15.5 g, 71 mmol) in 20 ml of t-butanol. The reaction mixture was stirred at pH 10.0 overnight at room temperature. The t-butanol was removed in vacuo, and the aqueous remainder was adjusted to 5.0 using 6N HC1. The solution was concentrated in vacuo to a small volume, and then the pH was adjusted to 3.0 (6N HC1). Removal of solvent in vacuo gave a solid (20 g) containing the desired product in free acid form and in about quantitative yield, along with inorganic salts. A portion (2.9 g) of this solid was taken up in water and dilute KOH at pH 5.5 and chromatographed through 100 ml of HP20 resin using water and then acetone-water (1:9) to give the desired potassium salt as a residue (1.8 g). E) Aminoxymethanesulfonic acid, tetrabutylammonium salt Tetrabutylammonium hydrogen sulfate (1.02 g, 3 mmol) was added to a solution of 0.635g(5 mmol) of aminoxymethanesulfonic acid in 2 ml of water, and that pH was adjusted to 10.0 using dilute KOH. The water was removed in vacuo, and the residue was triturated with methylene chloride. After filtration, the filtrate was dried over sodium sulfate and evaporated to give the desired product as a residue (1.06 g, 2.88 mmol). ,r .. ,*-y 205642 37 F) O-sulfomethyl-g-N-t-butoxycarbonyl-erythro-3-hydroxy-dl-asparaqine hydroxamate, potassium salt N-t-butoxycarbonyl-erythro-3-hydroxy-dl-asparagine, potassium salt (0.792 g, 2.77 mmol) was dissolved in water (3 ml) and adjusted to pH 2.4 (Dil. H2S04). The solution was concentrated in vacuo to a residue, which was concentrated from water (2 times) and then from benzene (2 times). This residue was dissolved in dry acetonitrile (4 ml) and dry tetrahydrofuran ( 8 ml) and cooled to 0°C. To this stirred solution was added 0.424 g (2.77 mmol) of 1-hydroxybenzo-triazole monohydrate followed by 0.572 g (2.77 mmol) of N,N1 -dicyclohexylcarbodimide. The mixture was stirred at 0°C for 2 hours, and then the above aminoxymethanesulfonic acid, tetrabutylammonium salt (1.06 g, 2.88 mmol) in 5 ml of acetonitrile was added dropwise. After the addition, the reaction was stirred at 0°C for 4 hours. The reaction was filtered and concentrated in vacuo to a residue. Water (10 ml) was added, and the residue was triturated at 0°C until it solidified. The solid was removed by filtration, and the aqueous filtrate was concentrated to about 3 ml. The pH was adjusted to 4.0, and the tractionation was performed over 80 ml of dowex 50 (k) ion exchange resin. Appropriate fractions were collected and concentrated to a small volume. The pH was adjusted to 3.4, and the solution was chromatographed over HP20 resin to give, after lyophi1ization, 502 mg (46 percent) of desired product as a solid having m.p. 145°C. Anal, calcd. for C10H18N309SK.0.71H20: C, 29.42: H.4.80 Found: C,29.42: H,4.73: N, 10.04: S, 7.45 G) O-sulfomethyl-aN-t-butoxycarbonyl-erythro-3-hydroxy-dl-asparaqine hydroxamine, tetrabutylammonium salt To a solution of the above asparagine hydroxamate, potassium salt (104 mg, 0.263 mmol) in 1 ml of water was added 2.63 ml of 0.1m tetrabutylammonium hydrogen sulfate in 0.5 m pH 5.5 KH2P04 buffer. The solution was concentrated to dryness, and the residue was triturated with methylene chloride. Filtration and evaporation of the methylene :hloride gave the desired product as a residue (156 mg, HZ0.26 mmol). N, 10.29: S,7.85 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> •vi'Vw. 205642 - 38 - H) (2a,3a)-l-sulfomethoxy-2-(aminocarbonyl)-3-(((l,l-dimethylethoxy)carbonyl)amino)-4-oxoazetidine, potassium salt The above 0-sulfomethyl hydroxamate, tetrabutylammonium salt (140 mg, 0.234 mmol) was dissolved in 1.6 ml of dry methylene chloride and stirred with 1 g of dried 3 a molecular sieves overnight. The solution was removed via syringe and diluted with 0.8 ml of dry methylene chloride. To this stirred solution at -50°C under argon was added 0.12 ml (0.85 mmol) of triethylamine followed by dropwise addition of 0.08 ml (0.42 mmol) of trifluoromethanesulfonic anhydride. The reaction was allowed to warm to -30°C over one hour, and then 0.06 ml of triethylamine was added. After 5 minutes, the reaction was concentrated in vacuo, and the residue was dissolved in 2 ml of acetone. The solution was cooled to 0°C, and a solution of 79 mg of potassium perfluorobutane sulfonate in 1 ml of acetone was added. Ether was then added, and the solids were collected by centrifugation. Treatment of this solid by stirring with 2 ml of dowex 50 (k) resin in water, filtration and removal of the water in vacuo gave crude desired potassium salt containing no amines. Chromatography of this crude potassium salt on HP20 resin using water gave 15 mg (20 percent yield) of desired potassium salt, after lyophilization having M.P. 149°C and IR(KBR) 1786 reciprocal cm ((3-lactam carbonyl) and 1696 reciprocal cm (broad, amide and carbamate carbonyl). GC19 20°^ What io claimed io: WHAT j"/WI: CLAIM IS;

1. A 8-lactam having an -O—C—SO^H substituent in the 1-position and an acylamino substituent in the 3-positionJ 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 Rg together with the carbon atom to which they are attached are cycloalkyl or a 4,5,6 or 7-membered heterocycle, or one of R^ and Rg is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2X1, -S-X2, -0-X2, or -A-C-NX6X7; X± is azido, amino, hydroxy, alkanoylamino, alkyl-sulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2, or -0-X2; X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, (substituted phenyl)-carbonyl, or heteroarylcarbonyl; A is -CH=CH-, "CH 2~CH=CH-, -(CH2)n-, -(CH2)n,-0-, -(CH2) ,-NH-, or -(CH2)n,-S-CH2~; n is 0, 1, 2 or 3; n' is 1 or 2; and Xg and are the same or different and each is hydrogen or alkyl, or Xg is hydrogen and X? is amino, substituted amino, acylamino or alkoxy, or a salt or ester thereof. 0 II ^ GC198- Product 2 05642

2. A B-lactaro in accordance with claim 1 wherein R^ and Rg are each hydrogen.

3. A S-lactam in accordance with claim 1 having the formula §2 §4 R1 -NH-C C-R3 I "SsA O' ,JZ N—0—C- -S03H or a salt or ester thereof, wherein R^ is acyl; r2 is hydrogen or uiethoxy; R, and R, are the same or differont-nnd 3 4 c-Tch is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phony 1, substituted phenyl or a 4,5,6 or 7-rne:;)bored heterocycle, or one of R^ and R^ is hydro'jen and (-he other is azido, halomethyl, dihaloine thyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CI^-X^ -S-X2, X X- O I3 I3 II ~°~X2' ~0-(y~X4' -S-C-X4 , or -A-C-NXgX?; X5 X5 wherein R,., Rg, X^, X2, A, Xg and X^ are as defined in claim 1 ; and one of X3 and is hydrogen and the other is hydrogen or alkyl, or X^ and X^ when taken together with the carbon atom to which they are attached form a cycloalkyl group; X^ is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl or cyano.

4. A S-lactara in accordance with claim 3 wherein R2 is hydrogen. GC198 - Product 205642

5. A 0-lactam in accordance with claim 4 wherein one of R3 and R4 is other than hydrogen.

6. A 0-lactam in accordance with claim 4 wherein R^ is hydrogen and R^ is methyl.

7. A 6-lactam in accordance with claim 4 wherein R^ is methyl and R^ is hydrogen.

8. A S-lactam in accordance with claim 4 wherein and Rg are each hydrogen.

9. A 0-lactam in accordance with claim 4 wherein R,. and Rg are each methyl.

10. A 0-lactam in accordance with claim 4 wherein R^ is (2)-2-amino-a-I(1-carboxy-l-methyl-ethoxy)imino)-4-thiazoleacetyl.

11. A 6-lactam in accordance with claim 3 wherein Rj, R5 and R6 are each hydrogen and one of R3 and R4 is alkyl and the other is hydrogen.

12. A 6-lactam in accordance with claim 3 wherein R2, R3, R5 and Rg are each hydrogen and R4 is methyl.

13. A 0-lactam in accordance with claim 3 wherein R2# R4 / R5 and Rg are each hydrogen and R^ is methyl.

14. A S-lactam having the formula h NH--CH C-R, 2 I I 3R5^R6 /C N—0—C—S0,H . o 3 or a salt thereof, wherein R_ and R. are the same or different and 3 4 each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a IT':! * GC198- Product ** 205642 4,5,6 or 7-membered heterocycle, or one of R^ and is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, carboxyl, -CH2X^, X. X, 0 I 3 13 11 -S-X2, -0-X2, -0-C-X4, -S-C-X4, or -A-C-NXgX7 ; X5 X5 and Rg 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 R^ and Rg together with the carbon atom to which they are attached are cycloalkyl or a 4,5,6 or 7-membered heterocycle, or one of R,. and Rg is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, alkenyl, alkynyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, 0 II -CH2~X1, -S-X2, -0-X2, or -A-C-NXgX7 ; X^ is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2 or -0-X2 ; X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl or heteroarylcarbonyl; one of X^ and X^ is hydrogen and the other is hydrogen or alkyl, or X^ and X^ when taken together with the carbon atom to which they are attached form a cycloalkyl group; I - - / GC198- Product 4* 205642 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; A is -CH=CH-, -CH2-CH=CH-, -(CH^-, -(CH2)n,-0-, -(CH2)nI-NH-, - (CHj) n,-S-CH2- ; n is 0, 1, 2 or 3; n' is 1 or 2; and Xg and X? are the same or different and each is hydrogen or alkyl, or Xg is hydrogen and X7 is amino, substituted amino, acylamino or alkoxy.

15. A 8-lactam in accordance with claim 1, a salt of [3S-[3a (Z),48]]-2-[[[1-(2-amino-4-thiazolyl)-2-[[4-methyl-2-oxo-l-(sulfomethoxy)-3-azetidinyl]amino]-2-oxoethylideneJ amino]oxy]-2-methylpropanoic acid.

16. A 8-lactam in accordance with claim 14, [3S-(3a,4 8)]-1-sulfomethoxy-3-amino-4-methyl-2-oxo-l-azetidine. .-Aito i HIS I 9"^ DAT o A. J. PARK & SON per AGEMTS FOI THE APPUCAMTB; </div>