NL8303410A - AZETIDINYLOXYMETHANE SULPHONIC ACIDS AND PREPARATIONS CONTAINING THEM. - Google Patents

Description

r —------ - i -

Azetidinyloxymethanesulfonic acids and preparations containing them.

This invention relates to a new class of lactam antibiotics with antibacterial activity.

It has been found that the -lactam core can be biologically activated by a substituent of the formula -O-C (R, _) (R_) SO_H at the nitrogen atom of the core.

5 6 3/3 -Lactams with a substituent -OC (R ^) (Rg) SO ^ H in the 1-position and an acylamino group in the 3-position, and the pharmaceutically acceptable salts thereof, act against a variety of gram negative and gram positive bacteria. Representative representatives of the new class of 1-lactam antibiotics of the invention are the compounds of formula 1 and their esters and salts. Throughout the description, the symbols of formula 1 have the following meanings: is acyl, R2 is hydrogen or methoxy, and R4 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a heterocyclic 4-, 5-, 6- or 7-ring (hereinafter referred to as "R ^"), or of R ^ and R ^ one hydrogen and the other azido, halo-methyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylvinyl, 2-phenylethynyl, carboxyl or a group according to any of the formulas -CH 'X., -O-X', -SX. , -0-C (X_) (X.) (Xc), -S-C (X -) -

Al AAJ 4 O o - (Χ, ΗΧ ,.} Or -A-CO-NX.X-, 4 o 6 7 where azido, amino, hydroxy, alkanoylamino, alkylsulfonyl-oxy, phenylsulfonyloxy, substituted phenylsulfonyloxy, phenyl, substituted phenyl, cyano, -QX ^ or -S-X2, wherein X2 represents alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, substituted phenylcarbonyl or heteroarylcarbonyl, whereof X and R 1 is hydrogen and the other is hydrogen, 2 - or alkyl, or wherein X 3 and X 4 together with the carbon atom to which they are attached form a cycloalkyl group, where X, formyl, alkanoyl, phenylcarbonyl, substituted phenylcarbonyl, phenylalkylcarbonyl, substituted phenylalkyl-5 carbonyl, carboxyl, alkoxycarbonyl, carbamoyl, substituted carbamoyl, or cyano, A is -CH = CH-, -CH_-CH = CH-, - (CH,) -, - (CH_), -0-. - (CH „), Z Zn Zn Zn -NH-, or - (CE ^), -S-CH2 where ^ ^ ^ n 0, 1, 2 or 3 and n '1 or 2. Xg e n Kj are independently hydrogen or alkyl, or Xr is hydrogen and X_ is amino, substituted amino, acylamino or alkoxy, and Rg and Rg are independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or R 2, or R 2 and R, together with the carbon atom to which they are attached form a cycloalkyl group or R 2, or of R 1 and R 8 there is one hydrogen and the other azido, halomethyl, dihalogen -methyl, trihalomethyl, alkoxycarbonyl, 2-phenylvinyl, 2-phenylethynyl, carboxyl, or a group of the formula -CH 2, "0-X2," S-X2 or -A-CO-NXgX7.

Now comes a list of definitions of the various terms used to describe the β-lactams of this invention. These definitions apply throughout the description (unless otherwise stated in a particular case), both individually and for parts of larger groups.

The terms "alkyl" and "alkoxy" refer to both branched and unbranched groups. Preference is given to groups with 1 to 10 carbon atoms.

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 with one or more azido, amino, halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenoxy, substituted phenoxy - R 1 - O -, mercapto, alkylthio, phenylthio, substituted phenylthio, - »- - 3 - alkanesulfinyl and / or alkanesulfonyl groups.

The terms "alkanoyl", "alkenyl" and "alkynyl" refer to both branched and unbranched groups. Preference is given to such groups with 2 to 10 carbon-5 atoms.

Surprisingly, "halogen" here means fluorine, chlorine, bromine and iodine.

The term "protected carboxyl" refers to a carboxyl group esterified with a conventional acid protecting group. Such groups are well known in the art, see, for example, U.S. Patent 4,144,333. The preferred protecting groups are benzyl, benzhydryl, t-butyl and p-nitrobenzyl.

The term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino, halogen, hydroxy, trifluoromethyl, alkyl, alkoxy and / or carboxyl groups, with 1 to 4 carbon atoms in optional alkyl and / or alkoxy groups.

The term "a heterocyclic 4-, 5-, 6-, or 7-ring" "(often referred to as" R ^ ") refers to unsubstituted or substituted aromatic and non-aromatic groups having one or more nitrogen, oxygen and / or sulfur atoms Examples of such substituents are oxygen and halogen atoms, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl, alkoxy, alkanesulfonyl, phenyl, substituted phenyl, 2-furyl - imino, benzylimino and substituted alkyl groups (with 1 to 4 carbon atoms in the optional alkyl groups) A group of 4, 5, 6 and 7 heterocyclic rings form the "heteroaryl groups" These are understood to mean those heterocyclic 3Q 4-, 5-, 6- and 7-rings which are aromatic Examples of heteroaryl groups are unsubstituted or substituted pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1 , 2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl and tetrazolyl Examples of non-aromatic hetero-cyclic compound The gene is unsubstituted or substituted azetinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothia-4-zolyl and hexahydroazepinyl. Examples of the substituted 4-, 5-, 6-, and 7-ring heterocycles are 1-alkylazetinyl-3, 2-oxoimidazolidinyl-1,3-alkylsulfonyl-2-oxoimidazolidinyl-1,3-benzylimino-2-oxoimidazolidinyl-1,3 3-alkyl-2-oxoimidazolidinyl-1, substituted or unsubstituted 3-phenyl-2-oxoimidazolidinyl-1,3-benzyl-2-oxoimidazolidinyl-1,3- (2-aminoethyl) -2-oxoimidazoli- dinyl-1,3-amino-2-oxoimidazolidinyl-1,3- / (alkoxycarbonyl) -amino / -2-oxoimidazolidinyl-1. 3- / 2- / (alkoxycarbonyl) amino / -ethyl / -2-oxoimidazolidinyl-1,2-oxopyrrolidinyl-1,2-oxo-10 oxazolidinyl-3,4-hydroxy-6-methylpyrimidinyl-2,2-oxohexahydro- azepinyl-1,2-oxopyrrolidinyl-3,2-oxofuranyl-3, 2,3-dioxopiperazinyl-1, 2,5-dioxopiperazinyl-1,4-alkyl-2,3-dioxopiperazinyl-1 and 4- phenyl-2,3-dioxopiperazinyl-l.

The term "substituted amino" refers to a group of the formula -NY ^ Y ^ wherein Y ^ is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl, or substituted phenyl-alkyl, and wherein Y ^ is alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, hydroxy, cyano, alkoxy, phenylalkoxy or amino.

The term "substituted alkanoyl" includes compounds having a substituted alkylcarbonyl or a phenylalkanoyl group, wherein the same substituents may occur as under "substituted alkyl".

The term "acyl" refers to all organic groups derived from a carboxylic acid by depriving thereof of the hydroxy group. Certain acyl groups are of course preferred, but this preference should not be construed as limiting the scope of this invention. Examples of acyl groups are those that have occurred and occurred in the past in lactam antibiotics, including the 6-aminopennicillanic acid and 7-aminocephalosporanoic acid derivatives.

See, for example, "Cephalosporins and Penicillins" edited by Flynn (Academie Press, 1972), and German Patent Application 2,716,677, Belgian Patent 867,994, 35 U.S. Patents 4,152,432, 3,971,778 and 4,172,199, and British U.S. Patent 1,348,894. To further illustrate the term "acyl", a list of acyl groups follows, but this should not be taken as limiting. Examples of acyl groups are: (a) Aliphatic groups of the formula R -CO-, wherein R is alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, cyclohexadienyl or with halogen, cyano, nitro, amino, mercapto, alkylthio or cyanomethylthio substituted alkyl or alkenyl.

(b) Aromatic groups of formulas 10 2a, 2b, 2c, 2d, 2e and 2f, wherein n is 0, 1, 2 or 3, R ^, Rc and independently hydrogen, halogen, hydroxy, nitro, amino, cyano , trifluoromethyl, alkyl or alkoxy of 1 to 4 carbon atoms and aminomethyl and wherein Rq is amino, hydroxy, carboxylate, protected carboxyl, formyloxy, sulfonate, sulfaminate, azido, halogen, hydrazino, alkylhydrazino, phenylhydrazino or / (alkylthio) thioxomethyl_ / thio ("carboxylate", "sulfonate" and "sulfaminate" refer to salts).

Preferred aromatic acyl groups are groups of formulas 3a, 3b, 3c and 3d, wherein Re is preferably carboxylate or sulfonate.

(c) Heteroaromatic groups of the formulas R - (CH) -CO-, R -CH (R) -CO-, R -O-CH.-CO-, f 2 n f e f 2.

R -S-CH2 -C0- and R ... -C0 -C0-, wherein n is 0, 1, 2 or 3, R has the meanings f 2 fe given above and Rj has a heterocyclic or substituted heterocyclic 5-, 6- or 7-ring with 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and / or sulfur atoms. Examples of heterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl. Examples of substituents are halogen, hydroxy, nitro, amino, protected amino, cyano, trifluoromethyl, alkyl and alkoxy with 1 to 4 carbon atoms and the group HOOC-CH (NH4) -Cl2 -O-CO- NH-.

Preferred heteroatomatic acyl groups are those according to the above formulas wherein R ^ 35 2-aminothiazol.yl-4,2-amino-5-halo-thiazolyl-4,4-amino-pyrimidinyl-2,5-amino-1,2,4 -thiadiazolyl-3, thienyl-2, fura-? * - 6-nyl-2 or 6-aminopyridinyl-2.

(d) / (2,3-dioxopiperazino) carbonyl-amino / arylacetyl groups having a substituent in the 4-position of the formula 4, wherein R 1 is an aromatic or heteroaromatic group and R 1 is alkyl, substituted alkyl , arylmethyleneamino (especially R -CH = N-, where R has the definition given above), arylcarbonylamino (especially R 1 -CO-NH-where Rg has the definition given above) or alkoxycarbonylamino .

Preferred / (2,3-dioxopiperazino) -carbonylamino-aryllacetyl groups are those wherein R 1 is ethyl, phenylmethyleneamino or cc-furylmethyleneamino.

(e) Substituted oxyiminoarylacetyl groups of the formula R.-O-N = C (R) -CO-, wherein R has the definition given above and R 1 is hydrogen, R 1, alkyl, cycloalkyl, alkylaminocarbonyl, arylaminocarbonyl (especially R -NH-CO-, where R has the definition given above) or is substituted alkyl, wherein the alkyl group may be substituted with halogen, cyano, nitro, amino, mercapto, alkylthio, a group R, carboxyl and carboxylate, amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkylphosphinyl, dihydroxyphosphinyl, hydroxyphenylmethoxyphosphinyl and dialkoxyphosphinyl.

Preferred oximinoarylacetyl groups are those wherein R is 2-aminothiazolyl-4. Also preferred are 9 those groups in which R 1 is methyl, ethyl, carboxymethyl, 1-carboxy-1-methyl ethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl.

(f) Acylaminoarylacetyl groups of the formula R1, -CO-NH-CH (R) -CO-, wherein R has the definition given above and R. amino, alkylamino, cyanoalkylamino, amido, alkylamido, cyanoalkylamido 1,1-amino-2- (methylcarbamoyl) is ethyl or a group of formula ^ a, 4h, 4d, 4d, 4S, 4l or 4g.

Preferred acylaminoarylacetyl groups according to these formulas are those groups wherein R_. amino or 35 amido. Also preferred are those groups wherein R 1 is phenyl or O-thienyl.

* * - 7 - (g) 3-substituted / (2-oxoimidazoli-dinyl-1) -carbonylamino aryl acetyl groups of formula 5, wherein R ^ has the above definition and R ^ is hydrogen, alkanesulfonyl, arylmethyleneamino (especially R ^ -CH = N- where 5 has the definition given above), R ^ -CO- (where R ^ is hydrogen, alkyl or haloalkyl), an aromatic group (as defined for R), alkyl or containing halogen, cyano, nitro , 9 "amino or mercapto substituted alkyl.

Preferred / (2-oxoimidazolidiny1-1) -10 carbonylamino / arylacetyl groups are those in which phenyl or CC-thienyl. Also preferred are those groups in which R1 is hydrogen, methylsulfonyl, phenylmethyleneamino or tt-furylmethyleneamino.

Where reference is made in this description to "salts", these are salts with organic or inorganic bases. These can be ammonium salts and salts of alkali languages such as sodium and potassium (preferred), of alkaline earth metals such as calcium and magnesium and of organic bases such as dicyclohexylamine, benzathine, N-methyl-D-glucamine, hydrabamine, and amino acids such as arginine, lysine, etc. The non-toxic, pharmaceutically acceptable salts are preferred, although other salts are also useful, for example, in isolating or purifying the product.

The salts are conventionally formed by reacting the free acid with one or more equivalents of the appropriate base in a solvent or medium in which that salt is insoluble, or in water, after which the water is removed by freeze-drying. By neutralizing the salt with an insoluble acid such as a cation exchanger in hydrogen form (eg polystyrene sulfonic acid such as Dowex 50) or with an aqueous acid and extraction with an organic solvent (eg ethyl acetate, dichloromethane, etc.) comb the free acid from which one can form another salt if desired.

fi-Lactams with a substituent -O-C (Rc) (R ^) -S0oH (or salt thereof) in the 1 position and an amino or acylamino group in the 3 position have at least one center from asym-

♦ Q

- 8 - metric, the carbon atom in the 3-position containing the amino or acylamino group. This invention relates to those lactides whose stereochemistry at the carbon atom in the 3 position of the β-lactam ring is the same as the configuration at the carbon atom in the 6 position of the naturally occurring penicillins ( e.g. penicillin G) and as the configuration at the carbon atom in the 7 position in the naturally occurring cephalosporins (e.g. cephamycin C).

On the associated formula sheets 10 the β-lactams have already been drawn at the 3-position with that stereochemistry.

Within the scope of the invention are also racemic mixtures containing the aforementioned desired lactides.

15 β-Lactams with a substituent -OC- (Rj-) (R ^ -SO ^ H (or salt thereof) in the 1-position and an acylamino group in the 3-position show activity against a range of grams- negative and gram positive organisms The substituent -QC (R ^) (R8) -SO ^ H (or salt thereof) is essential for the action of the compounds of this invention.

The compounds of this invention can be used as agents for combating bacterial infections (including those of the urinary and respiratory tract) in mammals such as pets (eg dogs, cats, cows, horses, etc.) and humans.

For controlling bacterial infections in mammals, a compound of the invention can be administered to an animal in need thereof at a dose between 1.4 and 350 mg / kg per day, preferably between 14 and 100 mg / kg per day . All modes of administration used in the past for penicillins and cephalosporins are now eligible. This can therefore be done orally, intravenously, intramuscularly and rectally.

The α-lactams of this invention can be prepared from an amino acid of formula 6. First, the amino group with a classic protecting group (eg.

- 9 - t-fautoxycarbonyl, benzyloxycarbonyl, o-nitrophenylsulfinyl, etc.) protected to give a compound of formula 7, wherein A 1 represents a nitrogen protecting group.

The carboxyl group of the protected 5 amino acid of formula 7 is then reacted with an amine of formula 8. The reaction is carried out in the presence of a linker such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or dicyclohexylcarbodiimide, and that leads to a salt. of a compound of formula 9.

The hydroxy group of the compound of formula 9 (or salt thereof) is converted into a leaving group, for example, with a conventional reagent such as methanesulfonyl chloride (methanesulfonyl is hereinafter referred to as "Ms").

In the fully protected compound of formula 10 (or salt thereof) a ring closure is now effected with a base, eg K 2 CO 2. The reaction preferably takes place in an organic solvent such as acetone at a boiling temperature, which leads to a compound of formula II 11 (or salt thereof).

Ring closure can also be effected in a compound of formula 9 without first converting the hydroxy group to a leaving group. Treatment of a compound of formula 9 (or salt thereof) with triphenylphosphine and diethylazodicarboxylate or tetrachlorocarbon and triethylamine also results in a compound of formula 11.

Both modes of cyclization lead to reversal of the configuration of the carbon atom to which the and groups are attached.

Cleavage of the protection at the 3-amino group of the compound of formula 11 can be effected by methods known in the art. For example, if the protecting group is t-butoxycarbonyl, trifluoroacetic acid can be used for it. If the protecting group is benzyloxy carbonyl, one can use catalytic hydrogenation (e.g.

# * - 10 - with palladium on charcoal). When the protecting group is o-nitrophenyl-sulfenyl, p-toluenesulfonic acid can be used in combination with p-thiocresol.

The deprotected compound 5 has the formula 12 (or is a salt thereof) and is a key substance in the preparation of the compounds of the invention. They are also within the scope of this invention.

With known acylation techniques, one can convert the compound of formula 12 into a compound of formula 1 wherein there is hydrogen. Examples of such techniques are reaction with a carboxylic acid (R 1 -OH) or a corresponding acid chloride or anhydride. Reaction with a carboxylic acid is best done in the presence of a carbodiimide such as dicyclohexylcarbodiimide and of a substance which can form a reactive intermediate in situ such as N-hydroxybenzotriazole or 4-dimethylaminopyridine. In cases where the acyl group R 1 has a reactive functional group (such as amino or carboxyl), it may be necessary to protect this functional group first, then perform the acylation and finally deprotect the end product.

The compounds of formula 1 wherein R 1 is methoxy can be prepared from the corresponding compound of formula 11 wherein A is benzyloxycarbonyl. Halogenation (preferably chlorination) of a compound of formula 11 wherein A is benzyloxycarbonyl results in a compound of formula 13 or salt thereof. Reagents and methods for N-chlorination of amides are known in the art. Examples of suitable reagents are t-butyl hypochlorite, sodium hypochlorite and chlorine. The reaction can take place in an organic solvent (eg in a lower alkanol such as methanol) and also in a two-phase system (eg in water / methylene chloride) in the presence of a base such as borax. The reaction preferably takes place at a lower temperature.

Reaction of a compound according to Formula 13 with a methoxylating agent, eg with an alkali metal methoxide, results in a compound according to formula 14, or - 11 - •% salt thereof (in combination with its enantiomer if and R4 are the same or if the compound of formula 13 was a racemic mixture). The reaction can take place in an organic solvent (eg a polar solvent such as tetrahydrofuran) and at a lower temperature.

Also, a compound of formula 11 wherein A 1 benzyloxycarbonyl is converted into a compound of formula 14 in a single step. The compound of formula 11 (wherein A 1 is benzyloxycarbonyl) can first be mixed with the methoxylating agent and then the N-chlorination - add reagent.

Conversion of a compound of formula 14 into the desired compound of formula 1 can be accomplished by the methods described above for converting an intermediate of formula 11 into a compound of the invention.

The starting materials of formula 6 are readily available by methods well known in the art, see, for example, "Synthesis" (1979) pp. 216 and 20 J. Org. Chem. 44 (1979) 3967.

The invention is further illustrated by the following examples.

Example I.

- Dikalxum salt of Γ3S-Γ3a- (Z) / 4 ^ 7 ^ -2 - ^ "^ T- (2-aminothiazolyl-4) -2 - /" ^ 4-methyl-2-25 oxo-1- (sulphomethoxy) -azetidiny1-3 _ƒ-amino _j / -2-oxoethylidene J-aminooxy _J7-2-methylpropionic acid A) Aminoxymethanesulfonic acid

To a suspension of 0.8 g of 60% (20 mg-mol) NaH in 16 ml of dry dimethyl sulfoxide, 1.46 g (20 mg-mol) of acetone oxime was added, and then in bits 3.94 g (20 mg mol) of sodium bromomethanesulfonate . The mixture was heated to 90-95 ° C under nitrogen for 4 hours, cooled and washed twice with 250 ml of ether. The product solidified and was washed with 100 ml of dichloromethane, filtered off and filtered over P2 ° 5 to give 15.3 g of crude material.

35 ♦ 'i, - 12 -

This was dissolved in 20 ml of water and 7.5 g (22 mgmol) of tetrabutyl ammonium bisulfate was added. The ion pair thus formed was extracted with 2 x 200 ml of dichloromethane and the extract was dried over Na 2 SO 4 and evaporated in vacuo.

Hydrolysis of the acetone oxime was achieved by heating at 120 ° C with 120 ml 2N HCl for 4 hours. The solution was evaporated in vacuo, taken up in water and evaporated to dryness again, taken up in acetonitrile and evaporated to dryness again. The product solidified on addition of dichloromethane and filtered and dried under vacuum to give 2.5 g of the title compound.

B) Potassium salt of O-sulfomethyl - ^ - Nt-butoxycarbonyl-L-threonine hydroxamate. 15 To a solution of 1.96 g (8.9 mgmol) of t-butoxycarbonyl-L-threonine in 16 ml of water and 4 ml tetrahydrofuran was added 1.14 g (8.9 mg mol) aminoxymethanesulfonic acid at 0 ° C. The pH was adjusted to 4.5 with 1N KOH and a solution of 1.87 g ~ (9.7 mg mol) of 1-ethyl-3-20 (3-dimethylaminopropyl) carbodiimide.HCl in 8 ml of water was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, keeping the pH at 4 to 4.5 by occasional addition of IN.

An ion pair was again made with 3.05 g (8 mg mol) of tetrabutyl ammonium bisulfate, and extracted with 4 x 100 ml of dichloromethane at pH = 2.8. The extract was dried over Na2 SO4 and concentrated in vacuo to give 4.5g of product as tetrabutyl ammonium salt. This was converted to the potassium salt by ion exchange over 150 ml of Dowex 50 X 30 (with 0.7 meq K / ml) and after freeze drying, there was 2.63 g of the title compound.

C) Tetrabutyl ammonium salt of O-sulfomethyl-d-N-t-butoxycarbonyl-L- (O-methanesulfonylthreonine) hydroxamate.

To a partial solution of 2.37 g (6.5 mg mol) of potassium salt of O-sulfomethyl-oC-Nt-butoxycarbonyl-L-threonine hydroxamate in 50 ml of dry pyridine, f * - 13 - at 0 -5 ° C and 0.8 ml (excess) of methanesulfonyl chloride were added dropwise under nitrogen. After reaction at room temperature for 4 hours, the mixture was evaporated to dryness under vacuum and the residue was taken up in 10 ml of water, to which 2.0 g of 5 (6 mg mol) of tetrabutylammonium bisulfate was added. At pH = 2.8, the ion pair was extracted with chloroform. The extract was dried and evaporated to dryness under vacuum to give 2.6 g of crude product.

D) Potassium salt of / 3S- (3cC, 4β) / -3- / (t-butoxycarbonyl) -10 amino-4-methyl-2-oxo-1- (sulfomethoxy) -azetidine.

A solution of 2.6 g (4.0 mg mol) of tetrabutyl ammonium salt of O-sulfomethyl-dNt-butoxy-carbonyl-L- (0-methanesulfonylthreonine) hydroxamate in 5 ml of acetone was added to a boiling suspension of 2.2 g of potassium carbonate ^ drop into 65 ml of acetone. After refluxing for an additional 3 hours, the mixture was cooled, filtered and evaporated in vacuo. The residue was taken up in 10 ml 0.5 M KH 2 PO 4 solution with pH 5.5 and the pH was adjusted to 2.8, and that solution was extracted with 4 x 100 ml dichloromethane. The extracts were dried together and evaporated in vacuo to yield 1.52 g of crude tetrabutyl ammonium salt of the

sulfonic acid. By ion exchange over 50 ml Dowex 50 X

(with 0.7 meq / ml K) and lyophilization, 0.53 g of crude potassium salt was obtained, which was further purified by chromatography on 100 ml of HP-20 with water as the running liquid. The appropriate fractions were combined and lyophilized to give 0.245 g of product.

Elemental analysis: C 32.52%, H 4.76%, N 7.43%, S 8.30%;

Calculated for C n H N N 0 O SK 1.2 H 0: 30 10 1 / Z / l C 32.46%, H 5.28%, N 7.57%, S 8.66%.

E) / 3S- (3 £ 4 ƒ? _) 7-1-sulfomethoxy-3-amino-4-methyl-2-oxo-azetidine

In a mixture of 0.5 ml of dichloromethane and 0.5 ml of anisole, 0.245 g (0.68 mgmol) of potassium salt of / 3S- (3QL., 4 /?) _7_3- / (t-butoxycarbonyl) amino_7 ~ 4 - - 14 - Methyl-2-oxo-1- (sulfomethoxy) azetidine. The reaction mixture was cooled to 0 ° C and 1.0 ml of trifluoroacetic acid was added under nitrogen. After stirring for 1 hour, the reaction mixture was concentrated in vacuo and the residue was evaporated twice with benzene. It was then stirred with ether, which was decanted, and the desired product was thus obtained as a white solid.

F) Potassium salt of the benzhydryl ester of / 3S- / 3ct (Z), 4yS 7 7-2- / / 1- (2-amino-thiazolyl-4) -2- / / 4-methyl-2- oxo-1- (sulfomethoxy) azetidinyl-3 7 amino-7-2-oxoethylidene-7-aminoxy-7-2-methylpropionic acid.

In 4 ml of dry dimethylformamide, 0.30 g (0.68 mgmol) (7.) -2-amino-0 (- / 2-benz-hydryloxy-1,1-dimethyl-2-oxoethoxy) imino 7thiazole- was added under nitrogen. 4-acetic acid 15 dissolved. After cooling to 0 ° C, 0.14 g (.0.68 mgmol) of N, N1 -dicyclohexylcarbodiimide were added in bits. After stirring at 0 ° C for an hour, a solution of the crude 3-amino-1- (sulfomethoxy) azetidine (0.68 mgmol) obtained in E) in 10 ml of dimethylformamide and 0.5 ml of diisopropylethylamine at 0 ° C was added thereto. added. After stirring for an additional hour at 0 ° C and stirring overnight at room temperature, the mixture was filtered and the filtrate evaporated to dryness under vacuum. The residue was taken up in 50 ml of dichloromethane and the solution was washed with 2 ml of water. By evaporation of that solution, 0.372 g of crude product was obtained. This was passed with water through 30 ml of Dowex 50 (with 0.7 meq / ml k) to give 0.211 g of crude product after freeze-drying, still contaminated with hydroxybenzotriazole.

G) Dipotassium salt of / 3S- / 3 (X (Z), 4 / _7_7 ~ 2- / / l- (2-amino-thiazolyl-4) -2- / / 4-methyl-2-oxo-1- ( sulfomethoxy) -aze- tidinyl-3-7-amino-7-2-oxoethylidene 7 aminoxy-7-2-methyl-propionic acid_

In a mixture of 1.8 ml of dichloromethane, 0.5 ml of anisole and 1.5 ml of trifluoroacetic acid, 0.211 g of potassium salt of the benzhydryl ester of / 3S- / 3¾ (Z), 35 4 / 7-7-2 - / / 1- (2-aminothiazolyl-4) -2- / / 4-methyl-2-oxoethylidene 7aminooxy 7-2-methylpropionic acid dissolved, and this was stirred at 0 ° C for 15 - 2 hours and then concentrated under vacuum. The residue was evaporated to dryness twice with benzene and then washed successively with ether / ethyl acetate 1: 1 and ether / acetonitrile 1: 1 to give a white solid. This was dissolved in 1.0 ml KE 2 PO 4 with pH 5.5, and the pH was adjusted to 6.5 with 1N KOH. Chromatographed with water over 40 ml of HP-20 to give 53 mg of the title compound, m.p. 200 ° C (dec.).

Elemental analysis: C 28.32, H 3.36, N 11.90, S 10.37%, - 10 Calculated for c 4 H 7 N 5 O 9 S 2 K 2 · 2'75 H ^ O: C 28.44, H 3.84, N 11.85, S 10.84%.

Example IX

/ 2S- / 2 *, 3 ^ (Z) 7 7- / 3- / / (2-aminothiazolyl-4- (methoxyimino) acetyl 7amino 7-2-methyl-4-oxoazetidinyl-1-oxy_7methane-sulfonic acid_

In the manner of Example 1, replacing the thiazole acetic acid used therein at (F) with 2-amino-CC- (methoxyimino) thiazole-4-acetic acid, the title compound was prepared as monopotassium salt, which after dissolving several times in acetonitrile and evaporating to dryness under vacuum, a hygroscopic solid was and remained.

-1 -1

In the IR spectrum peaks at 1030 cm (SO ^) and at 1778 cm (p-lactam).

Elemental analysis: C 37.94, H 5.36, N 15.92, S 12.56% 25 Calculated for C ^ H ^ ^ O ^ K 0.1 C ^ CN: C 38.11, H 4 .82, N 15.92, S 12.56%.

Example III

/ 2S- / 2¾. .3β U07_7-7 3- / / / (4-ethyl-2,3-dioxopiperazino) -carbonylamino 7phenylacetyl 7 amino_7-2-methyl-4- oxoazetidiny1-1-30 oxy_7methanesulfonic acid

In the manner of Example I, replacing the thiazole acetic acid used in (F) with CC- / (4-ethyl-2,3-dioxopiperazino) carbonylamino-7-phenylacetic acid, the title compound as monopotassium salt was obtained, a hygroscopic solid. In the IR spectrum signals for SO4 (at 1038 cm *) and for y-lactam (1775 cm V Element analysis: C 41.53, H 4.46, N 11.13, S 5.61% ' i - 16 -

Calcd for ^ 20 ^ 4 ^ 0 ^ 1 ^ * ^ H2 °: C 41.53, H 4.74, N 12.11, S 5.54%.

Example IV

(S) -3-benzyloxycarbonylamino) -4-methyl-2-oxo-1- (sulfomethoxy) azetidine_

In the manner of Example I, parts (A) to (D), replacing the t-butoxycarbonyl-L-threonine used in (B) with benzyloxycarbonylserine, the title compound was prepared as potassium salt. In the -1 h 10 IR spectrum signals for SO ^ (at 1025 cm) and for y9-lactam (at 1775 cm -1).

The following compounds were also prepared according to the methods described:

Monopotassium salt of (3S-trans) - / (2-aminothiazolyl-4) (methoxy-15 imino) acetylamino / -4-methyl-2-oxoazetidinyl-1-oxy 7-methanesulfonic acid

Monopotassium salt of (3S-trans) - / (2-aminothiazolyl-4) / (2,2,2-trifluoroethoxy) imino / acetylamino / -4-methyl-2-oxoazetidinyl-1-oxy / methanesulfonic acid 20 Monopotassium salt of (3S-trans- / (2-aminothiazolyl-4) / (2-amino-2-oxoethoxy) imino 7acetylamino 7 ~ 4-methyl-2-oxoazetidinyl-1-oxy7-methanesulfonic acid

Dipotassium salt of (3S-trans) - / (2-amino-4-thiazolyl) / (carboxy-methoxy) imino 7acetylamino-7-4-methyl-2-oxoazetidinyl-1-oxy_7-25 methanesulfonic acid

Dipotassium salt of (3S-trans) - / (2-aminothiazolyl-4) / / (1-carboxypropyl) oxy 7imino-7acetylamino 7-4-methyl-2-oxoazetidinyl-1-oxy-7-methanesulfonic acid

Monopotassium salt of / 3S- / 3 cC (R), 4 Pj / 3- / (aminophenyl) -30 acetylamino 7-4-methyl-2-oxoazetidinyl-1-oxy_7methanesulfonic acid

Monopotassium salt of (3S-trans) - / / 3- / (phenylacetyl) amino-7-4-methyl-2-oxoazetidinyl-1-oxy ~ / m & thanesulfonic acid Monopotassium salt of (3S-trans) - / / 3- / ((-Thienylacetyl) -35 amino-7-4-methyl-2-oxoazetidinyl-1-oxy_7methanesulfonic acid

Monopotassium salt of (3S-trans) - / / 3- / (2,6-dimethoxyphenyl) - 'ΛΛ, - - 17 - acetylamino-7-4-methyl-2-oxoazetidinyl-1-oxy-7methanesulfonic acid

Mono-potassium salt of / 3S- / 3 (R) -β J- / 3- (ot-urido-Ct-thienylacetyl) amino 7 ~ 4-methyl-2-oxoazetidinyl-1-oxy_7methane-5 sulfonic acid

Dipotassium salt of / 3S- / 3 & (R), 4β7_7 ~ / _ 3- / (carboxyphenyl-acetyl) -amino 7-4-methyl-2-oxoazetidinyl-1-oxy_7methanesulfonic acid

Dipotassium salt of / 3S- / 3 4 (±) ApJ J- / / 3- / (phenylsulfo-10 acetyl) amino 7-4-methyl-2-oxoazetidinyl-1-oxy 7methanesulfonic acid

Monopotassium salt of (3S-trans) - / 3- / / (2-aminothiazolyl-4) -oxoacetyl 7amino 7-4-methyl-2-oxoazetidinyl-1-oxy_7methane-sulfonic acid 15 Monopotassium salt of / 3S- / 3 tt (R) ΛβΊJ ~ (_ 3- / / / 2-oxo-3- / (phenylmethylene) amino 7imidazolidiny1-1-carbonylamino_7 ~ phenylacetyl 7a®ino 7 "4-methyl-2-oxoazetidinyl-l-oxy 7methane sulfonic acid

Monopotassium salt of / 3S- / 3 (Z), 4 / _7_7- / 3- / / & -furanyl- 20 (methoxyimino) acetyl 7amino 7-4-methyl-2-oxoazetidinyl-1-oxy_7-methanesulfonic acid

Monopotassium salt of / 3S (Z) 1 ~ / _ 3- / (2-aminothiazolyl-4) - (methoxyimino) acetylamino 7-2-oxoazetidinyl-1-oxy 7methane sulfonic acid 25 Potassium salt of / 3S (Z) / - / 3- / (2-aminothiazolyl-4) / (1-carboxy-1-methylethoxy) imino-7acetylamino-7-2-oxoazetidinyl-1-oxy / methanesulfonic acid

Monopotassium salt of / 3S (Z) _7 ~ / 3- / (2-aminothiazolyl-4) - / (2,2,2-trifluoroethoxy) imino_7acetylamino_7-2-oxoazetidinyl-1-30 oxy_7methanesulfonic acid

Monopotassium salt of / 3S (Z) 7- / 3- / (2-aminothiazolyl-4) - / (2-amino-2-oxoethoxy) imino 7acetylamino 7-2-oxoazetidinyl-1-oxy / methanesulfonic acid

Monopotassium salt of / 3S- / 3 ^ (S), 4/7-7- / / 3- (¢, -ureido-i -35 thienylacetyl) amino _ / - 2-oxoazetidinyl-1-oxy 7methanesulfonic acid - 18 -

Dipotassium salt of / 3S- / 3 Λ · (±) 3- / (phenylsulfoacetyl) - amino / -2-oxoazetidinyl-1-oxy / methanesulfonic acid Monopotassium salt of / 3S- / 3 & (R), 4 / _ / _7- / / 3- / / / (4-ethyl-2,3-dioxo-1-piperazino) carbonylamino / phenylacetyl / amino _ / - 2-5 oxoazetidinyl-1-oxy / methanesulfonic acid

Monopotassium salt of / (3S (Z) _ / - / / 3- / (phenoxyacetyl) amino _ / - 2-oxoazetidinyl-1-oxy / methanesulfonic acid

Monopotassium salt of (3S-cis) - / (2-aminothiazolyl-4) (methoxyimino) -acetylamino / -4-methyl-2-oxoazetidinyl-1-oxy / methanesulfonic acid

Monopotassium salt of (3S-cis) - / / (2-aminothiazolyl-4) / (2,2,2-trifluoroethoxy) imino / acetylamino / -4-methyl-2-oxoazetidinyl-1-oxy / methanesulfonic acid

Dipotassium salt of (3S-cis) - / (2-aminothiazolyl-4) / (carboxy-15 methoxy) imino / acetylamino _ / - 4-methyl-2-oxoazetidinyl-1-oxy _ / - methanesulfonic acid

Dipotassium salt of (3S-cis) - / 3- / (2-aminothiazolyl-4) _ / (1-carboxy-1-methylethoxy) imino / acetylamino _ / - 2-oxo-4-methylazetidinyl-1-oxy_ / methanesulfonic acid 20 Dipotassium salt of (3S-cis) - / (2-aminothiazolyl-4) / (1-carboxycyclopropyl) oxy / imino / acetylamino / - 4-methyl-2-oxoazetidinyl-1-oxy / methanesulfonic acid

Monopotassium salt of (3S-cis) - / / (2-aminothiazolyl-4) / (2-amino-2-oxoethoxy) imino / acetylamino / -4-methyl-2-oxoazetidinyl-1-25 oxy / methanesulfonic acid

Dipotassium salt of / 3S- / 3 A (R), 4 & 7 / - / 3- / (carboxyphenylacetyl) amino 7-4-methyl-2-oxoazetidinyl-1-oxy / methanesulfonic acid

Monopotassium salt of / 3S- / 3 «. (R), 4» 7 7- / 3- / / / (4-ethyl-2,3-30 dioxo-1-piperazino) carbonylamino-7phenylacetyl 7amino 7-4-methyl- 2-oxoazetidinyl-1-oxy_7-nonhane sulfonic acid Monopotassium salt of / 3S- / 3% (S), 4,7,7- / 3- (OC-ureido - <% -thienylacetyl) amino 7-4-methyl-2-oxoazetidinyl- 1-oxy 7-methane-sulfonic acid 35 Mono-potassium salt of / 3S- / 3 a (R), 4 7 7- / 3- / (aminophenyl-acetyl) amino-7-4-methyl-2-oxoazetidinyl-1-oxy 7-methanesulfonic acid.

J

- 19 -

Example V

(2 ^ 3 CC) -1-sulfomethoxy-2-aminocarbonyl) -3- (t-butoxycarbonyl-amino) -4-oxoazetidine. A) Erythro-3-hydroxy-DL-aspartic acid.

5 In the manner by G.B. Payne et al. In J. Org. Chem. 24 (1959) 54, trans-epoxy succinic acid was prepared from fumaric acid. In the manner by C.W. Jones et al. In Can. J. Chem. 47. (1969) 4363, erythro-3-hydroxy-DL-aspartic acid was prepared from this trans-epoxy succinic acid.

B) Erythro-methyl-1-3-hydroxy-DL-aspartate.

To a suspension of 5.0 g (33.5 mgmol) erythro-3-hydroxy-DL-aspartic acid in 50 ml dry methanol, 6 ml concentrated hydrochloric acid was added. After refluxing for 3 hours, the mixture was cooled to room temperature and evaporated to dryness under vacuum. The residue was taken up in 95% ethanol and the pH adjusted to 8.0 with pyridine. The white material that precipitated was filtered and dried to give 5.2 g (yield 95%) of the desired methyl ester; mp. 210 ° C (dec.).

C) Erythro-3-hydroxy-Di-asparagine.

4.0 g (24.5 mg mol) of this β-methyl spartate were dissolved in 40 ml of concentrated ammonia. After stirring overnight at room temperature, the reaction mixture was evaporated to dryness under vacuum, and the solid residue was dissolved in hot water. The pH was adjusted to 5.0 with 6N HCl and the solution evaporated to about 20 ml under vacuum. After standing overnight at 5 ° C, the white crystals which had separated were collected and dried. This gave 3.4 g (95% yield) of the desired amide? mp. 233 ° C (dec.).

D) Potassium salt of erythro-N-t-butoxycarbonyl-3-hydroxy-DL-asparagine.

7.0 g (47 mgmol) of erythro-3-hydroxy-DL-asparagine were suspended in 50 ml of water and dissolved by addition of 3N KOH. In this solution, the pH was adjusted to 10.0 and held there while adding dropwise a solution of 15.5 g (71 mgmol) of di-t-butyl dicarbonate in 20 ml of t-butanol. After stirring overnight at room temperature at pH = 10.0, the t-butanol was removed in vacuo, and the pH was adjusted to 5.0 with 6N HCl in the aqueous residue. This solution was concentrated to a small volume under vacuum and now the pH was adjusted to 3.0 with 6N HCl. Removal of the solvent under vacuum gave 20 g of solid containing the desired product in the form of the free acid in approximately quantitative yield, together with inorganic salts. A portion of this substance (2.9 g) was taken up in water and after adjusting the pH chromatographed with diluted KOH to 6.5 by 100 ml HP 20, first with water and then with water / acetone 9: 1 as the running liquid. This gave 1.8 g of the desired potassium salt.

E) Tetrabutyl ammonium salt of aminoxymethanesulfonic acid.

To a solution of 0.635 g (5 mgmol) aminoxymethanesulfonic acid in 2 ml water was added 1.02 g (3 mgmol) tetrabutylammonium bisulfate, and the pH was adjusted to 10.0 with dilute KOH. The water was removed under vacuum and the residue stirred in methylene chloride. After filtration, the filtrate was dried over Na 2 SO 4 and evaporated to dryness to give 1.06 g (2.88 mgmol) of the desired product as a residue.

ei-F) Potassium salt of erythro-Nt-butoxycarbonyl-3-hydroxy-O-sulfomethyl-DL-asparagine hydroxamate. -butoxycarbonyl-3-hydroxy-DL-asparagine dissolved and the pH adjusted to 2.4 with dilution.

The solution was concentrated in vacuo to a residue which was evaporated twice with water and then twice with benzene. That residue was dissolved in a mixture of 4 ml dry acetonitrile and 8 ml dry tetrahydrofuran. After cooling to 0 ° C, 0.424 g (2.77 mg mol) of 1-hydroxy-benzothriazole monohydrate was added thereto with stirring, and then 0.572 g (2.77 mg mol) of Ν-dicyclohexylcarbodiimide. The mixture was stirred at 0 ° C for 2 hours, and now 1.06 g (2.88 mgmol) of the above-mentioned tetrabutylammonium-aminoxymethane-

a

- 21 - Sulfonate added in 5 ml of acetonitrile. After stirring for an additional 4 hours at 0 ° C, the mixture was filtered and concentrated in vacuo. 10 ml of water was added to the residue, which was stirred at 0 ° C until it solidified. The solid was filtered off and the aqueous filtrate concentrated to about 3 ml. The pH was now adjusted to 4.0 and fractionated over 80 ml of Dowex 50 in K-form. The appropriate fractions were collected and concentrated to a small volume. The pH was adjusted to 3.4 and that solution was chromatographed on HP 20, yielding 502 mg (46% yield) of the desired product as a solid, m.p. 145 ° C. Elemental analysis: C 29.42, H 4.73, N 10.04, S 7.45%

Calcd for C 7 H 15 N 5 Og SK 0.71 ^ O: C 29.42, H 4.80, N 10.29, S 7.85%.

G) Tetrabutyl ammonium salt of erythro-N-t-butoxycarbonyl-3-hydroxy-O-sulfomethyl-DL-asparagine hydroxamate.

To a solution of 104 mg (0.263 mgmol) of the above-mentioned asparagine hydroxamate in 1 ml of water was added 2.63 ml of 0.1 M tetrabutyl ammonium bisulfate in 0.5 M KH2 PO4 buffer with pH 5.5. The solution was evaporated to dryness and the residue was stirred with methylene chloride.

Filtration and evaporation of the filtrate gave 156 mg (0.26 mgmol) of the desired product as a residue.

H) Potassium salt of (2oC, 3Λ) -2- (aminocarbony1) -3- (t-butyloxy-carbonylamino) -4-oxo-1-sulfomethoxyazetidine.

140 mg (0.234 mgmol) of said tetrabutylammonium-O-sulfomethylhydroxamate was dissolved in 1.6 ml of dry methylene chloride and this was stirred overnight with 1 g of a dry molecular sieve. The solution was removed with a syringe and diluted with 0.8 ml of dry methylene chloride. To this was added 0.12 ml (0.85 mgmol) triethylamine under argon at -50 ° C, then 0.08 ml (0.42 mgmol) trifluoromethanesulfonic anhydride was added dropwise. The mixture was allowed to warm to -30 ° C over 1 hour and now 0.06 ml of tri-35 ethylamine was added. 5 minutes later, the reaction mixture was concentrated in vacuo and the residue dissolved in 2 ml of acetone. This 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 solid collected by centrifugation.

This solid was mixed with 2 ml of Dowex 50

stirred in K-form and water. Filtration and removal of the water under vacuum gave the desired potassium salt, which was still crude but did not contain amine. Chromatography of this crude potassium salt on HP-20 with water after freeze drying gave 15 mg of 10 (20% yield) of the desired potassium salt with mp. 149 ° C

(dec.).

In the IR spectrum (in KBr) signals at 1786 cm (β-lactam -1 carbonyl) and at 1696 cm (wide, for amide and carbamate carbonyl).

15 i

Claims (5)

L-10 lactam according to claim 4, wherein R 1 is the group (Z) -2-amino-¢ /. ((1-carboxy-1-methylethoxy) imino-thiazol-4-acetyl. -Lactam according to claim 3, wherein R 1, Rr and R 1 are all hydrogen and of R * and R 1 one is 2 5 6 3 4 alkyl and the other is hydrogen. 12. The lactam of claim 11, wherein R 2, R 1, R 9 and R 8 are all hydrogen and R 1 is methyl. The β-lactam of claim 11, wherein R 2, R 1, R 1. and R 8 are all hydrogen and R 6 is methyl. 14/3 -Lactam of formula 12 or salt thereof, in which formula R 1 and R 4 independently of each other are hydrogen, alkyl, alkenyl, -25-c. alkynyl, cycloalkyl, phenyl, substituted phenyX or a heterocyclic 4-, 5-, 6- or 7-ring, or where of R 1 and R 4 one is hydrogen and the other azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl , 2-phenyl-5 vinyl, carboxyl or a group -CH ^ X ^> -OX ^, -OC (X ^) (X ^) (X ^), -SC (X3) (X4) (X5) or - A-CO-NXgX7, wherein R and Rc independently of one another are hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or a 4-, 5-, 6- or 7-membered heterocycle, or wherein Rg is 10 and Rg together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic 4-, 5-, 6- or 7-ring, or wherein of R 1 and R 1 one is hydrogen and the other azido, DO halomethyl, dihalomethyl, trihalomethyl , alkoxy-carbonyl, alkenyl, alkynyl, 2-phenylvinyl, 2-phenylethynyl, 15-carboxyl or a group -CH -X., -0-X „, -SX“ or -A-CO-NX X, Δ X Δ Δ O / where X ^ azido, amino, hydroxy, alkanoylamino, alkylsulfonyl oxy, phenylsulfonyloxy, substituted phenylsulfonyloxy, phenyl, substituted phenyl, cyano, or a group -O-X2 - ^ X2 * Sf where X ^ alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, substituted phenyl carbonyl or heteroaryl carbonyl, of Xg and X4 one being hydrogen and the other hydrogen or alkyl, or wherein Xg and X4 together with the carbon atom to which they are attached form a cycloalkyl group, where Xg is formyl, alkanoyl, phenylcarbonyl, substituted phenylcarbonyl, phenylalkylcarbonyl, substituted phenylalkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl or cyano, where A is -CH = CH-, -CH „-CH = CH-, - (CH„) -, - (CEL ), -0-, 2. n 2 n - (CH_) -NH- or - (CH2), -S-CH_-, 2 n 2 n 2 where n is 0, 1, 2 or 3 and n1 is 1 or 2, and wherein Xg and X ^ are independently hydrogen or alkyl, or wherein Xg is hydrogen and X ^ amino, substituted 35 amino, acyl amino or alkoxy. A salt of a β-lactam according to y ^ c * - 26 - claim 1, namely of / 3S- / 3 λ (Z), 4 ^ 7 7-2- / l- (2-amino-thiazolyl-4) -2- / / 4-methyl-2-oxo-1- (sulfomethoxy) -3-azetidinyl-3-amino 7-2-oxoethylidene 7aminooxy 7-2-methylpropionic acid. A β-lactam according to claim 14,5 / 3S- (3 #, 4/3) 7-1-sulfomethoxy-3-amino-4-methyl-2-oxo-azetidine. A composition containing a lactam according to any one of the preceding claims. 10